Immune-mediated necrotizing myopathy (IMNM), also known as necrotizing autoimmune myopathy, is characterized by markedly elevated creatinine kinase and histologically scattered necrotic muscle fibers and generally associated with autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coA-reductase (HMGCR) (1). Poor clinical response to conventional therapies and relapses commonly occur in severe cases.

In previous reports, anti-B-cell therapy, especially rituximab (RTX), an anti-monoclonal CD20 antibody, has been used in IMNM (2–12). In some cases, patients benefited from RTX, while in other cases, patients showed poor response or died from complications, such as infection (2–12).

Belimumab is a human monoclonal antibody targeting B-cell-activating factor (BAFF). Belimumab has been used in several rheumatoid diseases, including systemic lupus erythematosus, Sjogren’s syndrome, systemic sclerosis, and antiphospholipid syndrome (13–16).

In this study, we report a case of a patient with anti-SRP IMNM who relapsed twice after conventional therapy but showed a good response and tolerance to belimumab. We also reviewed patients with anti-SRP IMNM who received anti-B-cell therapy in our department and in the literature.

To our knowledge, this is the first case of belimumab in anti-SRP IMNM. The patient showed good response and tolerance to belimumab.

There are still no randomized trials or large enough case series to make formal recommendations for IMNM treatment. Based on the European Neuromuscular Center workshop, corticosteroids are considered the first-line treatment (1). High-dose corticosteroids should be used immediately upon diagnosis. For patients with an incomplete response to corticosteroid monotherapy or multisystem involvement, second-line treatments are warranted; these include methotrexate, azathioprine, and mycophenolate mofetil. In some cases, cyclosporine and tacrolimus may be used as adjuncts. In addition to conventional immunosuppression, IVIg is considered an effective treatment for initial therapy, especially in anti-HMGCR myopathy (1).

In our study, we reviewed all B-cell therapies for IMNM, and only RTX was identified to be effective (1–12, 18–21). B-cell depletion therapy with RTX in anti-SRP IMNM is commonly effective. As our study showed, all patients from case reports and case series showed a decline in CK, while three patients relapsed during tapering. In addition, five patients developed infections after RTX therapy, and one patient died from pneumonia and congestive heart failure. From the reported literature, it was gathered that most patients responded; in one study, however, only half of patients achieved remission (1). The author of the study supposed that a low ratio of remission might be related to the delay in RTX use. Despite a lack of rigorous clinical trials, considerable experience has demonstrated that anti-B-cell therapy might be effective for patients with IMNM.

Although belimumab has never been reported for use in IMNM treatment, the important role of BAFF or B-lymphocyte stimulator in the pathogenesis of idiopathic inflammatory myopathies (IIM) has been demonstrated in previous studies (22–24). In a study by Yuan, 10 of 29 patients with refractory anti-SRP IMNM showed positive BAFF in necrotic tissue regenerated muscle fibers and individual lymphocytes, while BAFF receptor was found in 24 of 29 patients. Moreover, refractory patients with anti-SRP IMNM had more BAFF receptors than nonrefractory patients. These findings suggest that BAFF and its receptors may participate in muscle fiber injury (22).

The efficacy and safety of belimumab in other autoimmune diseases have been evaluated in randomized clinical trials. The BLISS trial, a randomized, double-blind, placebo-controlled trial, demonstrated the efficacy of belimumab in SLE (13). The BLISS-LN study, a multicenter, randomized, double-blind trial included 448 patients with lupus nephritis. At week 104, primary responses occurred more often in the belimumab group than in the placebo group. Infection and infestation occurred in 15 of 224 patients in the belimumab group and 18 of 224 patients, while the number of infection-associated deaths were equal to the two groups (three patients in each group) (25). In a bicentric prospective 1-year open-label trial on Sjogren’s syndrome, patients achieved improvement in several aspects, including disease activity index, dryness, fatigue, and VAS scores. Only one of 30 patients suffered from a severe adverse event (pneumococcus meningitis) (14). A multicenter, double-blind, placebo-controlled trial on the efficacy and safety of belimumab in IIMs is ongoing by Northwell Health (NCT02347891).

Consistent with previous reports, not only improvement of disease activity but also a decline in anti-SRP antibodies was observed in our case. Some evidence has demonstrated that anti-SRP antibodies may participate in the pathogenesis of IMNM by triggering an immune reaction, resulting in the release of myotoxic cytokines (8, 22, 26). In vitro, positive SRP was found on the plasma membrane of cultured myoblast cells stained with anti-SRP serum (27). In animal models, muscle weakness was observed in C57/Bl6 or Rag2-deficient or complement 3-deficient mice after passive IgG transfer from patients with anti-SRP IMNM (28). Moreover, SRP protein was identified in the muscle of anti-SRP IMNM patients via colabeling with the transsarcolemmal protein dysferlin and sarcoplasmic neural cell adhesion molecule, respectively, and further cellular experiments demonstrated exposed SRP protein localized at the surface of myotubes (29).

There are some limitations to this case: since this is the first case describing belimumab in IMNM, more cases and studies are needed to confirm the effects. Based on this case, we observed that belimumab was effective in IMNM associated with anti-SRP antibodies and suggest that belimumab might be option for severe cases.

Belimumab improved the clinical condition of our patient without any severe adverse events. In the review of the records of our center and literature, B-cell therapy with RTX benefited some patients with anti-SRP IMNM, but at the same time, increased the risk of infection. In conclusion, the present study demonstrates that belimumab in association with steroids might be an encouraging option for refractory/relapsing cases.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the ethics committee of West China Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

All authors contributed to one or more of the following aspects of the manuscript: conception, acquisition of data, drafting, and revising the article. All authors contributed to the article and approved the submitted version.

This work was supported by the Clinical Research Incubation Project, West China Hospital, Sichuan University (2019HXFH038).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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