By Daniel MacGowan, MD, MRCPI
Assistant Professor of Clinical Neurology, Weill Cornell Medical College, Cornell University
Dr. MacGowan reports no financial relationships relevant to this field of study.
SYNOPSIS: Dermatomyositis is an autoimmune disorder of skeletal muscle associated with a variety of auto-antibodies and specific muscle pathology but it may not have a skin rash. Muscle pathology and antibody determinations are important for accurate diagnosis and treatment.
SOURCE: Inoue M, Tanboon J, Hirakawa S, et al. Association of dermatomyositis sine dermatitis with anti-nuclear matrix protein 2 autoantibodies. JAMA Neurol 2020;77:1-6.
Inoue et al reported an 8% rate of dermatomyositis without skin or nail involvement (heliotrope rash, Gottron’s sign, shawl or V-sign, Gottron’s papules, or any kind of rash) in a cohort of 182 patients with muscle biopsies consistent with dermatomyositis, drawn from the primary referral center for muscle biopsies in Japan.
These 14 patients all were diagnosed incorrectly with polymyositis until muscle biopsy. Clinical information (skin findings, presence of muscle weakness, myalgia, dysphagia, interstitial lung disease or malignancy), serum creatine kinase level and serum results for the myositis specific antibodies (MSAs), anti-transcription intermediary factor 1-gamma (anti-TIF1-γ), Mi-2, melanoma differentiation-associated protein 5 (MDA5), nuclear matrix protein (NXP-2), and small ubiquitin-like modifier-1 activating enzyme (SAE) also were provided. Twelve of these 14 (86%) patients without rash were found to be positive for anti-NXP-2, compared with only 28% of the 168 patients with rash (P < 0.001).
One of the 14 patients without rash was positive for anti-TIF1-γ, and another for anti-Mi-2, compared with 38% who were TIF1-γ positive and 15% who were Mi-2 positive in those patients with rash. None of the patients without rash were positive for MDA5 or SAE antibodies. Of those patients with rash, 22 (13%) were positive for MDA5 antibodies and four (2%) were positive for SAE antibodies. All of the 182 muscle biopsies showed evidence of sarcolemmal expression of the myxoma virus resistance protein A (MxA), an interferon 1-induced antiviral product of the Mx1 gene on chromosome 21. Autoimmune diseases that are associated with strong activation of interferon 1-induced proteins include dermatomyositis, Sjögren’s syndrome, systemic sclerosis, and rheumatoid arthritis.
This same Japanese group recently demonstrated 71% sensitivity and 98% specificity of MxA expression for a diagnosis of dermatomyositis in 34 biopsies from 12 patients with definite, 18 with probable, and four with possible diagnoses of dermatomyositis, based on The European Neuromuscular Criteria for dermatomyositis. The criteria define definite as myositis patients with typical rash and perifascicular atrophy (PFA) on biopsy; probable as those with typical rash but no PFA; and possible as those with PFA but no rash.
The 71% sensitivity and 98% specificity of MxA expression for a diagnosis of dermatomyositis compared with 47% and 98% for PFA, and 35% and 93% for capillary endothelial C5-9b membrane attack complement deposition (MAC), represents a significant improvement in the sensitivity of muscle pathology for the diagnosis of dermatomyositis. In the 14 biopsies from patients without rash, all but one (93%) showed MAC positive capillaries and 9/14 (64%) showed PFA. The malignancy rate in the 168 patients with rash was 21%, and the rate was 2% in the 14 without rash.
This study represents yet another nail in the coffin for the diagnostic entity “polymyositis,” an increasingly rare disease entity that should be reserved for cases of inflammatory myopathy without MSA or anti-tRNA synthetase antibody, and pathological features of endomysial inflammation with invasion of non-necrotic MHC-1 expressing myofibers by CD-8 T cells without PFA, MAC, or rimmed vacuoles. The diagnosis of polymyositis carries with it a frequently false impression of less response to treatment and lower risk of malignancy than dermatomyositis.
Dermatomyositis usually responds to glucocorticoids and/or intravenous immune globulin, with refractory cases recently demonstrating responsiveness to tofacitinib, an oral agent currently approved to treat moderate to severe rheumatoid arthritis and ulcerative colitis. Tofacitinib is a disruptor of interferon 1-induced activation of the Janus kinase/signal transducer and activator of the transcription pathway (JAK/STAT), which is crucial for cytokine signaling and transcription. Tofacitinib has been promising in case reports of anti-MDA5 dermatomyositis with severe interstitial lung disease. Recently, in an open-label, 12-week trial of 10 patients with refractory dermatomyositis treated with tofacitinib, all reached the end point of an at least 20% improvement in a core set of measures derived from physician and patient impression, global activity, muscle strength, CK level, and health assessment questionnaire.
This study further reinforces the importance of performing muscle biopsy and antibody testing in all but the most obvious cases of dermatomyositis with classic rash and Gottron’s papules, since cases may occur without rash and without weakness.
Coexisting specific antibodies often are clinically significant — more than half of TIF1-γ cases will have concurrent or future malignancy; MDA5 cases involve a hypomyopathic presentation associated with rash and severe interstitial lung disease; NXP-2 cases are associated with subcutaneous edema, calcinosis, risk of contractures, and malignancy; and Mi-2 is associated with classic presentation and very good treatment response.
Signal recognition particle antibody (SRP) and HMGCoA reductase antibody positive cases may present with severe, rapidly progressive necrotizing myopathy requiring treatment with intravenous immunoglobulin and/or rituximab, and anti-tRNA synthetase cases may present with interstitial lung disease, arthritis, mechanic’s hands, Raynaud’s phenomenon, and overlap with scleroderma/CREST syndrome.