Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases

Abstract

Objectives: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease.

Methods: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data.

Results: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis.

Conclusion: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

Figure 1. Unsupervised analysis of anti–melanoma differentiation-associated gene 5 antibody–positive (anti-MDA5+) patients

(A) The hierarchical cluster analysis of anti-MDA5+ patients showed 3 clusters (the variables included in the unsupervised analysis were sex, ethnicity, skin changes, typical dermatomyositis skin rash, mechanic's hands, skin ulcers, calcinosis, digital necrosis, sclerosis, Raynaud phenomenon, abnormal creatine kinase [CK] level, CK level, proximal muscle weakness, manual muscle testing score of the psoas [Medical Research Council score], arthritis/arthralgia, synovitis, dyspnea, interstitial lung disease [ILD], rapidly progressive ILD, resuscitation, deterioration of general status, malignancy, intensive care unit admission, malignancy within 3 years before or after the myositis diagnosis, and early mortality). (B) Multiple correspondence analysis confirmed the presence of 3 groups of anti-MDA5+ patients. All above-mentioned variables except intensive rapidly progressive ILD, care unit admission, and mortality were included in the classification algorithm regression tree analysis.

Figure 2. Anti–melanoma differentiation-associated gene 5 antibody–positive (anti-MDA5+) prognosis

(A) The survival curves showed that cluster 1 (black) had a poor prognosis, cluster 2 (red) had a good prognosis, and cluster 3 (green) had a mild prognosis. (B) Pruned model of prediction without obvious signs of severity (the variables included in the classification algorithm regression tree analysis did not encompass obvious signs of severity [rapidly progressive interstitial lung disease (ILD), intensive care unit admission, and mortality], sex, ethnicity, skin changes, typical dermatomyositis skin rash, mechanic's hands, skin ulcers, calcinosis, digital necrosis, sclerosis, Raynaud phenomenon, abnormal creatine kinase [CK] level, CK level, proximal muscle weakness, manual muscle testing score of the psoas [Medical Research Council score], arthritis/arthralgia, synovitis, dyspnea, ILD, deterioration of the general status, malignancy, and malignancy within 3 years before or after the myositis diagnosis).

Figure 3. Unsupervised analysis of anti–melanoma differentiation-associated gene 5 antibody–positive (anti-MDA5+) and anti-MDA5− patients

(A) Hierarchical cluster analysis of anti-MDA5+ patients and anti-MDA5− myositis patients without including the anti-MDA5 antibody status as variable (the variables included for the unsupervised analysis were sex, ethnicity, proximal muscle weakness, abnormal creatine kinase [CK] level, CK level, skin changes, typical dermatomyositis skin rash, mechanic's hands, skin ulcers, calcinosis, Raynaud phenomenon, arthritis/arthralgia, dyspnea, interstitial lung disease, and malignancy within 3 years before or after the myositis diagnosis). The analysis permitted the identification 2 main clusters. (B) Using multiple correspondence analysis, both clusters were positioned on the factor map of individuals, which confirmed that patients were segregated into 2 groups. When the variable anti-MDA5 was next positioned, it appeared that cluster 2 was mainly composed of anti-MDA5+ patients (87.1%).