immunomodulatory and immunsuppressive drugs in ...

IMMUNOMODULATORY AND IMMUNSUPPRESSIVE DRUGS IN DERMATOLOGY Prof. Dr. Ümit TÜRSEN

Ankara 2016

© 2016 AKADEMISYEN TIP KITABEVI Yayın Dağıtım ve Pazarlama Ltd. Şti. Halk Sokak 5/A Yenişehir / ANKARA Tel: (0312) 431 16 33 Kitabın Adı Editör ISBN

: Immunomodulatory and Immunsuppressive Drugs in Dermatology : Umit TURSEN, MD :

Yayın Koordinatörü : Yasin DILMEN Dizgi : Dilek MERAKI Baskı : Soncag Matbaacılık

Bu kitabın basım, yayın ve satış hakları Akademisyen Tıp Kitabevi’ne aittir. Anılan kuruluşun izni alınmadan kitabın tümü ya da bölümleri mekanik, elektronik, fotokopi, manyetik kağıt ve/veya başka yöntemlerle çoğaltılamaz, basılamaz, dağıtılamaz. Tablo, şekil ve grafikler izin alınmadan, ticari amaçlı kullanılamaz. Bu kitap T.C. Kültür Bakanlığı bandrolü ile satılmaktadır.

SATIŞ ŞUBELERİMİZ ADANA 0322 233 00 29

ESKİŞEHİR 0222 239 35 75-0555 690 91 58

KIRIKKALE 0544 484 66 45

ANKARA 0312 431 16 33

GAZİANTEP 0342 215 14 00-0555 737 60 41

KOCAELİ 0262 323 33 50-0262 323 33 74

HATAY 0532 584 41 11

KONYA 0332 350 66 46- 0555 690 86 92

ISPARTA 0505 897 74 28

MALATYA 0422 325 12 84-0422 325 12 84

İSTANBUL/KADIKÖY 0216 330 59 59

MANİSA 0507 200 01 66

İSTANBUL/HASEKİ 444 4 887-0212 589 05 82

MERSİN 0555 732 70 48

İSTANBUL/PENDİK 0216 597 07 42

SAMSUN 0362 432 89 78-0555 690 86 93

İZMİR 0232 445 71 47-0232 445 71 57

SİVAS 0346 224 22 29-0507 777 00 28

İZMİR/ASYA TIP 0232 342 21 21-0232 342 42 62

ŞANLIURFA

EDİRNE 0284 225 58 58-0284 212 66 77

İZMİR/BALÇOVA 0232 279 09 42

TRABZON 0462 321 20 25

ELAZIĞ 0424 236 93 33

KAHRAMANMARAŞ 0344 221 32 80

VAN 0432 214 70 44-0505 794 22 65

ERZURUM 0442 235 18 25-0533 490 09 09

KAYSERİ 0352 231 56 70-0505 662 61 18

ZONGULDAK 0372 222 00 10-0505 454 58 11

AFYON 0506 834 89 69 ANTALYA 0242 228 46 57 AYDIN 0555 341 55 27 BOLU 0374 217 33 99 BURSA 0224 441 58 87-0224 441 80 77 DENİZLİ 0258 213 44 20-0555 732 70 47 DİYARBAKIR 0412 228 09 65-0555 690 91 56 DÜZCE 0506 654 36 35

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0506 397 18 65

INTRUDUCTION Recently, dermatologists have witnessed a revolution in our therapeutic armamentarium with the development of several novel immunomodulators. Although psoriasis remains the only condition in dermatology for which the use of immunomodulators has been approved by the Food and Drug Administration, these drugs have the potential to significantly impact the treatment of several inflammatory conditions in dermatology. This books includes a review of the mechanism of action, dosing, and side-effect profile, as well as a review of the current literature on immunomudulatory and immunosuppressive drugs in dermatology, and also off-label uses of the CD20-positive B-cell antagonist rituximab, the IgE antagonist omalizumab, the tumor necrosis factor-α antagonists infliximab, etanercept, and adalimumab, the pathogenic autoantibody antagonist IVIG, the antirheumatic drug leflunomide, the T-cell response modifiers alefacept, the toll-like receptor 7 agonist topical imiquimod, the oral hypoglycaemic agent metformin, the phosphodieasterase-4 inhibitor Apremilast, and also the new other immunomodulatory drugs and herbs. Prof. Dr. Ümit Türsen, MD, Editor Mersin University, Department of Dermatology Mersin, Turkey

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CONTENTS CHAPTER 1.

DEVELOPMENT OF NOVEL IMMUNOMODULATORY DRUGS AND IMMUNOTHERAPEUTIC STRATEGIES.......................................................................1 Özgür Gündüz, MD

CHAPTER 2.

ABATACEPT .....................................................................................................................7 Şule Güngör, MD

CHAPTER 3.

ADALIMUMAB IN DERMATOLOGY ..........................................................................11 Aysin Köktürk, MD

CHAPTER 4.

IMMUNOMODULATION WITH ANTIBIOTICS .......................................................19 Özgür Gündüz, MD.

CHAPTER 5.

ANTIOXIDANTS IN DERMATOLOGY ......................................................................25 Lülüfer Tamer, PhD, Aysegul Görür, PhD

CHAPTER 6.

ANAKINRA ....................................................................................................................33 Pelin Ülkümen, MD, Emek Kocatürk Göncü, MD.

CHAPTER. 7

ANTIMALARIAL TREATMENT IN DERMATOLOGY ...............................................43 Mehmet Demirel, MD, Ufuk Kavuzlu, MD

CHAPTER. 8

APREMILAST IN DERMATOLOGY ............................................................................51 Ulas Güvenc, MD, Belma Türsen, MD, Ümit Türsen, MD

CHAPTER 9.

BLEOMYCINE ................................................................................................................61 Evren Odyakmaz Demirsoy, MD

CHAPTER 10.

CANAKINUMAB USES IN DERMATOLOGY .............................................................65 Bilge Bülbül Şen, MD

CHAPTER 11.

CERTOLIZUMAB PEGOL .............................................................................................71 Hatice Duman, MD.

CHAPTER 12.

CHLORAMBUCIL..........................................................................................................75 Evren Odyakmaz Demirsoy, MD.

CHAPTER 13.

CURCUMIN....................................................................................................................79 Anıl Gülsel Bahalı, MD

CHAPTER 14.

CYCLOSPORIN-A ..........................................................................................................83 Simge Bardak, MD, Kenan Turgutalp, MD, Ahmet Kıykım, MD

CHAPTER 15.

COLCHICINE ................................................................................................................91 Mehmet Demirel, MD, Ufuk Kavuzlu, MD.

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VI

CHAPTER 16.

DAPSON TREATMENT IN DERMATOLOGY .............................................................95 Pınar Özuğuz, MD, Seval Doğruk Kaçar, MD

CHAPTER 17.

FUMARIC ACID ESTERS IN DERMATOLOGY .......................................................105 Selma Emre, MD, Duriye Deniz Demirseren, MD

CHAPTER 18.

IMIQUIMOD ...............................................................................................................113 Aysun Şikar Aktürk, MD

CHAPTER 19.

INFLIXIMAB TREATMENT IN DERMATOLOGY ...................................................117 Ufuk Kavuzlu, MD, Kıymet Baz, MD

CHAPTER 20.

INTERFERON THERAPY IN DERMATOLOGY .......................................................125 Engin Senel, MD

CHAPTER 21.

INTRAVENOUS IMMUNOGLOBULIN TREATMENT .............................................133 Belma Türsen, MD, Erdinc Terzi, MD

CHAPTER 22.

LEVAMISOLE USES IN DERMATOLOGY .................................................................157 M. Kamil Mulayim, MD, Perihan Ozturk,MD, Selma Korkmaz, MD.

CHAPTER 23.

MATRIX METALLOPROTEINASES AND MATRIX METALLOPROTENASE INHIBITORS IN DERMATOLOGIC DISORDERS ...................................................165 Bahadır ERCAN, PhD

CHAPTER 24.

METFORMIN ..............................................................................................................173 Pınar Tabakçı, MD, Ayça Cordan Yazıcı, MD.

CHAPTER 25.

METHOTREXATE ......................................................................................................179 İlteriş Topal Oğuz, MD

CHAPTER 26.

METHOTREXATE USES IN DERMATOLOGY .........................................................191 Perihan Ozturk, MD, M. Kamil Mulayim, MD, Kemal Ozyurt, MD

CHAPTER 27.

MICRORNAS TREATMENT IN MELANOMA ..........................................................201 Lülüfer Tamer, PhD, Şenay Balcı, PhD

CHAPTER 28.

MILTEFOSINE..............................................................................................................211 Ralfi Singer, MD.

CHAPTER 29.

MYCOPHENOLIC ACID .............................................................................................219 Simge Bardak, MD, Serap Demir, MD

CHAPTER 30.

OMALIZUMAB TREATMENT IN DERMATOLOGY................................................227 Erdinç Terzi,MD, Belma Türsen, MD.

CHAPTER 31.

PENTOXIFYLLINE ......................................................................................................243 Evren Odyakmaz Demirsoy, MD.

CHAPTER 32.

OFF-LABEL USES OF THE RITUXIMAB IN DERMATOLOGY ..............................247 Tamer Irfan Kaya, MD

CHAPTER 33.

SYSTEMIC STEROIDS .................................................................................................255 Deniz Kaya, MD

CHAPTER 34.

TACROLIMUS ..............................................................................................................259 Mehmet Horoz, MD

CHAPTER 35.

THALIDOMIDE THERAPY IN DERMATOLOGY ....................................................265 Engin Senel, MD

CHAPTER 36.

TOCILIZUMAB: A NEW ALTERNATIVE THERAPY IN DERMATOLOGY ...........271 Özgül Muştu Koryürek, MD, Göknur Kalkan, MD

CHAPTER 37.

TOFACITINIB IN PSORIASIS.....................................................................................281 Burhan Engin, MD, Uğur Çelik MD, Zekayi Kutlubay, MD, Server Serdaroğlu, MD, Yalçın Tüzün, MD

CHAPTER 38.

VITAMIN D TREATMENT IN DERMATOLOGY......................................................287 Ufuk Kavuzlu, MD

CHAPTER 39.

ULTRAVIOLET TREATMENTS IN DERMATOLOGY ..............................................295 Işıl Kılınç Karaarslan, MD

CHAPTER 40.

EXTRACORPOREAL PHOTOCHEMOTERAPY (ECP) IN DERMATOLOGY........301 Erden ATİLLA, MD, Pınar ATACA, MD, Selami Kocak TOPRAK, MD.

VII

CONTRIBUTORS Pınar ATACA, MD Ankara University, School of Medicine,  Department of Hematology, Ankara, Turkey Erden ATILLA, MD Ankara University, School of Medicine,  Department of Hematology, Ankara, Turkey Şenay BALCI, PhD Mersin University, School of Medicine, Department of Biochemistry, Mersin-Turkey Simge BARDAK, MD Mersin University, School of Medicine, Department of Nephrology, Mersin-Turkey Kıymet BAZ, MD Mersin University, School of Medicine, Department of Dermatology, Mersin-Turkey Bilge BULBUL SEN, MD Mustafa Kemal University School of Medicine,  Department of Dermatology,  Hatay, Turkey Ayça CORDAN YAZICI, MD Mersin University, School of Medicine, Department of Dermatology, Mersin-Turkey Uğur CELIK, MD Istanbul University, Cerrahpaşa Medical Faculty, Dermatology of Department, Istanbul, Turkey  Serap DEMIR, MD Mersin University, School of Medicine, Department of Nephrology, Mersin-Turkey Mehmet DEMIREL, MD Mersin University, School of Medicine, Department of Dermatology, Mersin-Turkey Duriye Deniz DEMIRSEREN, MD Ankara Ataturk Training and Research Hospital, Dermatology Department, Ankara-Turkey Seval DOGRUK KACAR, MD Afyon Kocatepe University, School of Medicine,  Department of Dermatology,  Afyonkarahisar, Turkey Hatice DUMAN, MD Okmeydanı Training and Research Hospital,

Department of Dermatology, Istanbul-Turkey Selma EMRE, MD Ankara Ataturk Training and Research Hospital,  Dermatology Department,  Ankara-Turkey Burhan ENGIN, MD Istanbul University, Cerrahpaşa Medical Faculty, Dermatology of Department, Istanbul, Turkey  Bahadır ERCAN, PhD Mersin University, School of Medicine, Department of Biochemistry, Mersin-Turkey Aysegul GORUR, PhD Mersin University, School of Medicine, Department of Biochemistry, Mersin-Turkey Anıl Gülsel BAHALI, MD Bezmialem Vakif University,  Department of Dermatology and Venereology, Istanbul-Turkey Ozgür GUNDUZ, MD Kırıkkale University, School of Medicine, Department of Dermatology, Kırıkkale-Turkey Sule GUNGOR, MD Okmeydanı Training and Research Hospital,  Department of Dermatology, Istanbul-Turkey Ulas GUVENC, MD Mersin Yenişehir Hospital, Department of Dermatology, Mersin Turkey Mehmet HOROZ, MD Acıbadem University, Department of Nephrology, Turkey Göknur KALKAN, MD Aksaray State Hospital, Department of Dermatology, Aksaray-Turkey Ufuk KAVUZLU, MD Mersin University, School of Medicine, Department of Dermatology, Mersin-Turkey Tamer Irfan KAYA, MD Mersin University, School of Medicine, Department of Dermatology, Mersin-Turkey

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Deniz KAYA, MD Istanbul State Hospital, Department of Dermatology, Istanbul-Turkey

Kemal OZYURT, MD Sütçü Imam University, School of Medicine,  Department of Dermatology,  Kahramanmaraş, Turkey

Isıl KILINC KARAARSLAN, MD Ege University, Medical Faculty, Department of Dermatology, İzmir-Turkey

Engin SENEL, MD Hitit University, School of Medicine, Department of Dermatology, Çorum, Turkey

Ahmet KIYKIM, MD Mersin University, School of Medicine, Department of Nephrology, Mersin-Turkey

Server SERDAROGLU, MD Istanbul University, Cerrahpaşa Medical Faculty, Dermatology of Department, Istanbul, Turkey 

Selami KOCAK TOPRAK, MD Ankara University, School of Medicine,  Department of Hematology, Ankara, Turkey

Ralfi SINGER, MD Okmeydanı Training and Research Hospital,  Department of Dermatology, Istanbul-Turkey

Emek KOCATURK GONCU, MD Okmeydanı Training and Research Hospital,  Department of Dermatology, Istanbul-Turkey

Aysun SIKAR AKTURK, MD Kocaeli University Faculty of Medicine,  Department of Dermatology,  Kocaeli, Turkey

Selma KORKMAZ, MD Sütçü Imam University, School of Medicine, Department of Dermatology, Kahramanmaraş, Turkey

Pınar TABAKCI, MD Mersin State Hospital, Department of Dermatology Mersin-Turkey

Aysin KOKTURK, MD Mersin University, School of Medicine, Department of Dermatology, Mersin-Turkey

Lülüfer TAMER, PhD Mersin University, School of Medicine, Department of Biochemistry, Mersin-Turkey

Zekayi KUTLUBAY, MD Istanbul University, Cerrahpaşa Medical Faculty, Dermatology of Department, Istanbul, Turkey 

Ilteris TOPAL OGUZ, MD Okmeydanı Training and Research Hospital,  Department of Dermatology, Istanbul-Turkey

M. Kamil MULAYIM, MD Sütçü Imam University, School of Medicine,  Department of Dermatology,  Kahramanmaraş, Turkey

Kenan TURGUTALP, MD, Mersin University, School of Medicine, Department of Nephrology, Mersin-Turkey

Ozgül MUSTU KORYUREK, MD Aksaray State Hospital, Department of Dermatology, Aksaray-Turkey

Belma TURSEN, MD Mersin Sistem Hospital, Department of Dermatology, Mersin-Turkey

Evren ODYAKMAZ DEMIRSOY, MD Kocaeli University, School of Medicine,  Department of Dermatology,  Kocaeli, Turkey

Umit TURSEN, MD Mersin Sistem Hospital, Department of Dermatology, Mersin-Turkey

Perihan OZTURK, MD Sütçü Imam University, School of Medicine,  Department of Dermatology,  Kahramanmaraş, Turkey

Yalcın TUZUN, MD Istanbul University, Cerrahpaşa Medical Faculty, Dermatology of Department, Istanbul, Turkey 

Pınar OZUGUZ, MD Afyon Kocatepe University, School of Medicine,  Department of Dermatology,  Afyonkarahisar, Turkey

Pelin ULKUMEN, MD Okmeydanı Training and Research Hospital,  Department of Dermatology, Istanbul-Turkey

CHAPTER 1

DEVELOPMENT OF NOVEL IMMUNOMODULATORY DRUGS AND IMMUNOTHERAPEUTIC STRATEGIES Özgür Gündüz, MD Recent advances in our understanding of the molecular basis of inflammatory and oncogenic processes provided the researchers with new targets for the development of new drugs. Many new cells participating in inflammation, immunity, such as innate lymphoid cells (ILCs), regulatory T lymphoids (Tregs) are defined in recent years and key roles of various related cytokines in many diseases are appreciated, shedding light on their previously obscure parts of pathogenetic mechanisms. Due to current advanced bioengineering techniques, more effective drugs find their way continiuosly into clinical use, the most popular of them being the artificially obtained monoclonal antibodies, the so-called “biologics”.

BIOLOGICS IN DERMATOLOGY What are the “Biologics”? The term “biologics”define the molecules, monoclonal antibodies, generated by living cells through strict biotechnological interventions. They are the end result of “hybridoma technology”. This technology, invented by the Nobel prize laureates César Milstein and Georges J. F. Köhler1, enable today’s researchers to produce very specific antibodies against selected antigenic targets, which are designed to imitate or inhibit natural proteins in living tissues, such as cellular receptors, interleukins or antibodies. Creation of such molecules requires fusion of two different cells; an antibody-producing B cell and the clonal cells of a specific myeloma cell line lacking the hypoxanthine–guanine phosphoribosyl-transferase gene. The initial step is to expose a laboratory animal, preferably mice, to the antigen of interest by repeated injections and force them to mount an immune response including antibody production against the injected antigen. After the immunization of mice, their splenocytes are isolated from their spleen and the myeloma cells are fused with immortalised myeloma cells by means of electrofusion2 to obtain the so-called “hybridoma” cells. These hybrid cells are then placed in Hypoxanthine – aminopterin – thymidine (HAT) medium for an incubation period of 10 – 14 days. Due to blockage of nucleotide synthesis pathways by ami-

nopterin, the unfused myeloma cells die and the fused myeloma cells, the ones who gained the ability to synthesize nucleotides through this fusion, survive. These survivor cells are immortal and are able to produce antibodies. The last step of the procedure is to identify the cells producing the appropriate antibody. The incubated cells are distributed into the wells of multi-well plates after dilution. The distribution is arranged so that every well contains only one cell, enabling the monoclonal antibodies to be collected “in seperate wells. Then, hybridoma cells in every well are incubated with an enzyme labeled antigen and a chromogenic substrate for the enzyme to visualize an expected antibody – antigen reaction. Coloration of a well indicates the hybridoma cell clone with the capability to produce antibodies against the antigen in question. Due to this technological advances, researchers now are able to create immortal cells with the antibody-producing ability against any molecule in question, including the many cytokines, which (or roles of which) are recently defined in the pathogenesis of various dermatological diseases, such as psoriasis, atopic dermatitis, etc.

Advances in our understanding of psoria c pathogenesis Psoriasis is a common3 chronic inflammatory of skin and joints, which is also suspected to have pathogenic effects on other systems.4 Although the exact nature of etiologic factors stil eludes us, recent studies have shown immune-mediated, proinflammatory cytokine driven mechanisms in psoriatic pathogenesis5. Release of various inflammatory cytokines triggered by an enviromental factor has been suggested and shown by different research groups.6,7 Interleukin (IL)-17producing CD4+ T helper (Th) cells (Th17) are current focus of attention of psoriasis researchers. Current opinion for psoriatic pathogenesis is that it starts with the recruiting of myeloid dendritic cells by activated keratinocytes.8 Current data from various studies point out the potential role of the protein “chemerin” in psoriatic pathogenesis.9,10 These activated dendritic cells release in turn interleukin (IL) -12 and 23, which have been shown to have prominent roles in differrentiation of T Helper cells in (Th) 1 pathway and into Th17

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IMMUNMODULATORS IN DERMATOLOGY pathway respectively.12 In recent years, the attention of researchers has shifted to the Th17 cells11. The role of cytokines released by Th17 cells ( IL-17A, IL-17F, IL-21, IL-22 etc.) are well-established in the pathogenesis of psoriasis,13-15 supported by the evidence that the transcription factors RORγ and the chemokine CCL20 of Th17 pathway are found in abundance in cutaneous areas afflicted with psoriasis.15

An overview of classical agents in the treatment of psoriasis Classical therapies for widespread psoriasis consist of methotrexate, cyclosporine, retinoids and, especially in European countries, fumarate esters (FAEs). Methotexate, an antimetabolite which inhibits the enzyme “tetrahydrofolate” and cyclosporin, a blocker of intercellular calcineurin signaling pathway, exert their antipsoriatic effects via inhibition of T lymphocytes. In vivo concentrations of methotrexate has been postulated to inhibit lymphocyte proliferation16,17 and migration of activated lymphocytes.17 Cyclosporin forms a complex with an intercellular protein “cyclophilin” and formation of the “cyclosporin – cyclophilin” complex leads to inhibition of a transcription factor responsible for the regulation of many cytokine genes, the nuclear factor of activated T-cells (NFAT-1). The cytokines, production of which are inhibited by cyclosporin includevery important proinflammatory cytokines, such as interleukin-2 (IL-2), interferon gamma (IFN-γ). FAEs, another option for the systemic therapy for psoriasis and most frequently used in Germany, are postulated to inhibit the production of IL-12 and IL-13.18 Although all the above mentioned drugs are established treatment options for the psoriasis, neither are they curative nor free from serious side effects. Since these drugs are not designed as targeted molecules, some global anti-proliferative and immunosuppresive side-effects, such as hepatotoxicity of Mtx, nephrotoxicity of cyclosporin or the lymphopenia19 and progressive multifocal leuko-encephalopathy20 may develop during the therapy, limiting their use.

Biologics in psoria c treatment Alefacept and efaluzimab were the very first biologics

used in the treatment of psoriasis. Alefacept was a fusion protein targeting CD2 molecules on T-cell lymphocytes and efaluzimab was a humanized antibody targeting LFA-1 on T lymphocytes. Although these both molecules were designed to interact with specific molecules, their ultimate target was also T-lymphocytes like the afforementioned drugs. Both of these drugs are no longer in use and replaced by new biologics. Current anti-psoriatic biologics have more specific targets than their predecessors. Most of them are manufactured to neutralize cytokines involved in psoriatic pathogenesis rather than directly targeting the lymphocytes. The cytokines targeted by the modern biologics are determined by the results of recent researches. Modern anti-psoriatic biologics in use include Infliximab, Etanercept, Adalimumab, and Ustekunimab.11,21 The first three of anti-psoriatic biologics have tumor necrosis factor (TNF) as their target. TNF is produced by Th1 and Th17 cells, which are among the key elements of psoriatic cutaneous15 and arthritic inflammation.22 The most recent (and by FDA approved) addition to TNF-blockers are golimumab23 and certozulimab.24 Current investigations seem to be more concentrated on cytokines, such as IL-12, IL-23 and IL-17s as potential targets for anti-psoriatic drug development rather than on TNF. The drug ustekunimab can be referred as a forerunner of many other therapeutic, most of which are in the third phase of development. Ustekunimab, unlike its predecessors, targets a common subunit of IL-12 and IL-23,12 p40. The rationale for targeting these cytokines relies on some studies, in which these cytokines have been shown to play an important role in the pathogenesis of psoriasis and the psoriatic arthritis.24-26 It has beeen well-established that the proinflammatory cytokine IL-23 stimulates the Th17 cells, and consecutively induces the release of other inflammatory cytokines, IL-17 and IL-22, which, in turn, cause stimulation of keratinocytes by their interaction with other proinflammatory cytokines, i.e. TNF and interferon-γ. Of these two cytokines, IL-17 has been more extensively investigated. IL-17 is prominently produced by neutrophils by the cells of the immune system (T cells, neutrophils) in psoriatic lesions27 and known for its role in the

TABLE 1. Current Anti-psoriatic Biologics in Use Drug Name

Type

Target

Mode of Action

Approved since

Etanercept

Human fusion protein

Extracellular p75 portion of human TNF

Blockade of TNF-

2004

Infliximab

Chimeric antibody (Constant part human, variable part murine)

Human TNF

Inhibition of TNF-α

2006

Adalimumab

Fully human monoclonal antibody

Human TNF

Neutralization of TNF-α

2008

Ustekunimab

Monoclonal Human Antibody

p40 subunit of IL-12 and IL-23

Neutralization of the cytokines IL-12, IL-23

2008

CHAPTER 1: DEVELOPMENT OF NOVEL IMMUNOMODULATORY DRUGS AND IMMUNOTHERAPEUTIC STRATEGIES

TABLE 2. Anti-psoriatic biologics modulating IL-17 pathway Drug Name

Type

Target

Mode of Action

Approved since

Brodalumab

Fully Human anti-IL-17A receptor monoclonal antibody

IL-17RA

Blockage of I-17 receptor, IL-17A

Phase III trials

Ixekizumab

Humanized anti-17 IL-A monoclonal antibody

IL-17A

Inhibition of IL-17

Phase III trials

Secukunimab

Fully Human anti-IL-17A monoclonal antibody

IL-17A

Inhibition of IL-17

Phase III trials

TABLE 3. Anti-psoriatic biologics targeting IL-23 Drug Name

Type

Target

Mode of Action

Approved since

Ustekunimab

Monoclonal Human Antibody

p40 subunit of IL-12 and IL-23

Neutralization of the cytokines IL-12, IL-23

2008

Tildrakizumab

Humanized (mouse) anti –IL23p19 monoclonal antibody

p19 subunit of IL-23

Inhibition of IL-23

Phase III trials

Guselkumab

Fully Human anti-IL23p19 monoclonal antibody

p19 subunit of IL-23

Inhibition of IL-23

Phase II trials

migration of Th17 cells and myeloid dendritic cells to psoriatic plaques and leukocytes, and also stimulation of angiogenesis. In the light of these findings, IL-23 and IL-1728,29 have become the recent center of attention. Current “new” anti-psoriatic drugs targeting IL-17 or its receptor are now in the third phase of the developmental period and consist of Brodalumab, Ixelzumab and secukinumab. Results from the previous steps of trials, such as PASI75 responses in 70% of patients, indicate these drugs as very promising anti-psoriatic agents.30,31 In 2004, Piskin et al showed a decrease in the expression of I-12. IL-18 and IL-23 expression in the psoriatic plaques during recovery period26 and in 2006, Chan et al32 suggested an important role for IL-23 in psoriatic pathogenesis, particularly in the epidermal hyperplasia, paving the way for IL-23 targeting drugs. As of today, there is only one IL-23 targeting the only long-term results for therapeutic effcieny for an anti-IL-23 agent comes from the follow-up from the patients treated with the first approved anti-psoriatic biologic targeting IL-23,33 Ustekunimab (approved in 2008). Ustekunimab inhibits the effects of IL-23 binding its subunit p40, which is also known as IL-12 subunit beta, IL-12β). So Ustekunimab not only inhibits IL-23, but also IL-12, by neutralization of this common subunit p40. With the inhibition of IL-12 comes theoretical risk of carcinogenesis and systemic infections.34 Thaci et al. has shown that p19 levels (a subunit of IL-23) are higher in psoriatic plaques and p35 levels (a subunit of IL-12) are not, implying a more important role for IL-23 in the pathogenesis of psoriasis than IL-12.35 Further supporting evidence came from the recent PHOENIX I trial of ustekunimab.36 At the 16th week. PASI 75 scores were found to be similar with the scores in Thaci’s study, suggesting that IL-23 blockage is more pivotal than IL-12

inhibition in psoriatic therapy. Tildrakizumab seems also more advantegous than Ustekunimab since its side-effects are found to be similar to the side-effects in the placebo group and extension study shows that it has long-lasting therapeutic effects on patients.37

New “ Non-biologic” An -psoria cs – Small molecule inhibitors Phosphodiesterases (PDE) are a large family of enzymes consisting of 11 subfamilies, each with a unique function and tissue-specifity.38 PDE4 is known to be present in various tissues, i.e. in airway epithelium, leukocytes, skeletal and vascular muscles, central nervous system, dermis, smooth muscle, vascular endothelium, chondrocytes, and particulary in cells of immune system such as, dendritic cells, T cells, macrophages, and monocytes.38-43 The primary role of PDE 4 is to promote the inflammatory response by degrading cyclic AMP (cAMP), which is known to take part in pathways associated with the downregulation of the production of proinflammatory mediators44-46 and the suppression of T-cell activation,47 providing the rationale for the use of PDE4 inhibitiors in psoriasis. Apremilast is the forerunner of the recently emerging, “non-biologic”, anti-psoriatic agents. Apremilast inhibits the enzyme PDE4, but it is suspected that apremilast may have other mechanisms of action, through which it exerts its anti-inflammatory effects.48 TNF-α, IL-2, interferon-ϒ levels are found to be decreased and synthesis of inducible nitric oxide synthase, matrix metalloproteinase enzymes to be supressed during aprelimast use. Aprelimast also distinguishes itself from the biologics by its mechanism of action, since it effects at mRNA level.49 Apremilast was evaluated in clinical studies for psoriasis and psoriatic arthritis.50,51 In both of these

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IMMUNMODULATORS IN DERMATOLOGY

TABLE 4. Small-molecule inhibitors Drug Name

Type

Target

Mode of Action

Approved since

Apremilast

Small molecule

Promoter regions of Phosphodiesterase 4 coding genes

Increases the intracellular cAMP levels by PDE4 inhibition, Inhibition of proinflammatory cytokine synthesis

March 2014 for psoriatic arthritis

Tofacitinib

Enzyme Inhibitor protein

Janus Kinase (JAK1, JAK2)

Inhibiton of JAK, modulation of JAK/ STAT pathway

Phase II trials

studies, apremilast was found to be effective than placebo, but rate of PASI 75 responses in the psoriasis study at the 16th week was lower than the afforementioned biologics. Tofacitinib is a Janus Kinase(JAK) inhibitor, which has been recently approved for the treatment of rheumatoid arthritis. JAKs are intracellular tyrosine kinases, and are part of of the Janus Kinase - Signal Transducer and Activator of Transcription (JAK- STAT) pathway. JAK-STAT pathway acts as an second messenger system and transmits signals from the receptors located on the cell membrane to the cell nucleus, to the gene promoters, altering the transcription status.52 Tofacitinib has been shown to be effective in rheumatoid arthritis (RA)53 and is approved for the treatment of RA. Tofacitinib is also being evaluated for its efficacy and effectiveness in psoriasis. Results from various recent phase II trials are promising54 – 56 and reports indicate a rapid response to tofacinitib in plaque type psoriasis. There is even a case report regarding the remission of both alopecia areata and psoriasis in a patient.57

17. Cytokine Growth Factor Rev. 2014; S1359-6101(14): 00137-3. 6.

Gudjonsson JE, Johnston A, Sigmundsdottir H, Valdimarsson H. Immunopathogenic mechanisms in psoriasis. Clin Exp Immunol 2004;135:1–8.

7.

Nickoloff BJ, Nestle FO. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest 2004;113:1664–75.

8.

Skrzeczyńska-Moncznik J, Stefańska A, Zabel BA, Kapińska-Mrowiecka M, Butcher EC, Cichy J. Chemerin and the recruitment of NK cells to diseased skin. Acta Biochim Pol. 2009;56(2):355-60.

9.

Albanesi C, Scarponi C, Pallotta S, Daniele R, Bosisio D, Madonna S, Fortugno P, Gonzalvo-Feo S, Franssen JD, Parmentier M, De Pità O, Girolomoni G, Sozzani S. Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment.J Exp Med. 2009;206(1):249-58.

10.

Christophers E, Metzler G, Röcken M. Bimodal immune activation in psoriasis. Br J Dermatol. 2014;170(1):59-65.

11.

Belge K, Brück J, Ghoreschi K. Advances in treating psoriasis. F1000 Prime Reports 2014; 6: 4.

12.

Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol, 2009:129:1339–50.

13.

Baliwag J, Barnes DH, Johnston A. Cytokines in psoriasis. Cytokine. 2015: S1043-4666(14): 00628-0

14.

Kupetsky EA, Mathers AR, Ferris LK. Anti-cytokine therapy in the treatment of psoriasis. Cytokine. 2013;61(3):70412.

15.

Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron J, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R: Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007, 8: 950-7.

16.

Jeffes EWB III, McCullough JL, Pittelkow MR, et al. Methotrexate therapy of psoriasis. Differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate. J Invest Dermatol 1995;104:183-8.

17.

Sigmundsdottr H, Johnston A, Gudjonsson JE, et al. Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin. Exp Dermatol 2004;13: 426-34.

18.

Litjens NHR, Rademaker M, Ravensbergen B, Rea D, van der Plas MJA, Thio B, Walding A, van Dissel JT, Nibbering PH: Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses. Eur J Immunol 2004,34: 565-75.

Summary In recent years, new anti-psoriatic agents with very good response rates have been steadily emerging more than before. Although none of them are curative, these new molecules provides faster and longer remissions. Advances in our knowledge of psoriatic pathogenesis made it possible for pharmaceutical companies to design specific agents and to avoid the serious-side effects of the establishd drugs. Of these new drugs, IL-23 inhibitors and small-molecule inhibitiors seem to be promising candidates for therapy for psoriasis.

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Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol. 2003;149(2):363-9.

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Sweetser MT, Dawson KT, Bozic C: Manufacturer’s response to case reports of PML. N Engl J Med 2013; 368:1659-61.

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Boehncke WH. Biologics in the Treatment in Psoriasis J Rheumatol. 2006;33(7):1447-51

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Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, Skapenko A: Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 2010; 62: 2876-85.

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Torregrosa Calatayud JL1, Garcías Ladaria J, Sánchez Carazo JL, Pérez-Ferriols A, Oliver Martínez V, Calvo Catalá J, Alegre de Miquel V. Intensification therapy with golimumab: a new treatment strategy for moderate-severe refractory psoriasis. Int J Dermatol. 2014; 53(12):e585-7.

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McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, Brodmerkel C, Li S, Wang Y, Mendelsohn AM, Doyle MK: Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 2013; 382:780-9.

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Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665-1674.

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Cheng J, Tu Y, Li J, Huang C, Liu Z, Liu D. A study on the expression of interleukin (IL)-10 and IL-12 P35, P40 mRNA in the psoriatic lesions. J Tongji Med Univ. 2001; 21(1):86-8.

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Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris J Exp Med. 2004; 199(1):125-30.

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Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 2005; 10: 1503-1519

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Ma R, Yang BY, Wu CY. A selective phosphodiesterase 4 (PDE4) inhibitor Zln91 suppresses IL17 production by human memory Th17 cells. Int Immunopharmacol. 2008; 8:14081417.

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Sobell JM, Leonardi CL. Therapeutic Development in Psoriasis. Semin Cutan Med Surg. 2014 Jun;33(4 Suppl):S69-72.

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Piskin G, Tursen U, Sylva-Steenland RM, Bos JD, Teunissen MB. Clinical improvement in chronic plaque-type psoriasis lesions after narrow-band UVB therapy is accompanied by a decrease in the expression of IFN-gamma inducers --IL-12, IL-18 and IL-23. 2004;13(12):764-72.

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Mamolo, C., Harness, J., Tan, H. and Menter, A. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, improves patient-reported outcomes in a phase 2b, randomized, double-blind, placebo-controlled study in patients with moderate-to-severe psoriasis. Journal of the European Academy of Dermatology and Venereology, 2014; 28: 192–203.

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Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014; 134(12):2988-90.

CHAPTER 2

ABATACEPT Şule Güngör, MD Abatacept (Orencia™) is a novel biologic agent that is a fully human fusion protein made by the extracellular domain of cytotoxic T-lymphocyte antigen (CTLA)4 linked to the Fc portion of human IgG1 and has been approved for the treatment of rheumatoid arthritis (RA) and juvenile idiopatic arthritis.1-3 It blocks activation of T cells by blocking the CD80/CD86:CD28 co-stimulatory signal from antigen-presenting cells by blocking binding of B7 protein on antigen-presenting cells.(3) As an indirect effect within the inflammatory cascade, the production of cytokines and autoantibodies is inhibited.4,5 In clinical trials with abatacept at doses approximating 10mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor, interleukin-6, rheumatoid factor, C-reactive protein, matrix metalloproteinase-3 and TNFα.6 Abatacept for psoriasis and psoriatic arthritis:Psoriasis vulgaris is an inflammatory skin disease. Cytokines released from the activated T cells are believed to contribute to the pathologic changes induced in lesional keratinocytes and vascular endothelium in psoriasis.7 Firstly Abrams et al investigated the role of the CD28/CTLA-4 pathway in psoriasis vulgaris in a 26-week, phase I study. Forty-three psoriatic patients received four infusions of the soluble chimeric protein CTLA4-Ig, 46% of these patients achieved a 50% or greater improvement correlated with the reduction in epidermal hyperplasia and skin-infiltrating T cells.8 Mease P. et al9 performed a phase II study in 170 psoriatic arthritis patients with psoriatic skin lesions. The patients received placebo or three different dosage regimens of abatacept. Abatacept-treated patients received 3mg/kg, 10mg/kg or 30/10mg/kg (two initial doses of 30mg/kg, followed by 10mg/kg) on days 1, 15 and 29 and then once every 28 days thereafter until 169th day. By means of improvement in psoriatic arthritis American College of Rheumatology 20% response was significant compared with placebo in the groups receiving abatacept 10mg/kg and 30/10mg/kg but not 3mg/kg. Improvements in the psoriasis area and severity index (PASI) 50 response were observed in all abatacept regimens. On day 169, the proportions of patients achieving a PASI50 response were 43% at 3mg/kg, 29% at 10mg/kg, 35% at 30/10mg/kg and 14% for placebo. On day 169, PASI75 response were 38% at

3mg/kg, 14% at 10mg/kg, 10% at 30/10mg/kg and 5% for placebo; with only those taking the 3mg/kg dose of abatacept showed improvement compared to placebo. On day 169, investigator’s global assessment response (lesions judged to be “clear or almost clear”) were 38% of those taking 3mg/kg of abatacept, 25% taking 10mg/ kg, 21% taking 30/10mg/kg and %26 taking placebo, with only the 3mg/kg group showing a modest improvement compared to placebo. Interestingly psoriatic skin response was seen optimum in 3mg/kg dose conversely to recommended dose for psoriatic arthritis and romatoid arthritis. Authors commented that the different effects of abatacept on the joints and the skin may indicate the inflammation in the skin differs from that in the joints. Additionally authors also pointed that the highest PASI75 response was 38% while other studies with anti-TNF agents PASI75 response was up to 68%.10,11,12 On the other hand the subjects included in this study were inadequate responsed patients to anti-TNF therapy may have resulted in a more treatment-resistant population and may thus have lessened the abatacept response. In an other study Varada et al13 retrospectively evaluated 96 patients given the diagnoses of psoriasis and lupus erythematosus. In this study there were three patients receiving abatacept. All three patients had SLE, chronic plaque psoriasis and psoriatic arthritis. Improvements in SLE symptoms and cutaneous psoriasis were noticed while cutaneous photosensitivity was reported in two of three patients. Ursini et al4 report a psoriatic arthritis patient with vulvar psoriatic lesions. Though they report that patient disease activity score was significantly reduced three months after the initiation of abatacept treatment, they did not point psoriatic skin lesions enough if the lesions cleared or not. Rodriges et al14 used abatacept (two infusions, with a 20-day interval) for DMARDS and anti-TNF resistant psoriatic arthritis; beside joint symptoms they also report the improvement of psoriatic skin lesions, anemia and inflammatory markers. Also there are uncompleted studies investigating the combination of abatacept with other biologicals for psoriasis. A phase II study was started at February 2014,

7

8

IMMUNMODULATORS IN DERMATOLOGY official titled “Efficacy of Ustekinumab (Anti-IL-12/23) Followed by Abatacept (CTLA4-Ig) for the Treatment of Psoriasis Vulgaris (ITN059AI)”, estimated primary completion date December 201715 On the other hand there are several articles reporting psoriatic eruptions after initiation of abatacept. A study integrating safety analysis of five randomized, placebo-controlled abatacept clinical trials revealed that nine patients out of 1955 abatacept-treated subjects presented with psoriasis, compared to zero cases in the patients receiving placebo.16 Additionaly there are sporadically reported cases about development or recrudescence of skin psoriasis during treatment with abatacept.17-23 The mechanism of paradoxical psoriasis due to abatacept is still unclear. Abatacept may interfere with CTLA-4 signals in regulatory T cells, which results in the impared suppressive functions of those cells and in the exacerbation of Th17 immunity.20 As described in above studies, though the efficacy of abatacept for psoriatic arthritis is well defined, the benefical effects of abatacept in cutaneous psoriasis is conflicting. Future studies are needed to understand the role of abatacept in psoriasis.

20 abatacept treatments. But the second patient could not continue abatacept treatment, as the patient was diagnosed with breast cancer.29 In another multicenter study, 12 patients with systemic sclerosis received abatacept for 11 months. While joint parameters improved significantly, no significant change was seen for skin or lung fibrosis at the end of the therapy.30 There is an ongoing phase II study, estimated completion date March 2016 which evaluates the subcutaneous abatacept vs. placebo in diffuse cutaneous systemic sclerosis.31 Abatacept for graft-versus-host disease: Activation of donor T lymphocytes by antigen-presenting cells in the transplant recipient, causing an alloreactive T-cell response to recipient tissues mediated by cytotoxic T cells and inflammatory cytokines, is responsible fort he development of graft-versus-host disease. So abatacept can prevent this pathway by blocking activation of T cells. There are graft-versus-host disease patients treated with abatacept in the literature.32,33. Abatacept for Wegener’s Granulomatosis: Wegener’s granulomatosis (WG) is a rare disease that causes inflammation of blood vessels, or vasculitis. Current standard treatment for WG involves various medications and is based on disease severity. Unfortunately, more than 50% of people experience a relapse after remission, placing them at risk for additional organ damage and medication toxicity. Several studies have shown that activated T cells, a type of white blood cell important in regulating immune responses, play a role in WG. So abatacept can prevent these activated T cells and can lead to improve WG symptoms. In an open-label study, it was found that, abatacept was well tolerated and was associated with a high frequency of disease remission and prednisone discontinuation in WG patients.34

Abatacept for systemic lupus erythematosus (SLE): SLE is a multisystem autoimmune disease. Exacerbation of disease in SLE has been associated with increased levels of activated peripheral B cells and T cells.24,25 The interaction of T cells with B cells plays role in the production of high-affinity IgG autoantibodies that are associated with SLE pathology.25 Studies of abatacept use in SLE have been variable.13,25 Merrill et al evaluate the efficacy and safety of abatacept in 175SLE patients, 118 patients were randomized to receive abatacept and 57 to receive placebo, and though they detected the benefical effects in SLE symptoms they also report high frequency of serious adverse events in abatacept-treated patients. And they concluded that further studies are needed to assess the efficacy and safety of abatacept in SLE disease.25 Varada et al (13) retrospectively evaluated 96 patients given the diagnoses of psoriasis and lupus erythematosus. In this study there were three patients receiving abatacept. All three patients had SLE, chronic plaque psoriasis and psoriatic arthritis. Improvements in SLE symptoms and cutaneous psoriasis were noticed while cutaneous photosensitivity was reported in two of three patients. On the other hand abatacept is off-label recommended for SLE for joint and renal symptoms but not for cutaneous symptoms.26-28

Future expects for abatacept in dermatology: The autoimmune dermatological diseases, which CTLA4 pathway is critical in the pathogenesis, seems to be improved by abatacept therapy. As antigen presentation in association with CTLA4-CD80/86 co-stimulation is implicated in the development of alopecia areata; Sundberg et al. suggest to use abatacept for alopecia areata.35 wthere is already an ongoing, uncompleted, open-label, single-arm, clinical trial, to evaluate the efficacy of abatacept in moderate to severe patch type alopecia areata, estimated completion date is July 2016.36

Abatacept for scleroderma and morfea:As effector T cells have a key role in scleroderma and morphea, T-cell directed therapies are expected to have benefical effects for these diseases. Two disseminated morphea profunda patients resistant to conventional therapies were treated with abatacept with good clinical reponse. The first patient had a modified Rodnan skin score of 18 before abatacept treatment, and a score of 2 after

Matsui et al detected CTLA4 autoantibodies 8.2% of the patients with systemic lupus erythematosus, 18.8% of rheumatoid arthritis, 3.1% of systemic sclerosis, 31.8% of Behçet’s disease, 13.3% of Sjögren’s syndrome, and 0% of healthy donors.37 They also showed autoantibodies to CTLA4 enhace T cell proliferation.38 Abatacept can be a promising agent to improve symptoms of resistant Behçet’s disease. There is an ongoing study,

CHAPTER 2: ABATACEPT estimated completion date February 2016, officially titled as “a pilot study of the safety and efficacy of abatacept injections in the treatment of mucocutaneous manifestations of Behcet’s syndrome” investigating the efficacy of abatacept treatment in Behçet’s disease.39 There is a newly started phase I study, officially titled as “open-label pilot study of abatacept for the treatment of vitiligo” estimated completion date January 2017 investigating vitiligo lesions improvement by weekly injections of abatacept.40

DOSAGE For RA treatment, an initial dose of approximately 10 mg/kg iv, repeated by additional doses after 2 and 4 weeks, with further doses every 4 weeks. After the initial intravenous dose, 125 mg subcutaneous injection 24 hours later, repeated by weekly subcutaneous injections of 125mg is an other choice of the abatacept treatment.41,42 Merrill used the same protocol as desribed above for patients with RA in a phase II study for SLE patients, and reported efficacy of abatacept in SLE.25 Adverse events and safety:Adverse effects of abatacept include increased risk of infections and malignancies. All patients should be screened for tuberculosis and hepatitis B and C before treatment, live attenuated vaccines should be avoided during therapy. Infusion reactions include dizziness, headache, nausea, fever and hypertension. In a study of long-term safety, 96% of patients experienced adverse events; however, most of them were mild to moderate. No significant differences in adverse events were noted when the abatacept group and placebo group (receiving DMARDs only) were compared.43 The other studies showed that; the risk of apperance of tumors in patients treated with abatacept is not higher to what is expected in RA patients; the use of abatacept in patients with stage IV heart failure must be approached with caution; in patients with demyelinating disease, the use of abatacept is not contraindicated; in case of use, close neurological follow up is needed.44-47 Pregnancy category of abatacept is C.(6) Abatacept should be avoided in patients receiving TNF antagonist, such as adalimumab, etanercept and infliximab because such combination therapy may increase the risk for severe infections.6

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Korhonen R, Moilanen E. Abatacept, a novel CD80/86CD28 T cell co-stimulation modulator, in the treatment of rheumatoid arthritis. Basic Clin Pharmacol Toxicol 2009; 104:276-84.

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basic science and clinical review and a practical guide to tuberculosis monitoring. Clin Rev Allergy Immunol. 2013; 44(2):121-40. 4.

Ursini F, Naty S, Russo E, Grembiale RD. Abatacept in psoriatic arthritis: Case report and short review. J Pharmacol Pharmacother. 2013;4 (Suppl 1):S29-32.

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Weisman MH, Durez P, Hallegua D, Aranda R, Becker JC, Nuamah I, Vratsanos G, Zhou Y, Moreland LW. Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis. J Rheumatol. 2006 Nov;33(11):2162-6.

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Baadsgaard O, Tong P, Elder JT, Hansen ER, Ho V, Hammerberg C, Lange-Vejlsgaard G, Fox DA, Fisher G, Chan LS. UM4D4+ (CDw60) T cells are compartmentalized into psoriatic skin and release lymphokines that induce a keratinocyte phenotype expressed in psoriatic lesions. J Invest Dermatol. 1990;95(3):275-82

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Abrams JR, Lebwohl MG, Guzzo CA, Jegasothy BV, Goldfarb MT, Goffe BS, Menter A, Lowe NJ, Krueger G, Brown MJ, Weiner RS, Birkhofer MJ, Warner GL, Berry KK, Linsley PS, Krueger JG, Ochs HD, Kelley SL, Kang S. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest. 1999;103(9):1243-52

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Mease P, Genovese MC, Gladstein G, Kivitz AJ, Ritchlin C, Tak PP, Wollenhaupt J, Bahary O, Becker JC, Kelly S, Sigal L, Teng J, Gladman D. Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum. 2011;63(4):939-48.

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Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, Guzzo C, Zhou B, Dooley LT, Kavanaugh A; IMPACT 2 Trial Investigators. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005; 64(8):1150-7.

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Antoni CE, Kavanaugh A, van der Heijde D, Beutler A, Keenan G, Zhou B, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman DD, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen JS. Two-year efficacy and safety of infliximab treatment in patients with active psoriatic arthritis: findings of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). J Rheumatol. 2008; 35(5):869-76.

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Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, Sharp JT, Ory PA, Perdok RJ, Weinberg MA. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005; 52(10):3279-89.

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Varada S, Gottlieb AB, Merola JF, Saraiya AR, Tintle SJ. Treatment of coexistent psoriasis and lupus erythematosus. J Am Acad Dermatol. 2015; 72(2):253-60

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Rodrigues CE, Vieira FJ, Callado MR, Gomes KW, de Andrade JE, Vieira WP. Use of the abatacept in a patient with psoriatic arthritis. Rev Bras Reumatol. 2010; 50(3):340-5.

15.

www.clinicaltrials.gov. Identifier:NCT01999868.

16.

Sibilia J, Westhovens R. Safety of T-cell co-stimulation modulation with abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007; 25(5 Suppl 46):S46-56.

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Jost C, Hermann J, Caelen Lel-S, Graninger W. New onset psoriasis in a patient receiving abatacept for rheumatoid arthritis. BMJ Case Rep. 2009;2009. pii: bcr09.2008.0845.

18.

Brunasso AM, Laimer M, Massone C. Paradoxical reactions to targeted biological treatments: A way to treat and trigger? Acta Derm Venereol. 2010; 90(2):183-5.

19.

Florent A, Albert C, Giacchero D, Roux C, Euller-Ziegler L. Reactivation of cutaneous psoriasis during abatacept therapy for spondyloarthropathy. Joint Bone Spine. 2010; 77(6):626-7.

20.

Kato K, Satoh T, Nishizawa A, Yokozeki H. Psoriasiform drug eruption due to abatacept. Acta Derm Venereol. 2011; 91(3):362-3.

21.

Brigant F, Clavel G, Chatelain D, Lok C, Chaby G. A case of generalized guttate psoriasis induced by etanercept with relapse after abatacept. Dermatology Online Journal 2011; 17(6).

22.

Silverman D, Oliver A. Abatacept-induced psoriasis. Cutis. 2011; 88(3):117-8.

23.

Konsta M, Rallis E, Karameris A, Stratigos A, Sfikakis PP, Iliopoulos A. Psoriasiform lesions appearing in three patients with rheumatoid arthritis during therapeutic administration of abatacept, a selective inhibitor of T-cell costimulation. J Eur Acad Dermatol Venereol. 2012; 26(2):257-8.

24.

Spronk PE, Horst G, Van Der Gun BT, Limburg PC, Kallenberg CG. Anti-dsDNA production coincides with concurrent B and T cell activation during development of active disease in systemic lupus erythematosus (SLE). Clin Exp Immunol. 1996; 104(3):446-53.

25.

Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace DJ, Bae SC, Sigal L, Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010; 62(10):3077-87.

26.

Belmont HM. Treatment of systemic lupus erythematosus - 2013 update. Bull Hosp Jt Dis 2013;71(3):208-13.

27.

ACCESS Trial Group. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study.Arthritis Rheumatol. 2014; 66(11):3096-104

28.

Ikeda K, Sanayama Y, Makita S, Hosokawa J, Yamagata M, Nakagomi D, Takabayashi K, Nakajima H. Efficacy of abatacept for arthritis in patients with an overlap syndrome between rheumatoid arthritis and systemic lupus erythematosus. Clin Dev Immunol. 2013; 2013:697525.

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Stausbøl-Grøn B, Olesen AB, Deleuran B, Deleuran MS. Abatacept is a promising treatment for patients with disseminated morphea profunda: presentation of two cases. Acta Derm Venereol. 2011; 91(6):686-8. Elhai M, Meunier M, Matucci-Cerinic M, Maurer B, Riemekasten G, Leturcq T, Pellerito R, Von Mühlen CA, Vacca A, Airo P, Bartoli F, Fiori G, Bokarewa M, Riccieri V, Becker M, Avouac J, Müller-Ladner U, Distler O, Allanore Y; EUSTAR (EULAR Scleroderma Trials and Research group). Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis. 2013; 72(7):1217-20.

31.

www.clinicaltrials.gov Identifier:NCT02161406.

32.

Elfeki MA, Genco PV, Pungpapong S, Nakhleh RE, Nguyen JH, Harnois DM. Abatacept use in graft-versus-host disease after orthotopic liver transplantation: a case report. Transplant Proc. 2014; 46(7):2422-5.

33.

Koura DT, Horan JT, Langston AA, Qayed M, Mehta A, Khoury HJ, Harvey RD, Suessmuth Y, Couture C, Carr J, Grizzle A, Johnson HR, Cheeseman JA, Conger JA, Robertson J, Stempora L, Johnson BE, Garrett A, Kirk AD, Larsen CP, Waller EK, Kean LS. In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant. 2013; 19(11):1638-49.

34.

Langford CA, Monach PA, Specks U, Seo P, Cuthbertson D, McAlear CA, Ytterberg SR, Hoffman GS, Krischer JP, Merkel PA; Vasculitis Clinical Research Consortium. An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener’s). Ann Rheum Dis. 2014; 73(7):1376-9.

35.

Sundberg JP, McElwee KJ, Carroll JM, King LE Jr. Hypothesis testing: CTLA4 co-stimulatory pathways critical in the pathogenesis of human and mouse alopecia areata. J Invest Dermatol. 2011; 131(11):2323-4.

36.

www.clinicaltrials.gov Identifier: NCT02018042.

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Matsui T, Kurokawa M, Kobata T, Oki S, Azuma M, Tohma S, Inoue T, Yamamoto K, Nishioka K, Kato T. Autoantibodies to T cell costimulatory molecules in systemic autoimmune diseases. J Immunol. 1999; 162(7):4328-35.

38.

Matsui T, Nishioka K, Kato T, Yamamoto K. Autoantibodies to CTLA-4 enhance T cell proliferation. J Rheumatol. 2001; 28(1):220-1

39.

www.clinicaltrials.gov Identifier:NCT01693640.

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www.clinicaltrials.gov Identifier: NCT02281058.

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Rosman Z, Shoenfeld Y, Zandman-Goddard G. Biologic therapy for autoimmune diseases: an update. BMC Med. 2013;11:88.

42.

Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W, Steinfeld S, Tindall E, Becker JC, Li T, Nuamah IF, Aranda R, Moreland LW. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52(8):2263-71.

43.

Kremer JM, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Westhovens R, Li T, Zhou X, Becker JC, Aranda R, Peterfy C, Genant HK. Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial. Ann Rheum Dis. 2011; 70(10):1826-30.

44.

Simon TA, Smitten AL, Franklin J, Askling J, Lacaille D, Wolfe F, Hochberg MC, Qi K, Suissa S. Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment. Ann Rheum Dis. 2009;68(12):1819-26.

45.

Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):R45.

46.

Viglietta V, Bourcier K, Buckle GJ, Healy B, Weiner HL, Hafler DA, Egorova S, Guttmann CR, Rusche JR, Khoury SJ. 24CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology 2008: 16;71(12):917-24.

47.

Martín Mola E, Balsa A, Martínez Taboada V, Sanmartí R, Marenco JL, Navarro Sarabia F, Gómez-Reino J, Alvaro-Gracia JM, Román Ivorra JA, Lojo L, Plasencia C, Carmona L; Spanish expert panel of rheumatologists. Abatacept use in rheumatoid arthritis: evidence review and recommendations. Reumatol Clin. 2013; 9(1):5-17.

CHAPTER 3

ADALIMUMAB in DERMATOLOGY Aysin Köktürk, MD Adalimumab (ADA) is a recombinant, fully humanized IgG1 monoclonal antibody targeted against TNF-α. and. It has been in use since 2003 and is an increasingly important drug in dermatology. Treatment with ADA proved to be effective for the management of chronic moderate to severe plaque-type psoriasis in patients whose disease had been refractory to systemic conventional therapies. Pivotal trials such as CHAMPION, REVEAL have proved this biological agent to be generally safe and well tolerated by patients.1,2 Besides psoriasis, ADA was approved by FDA for use in psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis3. After subcutaneous administration of a single 40-mg dose, ADA’s absorption and distribution is slow, with peak concentrations reached 5 days after administration. The terminal half-life of ADA is between 10 and 20 days.4 In the management of chronic moderate to severe plaque-type psoriasis, the FDA-approved standard dosing regimen for ADA is an initial dose of 80 mg at week 0 that is followed by 40 mg every other week starting at week 1. According to a study, the therapy should be reconsidered in a patient not responding within 12 weeks regarding dose escalation. It was reported that, dose escalation to 40 mg once a week improves clinical response in non-responders to standard therapy.5 When the relapse occured after withdrawal of the drug, it was reported that there was a good likelihood of regaining clinical efficacy following ADA reinitiation.6 The production of antibodies to ADA in autoimmune patients treated with ADA has been shown to diminish treatment efficacy.1 Adalimumab (ADA) is generally considered safe and well tolerated. The most common side effects of ADA are injection site reactions.7-9 Rare but serious adverse effects such as demyelination, infection, lymphoma, non-melanoma skin cancer, cardiovascular complications, hepatitis have been observed.8-14 A report of results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) which comparing the infection risk of the most used psoriatic biologic

agents across patients, suggests that treatment with ADA and infliximab are associated with a higher risk for serious infections than nonmethotrexate and nonbiologic therapies.16 Therefore, attention to specific aspects of patient management such as prescreening requirements and symptoms to watch for is required to reduce risk. In psoriais treatment, combination therapy of ADA, like the other biologics, with topicals, traditional systemics, phototherapy, may enhance efficacy and can permit discontinuation or dose reduction of traditional systemic agents. Combination therapy seems better rather than changing biologic agents, in circumstances of inadequate efficacy or relapses with monotherapy. Numerous case reports suggest ADA could be helpful in treating some skin disorders other than psoriasis, such as Behçet’s Disease (BD), hidradenitis suppurativa, pyoderma gangrenosum, pemphigus, cutaneous sarcoidosis and aphthous stomatitis. TNF-α is believed to be a central inflammatory mediator in Behçet’s Disease (BD). ADA therapy is reported to be successful in treating BD with different manifestations.15-24 Arida et al. analyzed published data on anti-tumor necrosis factor TNF agents’ efficacy on 369 Behcet’s disease patients from 20 different countries who were refractory to conventional therapies They found 13 articles on ADA reporting on 28 patients.25 In these patients, prompt remission of oral ulcers, genital ulcers, erythema nodosum, and other skin lesions was noted to be induced in 73%, 86%, 100%, and 80%, respectively. Regarding the therapeutic efficacy of ADA on ocular involvement, switching from infliximab to ADA in 2 patients due to advers reactions, was noted to be successful with complete remission. They noted that 3 patients with gastrointestinal involvement were treated succesfully with ADA.21,26 Perra D et al. evaluated 19 patients with severe clinical manifestations of BD who unresponsive to immunosupressive therapy including TNF-alpha inhibitors (five had received infliximab and two had Etanercept) or suffered from adverse effect of previous drugs.27

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IMMUNMODULATORS IN DERMATOLOGY They achieved clinical improvement in 17 of the 19 patients with ADA and found it to be a good option for patients with BD who have severe and recalcitrant manifestations. Regarding mucocutaneous disease, complete response was documented in 5 of 8 patients (62.5%) with severe aphtous disease and partial response was in the rest.3 Three patients with severe and extensive folliculitis who were unresponsive other some immunosupressives and 1 patient with erythema nodosum showed a partial response in their study. While 1 of the 2 patient with cutaneous vasculitis had showed complete remission, ADA was recorded as inefective in the other patient. ADA was noted to be withdrawn in only one patient due to severe infusional reaction in the form of urticaria and angioedema. Perra et al. also recorded the number and dosage of immunosuppressive drugs used by each patient before and after ADA treatment and found that, treatment with ADA was associated with reduction in the number and dose of standard immunosuppressive agents. In accordance with other studies using ADA in BD with ocular inflammation, they recorded complete resolution in these patients in a short time (after an avarage period of 2.9 weeks).25,28 Interlandi et al. found ADA to be a very effective and safe option for treatment of patients with severe and resistant Behçet’s uveitis, providing an appropriate and long-term control of ocular inflammation after mean follow-up of 21 months. They stated that all of the 12 patients but one (92%) achieved uveitis remission in their retrospective long-term follow-up study.29 Calvo Catala J et al. analyzed the effects of ADA on six patients with BD pretreated with inmunosupressive therapy and found a good clinical response in all patients with no advers effects.22 In the study of Olivieri et al, they aimed to evaluate the clinical response after switching from infliximab to ADA in patients with BD.30 They evaluated a total of 69 patients with BD who had been treated with infliximab. Seventeen of those (25%) patients who failed to infliximab therapy were treated with ADA, and 12 of 17 had a good response. In 10 of those 17 patients, mucocutaneous lesions were reported to be the main manifestations requiring switching. No side effects were observed in any patient.

Aphtous Stoma

s

Like BD, the immune mechanisms involved in aphtous stomatitis are considered to be mediated by TH1 cytokines including TNF-α. TNF- α antagonists have known to be effective in Crohn Disease where extensive oral involvement was a component of the disease. There are publications about the effectiveness of infliximab in Crohn Disease with severe oral ulcerations.31,32 In a patient with Crohn Disease who was resistant

to infliximab therapy, ADA has been found to be safe and effective substitute: He was reported to have long-standing severe oral and oesophageal ulceration despite treatment with infliximab and numerous systemic immunosuppressive agents. The patient was treated succesfully with the regimen of ADA which was applied as 80 mg loading dose s.c. followed by maintenance therapy with 40 mg s.c. weekly; plus dapsone.33 Although TNF-α antagonists may represent an option in severe refractory aphthosis there are limited data for efficacy of these agents in aphthous stomatitis. In the review of O’Neil et al., composed of 16 cases from individual case reports and small case-series, it is suggested that TNF-α antagonists have some efficacy in the treatment of aphthous stomatitis by both inducing ulcer resolution and also reducing recurrence.34 The first report demonstrating effectiveness of ADA for the treatment of aphthous stomatitis was a 18-year-old man with severe major aphthous stomatitis refractory to multiple standard therapies.35 It was noted that the patient responded completely to therapy with ADA at a dose of 40 mg injected subcutaneously every other week. Two weeks after the first subcutaneous injection, their patient showed 90% clinical improvement of ulcerations and in the next several weeks, all remaining ulcerations were observed to be completely healed. Afterwards, a 64-year-old man presented with history of aphthous stomatitis causing dysphagia. He was noted to respond to treatment dramatically after the first dose of ADA. The tretment was applied in a dose of 40 mg subcutaneously every other week and complete remission was achieved following the second dose. After 5 months of follow-up, the patient remains free of aphtae and no adverse effects were reported in that period.36 In a study aimed to evaluate the efficacy and safety of TNF- α antagonists in primary complex aphthosis, these agents, including ADA, found to be effective and safe treatment option for these patients who do not respond sufficiently to standard therapies.37

PYODERMA GANGRENOSUM In addition to classic immunosuppressive medications, pyoderma gangrenosum (PG) was reported to respond well to the anti-TNF agents including ADA There are some case reports and limited number of reviews about the effectiveness of ADA in PG. Firstly, Hubbard et al reported a patient with idiopathic PG with systemic involvement who was unresponsive to conventional immunosuppressant therapy and was completely healed with Inliximab and ADA.38 Hinterberger et al. reported a case with recurrent PG

CHAPTER 3: ADALIMUMAB IN DERMATOLOGY unresponsive to systemic standard therapies including azathioprine, corticosteroids, mycophenolate mofetil, and cyclophosphamide in combination with intensive topical treatment. They administered ADA subcutaneously, as a monotherapeutic agent, starting with 80  mg in week 0 and 40  mg in week 1, followed by 40 mg every other week. They observed that the ulceration got steadily smaller and healed nearly completely within 64 weeks without any side effects. They noted an increased quality of life according to Dermatology Life Quality Index.39 Regarding IBD-associated PG, Agarwal and Andrews published a systematic review about the treatment efficacy of currently available TNF- α therapies for IBD-related PG in 60 patients from 49 publications40. They considered anti-TNFα therapy as a first-line agent for the treatment of PG as they observed them to be highly effective. In their analyze they mentioned 4 patients with PG who received ADA (2 received both infliximab and ADA; 2 received only ADA). ADA was only used as second-line therapy and was successful in all that four cases.41-44 One patient whose prior regimen was infliximab and who was refractory to increasing infliximab dosage + AZA + ciclosporin + immunoglobulin + prednisolone and topical tacrolimus + triamcinolone, responded to treatment after the addition of ADA. Then, after the other agents ceased, complete healing was observed with ADA monotherapy by 16 weeks.42 The second patient, whose ongoing treatment was Methotrexate, was refractory to infliximab, but responded to ADA + steroid43. The other two cases were anti-TNFα naïve, and refractory to treatment agents such as steroid, ciclosporin, mycophenolate mofetil, meselazine and topical tacrolimus. One of them achieved complete healing in 4 weeks with induction of ADA followed by oral tacrolimus and the other healed completely with ADA monotherapy.41,44. Agarwal and Andrews stated that there was no correlation of PG duration or size with healing times. In Malaga, in a retrospective, observational study of Suarez-Perez ADA was prescribed as first-line treatment in 4 patients with PG.45 Three of those patients had inflammatory bowel disease, 1 had ankylosing spondylitis. In inflammatory bowel disease, an initial dose of 80mg followed by 40mg every 2 weeks was used. In the 2 patients with ulcerative colitis, complete resolution of PG was achieved 30 days after initiation of treatment, although adjuvant sulfasalazine was required in 1 patient. The patient with Crohn disease, who had additional concomitant disease, required weekly dosing of ADA in order to control the disease. The patient with ankylosing spondylitis required combination with sulfasalazine when positive results were not obtained with ADA and oral prednisone or cyclosporin.There was no loading dose; ADA at a dose of 40mg every 2 weeks was used in this patient. There were no any adverse reactions in all 4 patients with ADA. They considered

ADA to be a good alternative for the treatment of PG with concomitant systemic disease, which can be used in combination with other immunosuppressant drugs with favorable safety profile. Carinanos et al. reported 4 IBD related PG cases (Three were localized on lower limbs, one was universal) treated with ADA who were refractory to conventional therapies such as corticosteroids and/or cyclosporin46. Two of the cases were treated with IFX previously but the drug had to be stopped because of loss of response and acute infusion reactions. ADA was administered in a dose of 160-80 mg induction regimen with the maintenance dose of 40 mg every other week. Complete remission was observed after a median of 34 days in all patients. The patients were maintained with ADA for mean time of 22 months and no adverse events were seen. Two of the patients were on combination therapy with thiopurines. Two patients (one of them had universal PG and on combination therapy) needed to increase the dose because of loss of response in one and PG reapperance in the other who had universal lesions at the beginning. Lipka et al. reported a case with massive PG in a patient with Crohn’s disease responsive to ADA. They observed the perineal disease showed marked improvement after 2 months of weekly dosed of the drug and completely healed by 1 year of the therapy.47 An other author, however, described a case with severe PG unresponsive to both Etanercept and ADA. In a patient who unresponsive or intolerant to classical immunsupressive treatments for a long time, he applied firstly Etanercept. After they observed temporary and limited improvement, decided its failure and started ADA. However after 6 months, because of no clinical improvement they stopped ADA and had to continue with systemic corticosteroids with good result.48 Although contradictory results, ADA seems to be a valuable alternative for the treatment of PG.

Hidradeni s Suppura va Until recently, there are no good and effective therapies for patients with hidradenitis suppurativa. Biologic agents have been shown to have variable results in the treatment of refractory Hidradenitis Suppurativa (HS). In 2006, Moul and Korman represented the first case about the use of ADA for HS in a patient with inflammatory bowel disease who was treated succesfully.49 Scheinfeld reported a case of stage III HS with arthritis treated with ADA.50 More recently, Quesada et al. reported that ADA could represent a new alternative in the management of severe HS.51 Their report based on a retrospective study including 6 patients. In their study, 4 patients were treated with loading doses of 160 and 80 mg ADA; administered subcutaneously at week 0 and 1 re-

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IMMUNMODULATORS IN DERMATOLOGY spectively, and 2 patients with loading dose of 80 mg at week 0. The maintenance regimen was 40 mg every other week in those 2 cases and 40 mg weekly in the other 4 cases. They didn’t reported a significant side effect despite they administered the drug at high doses during the induction phase without a weekly break but severe headeache in one. All patients were reported to be improved with the mean treatment duration of 4.8 ± 2.7 months.

In 2005, Philips MA reported the first patient with ulcerative cutaneous sarcoidosis who experienced complete healing after a dose of 40 mg weekly ADA, which was added to her ongoing regimen of prednisone and hydroxychloroquine, at the end of 9 weeks.57 In 2006, Heffernan et al.published a case of cutaneous sarcoidosis which was treated with ADA.58 They reported most of the lesions to be healed after 5-10 weeks of the therapy, without any side effects.

On the other hand, some other investigators results are in contradiction to the results of the studies that reported ADA to have promising positive effects in the treatment of HS.52 ADA was administered subcutaneously in a dose of 160 mg induction regimen at week 0, followed by 80 mg at week 1, and 40 mg at every other week for 12 weeks in 10 patients. It is reported that there was no statistically significant clinical improvement in HS with ADA. It may be explained by the difference of dose administration interval and duration of the treatment as well as the dose of the drug. In accordance with this hypothesis, in the study of Sotiriou et al.’s, a treatment for moderate to severe HS patients was applied with 80 mg ADA at baseline, followed by 40 mg ADA which was administired every week for 24 weeks.53 Patients were observed a period of another 24 weeks. They evaluated the patients with Sartorius scoring system, VAS (Visual Analogue Scale) and DLQI (Dermatology Life Quality Index) during the study period (total of 48 weeks). Significant improvement was observed at the end of the week 24 according to all these scoring systems in the weekly dose regimen. Although the author observed significant worsening at week 48, he also observed that scores were still remained significantly lower according to VAS score and DLQI.

ADA at a dose of 40 mg once weekly was added to the patient’s prior regimen of hydroxychloroquine and pentoxifylline. Significant improvement with complete healing of many lesions was seen after 5 weeks of the start of ADA and continued improvement was noted throughout the 10 weeks of follow-up period.

In accordance with these results, the results of a phase 2 study composed of 2 periods were published comparing placebo, 40 mg ADA every other week, and 40 mg ADA weekly in 154 patients.54 The response rate was 3.9 %, 9.6 %, and 17.6 %, respectively at the end of Period 1 which was for 16 weeks. During Period 2, consisting of 36 weeks, all patients received open-label ADA 40 mg every other week with the option to escalate to 40 mg weekly. Researchers observed a decrease in response after the switching the dose from weekly to every other week. At the end of the study, they concluded that, ADA dosed once per week alleviates moderate to severe HS. Scheinfeld N suggested that dosing should be weight based and stated that higher doses up to 80 mg biweekly are needed in obese patients.55 He postulated that the less severe the scarring is and the shorter the duration of HS is, the better adulimumab works.

Sarcoidosis Because TNF plays an important role in formation and maintenance of the granulomas, it is reasonable to expect ADA to be effective in the treatment of sarcoidosis.56

Afterwards, in some other reports, ADA were found to be efficacious subcutaneously at the dose of 40 mg either weekly or every 2 weeks in cutaneous sarcoidosis with or without systemic involvement.59-62 Kaiser CA et al. reported a case whose disfiguring annular lesions were resistant to multipl therapies, responded within 4 months to ADA61. The patient received a loading dose of 80 mg ADA and then 40 mg subcutaneously every second week. Parisier RJ. et al. administired an initial loading dose of 80 mg ADA at the baseline and then, 40 mg/weekly for a duration of 24 weeks in a small group of patients(10 persons). As a result of their study, they concluded that ADA may be a useful and safe treatment for cutaneous sarcoidosis63. Clinical effectiveness varies patients to patients and depends on the dose of ADA: According to Thielen et al.’s, the dose of ADA needed to supress sarcoidosis is higher than the doses generally used to suppress other inflammatory diseases. They observed that ADA was more effective at double dosage (80 mg every other week).64 In onether study, ADA was reported to be effective, in the doses of 160, 80, and 40 mg at weeks 0, 2, and 4 respectively, thereafter biweekly 40 mg for 1 year in a case series of 5 patients with both pulmonary and extrapulmonary sarcoidosis.65 On the other hand, surprisingly, TNFα inhibitors have been reported to not only treat but also to induce both cutanous and systemic sarcoidosis.66-68 There are at least 50 reported cases of sarcoidosis paradoxically induced by TNF antagonists; more than 15 such cases were observed in individuals receiving ADA.68-69 Symptoms of sarcoidosis were reported to develop within 1-27 months. Most showed complete resolution after discontinuance of the TNFantagonist.63,68 Clementine claimed that the role of TNF α seems to change as the disease evolves: TNF α is important in T-cell mediated granuloma formation, and TNF-α signaling is important for regulatory T cells found in sarcoidosis. The role of TNFα changes as the granuloma

CHAPTER 3: ADALIMUMAB IN DERMATOLOGY progress to fibrosis. It appears that TNF α serves as a mediator of cell signaling in various immune responses, rather than for a specific immune response. Thus, the actions of TNF α likely depend upon its interaction with surrounding cells and cytokines.70,71 ADA seems to be more effective than Etanercept in the treatment of cutaneous sarcoidosis.64,72,73 In the case of Field et al. which was a recalcitrant cutaneous sarcoidosis and didn’t respond to Etanercept; the combination of ADA, methotrexate and prednisolone resulted in clearing of cutaneous sarcoidosis at all sites73. Burns AM et al. presented a patient, who had resolution of Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas, following replacement with ADA.74 When it comes to Infliximab, regarding that it is delivered intravenously in the physician’s office, treatment with ADA has advantages over infliximab: ADA can be administered by the patient at home, which most patients find it to be convenient. In regard to side effects, TNF-blocking agents seems to be superior to other immunsupressive treatments described for sarcoidosis such as steroids, methotrexate, azathioprine, cyclosporin, cyclophosphamide and leflunomide.61 In selected cases ADA may be beneficial for the treatment of cutaneous and/or systemic sarcoidosis but prospective randomized controlled trials on larger series will be necessery to asses objectively the efficacy of ADA in sarcoidosis skin lesions,.

Pemphigus Because Tumor necrosis factor- α causes aggregation and augmented responses of neutrophils which are responsible for the acantholysis of the epidermis, it is logical to expect TNF-α blokers may improve pemphigus. Howell SM et al reported a patient with IgA pemphigus who failed multiple treatments, completely cleared after the third dose of ADA. It was applied at a dose of 40 mg biweekly together with Mycophenolate mofetil (1 gm daily), which had been started 2 weeks prior with no significant improvement as monotherapy.75 Vojáčková et al. reported a patient with pemphigus, to whom ADA was administered because of the inadequate effect of combined immunosuppressive therapy (steroids+azathioprine+ cyclophosphamide) and noted to achieve a very good clinical response.76 In the literature, a case with IgA Pemphigus unresponsive to multipl drug therapies, has been noted to show partial remission with ADA 40 mg biweekly.77 In addition to these diseases mentioned above, there have been some case reports describing off-label use of ADA that show possible indications such as Sweet’s Syndrome, Wegener Granulomatosis, connective tissue diseases, multicentric reticulohistiocytosis, GVHD, subcorneal pustular dermatosis and lichen planus.78-80

Conclusion: ADA is an increasingly important drug in dermatology. Combination therapy of biologics with topicals, phototherapy, and/or conventional systemics may enhance efficacy including speed of onset and maintenance of response. ADA has also been shown to improve patients’ life quality significantly. Although available data indicate that ADA is safe and well tolerated because of its rare but severe side effects and expensivity, attention to specific aspects of patient management (ie, prescreening requirements, symptoms to watch for) is required to reduce risk

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Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from the randomized controlled comparative study of ADA vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558-66.

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Menter A, Tyring SK, Gordon K, et al. ADA for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58: 106-15.

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Nestorov I. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum. 2005 Apr;34(5 Suppl1):12-8.

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Gordon KB, Langley RG, Leonardi C, et al. Clinical response to ADA treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 2006; 55: 598-606.

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Papp K, Crowley J, Ortonne JP, et al. ADA for moderate to severe chronic plaque psoriasis: efficacy and safety of retreatment and disease recurrence following withdrawal from therapy. British Journal of Dermatology 2011; 164: 434-441.

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Wells AF, Kupper H, Fischkoff S, Chartash E. Injection site reactions in ADA rheumatoid arthritis (RA) pivotal clinical trials. Ann Rheum Dis. 2003; 62(Suppl I):411.

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Weinberg JM. A review of the safety of the tumor necrosis factor inhibitors infliximab, etanercept, and ADA. In: Weinberg JM, Buholtz R, editors. TNF-alpha Inhibitors. Basel: Birkhäuser Verlag; 2006. pp. 115-27.

9.

Scheinfeld N. ADA: a review of side effects. Expert Opin Drug Saf. 2005; 4: 637-41.

10.

Bakleh M, Tleyjech I, Matesson EL, Osmon DR, Berbari EF. Infectious complications of tumour necrosis factor-alfa-antagonists. Int J Dermatol. 2005; 44:443-8.

11.

Flendrie M, Vissers WHPM, Creemers MCJ, et al. Dermatological conditions during TNF-a-blocking therapy in patients with rheumatoid arthrit. Arthritis Res Ther. 2005; 7(3): R666-76.

12.

Sorenson E, Koo J. Evidence-based adverse effects of biologic agents in the treatment of moderate-to-severe psoriasis: Providing clarity to an opaque topic. J Dermatolog Treat. 2015; 17: 1-9.

13.

Papp KA, Dekoven J, Parsons L, et al. Biologic therapy in psoriasis: perspectives on associated risks and patient management. J Cutan Med Surg. 2012; 16(3): 153-68.

15

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Kalb RE, Fiorentino DF, Lebwohl MG. Risk of Serious Infection with Biologic and Systemic Treatment of Psoriasis: Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR)JAMA Dermatol. 2015; doi:10.1001/jamadermatol.2015.0718.

15.

Atzeni F, Leccese P, D’Angelo S, et al. Successful treatment of leg ulcers in Behcet’s disease using ADA plus methotrexate after the failure of infliximab. Clin Exp Rheumatol 2010; 28 4 Suppl. 60:S94.

16.

Belzunegui J, Lopez L, Paniagua I, et al. Efficacy of infliximab and ADA in the treatment of a patient with severe neuro-Behcet’s disease. Clin Exp Rheumatol 2008; 26 4 Suppl. 50:S133-4.

17.

18.

Leccese P, D’Angelo S, Angela P, et al. Switching to ADA is effective in a case of neuro-Behcet’s disease refractory to infliximab. Clin Exp Rheumatol 2010;28 4 Suppl. 60:S102. Lee SW, Lee SY, Kim KN, et al. ADA treatment for life threatening pulmonary artery aneurysm in Behcet disease: a case report. Clin Rheumatol 2010; 29: 91-3.

with infliximab. Clin Exp Rheumatol. 2011; 29(4 Suppl 67):S54-7. 31.

Kaufman I, Caspi D, Yeshurun D, et al. The effect of infliximab on extraintestinal manifestations of Crohn’s disease Rheumatol Int 2005 25: 406-10.

32.

Staines KS, Green R, Felix DH. The management of fistulizing oral Crohn’s disease with infliximab. J Oral Pathol Med 2007; 36: 444-6.

33.

Sánchez AR, Rogers RS, Sheridan PJ. Oral ulcerations are associated with the loss of response to infliximab in Crohn’s disease. J Oral Pathol Med. 2005; 34(1):53-5.

34.

O’Neill ID. Efficacy of tumour necrosis factor-α antagonists in aphthous ulceration: review of published individual patient data. J Eur Acad Dermatol Venereol 2012; 26(2): 231-5.

35.

Vujevich J, Zirwas M. Treatment of severe, recalcitrant, major aphthous stomatitis with ADA. Cutis 2005; 76(2): 129-32.

36.

Sánchez-Cano D, Callejas-Rubio JL, Ruiz-Villaverde R, Ortego-Centeno N. Recalcitrant, recurrent aphthous stomatitis successfully treated with ADA. J Eur Acad Dermatol Venereol. 2009; 23(2):206.

37.

Sand FL, Thomsen SF. Efficacy and safety of TNF-α inhibitors in refractory primary complex aphthosis: a patient series and overview of the literature. J Dermatolog Treat 2013; 24(6):444-6.

38.

Hubbard V. Friedmann A, Goldstnith P. Systemic pyoderma gangrenosum responding to infliximab and ADA. Br J Dermatol 2005; 152 (5); 1059-61.

39.

Hinterberger L, Müller CS, Vogt T, Pföhler C. ADA: a treatment option for pyoderma gangrenosum after failure of systemic standard therapies. Dermatol Ther (Heidelb). 2012; 2(1):6.

19.

Mushtaq B, Saeed T, Situnayake RD, et al. ADA for sight-threatening uveitis in Behcet’s disease. Eye 2007; 21: 824-5.

20.

Takase K, Ohno S, Ideguchi H. Successful switching to ADA in an infliximab-allergic patient with severe Behcet disease-related uveitis. Rheumatol Int 2011; 31: 243-5.

21.

Van Laar JA, Missotten T, van Daele PL, et al. ADA: a new modality for Behcet’s disease? Ann Rheum Dis 2007; 66: 565-6.

22.

Calvo Catala J, Campos Fern´andez C, Rueda Cid A, et al. Efficacy of ADA in Behcet’s disease. Description of 6 cases. Reumatologia Clinica 2011; 7(4): 258-261.

23.

Cassan C, Vroey B, Dussault C, et al. “Successful treatment with ADA in a familial case of gastrointestinal Behcet’s disease,” Journal of Crohn’s and Colitis 2011; 5(4): 364-368.

40.

Agarwal A, Andrews JM. Systematic review: IBD-associated pyoderma gangrenosum in the biologic era, the response to therapy. Aliment Pharmacol Ther. 2013; 38(6):563-72.

24.

Kerns MJJ, Graves JE, Smith DI, et al. Offlabel uses of biologic agents in dermatology: a 2006 update. Seminars in Cutaneous Medicine and Surgery 2006; 25(4): 226-240.

41.

Alkhouri N, Hupertz V, Mahajan L. ADA treatment for peristomal pyoderma gangrenosum associated with Crohn’s disease. Inflamm Bowel Dis 2009; 15: 803-6.

25.

Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behçet’s disease: analysis of published data on 369 patients. Semin Arthritis Rheum 2011; 41(1):6170.

42.

Fonder MA, Cummins DL, Ehst BD, et al. ADA therapy for recalcitrant pyoderma gangrenosum. J Burns Wounds 2006; 5: e8.

43.

Zold E, Nagy A, Devenyi K, et al. Successful use of ADA for treating fistulizing Crohn’s disease with pyoderma gangrenosum: Two birds with one stone. World J Gastroenterol 2009; 15: 2293-5.

26.

Aikawa NE, Gonçalves C, Silva CA, et al. Late response to anti-TNF-α therapy in refractory mucocutaneous lesions of Behçet’s disease. Rheumatol Int. 2011; 31(8):1097-9.

44.

27.

Perra D, Alba MA, Callejas JL, et al. ADA for the treatment of Behçet’s disease: experience in 19 patients. Rheumatology (Oxford). 2012; 51(10):1825-31.

Eaton PA, Callen JP. Mycophenolate mofetil as therapy for pyoderma gangrenosum. Arch Dermatol 2009; 145: 781-5.

45.

28.

Bawazeer A, Raffa LH, Nizamuddin SH. Clinical experience with ADA in the treatment of ocular Behçet disease. Ocul Immunol Inflamm. 2010; 18(3): 226-32.

Suárez-Pérez JA, Herrera-Acosta E, López-Navarro N, et al. Pyoderma gangrenosum: a report of 15 cases and review of the literature]. Actas Dermosifiliogr. 2012; 103(2):120-6.

29.

Interlandi E, Leccese P, Olivieri I, Latanza L. ADA for treatment of severe Behçet’s uveitis: a retrospective long-term follow-up study. Clin Exp Rheumatol. 2014;32(4 Suppl 84):S58-62.

46.

Cariñanos I, Acosta MB, Domènech E. ADA for pyoderma gangrenosum associated with inflammatory bowel disease. Inflamm Bowel Dis. 2011; 17(12): E153-4.

47.

30.

Olivieri I, Leccese P, D’Angelo S et al. Efficacy of ADA in patients with Behcet’s disease unsuccessfully treated

Lipka S, Katz S, Ginzburg L. Massive pyoderma gangrenosum in a 77 year old female with Crohn’s disease responsive to ADA. J Crohns Colitis. 2013; 7(5):427-8.

CHAPTER 3: ADALIMUMAB IN DERMATOLOGY 48.

Kleinpenning MM et al. Severe pyoderma gangrenosum unresponsive to etanercept and ADA. J Dermatolog Treat. 2011; 22(5):261-5.

65.

LS, Lam-Tse WK, Dik WA, et al. Efficacy of ADA in chronically active and symptomatic patients with sarcoidosis. Am J Respir Crit Care Med. 2011; 184(10):1214-6.

49.

Moul DK, Korman NJ. Severe hidradenitis suppurativa treated with ADA. Arch Dermatol 2006; 142: 1110-1112.

66.

50.

Scheinfeld N. Treatment of coincident seronegative arthritis and hidradentis supprativa with ADA. J Am Acad Dermatol. 2006; 55:163-4.

Daïen CI, Monnier A, Claudepierre P, et al. Club Rhumatismes et Inflammation (CRI). Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases. Rheumatology (Oxford). 2009; 48(8):883-6.

67.

51.

Quesada MP, Marmesat B,Guerra D, Ramos JJ. Drug Information and Pharmacotherapy. DI-056 Off label use of ADA in the management of severe suppurative hidradenitis. Eur J Hosp Pharm 2014;21:A92-A93.

Scailteux LM, Guedes C, Polard E, Perdriger A. [Sarcoidosis after ADA treatment in inflammatory rheumatic diseases: a report of two cases and literature review]. Presse Med. 2015;44(1):4-10..

68.

52.

Amano M, Grant A, Kerdel FA. A prospective open-label clinical trial of ADA for the treatment of hidradenitis suppurativa. Int J Dermatol 2010; 49: 950-955.

Vigne C, Tebib J, Pacheco Y, Coury F. Sarcoidosis: an underestimated and potentially severe side effect of anti-TNF-alpha therapy. Joint Bone Spine 2013;80(1):104-7

69.

53.

Sotiriou E, Goussi C, Lallas A, et al. A prospective open-label clinical trial of efficacy of the every week administration of ADA in the treatment of hidradenitis suppurativa. J Drugs Dermatol. 2012; 11(5 Suppl):s15-20.

Sauder MB, Beecker J, Ramsay T. Comment on ‘A double-blind, randomized, placebo-controlled trial of ADA in the treatment of cutaneous sarcoidosis J Am Acad Dermatol. 2014; 70(5):950-1.

70.

54.

Kimball AB, Kerdel F, Adams D, et al. ADA for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med. 2012;157:84655.

Clementine RR, Lyman J, Zakem J, et al. Tumor Necrosis Factor-Alpha Antagonist-Induced Sarcoidosis. Journal of Clinical Rheumatology: 2010; 16: 274-279.

71.

Gerke AK, Hunninghake G. The immunology of sarcoidosis. Clin Chest Med. 2008; 29: 379-390.

72.

Ramos-Casals M, Brito-Zerón P, Muñoz S, Soto MJ, y el BIOGEAS Study Group. Asystematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine (Baltimore) 2008; 87: 345-64.

55.

Scheinfeld N. Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients. Dermatol Online J. 2013; 15;19(4):1

56.

Philips MA, Lynch J, Azmi FH. Ulcerative cutaneous sarcoidosis responding to ADA. J Am Acad Dermatol, 2005; 53: 917.

73.

57.

Callejas-Rubio JL, Ortego-Centeno N, Lopez-Perez L, Benticuaga MN. Treatment of therapy-resistant sarcoidosis with ADA.Clin Rheumatol, 2006; 25: 596-597

Field S, Regan AO, Sheahan K, Collins P. Recalcitrant cutaneous sarcoidosis responding to ADA but not to etanercept. Clin Exp Dermatol. 2010; 35(7):795-6.

74.

58.

Heffernan MP, Smith DJ. ADA for treatment of cutaneous sarcoidosis. Arch Dermatol 2006; 142: 17-9.

Burns AM, Green PJ, Pasternak S. Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with ADA. J Cutan Pathol. 2012; 39(2):289-93.

75.

59.

Judson MA. Successful Treatment of Lupus Pernio With ADA Arch Dermatol. 2011;147(11):1332-1333.

60.

Díaz-Lagares C, Belenguer R, Ramos-Casals M. [Systematic review on the use of ADA in autoinmune. Efficacy and safety in 54 patients]. Reumatol Clin. 2010; 6(3):121-7.

Howell SM, Bessinger GT, Altman CE, Belnap CM. Rapid response of IgA pemphigus of the subcorneal pustular dermatosis subtype to treatment with ADA and mycophenolate mofetil. Am Acad Dermatol. 2005; 53(3):541-3.

76.

Vojáčková N, Fialová J, Vaňousová D, Hercogová J. Pemphigus vulgaris treated with ADA: case study. Dermatol Ther. 2012; 25(1):95-7.

61.

Kaiser CA, Cozzio A, Hofbauer GF, et al. Disfiguring annular sarcoidosis improved by ADA. Case Rep Dermatol. 2011; 3(2):103-6.

77.

Moreno AC, Santi CG, Gabbi TV, et al. IgA pemphigus: case series with emphasis on therapeutic response. J Am Acad Dermatol. 2014; 70(1):200-1.

62.

Zimmermann A, Dubaniewicz A, Slominski JM. Pharmacotherapy for sarcoidosis: an example of an off-label procedure. Adv Exp Med Biol. 2013;755:251-6.

78.

63.

Parisier RJ. A double-blind, randomized, placebo-controlled trial of ADA in the treatment of cutaneous sarcoidosis 2013, Pages 765-7732013, Pages 765-773JAAD 2013; 68:5, 765-73.

Karamlou K, Gorn AH. Refractory Sweet syndrome with autoimmune organizing pneumonia treated with monoclonal antibodies to tumor necrosis factor. J Clin Reumatol. 2004; 10: 331-5.

79.

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Thielen AM, Barde C, Saurat JH, E. Faffitte. Refractory chronic cutaneous sarcoidosis responsive to dose escalation of TNF-alpha anthagonists. Dermatology 2009; 219: 59-62.

Shannon SE, Schumacher HR, Self S, Brown AN. Multicentric reticulohistiocytosis responding to tumor necrosis factor-alpha inhibition in a renal transplant patient. J Rheumatol. 2005; 32: 565-7.

80.

Traczewski P, Rudnicka L. ADA in dermatology. Br J Clin Pharmacol. 2008; 66(5):618-25.

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CHAPTER 4

IMMUNOMODULATION WITH ANTIBIOTICS Özgür Gündüz, MD

Introduc on “Antibiosis” defines a close relationship between two or more organisms that is hazardous at least to one of them. This kind of relationship can be observed particularly between microorganisms, forcing them to develop special traits to become more advantegous in their struggle for the vital nutrients, elimination of the competition and survival. Bacteria have shorter reproduction time than most of the organisms, giving them the advantage of rapid production to overcome the immune response of other organisms. The fungi are specialized in the synthesis of unique substances, which they can kill their rivals with. The first report of antibosis was made by Sir Alexander Fleming, in which he described the eradication of the bacteria Staphylococcus aureus by the fungi Penicillium notatum via its secretions (Penicillin) in 1926. Antibiosis is also one of the prominent factors underlying the bacterial mutations. Bacteria mutate to become more resistant to the detrimental effects of the substances secreted by fungi, the so-called “antibiotics”. A more precise definition of “antibiotics” is that they are substances produced by one microorganism that selectively inhibits the growth of another. In the course of time, this definition has been changed to cover semi-synthetically produced antibacterial drugs. Microorganisms can also become resistant to these semi-synthetic molecules and render their antimicrobial effects useless, causing huge amounts of money and efforts to be invested in development of new antimicrobial agents. But, that does not mean the “old” antibiotics are no longer useless. Far from it, with the discovery of the new modes of action of the antibiotics, particularly anti-inflammatory effects, it seems these drugs will be in use for a long time. This text summarizes notable antibiotic groups and their immunomodulatory effects.

Macrolides This class of antibiotics consists of erythromycin, roxythromycin, clarithromycin, azithromycin, and spiramycin. They possesss a macrocyclic lactone ring, which consists of 14 to 16 atomic members. Their main mechanism of antimicrobial action is inhibition

of bacterial protein synthesis. Macrolides bind to 50S subunit of the ribosomes and interfere the translocation of the growing polypeptide chain from the acceptor site (A-site) to the peptidylsite (P-site or donor site). They have a wide spectrum, which covers gram-positive cocci (except methicillin resistant Staphylococcus aureus – MRSA), Legionella pneumophila, Campylobacter jejuni, Mycobacterium avium-intracellulare, Helicobacter pylori and also the bacteria without cell walls, Chlamidia, Mycoplasma and Ureaplasma species. Since C.pneumonia, M.pneumonia are among the most common bacterial pathogens associated with community-acquired pneumonia, macrolides have become one of the most prescribed antibiotics in clinical practice. Particularly, azithromycin has been found to be very effective1. They are also frequently used to treat infections of upper respiratory tract and skin. First observation of immunomodulatory effects of the macrolides was reported in 1987.1 Kudoh et al reported a marked improvement in clinical symptoms and increased life expectancy in patients with diffuse panbronchiolitis (DPB), an inflammatory airway disorder with a rapid progression and poor prognosis, treated with eryhtromycin. Serum erythromycin level measurements were below the minimal inhibitory concentrations, which led the researchers to associate these clinical improvements with possible anti-inflammatory properties of erythromycin rather than its antibacterial effects. Since then, numerous studies also confirmed the observations of Kudoh et al. As of today, not only macrolides, but several other antibiotics have been shown to possess anti-inflammatory and/or immunomodulatory properties. Macrolides are known to exert their effects on the immune system on various levels. They have been shown to modulate the production of proinflammatory cytokines (interleukin (IL)-1, IL-2, (interferon) IFN-γ, (tumor necrosis factor) TNF-α, etc) and anti-inflammatory cytokines, (IL-10, transforming growth factor (TGF)-β,etc).3 In vivo studies indicate that inhibitory effects of macrolide antibiotics on proinflammatory cytokines are particularly evident in patients with cystic fibrosis (CF) and asthma.4,5 Macrolides also stimulate the phagocytotic abilities

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IMMUNMODULATORS IN DERMATOLOGY of alveolar macrophages, preventing an exagerated inflammatory response by rapidly removing any antigenic stimulants, including apopitotic epithelial cells.6-8 Another cell type involved in immune system and affected by the macrolides is neutrophils. The cytokines IL-6 and TNF-α are crucial cytokines in the recruitment of neutrophiles. Several studies have shown that the macrolides (roxithromycin, eryhtromycin and particularly azithromycin) can block IL-8 and TNF-α mediated recruitment of neutrophiles in inflammation.9-13 Moreover, decreased expression of intercellular adhesion molecules have been observed in epithelial cells during treatment with erythromycin, which suggest a possible inhibitory effect of macrolides on leukocyte adhesion.14,15 Some studies also indicate that oxidant production is reduced with the use of erythromycin through cyclic AMP (cAMP)-dependent protein kinase.16 There are various reports regarding stimulation of neutrophile degranulation (exocytosis) by macrolides.17-19 Abdelghaffar et al. suggested the changes in the phospholipase D-phosphatitide phosphohydrolase transduction pathway as the underlying cause for the stimulated exocytosis.20 It has also been shown by several research groups that macrolides promote the apoptosis of neutrophils limiting their time to exert their inflammatory actions.21,22 Adaptive immune system also seems to be affected by macrolides. Decreased numbers of lymphocytes in the bronchoalveolar lavage fluids of patients with diffuse panbronchiolitis has been observed by Kawakami et al.23 A study by Brambriket al.24 provided us with new insights in how macrolides have immunomodulatory effects. In this study, Brambrik et al. observed improved resistance of hippo-campal neurons of rats to cerebral ischemia when pretreated with erythromycin and found the mRNA of antiaptotic B-cell lymphoma 2 (bcl-2) protein to be upregulated. Another study by Koerner et al. also showed marked suppression of the expression pro-inflammatory genes in rats with cerebral ischemia, when pretreated with erythromycin.25

Tetracyclines Tetracyclines are a group of “protein-synthesis inhibitor” proteins, which areknown as the “first broad spectrum” antibiotics. Tetracycline, minocycline, doxycycline, oxytetracycline and tigecycline are included in this group. They are taken up by the susceptible bacteria and inhibit bacterial protein synthesis through reversible binding to bacterial ribosomal subunit. New aminoacyl-tRNA’s can not bind to A-site of the ribosome – tetracycline complex, which effectively terminates the further elongation of aminoacid chain. Antibacterial spectrum of tetracyclines cover gram positive cocci (Staphylococcus aureus, S.epidermidis), gram positive bacilli (Clostridium perfringens), gram negative cocci (Moraxella catharalis) and bacilli (Legionella spp., Pasteurella multiocida) and also some atypicalbacteria

(Chlamydia pneumonia, Chlamydia trachomatis, Mycoplasma pneumoniae, Treponema pallidum, Borrelia burgdorferi). Since they have been in clinical use for a long time and are frequently prescribed, many tetracycline-resistant bacteria species (with efflux pumps to eject tetracyclines or ribosomal resistance) have been emerged limiting their “once broad-spectrum”. Some of thespecific features of these drugs are as follows; doxycycline can reach high levels in prostatic fluid, high concentrations of minocycline can be measured in saliva and tears and is preferred in in meningococcal carrier states, demeclocycline is used in inappropriate secretion of antidiuretic hormone (SIADH) and tigecycline is particularly useful in the infections with MRSA and vancomycin-resistant enterococcus faecium (VREF). Tetracyclines are eliminated by kidneys with the exception of doxycycline and chelate with divalent cations, such as Fe+2, Ca+2, Zn+2. Tetracyclines are also known for their inhibitory effects on several enzymes, particularly when used in an inflammatory setting. Theyhave been shown to inhibit collagenase activity of neutrophils26 (particularly doxycycline) and matrix metalloproteinases (MMPs), a group of endopeptidases involved in degredation and reshaping of extracellular matrix. Since MMPs need Zn+2 as cofactor to function, their inhibiton by tetracylines is attributed to the chelation between tetracylines and Zn+2. Tetracyclines’ tendency for chelation is also suspected to play a role in the inhibtion of leukocyte adhesion.27 In recent years, MMPs have been shown to participate in the release of apoptotic ligands and chemokine/cytokine inactivation.28 Immunomodulatory action of tetracyclines is also supported by in vivo studies and several clinical observations. These drugs are used as steroid-sparing agents in dermatology for a long time.29 There are also reports about beneficial effects of tetracyclines in the prevention hypoxia induced neuronal damage. Jiang et al. reported that tetracycline supresses inflammation induced by hypoxia in rat brains and proposed inhibition of nuclear factor kappa B pathway as possible anti-inflammatory action mechanism.30 Another study by Edan et al. revealed that a modified tetracycline, COL-3, inhibits the microglia activation and supresses cytokine expression in the brain31 supporting the previosly mentioned study. Lai et al. also evaluated anti-inflammatory and neuroprotective effects of minocycline and tetracycline in rats. They found microglial activation induced by hypoxia to be selectively supressed by minocycline and doxycycline,32 protecting the neurons from hypoxia induced damage. This outcome from animal studies is also supported by another open-label study by Lampl et al,33 which one hunderd fifty-two stroke patients were included in. Seventy-four of the patients were treated with 200 mg minocycline daily for five days after the stroke. NIH stroke scale (NIHSS) and modified Rankin scale(mRS) were found to be significantly lower in the minocycline-treated group, although the rates of the

CHAPTER 4: IMMUNOMODULATION WITH ANTIBIOTICS recurrent strokes, myocardial infarctions, and deaths did not differ between the two groups. In addition to neurological studies, there are also reports about anti-inflammatory effects of tetracycline in periodontal diseases. When used in periodontitis as adjuvant drug, tetracycline is reported to inhibit excessive inflammatory damage to periodontal tissues, which is attributed to inhibition of MMPs by tetracycline.34

Βeta–lactams Penicillins and cephalosporins are the major representatives of this group.β-lactams’main mechanism of action is the inhibition of bacterial cell wall synthesis via inhibiting the bacterial enzymes, transpeptidases. Bacterial cell wall is a mesh-like structure made-up from peptidoglycan polymers (murein)and synthesized via a multi-step process. Initially, bacteria synthesize carbohydrate units N-acetyl muramic acid (NAM) and N-acetylglucoseamine (NAG) in the cytoplasm. These carbohydrates are activated via addition of the nucleotide uridine diphosphate (UDP). A pentapeptide (PEP) is then attached to NAM-UDP, enabling the transfer of NAM from the UDP to bacteprenol phosphate (BPP), another carrier molecule located in the bacterial cell membrane. NAG is transferred from NAG-UDP to the BPP-NAM-PEP. BPP carries PEP-NAM-NAG complex to outer surface of the cell membrane, where it is attached to the existing peptidoglycan. PEPs are then linked directly or via a glycine bridge to the other PEPs, stabilizing the bacterial cell wall. The enzymes, called, transpeptidases, are responsibleof the crosslinking the carbohydrate polymers consisting of repeating NAM-NAG units. Inhibition of these enzymes by β-lactams leads to termination of cell-wall biosynthesis, leaving the bacteria vulnerable to internal and external insults. β-lactams target transpeptidasesand also other enzymes called penicillin-binding proteins (PBPs),

which include bacterial autolysins and endopeptidases. Interaction with β-lactam antibiotics causes the stimulation of the latter two, which, in turn, leads to enzymatic destruction of bacterial cell. Penicillins are divided into subgroups according to their spectrum; beta-lactamase sensitive penicillin G and penicillin V (frequently prescribed for streptococcal, pneumococcal, meningococcal infections and Treponema palliduminfections); beta-lactamase resistant penicllins with a very narrow spectrum (nafcillin, methicillin, oxacillin; preferred for staphylococcal infections); beta-lactamase sensitive aminopenicillins (amoxicillin and ampicillin; used for the treatment of infections with gram-positivie cocci – with the exception of staphylococcci-, E.coli, H.influenza, Listeria monocytogenes, Borrelia burgdorferi, H.pylori), and antipseudomonal penicillins (gram-negative rods, particularly Pseudomonas aeruguinosa). Cephalosporins have a similiar action and resistance to penicillins. They are divided into four groups called generations. The antibacterial spectrum shifts from gram-positive bacteria to gram-negative with each subsequent generation. Most drugs of third and fourth genera can also enter the central nervous system and are used in the empiric treatment of meningitis and sepsis. Currently, there are scarce reports concerning anti-inflammatory effects of beta-lactams, most of which is about cefaclor,35 a third generation cephalosporin. Cefaclor is reported to enhance phagocytosis, chemotaxis and also promote bactericidal activity by stimulating type I cytokine response,36 but also, it is reported to inhibit the synthesis of IL-6 and TNF-α.37 A study by Mangano et al.also supports these previous reports. Mangano et al. showed that after treatment with cefaclor, lymphoproliferative activity and secretion various cytokines (IL-2, IL-10, IFNϒ) has been increased in ex vivo rat spleen cell cultures38.

TABLE 1. Several group of antibiotics observed to have immunomodulatory effects and their proposed mechanisms of action. Group of Antibiotics

Possible Mechanisms for Anti-inflammatory Effects

Anti-inflammatory/Immunomodulatory Effects reported in:

Macrolides (Erythromycin)

Inhibition of pro-inflammatory cytokine secretion Inhition of neutrophil recruitment, adhesion, and degranulation Promotion of neutrophil and lymphocyte apoptosis

Diffuse panbronchiolitis Cystic Fibrosis Chronic obstructive pulmonary disease Pseudomonas infection of bronchioles

Tetracyclines (Doxycycline)

Inhibition of MMPs Inhibition of microglial activation

Periodontitis Strokes As steroid sparing agents in several dermatological diseases

Β-lactams (Cefaclor, Nafcillin)

Enhancing phagocytosis (cefaclor) Stimulation of type I cytokine secretion (cefaclor) Senstizing MRSA to cathelicidins (nafcillin)

The immunomodulatory effects of β-lactams are usually observed in cell cultures

Fluoroquinolones (moxifloxacin)

Inhibition of proinflammatory cytokines (IL-1α, IL-1β, ΤΝF-α, IL-6, and IL-8)

In vitro human monocyte cultures In vivo lungs of immunocompromised rats

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IMMUNMODULATORS IN DERMATOLOGY In 2011, Dhand and et al. reported rapid clearanceof persistant bacteriemia due to methicillin-resistant Staphylococcus aureus (MRSA) via combined use of anti-staphylococcal β-lactams and daptomycin.39 A subsequent study by Sakoulas and et al. revealed similar results. Sakoulas et al. proposed that nafcillin facilitates the killing of MRSA by innate immune system by sensitizingthe bacteria) to host defense proteins (HDPs), particularly to cathelicidin LL-37.40

Fluoroquinolones This class of antibiotics inhibit several enzymes involved in the biosynthesis of bacterial deoxy-ribonucleic acid (DNA). Primary targets of fluoroquinolones are DNA gyrase, also known as topoisomerase II, and topoisomerse IV. DNA gyrase relaxes the supercoiled DNA, which occurs during the unwinding of DNA by the enzyme helicase. Topoisomerase IV unlinks the bacterial DNA after its replication. (Gemifloxacin targets both of these enzymes). Besifloxacin, ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, moxifloxacin, and ofloxacin are the other members of fluoroquinolone antibiotics. The spectrum of early quinolones, cipprofloxacine, covers gram-negative bactreria, i.e. Pseudomonas aeruginosa, Haemophilus influenza, Moraxella catarrhalis. They are predominantly used to treat urinary tract infections. The newer ones (group IV – I.E., moxifloxacin, gemifloxacin) have a wider coverage and are effective against gram-positive bacteria, atypical bacteria, such as Streptococcus, Chlamidya pneumoniae, Mycoplasma pneumonia and also some anaerobs. Except central nervous system, fluoroquinolones can penetrate into all other tissues and body compartments and therefore, they are frequently used to treat to infections of skin, bone, intra-abdominal cavity and also pneumonia. Their prominent side-effects are cartilage toxicity, increase risk of Steven-Johnson syndrome, prolonged QT syndrome and tendinitis. Most reports regarding the immunomodulatory properties of quinolones come from in vitro studies with lipopolysaccharide-stimulated human monocytes. Inhibitory effects of many fluoroquinolones (i.e., ciprofloxacin, trovafloxacin, moxifloxacin, grepafloxacin, and levofloxacin) on proinflammatory cytokines (IL-1α, IL-1β, ΤΝF-α, IL-6, and IL-8) have been reported.41 – 47 In a similar study, Weiss et al. have also reported inhibition of IL-8, TNF-α, and IL-1β in LPS-stimulated human peripheral blood monocytes and in the THP-1 monocytic cell line with moxifloxacin and proposed inhibition of major inflammatory signal transduction pathways (NF-κB and mitogen-activated protein kinase activation) as a possible underlying mechanim.48 Similar outcomes were also reported by Shalit et al in when they treated immunocompromised rats with moxifloxacin after intratracheal Candida albicans injection.49 They found significantly decreased levels of IL-8, TNFα and IFNγ in lung tissue.

Conclusion Over the last 20 years, clinical and experimental evidence regarding immunomodulatory properties of antibiotics is steadily increasing. Relevant reports are coming from a wide spectrum of studies. Although most of them have been observed in vitro settings, there are also very promising clinical observations – i.e., doxycyclin in stroke patients- , which be the first stepstones to form immunomodulatory treatment regimens with classical antibiotics.

REFERENCES 1.

Noguchi S, Yatera K, Kawanami T, Yamasaki K, Uchimura K, Hata R, Tachiwada T, Oda K, Hara K, Suzuki Y, Akata K, Ogoshi T, Tokuyama S, Inoue N, Nishida C, Orihashi T, Yoshida Y, Kawanami Y, Taura Y, Ishimoto H, Obata H, Tsuda T, Yoshii C, Mukae H. Efficacy and safety of azithromycin infusion in patients with mild or moderate community-acquired pneumonia. .Jpn J Antibiot. 2014; 67(3):193-203.

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Kudoh S, Uetake T, Hagiwara K. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbrochiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 1987;25: 632-642.

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Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol 2001;429:209-229.

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Hodge S, Hodge G, Jersmann H. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 178: 139–148.

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Tamaoki J, Nakata J, Tagaya E. Effects of roxithromycin and erythromycin on interleukin 8-induced neutrophil recruitment and goblet cell secretion in guinea pig tracheas. Antimicrob Agents Chemother 1996; 40: 1726–1728.

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Tsai WC, Rodriguez ML, Young KS. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med 2004; 170: 1331–1339.

10. Piacentini GL, Peroni DG, Bodini A. Azithromycin reduces bronchial hyperresponsiveness and neutro-philic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc 2007; 28: 194–198. 11. Sakito O, Kadota J, Kohno S. Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration 1996; 63: 42–48. 12. Suzuki H, Shimomura A, Ikeda K. Effects of long-term low-dose macrolide administration on neutrophil recruitment and IL-8 in the nasal discharge of chronic sinusitis patients. Tohoku J Exp Med 1997; 182: 115–124. 13. Verleden GM, Vanaudenaerde BM, Dupont LJ. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with

CHAPTER 4: IMMUNOMODULATION WITH ANTIBIOTICS bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2006; 174: 566–570.

these low toxicity agents. J Am Acad Dermatol. 2014;71(3):4759.

14. Khair OA, Devalia JL, Abdelaziz MM. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells. Eur Respir J 1995; 8: 1451–1457.

30. Jiang Y, Zhu J, Wu L, Xu G, Dai J, Liu X.Tetracycline inhibits local inflammation induced by cerebral ischemia via modulating autophagy. PLoS One. 2012;7(11):e48672

15. Sanz MJ, Nabah YN, Cerdá-Nicolás M, O’Connor JE, Issekutz AC, Cortijo J, Morcillo EJ. Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression. Br J Pharmacol. 2005; 144(2):190-201. 16. Mitsuyama T, Tanaka T, Hidaka K, Abe M, Hara, N. Inhibition by erythromycin of superoxide anion production by human polymorphonuclear leukocytes through the action of cyclic AMP dependent protein kinase. Respiration 1995, 62, 269-273. 17. Abdelghaffar H, Vazifeh D, Labro MT. Comparison of various macrolides on stimulation of human neutrophil degranulation in vitro. J Antimicrob Chemother 1996; 38: 81–93. 18. Culic O, Erakovic V, Cepelak I. Azithromycin modulates neutrophil function and circulating inflam-matory mediators in healthyhuman subjects. Eur J Pharmacol 2002; 450:277–289. 19. Labro MT, el Benna J, Babin-Chevaye C. Comparison of the in-vitro effect of severalmacrolides on the oxidative burst of humanneutrophils. J Antimicrob Chemother 1989;24: 561–572. 20. Abdelghaffar H, Vazifeh D, Labro MT. Erythromycin Aderivedmacrolides modify the functional activities of human neutrophilsby altering the phospholipase D-phosphatidate phosphohydrolase-transduction pathway: L-cladinose is involved both in alterationsof neutrophil functions and modulation of this transductionalpathway. J. Immunol. 1997, 159, 3995-4005. 21. Aoshiba K, Nagai A, Konno K. Erythromycin shortens neutrophil survival by accelerating apoptosis. Antimicrob Agents Chemother 1995; 39: 872–877. 22. Inamura K, Ohta N, Fukase S: The effects of erythromycin on human peripheral neutrophil apoptosis. Rhinology 2000; 38: 124–129.

31. Edan RA, Luqmani YA, Masocha W. COL-3, a chemically modified tetracycline, inhibits lipopoly-saccharide-induced microglia activation and cytokine expression in the brain. PLoS One 2013; 8(2):e57827 32. Lai AY, Todd KG. Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines. Glia 2006; 53(8):809-16. 33. Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007; 69(14):1404-10. 34. Tilakaratne A, Soory M. Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities. Open Dent J 2014; 8: 109-24. 35. Tauber SC, Nau R. Immunomodulatory Properties of Antibiotics. Curr Mol Pharmacol 2008; 1:68-79. 36. Periti, P. Immunopharmacology of oral betalactams. J Chemother 1998, 10, 91-96. 37. Scheffer J, Konig W. Cephalosporins and inflammatory host reactions. Respiration 1993;60(Suppl. 1): 25-31. 38. Mangano K, Quattrocchi C, Aiello C, Scalia, G, Speciale A, Nicoletti G, Di Marco R. Immunomodulatory properties of cefaclor: in vivo effect on cytokine release and lymphoproliferative response in rats. J Chemother 2006;18, 641-647. 39. Dhand A, Bayer AS, Pogliano J, Yang SJ, Bolaris M, Nizet V, Wang G, Sakoulas G. Use ofantistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistentbacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycinbinding. Clin Infect Dis. 2011; 53: 158–163.

23. Kawakami K, Kadota J, Iida K. Phenotypiccharacterization of T cells in bronchoalveolarlavage fluid (BALF) and peripheral bloodof patients with diffuse panbronchiolitis: theimportance of cytotoxic T cells. Clin ExpImmunol 1997; 107: 410–416.

40. Sakoulas G, Okumura CY, Thienphrapa W, Olson J, Nonejuie P, Dam Q, Dhand A, Pogliano J, Yeaman MR, Hensler ME, Bayer AS, Nizet V.Nafcillin Enhances Innate Immune-Mediated Killing ofMethicillin-Resistant Staphylococcus aureus. J Mol Med (Berl) 2014; 92(2): 139–149.

24. Brambrink AM, Koerner IP, Diehl K, Strobel G, Noppens R, Kempski O. The antibiotic erythromycin induces tolerance against transient global cerebral ischemia in rats (pharmacologic preconditioning). Anesthesiology 2006;104: 1208-1215.

41. Araujo, FG, Slifer TL, Remington JL Effect of moxifloxacin on secretion of cytokines by human monocytes stimulated with lipopolysaccharide. Clin. Microbiol. Infect.2002; 8: 26–30.

25. Koerner IP, Gatting M, Noppens R, Kempski O, Brambrink AM. Induction of cerebral ischemic tolerance by erythromycin preconditioning reprograms the transcriptional response to ischemia and suppresses inflammation. Anesthesiology 2007, 106: 538- 547. 26. Suomalainen K, Sorsa T, Golub LM, Ramamurthy N, Lee HM, Uitto VJ, Saari H, Konttinen YT. Specificity of the anticollagenase action of tetracyclines: relevance to their antiinflammatory potential. Antimicrob Agents Chemother 1992, 36: 227-229. 27. Gabler WL, Smith J, Tsukuda N.Comparison of doxycycline and a chemically modified tetracycline inhibition of leukocyte functions. Res Commun Chem Pathol Pharmacol 1992;78(2):151-60. 28. Van Lint P, Libert C. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol 2007; 82 (6): 1375–81. 29. McCarty M, Fivenson D. Two decades of using the combination of tetracycline derivatives and niacinamide as steroid-sparing agents in the management of pemphigus: defining a niche for

42. Bailly S, Mahe Y, Ferrua B, Fay M, Tursz T, Wakasugi H, Gougerot-Pocidalo MA. Quinolone-induced differential modification of IL-1 alpha and IL-1 beta production by LPS-stimulated human monocytes. Cell Immunol 1990; 128(1):277-88. 43. Choi JH, Song MJ, Kim SH, Choi SM, Lee DG, Yoo JH, Shin WS. Effect of moxifloxacin on production of proinflammatory cytokines from human peripheral blood mononuclear cells http:// www.ncbi.nlm.nih.gov/pubmed/146384692003; 47(12):3704-7. 44. Khan AA, Slifer TR, Remington JS. Effect of trovafloxacin on production of cytokines by human monocytes. Antimicrob Agents Chemother 1998; 42(7):1713-7. 45. Ono Y, Ohmoto Y, Ono K, Sakata Y, Murata K. Effect of grepafloxacin on cytokine production in vitro. J Antimicrob Chemother 2000; 46(1):91-4. 46. Williams AC, Galley HF, Webster NR. The effect of moxifloxacin on release of interleukin-8 from human neutrophils. Br J Anaesthesiol 2001; 87: 671–672. 47. Zhao D, Keates AC, Kuhnt-Moore S, Moyer MP, Kelly CP, Pot-

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IMMUNMODULATORS IN DERMATOLOGY houlakis C. Signal transduction pathways mediating neurotensin-stimulated interleukin-8 expression in human colonocytes. J Biol Chem 2001; 276(48):44464-71. 48. Weiss T, Shalit I, Blau H, Werber S, Halperin D, Levitov A, Fabian I. Anti-inflammatory effects of moxifloxacin on activated human monocytic cells: inhibition of NF-kappa B and mitogen-activated protein kinase activation and of synthesis of proinflammatory cytokines. Antimicrob Agents Chemother 2004; 48:1974-1982. 49. Shalit I, Horev-Azaria L, Fabian I, Blau H, Kariv N, Shechtman I, Alteraz H, Kletter Y. Immunomodulatory and protective effects of moxifloxacin against Candida albicans-induced bronchopneumonia in mice injected with cyclophosphamide. Antimicrob Agents Chemother 2002; 46:2442-2449.

CHAPTER 5

ANTIOXIDANTS IN DERMATOLOGY Lülüfer Tamer, PhD, Aysegul Görür, PhD

OXIDANTS AND ANTIOXIDANTS Reactive oxygen species: Oxygen free radicals or, more generally, reactive oxygen species (ROS), as well as reactive nitrogen species (RNS), are products of normal cellular metabolism continuously produced in all aerobic organisms, mostly as a consequence of aerobic respiration.1 Reactive oxygen species belong to the class of free radicals derived from oxygen and are highly reactive oxidizing agents such as superoxide (O2) anion, hydrogen peroxide (H2O2), the very reactive hydroxyl (OH), peroxyl (ROO) radicals and can also be taken to cover nitric oxide-derived reactive molecules such as nitric oxide (NO) and peroxynitrite anion (ONOO). A free radical contains one or more unpaired electrons ready to be shared by other molecules, and this makes them very reactive. These different metabolites called ROS are either free radicals (with an unpaired electron in their outer orbital sphere) (O2, OH) or nonradical [H2O2, singlet oxygen (1O2)].2 Free radicals and other ROS are derived either from normal essential metabolic processes in the human body or from external sources such as exposure to ionizing radiation, ozone, cigarette smoking, air pollutants, herbicides, pesticides, fried foods, and other industrial chemicals.3 Free radical formation occurs continuously in the cells as a consequence of both enzymatic and non enzymatic reactions. Enzymatic reactions, which serve as source of free radicals, include those involved in cellular respiration chain, in phagocytosis (NADPH oxidase, myeloperoxidases), in prostaglandin synthesis, and in the cytochrome P-450 system.4 Electron transport chain is the major site of oxidative stress cause of premature electron leakage to oxygen generating superoxide. Superoxide released by oxidative phosphorylation is first converted to hydrogen peroxide and then further reduced to give water. This detoxification pathway is the result of multiple enzymes, with superoxide dismutases catalyzing the first step and then catalases and various peroxidases removing hydrogen peroxide.5 ROS and RNS are well recognised for playing a dual role as both deleterious and beneficial species, since they can be either harmful or beneficial to living systems.1 Beneficial effects of ROS occur at low/moderate concentrations and exert essential intracellular functions,

as second messengers, gene regulators, and mediators for cell activation (kinases and transcription factors). They also play a key role in our body’s defense against infectious organisms. Besides, ROS are modulators of cell death, whether apoptosis or necrosis.6 The harmful effect of free radicals causing potential biological damage is termed oxidative stress and nitrosative stress.7,8 Oxidative stress occurs in biological systems when there is an overproduction of ROS/RNS on one side and a deficiency of enzymatic and non-enzymatic antioxidants on the other. In other words, it is defined by an imbalance between ROS and antioxidants, ROS being in excess.9 Antioxidants: Living organisms have a control mechanism to keep ROS in balance. Antioxidants, in general, are compounds and reactions that scavenge and/or suppress the formation of ROS, or oppose their actions.2 Antioxidant and other cell redox state modulating enzyme systems act as the first-line defense against ROS in all cellular compartments and also extracellularly. Their relative importance depends upon which ROS are generated, how and where they are generated, and which target of damage is considered. Our body defends itself from these phenomena via endogenous antioxidants. Defense mechanisms against free radical-induced oxidative stress involve: (i) preventative mechanisms, (ii) repair mechanisms, (iii) physical defences, and (iv) antioxidant defences. Antioxidants act as radical scavenger, hydrogen donor, electron donor, peroxide decomposer, singlet oxygen quencher, enzyme inhibitor, synergist, and metal-chelating agents. Both enzymatic and nonenzymatic antioxidants exist in the intracellular and extracellular environment to detoxify ROS.10 Enzymatic antioxidant defenses include superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). Non-enzymatic antioxidants are represented by ascorbic acid (Vitamin C), tocopherol (Vitamin E), glutathione (GSH), carotenoids, flavonoids, and other antioxidants. Under normal conditions, there is a balance between both the activities and the intracellular levels of these antioxidants.11-13

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THE ROLE OF OXIDATIVE STRESS IN DERMATOLOGIC DISORDERS Skin exposure to ionizing and UV radiation and/or xenobiotics/drugs generates ROS in excessive quantities that quickly overwhelm tissue antioxidants and other oxidant-degrading pathways. Uncontrolled release of ROS is involved in the pathogenesis of a number of human skin disorders. The agents that produce oxidative stress in skin include gaseous airborne environmental pollutants generated by automobile and other industrial sources, UV radiation, food contaminants/additives/preservatives, cosmetic products, drugs, etc.14 As we mentioned before, ROS can be both beneficial and deleterious. However, excess levels of ROS due to overproduction or because of insufficient scavenging generate oxidative stress, leading to injurious effects via1 oxidative modification and damage of biomolecules, altering lipid/protein/DNA structure and function;2 further irreversible oxidation of reactive protein thiol groups which is hallmark of oxidative stress; and3 dysregulation of cell signaling pathways, triggering downstream signaling cascades leading to altered cytokine release and exacerbation of inflammation.15,16 As a result of distortion of balance between free radicals and endogenous antioxidants, excess ROS or insufficient ROS detoxification lead to pathological changes in cells and tissues. Chronic oxidative stress has been suggested as being the cause or consequence of many acute and chronic human diseases e.g. obesity, cardiovascular diseases, cancer, acute lung injury, retinal degeneration, Alzheimer’s disease, Parkinson disease and multiple sclerosis.17 Oxidative stress also play a role in various dermatological disorders like aging of skin e.g., solar elastosis, deep wrinkles, coarse texture, telangiectasia and pigmentation, psoriasis, allergic contact dermatitis, atopic dermatitis, vitiligo, acne vulgaris, pemphigus vulgaris (PV), lichen planus, alopecia areata, and melanomas.18,19

THE THERAPEUTIC ROLE OF ANTIOXIDANTS IN TREATMENT OF DERMATOLOGIC DISORDERS Although the skin possesses an elaborate antioxidant defense system to deal with oxidative stress, excessive and chronic exposure to UV light or other oxidizing agents can overwhelm the cutaneous antioxidant and immune response capacity, leading to oxidative damage and immunotoxicity, premature skin aging, and skin cancer. The skin is equipped with a network of protective antioxidants. In general, the outer part of the skin, the epidermis, contains higher concentrations of antioxidants than the dermis. The antioxidants system include enzymatic antioxidants such as glutathione peroxidase, superoxide dismutase and catalase, and nonenzymatic low-molecular-weight antioxidants

such as vitamin E isoforms, vitamin C, glutathione (GSH), uric acid, and ubiquinol. Various other components present in skin are potent antioxidants including ascorbate, uric acid, carotenoids, and sulfhydrils. Water-soluble antioxidants in plasma include glucose, pyruvate, uric acid, ascorbic acid, bilirubin, and glutathione. Lipid-soluble antioxidants include alpha-tocopherol, ubiquinol-10, lycopene, carotene, lutein, zeaxanthin, and alpha-carotene.20 In the lipophilic phase, tocopherol is the most prominent antioxidant, while vitamin C and GSH have the highest abundance in the cytosol. On molar basis, hydrophilic nonenzymatic antioxidants including L-ascorbic acid, GSH, and uric acid appear to be the predominant antioxidants in human skin. Their overall dermal and epidermal concentration are more than 10- to 100-fold greater than those found for vitamin E or ubiquinol.21 Vitamin C: Vitamin C (Vit. C), of which L-ascorbic acid (LAA) is the chemically active form, is one of the naturally occurring antioxidants in nature. Although most plants and animals are able to synthesize Vit. C in vivo from glucose, humans and certain other vertebrates must acquire it from natural sources such as citrus fruits, green leafy vegetables, strawberries, papaya and broccoli because of lacking the enzyme L-glucono-gamma lactone oxidase required for in vivo synthesis of Vit. C.20,22 Vit. C, the most plentiful antioxidant in human skin, forms a part of the complex group of enzymatic and non-enzymatic antioxidants that co-exist to protect the skin from ROS. As a water soluble molecule, Vit. C functions in the aqueous compartments of the cell. When the skin is exposed to UV light, ROS such as the superoxide ion, peroxide and singlet oxygen are generated. Vit. C protects the skin from oxidative stress by sequentially donating electrons to neutralize the free radicals. The oxidized forms of Vit. C are relatively non-reactive. Furthermore, they can be converted back to Vit. C by the enzyme dehydro ascorbic acid reductase in the presence of glutathione. Exposure to UV light reduces the availability of Vit. C in the skin.23 Although Vit. C alone can provide photoprotection, it works best in conjunction with Vitamin E (Vit. E), which potentiates the action of Vit. C four-fold. Hydrophilic Vit. C helps regenerate Vit. E that is a liphophilic antioxidant. Thus, Vit. C and Vit. E together protect the hydrophilic and lipophilic compartments of the cell, respectively. Vit. C and Vit. E synergistically limit chronic UV damage by significantly reducing both cell apoptosis and thymine dimer formation.24 It is important to note that Vit. C is equally effective against both UVB (290-320 nm) and UVA (320-400 nm). UVA causes skin ageing and possibly melanoma formation by destroying collagen, elastin, proteoglycans and other dermal cellular structures as UVB causes sunburn, ROS, epidermal mutations and skin cancer.25

CHAPTER 5: ANTIOXIDANTS IN DERMATOLOGY Both vitamins C and E have been demonstrated to have differential UVB photoprotective effects when applied both topically and orally for skin ageing. Moreover, oral combination therapies of vitamins C and E resulted in a dramatically increased photoprotective effect compared to monotherapies.26,27

vitamin C (ascorbyl tetraisopalmitate), and bioflavonoids from Ginkgo biloba possesses a higher in vitro antioxidant activity against UV damage, due to its free radical scavenging properties (almost 100% of inhibition of free radical production) compared with the separate use of the components.33

Vitamin E: Vitamin E is a lipophilic, non-enzymatic important antioxidant in skin therapy. Numerous data indicate that the antioxidant function of vitamin E is supplemented and linked to many enzymatic and non-enzymatic antioxidant systems. Vitamin E is a collective name for all tocopherols and it’s most biologically active form is α-tocopherol.28

Ubiquinone - Coenzyme Q10: Ubiquinone (coenzyme Q10 or CoQ10) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. its central role in the mitochondrial respiratory chain as electrons carrier from complex I and II to complex III. The well known functions are in mitochondrial energy coupling and its action as a primary regenerating antioxidant. Less well established functions include oxidant action in the generation of signals and control of cellular redox state. By participation in transmembrane electron transport CoQ10 can carry reducing equivalents to the inside of vesicles or to the outside of cells. There is also evidence for a role in proton gradient formation in endomembranes and at the plasma membrane. There is also evidence that coenzyme Q can take part in control of membrane structure and phospholipid status.34,35 CoQ10 protects against UVA-induced collagen degradation. Together with tocopherol, it inhibits the production and expression of fibroblast collagenase. The concentration of CoQ10 in the skin is quite low, and arranged so that CoQ10 levels are ten times higher in the epidermis than in dermis; epidermis thus may have potential benefit of topical applications of CoQ10. It turned out that CoQ10 was absorbable after topical applications. After topical applications of 0.3% CoQ10, for one week two times a day on the skin previously exposed to UVA radiation, causing a drop in antioxidant activity of the skin, there was a significant improvement in antioxidant activity.36 A study has shown that CoQ10 in the formulation of nano structure of lipid carriers (NLCCoQ10) has a higher antioxidant capacity and topical penetration through the skin-emulsion of CoQ10. The new formulation of Co Q10-NLC called “drug delivery system”, mainly lipophilic in structure, shows a high solubility of substances, high stability, good penetration through the SC and low skin irritation.37 In summary, CoQ10 as a very effective antioxidant in the protection of the dermal matrix and photoaging and chronological aging of the skin is an important cosmetic agent.

Alpha-tocopherol is the most active and is important in protecting cellular membranes from lipid peroxidation by free radicals. Vitamin E can be regenerated back to its reduced form by vitamin C or L-ascorbic acid after oxidation. Alpha-tocopherol also acts synergistically with vitamins A and C in combined products, in the protection against photoaging and skin cancer.29 Of all the ester forms such as vitamin E acetate, succinate and linoleate, vitamin E acetate is mainly used in the products intended for skin care and protection becuase of its efficiency, stability, good compatibility (does not cause skin sensitization and allergies) and relatively low cost. In cosmetic products, it is recommended that vitamin E acetate should be used at a concentration of 1-10%, although the results of other authors have shown that the best effect in the skin is achieved with 5% concentration.30 Membrane stabilization is achieved via the interaction between vitamin E and poly-unsaturated fatty acids that constitute the membrane lipids. Unsaturated fatty acids present in phospholipids of cell membranes produce lipid peroxides after oxidation. Then these lipid peroxides damage structural and functional elements of biological membranes by reacting them. Vitamin E has the ability to neutralize lipid peroxides. In this way, it protects cell membranes from peroxidative damage, phospholipase A activity, and action of free fatty acid peroxides and lisophospholipids.31 There are some studies about vitamin E in treatment of skin conditions. It is reported that some diseases as yellow nail syndrome and vibration disease are the conditions for which there is some proof of vitamin E’s effectiveness. There are mixed claims of vitamin E’s effectiveness in conditions such epidermolysis bullosa, cancer, claudication, cutaneous ulcers, collagen synthesis and wound healing. Furthermore, it has been proven to be ineffectiveness of vitamin E in conditions such as atopic dermatitis, psoriasis, dermatitis herpetiformis, subcorneal pustular dermatosis, porphyria, acute erythema induced by ultraviolet light.32 Maia Campos et al analyzed a new formulation, called as a “biological filter”, with the association of vitamin E (tocopheryl acetate), vitamin A (retinyl palmitate),

Superoxide Dismutase (SOD): Superoxide dismutases (SODs) are a class of closely related enzymes that catalyze the breakdown of the superoxide anion into oxygen and hydrogen peroxide. SOD enzymes are present in almost all aerobic cells and in extracellular fluids. There are three major families of SOD, depending on the metal cofactor: Cu/Zn (which binds both copper and zinc), Fe and Mn types (which bind either iron or manganese), and finally the Ni type which binds nickel. In humans as in all other mammals and most chordates, three forms of SOD are present.

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IMMUNMODULATORS IN DERMATOLOGY SOD1 is located in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular.38,39 SOD is defined as the first line of antioxidant defence of the body, known as a primary antioxidant. As an enzyme, SOD exhibits a very high catalytic rate of reaction and is constantly renewing itself. SOD converts the extremely reactive superoxide anion O2 into hydrogen peroxide H2O2. Excessive amounts of H2O2 are harmful to cells and rapid scavenging hereof is thus important. By dismuting O2, SOD prevents the liberation of free iron ions and, thus, the formation of harmful ROS such as OH At the same time, SOD protects the vascular signalisation from NO by preventing its reaction with O2 and the formation of peroxinitrite ONOO–, a harmful reactive nitrogen species (RNS).40 It is necessary to understand the anti-inflammatory properties of SOD in the prevention or suppression of skin inflammation because of skin is the primary contact with the exogenous environment. Kwon et al. studied the role of SOD (EC-SOD or SOD3, located in the ECM and specifically expressed in the epidermis and dermis) in the inhibition of inflammation. Unlike other SODs, SOD3 has a heparin-binding domain that interacts with heparan sulphate proteoglycans on cell surfaces and in the ECM. Thus, the cleavage of SOD3 following exposure to exogenous and endogenous threats, the enzyme no longer protect against stimuli and an inflammatory reaction is initiated. The authors also mentioned that SOD levels in skin were altered upon the progression of inflammation.41 Kim et al. assessed the involvement of redox-sensitive pathways to determine the anti-angiogenic and anti-inflammatory properties of SOD in the skin. They showed that anti-angiogenic and anti-inflammatory effects of SOD might be due to suppression of hypoxia-inducible factor- 1a (HIF-1α), protein kinase C (PKC) and NF-κB expression by decreasing phosphorylation of PKC and both expression and nuclear translocation of NF-κB. SOD is able to inhibit expression of VEGF, MMPs (by increasing the expression of tissue inhibitor of matrix metalloproteinases (TIMP)) and other pro-angiogenic and pro-inflammatory mediators. Like others, NF-κB-dependent expression of pro-inflammatory enzymes such as COX-2 and iNOS was also decreased in the skin.41,42 Numerous studies have investigated the antioxidative effects of elevated SOD levels in tissues by different means. For instance, intramuscular injections of SOD1 were successfully applied as anti-fibrotic therapy in treating cutaneous radiation-induced fibrosis in humans and similar promising results were obtained with SOD2 in a porcine model of radiation-induced fibrosis.43 Additionally, SOD has an anti-fibrotic action. This acts by reducing collagen accumulation in the dermis of irradiated skin and reactivating cellular functions in dermal fibroblasts and epidermal cells, as demonstrated by phenotypic changes of myofibroblasts.44 Specifically,

cutaneous SOD2 reduced superoxide levels and normalized wound healing and acne, which are characterised by a fibrosis process. It has also been demonstrated that SOD reduces cellulite in women.45,46 Catalase: Catalase is a common enzyme found in nearly all living organisms, which are exposed to oxygen. It functions to catalyze the decomposition of hydrogen peroxide to water and oxygen. Hydrogen peroxide is a harmful byproduct of many normal metabolic processes must be quickly converted into other, less dangerous substances to prevent damage. For this, catalase is frequently used by cells to rapidly catalyze the decomposition of hydrogen peroxide into less reactive oxygen and water. All animals use catalase in every organ, especially in the liver with particularly high concentrations.47 Reduction in catalase activity has been demonstrated in the epidermis support the concept of possible systemic oxidative stress in vitiligo. It has been reported that low catalase activity and high hydrogenperoxide levels in the cutaneous epidermis of vitiligo patients. This might result in epidermal oxidative stress and consequently damage to pigment cells.48 Similarly, Sravani et al has been reported that a lower level of catalase activity was found in vitiligo patients when compared with controls.49 On the other hand, Hazneci et al show that erythrocyte catalase levels in patients with vitiligo are not significantly different from those in healthy agematched controls.50 Rhie et al previously reported that catalase activity is reduced in the dermis of aged and photoaged human skin in vivo, whereas the activity of catalase increased significantly in photoaged and aged epidermis.51 Shin et al also found that catalase activity was reduced more in photoaged fibroblasts than in intrinsically aged fibroblasts, and as a result of this, H2O2 accumulated more in photoaged fibroblasts. Moreover, treating aged fibroblasts with catalase reduced H2O2 levels, and reversed the aging-dependent changes in ERK and JNK activities and reduced the basal expression of MMP-1. Therefore, it is possible that the accumulation of H2O2 due to catalase attenuation in aged and photoaged fibroblasts may increase oxidative stress and affect MAP kinase signaling pathways to promote skin aging and photoaging.52 Glutathione system: The glutathione system that includes glutathione, glutathione reductase, glutathione peroxidases, and glutathione S-transferases is found in animals, plants, and microorganisms. Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyze the breakdown of hydrogen peroxide and organic hydroperoxides. Among four different glutathione peroxidase isozymes, glutathione peroxidase 1 is the most abundant and is a very efficient scavenger of hydrogen peroxide, while glutathione peroxidase 4 is most active with lipid hydroperoxides. By the way, the glutathione S-transferases show high activity with lipid peroxides. These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism.53,54

CHAPTER 5: ANTIOXIDANTS IN DERMATOLOGY §

Glutathione (GSH) or GSH sulfhydryl is a tripeptide which includes three amino acids, glycine, glutamate, and cysteine. Decrease GSH and increased oxidative stress levels is associated with psoriasis both locally and systemically. Levels of GSH activity as an antioxidant can also be associated with potential response to treatment. Patients who don’t respond to the biologic agent, efalizumab had increased GSH peroxidase (GPx) and GSHS-transferase and decreased catalase activity in granulocytes versus responders. Clinical response correlated with GPx activity in blood cells, suggesting high oxidative stress levels is involved in psoriasis persistence.55 It is also reported that increased oxidative stress with a consequent induction of H2O2 accumulation in the epidermis of patients with active disease, lower levels of GPX and catalase were demonstrated in the epidermis of both lesional and non lesional skin of vitiligo patients.56 Ikeno et al showed that the amount of GSH in stratum corneum from each area (facial acne-involved lesion, facial uninvolved area, and the medial side of the upper arm) was significantly lower in acne vulgaris patients than healthy subjects. There was no significant difference in amount of GSH between the acne-involved lesion and uninvolved area in acne patients.57 Furthermore, although reduced GSH has a skin-whitening effect in humans by suppressing the activity of tyrosinase, and oral administration of GSH in humans reduces melanin production in the skin, oxidized glutathione (GSSG) this effect is unclear. Watanable et al examined the skin-whitening and skin-condition effects of topical GSSG in healthy women. They observed that skin melanin index was significantly lower after the 10 weeks GSSG treatment. In addition, GSSG-treated sites had significant increases in moisture content of the stratum corneum, suppression of wrinkle formation, and improvement in skin smoothness. They also reported that topical GSSG is safe and effectively whitens the skin and improves skin condition in healthy women.58 Selenium: Selenium (Se), an essential trace element that has a protective, immune modulating and anti-proliferative properties. Many of the functions of Se are thought to be mediated by selenoproteins that contain Se in the form of the amino acid, selenocysteine.59 There are 25 selenoproteins in humans and several of these; including three different thioredoxin reductases (TRs), four GPxs and selenoprotein P are believed to detoxify ROS. Although GPx2 and GPx4 are thought to be important regulators of redox homeostasis in this tissue the roles of selenoproteins in the skin are not well characterized.60 Although organic forms selenomethionine (SM), appear to be reutilized by the body more efficiently than inorganic forms sodium selenite (SS), organic Se is biologically less available because SM substitutes nonspecifically for methionine residues in proteins and in such circumstances that Se

has no bioactivity.61 Se was shown to be incorporated covalently into proteins of the GPX family of selenoenzymes. Se can exert its biological effects by a mechanism that GPXs detoxify harmful organic hydroperoxides, as well as hydrogen peroxide and peroxynitrites, which are produced during oxidative metabolism. On the other hand, Se is incorporated into other selenoproteins and it may be the effects of other less well-defined selenoproteins that mediate some of the protective effects of Se on UVB-induced cell damage.62 Se appears to prevent the accumulation of free radical species which would otherwise result in oxidative damage to DNA, proteins, and to cellular membranes by lipid peroxidation. In one supplementation trial for psoriasis symptoms, seven patients with psoriasis received selenium 400 μg daily for 6 weeks as selenomethionine-enriched yeast. After supplementation blood and serum selenium levels were normal at baseline. Selenium supplementation had no marked effect on the clinical condition of the patients.63 A previous study also showed no effect of daily supplementation of 600 μg selenium-enriched yeast alone or together with 600 IU of vitamin E on the clinical symptoms of 69 patients with psoriasis. In this placebo-controlled study, blood, plasma and platelet selenium concentrations as well as platelet glutathione peroxidase activity and plasma vitamin E markedly increased in the supplemented group. However, the mean skin selenium concentration and red cell glutathione peroxidase activity remained unchanged (64). Low plasma Se levels have been linked inversely to skin cancer.patients with malignant melanoma were examined for stage of tumor development and patients with stage 3 disease had the lowest of Se levels. Clark et al have reported than 240 cancer patients had a significantly lower mean plasma Se concentration than did controls without skin cancer.65 Polyphenols: Polyphenols are a group of chemical compounds diverse in terms of structure and properties, which are classified as secondary metabolites. They are widely distributed in plant foods, including fruits, vegetables, nuts, seeds, flowers and bark. Important dietary sources of polyphenols are onions (flavonols); cacao, grape seeds (proanthocyanidins); tea, apples and red wine (flavonols and catechins); citrus fruits (flavanones); berries and cherries (anthocyanidins); and soy (isoflavones).66,67 Polyphenols’ main biological activity is to protect against biological stressors, harmful effects of ultraviolet (UV) radiation, viruses, bacteria and fungi and also to assist in the process of adaptation to changing environmental conditions, cellular signal transduction or gene expression. According to different classifications, phenolic acids, flavonoids, stilbenes, lignans, coumarins and tannins are classified to the group of polyphenols.68 However, in cosmetology and dermatology, the most important are flavonoids and phenolic acids.

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IMMUNMODULATORS IN DERMATOLOGY Polyphenols such as green tea possess antioxidant, antiinflammatory, immunomodulatory, anticarcinogenic, proapoptotic, and photoprotective properties. Naturally occurring polyphenols, such as green tea polyphenols (GTPs), silymarin from milk thistle and proanthocyanidins from grape seeds (GSPs), against UV radiation-induced inflammation, oxidative stress, DNA damage and suppression of immune responses.69 Various polyphenols have been reported to be photoprotectors. Oral as well as topical application of green tea polyphenols to mice protected in a time-dependent manner against UV-induced cutaneous edema, depletion of the epidermal antioxidant defense, and cyclooxygenase induction.70 Resveratrol: Resveratrol (RES), a trihydroxy derivative of stilbene (3,5,4’-trihydroxystilbene), is a naturally occurring polyphenolic phytoalexin antioxidant present in grapes, berries, peanuts and red wine. Resveratrol and its chemical analogues have photoprotective, antioxidant, antiinflammatory, and anticarcinogenic capabilities. The introduction of resveratrol in cell cultures and topical application in human skin resulted in increased cell survival, decreased production of reactive oxygen species, and diminished clinical erythema after UV irradiation.71,72 Because resveratrol has strong antioxidant properties, and oxidative stress is believed to be a critical factor in a variety of cutaneous conditions including skin cancers, a number of in vitro and in vivo studies have been done to determine the anti-proliferative effects as well as photo-protective effects of resveratrol. Ndiaye et al demonstrated that the topical application of skin with resveratrol (both preand post- treatment) resulted in a highly significant inhibition in tumor incidence, and delay in the onset of tumorigenesis in their recent study that they evaluated the skin cancer chemopreventive effects of resveratrol in a photocarcinogenesis model of skin cancer.73

Conclusions As it is known, skin is the major target of oxidative stress mostly due to ROS originating from both normal and abnormal epidermal physiology as well as the environment. Endogenous and exogenous antioxidants such as vitamin C and E, ubiquinone, superoxide dismutase, glutathione, catalase, selenium, polyphenols and resveratrol reduce the harmful effects of ROS and mediate molecular mechanism and the identification of distinct ROS involved in a variety of dermatologic disorders. Although it is still unknown the molecular mechanism of the regulation of ROS-mediated signaling pathways, antioxidant strategies have proven to be beneficial therapeutics in dermatology. Finally, targeting oxidative stress by using antioxidants may play a role in reduction of dermatologic disorders.

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CHAPTER 6

ANAKINRA Pelin Ülkümen, MD, Emek Kocatürk Göncü, MD. Anakinra is a recombinant, soluble, selective nonglycosylated short acting IL-1 receptor antagonist (IL-1Ra), produced by recombinant DNA technology using an Escherichiacoli (E. Coli) bacterial expression system.1 Anakinra (Kineret; Biovitrum, Stockholm, Sweden) was approved by food and drug administration (FDA) in 2001 for the treatment of rheumatoid artiritis which is safe and well tolerated.2,3 After that, it was approved for the treatment of patients with neonatal onset multi inflammatory diseases in 2012.3,4 Anakinra has been used for the diseases which have IL-1-mediated pathology like monogenetic autoinflammatory disease which is a group of syndromes named cryopyrin associated periodic syndromes (CAPS). Although it has been used for monogenetic autoinflammatory disease, it has been also used for SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome); CRMO (chronic recurrent multifocal osteomyelitis); PFAPA, and PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne syndrome), Blau syndrome, Crohn’s disease, Still’s, Behcet’s, and Schnitzler diseases which are the autoinflammatory disorders with unknown genetics. IL-1-blocking agents have been studied for the diseases of classic hereditary periodic fever syndromes including familial mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D (HIDS). Usage of anakinra in metabolic conditions associated with IL-1 pathway such as gout/pseudogout, metabolic syndrome, type 1 and type 2 diabetes mellitus, stroke, and myocardial infarction has also been reported in the literature.4,5

Mechanism of Ac on Anakinra competitively inhibits the binding of IL-1 at the level of type I receptor (IL-1RI) which is expressed on a wide variety of tissues.2,6,7 Interleukin 1 is a proinflammatory cytokine that regulates inflammation and immune response. IL-1 gene family consists of genes encoding IL-1α, IL-1β, and IL-1RA.8 There are two molecular species of IL-1.5,9 They are interleukin-1α and IL-1β which induce inflammatory responses such as fever, anorrhexia, tissue damage and remodeling. IL-1Ra is a natural antagonist that competes with IL-1α and IL-1β for the IL-1 receptor as anakinra doeS.8 While

IL-1α is present in most of the healthy tissues such as normal keratinocytes of the skin, platelets, the epithelial cells of mucosal membranes and the cells of the liver, lung and kidney, endothelium of the vessels.4,5 IL-1β is not present in healthy tissues and its blood levels can not be detected by standard assays. Blood monocytes, tissue macrophages and dendritic cells secrete IL-1β as a product in response to a stimulus. That stimulus can be in microbial origin or other cytokines can stimulate IL-1β, the cytokines which stimulates IL-1 are tumour necrosis factor (TNF)α, IL-18, IL-1α. IL-1β can also induce IL-1β itself. IL-1 induction of itself is the cause of autoinflammation and these autoinflammatory disorders usually occur due to genetic mutations.4,5 This group of genetic disorders have common clinical symptoms like recurrent fevers, fatigue, myalgia, arthralgia, gastrointestinal symptoms and skin rashes.4 More recently, anakinra has also been successfully used to treat patients with neutrophilic dermatoses such as neutrophilic panniculitis, pustular psoriasis, pyoderma gangrenosum, and Sweet syndrome too.4,9

Recommenda ons for administra on Anakinra, which blocks IL-1α and -β binding to the IL-1 receptor, has a half-life of 4–6 hours and requires daily dosing self-administered via subcutaneous injection at a dose of 100 mg.4,6,10 Anakinra is a clear, colourless to white solution for injection and is supplied ready for use in a pre-filled syringe. It may contain some translucent to white particles of protein. The presence of these particles does not affect the quality of the product. Anakinra has recently been approved for use in children aged ≥8 months. According to the literature, patients diagnosed in younger age needed higher doses of anakinra and required more  frequent treatment adjustments than adults.11 Pack sizes of 1, 7 or 28 (multipack containing 4 packs of 7 pre-filled syringes) pre-filled syringes are available.12 Treatment with anakinra seems to be safe in children but it is not used at neonatal age. The treatment has to be applied as earlier as possible in order to prevent secondary complications in young patients and newborns. At this age, few are known on anti‐IL-1 blood concentration and distribution in the tissues. Previous reports have shown that higher doses were usually

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IMMUNMODULATORS IN DERMATOLOGY needed to obtain complete efficacy. A retrospective study showed that patients with chronic infantile neurologic, cutaneous and articular (CINCA) syndrome treated with anakinra at doses between 1 and 2 mg/kg in children appeared effective on disease symptoms but higher doses like 6-10 mg/kg were required to achieve an effect on the neurological manifestations, eye and hearing loss.13 Changing the injection site is recommended to avoid discomfort at the site of injection. Warming the injection liquid, use of cold packs before and after the injection and use of topical corticosteroids and antihistamines after the injection can reduce symptoms of injection site reactionS.12,14 Although data in elder CAPS patients are limited, no dose reduction is expected to be required. Posology and administration in children and infants aged 8 months and older with a body weight of 10 kg or above are the same as for adult CAPS patients, based on body weight. No data are available in children under the age of 8 months.12 Anakinra should be used with a caution in patients with severe hepatic impairment but no dose adjustment is required for patients with moderate hepatic impairment (Child-Pugh Class B). Anakinra must not be used in patients with a creatinine clearance of < 30 ml/minute, but no dose reduction is needed for patients with mild renal impairment with a creatinine clearance changing from 50 to 80 ml/minute. Patients with creatinine clearance changing between 30 to 50 ml/minute, anakinra should be used with caution.12 Its pregnancy category is B and it is not known if anakinra is secreted in human milk.15

DERMATOLOGICAL INDICATIONS OF ANAKINRA 1- Monogene c autoinflammatory disease Cryopyrin associated periodic syndrome (CAPS) Genes mutations encoding of IL-1 pathways leads to some monogenic autoimmune disorders. There is a macromolecular complex called Nalp3 inflasomme which is critical for the synthesis of IL-1β. One of the components of inflammasome is Cryopyrin. And it brings caspase 1 (anIL-1 β-converting enzyme) molecules together to process IL-1β to its active form.2,16 Mutation of NALP3/CIAS1/PYPAF1 genes enhance caspase-1 activity and causes IL-1β production and secretion from monocytes which is characteristic of autoinflammatory diseases termed “cryopyrin associated periodic syndrome (CAPS)”. There are more than 170 mutations described.2,11 CAPS is characterized by recurrent fever, myalgia and skin rash, increased cytokine expression, and episodic inflammation with end-organ damage. An urticaria like rash usually presents in all types of cryopyrinopathies but histology differs from urticaria

as lymphocyte and neutrophils dominate in the infiltrations inspite of mast cells. This improves that the rash is not a real urticaria.17 CAPS includes three syndromes called familial cold autoinflammatory syndrome(FCAS), Muckle–Wells syndrome (MWS) and neonatal onset multi inflammatory diseases (NOMID) which are also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome.2,5,16 Familial cold autoinflammatory syndrome (FCAS) is the mildest from of CAPS presented by remitting fevers, urticaria like rash, arthritis following cold exposure. The risk of developing complications like AA amyloidosis is little.17 More severe forms of CAPS are named Muckle-Wells syndrome (MWS) and CINCA/NOMID. In MWS is characterized by excessive IL-1 release, resulting in recurrent urticaria-like rash, cutaneous vasculitis, fever, malaise, arthralgia, abdominal pain, lymphadenopathy and conjunctivitis. Patients with MWS can also develop sensorineural hearing loss and systemic AA amyloidosis but attacks are not necessarily triggered by cold as in FCAS.17 CINCA/NOMID is the most severe form of CAPS, presented by fever and rash with eye, central nervous system (CNS), and inner ear inflammation, bony overgrowth and mental retardation. Investigated levels of IL-1β is reported five fold higher than in healthy subjects in CAPS, which leads to systemic inflammation.3,13 Anakinra is highly efficacious in the treatment of CAPS and has been approved for the treatment of patients with NOMID in 2012.3,5 IL-1 inhibition with anakinra improves clinical symptoms such as fever, rash, joint pain, and headache and it shows rapid decrease in inflammatory markers like CRP, SAA levels or it can reduce flares of patients within all CAPS subtypes. It is indicated in adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above with a starting dose of 1 to 2 mg/kg/day by subcutaneous injection. Required maintenance dose is usually 1-2 mg/kg/day. In severe cases dose may necessarily be increased to 3-4 mg/kg/day after the first 2 months which is the usual maintanance dose for severe cases to achieve therapeutic response. And up to doses of 8-10 mg/kg/day can be applied stepwise as a maximum dose to control headaches and papilledema.7,12,13 In children, young patients and eventually newborns with persistent disease activity, high doses were required to achieve an effect and anti-IL-1 treatment should be initiated very early to avoid irreversible complications.3,7,13 Assessments of inflammation of the CNS including the inner ear (MRI or CT, lumbar puncture, and audiology) and eyes (ophthalmological assessments) are recommended after 3 months of treatment, and then every 6 months, until effective doses have been achieved. When patients are clinically well-controlled, CNS and ophthalmological monitoring can be done once a year.12

CHAPTER 6: ANAKINRA Continuous daily treatment is necessary to achive sustained response. Because the drug has a short half-life of 6 hours, flare ups can be seen when daily treatment was distrubuted.12,13 The use of IL-1-blocking agents may prevent organ damage and disability when they are applied aggressively and immediately. Classic Hereditary Periodic Fever Syndromes IL-1-blocking agents have been reported to decrease the frequency of attacks and duration of familial mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D syndrome (HIDS) and it also reduces systemic inflammation.4 FMF is caused by autosomal recessive mutations in MEFV resulting in pyrin formation which have a role in the activation of caspase-1 and production of IL-1 β.9,4,18 FMF is characterized by lasting 3-4 day lasting episodes of fever, mostly abdominal serositis, pericarditis or pleuritic chest pain, leukocytosis and arthritis. FMF is the most common autoinflammatory disease. The main treatment for FMF is colchicine, but % 5-10 of the patients are unresponsive to colchicine. IL-1 blocking agents can be the treatment of choice for these patients who are unresponsive or resistant.4,18,19 Amyloidosis is one of the main complication of FMF, anakinra can also be used in patients with amyloidosis.9,18,19 Early onset FMF and having homozygous M694V mutations are reported to be assosiciated with more severe disease.19 To reduce risk for developing complications, anakinra can be the treatment of choice for the patients who are unresponsive or resistant to colchicine treatment. TRAPS is an autosomal dominant disease caused by mutations in TNFRSF1A gene encoding the TNF-receptor type 1. TRAPS present with attacks which is similar to FMF symptoms but attacks last several weeks and rash is migratory in TRAPS. Conjunctivitis and periorbital edema can also be seen.4,9 TRAPS does not respond to colchicine but it responds to corticosteroids and TNF-inhibiting drugs. Like FMF, anakinra is reported to be effective in patients with high risk for the development of amyloidosis and may benefit from earlier and more aggressive IL-1-blocking therapy.4,9,20 HIDS is an autosomal recessive disorder which is caused by MVK gene mutation encoding an enzyme of the cholesterol pathway called mevalonate kinase. Patients clinically present with episodes of fever, lymphadenopathy, vomiting, diarrhea, maculopapular rash and splenomegaly. Treatment includes insufficient responses to nonsteroidal anti-inflammatory drugs and intolerance to corticosteroids, which led to the use of IL-1-blocking agents.4 Several cases have reported the success of IL-1 blockade in reducing the frequency and severity of the attacks.5 In a review, 21 patients with HIDS who were treated with anakinra, showed complete or partial responses in 90% of cases. Reported 90 % response rate

suggests that anakinra is the treatment of choice for HIDS in children.21

IL-1 mediated bone disease Deficiency of IL-1 receptor antagonist (DIRA) A rare monogenic condition is the deficiency of IL-1 receptor antagonist. It is an autosomal-recessively inherited autoinflammatory disease which is caused by mutations in the IL-1 receptor antagonist gene, IL1RN. It clinically presents within the first weeks of life with symptoms of systemic inflammation, neutrophilic pustular rashes, joint swelling, oral mucosal lesions, and periostitis, aseptic multifocal osteomyelitis, and high acute-phase reactants. Vasculitis in central nervous system is also rarely seen. IL-1 receptor antagonist anakinra can prevent the development of severe inflammatory response and multiorgan failure.4,22 Although antibiotics and antirheumatic drugs, steroids, indomethacin, and interferon gamma shows limited improvement, anakinra improves clinical symptoms and lowers the acute-phase reactants, rapidly reverses the inflammation, and leads to remission. But stopping the treatment causes flares. So daily treatment with anakinra should be given lifelong to patients with DIRA to prevent multiorgan failure and death from the disease.5,23-25 Majeed Syndrome Majeed syndrome is characterised by similar clinical manifestations as DIRA and is caused by autosomal recessive mutations in LPIN2 gene. It presents with neutrophilic pustular skin lesions, systemic inflammation, chronic recurrent multifocal osteomyelitis, and dyserythropoietic anemia.4,5,25 Long-term prognosis of disease is poor. In a case series with 2 patients, rapid clinical and laboratory improvement has been reported with the treatment of anakinra at a dose of 1.7 mg/kg/ day for 6 weeks. But flare up after cessation of anakinra has also been reported.25

2- Other monogenic autoinflammatory diseases Pyogenic arthri s, pyoderma gangrenosum and acne syndrome (PAPA) PAPA syndrome is a rare autosomal dominant disease caused by mutations of PSTPIP1 gene and shows a limited response to systemic glucocorticosteroids, immunosuppressive therapies and no response to antibiotics. The syndrome is associated with elevated levels of IL-1β.26,27 Anakinra has been reported to be effective to prevent arthritis flares associated with PAPA syndrome and appears to be an effective therapy to treat disease flares in PAPA syndrome. In a case report, a targeted therapy with anakinra at the dose of 100 mg daily improved the skin lesion only in 5 days. And after 1

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IMMUNMODULATORS IN DERMATOLOGY month of continuous treatment with anakinra, the lesion was completely healed.26,27 AlthoughTNF inhibitors alone or in combination with IL-1-blocking agents improve disease control, responses to IL-1 and TNF inhibitors are incomplete.4 Response to anakinra is variable and it is more effective in symptoms of arthritis than skin manifestations.28 Blau Syndrome Also named as pediatric granulomatous arthritis (PGA), Blau syndrome presents with a triad of granulomatous polyarthritis, panuveitis, and granulomatous exanthema. NSAIDs, systemic corticosteroids and immunosuppressants, as well as biologics targeting TNF and IL-1, result in clinical improvement.29 In a reported patient with Blau syndrome, all clinical inflammatory symptoms and plasma cytokine levels improved following  anakinra  treatment.30 However 2 cases of Blau syndrome has been reported to be unresponsive to anakinra treatment.31 Familial cold autoinflammatory syndrome 2 It is a periodic fever syndrome with recurrent maculopapular rash, arthralgias, myalgias, swelling of the extremities, and conjunctivitis after exposure to cold. It is caused by mutations in NLRP12. In two cases with more severe disease, only partial responses with the treatment of anakinra has been reported.4,32

3-Autoinflammatory diseases with unknown gene cs Other autoinflammatory diseases which includes immune dysregulatory conditions that are not genetically well known, including Schnitzler’s, Behcet’s, Still’s diseases. There are also periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) and CRMO, SAPHO syndrome.4 Schnitzler syndrome Schnitzler syndrome is a rare acquired systemic inflammatory disease that presents with fever flares, chronic neutrophilic urticaria, and monoclonal IG gammopathy. Multiple case reports and small series indicate rapid and long term response to monotherapy with IL-1-blocking agents (4). Excessive secretion of IL-1, IL-6 and TNF has been reported (10). Therapies like antihistamines, non-steroidal antiinflammatory drugs (NSAID), corticosteroids, immunomodulators and pefloxacin, usually causes partial or transient improvement of the symptoms. Disease-modifying anti-rheumatic drugs are rarely useful.33 And blocking TNFα had no effect.10 Recently anakinra provided remarkable efficacy on this disease. Anakinra, initiated as first-line monotherapy and administered 100 mg daily, showed complete remission of symptoms within 2 days and long-lasting remission for more than 3 years.10 A mul-

ticentral retrospective study with six patients treated with anakinra  monotherapy was initiated in standard dosing 100 mg subcutaneously daily. Complete remission which was defined as regression in urticaria and pain, normalization of inflammatory markers and bone metabolism improvement was achieved in 83%, while partial remission had been reported in 17% of the patients with a median treatment follow-up of 30.5 months.34 In another multicentral retrospective study, long-term effectiveness and safety of off-label use of anakinra in 29 patients had been reported. And clinical signs and disease activity of all patients improved dramatically within 48 hours. During the follow-up of 36 months, the effectiveness reported to be unchanged. In this study 83% of the patients were in complete remission while 17% were in partial remission. This study also improved that anakinra also has a major corticosteroid sparing effect and a favorable tolerance.33 Behçet’s disease (BD) Behçet’s disease is also multisystem inflammatory disorder that is characterized by recurrent oral aphthosis and genital ulcers, skin pathergy, uveitis, intermittent rashes and arthritis. Involment of vascular system, gastrointestinal system and neurologic system can also be observed.4 It is reported that anti-IL-1 agents can be a successful therapeutic choice in BD with ocular involvement, although relapses of retinal vasculitis during treatment with anakinra have been reported. For the gastrointestinal and neurological involvement, single case reports indicated that anakinra treatment relieves abdominal pain and headache. Both arthralgia, artiritis and a case of BD-related sacroileitis responding to anakinra has also been reported in the literature.35 Anakinra has been successfully used in one patient with a prevalent mucocutaneous involvement and another case report have indicated response to anakinra in a patient with FMF and BD, who have aphthous lesions and skin lesions unresponsive to the conventional therapies.36, 37 Patients with aphthosis and skin manifestations like erythema nodosum, pseudofolliculitis, and papulopustular lesions are reported to be refractoryto anakinra, but combination therapy with colchicine can improve their control. Thrombotic lesions of BD which are shown to be unresponsive to anakinra, also need a combination therapy with immunosuppressive agents.35 In a study nine patients with BD who were unresponsive to tumor necrosis factor blockers and standardized therapies had been treated mostly with 100 mg/day of anakinra and low doses of prednisone. One or 2 weeks following treatment with anakinra, eight patients responded to anakinra with low doses of prednisone. But most patients had been reported to have relapse in one or more clinical manifestations at a mean time

CHAPTER 6: ANAKINRA of 29 weeks and only one patient had been reported to be under complete control on anakinra monotherapy. Despite a relapse, the treatment had been continued in most patients for a mean period of 13.75  months. In this survey, while 7 patients responded to 100 mg/ day of anakinra, 2 patients had no improvement. By increasing the dose to 150mg/day, complete resolution had been achieved. Responses had been reported to be within 1-2 weeks in six patients. Oral aphthosis, genital ulcers and skin lesions were the most resistant manifestations and seven out of nine patients treated with anakinra showed poor response. In order to control mucocutaneous manifestations, colchicine was successfully introduced in three patients. Thrombotic lesions were also reported to be refractory to anakinra and trombosis had been reported in two patients on anakinra treatment. In conclusion anakinra rapidly reduced ocular inflammation while it had no effect on oral ulcers. However, relapses of ocular manifestations occurred after an average period of 24 weeks.38 Periodic fever, aphthous stoma s, pharyngi s and adeni s (PFAPA) PFAPA is a childhood disease which is the most common periodic fever disease in children. After puberty frequency of flares decreaseb.4,39 Treatment varies and includes NSAIDS and oral corticosteroids, tonsillectomy which may reduce the frequency of attacks. Recently on-demand IL-1-inhibiting drugs (anakinra) have been used with complete response.4 In a study, 5 patients with PFAPA received anakinra at a dose of 1 mg/kg/day subcutaneously within 48 hours following the onset of an attack. One patient received a second dose 24 hours after the first dose. All patients showed clinical response, with decreasing their fevers and inflammatory symptoms within hours of the injection. Two patients had a fever relapse first day and second day after treatment. Leukocyte count and CRP declined 48 h after anakinra.39 Adult-onset S ll’s disease (AOSD) and Systemic-onset juvenile idiopathic arthri s (SoJIA) Adult-onset Still’s disease (AOSD) and Systemic-onset juvenile idiopathic arthritis (SoJIA) diseases are characterized by high spiking fevers, joint pain, and typical nonpruritic salmon-coloured rash during high fevers. Patients have neutrophilia, high CRP, elevated serum ferritin levels, and elevated liver enzymes. AOSD and SoJIA belong to the same disease spectrum and are polygenic autoinflammatory disorders.4,40,41 In the pathogenesis of AOSD, IL-1 family, IL-6 and tumor necrosis factor alpha (TNF-α) are involved.40 Many retrospective case series have reported the efficacy of anakinra in AOSD.41-47 In one prospective, randomized, open-label trial, anakinra is reported to be efficient in

the rapid relief of systemic symptoms. Daily anakinra 100 mg subcutaneous injections was applied to 12 patients who achieved remission. At week 4, 6 of 12 patients, at week 8, 7 of 12 patients, at week 24, 6 of 12 patients were reported to be in remission. By week 24 mean prednisolone doses had been reduced in three patients on anakinra. Its effects on articular symptoms is less frequently reported. In almost all cases, inflammatory markers reached normal within about 2 weeks. But relapses occurred frequently as soon as the treatment was stopped. This study has demonstrated that more patients on anakinra than on a disease-modifying antirheummatic drugs (DMARD) have achieved disease remission.47 In a meta-analysis of  anakinra in AOSD, the overall remission rate and complete remission rate were reported to be 81.66% and 66.75%, respectively. Compared to controls, anakinra was associated with a significant remission in AoSD, there were also significant reductions of the dosage of corticosteroids. Clinical and laboratory parameters were all improved, and anakinra was well tolerated in patients with AoSD.41 In a case series, 7 patient with SoJIA treated with anakinra at the dose of 2 mg/kg daily showed persistent remission in 6/7 patients without the use of corticosteroids during the 3 week follow up. Fever and exanthema also had been reported to disappear within 24 hours, while arthritis within 3 days. One child had a recurrence of arthritis without fever or exanthema after 2 weeks and laboratory parameters were all improved.48 Long term follow up with anakinra at the dose of 1 mg/ kg/day in 34 patients with SoJIA had been reported. The mean follow-up was 4.02 year and 13 patients were reported to be complete responders, while 5 patients were partial responders and 16 were non-responders. But in the group of responders during the follow ups, 11/13 displayed at least one relapse, 4 patients withdrawn anakinra without relapses after a mean of 3 years of treatment and 7 are in remission using anakinra only.49 A retrospective study including 22 SoJIA patients treated with anakinra at a dose of 1-3 mg/kg/day were followed up 11 to 56 months. In the first 3 months fever and rash were resolved in 82% of the patients while active arthritis persisted at 3 months in 22% of patients, at 6 months in 14%, and at 12 months in 22%. Seventy percent of the patients receiving anakinra as first-line therapy, attained a complete response.20 A case series with 9 SoJIA patients who had active disease treated with anakinra with daily dosing of 2 mg/kg, up to 100 mg, patients were followed up every 2 months. All patients responded to therapy and became afebrile within the first week and during the follow up to 2- 12 months. Arthritis score completely decreased in 6/8 patients. And intravenous and oral, prednisolon reported to be discontinued or tapered in most

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IMMUNMODULATORS IN DERMATOLOGY of the patients. Complete remission was observed in seven out of nine patients while a partial response was obtained in the other two patients. Anakinra seems to be an effective treatment for the patients to prevent development of severe, deforming arthritis and prolonged treatment with corticosteroids.50 Synovi s, acne, pustulosis, hyperostosis and ostei s (SAPHO) syndrome and chronic recurrent mul focal osteomyeli s (CRMO) Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome and chronic recurrent multifocal osteomyelitis (CRMO) are autoinflammatory disorders which be might pathogenically be related conditions. While SAPHO syndrome usually is seen in adolescents or adults, CRMO is seen in school-aged children with multifocal, sterile, osteolytic bone lesions, with or without fever. IL-1 blockers have been reported to be at least partially effective in both conditions.4 Short-term results of an open study, anakinra administered at a dose of 100 mg/day in six patients with SAPHO syndrome.51 And one case of SAPHO in a 47year-old woman was successfully treated with anakinra with cutaneous, systemic, bone and synovial response after 2 months.52 Although a case of pediatric patient with CRMO showed a partial and nonsustained response to anakinra,4 two other cases with chronic recurrent multifocal osteomyelit who is refractory to steroids, sulfasalazin, pamidronate, NSAIDs; had been reported. And all symptoms resolved within a few weeks of anakinra therapy.51

4. Other Dermatological Diseases Hidradeni s Suppura va Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that presents with painful and suppurating lesions which are resistant to current treatments. There is an open-label study reported that six patients with moderate to severe hidradenitis suppurativa treated with daily anakinra 100 mg injections had been reported. Eight weeks of treatment applied to all the patients and after 8 weeks of follow up, an improvement was observed in modified Sartorius score, physicians global assessment, and all patient’s subjective measures. Anakinra reported to be well tolerated. Statistically significant decrease in disease activity of both objective and subjective measures had been reported. But disease activity increased rapidly when therapy was off.53 A dose of 200 mg once daily subcutaneous application was found effective in a patient with HS. Within 1 month reduction in pain, suppuration, and malodor was observed during the following months, and decrease in disease activity was reported. After 3 months of therapy a decrease in the dermatology life

quality index score and after 1 year disease remission occured.8 A patient with therapy resistant HS who had comorbid psoriatic arthritis treated with anakinra at a dose of 100 mg daily for 5 months was reported. During the treatment, physicians global assessment and arthritis of the patient was reported to improve(54). In another report, failure of anakinra in two cases of severe hidradenitis suppurativa with the treatment dose of 100mg daily was observed. In the first case who had pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH syndrome) no changes were observed in the scores (DLQI, PGA) after 12 weeks of treatment. Worsening of the symptoms had been reported in the second case at the second month of treatment.55 While in a patient with PASH syndrome 75% improvement in the size and depth of pyoderma gangrenosum was achieved, another case report provided minimal improvement in overlapping pyoderma gangrenosum and HS.8,56 Psoriasis Deficiency of IL-36 receptor antagonist, DITRA is an autoinflammatory disease which is caused of mutation in the IL36RN gene. And it is characterized by sudden onset, repeated flares of generalized pustular psoriasis(GPP), high fever, asthenia, and systemic inflammation.57,58 IL-36 receptor antagonist which has been recently found to be also mutated in patients with generalized pustular psoriasis, palmoplantar pustular psoriasis (PPPP) and acrodermatitis continua of Hallopeau (ACH).58,59 The interleukin-36-receptor antagonist (IL-36Ra) is an anti-inflammatory cytokine which reduces the activity of IL-36α, IL-36β, and IL-36γ. These tree cytokines belong to the interleukin- 1 family.58 And high production of IL-βhas been reported in several psoriatic conditions.59 A patient diagnosed with DITRA at the 6th month of life responded to anakinra treatment at the dose of 2 mg/kg/day without any improvement of skin lesions. When the dose was increased to 4 mg/kg/day, skin involvement responded at the first week of treatment and no flares were reported at 2 months of follow-up.58 Variable responses are avaliable in cases with GPP carrying mutations of the IL-36 receptor antagonist or without mutation.58-60 A case of GPP with IL36RN mutations was treated with subcutaneous anakinra 100 mg daily responded 9 days after the treatment and was nearly clear for 6 weeks. But after 12 weeks of anakinra treatment, recurrence of the palmoplantar pustules with hiperkeratosis and plaques on trunk and legs had been reported.60 And there is also a GPP case previously published, suggest aclinical response to anakinra without deficiency of IL-36 receptor antagonist.59,61

CHAPTER 6: ANAKINRA Palmoplantar pustular psoriasis (PPPP) is a chronic inflammatory skin disease which is usually resistant to available therapeutics. Two patients with severe palmoplantar pustular psoriasis refractory to available antipsoriatic therapies were treated with anakinra 100 mg daily. In both patients there were no mutation of IL-36 receptor antagonist gene detected. In the first patient with the treatment, Psoriasis Area and Severity Index and DLQI showed a significant decrease at week 6, however a relapse of palmar pustular lesions after 3 months of anakinra therapy was observed and treatment was withdrawn. Other case with therapy resistant PPPP was treated with anakinra at the daily dose of 100 mg showed partial regression of erythema, absence of pustules and desquamation after 1 month of therapy, but the treatment was interrupted at the second month of the treatment due to a fever with unknown ethiology. Clinical response persisted after 1 month after anakinra treatment was withdrawn.59 The acropustular form of psoriasis is called acrodermatitis continua of Hallopeau (ACH) and case reports are avaliable with variable response to anakinra treatment in the literature.57 An ACH unresponsive to tumour necrosis factor blocker and unresponsive to anakinra 100 mg daily for 7 weeks with no clinical improvement that responded to ustekinumab and acitretin was reported.57 Another case report is available describing the efficacy of anakinra which provide quick response of the lesions.62 There is also a case of new onset plaque psoriasis in a patient with RA following anakinra therapy. Nine months after the 100 mg daily anakinra treatment, patient presented with typical plaque psoriasis on the elbows. With discontinuation of treatment, lesions regress significantly with topical treatments.63 There are also anecdotal case reports published showing efficicacy of anakinra in patients with neutrophilic dermatosis such as sweet syndrome, neutrophilic panniculitis and also a case of lammeler ichtiyosis.64-66

5. Metabolic disease with proposed IL-1 pathology Metabolic substrates like monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome which leads to IL-1β production. Anakinra has been showed to be effective in a group of metabolic conditions which are gout, metabolic syndrome, diabetes mellitus, and coronary artery disease, stroke, and myocardial infarction.4,5 Adverse effects Some adverse reactions to anakinra are reported. The most common reported treatment related side effect with anakinra is an injection site reaction (ISR) within thefirst month of therapy. Injection site reactions are 

grouped as acute and delayed types.14 In a review of five clinical trials with the doses of of 50–150 mg/day, the reported rates of ISR were 71% for the anakinra-treated groups while it was 28% for placebo group. The median duration of symptoms were reported 14–28 days.67 Acute reactions are stinging and burning feeling, while delayed reactions present with erythema, ecchymosis, inflammation and pain.14 Due to short half-life of anakinra, daily injections are required. To avoid acute ISRs it is advised to warm the syringe to room temperature before the injection. And application of a cold pack to injection side is also recommended 2-3 minutes before the injection and after the injection. Topical hydrocortisone or anti-histamine creams can reduce the delayed type reactions and recall reactions. Patients who are treated with oral steroids have less reactions than who does not. Patients who do not have an ISR within 4 weeks are less likely to have any ISR. Informing about the ISR may cause patients to push up the treatment because ISR will disappear over time and they are transient in nature.14 Headache, vomiting, arthralgia, pyrexia, and upper respiratory tract infections, sinusitis, ear infections, nasopharyngitis and rash are also reported.12 Infectious adverse effects are more frequently reported in the patients younger than 2 years.14 Although viral-type upper airway infections are more compared to placebo-treated patients,3,5,19 there is no increase of opportunistic infections and malignancies.5,68 But combination therapies with the tumor necrosis factor blocking agents can increase the incidence of infections up to 7%.3 In a large placebo-controlled safety study of anakinra reported that although it was not statistically significant serious infections occurred more frequently in the anakinra group than in the placebo group. The infections observed consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections.12,68 Commonly reported organisms are Streptococcus pneumoniae in pneumonia and Staphylococcus aureus in bone or joint infections. But all serious infections had resolved when resumed therapy with anakinra once and had no further problems with serious infections. On the other hand no opportunistic infections such as tuberculosis, histoplasmosis, listeriosis, and aspergillosis were reported.68 There is a little or absent risk of tuberculosis infection in patients treated with anti-IL-1 agents because the cytokine does not seem to play a main role in mycobacterium tuberculosis control; but reactivation of pulmonary mycobacterium tuberculosis infection in a patient who is treated with anakinra for rheumatoid arthritis has been reported.5,68Patients should be screened for latent tuberculosis prior to initiating anakinra.12 Anakinra can have a mild to modest reduction in circulating neutrophils. It can rarely reduce neutrophils

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IMMUNMODULATORS IN DERMATOLOGY below normal range. It is reported that intra-venous infusions of anakinra in healthy subjects at dose of 10 mg/kg did not reduce peripheral neutrophil counts. And neutropenia is not persistant, neutrophils rapidly rise with the cessation of treatment.5 A higher rate of serious infections and two percent of neutropenia had been observed in patients treated with anakinra and etanercept combination therapy; therefore combination of anakinra with TNF blocking agents is not recommended.15 And anakinra treatment must not be initiated in patients with neutropenia (ANC < 1.5 x 109/l). And neutrophil counts should be assessed prior to initiating anakinra treatment, and while receiving anakinra, monthly during the first 6 months of treatment and quarterly thereafter.12

CINCA. Curr Rheumatol Rep. 2011;13(2):123-31. 4.

Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014; 65:22344.

5.

Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol.2013;25(6):469-84.

6.

Chang Z, Spong CY, Jesus AA et al. Anakinra use during pregnancy in patients with cryopyrin-associated periodic syndromes (CAPS). Arthritis Rheumatol. 2014;66(11):3227-32.

7.

Kuemmerle-Deschner JB, Wittkowski H, Tyrrell PN et al. Treatment of Muckie-Wells syndrome: analysis of two IL1-blocking regimens. Arthritis Res Ther. 2013;15(3):R64.

8.

Zarchi K, Dufour DN, Jemec GB. Successful treatment of severe hidradenitis suppurativa with anakinra. JAMA Dermatol. 2013;149(10):1192-4.

9.

Cohen PR, Kurzrock R. Anakinra-responsive lichen planus in a woman with Erdheim- Chester disease: a therapeutic enigma. Dermatol Online J. 2014;20(1):21241.

10.

Volz T, Wolbing F, Fischer J et al. Dermal interleukin-1 expression and effective and long-lasting therapy with interleukin- 1 receptor antagonist anakinra in Schnitzler syndrome. Acta Derm Venereol. 2012;92(4):393-4.

Anakinra also does not seem to cause hepatic toxicity, serious hematologic events, or serious cardiovascular events.68

11.

Paccaud Y, Berthet G, Von Scheven-Gete A et al. Neonatal treatment of CINCA syndrome. Pediatr Rheumatol Online J. 2014;12:52.

No data are available of the effects of live vaccination or on the secondary transmission of infection by live vaccines in patients receiving anakinra. So live vaccines should not be given concurrently with anakinra treatment.12

12.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product information/ human/000363/ WC500042 310. pdf

13.

Kone-Paut I, Piram M. Targeting interleukin-13 in CAPS (cryopyrin- associated periodic) syndromes: what did we learn? Autoimmun Rev. 2012;12(1):77-80.

Although no treatment-related risk of malignancy had been reported, four malignancies were diagnosed in the anakinra treatment group. They are melanoma, diffuse metastatic melanoma, adenocarcinoma of the cecum, uterine carcinoma, and basal cell carcinoma. Anakinra does not appear to increase the risk of death or malignancy in the broad patient group(68). But the use of anakinra in patients with pre-existing malignancy is not recommended.12

14.

Kaiser C, Knight A, Nordstrom D et al. Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations. Rheumatol int. 2012;32(2):295-9.

15.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf

16.

Shinkai K, McCalmont TH, Leslie KS. Cryopyrin- associated periodic syndromes and autoinflammation. Clin Exp Dermatol. 2008;33(1):1-9.

17.

Hedrich CM, Bruck N, Paul D et al. “Mutation negative” familial cold autoinflammatory syndrome (FCAS) in an 8-year- old boy: clinical course and functional studies. Rheumatol lnt. 2012;32(9):2629-36.

18.

Başaran Ö, Uncu N, Çelikel BA et al. Interleukin-1 targeting treatment in familial Mediterranean fever: an experience of pediatric patients. Mod Rheumatol. 2014; 22:1-4.

19.

Ozçakar ZB, Ozdel S, Yilmaz S et al. Anti-IL-1 treatment in familial Mediterranean fever and related amyloidosis. Clin Rheumatol. 2014 Sep 13.

20.

I Marvillet, I Calvo Penades, B Lopez Montesinos, A Marco Puche. Anakinra treatment in patients with systemic-onset juvenil idiopathic arthritis: “The Valencia Experience”. Pediatr Rheumatol Online J. 2011;9(1): 71.

21.

Kostjukovits S, Kalliokoski L, Antila K, Korppi M. Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. Eur J Pediatr. 2015 Feb 27.

Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported infruequently and reactions were reported as maculopapular or urticarial rashes.1,41 Anakinra is contraindicated in patients with known hypersensitivity to E. coli-derived proteins or to any components of the product.15

Development of anakinra anti-drug antibodies had also been reported. This response was transient and it has not clinically significant effects on pharmacokinetics, adverse effects, efficacy, or safety.33,68

REFERENCES 1.

2.

3.

Desai D, Goldbach-Mansky R, Milner JD et al. Anaphylactic reaction to anakinra in a rheumatoid arthritis patient intolerant to multiple nonbiologic and biologic disease- modifying antirheumatic drugs. Ann Pharmacother. 2009; 43(5):967-72. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Weils syndrome and response to anakinra. Arthritis Rheum. 2004;50(2):607-12. Goldbach-Mansky R. Current status of understanding the pathogenesis and management of patients with NOMID/

CHAPTER 6: ANAKINRA 22.

Schnellbacher C, Ciocca G, Menendez R et al. Deficiency of interleukin-1 receptor antagonist responsive to anakinra. Pediatr Dermatol. 2013;30(6):758-60.

40.

Jamilloux Y, Gerfaud-Valentin M, Henry T, Seve P. Treatment of adult on set Still’s disease: a review. TherClin Risk Manag. 2014; 22;11: 33-43.

23.

Aksentijevich I, Masters S, Ferguson P, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N EngI JMed. 2009;360:24262437.

41.

Hong D, Yang Z, Han S et al. Interleukin 1 inhibition with anakinra in adult onset Still disease: a meta-analysis of its efficacy and safety. Drug Des Devel Ther. 2014;25: 2345-57.

24.

Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N EngI JMed. 2009; 360:2438-2444.

42.

25.

Herlin T, Fiirgaard B, Bjerre M et al. Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis 2013;72:410-3.

Lequerre T, Quartier P, Rosellini D, et al. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-on set juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis. 2008;67(3):302-308.

43.

26.

Brenner M, Ruzicka T, Plewig G et al. Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderm a gangrenosum and acne) syndrome with the recombinant human interleukin- 1 receptor antagonist anakinra. Br J Dermatol. 2009;161(5):1199-201.

Vasques Godinho FM, Parreira Santos MJ, Canas da Silva J. Refractory adult onset Still’s disease successfully treated with anakinra. Ann Rheum Dis. 2005;64(4):647-648. 47.

44.

Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello CA. Rapid responses to anakinra in patients with refractory adult onset Still’s disease. Arthritis Rheum. 2005;52(6):1794- 1803.

45.

Kalliolias GD, Georgiou PE, Antonopoulos IA, Andonopoulos AP, Liossis SN. Anakinra treatment in patients with adult onset Still’s disease is fast, effective, safe and steroid sparing: experience from an uncontrolled trial. Ann Rheum Dis. 2007;66(6):842-843 4

27.

Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens J J. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology(Oxford). 2005;44(3):406-8.

28.

Naik HB, Cowen EW. Autoinflammatory pustular neutrophilic diseases. Dermatol Clin. 2013; 31(3): 405-25.

29.

Rose CD, Martin TM, Wouters CH. Blau syndrome revisited. Curr. Opin. Rheumatol. 2011; 23: 411-18.

30.

Arostegui Jl, Arnal C, Merino R et al. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum. 2007;56(11):3805-13.

46.

Kotter I, Wacker A, Koch S, et al. Anakinra in patients with treatment resistant adult- onset Still’s disease: four case reports with serial cytokine measurements and a review of the literature. Semin Arthritis Rheum. 2007;37(3):189-197. 50.

31.

Martin TM, Zhang Z, Kurz P et al. The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum. 2009;60(2):611-8.

47.

32.

Caorsi R, Federici S, Gattorno M. Biologic drugs in autoinflammatory syndromes. Autoimmun Rev. 2012;12(1):816.

Nordstrom D, Knight A, Luukkainen R, et al. Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still’s disease. An open, randomized, multicenter study. J Rheumatol. 2012;39(10):2008-2011.

48.

33.

Neel A, Henry B, Barbarot S et al. Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler’s syndrome: a French multicenter study. Autoimmun Rev. 2014;13(10):1035-4.

NM Wulffraat, W de Jager, B Prakken, W Kuis. Early effects of Anakinra in corticosteroid naive SOJIA patients. Pediatr Rheumatol Online J. 2008; 6(1): 29.

49.

34.

Szturz P, Sediva A, Zurek M et al. Anakinra treatment in Schnitzler syndrome results ofthe first retrospective multicenter study in six patients from the Czech Republic. Klin Onkol. 2014;27(2):111-26.

Gattorno M, Naselli A, Accogli A et al. Long-term follow-up of systemic onset juvenile idiopathic arthritis patients treated with Anakinra. Pediatr Rheumatol Online J. 2011; 9(1): 158.

50.

35.

Cantarini L, Lopalco G, Caso F et al. Effectiveness and tuberculosis related safety profile of interleukin-1 blocking agents in the management of Behcet’s disease. Autoimmun Rev. 2015;14(1):1-9.

Pascual V, Ailantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL- 1 blockade. J ExpMed. 2005;201(9):147986.

51.

Wendling D, Prati C, Aubin F. Anakinra treatment of SAPHO syndrome: short term results of an open study. Ann Rheum Dis. 2012;71(6):1098-100.

52.

Colina M, Pizzirani C, Khodeir M et al. Dysregulation of P2X7 receptor inflammasome axis in SAPHO syndrome: successful treatment with anakinra. Rheumatology (Oxford). 2010;49(7):1416-8.

53.

Leslie KS, Tripathi SV, Nguyen TV, Pauli M, Rosenblum MD. An open-label study of anakinra for the treatment of moderate to severe hidradenitis suppurativa. J Am Acad Dermatol. 2014;70(2):243-51.

54.

van der Zee HH, Prens EP. Failure of anti-interleukin- 1 therapy in severe hidradenitis suppurativa: a case report. Dermatology. 2013;226(2):97-10.

55.

Menis D, Maroñas-Jiménez L, Delgado-Marquez AM, Postigo-Llorente C, Vanaclocha-Sebastián F. Two

36.

Botsios C, Sfriso P, Furlan A, Punzi L, Dinarello CA. Resistant Behcet disease responsive to anakinra. Ann lntern Med 2008;149:284-6.

37.

Bilginer Y, Ayaz NA, Ozen S. Anti-IL-1 treatment for secondary amyloidosis in an adolescent with FMF and Behcet’s disease. Clin Rheumatol. 2010;29(2):209-10.

38.

Cantarini L, Vitale A, Scalini P et al. Anakinra treatment in drug resistant Behcet’s disease: a case series. Clin Rheumatol. 2013 Dec 5.

39.

Stojanov S, Lapidus S, Chitkara P et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th 1 activation responsive to IL-1 blockade. Proc Natl Acad Sci USA. 2011;26;108(17):7148-53.

41

42

IMMUNMODULATORS IN DERMATOLOGY cases of severe hidradenitis suppurativa with failure of anakinra therapy. Br J Dermatol. 2015;172(3):810-1. 56.

Braun-Falco M, Kovnerystyy O, Lohse P, RuzickaT. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) – a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol 2012;66: 409-415.

57.

Saunier J, Debarbieux S, JullienD et al. Acrodermatitis continua of hallopeau treated successfully with ustekinumab and acitretin after failure of tumour necrosis factor blockade and anakinra. Dermatology. 2015; 230(2):97-100.

58.

Rossi-Semerano L, Piram M, Chiaverini C et al.First clinical description of an infant with interleukin-36 receptor antagonist deficiency successfully treated with anakinra. Pediatrics. 2013;132(4):e1043-7.

59.

Tauber M, Viguier M, Alimova E et al. Partial clinical response to anakinra in severe palmoplantar pustular psoriasis. Br J Dermatol. 2014;171(3):646-9.

60.

Huffmeier U, Watzold M, Mohr J, Schon MP, Mossner R. Successful therapy with anakinra ina patient with generalized pustular psoriasis carrying IL36RN mutations. Br J Dermatol. 2014;170(1):202-4.

61.

Viguier M, Guigue P, Pages C, Smahi A, Bachelez H. Successful treatment of generalized pustular psoriasis with the interleukin-1- receptor antagonist Anakinra: lack of correlation with IL1RN mutations. Ann lntern Med. 2010;6;153(1):66-7.

62.

Lutz V, Lipsker D.Acitretin- and tumor necrosis factor inhibitor-resistant acrodermatitis continua of hallopeau responsive to the interleukin 1 receptor antagonist anakinra. Arch Dermatol. 2012;148(3):297-9.

63.

Gonzalez-Lopez MA, Martfnez-Taboada VM, Gonzalez-Vela MC, Fernandez-Llaca H, Val-Bernal JF. New-onset psoriasis following treatment with the interleukin-1 receptor antagonist anakinra. Br J Dermatol. 2008;158(5):1146-8.

64.

Kluger N, Gil-Bistes D, Guillot B, Bessis D. Efficacy of anti-interleukin- 1 receptor antagonist anakinra (Kineret®) in a case of refractory Sweet’s syndrome. Dermatology. 2011;222(2):123-7.

65.

Lipsker D, Perrigouard C, Foubert A, Cribier B.Anakinra for difficuIt-to- treat neutrophilic panniculitis: IL-1 blockade as a promising treatment option for neutrophil-mediated inflammatory skin disease. Dermatology. 2010;220(3):264-7.

66.

O’Shaughnessy RF, Choudhary I, Harper Jl. lnterleukin- 1 alpha blockade prevents hyperkeratosis in an in vitro model of lamellar ichthyosis. Hum Mol Genet. 2010;19(13):2594-605.

67.

Mertens M, Singh JA. Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol. 2009;36(6):1118-25

68.

Fleischmann RM, Schechtman J, Bennett R et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHulL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum. 2003;48(4):927-34.

CHAPTER 7

ANTIMALARIAL TREATMENT IN DERMATOLOGY Mehmet Demirel, MD, Ufuk Kavuzlu, MD

INTRODUCTION Antimalarial drugs have been known since long time. Firstly quinine is founded as natural antimalarial.1 It extracted from South American cinchona bark tree.1 It was used for protect healty persons against to malaria. In 1894, Payne showed beneficial effects of antimalarials on the lupus erythematosus patients.2 Later, synthetic antimalarials are produced such as quinacrine( in 1930), chloroquine (in 1934), hydroxychloroquine (in 1955).3 Page succesfully treated 18 cutaneus lupus patiens with quinacrine (QC) although this patients were unresponsible to quinine treatment.4 But then chloroquine (CQ) and hydroxychloroquine (HCQ) became most appropriate drugs for the cutaneus lupus treatment.5 Because they are well-tolerated and more effective than other antimalarials on lupus patients.5 Usage of antimalarial drugs in dermatology is not limited only lupus; they are alse used various skin disease.

PHARMACOKINETICS CQ and HCQ are absorbed in gastrointestinal system about %90 to %100.6-7 They reach stable plasma levels after 4-6 weeks.6-7 CQ binds plasma proteins and this

Chloroquine

CI 7 6

8

5

1 N

2 3

4 HN

N

CH3

Hydrohloroquine

CI 7

8

6 5

1 N

4 HN

CH3

MECHANISM OF ACTION Antimalarial drugs have many different mechanisms. So they have very various effects on metabolism of patients. Some of them are antiinflamatory, immunomodulatory, antiproliferative and photoprotective effects.10 Antimalarials can cross to plasma membran easily and enter the asidic vesiculs, then start to accumulate in there(especially lisosoms).10 PH of the lisosom increases; thus, presentation of antigens to T-lymphocytes disrupts.31-12 Releasing of cytokines is blocked on this pathway and an anantiinflammatory effect occurs.31-12 On the other side, on a similar mechanism; when PH increases in lisosoms, exogen peptides show more affinity to MHC molecules than autoantigen peptides.1314 For this reason, antimalarials can play a role as a immunomodulators without causing any immunosupression.13-14 Other mechanism of antimalarials explained on table 1-2. TABLE 1. MECHANISMS OF ANTIMALARIAL DRUGS29-30-31 1.Inhibition of cytokine release: interleukin (IL) 1, IL-2, IL6,IL-18, tumor necrosis factor α , interferon γ 2.Inhibition of antigen presentation

2

3.Inhibition of the activity of cytotoxic CD8+ T lymphocytes and self-reactive CD4+ lymphocytes

3

OH N

CH3 CI

CH3

proteins accumulate tissues such as liver, kidneys, spleen,lungs,blood cells.6-7 On the other hand, it is also accumulate some tissues which include melanin.8 So it’s concentrations can be high in skin and retinal cells.8 CQ has a long half-life. It can stay in skin about 6-7 months after discontinuance of treatment.8 CQ and HCQ can pass to placenta and can join to milk as little amount.9

CH3

4.Regulation of apoptosis 5.Inhibition of stimulation of TLR (toll-like receptors) 9 that join in immune response 6.Decreasing activity of natural killer cells

N

7.Inhibition of lysosome protease activity

Quinacrine O CH3 HN H3C

N

Figure 1. Antimalarial’s Chemical Strustures.

CH3 CH3

8.Reduce in membrane receptor concentrations: reduced response to mitogenic stimuli 9.Inhibition of polymorphonuclear chemotaxis 10.Superoxide radical block

43

44

IMMUNMODULATORS IN DERMATOLOGY

TABLE 2. EFFECTS AND PATHWAYS OF CQ AND HCQ29-30-31 EFFECT

PATHWAY

RESULT

IMMUNOMODULATORY

Binding to DNA, competitive inhibition of anti-DNA antibodies Inhibits autoantigen processing

Diminished class II antigen presentation

Decreased cytokine production Decreased stimulation of autoreactive CD4+ T cells ANTI-INFLAMMATORY

Inhibition of Toll-like receptor 9 signal pathway

Diminished antigen presentation and immune stimulation

Inhibition of mast cells

Diminished leukotriene synthesis and histamine release

Inhibition of phospholipase A2

Diminished arachidonic acid release and prostaglandin synthesis; reduced bradykinin effect

Inhibition of formation of IL1beta, TNF alpha

mRNA and protein level

ANTI-INFECTIOUS

Antimicrobial effects on HIV, SARS, coronavirus, influenza viruses

UV ABSORPTION

Inhibition of UV-induced inflammatory reactions

Possibly due to interaction with UV-B induced C-jun transcription

COAGULATION

Inhibition of thrombocyte aggregation

Without prolonging time to coagulation

ANTIPROLIFERATIVE

Interaction with protein synthesis

Inhibition of DNA/RNA biosynthesis

METABOLIC

Decreased cholesterol, triglyceride, LDL levels Complex formation with porphyrins

Increased excretion

Decreasing of lipid levels effects

DOSAGE

Usage of antimalarials are associated with decreasing to serum total cholesterol, low density lipoprotein cholesterol and triglycerides levels.15

Dosage is may arranged according to patient’s body weight.26-27-28-29 Dosage Formula for men: (patient’s height [in cm]-100)-10%; And for women: (patient’s height [in cm]-100)-15%.26-27-28-29 Because of irreversible retinopathy that is the most undesirable complication of antimalarial treatment. 26-27-28-29 It should give attention for dosage arrangement.26-27-28-29

Improve glucose Antimalarials improve glucose tolerance because of they decreasing insulin degradation.16 it can be observed that usage of antimalarial therapy can cause reducing HbA1c levels and decreasing insulin resistance.17-18-19

An trombo c effects Antimalarials inhibit platelet aggregation, and also can reduce plasma viscosity.20-21-22 They Also reduce thromboxane A2 levels by the agency of deactivated phospholipase A2 and prostaglandins.23

Bone mineral density effects According to two studies about effect of antimalarial drugs it is observed that this drugs can be benefical on bone mineral density.24,25

CLINICAL USAGE IN DERMATOLOGY Lupus erythematosus Antimalarials are good option for treatment of lupus erythematosus(LE).32 According to a study about usage of HCQ for treatment of discoid LE; HCQ is found more effectice and usefull than plasebo.32 Antimalarials give us good results for spesific skin lesions of acute, subacute, chronic LE.33-34-35 Antimalarial treatment also heals other symptoms such as myalgias, serositis, fatigue, arthralgia and mucous membrane ulceration of systemic LE(SLE) patients.36 In addition it can heal other nonspesific skin disorders of SLE such as oral mucosal ulcerations, calcifying lupus panniculitis and calcinosis cutis.37 Unfortunately hypertropic plaque forms and verrucous forms more resistant than other

CHAPTER 7: ANTIMALARIAL TREATMENT IN DERMATOLOGY

TABLE 3. SOME INDICATIONS FOR USE OF ANTIMALARIALS IN DERMATOLOGY30-31-39 → Lupus erythematosus → Porphyria cutanea tarda → Chronic ulcerative stomatitis

Antimalarials primarily improve cutaneous lesions however they can improve muscle problems when they combinated with oral corticosteroids.48 When patient with dermatomiyositis do not respond to corticosteroids or HQ monotherapy it can be given HQ with QC as a combination treatment.49

→ Primary Sjögren syndrome → Skin manifestation of dermatomyositis → Polymorphous light eruption

Antimalarials are not first line therapy in sarcoidosis.51-52-53-54 Topical or systemic corticosteroids are first option.51-52-53-54 Second option is antimalarials agents which are effective in sacoidosis and not only skin lesions, also effective for pulmoner involvement.51-52-53-54 Antimalarials can be prefered in sarcoidosis if; chronic disfiguring skin lesions are occured or steroid therapy is contraindicated for patient.29

→ Atopic dermatitis → Sarcoidosis (skin) → Granuloma anulare → Oral lichen planus → Urticarial vasculitis → Lichen sclerosus et atrophicus → Actinic lichen planus

Granuloma anulare

→ Actinic reticuloid → Necrobiosis lipoidica → Lichen planopilaris → Eosinophilic fasciitis

forms to antimalarial therapy.35 If there is nonresponsive patient to an antimalarial, another antimalarial drug could be given or it could be combinated with another antimalarial. 38-39

Porphyria cutanea tarda Antimalarials can be alternative selection when patient don’t response to first line treatment of porphyria cutanea tarda(PCT).41-42-43 Antimalarials inhibit porphyrins synthesis. In addition they reduce hepatic and urinary excretions of porphyrins.30 Some research showed that doing a few phelebotomies before antimalarial therapy can be give us good results for PCT treatment.40-44

Chronic ulcera ve stoma

Sarcoidosis

s

Chronic ulcerative stomatitis(CUS) is a rare disease.29,45 It generally occurs in older womens painful ulcerations are occured in oral mucosa.29,45 Its pathologic and clinical findings are similar with oral lichen planus disease in addition CUS has immunological characteristic parameters .29,45 CUS is refractory to systemic and topical corticosteroids there is an effectice response to antimalarial agents.29,30,45 So antimalarials is first line therapy for CUS.29,30,45

Dermatomyosi s Systemic corticosteroids and other immunsuppresive drugs are effective especially muscle involvement in dermatomyositis.46-47 But unfortunately skin lesions can not healed with this agents.46-47 Using HQ 200-400 mg/ daily can improve skin lesions of dermatomyositis.46-47

There are a few case reports about granuloma anulare treatment with antimalarials.55-56-57 According to one of this study, children patients with granuloma annulare were treated with antimalarial drugs and 4-6 weeks later all of skin lesions were completely improved.55-56-57 This drugs can be try when patient does not respond to topical therapy.30

Polymorphous light erup ons Antimalarials are not first line treatment for polymorphous light eruptions(PLE). In two different study it is showed that increasing tolerance to sunlight and reducing in rash.58-59 Antimalarials can be administered when patient do not respond to photoprotection, topical corticosteroids.30-31

SIDE EFFECTS Ocular effects Antimalarials can cause some reversibl and irreversibl side effects.39-60 Retinopathy is worst side effect of antimalarials and this patology can cause irreversibl vision loss.39-60 Early stage of rethinopathy is named premaculopathy. This antitie is characterized by loss of visual field.62 An ophtalmological examination is recommended before treatment.61 Corneal deposites is the another side effect, this usually can not do any symptoms or can do blurred vision areas, halos of colors around lights.39-60 The conditions is reversibl after discontinuance of drug .29 If corneal deposite is detected, it should be awake and should do a closer follow-up to patient for discontinance of treatment is unnecessary.60 Risk factors for retinopathy of treatment with antimalarial agents:39 •

HCQ > 400 mg/d (> 6.5 mg/kg of ideal body weight in small individuals)

45

46

IMMUNMODULATORS IN DERMATOLOGY • • • • •

CQ > 250 mg/d (> 3 mg/kg of ideal body weight in small individuals) Cumulative dose: * CQ: > 460 gHCQ: > 1000 g History of retinopathy or maculopathy Renal or hepatic dysfunction Age > 60 years

Other reversibl ocular side effects are accomodation problems and diplopia.39-63 This effect usually has been observed with CQ.39-63 These symptoms clear spontaneously or with reducing dosage.39-63

Cutaneous effects Very different cutaneous side effects may occur with antimalarial treatment.31,64,65,66 Hyperpigmentation can be observed.31,64,65,66 Darker pigmentation especially associated with QC.31,64,65,66 In generally pigmentation regions are determined as face, forearms, shines, hardpalate.31,64,65,66 Another effects are bleaching of hair roots and transvers banding on nailbed.68,69 Some of other cutaneous side effects are exfoliative dermatitis, morbiliform eruption, hypersensitivity to sunlight,alopecia, erythema annulare centrifugum.31,3,71

Gastrointes nal effects Gastrointestinal effects are most common side effects of antimalarial drugs and they usually occur with QC therapy.31,3 Most frequently gastrointestinal effects are vomiting, nausea, diarrhea.31,3 Anorexia, abdominal distension are other events.31,3

Cardiac effects CQ/HCQ do not any cardiac problem in normal dosage range.29 However in some case reports a few adverse effects are reported such as conduction disturbances and congestive heart failure about antimalarial therapy.29

Neuromuscular effects Psychosis, depression, insomnia and nightmares are psychiatric disorders which are associated with antimalarials.39,72,73 But this disorders usually occurs in very high doses.39,72,73 Seizure is another serious side effects.39,74 In addition, antimalarials can cause myopathy which mainly affects proximal muscles.75

DRUG DRUG INTERACTIONS ► Synergistic antiarrhythmic effect (CQ): -- Amiodarone ► Reduced bioavailability of: -- Ampicillin ► Increased risk of myopathy: -- Aminoglycosides -- Corticosteroids ► Reduced effect of: -- Neostigmine -- Vaccines: typhus -- Physostigmine ► Increased bioavailability of antimalarial drugs: -- Ritonavir -- Cimetidine ► Reduced bioavailability of antimalarial drugs: -- Cholestyramine -- Antacids ► Increased plasma levels of: -- Methotrexate -- β-blockers -- Digoxin -- Ciclosporin TABLE 4. CONTRAINDICATIONS29-31-11 CERTAIN CONTRAINDICATIONS History of retinopathy Concomitant bone marrow suppressive therapy Known hypersensitivity RELATIVE CONTRAINDICATIONS Renal failure Hepatic disease Glucose 6-phosphato-dehydrogenase deficiency Neuromuscular disease Hematologic disease Psoriasis?

Hematologic effects

Psoriasis

Usage of antimalarials can result hemolysis in some patients who have glucose-6-phosphate-dehydrogenase deficiency.75 Rarely they can cause agranulocytosis and aplastic anemia.30,76 Hematologic side effects improve after stopping treatment.30,31,76 But in aplastic anemia bone marrow transplantation can be necessary.31,76

There are two theory about mechanism of action in psoriasis 1) Blockage of UV.77 2) Inhibition of transglutaminase with antimalarials contains the epidermal barrier function.78

CHAPTER 7: ANTIMALARIAL TREATMENT IN DERMATOLOGY

PREGNANCY Antimalarials can cross the placenta.79 However according to a few studies about safety of these drugs in pregnancy, it wasn’t detected increasing risk for congenital anomalies.80-83,9,85,70 According to some studies with pregnant patient who have SLE, continuing treatment is usually reasonable because when stopping drug, activity or complications of disease can more damage than usage of drug in fetus.31

CONCLUSION Antimalarials have important for every dermatologists. When comparing to other immunomodulatory drugs,antimalarials have quite safety profils. Most important subject in this therapy is arrangement of dosage. Various disease can be treated with antimalarials as safety with correct doses.

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Rekedal LR, Massarotti E, Garg R, Bhatia R, Gleeson T, Lu B, et al. Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases. Arthritis Rheum. 2010; 62: 3569-73.

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Penn SK, Kao AH, Schott LL, Elliott JR, Toledo FG, Kuller L, et al. Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol. 2010; 37: 1136-42.

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Bertrand E, Cloitre B, Ticolat R, Bile RK, Gautier C, Abiyou GO, et al. Antiaggregation action of chloroquine. Med Trop (Mars).1990; 50:143-6.

21.

Winocour PD, Kinlough-Rathbone RL, Mustard JF. The effect of phospholipase inhibitor mepacrine on platelet aggregation, the platelet release reaction and fibrinogen binding to the platelet surface. Thromb Haemost. 1981;45:257---62.

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Van Beek MJ, Piette WW. Antimalarials. Dermatol Clin. 2001; 19: 147-60.

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McChesney E, Fitch C. 4-Aminoquinolines. In: Peters W, Richards W, eds. Antimalarial drugs: II current antimalarials and new drug developments. Berlin: Springer-Verlag, 1984: 3–60.

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CHAPTER 8

APREMILAST IN DERMATOLOGY Ulas Güvenc, MD, Belma Türsen, MD, Ümit Türsen, MD Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), like apremilast, seems to have an improved therapeutic index. Apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNF-α). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. We discuss apremilast on skin inflammatory responses and also their future role in clinical practice.1-5

Mechanism of ac on The clinical symptoms of chronic inflammatory diseases are determined by a number of different inflammatory mediators. In psoriasis, for example, not only the well-recognized TNF is an important effector molecule, but IL-17, IL-22, INF-γ, IL-2, IL-36, CCL20, IL-8, chemokine CXCL10, IL-23, IL-1, IL-18, IL-12, VEGF, substance P, IFN-α, and many others contribute to the inflammatory response in the joint and skin. Conventional therapies have a broad range of action and inhibit, e.g. preferentially lymphocyte proliferation [cyclosporin (CsA), methotrexate] and lymphokine production (IFNγ, IL-17, IL-22, IL-2) or mainly target the hyperproliferation and abnormal differentiation of keratinocytes (dithranol, tar) or combine the latter with cytokine modifying properties (retinoids, vitamin D, glucocorticoids). Biologics currently used

in the clinic target one specific mediator which supposedly plays a key role upstream in the disease-specific cytokine network. cAMP is a key intracellular second Messenger and also cAMP signalling is activated by a variety of G protein-coupled receptor ligands. The effects of cAMP are transduced by two ubiquitously expressed intracellular cAMP receptors, protein kinase A (PKA) and exchange protein directly activated by cAMP. cAMP can also bind to cyclic nucleotide-gated ion channels in certain tissues. The local pools of cAMP expression/PKA activation are generated in distinct subcellular compartments. This allows for precisely regulated activity essential for response specificity. cAMP activates and enables PKA to phosphorylate substrate proteins. PKA activates cAMP response element binding protein which is a cAMP-responsive element possessed by several immune-related genes including IL-2, IL-6, IL-10, and TNFα. cAMP can directly or indirectly inhibit nuclear factor kappa B (NF-κB) pathway activation events. Low intracellular cAMP may thus lead to the preferential expression of proinflammatory mediators. Intracellular concentration of cAMP is determined by the activity of adenylyl cyclases on the one hand and PDE on the other. PDEs are also expressed in distinct cellular compartments and functionally coupled to individual receptors-thus providing a way to control sub compartment cAMP levels in a stimulus-specific manner. Substances which increase cAMP in monocytes/macrophages are among the most potent inhibitors of IL-12 family members including IL-12/IL-23 p40.1-3 This has been shown for cholera toxin, histamine, PGE2 and other mediators. Repression of cAMP greatly reduces the suppressive activity of human Treg. cAMP facilitates the functional activity of a transcriptional inhibitor called ICER (inducible cAMP early repressor) and this mechanism seems to be involved in the suppression of the key T cell growth factor IL-2 and other cytokines. In addition, immunosuppressive and anti-inflammatory actions of cAMP have been attributed in part to the ability of cAMP induced signals to interfere with the function of NF-κB. NF-κB activation is one of the master signalling pathways involved in inflammatory responses and a key target for anti-inflammatory drug design. Important cytokines downstream of NF-κB include TNFα, CCL20, IL-8; IL-1 family members (IL-36, IL-18, IL-1)

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IMMUNMODULATORS IN DERMATOLOGY and (in combination with a priming signal) also IL-12 family members (IL-12, IL- 23, IL-27) and many more. The cAMP system is also involved in a variety of epithelial functions and plays a role in maintenance of the skin barrier. In the keratinocyte cell line HaCat largely suppressed chemokine production (CXCL10, CCL17, and CCL22) has been described in the context of increased cAMP levels. There are several PDE families, all isoforms of which are concerned with the intracellular degradation of the phosphodiesterase bonds of cAMP and cyclic guanosine monophosphate (cGMP). PDE4, -7, and -8 degrade cAMP specifically. PDE4 is encoded by four separate genes (PDE4 A–D) and each PDE4 controls nonredundant cellular functions. Inhibition of PDE4 activity leads to elevated levels of intracellular cAMP4,5. Pentoxifylline is a competitive non-selective PDE inhibitor which raises intracellular cAMP levels to inhibit TNF and reduce inflammation. Theophylline inhibits to some extent PDE1-5, is a potent adenosine receptor antagonist and an activator of histone deacetylase 2 such that it might exert beneficial effects on lung inflammation. By increasing cAMP levels, PDE4 inhibitors show anti-inflammatory effects in almost all inflammatory cells. Numerous selective PDE4 inhibitors have been patented in the last decades and some of them have been evaluated in clinical trials for inflammatory conditions. Recent human clinical data on PDE4 inhibitors on skin diseases and in particular on psoriasis are available for apremilast. The effects of apremilast-which are in line with findings reported for increased intracellular cAMP levels—on a range of pro-inflammatory responses in a variety of cells have recently been comprehensively summarized. Unsurprisingly, all PDE4 inhibitors have the potential to reduce the expression of TNFα which is considered a key mediator in a number of inflammatory diseases.3 Crilly et al. have demonstrated that specific PDE4 inhibitors dose-dependently down regulate the release of TNFα and other cytokines including CCL2, CCL3, IL-1ß.6 McCann et al. have demonstrated TNFα inhibition in human rheumatoid synovial membrane cultures for apremilast. It is of interest that some PDE4 subtypes such as PDE4B seem to be more concerned with the inhibition of TNF production in murine monocyte/macrophages.7 Apremilast has inhibitory activity on TNFα release by UVB activated keratinocytes. Schafer et al observed that apremilast was a selective PDE4 inhibitor with regulatory effects on innate immunity.4

Side effects Doses needed for efficacy could not be reached due to doselimiting adverse events with nausea, diarrhoea, abdominal pain, vomiting, and dyspepsia being the most common. Apremilast is an orally available PDE4 inhibitor which does not show any marked selectivity among the PDE4 isotypes. It seems to elicit less emetic side effects while also having a wide therapeutic

window. The most common adverse events were gastrointestinal and generally occurred early, were selflimiting and infrequently led to discontinuation. Nausea and headache, upper respiratory tract infection (3.9 vs. 1.8% for placebo), vomiting, nasopharyngitis and upper abdominal pain were also reported. During clinical trials, 1.0% of patients treated with apremilast reported depression or depressed mood compared with 0.8% treated with placebo. Body weight loss of 5-10% was reported in 10% of patients taking apremilast. In a pooled safety analysis of the PALACE 1, PALACE 2, and PALACE 3 studies, the most common adverse events were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis. Most adverse events were mild to moderate in severity, and discontinuations due to adverse events were low. In addition, no relevant safety signals for opportunistic infection, cancer, demyelination, or lupus-like syndromes have been attributed to apremilast to date. There also have been no indications of significant laboratory or electrocardiographic abnormalities or clinically significant effects on liver function, white blood cells, blood pressure, or hemoglobin. Additional results from the PALACE 2, PALACE 3 and PALACE 4 studies demonstrate the clinical efficacy of apremilast in patients with active PsA, with no new safety signals observed and improved tolerability over phase II studies. Most adverse effects were mild to moderate. The most common adverse effects were nausea, vomiting, and diarrhea. Adverse effects were most prominent the first two weeks and with higher doses. Headaches were more severe at higher doses (30 mg BID). Most importantly, no significant laboratory abnormalities have been reported. So far, the side effect profile of phosphodiesterase 4 inhibitors is safer compared to many of the currently approved oral psoriasis medications, particularly, lowdose methotrexate, cyclosporine, and acitretin. These FDA approved medications are associated with myelosuppression, nephrotoxicity, and possible birth defects, respectively. PDE4 is also one of the major phosphodiesterase isoenzymes expressed in the central nervous system, and therefore nausea and emesis are common adverse effects of drug administration. Early PDE4 inhibitors actually failed in clinical trials due to the high prevalence of nausea and emesis. Other adverse effects associated with repeated administration of PDE4 inhibitors include headache, diarrhea, fatigue, dyspepsia, nasopharyngitis, and gastroenteritis. Mesenteric vasculitis is a more worrisome toxicity that may be associated with the PDE4 inhibitors. Studies performed in rodents have demonstrated medial necrosis of the mesenteric arteries after administration of the second generation PDE4 inhibitor cilomilast. However at a meeting convened by the FDA in 2003 to discuss cilomilast in phase III studies, the committee unanimously agreed that the risk of mesenteric vasculitis is not a safety concern based on human studies. The newer PDE4 inhibitor, apremilast, has been

CHAPTER 8: APREMILAST IN DERMATOLOGY well tolerated with few side effects in phase I, II and 3 studies. The most frequently reported adverse events have been headache, nausea and pharyngitis. Researchers used a recognized pharmacophore from the PDE4 inhibitors rolipram and roflumilast in the development of apremilast, and added it to a series of thalidomide analogs in efforts to optimize activity and reduce side effects classically seen with earlier PDE4 inhibitors.2,8-11

Dosage range In psoriasis, the pharmacokinetic profile of apremilast has also been characterized. Patients receiving 20mg apremilast once daily showed a mean steadystate maximal concentration (Cmax) of 207.07 ng/ml and the area under the curve (AUC) was 1799 ng/h/ ml. The median time oral administration of apremilast reached a maximal concentration (Tmax) was 2 hours, the mean half-life of the drug was 8.2 h. With respect to excretion of the drug, the mean clearance (CL/F) was 10.4 l/h, and mean volume of distribution (Vz/F) was 128 l [Gottlieb et al. 2008]. Liu et al observed that ketoconazole slightly decreased  apremilast  clearance. However, the effect of CYP3A4 induction by rifampicin on  apremilast  clearance was much more pronounced than that of CYP3A4 inhibition by ketoconazole. They concluded that strong CYP3A4 inducers could result in a loss of efficacy ofapremilast because of decreased drug exposure.12,13

Pharmacokine cs Apremilast  is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [(14)C] apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean C(max), AUC(0-∞) and t(max) values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h.  Apremilast  was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and 4% of the excreted radioactivity were O-demethylated  apremilast  and its hydrolysis product. Additional minor circulating and excreted compounds were formed via O-demethylation, O-deethylation, N-deacetylation, hydroxylation, glucuronidation and/or hydrolysis. The major metabolites were at least 50-fold less pharmacologically active than apremilast. Metabolic clearance of apremilast was the major route of elimination, while non-en-

zymatic hydrolysis and excretion of unchanged drug were involved to a lesser extent. Apremilast has been evaluated for its pharmacokinetic properties and disposition following oral administration. Multiple daily doses showed rapid absorption (Tmax = 2 h) and a moderately long half-life (8.2 h). A separate study monitored healthy male subjects following a single, 20  mg, oral dose and found that apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and