BALTIMORE—Many rheumatologists are aware of the 1975 Bohan and Peter criteria for the diagnosis of dermatomyositis and polymyositis, but fewer have been willing to reconsider these criteria in the era of recognized myositis-associated autoantibodies and their correlated phenotypes.1,2
At the 20th Annual Advances in the Diagnosis and Treatment of the Rheumatic Diseases Symposium at Johns Hopkins School of Medicine, Lisa Christopher-Stine, MD, MPH, professor of medicine, director of the Myositis Center, Johns Hopkins School of Medicine, Baltimore, delved deeply into this topic with her presentation, Updates in Myositis.
Subtypes
To begin with, Dr. Christopher-Stine made a bold claim: Polymyositis does not truly exist. She explained that what was once conceptualized as polymyositis may actually be an overlap syndrome with features of several different conditions presenting in the same patient.
Subtypes of idiopathic inflammatory myopathies include juvenile dermatomyositis, amyopathic dermatomyositis, immune-mediated necrotizing myopathy and antisynthetase syndrome.3
The last of these subtypes—antisynthetase syndrome—requires the presence of an antibody directed against members of the tRNA synthetase family. The syndrome typically has three cardinal features: interstitial lung disease (ILD), myositis and arthritis. Other manifestations are common in antisynthetase syndrome, such as Raynaud’s phenomenon, mechanic’s hands and fever, but Dr. Christopher-Stine considers these supportive rather than essential findings. Patients with antisynthetase syndrome may or may not have skin involvement as part of their disease, and interesting cutaneous findings, such as hiker’s feet, have been described in the literature.4
Dr. Christopher-Stine noted that about 40% of patients with arthritis as part of the syndrome will present with a rheumatoid arthritis-like pattern. This finding—coupled with the fact that some culprit antibodies have yet to be discovered and may be labeled as unidentified on certain test panels—can make the condition challenging to diagnose.
Novel Antibodies
Dr. Christopher-Stine was excited to inform the audience of two novel anti-aminoacyl tRNA synthetase antibodies that have recently been described in Japan. Muro et al. took the sera of more than 300 patients with myositis—mostly dermatomyositis—and screened them against four tRNA synthetases: CysARS, ValARS, SerARS and TrpARS. Sera from two patients were found to react to CysARS and ValARS. More specifically, the patient with anti-CysARS antibodies had a phenotype that included myositis, Gottron’s papule/sign, ILD, mechanic’s hands, non-erosive arthritis, fever and Raynaud’s phenomenon. The patient with anti-ValARS antibodies had Gottron’s sign, heliotrope rash, and mechanic’s hands and was classified with amyopathic dermatomyositis; this patient also had antibodies to transcriptional intermediary factor 1 gamma (TIF1γ).5
Dr. Christopher-Stine shared her hope that other novel antibodies can be identified in the future and that the clinical phenotypes associated with these antibodies can be explored to better inform diagnosis and treatment strategies.
Cancer & Myositis
With regard to cancer, the strongest association is in patients with myositis and antibodies to TIF1γ. Work from Dr. Christopher-Stine and her colleagues has shed light on the processes that may be at play in these patients. Using a proteomic approach, the team identified 10 potentially novel autoantibodies in anti-TIF1γ-positive patients with dermatomyositis, the most common being against cell division cycle and apoptosis regulator protein 1 (CCAR1). Patients whose only antibodies were to TIF1γ had a higher likelihood of developing cancer than patients with antibodies to CCAR1 and other antigens in addition to TIF1γ. Thus, the study hypothesized a model for describing the balance between cancer fitness and immune response.6
In the model’s first scenario, patients with a high fitness cancer and a lack of additional immune responses are most likely to see rapid, aggressive cancer emergence via what is termed immune escape and will only be found to produce antibodies to TIF1γ. In the model’s second scenario, the cancer and immune responses are more balanced—as evidenced by production of a broader range of autoantibodies, including those against CCAR1. The cancer that ultimately develops is less aggressive and delayed in onset from time of dermatomyositis emergence. In the third scenario, a broad and effective immune response capably eliminates the cancer or maintains it in the subclinical state. These patients will have a wide array of autoantibodies and will not show any overt signs of cancer.6
Screening: Although models such as this require further examination, Dr. Christopher-Stine provided clinical pearls gleaned from real-world observations to guide how clinicians should screen for malignancy in patients with idiopathic inflammatory myopathies. In general, the types of cancer most frequently seen in idiopathic inflammatory myopathies are lung, ovarian, colorectal, lymphoma, breast and nasopharyngeal cancer, and typically onset is within one to three years before or after the diagnosis of myositis.
Across all patients with idiopathic inflammatory myopathies, cancer risk appears highest in those with dermatomyositis, antibodies to TIF1γ or NXP-2, age of onset after 40, high disease activity despite immunosuppression, dysphagia, and cutaneous necrosis. Dr. Christopher-Stine cited the International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening as a particularly helpful resource for rheumatologists.7
Treatment
Dr. Christopher-Stine noted that identifying active disease domains (i.e., skin, muscle, lung or other) in individual patients makes the greatest difference in selecting the appropriate therapy to treat myositis. Treatment options include glucocorticoids, methotrexate, azathioprine, mycophenolate mofetil, rituximab and intravenous immunoglobulin (IVIG).
IVIG has received particular attention since the publication of the ProDERM study. In this study, patients with dermatomyositis on a stable dose of standard therapy (i.e., mycophenolate mofetil, methotrexate, glucocorticoids and/or hydroxychloroquine) were randomized to receive either 2 g/kg of IVIG or placebo every four weeks for 16 weeks. Patients who showed clinical deterioration in this period were switched to the alternative treatment and, at week 16, all patients on placebo and those without clinical deterioration on IVIG received 2 g/kg of IVIG every four weeks for 24 weeks. The study then measured the proportion of responders in each group with at least minimal improvement in the total improvement score (i.e., a composite response criteria) without deterioration at two consecutive visits up to week 16. Researchers found that 79% of patients receiving IVIG and 44% of patients receiving placebo met this end point, respectively.8
In 2021, largely based on these trial results, the U.S. Food & Drug Administration (FDA) approved IVIG for the treatment of adult dermatomyositis. A benefit of the approval has greater insurance coverage for the treatment. However, a downside is that insurance companies are now asking for biopsy proof of myositis even in patients with a clear clinical diagnosis.
In Sum
Dr. Christopher-Stine gave the audience a framework in which to evaluate and care for patients with idiopathic inflammatory myopathies.
Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
References
- Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975 Feb 13;292(7):344–347.
- Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975 Feb 20;292(8):403–407.
- Oldroyd A, Lilleker J, Chinoy H. Idiopathic inflammatory myopathies—a guide to subtypes, diagnostic approach and treatment. Clin Med (Lond). 2017 Jul;17(4):322–328.
- Cox JT, Gullotti DM, Mecoli CA, et al. “Hiker’s feet”: A novel cutaneous finding in the inflammatory myopathies. Clin Rheumatol. 2017 Jul;36(7):1683–1686.
- Muro Y, Yamashita Y, Koizumi H, et al. Two novel anti-aminoacyl tRNA synthetase antibodies: Autoantibodies against cysteinyl-tRNA synthetase and valyl-tRNA synthetase. Autoimmun Rev. 2022 Dec;21(12):103204
- Fiorentino DF, Mecoli CA, Rosen MC, et al. Immune responses to CCAR1 and other dermatomyositis autoantigens are associated with attenuated cancer emergence. J Clin Invest. 2022 Jan 18;132(2):e150201.
- Oldroyd AGS, Callen JP, Chinoy H, et al. International guideline for idiopathic inflammatory myopathy-associated cancer screening: An international myositis assessment and clinical studies group (IMACS) initiative. Nat Rev Rheumatol. 2023 Dec;19(12):805–817.
- Aggarwal R, Charles-Schoeman C, Schessl J, et al. Trial of intravenous immune globulin in dermatomyositis. N Engl J Med. 2022 Oct 6;387(14):1264–1278.
