Safety and Efficacy of Rituximab in Systemic Sclerosis: A Systematic Review and Meta-analysis

Background: Rituximab has been widely proposed to treat systemic sclerosis (SSc) by depletion of pathogenic B cells. Nonetheless, the clinical benefit of Rituximab in SSc remains contentious. Objective: This meta-analysis was conducted to systematically evaluate the safety and efficacy profile of Rituximab in SSc patients. Methods: We performed a systematic online query in PubMed, Cochrane, and Web of science. Available studies about the assessment of Rituximab in SSc patients were comprehensively reviewed and investigated. Results: In total, 14 studies comprising 597 participants were enrolled in our analysis. Pooled results showed the durable improvement of mRSS for skin involvement (∆mRSS: 7.00 at 6-month, 9.70 at 12-month, and 10.93 at 24-month), while FVC (∆FVC: -0.69 at 6-month, -2.62 at 12-month, -0.67 at 24-month) and DLCO (∆DLCO -2.39 at 6-month, -3.28 at 12-month, -0.79 at 24-month) for lung involvement remain stable in SSc patients after Rituximab treatment. And safety profile of Rituximab-related adverse events rate was 12% in the pooled result. Conclusion: The pooled results of this meta-analysis indicated that Rituximab was well-tolerated, and it was able to generate improvement of cutaneous function and stabilization of pulmonary function in SSc patients.


Introduction
Systemic sclerosis (SSc), or scleroderma, is a chronic rheumatic disease with multiorgan fibrosis, autoimmunity, and vasculopathy 1 . Even the prevalence of SSc is not as common as other rheumatic diseases, this immune-mediated disease, particularly its diffuse form, has the worst mortality even with great medical treatment and palliative care 2  The etiopathogenesis of SSc is as complicated as other autoimmune disease and it has not been completely defined yet. Current explanation of etiology is mainly addressed in environmental factors, genetic predisposition, and other epigenetic disorders 4 . Various cells are involved in the pathogenesis of SSc. The most often explored cell subsets consist of fibroblasts, endothelial cells, B lymphocytes, and T lymphocytes 5 . In particular, recent evidence suggests that hyperactivated B cells can contribute to fibrosis in SSc via releasing cytokines, autoantibodies, and cell-cell connection 6 . The important pathogenesis role of B cells in SSc urges clinicians to transfer them as a therapeutic target for the treatment. Lately, as a chimeric monoclonal antibody targeting CD20 of B cells, Rituximab has been widely studied in SSc treatment 7 . However, consensus has not been reached about the clinical efficacy and safety profile of Rituximab in SSc. And current conclusion drawn from open-labeled trials or single institute experience is not as solid as we expected. Small sample size due to disease rarity, lack of control arm, singlecenter experience, discrepancies in study designs and variable duration of follow-up can dramatically affect the consolidation 8 .
To apply Rituximab as first-line treatment in SSc, it is of great priority to clearly demonstrate the clinical efficacy and safety of Rituximab in SSc. In this systematic review and meta-analysis, we mainly focus on the clinical efficacy of Rituximab on the improvement of cutaneous and pulmonary functions. What's more, available data about severe adverse events rates are also summarized to comprehensively evaluate the safety profile. Data extraction and quality assessment Data were extracted by two independent reviews (Rui Tang and Jiangfan Yu) from eligible studies. The following parameters were extracted from each manuscript and supplementary materials: first author's name, year of publication, SSc condition, Rituximab regimen, and primary and/or secondary clinical outcome, adverse events, Newcastle-Ottawa Scale was used to assess the quality of the included studies. Each study was scored according to the selection, comparability, and outcome. Any discrepancies were solved by mutual discussion among all authors.

Statistical analysis
Stata version14 (Stata Corporation; college station, Tx, USA) and Review Manager version5 (Revman the Cochrane Collaboration; Oxford, England) was applied to perform meta-analysis. Pooled clinical outcomes of mRSS for skin involvement, FVC and/or DLCO for lung involvement were presented to evaluate the clinical outcome in SSc patients after Rituximab treatment. Heterogenicity among studies was evaluated by the Chi-squared test and I 2 . A fixed-effects model was applied when there was no significant heterogenicity (I 2 <50% or p-value>0.05). Otherwise, the random-effects model was in use. Funnel plot was applied to precisely estimate the publication bias of the eligible studies.

Literature search and study selection
The initial search strategy identified 399 records after systematic literature retrieval  Table 2, after treatment of Rituximab, mRSS for skin involvement in SSc were significantly improved during the follow-up period comparing with conventional-therapy group (6-month: p=0.06, 12-month: p=0.03, 24-month: p<0.00001).
Lung function improvement FVC and DLCO were applied to assess change of pulmonary function improvement in SSc.
Regarding to FVC in Figure 3, the mean difference in the conventional-therapy group was -

Safety profile
The safety profile of Rituximab in SSc patients was also summarized and pooled data was presented in Figure 5. Pooled results confirmed that the overall mean rate for Rituximabrelated severe adverse events rate was 12.1% (p=0.733, I 2 =0%) throughout treatment, which was acceptable and controllable for oncologist and rheumatologist to manage in clinic.

Publication bias
The funnel plot was applied to evaluate whether the publication bias exists in our meta- Rituximab in combination therapy and modify the combined regimen to better control the SSc-associated interstitial lung disease (ILD) 27 . For instance, the most recent data shows that patients treated concomitantly with mycophenolate mofetil had a trend for a better outcome both in skin/lung fibrosis as compared with patients receiving RTX alone 8 .
We have well-demonstrated the clinical efficacy, particularly for skin fibrosis, and safety of Rituximab in SSc. Whereas our study still has some limitations that should be concerned. Firstly, even improvement of skin involvement is significant in Rituximabtreated patients, the heterogenicity exits during follow-up period. Clinical outcome for skin involvement is variable among current studies, which means more insight should be drawn to reach a more consistent consensus 28    The safety profile of Rituximab in SSc patients was also summarized and pooled data was presented