Background: Anti–melanoma differentiation–associated gene 5 (MDA5) antibodies are often found in dermatomyositis with typical skin/vasculitic changes and high risk of rapidly progressive interstitial lung disease (ILD). MDA5 is a cytosolic pattern recognition receptor involved in antiviral immunity through the induction of type I interferon responses. Dysregulated activation of antiviral sensing pathways during viral infections may promote loss of immune tolerance and autoantibody production. During the COVID-19 pandemic, an increased incidence of anti-MDA5 antibodies positivity and related clinical syndrome was reported, suggesting a distinct phenotype named MIP-C (MDA5 autoimmunity and interstitial pneumonitis contemporaneous with COVID-19) [1-3]. The long-term follow-up of patients with MIP-C remains poorly defined.

Objectives: To describe the clinical, serological and pulmonary outcomes of a cohort of patients with anti-MDA5 related autoimmune disease identified during the COVID-19 pandemic after >3 years of follow-up since the disease onset.

Methods: We conducted a descriptive longitudinal follow-up study of a previously described cohort of 60 anti-MDA5–positive patients from Yorkshire during the COVID-19 pandemic (from 2020 to Dec 2022) with follow-up data from Jan 2023 to Dec 2025. Clinical features, disease flare, survival, autoantibody status when retested, ILD and pulmonary function, and additional SARS-CoV-2 vaccination were assessed over time.

Results: Eight of the 60 original patients included in the MIP-C cohort died, leaving 52 patients eligible for follow-up. Of these, only 4/52 died with a single early death attributable to rapidly progressive ILD, the remaining 3 deaths were later (one each acute myocardial infarction, pulmonary infection, and intestinal ischemia). Among the 48 survivors, 6 patients, all alive, were no longer followed by rheumatology or respiratory services. Of the remaining cases, disease flares occurred in 7/42 patients (16.7%) with flares predominantly confined to same organs as baseline activity, most commonly joints (synovitis), muscle (myositis), skin/Raynaud’s phenomenon anda lung in patients with pre-existing ILD. Pulmonary flares were mild and not consistent with rapidly progressive ILD or acute severe exacerbations. Isolated cardiac worsening was observed in one patient. Limited additional organ involvement occurred in 2 patients, including joints and skin, without multisystem disease escalation or progressive organ damage. Longitudinal serological assessment showed anti-MDA5 negativity in 10/14 available patients (71.4%), with no observed serological reactivation, including among patients experiencing clinical flares. Of the initial 52/60 survivors, ILD was present in 13/52 patients (25.0%) with baseline ILD fibrotic NSIP (46.2%), UIP (30.8%) and NSIP/organizing pneumonia overlap (23.1%). Imaging follow-up (available for n = 10/52) showed heterogeneous ILD pattern evolution over time with transitions between fibrotic NSIP, NSIP/organizing pneumonia overlap and UIP were observed but no rapidly progressive or uniformly fibrotic phenotype emerged at follow-up and no NSIP/OP flares/acute exacerbations were observed (Figure 1). Pulmonary function parameters were overall unchanged without signs of progression according to ATS/ERS criteria [4]. Among the original cohort of 60 patients, 48 received SARS-CoV-2 vaccination. During the study follow-up, 16 patients received multiple booster doses (range 0–6). Despite repeated vaccination, no temporal association was observed between SARS-CoV-2 vaccine exposure and anti-MDA5 serological reactivation, disease flares or treatment escalation. Overall, 27/42 patients (64.3%) continued systemic immunosuppressive therapy; notably, five patients who received multiple booster doses were off immunosuppressive treatment.

Conclusions: Longitudinal follow-up of patients with anti-MDA5 syndrome emerging during the COVID-19 pandemic revealed an overall long-term indolent disease course with limited incidence of clinical flares, frequent follow up autoantibody negativity and stable ILD despite evidence of some change in phenotype. Beyond the 13% ILD related mortality during the initial disease phase, only one additional patient subsequently died due to anti-MDA5–associated rapidly progressive ILD. Our findings represent a unique SARS-CoV-2 era experiment of nature linked to high circulation of virus in 2020-2022 with anti-MDA5 autoimmunity and early mortality in 13% of cases. The lack of ILD progression and stability in the remaining cases suggests a transient SAR-CoV-2 context-dependent immune phenomenon rather than a self-sustaining autoimmune disease. These observations support the concept of a dsRNA viral triggering mechanism that was self-limiting as distinct from progressive autoimmune disease for which MDA5 autoimmunity was initially linked.

REFERENCES: [1] David P, et al. MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C). EBioMedicine. 2024.

[2] Tonutti A, et al. Anti-MDA5 Antibody Linking COVID-19, Type I Interferon, and Autoimmunity: A Case Report and Systematic Literature Review. Front Immunol. 2022.

[3] Yoshida A, et al. Dysregulated type I/III interferon system in circulation from patients with anti-MDA5-positive dermatomyositis. Sci Rep. 2025.

[4] Raghu G, Am J Resp Crit Care Med. 2022.

Acknowledgments: NIL.

Disclosure of Interests: Francesca Trunfio: None declared, Antonio Tonutti: None declared, Kerem Abacar: None declared, andrew barr: None declared, Paula David: None declared, Gabriele De Marco GDM received speaker fees from Janssen, Novartis, EventsCo LTD. GDM received consultancy fees from Janssen, Novartis. GDM received transfer of value (congress fees and hospitality) from Janssen, Novartis, Pfizer, UCB., Gui Tran: None declared, Khizer Iqbal: None declared, Samuel Wood: None declared, Sharmin Nizam: None declared, Maria Slade: None declared, Zoe Ash: None declared, Lauren Coles: None declared, Sinisa Savic: None declared, Sheetal Maisuria: None declared, Gururaj Arumugakani: None declared, Chamila Hettiarachchi: None declared, Emma Payne: None declared, Gayle Smithson: None declared, Rahul Shah: None declared, Joanna Mclorinan: None declared, Hanu Reddy: None declared, Shabina Sultan: None declared, Ala Altaie: None declared, Dina Youssef: None declared, Mansoor Keen: None declared, Omer Sharif: None declared, Md Yuzaiful Md Yusof: None declared, Francesco Del Galdo: None declared, Aamir Aslam: None declared, Dennis McGonagle: None declared.