A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease

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Abstract

Objectives

Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment.

Methods

A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1–7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10).

Results

Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups.

Conclusions

Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.

Introduction

Systemic sclerosis (SSc) is a prototype, multisystem fibrotic disease which carries the worst standardized mortality ratio among all systemic rheumatic diseases [1]. The pathogenesis of SSc is not well understood, however, autoimmunity, endothelial dysfunction/vasculopathy, and eventually aberrant fibroblast activation are considered the cornerstones of the pathophysiologic process [2], [3], [4], [5], [6]. Nowadays, the leading cause of death in patients with SSc is interstitial lung disease (ILD). Treatment strategies for SSc-associated ILD have mainly relied on non-specific immunosuppression in the form of cyclophosphamide or mycophenolate [7], [8], [9], [10]. However, during the last years other immune based therapies have emerged such as B-cell depletion therapy and hematopoietic stem cell transplantation, which have shown encouraging results [11], [12], [13], [14], [15]. A great amount of data derived from both animal models and humans indicates that B cells are key players in the fibrotic process thus supporting the concept of B-cell depletion therapy in SSc [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. In our department we have conducted the first randomized controlled study assessing the efficacy of the B-cell depleting agent, Rituximab (RTX), in the treatment of SSc-associated ILD [27]. We have shown that treatment with RTX significantly improves pulmonary function as well as skin fibrosis in patients with SSc. The improvement in pulmonary function tests (PFTs) found in our study should be considered as strong evidence in favor of a disease modifying role of RTX in SSc since PFTs have a clear tendency to decline over time in SSc associated ILD [28]. The follow-up of patients enrolled in our study has shown that continuous treatment with RTX further enhances this beneficial effect [15]. During the last 5 years several research groups have also employed B-cell depletion therapy in patients with SSc and most have produced similar results [12], [13], [14], [29], [30], [31], [32], [33], [34], [35], [36]. These encouraging but preliminary results have been recently verified in large scale multicenter studies, including one from the European League against Rheumatism Scleroderma Trial and Research group, which reported improvement of pulmonary function following RTX administration [32], [37]

Since the completion of our randomized controlled study in 2009 we have been using RTX as an off label treatment in SSc-associated ILD, alongside with other research groups in our country. In the present study we aimed to assess the long-term effect of RTX treatment on pulmonary function in patients with SSc-associated ILD compared to patients on conventional treatment. Moreover, we provide data on the long-term safety profile of RTX in these patients.

Section snippets

Patients

Four major rheumatology centers (three academic units and one district hospital) covering a wide geographical area of Greece, participated in the study. All patients with SSc-associated ILD that were followed up in these centers were offered treatment with RTX either as monotherapy or in some cases as an add-on treatment to conventional therapy. Patients fulfilled the preliminary American College of Rheumatology criteria for the classification of the disease [38]. Retrospective analysis of our

Rituximab group

Patients were treated with two or more cycles of RTX. Each cycle consisted of four infusions of 375 mg of RTX per m2 of body surface area, once weekly. RTX cycles were repeated every 6 months. Thirteen patients in the RTX group received concurrent immune based therapies; methotrexate (n = 2), hydroxychloroquine (n = 1) and mycophenolate mofetil(n = 10, dosage 2 g/day). Patients on mycophenolate (MMF) had been on that treatment for a median of 24 months prior to enrollment. Moreover, 18/33

Lung and skin fibrosis assessment

Standard PFTs were performed at baseline and then every 6 months for the first 2 years and annually thereafter in all patients, including assessments of forced vital capacity (FVC), total lung capacity and diffusing capacity of carbon monoxide (DLCO) corrected for hemoglobin concentration. PFT parameters are expressed as a percentage of normal predicted values based on age, sex, and height.

The MRSS tool was used for clinical assessment of skin thickening at baseline, every 6 months for the

Statistical analysis

Comparisons between the treated and control groups were performed after appropriate adjustment for disease duration using an analysis of covariance (ANCOVA) model. The comparison of ANCOVA-based adjusted values of MRSS, FVC, and DLCO at various time points with their respective baseline levels was performed using t-test. The corresponding comparisons of observed means to baseline were performed using either paired t-test or Wilcoxon test, according to the significance of an initial

Results

Patients in the treatment and control group had similar epidemiologic and clinical characteristics apart from disease duration; patients in the control group had shorter disease duration. Mean disease duration (defined as duration from first non-Raynaud’s disease manifestation) at baseline was 5.73 years in the RTX group and 2.56 years in the control group. Baseline demographic and clinical characteristics of the patients, as well as their concurrent medication, are presented in Table.

Rituximab group

Treatment with RTX was generally well tolerated, even in cases of advanced disease with presence of comorbidities. Five deaths were reported during the follow-up period. Three of them concerned patients with end stage lung fibrosis before the initiation of RTX, with the cause of death being respiratory insufficiency. Another patient was diagnosed with lung cancer, approximately 1 year after starting treatment with RTX and consequently died because of this. The last death was a case of sudden

Discussion

Interstitial lung disease alongside pulmonary arterial hypertension (PAH) are the most fearful complications of SSc and are nowadays the leading causes of death. During the last decade there has been a substantial progress in the treatment of the vascular complications of SSc, such as PAH. However, therapeutic approaches for fibrotic complications such as ILD remain limited and exhibit only modest efficacy. During the last 5 years there has been an increasing interest in B-cell depletion as a

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    This study was partially funded by a “Karathodori” grant (D184).

    1

    These authors contributed equally to this work.

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