Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature

    Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature S´ebastien Sanges, S´ebastien Rivi`ere, Ars`ene Mekinian, Thierry Martin, Alain Le Quellec, Emmanuel Chatelus, Alain Lescoat, Patrick Jego, Claire Cazalets, Thomas Qu´em´eneur, No´emie Le Gouellec, Patricia Senet, Camille Franc`es, Alban Deroux, Bernard Imbert, Olivier Fain, Latifatou Boukari, Thomas Sen´e, Christophe Deligny, Alexis Mathian, Christian Agard, Gr´egory ´ Hachulla, Pugnet, Silvia Speca, Sylvain Dubucquoi, Pierre-Yves Hatron, Eric David Launay PII: DOI: Reference:

S1568-9972(17)30048-4 doi: 10.1016/j.autrev.2017.02.008 AUTREV 1974

To appear in:

Autoimmunity Reviews

Received date: Accepted date:

19 December 2016 26 December 2016

Please cite this article as: Sanges S´ebastien, Rivi`ere S´ebastien, Mekinian Ars`ene, Martin Thierry, Le Quellec Alain, Chatelus Emmanuel, Lescoat Alain, Jego Patrick, Cazalets Claire, Qu´em´eneur Thomas, Le Gouellec No´emie, Senet Patricia, Franc`es Camille, Deroux Alban, Imbert Bernard, Fain Olivier, Boukari Latifatou, Sen´e Thomas, Deligny Christophe, Mathian Alexis, Agard Christian, Pugnet Gr´egory, Speca Silvia, Dubucquoi ´ Sylvain, Hatron Pierre-Yves, Hachulla Eric, Launay David, Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature, Autoimmunity Reviews (2017), doi: 10.1016/j.autrev.2017.02.008

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ACCEPTED MANUSCRIPT TITLE Intravenous immunoglobulins in systemic sclerosis: data from a French nationwide

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cohort of 46 patients and review of the literature.

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AUTHORSHIP

Sébastien Sanges1,2,3,4,5, Sébastien Rivière6, Arsène Mekinian6, Thierry Martin7, Alain Le Quellec8, Emmanuel Chatelus9, Alain Lescoat10, Patrick Jego10, Claire Cazalets10,

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Thomas Quéméneur11, Noémie Le Gouellec11, Patricia Senet12, Camille Francès12, Alban Deroux13, Bernard Imbert13, Olivier Fain6, Latifatou Boukari14, Thomas Sené15,

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Christophe Deligny16, Alexis Mathian17, Christian Agard18, Grégory Pugnet19, Silvia Speca1,2, Sylvain Dubucquoi1,2, Pierre-Yves Hatron1,3,4,5, Éric Hachulla1,2,3,4,5*, David

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Launay1,2,3,4,5*

(1) Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International

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Center, F-59000 Lille, France

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(2) INSERM, U995, F-59000 Lille, France (3) CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France

(4) Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), F-59000 Lille, France (5) Healh Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), (6) AP-HP, Hôpital Saint Antoine, Service de Médecine Interne, Paris, France; UPMC Université Paris 06, Faculté de Médecine Pierre et Marie Curie, Paris, France.

ACCEPTED MANUSCRIPT (7) Service d'Immunologie Clinique, Hôpitaux universitaires de Strasbourg, UPR CNRS 3572, Strasbourg, France.

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(8) Service de Médecine Interne et Maladies Multi-Organiques de l'Adulte, Hôpital Saint-Éloi, Centre Hospitalier Régional Universitaire de Montpellier, Montpellier,

(9)

Hôpitaux

Universitaires

de

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France

Strasbourg,

CHU

Hautepierre,

Service

de

Rhumatologie, Centre de Référence des Maladies Auto-Immunes Systémiques

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Rares; Université de Strasbourg; Fédération de Médecine Translationnelle de

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Strasbourg; INSERM UMR 1109, Strasbourg, France. (10) Service de Médecine Interne, Centre Hospitalo-Universitaire de Rennes, Université de Rennes 1, Rennes, France

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(11) Service de Médecine Interne, Néphrologie et Médecine Vasculaire, Centre

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Hospitalier de Valenciennes, Valenciennes, France. (12) Service de Dermatologie, Hôpital Tenon, AP-HP, UPMC, Paris, France

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(13) Service de Médecine Interne, Université Grenoble Alpes, Centre Hospitalier

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Universitaire (CHU) de Grenoble, Grenoble. (14) Service de Médecine Interne, Hôpital Jean-Verdier, AP-HP, Université Paris-13, Bondy, France.

(15) Service de Médecine Interne et Rhumatologie, GH Diaconesses Croix Saint Simon, Paris, France. (16) Service de Médecine Interne et Rhumatologie 3C/5D, Centre Hospitalier Universitaire Pierre Zobda-Quitman, Fort-de-France, Martinique. (17) Service de Médecine Interne 2, Centre de Référence National pour le Lupus et le Syndrome des Antiphospholipides, institut E3M, Groupe Hospitalier Pitié-

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ACCEPTED MANUSCRIPT Salpêtrière, AP-HP, Paris, France; Sorbonne universités, UPMC université Paris 06, 75013 Paris, France.

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(18) Service de Médecine interne, Hôtel-Dieu, CHU de Nantes, Université de Nantes, Nantes, France.

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(19) CHU, Université de Toulouse, Faculté de Médecine, Service de Médecine Interne, Toulouse, France; INSERM, UMR 1027, Toulouse, France.

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* EH and DL contributed equally to this work.

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CORRESPONDENCE Prof. David Launay

Mailing address: Service de Médecine Interne et d’Immunologie Clinique, Hôpital

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Tel: + 33 3 20 44 56 50

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Claude-Huriez, CHRU Lille, Rue Michel Polonovski, 59037 LILLE Cedex, France

Fax: + 33 3 20 44 54 59

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E-mail: [email protected]

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ACCEPTED MANUSCRIPT ABSTRACT Background: As intravenous immunoglobulins (IVIG) exhibit immunomodulatory and

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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

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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

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a dosage > 1g/kg/cycle. Relevant data collected at IVIG discontinuation were

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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%,

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p<0.0001), muscle weakness (45% vs. 21%, p=0.01), joint pain (44% vs. 19%,

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p=0.02), CK levels (1069  1552 UI vs. 288  449 UI, p<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

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improvement of gastro-esophageal reflux disease (68% vs. 53%, p=0.06) and bowel

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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/d vs. 8.9  10.4 mg/d, p=0.01). Only two severe adverse events were reported (one case of deep vein thrombosis and one case of diffuse edematous syndrome). 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.

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ACCEPTED MANUSCRIPT

Systemic sclerosis



Intravenous immunoglobulins



Fibrosis



Inflammatory myopathies

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

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KEYWORDS

HIGHLIGHTS

IVIG therapy is a safe therapeutic option in SSc patients.



IVIG may improve muscle, joint and digestive tract involvements in SSc patients.



IVIG may facilitate corticosteroid tapering in SSc patients.

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

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ACCEPTED MANUSCRIPT 1. INTRODUCTION Systemic sclerosis (SSc) is a rare and severe condition classified within the

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connective tissue diseases [1]. It is associated with several debilitating complications (notably digital ulcers, interstitial lung disease (ILD), pulmonary hypertension and

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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

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immunological (dysregulation of cellular and humoral immune systems) components

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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])

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and immune-targeted therapies [7] (from conventional immunosuppressants and

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biologics to hematopoietic stem cell transplantation). However, there are currently no therapeutic strategy specifically aimed at preventing or reversing fibrogenesis [8], a

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major phenomenon in SSc pathogenesis.

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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

pathophysiological relevance to their use as a potential treatment in SSc [14].

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ACCEPTED MANUSCRIPT Several previous works have suggested the efficacy of IVIG therapy on skin, muscle, joint and digestive tract involvements [15–31]. However, most of these

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studies were case series or open-label single-center trials performed on limited patient samples.

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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

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nationwide patient cohort, as well as reviewed the available literature.

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2. PATIENTS & METHODS 2.1. Patient selection

Patients were recruited from 19 tertiary care centers across France. They were

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included in the study if they fulfilled all the following criteria: (1) a definite diagnosis of

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SSc according to the 2013 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) classification criteria [32]; (2) administration of

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at least one IVIG cycle; (3) completion of at least one follow-up visit; (4) an age over

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18 years old. They were excluded if IVIG were prescribed exclusively for hypogammaglobulinemia substitution (i.e. at a dosage < 1g/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,

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ACCEPTED MANUSCRIPT nailfold capillaroscopy; (2) SSc organ involvements: skin (Raynaud phenomenon, digital ulcers, calcinosis, telangiectasias), lung (ILD staged according to Goh’s criteria pulmonary

hypertension),

kidney

(scleroderma

renal

crisis),

heart

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[34],

(dysrhythmias, conduction disorders, diastolic dysfunction, systolic dysfunction,

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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, elevated

creatine-kinase

(CK)

levels,

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weakness,

myogenic

pattern

on

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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.

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Data regarding patient evolution during IVIG course were collected at baseline

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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

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Rodnan skin score (mRSS), digital ulcers, New York Heart Association (NYHA)

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functional score, 6-minute 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 < 3/5 according to the Medical Research Council (MRC) manual muscle strength scoring system [35]); (2) biological data: hemoglobin, platelets, creatinin and glomerular filtration rate (GFR) estimated by the Modification of Diet in Renal Disease (MDRD) equation, brain natriuretic peptide (BNP) and Ntpro-BNP, C-reactive 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

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ACCEPTED MANUSCRIPT (sPAP), pericardial effusion; (5) chest high-resolution CT-scan: ground-glass opacities (GGO), fibrotic lesions; (6) associated treatments: anti-inflammatory,

(including

nausea/vomiting,

tachycardia,

arterial

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immunosuppressing and immunomodulatory drugs; (7) adverse effects: minor events hypertension/hypotension,

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fever/chills, skin rash, headache), major events (including anaphylaxis, acute renal failure, arterial or venous thrombosis, aseptic meningitis).

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2.3. Statistical analyses

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Characteristics of the population were described using mean ± standard deviation (SD) for quantitative variables, and number (n), percentage (%) for qualitative variables.

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Relevant data from baseline evaluation (performed within a 3-month period before

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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 more than 2 years) were

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compared using Wilcoxon test. Significance was set p<0.05.

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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

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ACCEPTED MANUSCRIPT (20%). A vast majority of patients had an overlap syndrome with another connective tissue disease, especially with idiopathic inflammatory myopathies (85%).

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Major organ involvements related to SSc were common features in our cohort. Frequent complications notably included digital ulcers (52%), ILD (57%), digestive

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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-

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inflammatory, immunosuppressive or immunomodulatory drug for a mean duration of

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2.67 ± 3.65 years. Treatment regimens usually included corticosteroids (80%), either

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alone (26%) or combined with conventional immunosuppressants (54%).

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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of the study population. Value

46 46

37 (80%) 51.3 ( 15.4)

46 41 36

4.1 ( 5.2) 4.2 ( 4.8) 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%)

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20 (69%)

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

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%)

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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 autoantibodies* (n, %) Nailfold capillaroscopy Specific organic microangiopathy (n, %)

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Demographics Female (n, %) Age at IVIG initiation (mean  SD)

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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, %)

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ACCEPTED MANUSCRIPT 46 46 46 46 46 46 46 46 29 25

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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, %)

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History of treatments Delay between first treatment and IVIG initiation (years, mean  SD) No previous treatment (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, %)

45 45 45 45 45 45 45 45 45 45 45 45 45

23 (50%) 23 (50%) 5 (11%) 0 (0%) 36 (78%) 36 (78%) 32 (70%) 36 (78%) 24 (83%) 25 (100%) 2.67 ( 3.65) 7 (16%) 3 (7%) 36 (80%) 12 (27%) 2 (4%) 18 (40%) 4 (9%) 7(16%) 3 (7%) 1 (2%) 1 (2%) 3 (7%)

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dc: diffuse cutaneous; ILD: interstitial lung disease; IV: intravenous; IVIG: intravenous immunoglobulins; lc: limited cutaneous; n: number; SD: standard deviation; SSc: systemic sclerosis.

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*Other autoantibodies: rheumatoid factor (n=2); anti-Mi2 antibodies (n=1); anti-SRP antibodies (n=1); anti-phospholipid antibodies (n=1); anti-MPO antibodies (n=1).

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ACCEPTED MANUSCRIPT 3.2. IVIG treatment modalities Detailed IVIG treatment modalities are described in Table 2. Overall, patients

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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

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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 involvements (11%). IVIG were equally used as a recourse therapy in case of failure

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of a previous therapeutic regimen (50%) and as a first-line therapy (50%) for a given

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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

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immunomodulating drugs in the vast majority of cases (93%). In 35% of patients,

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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

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initiation and/or during IVIG course.

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ACCEPTED MANUSCRIPT Table 2. IVIG treatment modalities.

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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, %)

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%)

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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, %)

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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 therapy* at IVIG initiation Modification of background therapy* during IVIG course No modification of background therapy* at any time

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

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ACCEPTED MANUSCRIPT 3.3. Follow-up characteristics of the study population Data were collected at regular time points during follow-up until IVIG cessation

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and are detailed in Supplementary Table 1. To assess the potential benefits of IVIG

the first and after the last IVIG cycle (Table 3).

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administration in our patients, we compared relevant data from evaluations before

We observed a significant improvement of muscle involvement, with a reduction of pain (74% vs. 20%, p<0.0001), weakness (45% vs. 21%, p=0.01) and CK levels

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(1069  1552 UI vs. 288  449 UI, p<0.0001). We also noted a significant decrease in

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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. p=0.06) and

bowel

symptoms (42%

vs. 27%,

p=0.06).

Skin and

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53%,

cardiorespiratory involvements remained stable. Finally, corticosteroid daily dose was

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significantly lower by the end of treatment (13.0  11.6 mg/d vs. 8.9  10.4 mg/d, p=0.01).

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Only two severe adverse events were reported (one case of deep vein thrombosis

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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/1.73m2 vs. 114  61 mL/min/1.73m2, 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 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

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ACCEPTED MANUSCRIPT 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

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the study.

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ACCEPTED MANUSCRIPT Table 3. Characteristics of the study population at first and at last IVIG cycles. 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 <0.0001 0.01 0.31 0.12 0.14 0.07 0.85 0.75 0.99 0.001 <0.0001

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

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First IVIG Value

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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 < 3/5 (n, %) Hemoglobin (g/dL, mean ± SD) Platelets (G/L, mean ± SD) Creatinin (µmol/L, mean ± SD) 2 Estimated GFR (mL/min/1.73m , 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 (mmHg, 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/d, mean ± SD)

N

6MWD: 6-minute walk distance; BNP: brain natriuretic peptide; CK: creatin 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.

17

ACCEPTED MANUSCRIPT 4. DISCUSSION AND REVIEW OF THE LITTERATURE In this study, we tried to report on the efficacy and safety of IVIG treatment in a

PT

large multi-center cohort of SSc patients. Our results can be summarized as follows: (1) IVIG therapy may improve musculoskeletal involvement, systemic inflammation,

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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

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multicenter recruitment. It also has several limitations, in particular its retrospective

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design, the amount of missing data, the potential 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

ED

inflammatory myopathies, which constitutes a specific patient subset and is probably

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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

AC

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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] (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].

18

ACCEPTED MANUSCRIPT 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

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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

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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

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esophageal and bowel manifestations. Indeed, both studies described an

MA

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

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Gastro-Intestinal Tract 2.0 total score). Though only close to statistical significance,

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our results tend to confirm these observations as well. Regarding skin involvement, our findings contrast with those from previous

CE

publications. Indeed, several open-label studies [18,21,22,30,31] and case reports

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[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-penicillamin 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 placebocontrolled 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

19

ACCEPTED MANUSCRIPT 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

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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

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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].

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Regarding respiratory involvement, our results are in line with most previously

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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

ED

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

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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

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respiratory symptoms and PFT parameters in patients with progressive idiopathic

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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].

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ACCEPTED MANUSCRIPT 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

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on calcinosis [15,23] and tendon friction rubs [30], which could not be investigated in our work.

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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].

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Whether these results reflect an actual efficacy of this treatment on corticoresistance

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remains unclear.

4.2. Effects of IVIG in SSc experimental models

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Aside from studies on SSc patients, several observations made in experimental

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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

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in the fibrillarin gene causes systemic fibrosis, Blank et al. studied the effects of

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human IVIG administered from the 4th week of life during one month, for a total dose of 2g/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 hydroxyprolin 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

21

ACCEPTED MANUSCRIPT was indeed able to decrease lung hydroxyprolin and collagen contents, both in a

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preventive and curative setting.

4.3. Specific modes of action of IVIG in SSc

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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.

MA

exert their beneficial properties in SSc.

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Several previous works have highlighted specific mechanisms by which IVIG may

4.3.1. Modulation of pro- and anti-fibrotic cytokine production

ED

The first possible mechanism is by modulation of the production of pro- and anti-

PT

fibrotic cytokines.

In SSc patients, Kudo et al. observed that IVIG infusions significantly increased

CE

serum levels of anti-fibrotic cytokines (such as interleukin (IL)-12 and interferon

AC

(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 TGF-β 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

22

ACCEPTED MANUSCRIPT Another mechanism of action of IVIG in SSc may involve an action on skin fibroblasts, whose aberrant activation leads to excessive fibrosis.

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Indeed, Asano et al. showed that IVIG therapy was able to decrease the expression of several fibrosis markers (procollagen, transforming growth factor

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(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’

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[19].

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4.3.3. Neutralization of pathogenic autoantibodies

The beneficial properties of IVIG in SSc may also rely on their ability to neutralize pathogenic autoantibodies.

ED

Previous studies have shown that immunoglobulins G (IgG) from SSc patients

PT

with severe gastrointestinal involvement are able to inhibit contractions of colonic smooth muscle cells in vitro, probably through antibodies directed against type 3-

CE

muscarinic receptors (M3R) [43,44]. This is no longer the case when IVIG are added

AC

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.

23

ACCEPTED MANUSCRIPT 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

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[46], and an activation and FCγR expression on B cells, which can increase their susceptibility to apoptosis [12].

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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].

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Further studies are warranted to elucidate the exact mechanisms by which IVIG

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ED

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exert their action in SSc.

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ACCEPTED MANUSCRIPT 5. CONCLUSIONS In conclusion, our work suggests that IVIG is safe therapeutic option that may be

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effective in improving musculoskeletal involvement, systemic inflammation, digestive tract symptoms and corticosteroid tapering in SSc. Whether or not the stabilization of

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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

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results.

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ACKNOWLEDGMENTS

The authors wish to thank the Groupe Francophone de Recherche sur la Sclérodermie (GFRS), the Société Nationale Française de Médecine Interne

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(SNFMI), the Amicale des Jeunes Internistes (AJI) and the Club Rhumatismes et

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Inflammations (CRI) for their valuable assistance in this work.

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COMPETING INTERESTS

Behring.

AC

SS received travel fees from LFB. DL received grants from OctaPharma and CSL

FUNDING This work was supported by a grant from OctaPharma.

25

ACCEPTED MANUSCRIPT REFERENCES [1]

Hachulla E, Launay D. Diagnosis and Classification of Systemic Sclerosis. Clin

[2]

Desbois AC, Cacoub P. Systemic sclerosis: An update in 2016. Autoimmun

SC RI

Rev 2016;15:417–26. doi:10.1016/j.autrev.2016.01.007. [3]

PT

Rev Allergy Immunol 2011;40:78–83. doi:10.1007/s12016-010-8198-y.

Almeida C, Almeida I, Vasconcelos C. Quality of life in systemic sclerosis.

Autoimmun Rev 2015;14:1087–96. doi:10.1016/j.autrev.2015.07.012. Tamby MC, Chanseaud Y, Guillevin L, Mouthon L. New insights into the

NU

[4]

[5]

MA

pathogenesis of systemic sclerosis. Autoimmun Rev 2003;2:152–7. 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 Médecine Interne

Sobanski V, Launay D, Hachulla E, Humbert M. Current Approaches to the

PT

[6]

ED

2016. doi:10.1016/j.revmed.2016.02.016.

Treatment of Systemic-Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-

Steen V. Targeted therapy for systemic sclerosis. Autoimmun Rev

AC

[7]

CE

PAH). Curr Rheumatol Rep 2016;18:10. doi:10.1007/s11926-015-0560-x.

2006;5:122–4. doi: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. doi: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. doi: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

26

ACCEPTED MANUSCRIPT Rev Allergy Immunol 2010;38:201–69. doi:10.1007/s12016-009-8155-9. Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous

immunoglobulin

(IVIG)

therapy.

Autoimmun

doi:10.1016/j.autrev.2006.08.011.

modulate

the

immune

system?

Nat

doi:10.1038/nri3401.

Rev

Immunol

2013;13:176–89.

Molina V, Blank M, Shoenfeld Y. Intravenous immunoglobulin and fibrosis. Clin

NU

[13]

2007;6:257–9.

Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG

SC RI

[12]

Rev

PT

[11]

[14]

MA

Rev Allergy Immunol 2005;29:321–6. doi:10.1385/CRIAI:29:3:321. Cantarini L, Rigante D, Vitale A, Napodano S, Sakkas LI, Bogdanos DP, et al.

Intravenous immunoglobulins (IVIG) in systemic sclerosis: a challenging yet

Bodemer C, Teillac D, Bourgeois ML, Wechsler B, Prost Y de. Efficacy of

intravenous

PT

[15]

ED

promising future. Immunol Res 2015;61:326–37. doi:10.1007/s12026-014-8615-z.

immunoglobulins

in

sclerodermatomyositis.

Br

J

Dermatol

score

Levy Y, Sherer Y, Langevitz P, Lorber M, Rotman P, Fabrizzi F, et al. Skin

AC

[16]

CE

1990;123:545–6. doi:10.1111/j.1365-2133.1990.tb01462.x.

decrease

in

systemic

sclerosis

patients

treated

with

intravenous

immunoglobulin--a preliminary report. Clin Rheumatol 2000;19:207–11. [17]

Amital H, Rewald E, Levy Y, Bar-Dayan Y, Manthorpe R, Engervall P, et al.

Fibrosis regression induced by intravenous gammaglobulin treatment. Ann Rheum Dis 2003;62:175–7. doi:10.1136/ard.62.2.175. [18]

Levy Y, Amital H, Langevitz P, Nacci F, Righi A, Conforti L, et al. Intravenous

immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic

sclerosis:

An

open-label study.

doi:10.1002/art.20195.

27

Arthritis

Rheum

2004;50:1005–7.

ACCEPTED MANUSCRIPT [19]

Asano Y, Ihn H, Asashima N, Yazawa N, Mimura Y, Jinnin M, et al. A case of

diffuse scleroderma successfully treated with high-dose intravenous immune globulin

[20]

PT

infusion. Rheumatology 2005;44:824–6. doi:10.1093/rheumatology/keh600. Levy Y, Uziel Y, Zandman G, Rotman P, Amital H, Sherer Y, et al. Response

SC RI

of Vasculitic Peripheral Neuropathy to Intravenous Immunoglobulin. Ann N Y Acad Sci 2005;1051:779–86. doi:10.1196/annals.1361.121. [21]

Ihn H, Mimura Y, Yazawa N, Jinnin M, Asano Y, Yamane K, et al. High-dose

NU

intravenous immunoglobulin infusion as treatment for diffuse scleroderma. Br J

[22]

MA

Dermatol 2007;156:1058–60. doi:10.1111/j.1365-2133.2007.07777.x. Nacci F, Righi A, Conforti ML, Miniati I, Fiori G, Martinovic D, et al. Intravenous

immunoglobulins improve the function and ameliorate joint involvement in systemic a

pilot

study.

ED

sclerosis:

Ann

Rheum

Dis

2007;66:977–9.

Schanz S, Ulmer A, Fierlbeck G. Response of dystrophic calcification to

intravenous

immunoglobulin.

Arch

CE

[23]

PT

doi:10.1136/ard.2006.060111.

Dermatol

2008;144:585–7.

[24]

AC

doi:10.1001/archderm.144.5.585. Szekanecz Z, Aleksza M, Antal-Szalmás P, Soltész P, Veres K, Szántó S, et

al. Combined plasmapheresis and high-dose intravenous immunoglobulin treatment in systemic sclerosis for 12 months: follow-up of immunopathological and clinical effects. Clin Rheumatol 2008;28:347–50. doi:10.1007/s10067-008-1062-2. [25]

Zandman-Goddard G, Krauthammer A, Levy Y, Langevitz P, Shoenfeld Y.

Long-term therapy with intravenous immunoglobulin is beneficial in patients with autoimmune

diseases.

Clin

Rev

Allergy

Immunol

2012;42:247–55.

doi:10.1007/s12016-011-8278-7. [26]

Takehara K, Ihn H, Sato S. A randomized, double-blind, placebo-controlled

28

ACCEPTED MANUSCRIPT trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Clin Exp Rheumatol 2013;31:151–6. Mauhin W, Rivière S, Cabane J, Tiev KP. Improvement in lung fibrosis using

PT

[27]

intravenous immunoglobulin in systemic sclerosis with myositis. Scand J Rheumatol

[28]

SC RI

2014;43:170–1. doi:10.3109/03009742.2013.868510.

Abelha-Aleixo J, Bernardo A, Costa L. Benefit of intravenous immunoglobulin

in a patient with longstanding polymyositis/systemic sclerosis overlap syndrome. Acta

Clark KEN, Etomi O, Denton CP, Ong VH, Murray CD. Intravenous

MA

[29]

NU

Reumatol Port 2015;40:176–8.

immunogobulin therapy for severe gastrointestinal involvement in systemic sclerosis. Clin Exp Rheumatol 2015;33:S168-170.

Poelman CL, Hummers LK, Wigley FM, Anderson C, Boin F, Shah AA.

ED

[30]

cutaneous

PT

Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse systemic

sclerosis.

J

Rheumatol

2015;42:236–42.

Raja J, Nihtyanova SI, Murray CD, Denton CP, Ong VH. Sustained benefit

AC

[31]

CE

doi:10.3899/jrheum.140833.

from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis. Rheumatol Oxf Engl 2016;55:115–9. doi:10.1093/rheumatology/kev318. [32]

van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et

al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 2013;72:1747–55. doi:10.1136/annrheumdis-2013-204424. [33]

LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, et al.

Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202–5.

29

ACCEPTED MANUSCRIPT [34]

Goh NSL, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, et

al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J

Aids to the examination of the

peripheral nervous system. London: Her

Majesty’s Stationery Office; 1981. [36]

Dalakas

MC.

High-dose

SC RI

[35]

PT

Respir Crit Care Med 2008;177:1248–54. doi:10.1164/rccm.200706-877OC.

intravenous

immunoglobulin

in

inflammatory

myopathies: experience based on controlled clinical trials. Neurol Sci 2003;24 Suppl

Maurer B, Graf N, Michel BA, Müller-Ladner U, Czirják L, Denton CP, et al.

MA

[37]

NU

4:S256-259. doi:10.1007/s10072-003-0090-6.

Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann Rheum Dis 2015;74:1124–31.

Enomoto N, Chida K, Suda T, Kaida Y, Taniguchi M, Azuma A, et al. An

PT

[38]

ED

doi:10.1136/annrheumdis-2014-205226.

exploratory trial of intravenous immunoglobulin therapy for idiopathic pulmonary a

preliminary

CE

fibrosis:

multicenter

report.

Clin

Respir

J

2016;10:746–55.

[39]

AC

doi:10.1111/crj.12281.

Muangchan C, Harding S, Khimdas S, Bonner A, Canadian Scleroderma

Research group, Baron M, et al. Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group. Arthritis Care Res 2012;64:1405–14. doi:10.1002/acr.21716. [40]

Blank M, Levy Y, Amital H, Shoenfeld Y, Pines M, Genina O. The role of

intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice. Arthritis Rheum 2002;46:1689–90. doi:10.1002/art.10363. [41]

Kajii M, Suzuki C, Kashihara J, Kobayashi F, Kubo Y, Miyamoto H, et al.

Prevention

of

excessive

collagen

accumulation

30

by

human

intravenous

ACCEPTED MANUSCRIPT immunoglobulin treatment in a murine model of bleomycin-induced scleroderma. Clin Exp Immunol 2011;163:235–41. doi:10.1111/j.1365-2249.2010.04295.x. Kudo H, Jinnin M, Yamane K, Makino T, Kajihara I, Makino K, et al.

PT

[42]

Intravenous immunoglobulin treatment recovers the down-regulated levels of Th1

SC RI

cytokines in the sera and skin of scleroderma patients. J Dermatol Sci 2013;69:77– 80. doi:10.1016/j.jdermsci.2012.09.010. [43]

Singh J, Cohen S, Mehendiratta V, Mendoza F, Jimenez SA, Dimarino AJ, et

NU

al. Effects of scleroderma antibodies and pooled human immunoglobulin on anal

doi:10.1053/j.gastro.2012.07.109. [44]

MA

sphincter and colonic smooth muscle function. Gastroenterology 2012;143:1308–18.

Kumar S, Singh J, Kedika R, Mendoza F, Jimenez SA, Blomain ES, et al. Role

ED

of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease

PT

duration and effects of IVIG. Am J Physiol - Gastrointest Liver Physiol 2016;310:G1052–60. doi:10.1152/ajpgi.00034.2016. Chizzolini C, Raschi E, Rezzonico R, Testoni C, Mallone R, Gabrielli A, et al.

CE

[45]

AC

Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 2002;46:1602–13. doi:10.1002/art.10361. [46]

Lee S-Y, Jung Y-O, Ryu J-G, Kang C-M, Kim E-K, Son H-J, et al. Intravenous

immunoglobulin attenuates experimental autoimmune arthritis by inducing reciprocal regulation of Th17 and Treg cells in an interleukin-10-dependent manner. Arthritis Rheumatol Hoboken NJ 2014;66:1768–78. doi:10.1002/art.38627. [47]

Semple JW, Kim M, Hou J, McVey M, Lee YJ, Tabuchi A, et al. Intravenous

Immunoglobulin Prevents Murine Antibody-Mediated Acute Lung Injury at the Level of

Neutrophil

Reactive

Oxygen

Species

31

(ROS)

Production.

PLOS

ONE

ACCEPTED MANUSCRIPT 2012;7:e31357. doi:10.1371/journal.pone.0031357. [48]

Kavian N, Marut W, Servettaz A, Nicco C, Chéreau C, Lemaréchal H, et al.

PT

Reactive oxygen species–mediated killing of activated fibroblasts by arsenic trioxide

2012;64:3430–3440. doi:10.1002/art.34534. [49]

SC RI

ameliorates fibrosis in a murine model of systemic sclerosis. Arthritis Rheum

Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, et al.

Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med

AC

CE

PT

ED

MA

NU

2006;354:2667–76. doi:10.1056/NEJMoa052955.

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Follow-up data Mu Joi Dig Other scl nts esti visceral e ve involvement trac s t

NA NA NA NA

Activity, Toleranc severity, e function al impairm ent

Improved NA HAQ score

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Levy 2004 [18]

MA

Refe renc es

Disease Study characteristics characteristics Baseline data Treatment modalities Type N Inclus Excl Demo Dis Sero Sk Lu Mu Joi Dig Other Previous IGIV Dur Ass Eval Skin Lun ion usio graphi eas logic in ng scl nts esti viscer treatmen administrati atio ociat uati gs criteri n cs e al ve al ts on scheme n ed on (m, s e a (for crite (m, SD dur profi SD (m trac involv treat time trials) ria or atio le t emen ment poin ) , (for range) n ts s ts or S indicat trials (m, D) ) ion SD) (for case report s) Interv 15 Not None Femal 4.7 NA dc IL IIM NA GI Kidne NA IVIG 2g/kg 6 NA 6 Impr NA ention clearly e ± SS D (2/ (8/1 y over 5 days mo mont oved al stated (93%) 4.8 c (8/ 15) 5) (2/15) per cycle nth hs uncon 48 ± yea (10 15 Heart 1 cycle per s (11/1 mRS trolled 12 rs /15 ) (1/15) month (11/ 5) S openyears ) P 15) 4 18.9 label old lcS H 4 mont ± Sc (1/ mo hs 7.95 (5/ 15 nth (3/15 15) ) s ) (3/1 3 m 5) mont RS 3 hs S mo (1/15 28. nth ) 9± s 7.1 (1/1 5 5) Interv 5 Active None Femal 7.6 NA dc N NA NA NA NA NA IVIG 2g/kg NA None 2, 4, Impr NA ention diseas e ± SS A over 5 days 8, 12 oved al e (100% 6.8 c 1 cycle only? wee uncon (incre ) yea (5/ ks mRS trolled ase in 56.2 ± rs 5) 34 to S ≈ openmRSS 5.0 70 9.0 ± label ) years m wee 6.67 over old RS ks at more S week than 3 ≈ 4

Ihn 2007 [21]

NA NA NA DU healing in NA 1 patient

Headach e (1/5) Nausea (1/5)

ACCEPTED MANUSCRIPT 18. 2± 7.2 6

Interv 7 Sever RA Femal ention e and overl e al refract ap (100% uncon ory Unab ) trolled joint ility 51.8 openinvolv to (34label ement distin 68) guish years joint old from skin invol vem ent

3.6 NA ± 2.5 yea rs

dc IL NA SS D c (at (2/ lea 7) st lcS 3/ Sc 7) (5/ 7) m RS S 29. 2± 8.3

Art NA NA hrit is (7/ 7) SJ C 10 ± 1.7 TJ C 18. 8± 1.3 VA S 4.7 ±

AC CE

Nacc i 2007 [22]

PT ED

MA

NU

SC RI

PT

month s

NSAID (7/7) CS (7/7) MTX (4/7) CYC (3/7)

IVIG 2g/kg over 4 days per cycle 1 cycle per month

2

6 NA mo nth s (7/7 )

mRS S≈ 10 ± 5.74 at week 12 decr ease d histol ogica l thick ness at 6 mont hs 6 Impr NA NA Impr NA NA mont oved ove hs d: mRS S SJC 21.1 7.0 ± 4.6 ± 1.0 TJC 10.2 ± 2.3 VAS 0.7 ± 1.7

Improved No HAQ adverse score effect

ACCEPTED MANUSCRIPT

NU

CS IVIG 2g/kg 1 CS < 12 (23/31) over 5 days cycl 15 wee DMARD 1 cycle only e mg/d ks (17/31) only No DMA RD

MA

dc N NA NA NA NA SS A c (31 /31 ) m RS S 29. 2± 6.0

PT ED

antitopo I (17/3 1) antiCm (5/31 ) antiU1R NP (2/31 )

AC CE

Take hara 2013 [26]

31 dcSSc Seve Femal 6.1 IVIG with re e ± vs mRSS hepa (77.4% 7.4 32 > 20 tic, ) yea PCB No renal 54.3 ± rs chang , 12.1 e or cardi years worse ac old ning disor in ders mRSS Malig during nant Interv a 12- tumo ention week rs al evalu Histo rando ation ry of mized period strok place Failur e boe/CI IgA contr of defici olled previo ency doubl us eCS/D blind MAR D Age > 16 years old

SC RI

PT

1.9

3

No No NA NA NA NA differ diffe ence renc with e PCB with grou PC p: B grou ΔmR p SS - (FV 3.3 ± C, 4.2 DLC (IVIG O) ) vs 4.2 ± 4.6 (PCB ) Mea n chan ge in derm al fibrot ic thick ness 2.23 %± 34.4 8 (IVIG

No Adverse differenc effects e of HAQ (10/31): score fever, with PCB elevated group CRP, elevated ALT

IVIG 2g/kg over 5 days 2nd cycle

1 extr a cycl e (24 wee ks afte r 1st cycl e)

AC CE

PT ED

MA

NU

SC RI

18 No IVIG respo +IVI nse G (ΔmR vs SS < 19 5) PCB to a +IVI first G IVIG cycle

PT

ACCEPTED MANUSCRIPT

4

) vs 7.51 %± 25.5 5 (PCB ) 60 Signi NA NA NA NA NA wee ficant ks differ (afte ence r 1st with cycle place ) bo grou p: ΔmR SS 8.3 ± 1.0 (IVIG +IVI G) vs 4.1 ± 1.1 (PCB +IVI G)

NA

Adverse effects (7/18)

ACCEPTED MANUSCRIPT 8.5 CS ± (10/3 5.3 0) cycl MTX es (3/30 9.4 ) ± CYC 6.9 (6/30 mo ) nth HCQ s (1/30 ) MMF (21/3 0) Imati ninb (1/30 )

PT

IVIG 2g/kg over 3-5 days per cycle 1 cycle per month

SC RI

CS (19/30) MTX (8/30) AZA (3/30) CYC (8/30) D-Pen (3/30) HCQ (8/30) Minocycli ne (1/30) Colchicin e (1/30) Anti-TNF (2/30) MMF (25/30) LFL (1/30) Imatinib (2/30) Rapamyc ine (1/30) Other (4/30)

NU

anti- dc FV IIM NA NA NA topo SS C (5/ I c 83 30) (5/30 (30 .0 ) /30 ± anti- ) 19 Cm - .6 (0/30 m DL ) RS C anti- S O RNA 29. 76 pol III 6 ± .3 (14/3 7.2 ± 0) 21 anti.0 RNP (2/30 )

MA

24. 6± 19. 9 mo nth s

PT ED

Interv 30 Active Use Femal ention dcSSc of e al deter IVIG (80%) contr mined for 46.6 ± olled by the 12.3 opentreatin sole years label g purp old physic ose ian's of clinica treati l ng judgm IIM ent or other indic ation s

AC CE

Poel man 2015 [30]

5

6 Impr Sta Imp NA NA Improved and oved ble rov tendon 12 ed friction rubs mont mRS FVC Stable hs S 83.8 Me Medsger 24.1 ± dsg organ score ± 9.6 16.8 er at 6 at mus mont 12 cle hs mon sev (NS ths erity vs scor relaxi DLC e n) O 79.9 Mus mRS ± cle S 23.1 enz 22.5 at yme ± 12 s 10.0 mon (nor at 12 ths mal mont CK hs in (signi IIM ficant pati vs Dents pen ) and colla gen) mRS S 20.6 ± 11.8 at 18 mont hs mRS S 15.3

Improved 2 SAE HAQ-DI leading to score IVIG (NS) discontin Improved uation: patient TIA and (1/30), physician aseptic assesse meningiti ments of s (1/30) disease activity

ACCEPTED MANUSCRIPT

anti- dc IL topo SS D I c (5/ (3/15 (11 15 ) /15 ) anti- ) RNA lcS pol III Sc (4/15 (4/ ) 15) anti- U3R m NP RS (1/15 S ) 21. anti- 5 ± Jo1 13. (2/15 8 ) antiPL7 (1/15 ) antiSSA &SS B

IIM NA (15 /15 ) M RC su m sc ore 51. 7± 3.6 CK 19 2 U/l (ra ng e 3531 92)

GI Heart (4/15) RD Kidne Q: y sev (1/15) ere and freq uent sym pto ms UCL A SCT C GIT 1.07 ± 0.67

MTX IVIG 2g/kg 29. (6/15) over 1-3 7± MMF days per 37. (5/15) cycle 6 CYC 1 cycle per mo (7/15) month nth CSA (progressivel s (3/15) y extended to AZA 6 weeks, 8 (3/15) weeks, 3 HCQ months, or 4 (2/15) months) RTX (1/15) TOC (1/15) IFX (1/15) CS (1/15)

PT ED

7.0 ± 3.9 yea rs

AC CE

Raja Interv 15 Unsati None Femal 2015 ention sfacto e [31] al ry (87%) uncon clinica 47.3 ± trolled l 12 openrespo years label nse old of IIM to stand ard DMA RD

MA

NU

SC RI

PT

± 6.4 at 24 mont hs

6

MTX Last Impr Sta Imp NA (3/15 follo oved ble rov ) w-up ed MMF mRS (9/15 S 10 MR ) ± C HCQ 10.6 sum (4/15 scor ) e CS 56. (13/1 5± 5) 2.9 CK 77 U/l (ran ge 42465 )

Impr No ove recurrence of d DU in 4 out of 7 RD patients Q: with previous decr DU history eas e in sym pto m freq uen cy and inte nsit y UCL A SCT C GIT 0.60 ±

CS NA tapering (8/13): median dose reduction 8.75 mg (range 2.5-17.5)

ACCEPTED MANUSCRIPT 0.46

AC CE

PT ED

MA

NU

SC RI

PT

(1/15 ) ANA +, no speci ficity (3/15 )

7

ACCEPTED MANUSCRIPT

Abelh aAleix o 2015 [28]

Ca se re po rt

ANA + dcSS "ILD homog c with eneous restri pattern ctive (no syndr specific ome" ity)

"Gene ralized joint pain"

NA

"Bene NA ficial effect"

Impro NA ved RDQ:l ess than once a week UCLA SCTC GIT: 2.05

NA NA

"Bene NA ficial effect"

Impro NA ved RDQ: no signifi cant chang e UCLA SCTC GIT: 1.25 NA NA

NA NA

PT

IVIG NA NA 11. NA 2g/kg (MMF?) 5 over 5 mo days nth per s cycle Frequ ency?

SC RI

IIM Muscl e weak ness (MRC 3-4/5) Dysph onia, dysph

Heart CS + (cardiom MTX yositis?) CYC MMF

NU

1 Per No Fe 2 sist ne mal yea anc e rs e of 49 sev yea ere rs mu old scle invo lve me nt

IIM NA - CK norma l

GI Sever e sympt oms RDQ: "most days a week" UCLA SCTC GIT: 2.75 GI Sever e sympt oms (SIBO, CIPO) UCLA SCTC GIT: 1.69

MA

IIM NA Muscl e weak ness EMG + - CK norma l

Heart CS + (specific MMF cardiomy CYC opathy)

PT ED

2 Sev No Fe NA antidcSS Decr ere ne mal RNA c ease GI e pol III + d dise 43 mRS lung ase yea S volu unr rs 29/51 mes esp old (FVC onsi 68.3 ve %) to con ven tion al ther apy Mal NA antidcSS NA e U3c 48 RNP + yea rs old

AC CE

Clark Ca 2014 se [29] ser ies

"Esop NA hageal dysmo tility"

CS

IVIG NA NA 2g/kg over 5 days per cycle Frequ ency?

5 NA mo nth s

NA

IVIG NA CS + 2g/kg MTX over 5 days per cycle 1 cycle per month ?

12 NA mo nth s

Stable Impro NA ved muscl e weak ness (MRC 4/5) swallo wing

NA NA

ACCEPTED MANUSCRIPT

Ca se re po rt

1 Rel No Fe 3 antilcSSc Diffus aps ne mal yea PmScl ? e ILD e of e rs + mu 53 FVC scle yea 53% invo rs lve old DLC me O nt 50%

NU

SC RI

PT

disord ers muscl e enzy mes (CK 66 U/l, aldola se 4.1 U/l)

MA NA

NA

PT ED

Mauh in 2014 [27]

agia, dysart hria - CK 309 U/l, aldola se 16.1 U/l EMG + Muscl e biops y+ IIM NA Muscl e weak ness Swall owing disord er - CK 1224 U/l, aldola se 19 U/l EMG + Muscl e MRI +

CS

AC CE

with acti ve aspi rati on pne um oni a

2

IVIG 2g/kg per cycle 1 cycle per month

6 AZA mo nth s

6 NA mo nth s

Impro ved Dyspn ea - CTscan anom alies - PFT param eters

Impro NA ved muscl e weak ness muscl e enzy mes (norm al CK) muscl e MRI (norm al)

NA

NA

NA NA

ACCEPTED MANUSCRIPT

dcSS No c ILD - RSS 39/10 4

NA

Scha nz 2008 [23]

Ca se re po rt

1 Pro No Fe 8 antigre ne mal yea topo I + ssio e rs n of 56 calc yea inos rs is old

lcSSc mRS S 12

Asan o 2005 [19]

Ca se re po rt

1 Pati No Fe NA antient ne mal topo I disc e onti 62 nua yea tion rs of old Dpen

dcSS Limit NA c ed ILD mRS S 22 Histol ogical skin thickn ess 2.8 mm

Limit NA ed ILD (nor mal FCV and DLC O)

Small NA joint polyart hritis - SJC 10 - TJC 16

NA

SC RI

no SScrelated antibod ies

DU

CYC IVIG 10 Plasma 12 "Marke None NA CSA 15g yea pheresis mo d CS per rs every 2- nth improv cycle 3 s ement" 1 months - RSS cycle 41/104 per month

NU

18 mo nth s

MA

1 Pro No Mal gre ne e ssio 42 n of yea skin rs invo old lve me nt

Esoph Calcinosi Dageal s pen dysmo Warf tility arin

PT ED

Ca se re po rt

AC CE

Szek anec z 2009 [24]

PT

Muscl e biops y+

NA

No

NA

Dpen

3

IVIG 2g/kg over 4 days per cycle 1 cycle per month IVIG 2g/kg over 5 days per cycle 1 cycle per month ?

Impr NA oved SJC 0 TJC 5

5 NA mo nth s

5 mo nth s

Improv NA ed mRSS 9

NA

NA

NA

2 None yea rs ?

1 mo nth 2 yea rs

Improv NA ed mRSS 14 at 1 month, 7 at 2 years Histolo gical skin thickne ss 2.0

NA

NA

NA

Improvem NA NA ent of capillaros copy (decrease d Maricq index and increased neovascul arization) Improvem NA No ent of adv calcinosis ers (but e recurrenc effe e after ct discontinu ation)

NA

NA No adv ers e effe ct

ACCEPTED MANUSCRIPT

Mal e 48 yea rs old

Sever NA e GERD

3 antidcSS No yea PmScl c rs mRS S 34

NA

NA

Sever NA e GERD

8 antimo PmScl nth s

NA

Colc IVIG hicin 2g/kg e over 5 days per cycle 1 cycle per month for 6 month s Colc IVIG hicin 2g/kg e over 5 days per cycle 1 cycle per month Colc IVIG hicin 2g/kg e over 5 Ddays pen per cycle 1 cycle per month

6 None mo nth s

6 mRSS "No NA mo 16 effect" nth s

NA

"No "No NA No progre progressi adv ssion" on" ers e effe ct

6 None mo nth s

6 mRSS "No NA mo 20 progre nth ssion" s

NA

"No "No NA No progre progressi adv ssion" on" ers e effe ct

3 None mo nth s

3 mRSS NA mo 20 nth s

NA

NA

SC RI

NA

dcSS No c mRS S 32

MA

NU

20 antidcSS Limit NA yea PmScl c ed rs ILD mRS S 26

PT ED

3 Wor No Fe seni ne mal ng e of 49 skin yea invo rs lve old me nt des pite trea tme nt Fe mal e 28 yea rs old

AC CE

Levy Ca 2000 se [16] ser ies

PT

mm at 1 month

NA

Sever NA e GERD Weigh t loss

4

NA

NA

NA Acu te ren al failu re

ACCEPTED MANUSCRIPT

SC RI

PT

"involv Calcinosi CS IVIG 6 CS ement s Colc 2g/kg mo of the DU hicin over 5 nth middle e days s third per of the cycle oesop 1 hagus cycle with per 10 moder days ate for 2 reflux" month s then 2g/kg over 2 days per cycle 1 cycle per month for 4 month s

NU

IIM NA Muscl e weak ness, Esoph ageal involv ement ? - CK 1675 U/l, aldola se 25 U/l

MA

1 Sev No Fe 18 ANA +, lcSSc ILD? ere ne mal mo homog ? IIM e nth eneous FVC rela 13 s and 53% pse yea nucleol des rs ar DLC pite old pattern O CS s 58% ther (no apy specific ity)

PT ED

Ca se re po rt

AC CE

Bode mer 1990 [15]

5

6 Improv Impro mo ed ved nth FVC s Stable DLCO

Impro NA ved muscl e weak ness esoph ageal involv ement muscl e enzy mes (CK 29 U/l, aldola se 7.4 U/l)

NA

Improvem ent of calcinosis Improvem ent of DU

CS NA tap erin g

AC CE

PT ED

MA

NU

SC RI

PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Table 4. Previous studies reporting on the efficacy and safety of IGIV in SSc patients

AC CE

PT ED

MA

NU

SC RI

PT

ALT: alanine aminotransferase; ANA: antinuclear antibodies; anti-Cm: anti-centromere antibodies; anti-Jo1: anti-Jo1 antibodies; anti-PL7: anti-PL7 antibodies; anti-PmScl: anti-PmScl antibodies; anti-RNA pol III: anti-RNA polymerase III antibodies; anti-RNP: anti-ribonucleoprotein antibodies; anti-TNF: tumor necrosis factor α inhibitors; anti-topo I: anti-topoisomerase I antibodies; anti-U1RNP: anti-U1 ribonucleoprotein antibodies; anti-U3RNP: anti-U3 ribonucleoprotein antibodies; AZA: azathioprine; CI: contraindication; CIPO: chronic intestinal pseudo-obstruction; CK: creatin kinase; CRP: C-reactive protein; CS: corticosteroids; CSA: ciclosporin A; CYC: cyclophosphamide; D-Pen: D-penicillamine; dc: diffuse cutaneous; DLCO: diffusing capacity of the lung for carbon monoxide; DMARD: disease-modifying anti-rheumatic drug; DU: digital ulcer; EMG: electromyogram; FVC: forced vital capacity; GERD: gastro-esophagial reflux disease; GI: gastro-intestinal; HAQ(-DI): health assessment questionnaire (-disability index); HCQ: hydroxychloroquine; IFX: infliximab; Ig: immunoglobulin; IIM: idiopathic inflammatory myopathy; ILD: interstitial lung disease; IVIG: intravenous immunoglobulins; lc: limited cutaneous; LFL: leflunomide; m: mean; MMF: mycophenolate mofetil; MRC: Medical Research Council; MRI: magnetic resonance imaging; mRSS: modified Rodnan skin score; MTX: methotrexate; NA: not available; NS: not significant; NSAID: non-steroidal anti-inflammatory disease; PCB: placebo; PFT: pulmonary function tests; PH: pulmonary hypertension; RA: rheumatoid arthritis; RDQ: reflux disease questionnaire; RSS: Rodnan skin score; RTX: rituximab; SAE: serious adverse event; SD: standard deviation; SIBO: small intestine bacterial overgrowth; SJC: swollen joint count; SSc: systemic sclerosis TIA: transient ischemic attack; TJC: tender joint count; TOC: tocilizumab; UCLA SCTC GIT: University of California at Los Angeles Scleroderma Clinical Trials Consortium Gastro-Intestinal Tract 2.0 score; VAS: visual analogue scale; Δ: variation of.

2