Intravenous immunoglobulins in systemic sclerosis

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AUTREV-01974; No of Pages 8 Autoimmunity Reviews xxx (2017) xxx–xxx

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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature Sébastien Sanges a,b,c,d,e, Sébastien Rivière f,g, Arsène Mekinian f,g, Thierry Martin h, Alain Le Quellec i, Emmanuel Chatelus j, Alain Lescoat k, Patrick Jego k, Claire Cazalets k, Thomas Quéméneur l, Noémie Le Gouellec l, Patricia Senet m, Camille Francès m, Alban Deroux n, Bernard Imbert n, Olivier Fain f,g, Latifatou Boukari o, Thomas Sené p, Christophe Deligny q, Alexis Mathian r,s, Christian Agard t, Grégory Pugnet u,v, Silvia Speca a,b, Sylvain Dubucquoi a,b, Pierre-Yves Hatron a,c,d,e, Éric Hachulla a,b,c,d,e,1, David Launay a,b,c,d,e,⁎,1 a

Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France INSERM, U995, F-59000 Lille, France CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France d Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), F-59000 Lille, France e Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET) f AP-HP, Hôpital Saint Antoine, Service de Médecine Interne, Paris, France g UPMC Université Paris 06, Faculté de Médecine Pierre et Marie Curie, Paris, France h Service d'Immunologie Clinique, Hôpitaux universitaires de Strasbourg, UPR CNRS 3572, Strasbourg, France i Service de Médecine Interne et Maladies Multi-Organiques de l'Adulte, Hôpital Saint-Éloi, Centre Hospitalier Régional Universitaire de Montpellier, Montpellier, France j Hôpitaux Universitaires de Strasbourg, CHU Hautepierre, Service de Rhumatologie, Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, INSERM UMR 1109, Strasbourg, France k Service de Médecine Interne, Centre Hospitalo-Universitaire de Rennes, Université de Rennes 1, Rennes, France l Service de Médecine Interne, Néphrologie et Médecine Vasculaire, Centre Hospitalier de Valenciennes, Valenciennes, France m Service de Dermatologie, Hôpital Tenon, AP-HP, UPMC, Paris, France n Service de Médecine Interne, Université Grenoble Alpes, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France o Service de Médecine Interne, Hôpital Jean-Verdier, AP-HP, Université Paris-13, Bondy, France p Service de Médecine Interne et Rhumatologie, GH Diaconesses Croix Saint Simon, Paris, France q Service de Médecine Interne et Rhumatologie 3C/5D, Centre Hospitalier Universitaire Pierre Zobda-Quitman, Fort-de-France, Martinique r Service de Médecine Interne 2, Centre de Référence National pour le Lupus et le Syndrome des Antiphospholipides, institut E3M, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France s Sorbonne universités, UPMC université Paris 06, 75013 Paris, France t Service de Médecine interne, Hôtel-Dieu, CHU de Nantes, Université de Nantes, Nantes, France u CHU, Université de Toulouse, Faculté de Médecine, Service de Médecine Interne, Toulouse, France v INSERM, UMR 1027, Toulouse, France b c

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Article history: Received 19 December 2016 Accepted 26 December 2016 Available online xxxx Keywords: Systemic sclerosis Intravenous immunoglobulins Fibrosis Inflammatory myopathies

a b s t r a c t Background: As intravenous immunoglobulins (IVIG) exhibit immunomodulatory and antifibrotic properties, they may be a relevant treatment for systemic sclerosis (SSc). The objectives of this work were thus to report on the efficacy and safety of IVIG in a population of SSc patients and to review the available literature. Methods: 46 patients from 19 French centers were retrospectively recruited. They were included if they had a diagnosis of SSc and received at least 1 IVIG infusion at a dosage N1 g/kg/cycle. Relevant data collected at IVIG discontinuation were compared to those collected at IVIG initiation. A comprehensive literature review was performed. Results: We observed a significant improvement of muscle pain (74% vs. 20%, p b 0.0001), muscle weakness (45% vs. 21%, p = 0.01), joint pain (44% vs. 19%, p = 0.02), CK levels (1069 ± 1552 UI vs. 288 ± 449 UI, p b 0.0001) and CRP levels (13.1 ± 17.6 mg/L vs. 9.2 ± 16.6 mg/L, p = 0.001). We also noted a trend for an improvement of gastro-esophageal reflux disease (68% vs. 53%, p = 0.06) and bowel symptoms (42% vs. 27%, p = 0.06). Skin and cardiorespiratory involvements remained stable. Finally, corticosteroid daily dose was significantly lower by the end of treatment (13.0 ± 11.6 mg/day vs. 8.9 ± 10.4 mg/day, p = 0.01). Only two severe adverse events were reported (one case of deep vein thrombosis and one case of diffuse edematous syndrome).

⁎ Corresponding author at: Service de Médecine Interne et d'Immunologie Clinique, Hôpital Claude-Huriez, CHRU Lille, Rue Michel Polonovski, 59037 Lille Cedex, France. E-mail address: [email protected] (D. Launay). 1 EH and DL contributed equally to this work.

http://dx.doi.org/10.1016/j.autrev.2017.02.008 1568-9972/© 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Sanges S, et al, Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literatur..., Autoimmun Rev (2017), http://dx.doi.org/10.1016/j.autrev.2017.02.008

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S. Sanges et al. / Autoimmunity Reviews xxx (2017) xxx–xxx

Conclusion: Our work suggests that IVIG are a safe therapeutic option that may be effective in improving musculoskeletal involvement, systemic inflammation, digestive tract symptoms and could be corticosteroid sparing. © 2017 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients & methods . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Patient selection . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data collection . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Baseline characteristics of the study population . . . . . . . . . . 3.2. IVIG treatment modalities . . . . . . . . . . . . . . . . . . . . 3.3. Follow-up characteristics of the study population . . . . . . . . . 4. Discussion and review of the literature . . . . . . . . . . . . . . . . . 4.1. Effects of IVIG in SSc patients . . . . . . . . . . . . . . . . . . 4.2. Effects of IVIG in SSc experimental models . . . . . . . . . . . . 4.3. Specific modes of action of IVIG in SSc . . . . . . . . . . . . . . 4.3.1. Modulation of pro- and anti-fibrotic cytokine production. . 4.3.2. Correction of aberrant pro-fibrotic phenotype in fibroblasts 4.3.3. Neutralization of pathogenic autoantibodies . . . . . . . 4.3.4. Other possible mechanisms . . . . . . . . . . . . . . . 5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Systemic sclerosis (SSc) is a rare and severe condition classified within the connective tissue diseases [1]. It is associated with several debilitating complications (notably digital ulcers, interstitial lung disease (ILD), pulmonary hypertension and digestive tract fibrosis) [2] that greatly impact health-related quality of life [3]. SSc pathophysiology is complex and combines, to different degrees, a fibrotic (excessive synthesis of collagen fibers by activated fibroblasts), vascular (microangiopathy) and immunological (dysregulation of cellular and humoral immune systems) components on a background of genetic predisposition and environmental exposure [4,5]. Current standard of care for management of severe organ involvements is based on symptomatic treatments (such as vasodilators in pulmonary arterial hypertension [6]) and immune-targeted therapies [7] (from conventional immunosuppressants and biologics to hematopoietic stem cell transplantation). However, there are currently no therapeutic strategies specifically aimed at preventing or reversing fibrogenesis [8], a major phenomenon in SSc pathogenesis. Intravenous immunoglobulins (IVIG) have long been used as a therapeutic option in various autoimmune diseases [9,10], such as immune thrombocytopenia, idiopathic inflammatory myopathies, myasthenia gravis, Guillain-Barré syndrome, Kawasaki disease, ANCA-associated vasculitides and systemic lupus erythematosus. Their foremost advantage is an excellent safety profile [11]: in particular, they are not associated with an increased risk of infection, a very unique feature within the therapeutic armamentarium of these diseases. Although their precise mode of action remains debated, IVIG have been shown to display both immunomodulatory [12] and antifibrotic [13] properties. This gives a pathophysiological relevance to their use as a potential treatment in SSc [14]. Several previous works have suggested the efficacy of IVIG therapy on skin, muscle, joint and digestive tract involvements [15–31].

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However, most of these studies were case series or open-label singlecenter trials performed on limited patient samples. To address these issues, we performed a retrospective multicenter study and assess the efficacy and safety of IVIG on several SSc organ involvements on a large nationwide patient cohort, as well as reviewed the available literature. 2. Patients & methods 2.1. Patient selection Patients were recruited from 19 tertiary care centers across France. They were included in the study if they fulfilled all the following criteria: (1) a definite diagnosis of SSc according to the 2013 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) classification criteria [32]; (2) administration of at least one IVIG cycle; (3) completion of at least one follow-up visit; (4) an age over 18 years old. They were excluded if IVIG were prescribed exclusively for hypogammaglobulinemia substitution (i.e. at a dosage b 1 g/kg/cycle). The study was approved by our local institutional review board and complied with current French legislation. 2.2. Data collection All data were retrospectively retrieved from medical records. Data regarding patient history from SSc diagnosis up to IVIG initiation were collected and included: (1) SSc diagnosis: age, sex, cutaneous subset according to Leroy's classification [33], disease duration, immunological profile, overlap syndrome, nailfold capillaroscopy; (2) SSc organ involvements: skin (Raynaud phenomenon, digital ulcers, calcinosis, telangiectasias), lung (ILD staged according to Goh's criteria [34], pulmonary hypertension), kidney (scleroderma renal crisis), heart (dysrhythmias, conduction disorders, diastolic dysfunction,

Please cite this article as: Sanges S, et al, Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literatur..., Autoimmun Rev (2017), http://dx.doi.org/10.1016/j.autrev.2017.02.008

S. Sanges et al. / Autoimmunity Reviews xxx (2017) xxx–xxx

systolic dysfunction, myocarditis, pericarditis), digestive tract (gastroesophageal reflux disease (GERD), dysphagia, gastric antral vascular ectasias, diarrhea or constipation, malabsorption, chronic intestinal pseudo-obstruction), joints (pain, swelling, erosions), muscles (pain, weakness, elevated creatine-kinase (CK) levels, myogenic pattern on electromyography, myositic pattern on muscle pathology); (3) previous treatments: anti-inflammatory, immunosuppressing and immunomodulatory drugs; (4) IVIG treatment modalities: indication, number of cycles, dosage, frequency. Data regarding patient evolution during IVIG course were collected at baseline and at several predefined time-points during follow-up (month (M) 3, 6, 9, 12, 18, and 24) until IVIG discontinuation. They included: (1) clinical assessment: modified Rodnan skin score (mRSS), digital ulcers, New York Heart Association (NYHA) functional score, 6minute walk distance, GERD symptoms, abnormal bowel motion, joint pain, muscle pain, muscle weakness (defined by the existence of at least one muscle group with a score b3/5 according to the Medical Research Council (MRC) manual muscle strength scoring system [35]); (2) biological data: hemoglobin, platelets, creatinine and glomerular filtration rate (GFR) estimated by the Modification of Diet in Renal Disease (MDRD) equation, brain natriuretic peptide (BNP) and Nt-pro-BNP, Creactive protein (CRP) and CK levels; (3) pulmonary function tests (PFT): total lung capacity (TLC), forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO); (4) transthoracic echocardiography (TTE): left ventricular ejection fraction (LVEF), estimated systolic pulmonary artery pressure (sPAP), pericardial effusion; (5) chest high-resolution CT-scan: ground-glass opacities (GGO), fibrotic lesions; (6) associated treatments: anti-inflammatory, immunosuppressing and immunomodulatory drugs; (7) adverse effects: minor events (including nausea/vomiting, tachycardia, arterial hypertension/hypotension, fever/chills, skin rash, headache), major events (including anaphylaxis, acute renal failure, arterial or venous thrombosis, aseptic meningitis). 2.3. Statistical analyses Characteristics of the population were described using mean ± standard deviation (SD) for quantitative variables, and number (n), percentage (%) for qualitative variables. Relevant data from baseline evaluation (performed within a 3month period before the first IVIG cycle) and last follow-up evaluation (performed within a 3-month period after the last IVIG cycle; or at M24 for patients treated for N 2 years) were compared using Wilcoxon test. Significance was set p b 0.05. Statistical analyses were performed using the GraphPad Prism v6 (GraphPad Software). 3. Results 3.1. Baseline characteristics of the study population Overall, the study population comprised 46 patients (Table 1). Most of them were middle-aged females (sex ratio m/f: 0.24, mean age 51.3 ± 15.4 years old) recently diagnosed (4.1 ± 5.2 years before) with a diffuse cutaneous form of the disease (59%) associated with anti-topoisomerase I (27%) or anti-centromere antibodies (20%). A vast majority of patients had an overlap syndrome with another connective tissue disease, especially with idiopathic inflammatory myopathies (85%). Major organ involvements related to SSc were common features in our cohort. Frequent complications notably included digital ulcers (52%), ILD (57%), digestive tract involvement (89%), joint involvement (50%) and muscle involvement (78%). Pulmonary hypertension (7%) and renal crisis (11%) remained rare events. Before IVIG initiation, most patients (84%) had received at least one anti-inflammatory, immunosuppressive or immunomodulatory drug

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Table 1 Baseline characteristics of the study population. N Demographics Female (n, %) Age at IVIG initiation (mean ± SD)

Value

46 37 (80%) 46 51.3 (±15.4)

SSc diagnosis Disease duration at IVIG initiation Since SSc diagnosis (years, mean ± SD) Since first non-Raynaud symptom onset (years, mean ± SD) Since Raynaud phenomenon onset (years, mean ± SD) SSc subtype dcSSc (n, %) lcSSc (n, %) SSc sine scleroderma (n, %) Overlap syndrome Idiopathic inflammatory myopathy (n, %) Sjögren's syndrome (n, %) Other autoimmune disease (n, %) Immunological profile Antinuclear antibodies (n, %) Anti-topoisomerase I antibodies (n, %) Anti-centromere antibodies (n, %) Anti-RNA polymerase III antibodies (n, %) Anti-U1RNP antibodies (n, %) Anti-U3RNP antibodies (n, %) Anti-Ku antibodies (n, %) Anti-PmScl antibodies (n, %) Anti-SSA antibodies (n, %) Other autoantibodiesa (n, %) Nailfold capillaroscopy Specific organic microangiopathy (n, %)

46 4.1 (±5.2) 41 4.2 (±4.8) 36 5.9 (±7.8) 46 46 46 46 46 46 46

27 (59%) 17 (37%) 2 (4%) 41 (89%) 39 (85%) 3 (7%) 2 (4%)

45 44 44 44 44 44 44 44 44 44

44 (98%) 12 (27%) 9 (20%) 2 (5%) 2 (5%) 2 (5%) 2 (5%) 1 (2%) 4 (9%) 6 (14%)

29 20 (69%)

History of organ involvements Skin Raynaud phenomenon (n, %) Digital ulcers (n, %) Calcinosis (n, %) Telangiectasias (n, %) Lungs Interstitial lung disease (n, %) Limited ILD (n, %) Extensive ILD (n, %) Pulmonary hypertension (n, %) Kidney Scleroderma renal crisis (n, %) Heart Dysrhythmias (n, %) Conduction disorders (n, %) Diastolic dysfunction (n, %) Systolic dysfunction (n, %) Myocarditis (n, %) Pericarditis (n, %) Digestive tract Gastroesophageal reflux disease (n, %) Dysphagia (n, %) Gastric antral vascular ectasias (n, %) Abnormal bowel movements (n, %) Malabsorption (n, %) Chronic intestinal pseudo-obstruction (n, %) Joints Joint pain (n, %) Joint swelling (n, %) Joint erosions (n, %) Muscles Muscle pain (n, %) Muscle weakness (n, %) Elevated muscle enzymes (n, %) Myogenic pattern on electromyography (n, %) Myositic pattern on muscle pathology (n, %) History of treatments Delay between first treatment and IVIG initiation (years, mean ± SD) No previous treatment (n, %) IV corticosteroids (n, %) Oral corticosteroids (n, %)

45 2.67 (±3.65) 45 7 (16%) 45 3 (7%) 45 36 (80%)

46 44 32 35

45 (98%) 23 (52%) 11 (34%) 23 (66%)

46 46 46 46

26 (56%) 12 (26%) 14 (30%) 3 (7%)

46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 29 25

5 (11%) 14 (30%) 8 (17%) 6 (13%) 1 (2%) 5 (11%) 5 (11%) 3 (7%) 41 (89%) 37 (80%) 16 (35%) 0 (0%) 15 (33%) 2 (4%) 5 (11%) 23 (50%) 23 (50%) 5 (11%) 0 (0%) 36 (78%) 36 (78%) 32 (70%) 36 (78%) 24 (83%) 25 (100%)

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Please cite this article as: Sanges S, et al, Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literatur..., Autoimmun Rev (2017), http://dx.doi.org/10.1016/j.autrev.2017.02.008

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Table 1 (continued)

IV cyclophosphamide (n, %) Oral cyclophosphamide (n, %) Methotrexate (n, %) Azathioprine (n, %) Mycophenolate mofetil (n, %) Hydroxychloroquine (n, %) D-Penicillamine

(n, %) Rituximab (n, %) Other (n, %)

N

Value

45 45 45 45 45 45 45

12 (27%) 2 (4%) 18 (40%) 4 (9%) 7(16%) 3 (7%) 1 (2%)

45 1 (2%) 45 3 (7%)

dc: diffuse cutaneous; ILD: interstitial lung disease; IV: intravenous; IVIG: intravenous immunoglobulins; lc: limited cutaneous; n: number; SD: standard deviation; SSc: systemic sclerosis. a Other autoantibodies: rheumatoid factor (n = 2); anti-Mi2 antibodies (n = 1); antiSRP antibodies (n = 1); anti-phospholipid antibodies (n = 1); anti-MPO antibodies (n = 1).

for a mean duration of 2.67 ± 3.65 years. Treatment regimens usually included corticosteroids (80%), either alone (26%) or combined with conventional immunosuppressants (54%). 3.2. IVIG treatment modalities Detailed IVIG treatment modalities are described in Table 2. Overall, patients received a mean 14.5 ± 18.2 IVIG cycles administered during a mean 14.8 ± 19.4 months. Most of them were given the usual dosage of 2.0 g/kg/cycle (91%), spread over 2 (56%) or 4 days (23%), every 3 (4%) or 4 (80%) weeks. The main indications for IVIG prescription were muscle (80%) and digestive tract (11%) involvements. IVIG were equally used as a recourse therapy in case of failure of a previous therapeutic regimen (50%) and as a first-line therapy (50%) for a given organ involvement. Of note, contraindications to immunosuppressants were reported as one of the reasons motivating IVIG prescription in only 7% of patients. IVIG were associated with other anti-inflammatory, immunosuppressive or immunomodulating drugs in the vast majority of cases (93%). In 35% of patients, IVIG were used as an add-on treatment without modification of the patients' usual background therapy. In the rest of them, background therapy was modified at IVIG initiation and/or during IVIG course. 3.3. Follow-up characteristics of the study population Data were collected at regular time points during follow-up until IVIG cessation and are detailed in Supplementary Table 1. To assess the potential benefits of IVIG administration in our patients, we compared relevant data from evaluations before the first and after the last IVIG cycle (Table 3). We observed a significant improvement of muscle involvement, with a reduction of pain (74% vs. 20%, p b 0.0001), weakness (45% vs. 21%, p = 0.01) and CK levels (1069 ± 1552 UI vs. 288 ± 449 UI, p b 0.0001). We also noted a significant decrease in joint pain (44% vs. 19%, p = 0.02) and CRP levels (13.1 ± 17.6 mg/L vs. 9.2 ± 16.6 mg/L, p = 0.001), as well as a trend for a significant improvement of GERD (68% vs. 53%, p = 0.06) and bowel symptoms (42% vs. 27%, p = 0.06). Skin and cardiorespiratory involvements remained stable. Finally, corticosteroid daily dose was significantly lower by the end of treatment (13.0 ± 11.6 mg/day vs. 8.9 ± 10.4 mg/day, p = 0.01). Only two severe adverse events were reported (one case of deep vein thrombosis and one case of diffuse edematous syndrome), always leading to IVIG discontinuation. Although estimated GFR levels tended to be slightly lower by the time of IVIG cessation (122 ± 74 mL/min/ 1.73 m2 vs. 114 ± 61 mL/min/1.73 m2, p = 0.07), there was no reported case of acute renal failure during treatment. Few minor adverse events were noted (3 cases of fevers and chills, 3 cases of skin rash and 3

Table 2 IVIG treatment modalities.

Indications Indication for IVIG prescription First-line therapy for a given organ involvement (n, %) Recourse therapy for a given organ involvement (n, %) Contraindication to immunosuppressants (n, %) Other (n, %) Organ involvement motivating IVIG prescription Muscle (n, %) Digestive tract (n, %) Lungs (n, %) Skin (n, %) Other (n, %) Modalities Duration Number of cycles (mean ± SD) Treatment duration (months, mean ± SD) Dosage 1.0 g/kg/day for 2 days (n, %) 0.7 g/kg/day for 3 days (n, %) 0.5 g/kg/day for 4 days (n, %) 0.4 g/kg/day for 5 days (n, %) Other (n, %) Frequency 1 cycle per month (n, %) 1 cycle per 3 weeks (n, %) Other (n, %) Associated treatments Treatment prescribed during IVIG course None (n, %) IV corticosteroids (n, %) Oral corticosteroids (n, %) IV cyclophosphamide (n, %) Oral cyclophosphamide (n, %) Methotrexate (n, %) Azathioprine (n, %) Mycophenolate mofetil (n, %) Hydroxychloroquine (n, %) D-Penicillamine (n, %) Rituximab (n, %) Other (n, %) Background therapy Modification of background therapya at IVIG initiation Modification of background therapya during IVIG course No modification of background therapya at any time

N

Value

46 46 46 46

23 (50%) 23 (50%) 3 (7%) 3 (7%)

46 46 46 46 46

37 (80%) 5 (11%) 3 (7%) 3 (7%) 3 (7%)

46 45

14.5 (±18.2) 14.8 (±19.4)

45 45 45 45 45

25 (56%) 3 (7%) 10 (23%) 3 (7%) 4 (9%)

46 46 46

37 (80%) 2 (4%) 7 (15%)

46 46 46 46 46 46 46 46 46 46 46 46

3 (7%) 1 (2%) 39 (85%) 5 (11%) 0 (0%) 14 (30%) 6 (13%) 12 (26%) 2 (4%) 1 (2%) 2 (4%) 2 (4%)

46 46 46

19 (41%) 16 (35%) 16 (35%)

IV: intravenous; IVIG: intravenous immunoglobulins; n: number; SD: standard deviation. a Modification of background therapy: introduction, switch or dosage increase of immunosuppressants and/or corticosteroids.

cases of headaches) and were either limited to the first cycle or never recurred after adaptation of the infusion rate. The reasons reported for IVIG discontinuation were treatment success in 23 cases (50%), treatment failure in 8 cases (17%), dissociated response (improvement of an organ involvement but worsening of another) in 3 cases (7%), adverse event in 3 cases (7%), patient decision in 3 cases (7%) and death from an unrelated cause in 2 cases (4%). The remaining 4 patients (8%) were still under therapy by the end of the study. 4. Discussion and review of the literature In this study, we tried to report on the efficacy and safety of IVIG treatment in a large multi-center cohort of SSc patients. Our results can be summarized as follows: (1) IVIG therapy may improve musculoskeletal involvement, systemic inflammation, corticosteroid tapering, and possibly digestive tract symptoms, in SSc patients; (2) IVIG are a globally well-tolerated treatment in these patients. Our study draws strength from a large patient sample and its nationwide multicenter recruitment. It also has several limitations, in particular its retrospective design, the amount of missing data, the potential

Please cite this article as: Sanges S, et al, Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literatur..., Autoimmun Rev (2017), http://dx.doi.org/10.1016/j.autrev.2017.02.008

S. Sanges et al. / Autoimmunity Reviews xxx (2017) xxx–xxx

5

Table 3 Characteristics of the study population at first and at last IVIG cycles.

Modified Rodnan skin score all SSc patients (mean ± SD) lcSSc patients (mean ± SD) dcSSc patients (mean ± SD) Digital ulcers Active DU (n, %) Number of active DU (mean ± SD) NYHA score (mean ± SD) Class I (n, %) Class II (n, %) Class III (n, %) Class IV (n, %) 6MWD (m, mean ± SD) GERD (n, %) Abnormal bowel motion (n, %) Joint pain (n, %) Muscle pain (n, %) Muscle testing b3/5 (n, %) Hemoglobin (g/dL, mean ± SD) Platelets (G/L, mean ± SD) Creatinine (μmol/L, mean ± SD) Estimated GFR (mL/min/1.73 m2, mean ± SD) BNP (pg/mL, mean ± SD) Nt-pro-BNP (pg/mL, mean ± SD) Elevated BNP or Nt-pro-BNP (n, %) CRP (mg/L, mean ± SD) CK (UI, mean ± SD) FVC All SSc patients (% predicted, mean ± SD) SSc-ILD patients (% predicted, mean ± SD) TLC All SSc patients (% predicted, mean ± SD) SSc-ILD patients (% predicted, mean ± SD) DLCO All SSc patients (% predicted, mean ± SD) SSc-ILD patients (% predicted, mean ± SD) Left ventricular ejection fraction (%, mean ± SD) Estimated sPAP (mm Hg, mean ± SD) Pericardial effusion (n, %) Ground-glass opacities on chest CT (n, %) Stable (n, %) Better (n, %) Worse (n, %) Fibrotic lesions on chest CT (n, %) Stable (n, %) Better (n, %) Worse (n, %) Corticosteroid daily dose (mg/day, mean ± SD)

N

First IVIG Value

Last IVIG Value

p

29 8 20

17.6 (±10.9) 8.6 (±5.1) 22.0 (±9.8)

17.0 (±12.6) 5.9 (±4.6) 22.3 (±11.5)

0.57 0.13 0.79

33 33 34 34 34 34 0 6 34 33 32 35 38 37 34 35 33 10 3 13 37 35

6 (18%) 0.52 (±1.3) 1.71 (±0.8) 17 (50%) 10 (29%) 7 (21%) 0 (0%) 414 (±89) 23 (68%) 14 (42%) 14 (44%) 26 (74%) 17 (45%) 12.3 (±1.6) 320 (±93) 65.7 (±33.8) 122 (±74) 180 (±161) 674 (±781) 4 (31%) 13.1 (±17.6) 1069 (±1552)

4 (12%) 0.15 (±0.4) 1.68 (±0.8) 18 (53%) 9 (26%) 7 (21%) 0 (0%) 393 (±93) 18 (53%) 9 (27%) 6 (19%) 7 (20%) 8 (21%) 11.9 (±1.6) 295 (±94) 70.2 (±36.7) 114 (±61) 192 (±148) 2023 (±3268) 3 (23%) 9.2 (±16.6) 288 (±449)

0.72 0.19 0.96 0.99 0.99 0.99 / 0.40 0.06 0.06 0.02 b0.0001 0.01 0.31 0.12 0.14 0.07 0.85 0.75 0.99 0.001 b0.0001

16 9

73.3 (±18.7) 67.0 (±16.9)

75.1 (±18.9) 66.9 (±20.9)

0.91 0.99

16 9

78.3 (±16.8) 70.3 (±11.9)

74.7 (±17.7) 65.0 (±14.4)

0.80 0.48

14 8 13 13 17 27 27 27 27 27 27 27 27 38

50.2 (±22.9) 40.6 (±15.2) 58.3 (±8.1) 28.8 (±6.1) 3 (18%) 11 (41%) / / / 11 (41%) / / / 13.0 (±11.6)

53.8 (±23.2) 40.8 (±16.7) 59.5 (±13.4) 30.8 (±6.4) 3 (18%) 8 (30%) 23 (85%) 3 (11%) 1 (4%) 11 (41%) 11 (100%) 0 (0%) 0 (0%) 8.9 (±10.4)

0.30 0.91 0.80 0.35 0.99 0.38 / / / 0.99 / / / 0.01

6MWD: 6-minute walk distance; BNP: brain natriuretic peptide; CK: creatine kinase; CRP: C-reactive protein; CT: CT-scan; d: day; dc: diffuse cutaneous; DLCO: diffusing capacity of the lung for carbon monoxide; DU: digital ulcers; FVC: forced vital capacity; GERD: gastroesophageal reflux disease; GFR: glomerular filtration rate; ILD: interstitial lung disease; lc: limited cutaneous; NYHA: New York Heart Association; sPAP: systolic pulmonary arterial pressure; SSc: systemic sclerosis; TLC: total lung capacity.

interference of modifications in background therapy and the absence of a control group for the studied intervention. The study population also featured a large proportion of overlap syndrome with inflammatory myopathies, which constitutes a specific patient subset and is probably not representative of more frequent SSc phenotypes. However, in spite of these limits, we believe that it conveys an interesting signal that is largely supported by the available literature. 4.1. Effects of IVIG in SSc patients Several works have previously suggested the efficacy of IVIG on various organ involvements in SSc patients [15–31] (Supplementary Table 4). Regarding muscle involvement, we showed that IVIG therapy could improve muscle pain, MRC testing and CK levels. This confirms results from earlier studies that observed an improvement in muscle weakness [15,27,28,31] (including swallowing disorders [15,28]), a decrease in muscle enzymes [15,27,28,30,31] and a correction of muscle MRI

anomalies [27] under treatment. This is also in line with the efficacy of IVIG in idiopathic inflammatory myopathies [36]. Regarding articular involvement, the potential efficacy of IVIG was already noted in an open-label trial of 7 patients [22]. In this study, a course of 6 monthly infusions of IVIG was associated with a decrease in tender and swollen joint counts [22]. This is in line with our own findings, which also suggest an improvement in joint paint after treatment. Regarding digestive tract involvement, an uncontrolled trial of 15 patients [31] and a case series of 2 patients [29] reported possible benefits of IVIG therapy on esophageal and bowel manifestations. Indeed, both studies described an improvement in frequency and intensity of GERD symptoms (as assessed by the Reflux Disease Questionnaire) and of gastro-intestinal symptoms (evaluated by the University of California at Los Angeles Scleroderma Clinical Trials Consortium GastroIntestinal Tract 2.0 total score). Though only close to statistical significance, our results tend to confirm these observations as well. Regarding skin involvement, our findings contrast with those from previous publications. Indeed, several open-label studies [18,21,22,30,

Please cite this article as: Sanges S, et al, Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literatur..., Autoimmun Rev (2017), http://dx.doi.org/10.1016/j.autrev.2017.02.008

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31] and case reports [15,16,19,23] suggested an improvement of skin score and histological dermal thickness under treatment. Poelman et al. compared mRSS values at 12 months in SSc patients receiving monthly IVIG infusions to historical cohorts treated by ineffective therapies (like D-penicillamine or collagen): interestingly, skin scores were significantly lower in the IVIG group, suggesting that this treatment modified the natural course of the disease [30]. Moreover, in a randomized double-blind placebo-controlled trial, Takehara et al. prospectively studied the effect of IVIG in a cohort of active dcSSc patients: although there was no difference in skin score between the two groups after a single course of IVIG, the change in mRSS reached statistical significance when a second IVIG cycle was administered. To explain the discrepancy between our work and the literature, it should be noted that IVIG were only rarely prescribed for an active cutaneous disease in our population, which makes it difficult to adequately assess their potential efficacy in this setting. Furthermore, in patients with severe and extensive skin fibrosis, stability could also be considered as a relative success: indeed, recent studies suggested that worsening of skin involvement is the most anticipated natural history of SSc patients with an mRSS ≤22, which is the case in our cohort (mean mRSS 17.6 ± 10.9) [37]. Regarding respiratory involvement, our results are in line with most previously published studies, which failed to demonstrate any significant effect of IVIG therapy on lung fibrosis (and especially on PFT parameters) [16,26,28,30,31]. One notable exception though is a case report by Mauhin et al. [27] which described a complete regression of dyspnea, CT-scan anomalies and restrictive syndrome on PFT in a patient with SSc-ILD after a 6-month course of IVIG. Interestingly, a recent prospective uncontrolled trial suggested that IVIG could be efficient in stabilizing respiratory symptoms and PFT parameters in patients with progressive idiopathic pulmonary fibrosis [38]. Like skin involvement, the observation of a non-deterioration of PFT parameters during IVIG is reassuring. Whether this could be considered as a therapeutic success warrants further investigations in SSc-ILD patients. Regarding systemic inflammation, the potential efficacy of IVIG therapy in normalizing acute phase reactants has never been documented before in SSc. As elevated CRP levels are associated to disease activity, severity and prognosis [39], our result could indicate a better control of disease activity under treatment. This is in accordance with previous observations from open-label studies, which reported an improvement in patient and physician assessments of SSc activity, as well as in Health Assessment Questionnaire scores [18,22,30]. Regarding other organ involvements, IVIG therapy has been described to have a beneficial effect on digital ulcers [15,21,31], which was not observed here, as well as on calcinosis [15,23] and tendon friction rubs [30], which could not be investigated in our work. Finally, we found that corticosteroid daily doses were significantly lower at the end of IVIG treatment than at the beginning. A potential corticosteroid-sparing effect of IVIG has been reported in SSc [15,25, 31] and in other autoimmune diseases [25]. Whether these results reflect an actual efficacy of this treatment on corticoresistance remains unclear. 4.2. Effects of IVIG in SSc experimental models Aside from studies on SSc patients, several observations made in experimental models also suggested a potential benefit of IVIG in this disease. In tight-skin (TSK) mice, a murine model of SSc in which a spontaneous mutation in the fibrillarin gene causes systemic fibrosis, Blank et al. studied the effects of human IVIG administered from the 4th week of life during one month, for a total dose of 2 g/kg [40]. IVIG therapy was associated with a significant decrease in skin collagen, when compared to control mice. In another murine model of SSc induced by subcutaneous injections of bleomycin (BLM), Kajii et al. also observed that IVIG infusions successfully decreased dermal thickness, skin hydroxyproline levels and

skin collagen contents [41]. Interestingly, this effect was noted both in a “preventive” (IVIG started immediately after the first BLM injection) and a “curative” (IVIG started 28 days after the first BLM injection) setting. Of note, in an experimental model of pulmonary fibrosis (induced by BLM inhalations), Molina et al. made similar findings. In this work, they showed that IVIG was indeed able to decrease lung hydroxyproline and collagen contents, both in a preventive and curative setting. 4.3. Specific modes of action of IVIG in SSc There is a strong pathophysiological rationale that supports the use of IVIG in SSc. Indeed, IVIG have been shown to modulate many pathways that are involved in inflammation and fibrogenesis, two major phenomena underlying the disease. Several previous works have highlighted specific mechanisms by which IVIG may exert their beneficial properties in SSc. 4.3.1. Modulation of pro- and anti-fibrotic cytokine production The first possible mechanism is by modulation of the production of pro- and anti-fibrotic cytokines. In SSc patients, Kudo et al. observed that IVIG infusions significantly increased serum levels of anti-fibrotic cytokines (such as interleukin (IL)-12 and interferon (IFN)-γ) when compared to placebo [42]. Moreover, IVIG therapy was also associated with higher skin levels of IL-12 and IFN-γ, probably due to an enhanced production by infiltrating T CD4+ cells. In experimental models of SSc, treatment with IVIG has also been shown to lower the production of pro-fibrotic cytokines. Indeed, secretion of IL-4 and TGF-β by TSK splenocytes was significantly decreased in treated animals compared to controls [40]. Similarly, skin levels of TGFβ and monocyte chemoattractant protein (MCP)-1 were significantly lower in BLM mice receiving IVIG than in the control group [42]. 4.3.2. Correction of aberrant pro-fibrotic phenotype in fibroblasts Another mechanism of action of IVIG in SSc may involve an action on skin fibroblasts, whose aberrant activation leads to excessive fibrosis. Indeed, Asano et al. showed that IVIG therapy was able to decrease the expression of several fibrosis markers (procollagen, transforming growth factor (TGF)-β receptor, α-smooth muscle actin (α-SMA) and matrix metalloproteinase (MMP)-1) in SSc patients' skin fibroblasts down to a level similar to healthy controls' [19]. 4.3.3. Neutralization of pathogenic autoantibodies The beneficial properties of IVIG in SSc may also rely on their ability to neutralize pathogenic autoantibodies. Previous studies have shown that immunoglobulins G (IgG) from SSc patients with severe gastrointestinal involvement are able to inhibit contractions of colonic smooth muscle cells in vitro, probably through antibodies directed against type 3-muscarinic receptors (M3R) [43, 44]. This is no longer the case when IVIG are added to the culture medium, which results in a lower fixation of SSc IgG on M3R. These results suggest that IVIG may contain anti-idiotype antibodies that neutralized pathogenic anti-M3R antibodies in SSc sera. A similar phenomenon could occur with pro-fibrotic autoantibodies associated with SSc, and especially antifibroblast antibodies [45]. 4.3.4. Other possible mechanisms Although never specifically studied in SSc patients or experimental models, several other properties of IVIG may also be involved. For instance, IVIG have a direct action on immune cells, and have been shown to induce an expansion of regulatory T cells, a decrease in pro-inflammatory Th17 cells [46], and an activation of and FCγR expression on B cells, which can increase their susceptibility to apoptosis [12].

Please cite this article as: Sanges S, et al, Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literatur..., Autoimmun Rev (2017), http://dx.doi.org/10.1016/j.autrev.2017.02.008

S. Sanges et al. / Autoimmunity Reviews xxx (2017) xxx–xxx

Moreover, IVIG have been shown to modulate reactive oxygen species production [47], which are thought to play a major role in inducing fibrosis in SSc [48,49]. Further studies are warranted to elucidate the exact mechanisms by which IVIG exert their action in SSc. 5. Conclusions In conclusion, our work suggests that IVIG is safe therapeutic option that may be effective in improving musculoskeletal involvement, systemic inflammation, digestive tract symptoms and corticosteroid tapering in SSc. Whether or not the stabilization of skin and lung involvement can be considered as a therapeutic success of IVIG remains to be established. Randomized control trials are warranted to confirm these results. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.autrev.2017.02.008. Competing interests SS received travel fees from LFB. DL received grants from OctaPharma and CSL Behring. Funding This work was supported by a grant from OctaPharma. Acknowledgments The authors wish to thank the Groupe Francophone de Recherche sur la Sclérodermie (GFRS), the Société Nationale Française de Médecine Interne (SNFMI), the Amicale des Jeunes Internistes (AJI) and the Club Rhumatismes et Inflammations (CRI) for their valuable assistance in this work. References [1] Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol 2011;40:78–83. http://dx.doi.org/10.1007/s12016-010-8198-y. [2] Desbois AC, Cacoub P. Systemic sclerosis: an update in 2016. Autoimmun Rev 2016; 15:417–26. http://dx.doi.org/10.1016/j.autrev.2016.01.007. [3] Almeida C, Almeida I, Vasconcelos C. Quality of life in systemic sclerosis. Autoimmun Rev 2015;14:1087–96. http://dx.doi.org/10.1016/j.autrev.2015.07.012. [4] Tamby MC, Chanseaud Y, Guillevin L, Mouthon L. New insights into the pathogenesis of systemic sclerosis. Autoimmun Rev 2003;2:152–7. [5] Sanges S, Guerrier T, Launay D, Lefèvre G, Labalette M, Forestier A, et al. Role of B cells in the pathogenesis of systemic sclerosis. Rev Med Interne 2016. http://dx. doi.org/10.1016/j.revmed.2016.02.016. [6] Sobanski V, Launay D, Hachulla E, Humbert M. Current approaches to the treatment of systemic-sclerosis-associated pulmonary arterial hypertension (SSc-PAH). Curr Rheumatol Rep 2016;18:10. http://dx.doi.org/10.1007/s11926-015-0560-x. [7] Steen V. Targeted therapy for systemic sclerosis. Autoimmun Rev 2006;5:122–4. http://dx.doi.org/10.1016/j.autrev.2005.09.003. [8] Wei J, Bhattacharyya S, Tourtellotte WG, Varga J. Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy. Autoimmun Rev 2011; 10:267–75. http://dx.doi.org/10.1016/j.autrev.2010.09.015. [9] Hachulla E, Wibaux A, Hatron P, Michon-Pasturel U, Queyrel V, Fauchais A, et al. Home sequential high dose intravenous immunoglobulins in systemic autoimmune disease. Ann Rheum Dis 2002;61:277–8. http://dx.doi.org/10.1136/ard.61.3.277-a. [10] Kivity S, Katz U, Daniel N, Nussinovitch U, Papageorgiou N, Shoenfeld Y. Evidence for the use of intravenous immunoglobulins—a review of the literature. Clin Rev Allergy Immunol 2010;38:201–69. http://dx.doi.org/10.1007/s12016-009-8155-9. [11] Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev 2007;6:257–9. http://dx.doi.org/10.1016/j.autrev. 2006.08.011. [12] Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol 2013;13:176–89. http://dx.doi.org/10. 1038/nri3401. [13] Molina V, Blank M, Shoenfeld Y. Intravenous immunoglobulin and fibrosis. Clin Rev Allergy Immunol 2005;29:321–6. http://dx.doi.org/10.1385/CRIAI:29:3:321. [14] Cantarini L, Rigante D, Vitale A, Napodano S, Sakkas LI, Bogdanos DP, et al. Intravenous immunoglobulins (IVIG) in systemic sclerosis: a challenging yet promising future. Immunol Res 2015;61:326–37. http://dx.doi.org/10.1007/s12026-014-8615-z. [15] Bodemer C, Teillac D, Bourgeois ML, Wechsler B, de Prost Y. Efficacy of intravenous immunoglobulins in sclerodermatomyositis. Br J Dermatol 1990;123:545–6. http:// dx.doi.org/10.1111/j.1365-2133.1990.tb01462.x.

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