From Pages to Practice

By Clement Lee, MD, MSc

Published October 19, 2022


The idiopathic inflammatory myopathies (IIM) are a group of diseases characterized by muscle inflammation with resultant weakness, the potential presence of other autoimmune signs (e.g., rash and calcinosis), specific autoantibodies that correspond to unique syndromes, and a variable clinical course ranging from mild disease to respiratory failure. These diseases are distinguished from other myopathies that have well-known causes, including muscular dystrophies, endocrinopathies, inborn errors of metabolism, infiltrative disorders, infectious myositides, and toxic myopathies.

In 2017, the American College of Rheumatology identified dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myopathy as the four major IIMs. However, the refining of autoantibody testing has led to major categorization changes; many patients with a prior diagnosis of polymyositis are now reclassified as having inclusion body myositis, immune-mediated necrotizing myopathy, or antisynthetase syndrome, and the presence of “polymositis” itself has been debated by rheumatologists.

From this complicated backdrop emerged the Progress in Dermatomyositis (ProDERM) trial, which aimed to clarify the role of intravenous immune globulin (IVIG) in patients with dermatomyositis. In this industry-sponsored trial, researchers randomized 95 patients to receive monthly infusion of IVIG or normal saline. The primary endpoint, a response of at least minimal improvement based on the Total Improvement Score (TIS), was significantly greater in the IVIG group after 16 weeks. However, IVIG was associated with more adverse events (58% vs. 23%), including six thromboembolic events in five patients (9.6%).

The success of IVIG in this trial led to its approval by the FDA for dermatomyositis, the first drug to attain this indication. Although Aggarwal et al. should be commended for making a breakthrough in the world of inflammatory myopathy, an editorialist notes the heterogeneity of patients enrolled in the trial with a diagnosis of “dermatomyositis” based on currently outdated criteria. The researchers reported that patients with necrotizing myopathy, overlap syndromes, and polymyositis were excluded. However, five patients had anti-SRP antibodies characteristic of necrotizing myopathy, one each had anti-Scl-70 and anti-dsDNA antibodies (suggesting overlap with systemic sclerosis and systemic lupus erythematosus), and some patients with anti-U1RNP, anti-Ku, and anti-PM-Scl were included. These latter antibodies have been seen in mixed connective tissue disease, scleroderma dermatomyositis overlap, and scleroderma polymyositis overlap, respectively. Even more striking, 15 patients had antisynthetase antibodies; antisynthetase syndrome is now considered a separate IIM.

In addition to the potential inclusion of patients who would not be considered as having a diagnosis of dermatomyositis based on newer criteria used by rheumatologists, clarification of treatment options is needed for some patients with subtypes of dermatomyositis. The trial excluded patients with juvenile dermatomyositis, a disease that has similar diagnostic criteria as dermatomyositis with the main exception of age. Amyopathic dermatomyositis is an intriguing clinical entity of little or no muscle inflammation, anti-MDA5 antibodies, and rapidly progressive interstitial lung disease. The ProDERM trial only enrolled one patient with anti-MDA5 antibodies, and since all of the patients in the trial had classic dermatologic and muscle involvement, it is not clear if this patient had true anti-MDA5 syndrome. In addition, the anti-MDA5 syndrome is more common in patients of Asian descent, and only two Asian patients were included in the trial (perhaps a reflection of selective enrollment of North American and European patients).

Patients with dermatomyositis may also experience weakness that leads to immobility and a predisposition to venous clot formation; this, along with the hypercoagulable properties of IVIG is a concern. Further, the dose of IVIG used in this trial (2g/kg every 4 weeks) is the highest dose available on the market. What remains unclear is whether lower doses of IVIG (e.g., 0.5–1 g/kg, as prescribed for other autoimmune conditions such as autoimmune hemolytic anemia) would be equally efficacious without incurring as much venothromboembolic risk. Additionally, volume overload as an adverse event was not recorded, and patients with dermatomyositis may have cardiac involvement and interstitial lung disease that contraindicate such liberal use of intravenous products. Finally, the patients were already medically stabilized, as the maximum daily dose of prednisone allowed at study entry was 20 mg; it is not unusual for patients with severe dermatomyositis to receive 1 mg/kg of prednisone daily during the acute phase of the disease.

Dermatomyositis is a debilitating disease that has profound effects on quality of life, as it can compromise swallowing, limit sun exposure, and affect activities of daily living. A significant improvement in the TIS reflects a change in a core set of six measures of myositis and is no small feat. Even so, this trial leaves many questions for clinicians to answer for themselves and their patients, including whether to use IVIG in the upfront setting.

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Clement Lee, MD, MSc, was a 2021–2022 NEJM Editorial Fellow and is a 2022-2023 Senior Editorial Fellow. He is currently an internal medicine hospitalist at Newton-Wellesley Hospital and a pediatric hospitalist at Boston Children's Hospital. He completed his internal medicine-pediatrics residency at Penn-CHOP.