• polymyositis
• autoantibodies
• autoimmune diseases

Immune-mediated necrotising myopathy (IMNM) is a myositis subset characterised by severe muscle weakness with chronic and refractory disease course.1 It has been hypothesised that long-lived plasma cells are implicated in the pathogenesis of IMNM by secreting pathogenic autoantibodies unresponsive to standard immunosuppression.1 Daratumumab has recently been successfully reported in cases of refractory lupus2 and other treatment-refractory antibody-mediated autoimmune diseases.3 We describe here the successful use of daratumumab, an anti-CD38 human monoclonal antibody depleting plasma cells, in a patient with severe refractory anti-SRP+IMNM.

A 27-year-old Caribbean man presented with subacute muscle weakness and swallowing difficulties. No skin rash, arthritis, Raynaud or other connective tissue disease features were reported. Muscle strength examination revealed severe proximal muscle weakness (MRC-5 scale deltoid and psoas 2/5) resulting in major functional incapacities. Creatine kinase (CK) and troponin I levels were elevated at 19 824 IU/L (normal range 24–184) and 196 ng/L (normal range 0–20), respectively. Antinuclear antibody, extractable nuclear antigen, antidouble-stranded DNA were negative. Myositis panel using a line-blot assay method was positive for anti-SRP+++ and anti-Ro52+ (Euroimmun, Luebeck, Germany). Electromyogram showed a myopathic pattern and MRI showed T2/STIR thigh muscle hypersignals. Modified barium swallow demonstrated severe oropharyngeal dysphagia necessitating parenteral nutrition. Cardiac ultrasound was normal. Muscle biopsy revealed a pauci-immune necrotising pattern consistent with IMNM.

Despite treatment with glucocorticoids, methotrexate (MTX) and intravenous immunoglobulin (IVIg), CK levels remained elevated around 6 000 IU/L and rituximab4 was added at week 4 (figure 1). Nonetheless, muscle weakness progressively worsened and the patient was admitted to the intensive care unit (ICU) at month 2 for mechanical ventilation due to diaphragmatic dysfunction. Six plasma exchanges were performed with no clinical benefit. Maintenance rituximab was given at month 5, and tacrolimus was also added without improvement. Infusions of daratumumab5 were initiated at month 8, resulting in a clear clinical improvement within 4 weeks. After 13 infusions, quantitative muscle strength had importantly improved (hand grip from 5.1 to 19 kg (normal 50.2–54.9 kg); quadriceps from 56 to 121 kg (normal 215±41 kg)), parenteral nutrition discontinued and the respiratory assistance weaned. CK level decreased to <1000 IU/L and anti-SRP titre from+++ to +. Glucocorticoids and IVIg were progressively tapered, and MTX was decreased. The patient was discharged from the ICU at month 11. The immunosuppressive regimen was well tolerated clinically and biologically, and no infection was document in the hospital following daratumumab initiation. The patient developed as an outpatient non-severe COVID-19 infection at month 12 and a peripheral inserted central catheter line infection requiring transient intravenous antibiotics at month 13. Oral prophylactic trimethoprime-sulfamethazole DS three times a week was given to the patient, and varicella and herpes zoster prophylaxis with oral valacyclovir was also added at the initiation of daratumumab. No cytopenia developed after daratumumab and only total IgM and IgA levels were mildly decreased at 0.3 g/L (normal range 0.6–3.6) and 0.34 g/L (0.35–2.85), respectively.

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Figure 1

Clinical and biological findings following different therapeutic interventions in a patient with severe refractory IMNM. *Premedication with prednisone 100 mg was given prior to each rituximab infusion. **Premedication with dexamethasone 20 mg was given prior to each daratumumab infusion. ICU, intensive care unit; IVIg, intravenous immunoglobulin; MTX, methotrexate; M, months; PLEX, plasma exchange; RTX, rituximab; TAC, tacrolimus.

To our knowledge, this is the first case of refractory IMNM treated with daratumumab reported to date. The addition of daratumumab to conventional immunosuppressants and rituximab was associated with a rapid and spectacular clinical improvement in parallel to reduction of CKs and anti-SRP titres. Rituximab is currently recommended in the therapeutic management of IMNM4 and targets the CD20+ autoreactive naïve and memory B-cells, but it does not affect long-lived plasma cells (CD20−, CD38+).6 Our case highlights the relevance of targeting long-lived plasma cells in IMNM and daratumumab could represent a promising novel therapy for treatment-refractory autoantibody-mediated immune myopathies. A randomised controlled trial should be performed to further assess efficacy of anti-CD38 monoclonal antibodies in seropositive IMNM.