Management of Challenging Cases in Myositis

CHICAGO—Immune mediated inflammatory myopathies represent a heterogenous group of diseases with variable degrees of multisystem involvement, including the skin, joints, lungs, and muscles. The ACR Convergence 2025 session, Management of Challenging Cases in Myositis, featured a case-based approach to highlight this complexity, guiding attendees through the nuances of diagnosis and management of antisynthetase syndrome, immune mediated necrotizing myopathy and dermatomyositis.

Decoding Antisynthetase Syndrome

Dr. Aggarwal

The session opened with a presentation by Rohit Aggarwal, MD, professor of medicine at University of Pittsburg and co-director of the UPMC Myositis Center. Using two disparate cases, he illustrated the wide spectrum of clinical features in antisynthetase syndrome. The first patient was a 60-year-old woman with subacute onset of interstitial lung disease (ILD) and Raynaud’s, but notably had no rash, arthritis or muscle weakness, a negative anti-nuclear antibody (ANA) and only a modest elevation in muscle enzymes. The patient was found to have a cytoplasmic ANA, positive anti-Ro52 and anti-PL-7 antibodies. Dr. Aggarwal stressed the importance of identifying patients with ILD and minimal cutaneous or muscle disease, given that they too warrant immunosuppression and close monitoring.

He contrasted this case with that of a patient with classic proximal muscle and neck flexor weakness with marked elevation in CK, a seronegative rheumatoid arthritis-like pattern of synovitis, and mechanic’s hands. However the patient had no lung disease, rash, Raynaud’s or fever. Muscle biopsy demonstrated perivascular inflammation and antibody testing yielded positive ANA and anti-Jo-1 antibodies. He concluded the case by emphasizing that not every antisynthetase patient will have the classic triad of ILD, myositis and arthritis, and urged clinicians to consider antisynthetase syndrome when presented with seronegative rheumatoid arthritis.

Anti-Jo-1 is the most common antibody subtype in antisynthetase syndrome, seen in approximately 60% of cases. Other antisynthetase antibodies (e.g., PL-7, PL-12, OJ, EJ, KS) collectively account for the remaining 30–40% of cases, so it is important to test for these antibodies. Early identification and treatment may prevent development of more severe manifestations, such as ILD, which is the main contributor to mortality.¹ Dr. Aggarwal also advocated for routine cardiac monitoring with echocardiograms in antisynthetase syndrome, analogous to standard practice in systemic sclerosis, given that pulmonary hypertension was a cause of mortality in 11% of patients in their cohort.

Presently there are no published classification criteria for antisynthetase syndrome, but Aggarwal and colleagues proposed a new set of criteria being reviewed by the ACR and EULAR. These criteria include points in both clinical and serologic domains, with ranges of scores representing probable and definitive antisynthetase syndrome. The criteria have been tested in multiple cohorts and have a high sensitivity and specificity. To demonstrate this point, both of the cases he presented, although phenotypically distinct, would meet the criteria for definitive antisynthetase syndrome.

Dr. Aggarwal also touched on treatment, emphasizing the efficacy of rituximab, particularly for the first case, and its demonstrated benefit in increases in FVC and DLCO for refractory ILD. He also highlighted the advent of CAR T cell therapy as a paradigm shift in the management of myositis, noting its ability to effect sustained improvements in CK, anti-Jo-1 antibody levels, manual muscle testing, patient global activity scores and even ILD fibrosis.²

Immune-Mediated Necrotizing Myopathy

Dr. Eleni Tiniakou

The talk shifted focus to the presentation and management of a similar yet distinct form of inflammatory myopathy—immune mediated necrotizing myopathy (IMNM), presented by Eleni Tiniakou, MD, associate professor of medicine and director of the myositis clinic in the Division of Rheumatology at University of Texas Health Science Houston, McGovern Medical School.

IMNM is a new term, first defined in 2004, which refined our understanding of the now-outdated term polymyositis. Clinically, IMNM is characterized by proximal muscle weakness, with marked elevations in CK levels, typically over at least 1,000. Biopsies demonstrate necrosis, myophagocytosis, and a macrophage predominance. IMNM can either be seronegative or seropositive with anti-HMGCR or SRP autoantibodies, which help further characterize the disease phenotype.

Dr. Tiniakou shared a cautionary tale of a 65-year-old man with prior statin exposure who presented with diffuse weakness and a CK of 42,000. Did this represent IMNM or statin (toxic) myopathy? She emphasized that neither EMG, MRI nor muscle biopsy would be able to differentiate between the two entities and that the physician must rely on the patient’s clinical trajectory. The patient’s CK resolved to <1,000 by day 10 in the absence of treatment, supporting the diagnosis of statin myopathy, rather than IMNM.

In the second case, Dr. Tiniakou recalled a patient diagnosed with seronegative IMNM who was unusually refractory to steroids, methotrexate and mycophenolate, leading her to question the diagnosis. Thyroid studies demonstrated undetectable free T4, and the patient was diagnosed with myopathy secondary to central hypothyroidism and empty sella syndrome. With thyroid replacement, the patient’s weakness slowly improved. This case underscored the importance of considering alternative diagnoses, particularly endocrinopathies, in patients with continued weakness despite immunosuppressive treatment.

In another case, she emphasized that younger patients with anti-SRP IMNM tend to have more aggressive disease. She advocated for the use of rituximab and steroids up front in cases of moderate to severe IMNM due to anti-SRP, and IVIG and steroids in anti-HMGCR positive IMNM, which is reflected in consensus recommendations for IMNM.^3-5 She reviewed the limited evidence for plasmapheresis and cyclophosphamide, which may be options in cases of aggressive disease.

Before closing, she made note of two ongoing NIH-sponsored trials for IMNM, including one for IVIG and another for ublituximab. IVIG, although approved by the U.S. Food & Drug Administration (FDA) for dermatomyositis, is not yet approved for IMNM.

Management of Recalcitrant Dermatomyositis

Dr. Alisa Femia

The third speaker was Alisa Femia, MD, associate professor in the Department of Dermatology at NYU Gross School of Medicine with an expertise in management of patients with dermatomyositis. She highlighted that, distinct from patients with SLE, antimalarials are not as effective for dermatomyositis (DM), and that adverse cutaneous reactions to hydroxychloroquine are seen in up to 30% of patients with DM.⁶ More effective therapies include IVIG, which has an important role in recalcitrant cutaneous disease, given its corticosteroid sparing effect, reduction in CDASI skin scores, and overall patient tolerance.⁷ IVIG has even demonstrated survival benefit in patients with DM, likely attributable to patients being able to discontinue other DMARDs.⁸

Dr. Femia contrasted this with the more underwhelming results for rituximab, which likely has greater efficacy in muscle disease and showed no difference in skin severity indices in a pilot trial.⁹

Given the correlation of interferon signatures with disease activity in DM, she demonstrated case examples of success with tofacitinib, and looked ahead to agents like dazukibart, a humanized IgG1 neutralizing monoclonal antibody against interferon beta, which is currently being studied in a global phase 3 trial for patients with active DM.¹⁰ She also shared experience of positive results with anifrolumab in recalcitrant DM, and introduced the promising new agent brepocitinib, a TYK2 and JAK1 inhibitor, which functions via marked inhibition of type I and II interferon, IL-6 and IL-12/23 signaling.¹¹

Brepocitinib for Dermatomyositis

Dr. Paik

Before the conclusion of the session, Julie Paik, MD associate professor of medicine and co-director of the Myositis Center at the Johns Hopkins University School of Medicine, took to the podium to share the exciting results from a randomized, double-blind, multi-center, placebo-controlled, phase 3 VALOR trial, which studied the safety and efficacy of brepocitinib for patients with active dermatomyositis. The study met its primary and all key secondary end points for brepocitinib 30 mg, with clinically meaningful benefits on measures of myositis response, and skin, muscle, physical function and corticosteroid tapering. Benefits were observed by week 4 and sustained out to 52 weeks of treatment. Importantly, brepocitinib was well tolerated with a favorable safety profile comparable to approved TY2K and JAK inhibitors.

In Sum

This session was packed with high yield clinical pearls and management strategies for antisynthetase syndrome, IMNM and dermatomyositis, with an eye toward promising new therapeutics, such as CAR T cell therapy and novel biologics like brepocitinib. These advances offer patients hope for meaningful clinical improvements and ultimately, durable remission.

Michael Cammarata, MD, RhMSUS, is an assistant professor of medicine at the Johns Hopkins University School of Medicine in Baltimore.

References

1. Aggarwal R, Cassidy E, Fertig N, et al. Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients. Ann Rheum Dis. 2014;73(1):227–232.
2. Müller F, Boeltz S, Knitza J, et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet. 2023;401(10379):815–818.
3. Valiyil R, Casciola-Rosen L, Hong G, et al. Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: A case series. Arthritis Care Res (Hoboken). 2010;62(9):1328–1334.
4. Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med. 2015;373(17):1680–1682.
5. Allenbach Y, Mammen AL, Benveniste O, Stenzel W; Immune-Mediated Necrotizing Myopathies Working Group. 224th ENMC International Workshop: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 Oct 2016. Neuromuscul Disord. 2018;28(1):87–99.
6. Pinard J, Femia AN, Roman M, et al. Systemic treatment for clinically amyopathic dermatomyositis at 4 tertiary care centers. JAMA Dermatol. 2019;155(4):494–496.
7. Femia AN, Eastham AB, Lam C, et al. Intravenous immunoglobulin for refractory cutaneous dermatomyositis: A retrospective analysis from an academic medical center. J Am Acad Dermatol. 2013;69(4):654–657.
8. Danieli MG, Gambini S, Pettinari L, et al. Impact of treatment on survival in polymyositis and dermatomyositis. A single-centre long-term follow-up study. Autoimmun Rev. 2014;13(10):1048–1054.
9. Chung L, Genovese MC, Fiorentino DF. A pilot trial of rituximab in the treatment of patients with dermatomyositis. Arch Dermatol. 2007;143(6):763–767.
10. Huard C, Gullà SV, Bennett DV, et al. Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis. Br J Dermatol. 2017;176(5):1224–1230. 
11. Shaw KS, Hashemi KB, Castillo RL, et al. Anifrolumab in recalcitrant cutaneous dermatomyositis: A multicenter retrospective cohort study. J Am Acad Dermatol. 2024;91(6):1217–1219.