In this fiscal year, we have focussed on defining the functional role of myositis autoantigens in muscle differentiation and repair. As in other systemic autoimmune diseases, patients with myositis often have autoantibodies targeting self-proteins. We previously demonstrated that the dermatomyositis (DM) autoantibody CHD4 is upregulated in regenerating muscle and that reducing levels of this protein in cultured muscle cells accelerates their differentiation. Recently, we showed that another DM autoantigen, TRIM33, is similarly up-regulated during muscle repair and seems to play a role during muscle differentiation in cell culture. During this year, we have sought to extend these findings by generating mice that have no CHD4 or TRIM33 expressed in muscle cells. We have generated the first litters of such mice and will work in the coming fiscal year to analyze how deletion of these genes in muscle cells affects muscle cell development and regeneration following muscle injury. In addition to the basic science project described above, we also have been involved with several clinical projects involving myositis patients who are part of the Johns Hopkins Myositis Center Longitudinal Cohort. These projects include (a) analyzing a longitudinal cohort of patients with anti-HMG-CoA reductase antibodies to determine optimal treatments modalities, (b) demonstrating that unique patterns of muscle biopsy abnormalities are associated with individual dermatomyositis autoantibodies, (c) defining the spectrum of diseases associated with anti-NT5C1a autoantibodies and defining the associated clinical features in each disease, and (d) defining the clinical features of myositis patients with different autoantibodies. In collaboration with Dr. James Gulley and colleagues at the NCI, we have sought to characterize and identify pathogenic mechanisms in patients with metastatic thymoma who develop myositis following treatment with PD-L1 checkpoint inhibitors. In collaboration with Dr. Avi Nath and colleagues at NINDS, we helped characterize a mouse model for motor neuron disease (MND) created by over-expressing the endogenous retrovirus HERV-K. We showed that muscle from these mice had fiber-type grouping as seen in MND.

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Arthritis, Musculoskeletal, Skin Dis
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Pinal-Fernandez, Iago; Mammen, Andrew L (2018) Dermatomyositis etiopathogenesis: a rebel soldier in the muscle. Curr Opin Rheumatol 30:623-629
Yeker, Richard M; Pinal-Fernandez, Iago; Kishi, Takayuki et al. (2018) Anti-NT5C1A autoantibodies are associated with more severe disease in patients with juvenile myositis. Ann Rheum Dis 77:714-719
Selva-O'Callaghan, Albert; Pinal-Fernandez, Iago; Trallero-Araguás, Ernesto et al. (2018) Classification and management of adult inflammatory myopathies. Lancet Neurol 17:816-828
Mammen, Andrew L; Rajan, Arun; Pak, Katherine et al. (2018) Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1. Ann Rheum Dis :
Pinal-Fernandez, Iago; Parks, Cassie; Werner, Jessie L et al. (2017) Longitudinal Course of Disease in a Large Cohort of Myositis Patients With Autoantibodies Recognizing the Signal Recognition Particle. Arthritis Care Res (Hoboken) 69:263-270
Cox, Jacob T; Gullotti, David M; Mecoli, Christopher A et al. (2017) ""Hiker's feet"": a novel cutaneous finding in the inflammatory myopathies. Clin Rheumatol 36:1683-1686
Mammen, Andrew L (2017) Which nonautoimmune myopathies are most frequently misdiagnosed as myositis? Curr Opin Rheumatol 29:618-622
Weihl, C C; Mammen, A L (2017) Sporadic inclusion body myositis - a myodegenerative disease or an inflammatory myopathy. Neuropathol Appl Neurobiol 43:82-91
Amici, David R; Pinal-Fernandez, Iago; Mázala, Davi A G et al. (2017) Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis. Acta Neuropathol Commun 5:24
Mohassel, Payam; Foley, A Reghan; Donkervoort, Sandra et al. (2017) Anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase necrotizing myopathy masquerading as a muscular dystrophy in a child. Muscle Nerve :

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