Rosacea: Update on Management and ... - Skin Therapy Letter

Volume 17 • Number 10 • November-December 2012 Indexed by the US National Library of Medicine and PubMed

Rosacea: Update on Management and Emerging Therapies Robyn S. Fallen1 MD and Melinda Gooderham2 MD, MSc, FRCPC McMaster University, Hamilton, ON, Canada Skin Centre for Dermatology and Skin Laser Clinic, Peterborough, ON, Canada 1

2

aBSTRACT Rosacea is a common chronic skin disorder that has significant impact on the self-esteem and quality of life of affected individuals. Currently understood as an inflammatory condition that occurs in the context of an altered innate immune response, the available topical and systemic therapies function as immunomodulators to restore cutaneous homeostasis. The goals of therapy include reduction of papules, pustules, erythema and physical discomfort with improvement in quality of life. Standard topical treatments include metronidazole and azelaic acid, although many other agents and regimens have been presented. Subantimicrobial/antiinflammatory dose oral doxycycline was US FDA approved in 2006 for the management of rosacea, but Health Canada clearance was only recently granted for this indication. Furthermore, renewed research interest has led to the development of other emerging therapies including topical ivermectin, brimonidine and oxymetazoline that hold promise for patients suffering from this condition. Key words: erythema, inflammation, rosacea, telangiectasia

Introduction Rosacea is a chronic skin disorder characterized by facial erythema, telangiectasia, inflammatory papules and pustules with intermittent episodes of exacerbation and remission. There are four generally accepted clinical subtypes, which have been described by the National Rosacea Society: erythematotelangiectatic, papulopustular, phymatous, and ocular.1 Two variants, granulomatous and neurogenic, have also been presented.1,2 Affecting approximately 10% of the general population, rosacea is more prevalent in women, although impacted men often have more disfiguring skin changes.3 Patients often present between 30 and 50 years of age, but manifestations can occur throughout the life course.4 Given that up to a third of patients have a family history of rosacea and the increased prevalence among individuals of Northern European descent, an underlying genetic predisposition may help explain these patterns.3 While the etiology of rosacea remains unclear and despite clinical heterogeneity, basic science has developed a possible unified understanding of the condition as an inflammatory disorder in the context of an altered innate immune response.5 It is proposed that environmental changes, which may include UV light exposure, hormone balances, and microbe challenges (by pathogens such as Demodex folliculorum),

are sensed by pattern recognition receptors of the immune system. Subsequent signaling-induced effector molecules such as reactive oxygen species, cytokines, cathelicidin and chemokines may then modify dermal structure through vascular changes, collagen degeneration, lymphohistiocytic infiltration and neutrophil recruitment, which may perpetuate this response.6,7 Given this model, it is clear why most current therapies attempt to modulate various points of this inflammatory cascade. Furthermore, although the intricacies of the relationship between psychological factors and rosacea remains to be elucidated, 75% of affected patients report low self-esteem, with a significant odds ratio of 4.81 for a diagnosed depressive disorder in this population compared to the general population.8 The use of validated assessment tools has demonstrated the impact of rosacea on quality of life, and, importantly, the improvement in these psychological indices that can occur with treatment.9 Once rosacea is diagnosed, patients should be reassured of the benign, but chronic, nature of the condition. Counseling should be directed toward the identification and avoidance of triggers, diligent photoprotection, concealing cosmetics and proper skin care.3,10 It is also prudent to review medications to identify, and discontinue if possible, those that may exacerbate flushing such as beta blockers.3

Also in this issue: A Practical Approach to Accurate Classification and Staging of Mycosis Fungoides and Sézary Syndrome (page 5) & Update on Drugs (page 10)

Treatment Topical pharmacotherapeutic options include azelaic acid, erythromycin, metronidazole or sodium sulfacetamide 10% + sulfur 5%.11 As in the management of other dermatological conditions, vehicle selection for topical rosacea preparations is an important consideration. The choice of lotion, cream, gel or foam can influence efficacy, compliance, and tolerability, which is especially relevant for these patients who often have heightened skin sensitivity, but is beyond the scope of this review. 12 In patients with moderate to severe papulopustular subtype or ocular involvement, systemic therapy is often required and includes doxycycline, erythromycin, metronidazole, minocycline, tetracycline, or, in select severe cases, low-dose isotretinoin. 11 Laser, light-based therapies and surgical interventions may also be warranted in select patient populations.13 Recent research has added low-dose doxycycline to the therapeutic armamentarium and two additional treatments, ivermectin and alpha-adrenergic receptor antagonists, hold promise for the future. This article will review the topical and systemic options for the management of cutaneous manifestations of rosacea with a focus on emerging therapies. Topical Metronidazole Topical metronidazole has been used in the treatment of rosacea since the 1950s. It has demonstrated greater efficacy compared to placebo in multiple trials with both statistically significant and clinically important results. 14 There is no statistically significant difference between the two concentrations of topical metronidazole (0.75% or 1%) and it has also been shown to be effective in maintaining remission.14 Among available topical therapies metronidazole has also been proposed as the most costeffective regimen, which may be an important consideration for some patients.15 Topical Azelaic Acid Azelaic acid is a naturally occurring saturated dicarboxylic acid approved for the treatment of mild to moderate rosacea. Patients using azelaic acid showed an improvement of 70-80% in their rosacea compared with 50-55% in the placebo group.14 Azelaic acid 15% gel administered once daily has demonstrated equivalent efficacy to twice daily application, although the recommended dosing is twice daily.16 Metronidazole versus Azelaic Acid In two studies comparing topical metronidazole and azelaic acid, there was no statistically significant difference between the treatment groups with respect to patient-assessed outcomes.17,18 However, in the split-face comparison clinical trial by Maddin, patients favored the outcome of azelaic acid. 19 In both the Maddin and Elewski et al trials, the investigators were of the opinion that treatment with azelaic acid was more effective than metronidazole.17,19 Subantimicrobial Low-dose Oral Doxycycline Tetracyclines (pregnancy category D) have been a mainstay of rosacea therapy for more than half a century.3 However, a clear bacterial pathogen has not been implicated in the pathophysiology of rosacea. 20 Furthermore, standard antimicrobial dosing may affect endogenous flora and risks the development of antibiotic resistant strains. Antibiotic 2

stewardship is advocated in all medical disciplines in hopes of preserving efficacy for the management of bacterial infections.21 In light of these considerations, tetracyclines also have numerous anti-inflammatory properties thought to be responsible for their efficacy in the management of rosacea. They suppress neutrophil migration and chemotaxis, inhibit angiogenesis and the activation, proliferation and migration of lymphocytes, block production of matrix metalloproteinases (MMPs), and upregulate anti-inflammatory cytokines.22,23 Anti-inflammatory, low-dose doxycycline 40 mg capsules, formulated as 30 mg immediate-release and 10 mg delayedrelease beads and dosed once daily, provide a subantimicrobial dose that reduces the inflammatory response without producing drug concentrations required to treat bacterial diseases, thus avoiding concerns regarding selective pressures generating microbial resistance.24 The efficacy of oral doxycycline 40 mg capsules once daily in the treatment of adults with rosacea was demonstrated in two large, randomized, double-blind, placebocontrolled, multicenter trials. Assessed after 16 weeks of therapy, doxycycline 40 mg provided a significantly greater reduction in the total inflammatory lesion count (primary endpoint) than placebo.25 Furthermore, doxycycline 40 mg was associated with a rapid onset of action, with a significantly greater decrease in lesion count than placebo by first follow-up at 3 weeks in both studies.25 Interestingly, maximum anti-inflammatory effects appear to be achieved with doxycycline 40 mg capsules once daily. In a small, randomized, double-blind trial, no additional improvement in rosacea symptoms was achieved with oral doxycycline 100 mg once daily.26 The treatment was generally well-tolerated by patients; adverse events (experienced by approximately 4% of patients) were of mild to moderate intensity, with headache, nasopharyngitis and gastrointestinal side effects reported most frequently.25 No photosensitivity was observed, although tetracyclines as a class of medications have been associated with this effect.25 Doxycycline 40 mg capsules have been demonstrated as safe and effective monotherapy for rosacea in both males and females and in patients of all skin types.27,28 Furthermore, patientrated measures report improvement in symptoms, reduction in the interference of symptoms with life activities, and satisfaction with treatment.29 Combination therapy with doxycycline 40 mg plus either azelaic acid gel 15% or metronidazole gel 1% were also safe, efficacious and well-tolerated.30,31 Emerging Therapies Ivermectin cream (CD5024) An agent currently under investigation is CD5024 1% cream, which is a new topical formulation of the acaricidal compound, ivermectin. 32 Although the exact pathophysiology is yet to be elucidated, one well-known hypothesis for the etiology of rosacea is the presence of Demodex mites in the pilosebaceous unit of affected individuals.33 Reports have been published on cutaneous demodicidosis responding to oral ivermectin and topical permethrin, but data is lacking on the topical application of ivermectin alone.34 There are currently three Phase III studies ongoing, one comparing CD5024 1% cream to metronidazole cream 0.75% (ClinicalTrials.gov identifier NCT01493947) and two similar studies comparing CD5024 1% cream to azelaic acid 15% gel

• Editor: Dr. Stuart Maddin • Volume 17, Number 10 • November-December 2012

with an initial randomized controlled phase for 12 weeks, and a comparator extension phase for 40 weeks (ClinicalTrial.gov identifiers NCT01494467 and NCT01493687).35-37 The projected trial completion date is August 2013. Adrenergic Receptor Antagonists: Brimonidine and Oxymetazoline Novel therapies to treat the erythema associated with rosacea are under development and have the potential to fill a void in the arsenal of rosacea therapeutics. The adrenergic receptor antagonists brimonidine tartrate and oxymetazoline, which have potent vasoconstrictive activity and anti-redness capabilities, are currently found in eye drops for glaucoma and a nasal decongestant spray, respectively.38 Brimonidine tartrate, an alpha-2 agonist also known as CD07805/47, has been shown in a two part dose-finding Phase II study to be safe and efficacious in reducing the erythema of rosacea. A single application of the 0.5% gel reduced erythema between 30 minutes to 12 hours, as measured with an objective chromameter.39 In part B of the study, two dosages (0.18% and 0.5%) of the gel was compared to vehicle over a 4 week period in 269 subjects. No tachyphylaxis, aggravation of symptoms or rebound erythema was observed. The majority of adverse effects were skin-related and mild and transient in nature. The 0.5% gel once daily was significantly more effective according to both patient and clinician assessments (≥ two-grade improvement) and is the dose that has gone forward in Phase III clinical development to confirm safety and efficacy.38 Results of the Phase III randomized controlled trials are anticipated to be released in the fourth quarter of 2012. Oxymetazoline or AGN-199201, a potent alpha-1 and partial alpha-2 receptor agonist, has been shown in case reports to be an effective agent for reducing facial erythema. 40 It has been formulated into a cream and is currently in clinical development for the treatment of erythematotelangiectatic rosacea (ClinicalTrials.gov identifier NCT 01579084).41 Other Treatments • Available for more than 50 years, topical sodium sulphacetamide 10% + sulphur 5% has also been demonstrated to significantly reduce inflammatory lesions and facial erythema compared to vehicle.42 However, the quality of studies evaluating this therapy have been generally poor.14 • Systemic isotretinoin has also been used off-label in the treatment of patients with severe rosacea. A randomized, double-blind, non-inferiority trial comparing the use of different dosages of oral isotretinoin to both doxycycline or placebo found isotretinoin 0.3 mg/kg to be an effective therapy with a similar safety profile as for the treatment of acne.43 • Various topical regimens including an antibiotic and tretinoin preparations have been proposed. A recent randomized, doubleblind, placebo-controlled study assessing a combination gel of clindamycin phosphate 1.2% + tretinoin 0.025% found no difference in papule/pustule count, but mild improvement in the telangiectatic component of rosacea was observed.44 • Although not FDA approved for the management of rosacea, a randomized, double-blind, vehicle-controlled trial has demonstrated the efficacy of once daily topical benzoyl peroxide 5%/clindamycin 1% gel in patients with moderate

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to severe rosacea.45 Common adverse events include pruritus, burning, and bleaching of hair/clothing. In a randomized, controlled, single-blind, split-face trial of patients with erythematotelangiectatic rosacea, both pulsed dye laser and intense pulsed light treatments were found to have similar efficacy and safety.46,47 An open-label uncontrolled trial of the calcineurin inhibitor pimecrolimus 1% cream suggests it is effective and welltolerated for mild to moderate inflammatory rosacea.48 A small, single-centre randomized study found pimecrolimus 1% cream to be as effective as metronidazole 1% cream.49 The use of oral zinc sulfate has also been proposed for the management of rosacea. However, a randomized, doubleblind trial of 220 mg zinc sulfate dosed twice daily showed no difference in magnitude of improvement between subjects receiving zinc therapy versus placebo.50 Due to the chronic nature of the condition, patients frustrated with medical therapy may turn to marketed botanicals and herbal remedies in hopes of improved control. Although there is a paucity of data surrounding the effects of these cosmeceuticals, the prudent clinician should be aware of products that may be used by patients such as niacinamide, feverfew, turmeric, colloid.al oatmeal and quassia extract.51,52

Conclusion With the advent of novel therapeutic options for the treatment of rosacea such as subantimicrobial anti-inflammatory dose doxycycline, ivermectin and the alpha-adrenergic receptor antagonists, there is renewed interest in the study of this chronic inflammatory condition. There is ongoing need for well-designed, high-quality studies of widely used treatments for rosacea including isotretinoin, sodium sulphacetamide/sulphur, and light-based therapies, as well as comparative studies, given the emergence of new treatments. Lifestyle interventions such as avoidance measures for triggering factors, the use of sunscreen, dietary changes and patient education are additional areas of needed research. It would be beneficial for outcomes in future trials to be based on validated, standardized scales assessing both efficacy and improvement in quality of life. Where possible, therapeutic decision-making should take into account high-level evidence and be guided by clinical experience, individual patient characteristics and preferences until further evidence is available. References 1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002 Apr;46(4):584-7. 2. Scharschmidt TC, Yost JM, Truong SV, et al. Neurogenic rosacea: a distinct clinical subtype requiring a modified approach to treatment. Arch Dermatol. 2011 Jan;147(1):123-6. 3. Baldwin HE. Diagnosis and treatment of rosacea: state of the art. J Drugs Dermatol. 2012 Jun;11(6):725-30. 4. Leaute-Labreze C, Chamaillard M. [Paediatric rosacea]. Ann Dermatol Venereol. 2007 Oct;134(10 Pt 1):788-92. 5. Del Rosso JQ, Gallo RL, Kircik L, et al. Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin. J Drugs Dermatol. 2012 Jun;11(6):694-700. 6. Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. 2009 Aug;55(2):77-81. 7. Webster GF. Rosacea. Med Clin North Am. 2009 Nov;93(6):1183-94. 8. Gupta MA, Gupta AK, Chen SJ, et al. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National


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26. 27.

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31. 32. 33.

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Hospital Ambulatory Care Survey--Outpatient Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Br J Dermatol. 2005 Dec;153(6):1176-81. Aksoy B, Altaykan-Hapa A, Egemen D, et al. The impact of rosacea on quality of life: effects of demographic and clinical characteristics and various treatment modalities. Br J Dermatol. 2010 Oct;163(4):719-25. Del Rosso JQ. The use of moisturizers as an integral component of topical therapy for rosacea: clinical results based on the Assessment of Skin Characteristics Study. Cutis. 2009 Aug;84(2):72-6. Gooderham M. Rosacea and its topical management. Skin Therapy Lett. 2009 Feb;14(2):1-3. Jackson JM, Pelle M. Topical rosacea therapy: the importance of vehicles for efficacy, tolerability and compliance. J Drugs Dermatol. 2011 Jun;10(6):627-33. Little SC, Stucker FJ, Compton A, et al. Nuances in the management of rhinophyma. Facial Plast Surg. 2012 Apr;28(2):231-7. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011 Oct;165(4):760-81. Thomas K, Yelverton CB, Yentzer BA, et al. The cost-effectiveness of rosacea treatments. J Dermatolog Treat. 2009;20(2):72-5. Thiboutot DM, Fleischer AB, Jr., Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008 Jun;7(6):541-6. Elewski BE, Fleischer AB, Jr., Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003 Nov;139(11):1444-50. Wolf JE, Jr., Kerrouche N, Arsonnaud S. Efficacy and safety of once-daily metronidazole 1% gel compared with twice-daily azelaic acid 15% gel in the treatment of rosacea. Cutis. 2006 Apr;77(4 Suppl):3-11. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol. 1999 Jun;40(6 Pt 1):961-5. Mays RM, Gordon RA, Wilson JM, et al. New antibiotic therapies for acne and rosacea. Dermatol Ther. 2012 Jan-Feb;25(1):23-37. Chon SY, Doan HQ, Mays RM, et al. Antibiotic overuse and resistance in dermatology. Dermatol Ther. 2012 Jan-Feb;25(1):55-69. Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007 Apr;25(2):133-5, v. Korting HC, Schollmann C. Tetracycline actions relevant to rosacea treatment. Skin Pharmacol Physiol. 2009;22(6):287-94. McKeage K, Deeks ED. Doxycycline 40 mg capsules (30 mg immediaterelease/10 mg delayed-release beads): anti-inflammatory dose in rosacea. Am J Clin Dermatol. 2010;11(3):217-22. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007 May;56(5):791-802. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008 Jun;7(6):573-6. Del Rosso JQ, Preston NJ, Caveney SW, et al. Effectiveness and safety of modified-release doxycycline capsules once daily for papulopustular rosacea monotherapy results from a large community-based trial in subgroups based on gender. J Drugs Dermatol. 2012 Jun;11(6):703-7. Alexis AF, Webster G, Colon LE, et al. Effectiveness and safety of doxycycline 40 mg monotherapy for the treatment of rosacea in skin type subgroups. J Am Acad Dermatol. 2012 Apr;66(4):AB50. Johnson SM, LeVine P. Self-reported treatment impressions and satisfaction of papulopustular rosacea patients treated with doxycycline, USP, 40 mg capsules. J Drugs Dermatol. 2011 Dec;10(12):1376-81. Del Rosso JQ, Bruce S, Jarratt M, et al. Efficacy of topical azelaic acid (AzA) gel 15% plus oral doxycycline 40 mg versus metronidazole gel 1% plus oral doxycycline 40 mg in mild-to-moderate papulopustular rosacea. J Drugs Dermatol. 2010 Jun;9(6):607-13. Bhatia ND, Del Rosso JQ. Optimal management of papulopustular rosacea: rationale for combination therapy. J Drugs Dermatol. 2012 Jul;11(7):838-44. UK Medicines Information. New drugs online report for ivermectin. Available at: http://www.ukmi.nhs.uk/applications/ndo/record_view_open. asp?newDrugID=5617. Accessed: October 8, 2012. Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol. 2012 Jan;26(1):19-28.

34. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol. 1999 Nov;41(5 Pt 1):775-7. 35. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded extension comparing the long term safety of CD5024 1% cream versus azelaic Acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01493687. Last updated June 12, 2012. Available at: http:// clinicaltrials.gov/ct2/show/NCT01493687?term=NCT01493687&rank=1. Accessed: October 2, 2012. 36. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded. extension comparing the long term safety of CD5024 1% cream versus azelaic acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01494467. Last updated June 25, 2012. Available at: http://clinicaltrials. gov/ct2/show/NCT01494467. Accessed: October 2, 2012. 37. Galderma. Efficacy and safety of CD5024 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea over 16 weeks treatment, followed by a 36-week extension period (ATTRACT). In: ClinicalTrials.gov, Identifier: NCT01493947. Last updated September 5, 2012. Available: http:// clinicaltrials.gov/ct2/show/NCT01493947?term=NCT01493947&rank=1. Accessed: October 2, 2012. 38. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012 Mar;166(3):633-41. 39. Galderma. Randomized, double-blind, parallel-group, vehicle-controlled, dose-finding study investigating the pharmacodynamics and safety of three concentrations of CD07805/47 topical gel (0.07%, 0.18%, and 0.50%), applied in subjects with moderate to severe erythematotelangiectatic rosacea. In: ClinicalTrials.gov, Identifier: NCT00989014. Last updated July 24, 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT00989014. Accessed: September 25, 2012. 40. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor agonist, oxymetazoline. Arch Dermatol. 2007 Nov;143(11):1369-71. 41. Bikowski J. Rosacea therapy: current approaches and future directions. Pract Dermatol. 2012 Jul:31-2. 42. Korting HC, Schollmann C. Current topical and systemic approaches to treatment of rosacea. J Eur Acad Dermatol Venereol. 2009 Aug;23(8):876-82. 43. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea - doxycycline- and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010 Jul;8(7):505-15. 44. Chang AL, Alora-Palli M, Lima XT, et al. A randomized, double-blind, placebocontrolled, pilot study to assess the efficacy and safety of clindamycin 1.2% and tretinoin 0.025% combination gel for the treatment of acne rosacea over 12 weeks. J Drugs Dermatol. 2012 Mar;11(3):333-9. 45. Breneman D, Savin R, VandePol C, et al. Double-blind, randomized, vehiclecontrolled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol. 2004 May;43(5):381-7. 46. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009 Jun;35(6):920-8. 47. Kassir R, Kolluru A, Kassir M. Intense pulsed light for the treatment of rosacea and telangiectasias. J Cosmet Laser Ther. 2011 Oct;13(5):216-22. 48. Kim MB, Kim GW, Park HJ, et al. Pimecrolimus 1% cream for the treatment of rosacea. J Dermatol. 2011 Dec;38(12):1135-9. 49. Koca R, Altinyazar HC, Ankarali H, et al. A comparison of metronidazole 1% cream and pimecrolimus 1% cream in the treatment of patients with papulopustular rosacea: a randomized open-label clinical trial. Clin Exp Dermatol. 2010 Apr;35(3):251-6. 50. Bamford JT, Gessert CE, Haller IV, et al. Randomized, double-blind trial of 220 mg zinc sulfate twice daily in the treatment of rosacea. Int J Dermatol. 2012 Apr;51(4):459-62. 51. Emer J, Waldorf H, Berson D. Botanicals and anti-inflammatories: natural ingredients for rosacea. Semin Cutan Med Surg. 2011 Sep;30(3):148-55. 52. Ferrari A, Diehl C. Evaluation of the efficacy and tolerance of a topical gel with 4% quassia extract in the treatment of rosacea. J Clin Pharmacol. 2012 Jan;52(1):84-8.


A Practical Approach to Accurate Classification and Staging of Mycosis Fungoides and Sézary Syndrome Bjorn Rhys Thomas, MBBS1 and Sean Whittaker, MB, MD, FRCP2 Department of Genetics & Molecular Medicine, School of Medicine King’s College, London, UK Skin Tumour Unit, St. John's Institute of Dermatology, Guys and St. Thomas Hospital, London, UK 1

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Abstract Cutaneous T-cell lymphomas are rare, distinct forms of non-Hodgkin’s lymphomas. Of which, mycosis fungoides (MF) and Sézary syndrome (SS) are two of the most common forms. Careful, clear classification and staging of these lymphomas allow dermatologists to commence appropriate therapy and allow correct prognostic stratification for those patients affected. Of note, patients with more advanced disease will require multi-disciplinary input in determining specialist therapy. Literature has been summarized into an outline for classification/staging of MF and SS with the aim to provide clinical dermatologists with a concise review. Key words: CTCL, cutaneous T-cell lymphoma, mycosis fungoides, neoplasm staging, Sézary syndrome, therapy

Primary cutaneous lymphomas (PCL) are rare forms (2%) of non-Hodgkin's lymphomas with an annual incidence of 0.3-1 per 100,000.1 These lymphomas include both primary cutaneous T-cell (75%) and B-cell lymphomas defined by presentation at the time of diagnosis without any extracutaneous sites of disease.1 In 2005, the two classification systems for cutaneous T-cell lymphoma (CTCL), namely the World Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC), were combined, providing distinct subtypes based on clinico-pathologic criteria (Table 1).1,2 Mycosis fungoides (MF) represents the most common variant of CTCL3 and is characterized by a monoclonal proliferation of

epidermotropic CD4+/CD45RO+ T-cells often with aberrant expression of mature T-cell antigens.1,4 MF (Alibert-Bazin type) is characterized by the presence of polymorphic patches, plaques, and tumors.1 Sézary syndrome (SS) is a rare CTCL variant closely related to MF and has classically been described as a triad of erythroderma, generalized lymphadenopathy and Sézary cells (atypical neoplastic T lymphocytes with hyperconvoluted cerebriform nuclei) in the skin, blood, and lymph nodes.1,5,6 The WHO-EORTC system currently distinguishes SS as a separate entity from MF, but rare cases of SS preceded by typical MF have been described.3,7

Classification

Cutaneous T-cell and NK-cell lymphomas

Mycosis fungoides MF variants and subtypes

• Folliculotropic MF • Pagetoid reticulosis • Granulomatous slack skin

Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD30+ lymphoproliferative disorders

• Primary cutaneous anaplastic large cell lymphoma • Lymphomatoid papulosis

Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified • Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) • Cutaneous gamma/delta T-cell lymphoma (provisional) • Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional) Cutaneous B-cell lymphomas

Primary cutaneous marginal zone B-cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other

• Intravascular large B-cell lymphoma

Precursor hematologic CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) neoplasm Table 1: WHO-EORTC classification of cutaneous lymphoma with primary cutaneous manifestations1 • Editor: Dr. Stuart Maddin • Volume 17, Number 10 • November-December 2012

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In this article, we will focus primarily on the evaluation and classification of these conditions and summarize the available therapies. Evaluation A confident diagnosis of MF can only be made from a combination of clinical and pathologic findings. Characteristic pathologic features include cytologically atypical lymphocytes with cerebriform nuclei (described above) either colonizing the basal layer of the epidermis (epidermotropism) or forming clusters of cells in the epidermis (Pautrier microabscesses) with or without a band of cytologically atypical cells in the upper dermis.1,8,9 An algorithm for the diagnosis of early-stage MF has been suggested by the International Society of Cutaneous

Lymphoma (ISCL), which includes clinico-pathological correlation and immunophenotypic and clonal T-cell receptor gene rearrangement studies, providing minimum criteria for diagnosis (Table 2).2,8 For SS, ISCL recommends the presence of erythroderma and the demonstration of the same T-cell clone (using polymerase chain reaction [PCR] or Southern blot of the T-cell receptor [TCR] gene) in skin and blood plus one of the following: Sézary cell count >1000 cells/mm3; expanded CD4+ population with CD4/CD8 ratio >10; or loss of T-cell antigens (CD2, CD3, CD4, CD5 and CD7).1 It must be appreciated that the diagnosis of early MF can be difficult and repeated biopsies may be required. 2,8 Careful clinico-pathological evaluation with a dermatologist and experienced pathologist in PCLs is recommended (Table 3).

Criteria Essential

Additional

Scoring* Other

Major (2 points)

Minor (1 point)

Clinical

Persistent and/or progressive patches/ thin plaques

1. Non-sun exposed location 2. Size/shape variation 3. Poikiloderma

Any 2 additional criteria


Histopathologic

Superficial lymphoid infiltrate

1. Epidermotropism 2. Lymphoid atypia



Molecular biological

Clonal TCR gene rearrangement

N/A

Present

Immunopathologic

1. CD2+, CD3+ and/or CD5+ 1.5 cm or firm, irregular, clustered, or fixed • Choose largest node draining an involved area or the node with the highest standardized uptake value from FDG-PET scan

Tests • Light microscopy/immunophenotypic studies/TCR gene analysis Table 3: Evaluation/staging of patients with MF/SS2,3 ; CBC = complete blood count

FDG-PET = fluorodeoxyglucose-positron emission tomography; FNA = fine-needle aspiration; TCR = T-cell receptor 6


Classification/Staging The management of MF/SS is a stage-based approach derived from the TNM (tumor-node-metastasis) Classification of Malignant Tumours (Table 4). Patients with Stage IA, IB or IIA have an early stage disease compared to IIB (tumor), III (erythroderma), and IV (pathologically involved nodes - IVA; visceral involvement - IVB) have advanced-stage disease (Table 5).2 Of note , there are two main classifications for lymph node involvement. The

Dutch system defines atypical cells as cerebriform cells with a diameter >7.5 µm - increasing grade is associated with increased involvement of these cells.10 The second system, the National Cancer Institute and Veteran’s Administration Hospital (NCI-VA) classification focuses primarily on the number of cells within the paracortex of the lymph node and their subsequent effect on the structure of the node.11

TNM Classification

Skin

Node

Visceral Blood

Features

T1

Patches*, papules and/or plaques 10% of body surface (T2a: Patch - T2b: Plaque +/- patch)

T3

One or more tumors (>1 cm diameter)

T4

Confluent erythema >80% of body surface

N0

No abnormal peripheral lymph nodes (LN) - no biopsy required

N1

Abnormal LN - Dutch grade 1 - dermatopathic lymphadenopathy (DL) - NCI-VA+ LN0-2 (N1a: Clone - N1b: Clone +) - occasional to many lymphocytes

N2

Abnormal LN - Dutch grade 2 - DL: early atypical lymphocyte involvement - NCI-VA LN3 (N2a: Clone - N2b: Clone +) - aggregates of atypical lymphocytes

N3

Abnormal LN - Dutch grade 3 - many atypical lymphocytes with partial effacement of LN - Dutch grade 4 - complete effacement of LN - NCI-VA LN4 (N3a: Clone - N3b: Clone +) - partial/complete effacement of LN

Nx

Abnormal lymph nodes - no confirmatory histology

M0

No visceral organs involved

M1

Viscera involved (with pathological confirmation - imaging for spleen/liver)

B0

5% of peripheral blood lymphocytes are Sézary cells (B1a: Clone - B1b: Clone +)

B2

High tumour burden: >1000/µL Sézary cells with Clone +

Table 4: Classification of MF/SS (ISCL/EORTC revision)2,3,10,11

* Patches are without elevation or induration; + National Cancer Institute and Veteran’s Administration Hospital classification

Limited-stage Disease

IA

T1, N0, M0, B0-1

IB

T2, N0, M0, B0-1

IIA

T1-2, N1-2, M0, B0-1 Advanced-stage Disease

IIB

T3, N0-2, M0, B0-1

IIIA

T4, N0-2, M0, B0

IIIB

T4, N0-2, M0, B1

IVA1

T1-4, N0-2, M0, B2

IVA2

T1-4, N3, M0, B0-2

IVB T1-4, N0-3, M1, B0-2 Table 5: Staging of MF/SS (ISCL/EORTC revision)2,3

T1-4: tumor stage; N0-3: nodal stage; M0-1: visceral organs; B1-2: peripheral blood

Prognosis The prognosis of MF/SS is primarily based on stage, particularly the extent/type of lesions and presence of extracutaneous disease,1,2 emphasising the importance of thorough patient workup. Of note, MF/SS are thought as incurable diseases but the

majority of patients with MF have an indolent disease course with 65-85% of patients being stage IA or IB at diagnosis.2,12-14 Patients with stage IA disease have a median survival of more than 12 years and no decrease in survival when compared to an age-, sex- and race-match control population.1,2,15-17 It is now appreciated that for patients with stage IB, the presence of plaques (T2b) is associated with a worse prognosis and increased risk of disease progression when compared to those with only patches (T2a).12 In contrast, patients with more advanced stage disease (stages IIB, III, IVA) have a median survival of 5 years and stage IVB patients have a median survival of 2.5 years. 2,12,13,15,17 More specifically, patients with dermatopathic nodes (N1) also have a poorer survival when compared to those with no palpable nodes (N0). The presence of abnormal nodes with no histological confirmation (Nx) is also associated with mortality/poor outcome.14 A recent study also showed that patients with stage B0b (18 years of age.

Wilma Fowler Bergfeld, MD Cleveland Clinic, Cleveland, USA

Jan D. Bos, MD

University of Amsterdam, Amsterdam, Holland

Alastair Carruthers, MD

University of British Columbia, Vancouver, Canada

Bryce Cowan, MD, PhD


Jeffrey S. Dover, MD

Yale University School of Medicine, New Haven, USA Dartmouth Medical School, Hanover, USA

Boni E. Elewski, MD

University of Alabama, Birmingham, USA

Barbara A. Gilchrest, MD

Boston University School of Medicine, Boston, USA

Christopher E.M. Griffiths, MD

University of Manchester, Manchester, UK

Aditya K. Gupta, MD, PhD

University of Toronto, Toronto, Canada

Mark Lebwohl, MD

Mt. Sinai Medical Center, New York, USA

James J. Leydon, MD

University of Pennsylvania, Philadelphia, USA

Andrew N. Lin, MD

Approval Dates/Comments

Alan R. Shalita, MD

Hyaluronic acid injectable gel The FDA granted an additional indication in August 2012 Restylane-L® to this transparent hyaluronic acid gel dermal filler. The Medicis Aesthetics, Inc. expanded indication includes submucosal implantation for lip augmentation in patients >21 years of age. Restylane-L® is also approved for injection into facial tissue to smooth wrinkles and folds (e.g., nasolabial). The gel temporarily adds volume to the skin and can give the appearance of a fuller lip or a smoother surface. This formulation contains 0.3% lidocaine, a topical anesthetic intended to reduce pain experienced by patients during the procedure.

Wolfram Sterry, MD

Drug News

University of Alberta, Edmonton, Canada

Harvey Lui, MD


Howard I. Maibach, MD

University of California Hospital, San Francisco, USA

Jose Mascaro, MD, MS

University of Barcelona, Barcelona, Spain

Larry E. Millikan, MD

Tulane University Medical Center, New Orleans, USA

Jean Paul Ortonne, MD

Centre Hospitalier Universitaire de Nice, Nice, France

Jaggi Rao, MD

University of Alberta, Edmonton, Canada

Ted Rosen, MD

Baylor College of Medicine, Houston, USA SUNY Health Sciences Center, Brooklyn, USA Humboldt University, Berlin, Germany

Richard Thomas, MD


Stephen K. Tyring, MD, PhD

University of Texas Health Science Center, Houston, USA

John Voorhees, MD

University of Michigan, Ann Arbor, USA

Guy Webster, MD

Jefferson Medical College, Philadelphia, USA

Klaus Wolff, MD

University of Vienna, Vienna, Austria Skin Therapy Letter © (ISSN 1201–5989) Copyright 2012 by SkinCareGuide.com Ltd. Skin Therapy Letter © is published 10 times annually by SkinCareGuide.com Ltd, 1004 – 750 West Pender, Vancouver, British Columbia, Canada, V6C 2T8. All rights reserved. Reproduction in whole or in part by any process is strictly forbidden without prior consent of the publisher in writing. While every effort is made to see that no inaccurate or misleading data, opinion, or statement appears in the Skin Therapy Letter ©, the Publishers and Editorial Board wish to make it clear that the data and opinions appearing in the articles herein are the responsibility of the contributor. Accordingly, the Publishers, the Editorial Committee and their respective employees, officers, and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion, or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and techniques involving drug usage, and described herein, should only be followed in conjunction with the drug manufacturer’s own published literature. Printed on acid-free paper effective with Volume 1, Issue 1, 1995. Subscription Information. Annual subscription: Canadian $94 individual; $171 institutional (plus GST); US $66 individual; $121 institutional. Outside North America: US$88 individual; $143 institutional. We sell reprints in bulk (100 copies or more of the same article). For individual reprints, we sell photocopies of the articles. The cost is $20 to fax and $15 to mail. Prepayment is required. Student rates available upon request. For inquiries: [email protected]

10

In September 2012, the FDA issued a warning letter to Lancôme USA, a unit of L'Oréal SA, regarding the marketing of certain anti-wrinkle products, saying the products are promoted with claims and language suggestive of drugs. The letter specifically cited examples from the manufacturer’s website, including Lancôme's Génifique Youth Activating Concentrate, Génifique Eye Youth Activating Eye Concentrate, and Génifique Cream Serum Youth Activating Cream Serum with the claim Boosts the activity of genes and stimulates the production of youth proteins; Génifique Repair Youth Activating Night Cream Boosts the activity of genes; and Absolue Eye Precious Cells Advanced Regenerating and Reconstructing Eye Cream and Absolue Night Precious Cells Advanced Regenerating and Reconstructing Night Cream claim to contain A powerful combination of unique ingredients – Reconstruction Complex and Pro-Xylane™, a patented scientific innovation – has been shown to improve the condition around the stem cells and stimulate cell regeneration to reconstruct skin to a denser quality. The FDA states any product that is intended to affect the structure or function of the human body is classified as a drug and companies are prohibited from the sale of such products in the US without submitting an application to the agency proving safety and efficacy prior to being granted marketing approval. The current wording of the claims promotes therapeutic properties that cause the cosmeceutical products to be considered as drugs, therefore violating the Federal Food, Drug, and Cosmetic Act. More information is available at: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm318809.htm • Editor: Dr. Stuart Maddin • Volume 17, Number 10 • November-December 2012