Background: Anti–melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) is a distinct subtype of inflammatory myositis characterized by prominent cutaneous manifestations, minimal or absent myositis, and a high risk of rapidly progressive, potentially fatal interstitial lung disease (ILD) [1-2]. The pathogenesis of anti-MDA5 DM remains unclear. Notably, familial cases have not been reported in the medical literature to date. Here we present the case of a 40-year-old African woman with anti-MDA5 DM and a family history notable for anti-MDA5 DM and early ILD in her young son. We also present the results of murine humanization experiments using immune cells derived from this patient demonstrating the feasibility and power of this model for studying inflammatory myositis. Murine humanized mouse models have been used previously in Systemic sclerosis (SSc) and granulomatous polyangiitis (GPA) patients with varied success [3]. Bergua et al. successfully demonstrated pathogenicity through passive transfer of IgG from patients with anti-SRP or anti-HMGCR autoantibodies, inducing immune-mediated necrotizing myopathy in recipient mice [4]. However, direct humanization experiments transferring MDA5 DM patient PBMCs into immunodeficient mice have not been reported in the literature.

Objectives: To further investigate the genetic basis of anti-MDA5 DM through a familial case presentation and to establish a novel experimental model for studying disease pathogenesis using peripheral blood mononuclear cells (PBMC) into immunodeficient mice.

Methods: PBMC were isolated and expanded in culture for 3 days with IL2 and anti-CD3 and anti-CD28 stimulation prior to adoptive transfer into immunodeficient NOD-SCID IL2Rgamma ^null mice (NSG). Cells were infused via intraperitoneal (IP) injection of 10 e6 cells per mouse. At approximately 4 weeks post-infusion, mice were sacrificed and tissues were sent for histological analysis.

Results: A 40-year-old African American woman presented with abrupt polyarticular inflammatory arthritis and a violaceous ulcerative rash over extensor surfaces of fingertips, and MCPs. She developed progressive hypoxia and was hospitalized with non-specific interstitial pneumonia pattern (NSIP) ILD and myocarditis/pericarditis. Positive anti-MDA5 antibody testing confirmed clinically amyopathic DM. Her course was complicated at different times by recurrent skin ulceration, diabetic ketoacidosis, AKI requiring dialysis, macrophage activation syndrome as well as several severe infections. Treatments included high-dose steroids, anakinra, and IVIG and ultimately remission was achieved. The patient elected to stop treatment and subsequently developed colitis and recurrence of her skin disease. She endorsed worsening inflammatory arthritis, exertional dyspnea, reduced ejection fraction (EF) of 40–45%, moderate restrictive pulmonary function tests (PFTs), and persistent Gottron’s papules with preserved muscle strength. She was started on upadacitinib and regained remission. Importantly, her young son was also diagnosed with anti-MDA5 dermatomyositis, presenting with cutaneous disease, early ILD, inflammatory arthritis, and echocardiographic evidence of reduced ejection fraction with global hypokinesis. This case suggests a possible familial association, which, to our knowledge, has not been previously reported. PBMC isolated from the patient while she was in remission on upadacitinib were sufficient to induce organ-specific in NSG mice after in vitro expansion. Phenotypic features developed in proportion to engraftment of patient-derived cells. Histopathological analyses showed organ-specific inflammation, and functional and phenotypic analyses of engrafted cells are pending.

Conclusions: This is the first known instance of myositis elicited by adoptive transfer of DM patient-derived cells into NSG mice and represents an important advancement in small animal models of myositis. Additionally, the similarity in disease presentation between mother and son suggests a strong genetic or epigenetic component to the disease; further studies are pending and may provide unprecedented insight into the pathogenesis of dermatomyositis.

REFERENCES: [1] Nombel A, Fabien N, Coutant F. Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies. Front Immunol. 2021 Oct 20;12:773352. doi: 10.3389/fimmu.2021.773352. PMID: 34745149; PMCID: PMC8564476.

[2] Lu X, Peng Q, Wang G. Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress. Nat Rev Rheumatol. 2024 Jan;20(1):48-62. doi: 10.1038/s41584-023-01054-9. Epub 2023 Dec 6. PMID: 38057474.

[3] Yue X, Petersen F, Shu Y, Kasper B, Magatsin JDT, Ahmadi M, Yin J, Wax J, Wang X, Heidecke H, Lamprecht P, Müller A, Yu X, Riemekasten G. Transfer of PBMC From SSc Patients Induces Autoantibodies and Systemic Inflammation in Rag2-/-/IL2rg-/- Mice. Front Immunol. 2021 Jun 23;12:677970. doi:

[4] Bergua C, Chiavelli H, Allenbach Y, Arouche-Delaperche L, Arnoult C, Bourdenet G, Jean L, Zoubairi R, Guerout N, Mahler M, Benveniste O, Drouot L, Boyer O. In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy. Ann Rheum Dis. 2019 Jan;78(1):131-139. doi: 10.1136/annrheumdis-2018-213518. Epub 2018 Oct 11. PMID: 30309969.

Acknowledgments: NIL.

Disclosure of Interests: Pamela Gonzalez Manrique: None declared, Samantha Coss: None declared, Noah Weisleder: None declared, Wael Jarjour Navidea Biopharmaceuticals, Columbus, Ohio 2013-2016 and received grant from them.

Not relevant to this abstract, Navidea Biopharmaceuticals, Columbus, Ohio 2013-2016 and received grant from them

Not relevant to this abstract