Anti-signal recognition particle antibody–positive immune-mediated necrotizing myopathy treated with ofatumumab

Dear Editor, Anti-signal recognition particle (SRP)-type immune-mediated necrotizing myopathy is a common subtype of necrotizing myopathy, typically involving the myocardium, and it often indicates a poor prognosis. The present case report discusses a patient with immune-mediated necrotizing myopathy (IMNM) exhibiting myocardial involvement and concurrent SS, successfully treated with ofatumumab after ineffective conventional immunotherapy.

A 61-year-old female was admitted to our hospital on 22 August 2022, with weakness of the extremities for 5 years, with re-exacerbation for 3 months. She was diagnosed with inflammatory myopathy after a muscle biopsy 5 years ago. She had received AZA , MTX, and tacrolimus; however, her limb muscle strength failed to return to normal. Her creatine kinase level typically fluctuated between 400 and 500 U/l.

The patient received two doses of the coronavirus disease (COVID-19) vaccine by injection (at the end of March 2022 and in April 2022) and began experiencing recurrence at the beginning of May. Prednisone 60 mg/day and tacrolimus 3 mg/day were administered orally; however, the patient’s muscle weakness continued to worsen. In addition, the patient experienced panic, chest tightness, and wheezing after walking, accompanied by dryness of the mouth and eyes. She had Grade 2 head raising and neck flexion muscle strength, Grade 2–3 proximal muscle strength, and Grade 4 distal muscle strength.

The laboratory findings supported the diagnosis of anti-SRP-IMNM. The patient’s CK-MB isoenzyme (CK-MB) level was >300.0 μg/l↑, troponin I (TnI) was 0.282 μg/l↑, and myoglobin (Myo) was >1200.0 μg/l↑. Her cardiac enzyme profile was CK 1620 U/l, and brain natriuretic peptide (BNP) 176.50 pg/ml. She was positive for myositis-related anti-SRP and anti-SSA/Ro52 antibody IgG. Her left ventricular ejection fraction was 37%. Her coronary CT angiography indicated no significant stenosis of the anterior descending branch. Slit lamp examination indicated corneal fluorescein staining in both eyes was negative, and a tear film rupture time of ∼7 s. The labial gland biopsy report indicated, microscopically, the tissue area was ∼0.8 mm², and there was a lymphocyte count of <50 per foci.

According to the 2018 European Neuromuscular Disease Center diagnostic criteria [1], and the diagnostic criteria of the ACR/EULAR 2016 and the Brazilian Society of Rheumatology 2019 [2–4], the patient was diagnosed with an overlapping syndrome of IMNM combined with SS.

In regard to the treatment of IMNM, the initial treatment recommended by the guidelines typically consists of i.v. and/or oral steroids with the further addition of an immunosuppressive drug such as AZA, MTX or MMF within a month, depending on the severity and treatment response [1]. Regarding anti-SRP myopathy, rituximab may be added as appropriate [5].

After admission, the patient was treated and received hormonal shock therapy (methylprednisolone 500 mg 3 days, 250 mg 3 days, 120 mg 3 days, 60 mg 3 days), gammaglobulin drops (22.5 g 5 times), and a temporary continuation of the original treatment (tacrolimus 3 mg daily for 10 days). The patients’ limb soreness, panic, and chest tightness showed marginal improvements. However, her weakness of the limbs and dysphagia symptoms were not markedly alleviated.

Rituximab is a mAb that targets the CD20 antigen expressed on the surface of pre-B and mature B cells. It is a chimeric murine/human antibody. One of the main justifications for using rituximab for B cell–mediated illnesses is the fact that it causes B cell lysis after binding to CD20 [6]. Currently, there have been reports of about 30 cases of IMNM treated with rituximab [7].

Unlike rituximab, ofatumumab is a human IgG1 monoclonal anti-CD20 antibody that binds to a membrane-proximal epitope. Despite targeting the same cell type, ofatumumab has been shown to have the ability to improve B cell binding affinity, enhance complement-dependent cytotoxicity, and reduce immunogenic adverse reactions [8]. The slight toxicity is mostly limited to infusion responses. Moreover, ofatumumab is administered subcutaneously, which is convenient for patients and simple to handle. For patients who are unable to tolerate rituximab, ofatumumab is a viable alternative anti-CD20 treatment.

Given the patient’s advanced age, cardiac dysfunction, and the risk of rituximab infusion, it was advised to try ofatumumab. The patient did not experience any injection-related or other adverse reactions. On 5 September 2022, she had a total B lymphocyte count of 236.4 × 106/l, and an ofatumumab 20 mg s.c. injection was administered. On 1 November 2022, the total B lymphocyte count was 0, and a second s.c. ofatumumab injection of 20 mg was administered. On 20 February 2023, the patient’s total B lymphocyte count was 1.5 × 10⁶/l, and a third s.c. injection of ofatumumab 20 mg was administered.

After 2 weeks, the patient confirmed her ability to eat. After 2 months, the patient could walk independently, and her muscle strength was grade 4 in the proximal limb muscles. After 4 months, the patient was stable, with a grade 5 in proximal limb muscle strength. After 6 months, the patient could live a normal life; panic, chest tightness, and wheezing had disappeared, and she had a grade 5 in the proximal limb muscle strength and a left ventricular ejection fraction of 59% (normal being considered >50%, see Fig. 1).

Figure 1.

Schematic illustration of the disease course showing the temporal sequence of symptoms, disability, treatment details, CD19⁺ B cell count, serum creatine kinase and serum lgM level. FK506: tacrolimus; GCs: glucocorticoids; LLN: lower limits of normal

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In the present case report, the patient showed a gradual improvement in muscle strength and cardiac function after ofatumumab administration, suggesting that ofatumumab may be an effective treatment for patients with refractory IMNM. Thus, clinical observations or randomized controlled studies in a large sample are needed in order to generate corroborative data.

The study was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of The First Hospital of Wuhan (2021/34; approved 9 September 2021). Informed consent was obtained from the patient.

Data availability

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.

Funding

This study was supported by funding from the Wuhan Municipal Health Commission (number WZ21M01).

Disclosure statement: The authors have declared no conflicts of interest.

Acknowledgements

The authors thank the patient’s family members for their cooperation in providing the medical data necessary for this publication.

References

Author notes