The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study

Abstract

Background: Dermatomyositis (DM) is a multisystem autoimmune disease, in which serologic evidence of immune responses to disease-specific antigenic targets is found in approximately 50% to 70% of patients. Recently, melanoma differentiation-associated gene 5 (MDA5) has been identified as a DM-specific autoantigen that appears to be targeted in patients with DM and mild or absent muscle inflammation and with an increased risk of interstitial lung disease.

Objective: We wished to understand the role of MDA5 in DM skin inflammation by testing it to determine if a specific cutaneous phenotype is associated with MDA5 reactivity.

Methods: We retrospectively screened plasma from 77 patients with DM in the outpatient clinics at the Stanford University Department of Dermatology in California.

Results: We found that 10 (13%) patients had circulating anti-MDA5 antibodies, and had a characteristic cutaneous phenotype consisting of skin ulceration, tender palmar papules, or both. Typical areas of skin ulceration included the lateral nailfolds, Gottron papules, and elbows. Biopsy specimens of the palmar papules showed a vasculopathy characterized by vascular fibrin deposition with variable perivascular inflammation. Patients with anti-MDA5 antibodies also had an increased risk of oral pain and/or ulceration, hand swelling, arthritis/arthralgia, and diffuse hair loss. Consistent with previous reports, these patients had little or no myositis and had increased risk of interstitial lung disease.

Limitations: This study was conducted at a tertiary referral center. Multiple associations with MDA5 antibodies were tested retrospectively on a relatively small cohort of 10 anti-MDA5-positive patients.

Conclusion: We suggest that MDA5 reactivity in DM characterizes a patient population with severe vasculopathy.

Fig 1

Identification of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Plasma samples from patients with dermatomyositis (DM) and healthy control subjects were used to immunoprecipitate radiolabeled MDA5 generated by in vitro transcription/translation. All 10 of anti-MDA5 patient samples are shown (lanes 1–10), as are 3 DM samples that are anti-MDA5-negative (lanes 11–13) and 3 samples from healthy individuals (lanes 14–16). Leftmost lane (Input) refers to MDA5 protein loaded with no immunoprecipitation. Molecular weight markers (left).

Fig 2

Palmar papules of melanoma differentiation-associated gene 5–positive patients. A, Typical erythematous palmar macules or papules on either side of interphalangeal (IP) joints. B, Characteristic hyperkeratosis that is associated with palmar papules. C, Ulceration over palmar/lateral IP joint surface in second and fourth digits.

Fig 3

Histology of palmar papules demonstrates vasculopathy; hematoxylin-eosin stain. A, Mild interface activity with increased dermal mucin. B, Pauci-inflammatory pattern in perivascular region. C, Medium vessel wall infiltration with mononuclear cells. D, Intravascular fibrin and thrombus involving small vessels. E, Endothelial cell swelling and ballooning with fibrin deposition in vessel walls.

Fig 4

Different patterns of cutaneous ulceration in melanoma differentiation-associated gene 5–positive dermatomyositis patients. A, Lateral nailfold erythema and crusting. B, Deep ulceration overlying metacarpophalangeal joint. C, Back of left shoulder demonstrating noninflammatory, deep, “punched out” ulceration. D, Extensive ulceration and ischemic necrosis of digits.