Rituximab in the Treatment of Interstitial Lung Diseases Related to Anti-Melanoma Differentiation-Associated Gene 5 Dermatomyositis: A Systematic Review

Abstract

Objective: The effectiveness of rituximab in anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) with interstitial lung disease (ILD) has been explored only in isolated case reports and small series. This paper aims to review the current evidence regarding rituximab (RTX) use in the treatment of ILD related to anti-MDA5 DM (anti-MDA5 DM-ILD).

Methods: We conducted a review by searching PubMed, Web of Science, Embase, and Cochrane for articles with information on patients with anti-MDA5 DM and RTX treatment, published until August 2021, in English language. The selected studies listed variation in chest high-resolution computed tomography (HRCT) and/or pulmonary function test (PFT) as a primary outcome, in patients with anti-MDA5 DM-related ILD after using RTX.

Results: Of the 145 potentially eligible articles, 17 were selected. The information gathered from a total of 35 patients with anti-MDA5 DM-ILD was reviewed, including 13 men and 22 women. Patient age at onset was 47.60 ± 13.72 years old. A total of 11.43% (4/35) of the patients were found to have chronic ILD (C-ILD) and 88.57% (31/30) exhibited rapidly progressive ILD (RP-ILD). Most patients (29/30) had typical DM rashes. Prior to RTX administration, the majority of patients (27/35) were treated with medium- or high-dose glucocorticoids and at least one additional immunotherapeutic agent. With regard to RTX efficacy for ILD in anti-MDA5 DM, 71.43% (25/35) of the patients responded to treatment. Skin rash also improved in more than half of the patients after RTX treatment. The most common side effects were infections, reported by 37.14% (13/35) of the patients after using RTX.

Conclusion: As a CD20 targeting drug, RTX is a promising therapeutic tool for anti-MDA5 DM-ILD, although the risk of infections should be considered before treatment. Further prospective controlled studies are required to evaluate the optimal RTX treatment regimen.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289714, identifier CRD42021289714.

Keywords: dermatomyositis; interstitial lung disease; melanoma differentiation-associated gene 5; rituximab; targeting CD20.

Figure 1

Flow diagram according to Prisma guidelines (20).

Figure 2

Schematic representation of the hypothesized pathogenesis in anti-MDA5 DM-ILD. MDA5 protein can recognizes viral dsRNA then activates IFN-I pathway. Activation of the IFN-I system promote the production of MDA5 and cause MDA5 overexpression. Abnormal accumulation of MDA5 protein may lead to a loss of immune tolerance, resulting in the production of anti-MDA5 autoAb. Anti-MDA5 autoAbs may potential contribute to the pathogenesis through binding to MDA5 on cell surface, forming immune complexes, and interacting with cytoplasmic MDA5. In the lungs, CX3CL1 can be produced by endothelial cells when exposed to IFN-I and induce recruitment of alveolar M2 macrophages. Local production of TGF-β by M2 macrophages directly promotes pulmonary fibrosis. CD4⁺CXCR4⁺ T cell subset in anti-MDA5 DM-ILD can produce profibrotic agents (TGF-β, α-SMA, collagen I, and IL-21). The process of activated neutrophils releasing NETs could expose MDA5 autoantigens. MDA5, melanoma differentiation-associated gene 5; DM, dermatomyositis; ILD, interstitial lung disease; autoAb, autoantibody; RTX, rituximab; dsRNA, double-stranded ribose nucleic acid; NETs, neutrophil extracellular traps; NETosis, neutrophil extracellular traps externalization process; IFN-I, type I interferon; TGF-β, transformation growth factor-β; α-SMA, α-smooth muscle actin.