ReviewIntravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature
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], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. However, most of these studies were case series or open-label single-center 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.
Section snippets
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
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
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
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.
The following are the supplementary data related to this article.
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.
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EH and DL contributed equally to this work.