Dermatomyositis (DM) is a rare systemic inflammatory disease primarily characterized by muscle inflammation and skin involvement. However, it can also affect other organs and may be associated with malignancies. Several therapeutic options are currently available, including antimalarials, corticosteroids, conventional immunosuppressants, intravenous immunoglobulins (IVIG), and JAK inhibitors. However, their effectiveness may be limited, incomplete, or transient, and some patients remain refractory to all of these therapies.1,2 Type-I interferon (IFN) signaling pathways have recently been suggested as key drivers of disease pathogenesis.3 Therefore, treatment with anifrolumab, a monoclonal antibody that binds to IFN-α receptor-1 and blocks type-I IFN signaling, may represent an effective therapeutic option for DM.

A 43-year-old man with no relevant past medical history presented with a 1-year history of skin lesions. Dermatologic examination revealed facial erythema, heliotrope rash, Gottron papules on both hands, Gottron sign on the elbows and knees, flagellate erythema affecting the back, and alopecic patches accompanied by erythema on the scalp. Furthermore, he complained of significant pruritus and muscle weakness. A skin biopsy showed superficial and deep perivascular dermatitis with interstitial dermal mucin deposits. Positive circulating anti-MDA5 antibodies were detected, leading to a diagnosis of anti-MDA5 DM. Muscle biopsy and muscle MRI confirmed muscular involvement. Pulmonary function tests and PET-CT ruled out malignancy and pulmonary involvement at that time. No skin or oral ulcerations were observed, and the patient did not present calcinosis, livedoid eruption, or erythematous macules or papules on the palms.

The patient was treated with oral prednisone, mycophenolate, and topical corticosteroids without significant improvement. High-dose IVIG and off-label tofacitinib, replacing mycophenolate, were initiated, leading to cutaneous improvement. Oral prednisone was gradually tapered and eventually discontinued. Although body lesions improved with tofacitinib, facial and scalp involvement persisted, causing significant pruritus and affecting quality of life. Gottron papules and periungual changes also persisted. At that time, the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score was 19, with a damage score of 3. A blood type-I IFN signature based on the expression of 28 previously described IFN-stimulated genes4 was assessed while the patient was receiving tofacitinib (10mg twice daily), revealing increased z scores.

At this point, compassionate treatment with anifrolumab (300mg monthly) was initiated, replacing tofacitinib. After two doses, the patient reported overall improvement, and the CDASI activity score decreased to 10. After the fourth infusion, the CDASI activity score further decreased to 4, and a new IFN signature assessment showed normalization of IFN-inducible gene expression. No adverse events occurred during treatment with anifrolumab. However, the patient discontinued anifrolumab after leaving the country for 4 months and restarted tofacitinib. During this period, he experienced a cutaneous flare associated with an increase in the CDASI activity score, up to 21, and a rise in the IFN signature (Figs. 1 and 2).

Fig. 1.

Facial lesions of DM during treatment with tofacitinib (A) and after four doses of anifrolumab (B).

Fig. 2.

Longitudinal assessment of blood type-I IFN signature. The gray area represents the cutoff value of the 28-IRG score (≥1.7), above which a positive type-I IFN signature was considered. The 28-IRG score was calculated according to a previous publication (J Interferon Cytokine Res. 2018;38:171–185).

A 51-year-old man with no relevant past medical history was diagnosed with DM after several months of muscle pain and weakness. Cutaneous lesions included large violaceous plaques with central necrosis on the anterior trunk, as well as calcinosis in the same area. Initial workup revealed positivity for anti-Mi, anti-Ro, and anti-CN1a antibodies. Pulmonary function tests and PET-CT performed at that time yielded normal results.

Treatment with oral prednisone and IVIG was initiated, resulting in partial improvement. Over the following years, multiple therapies were administered, including hydroxychloroquine, azathioprine, mycophenolate, and tofacitinib. Despite these treatments, complete clinical remission was not achieved. Although cutaneous lesions improved with tofacitinib, muscular involvement worsened, eventually leading to tetraparesis. Consequently, tofacitinib was switched to rituximab, but cutaneous calcinosis progressed, affecting a large portion of the chest and back skin surface and leading to movement restriction compromising respiratory function.

At that time, the patient had a CDASI activity score of 8 and a damage score of 4. A blood type-I IFN signature performed at that time revealed increased levels of IFN-inducible genes. In this context, compassionate treatment with anifrolumab (300mg monthly) was initiated. After the fourth infusion, the CDASI activity score decreased to 0, whereas the damage score remained unchanged. A subsequent blood type-I IFN signature analysis performed at that time showed normalization of IFN-inducible gene expression (Fig. 2). No adverse events were observed during treatment with anifrolumab.

A wide range of treatments is available for DM, including topical and systemic therapies, although treatment responses are often inconsistent.1,2 The inflammatory pathways underlying this disease remain incompletely understood; however, serologic studies have demonstrated the involvement of type-I IFN signaling pathways, particularly in anti-MDA5-positive patients.3 Anifrolumab is a monoclonal antibody that selectively binds to subunit 1 of the type-I IFN receptor, thereby inhibiting its signaling pathway. It was approved by the US Food and Drug Administration in 2021 for the treatment of moderate-to-severe systemic lupus erythematosus.5

A limited number of refractory DM cases treated with off-label anifrolumab have been reported, showing rapid improvement of clinical signs.6–8 All previously reported cases experienced a decrease of at least 20% in CDASI activity score, supporting the pathogenic role of the type-I IFN signaling pathway in the cutaneous manifestations of DM. Moreover, higher IFN signature scores have been correlated with greater disease severity.8 Its role in muscular involvement remains unclear, since all reported patients with muscular DM on concomitant IVIG, making it difficult to attribute clinical improvement to a single therapy.

The observed differences in clinical responses between JAK inhibitors and anifrolumab may be directly related to their distinct mechanisms of action. JAK inhibitors partially reduce intracellular signaling across multiple pathways, including type-I IFNs, several inflammatory cytokines, and hematopoietic growth factors. These agents decrease pathway activity but do not completely abolish signaling. In contrast, anifrolumab selectively and completely blocks type-I IFN signaling by targeting the receptor itself. This mechanism may explain the different clinical responses observed in our patients. Similar observations have been reported when analyzing the different clinical evolution of patients with interferonopathies treated with baricitinib and anifrolumab.9

Regarding adverse events, Shaw et al.8 reported upper respiratory tract infections and one case of peritonsillar abscess during treatment with anifrolumab. Fortunately, none of these adverse events were observed in the patients included in the present report.

We herein present two novel cases of refractory cutaneous DM with previous incomplete responses to multiple immunosuppressive therapies, including JAK inhibitors, who achieved an almost complete cutaneous response with anifrolumab. The long-term evolution of cutaneous calcinosis in patient 2 during treatment with anifrolumab remains unknown. In addition, longitudinal analyses of blood type-I IFN signatures demonstrated a marked decrease during treatment with anifrolumab and relapse after treatment discontinuation. Overall, these findings strongly support the hypothesis that the type-I IFN signaling pathway plays a relevant role in DM pathogenesis.

Although currently available evidence remains limited and is derived from small case series rather than randomized controlled trials, our findings support the involvement of type-I IFN signaling pathways in DM and suggest that anifrolumab may represent a promising therapeutic option for patients with cutaneous DM.

The patients described in this manuscript provided written informed consent for publication of their case details.

This study was supported by grant PI19/01567 from Instituto de Salud Carlos III (ISCIII) and cofinanced by the European Union (A.M.-V.).

Xavier Bosch-Amate and José M. Mascaró Jr. have received honoraria from AstraZeneca for participation in scientific meetings.

The data supporting the findings of this study are available from the corresponding author upon reasonable request.