Improvement in dermatomyositis-associated muscle disease with anifrolumab

Dear Editor,

Novel therapeutics targeting type I interferon (IFN) signalling pathways have increasingly emerged as promising agents for the treatment of rheumatic disease. Our group previously demonstrated the striking and rapid improvement in recalcitrant cutaneous dermatomyositis (DM) with the novel, off-label use of anifrolumab, a type-I IFN receptor antagonist approved for the management of moderate-to-severe systemic lupus erythematosus.^1–2 However, the utility of anifrolumab in DM-associated myositis has yet to be reported. Given that aberrant type I IFN signaling has also been implicated in muscle disease pathogenesis in DM,³ we hypothesized that anifrolumab might be a viable, off-label therapeutic option for DM patients with active myositis. Herein, we describe two DM patients who experienced radiologic and symptomatic improvement in muscle disease after anifrolumab initiation.

Patient 1 is a 16-year-old male who presented with a two-year history of muscle weakness, progressive mid-facial erythema, and photodistributed, erythematous and scaly plaques on the chest, upper back, and lateral arms. Magnetic resonance imaging (MRI) demonstrated severe muscle inflammation involving the pelvic, gluteal, thigh, and proximal calf muscles. Creatine kinase (2689 U/L, ref [4–175 U/L]) and aldolase (27.8 U/L, ref [3.3–9.7 U/L]) were elevated, and a muscle biopsy of the left quadriceps femoris revealed degenerative changes, peripheral fascicular atrophy, and endomysial lymphocytic infiltrates, consistent with a diagnosis of juvenile DM. He was treated with intravenous (IV) methylprednisolone followed by a prolonged oral prednisone taper and methotrexate. After initial improvement on this regimen, the patient experienced recrudescence of both muscle and skin disease two years after presentation. Despite continued adherence to a combined regimen of subcutaneous methotrexate (25mg weekly) and oral prednisone (5mg daily) for an additional year, MRI of the patient’s right shoulder girdle demonstrated multifocal patchy muscle edema and subcutaneous reticular edema, consistent with active myositis (Fig 1A). After consideration of potential second- and third-line agents, the patient and his family opted to pursue adjunctive treatment with anifrolumab (300mg IV every 4 weeks). Within 3 months of starting anifrolumab, his skin and muscle symptoms dramatically improved, with normalization of muscle enzymes. Repeat MRI of the right shoulder after 6 anifrolumab infusions demonstrated resolution of multifocal myositis (Fig 1B). Within 8 months, the patient demonstrated a significant reduction in the Cutaneous Dermatomyositis Disease Area and Severity Index Activity Score (CDASI-A) from 22 to 2 (of note, a reduction in 4–5 points is considered clinically meaningful).

Fig 1.

A. Baseline axial fat-saturated, fluid sensitive MRI image of Patient 1’s right shoulder demonstrating multifocal patchy muscle edema (yellow arrows) and subcutaneous reticular edema (white arrow). B. Follow-up axial fat-saturated, fluid sensitive MRI image of Patient 1’s right shoulder after 6 infusions of anifrolumab demonstrating resolution of multifocal patchy muscle edema and subcutaneous reticular edema. C. Baseline axial fat-saturated, fluid sensitive MRI image of Patient 2’s proximal thighs demonstrating muscle edema most prominent in the quadriceps musculature bilaterally (yellow arrows), myofascial edema most prominent along the gracilis muscles bilaterally, diffuse reticular subcutaneous edema (white arrows), and skin edema. D. Follow-up axial fat-saturated, fluid sensitive MRI image of Patient 2’s proximal thighs after 5 infusions of anifrolumab demonstrating improvement in muscle edema, myofascial edema, and subcutaneous and skin edema.

Patient 2 is a 25-year-old female diagnosed with juvenile DM at age 6 based on skin findings and muscle pathology. She was initially treated with IV corticosteroids, hydroxychloroquine, methotrexate, and intravenous immunoglobulin (IVIg, 1g/kg every 2 weeks) with modest improvement in skin and muscle disease. She subsequently experienced repeated disease activity flares despite trials of oral tacrolimus (3mg twice daily) and oral prednisone (40mg daily); a trial of rituximab was complicated by anaphylaxis. While improvement in her skin and muscle disease was achieved with combination IVIg and oral tofacitinib (10mg twice daily), she ultimately experienced recurrent symptoms on this regimen 2 years later, with repeat MRI of her bilateral thighs demonstrating diffuse myositis, fasciitis, and subcutaneous reticular edema (Fig 1C). The patient discontinued tofacitinib and pursued treatment with anifrolumab (300mg IV every 4 weeks). After 2 infusions of anifrolumab, she reported improvement in strength and skin disease, and her CDASI-A score decreased from 31 to 20. Additionally, follow-up MRI after 5 anifrolumab infusions demonstrated improvement in myositis, fasciitis, and subcutaneous and skin edema (Fig 1D). At present, both patients continue to tolerate anifrolumab well and have experienced no treatment-related adverse events.

While anifrolumab has recently demonstrated rapid and sustained efficacy in skin-predominant DM,^4,5 improvement in DM-associated muscle disease has not been described. Given that muscle enzymes do not always correlate with muscle disease activity in DM, particularly in long-standing disease, MRI is considered the gold standard for evaluating ongoing myositis. To our knowledge, this is the first report of radiologic and clinical improvement in DM-associated myositis with anifrolumab use. Limitations of our report include potential confounding effects of concomitant therapies, albeit both patients were on stable doses of therapy at the time of initiation of anifrolumab, and small sample size.

Coupled with prior translational studies that have demonstrated elevated type I IFN-induced gene signatures in DM muscle compared to other myopathies,⁶ our results suggest that anifrolumab may be considered in those DM patients with recalcitrant muscle disease who have failed or have contraindications to standard therapies. Importantly, several phase III randomized controlled trials of anti-IFN directed therapies in DM are ongoing,^7,8 laying the groundwork for new therapeutic options for both skin and muscle disease in DM going forward.

Data Availability Statement:

The data underlying this article are available in the article.