Dermatomyositis takes your breath away!
Feb. 22, 2017
The dermatopulmonary syndrome (DPS) is a newly recognized subset of dermatomyositis (DM) associated with anti-MDA5 (melanoma differentiation-associated gene 5) antibodies. The hallmarks are palmar papules, cutaneous ulceration, a high risk of severe interstitial lung disease (ILD), a low risk of myositis, and a low risk of malignancy.
Forentino et al retrospectively screened 77 patients with DM for anti-MDA5 antibodies and 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. Patients had little or no myositis and had an increased risk of ILD (1).
In a study of 61 patients with clinically amyopathic dermatomyositis (CADM) who were matched to 61 DM controls, anti-MDA5 frequency was the same in both cohorts (13.1%), and anti-MDA5 was significantly associated with a higher likelihood of cutaneous ulcers, digital tip ulcerations, and puffy fingers as well as ILD. Most patients with ILD had rapidly progressive ILD (RPILD) leading to early death. Patients with CADM were more likely to have dysphagia, but there were no other clinical differences seen associated with CADM as compared to classic DM (2).
ILD is also a component of the antisynthetase syndrome. Per Hallowell and Danoff, “Antisynthetase antibodies (ARS-Abs) target one of the 20 specific enzymes required to load each tRNA with an amino acid and to date, eight such ARS-Abs have been identified. The presence of an ARS-Ab, combined with either ILD or inflammatory myositis, is termed as the antisynthetase syndrome, and it is often associated with additional clinical features, including arthritis, mechanic’s hands, Raynaud’s phenomenon, and fevers. The prevalence of ILD in the antisythetase syndrome ranges from 67 to 100% depending on the antibody type and the diagnostic methods used. Indeed, some research suggests that the various ARS-Abs are associated with different subphenotypes characterized by variations in their presentation of ILD, myositis, and dermatologic findings; however, such conclusions have been difficult to draw, given the rarity of many of these antibodies and a lack of large-scale trials. Treatment is with high dose steroids, and other immunosuppressive agents, including rituximab and IVIG. Despite aggressive multimodality treatment, patients may fail to respond (3).
The anti-MDA5 DPS may complicate chronic graft-versus-host disease following allogeneic hematopoietic stem call transplantations (AHSCT). In a study of 83 patients who underwent AHSCT, 6 patients tested positive for anti-MDA5 antibodies, including 4 patients with interstitial lung disease and 3 patients with cutaneous clinical features similar to anti-MDA5 skin symptoms encountered in patients who have not undergone AHSCT, namely finger pad inflammation, palmar violaceous papules, and digital ulcerations. Three patients had severe respiratory symptoms resistant to systemic steroids, and 1 patient died of severe interstitial lung disease (4).
It may be important to differentiate ILD due to anti-MDA5 antibodies from those with the antisynthetase syndrome. In a study of 22 patients with polymyositis/dermatomyositis-ILD (10 positive for anti-ARS Ab and nine positive for anti-MDA5 Ab), it was demonstrated that positivity for anti-MDA5 Ab, but not for anti-ARS Ab, was associated with mortality in the first 3 months. Evaluation of the therapeutic response in the first year showed that positivity for the anti-ARS Ab, but not for the anti-MDA5 Ab, was associated with an improvement in %DLCO. Positivity for the anti-ARS Ab or negativity for anti-MDA5 Ab was associated with a greater decrease in bronchial dilatation as seen by high resolution computerized tomography (5).
DM is breathtaking — literally and figuratively. With a further understanding of the immunologic subsets, perhaps future targeted therapies can breathe new life into therapeutic approaches for DM-associated ILD.
1. Fiorentino D, et al. The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): A retrospective study. J Am Acad Dermatol 2011; 65: 25-34.
2. Moghadam-Kia S, et al. Antimelanoma differentiation-associated gene 5 antibody: Expanding the clinical spectrum in North American patients with dermatomyositis. J Rheumatol 2017 Jan 15 [Epub ahead of print].
3. Hallowell RW, Danoff SK. Interstitial lung disease associated with the idiopathic inflammatory myopathies and the antisynthetase syndrome; Recent advances. Curr Opin Rheum 2014; 267: 684-9.
4. Lepelletier C, et al. Dermatopulmonary syndrome associated with anti-MDA5 antibodies after allogeneic hematopoietic stem cell transplantation. JAMA Dermatol 2017; 153: 184-8.
5. Yoshida N, et al. Association of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease. Respir Investig 2017; 55:24-32.
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