Background/Purpose: COPA syndrome is a rare monogenic cause of immune-mediated lung disease, and it can mimic rheumatic diseases including rheumatoid arthritis (RA) with ILD, lupus and vasculitis. Like most genetic disease, COPA syndrome typically develops in childhood, but adult-onset cases have been reported. We recently established that a 77-year-old female who is 14 years out from double lung transplantation for a diagnosis of idiopathic pulmonary fibrosis (IPF) onset at age 60 years, her son with RA-ILD, and her granddaughter with juvenile arthritis complicated by ILD all have COPA syndrome. We then decided to determine the prevalence of COPA syndrome-associated mutations in patients with ILD who received lung transplantation.

Methods: We retrospectively reviewed 10 years of lung transplant recipients for ILD at a large transplant center
and identified patients with pulmonary fibrosis with or without a rheumatologic diagnosis. Targeted Sanger sequencing of the COPA syndrome hotspot (exons 8 and 9 of the COPA gene) was performed on amplified DNA extracted from explanted lung tissue.

Results: 427 transplant patients were identified; 66% were men and the mean age was 61 years. 55% received bilateral lung transplant. 62% had a diagnosis of idiopathic pulmonary fibrosis, 28% had a comorbid autoimmune condition, and 10% had other ILDs. To date, COPA sequencing has been completed for 147 patients and we have identified 4 patients with COPA mutations (2.7%), 3 with the most commonly reported variant (c.698G >A, p.R233H) and 1 with a novel variant (c.716C >T, p.A239V). The 1 female and 3 male patients had been diagnosed with RA-ILD, IPF, IPF and combined pulmonary fibrosis and edema (CPFE) as adults. All received bilateral lung transplant at an average age of 61 years (range 55-66 years). The 3 surviving patients are 11, 11 and 5 years out from transplant, however, the female patient with RA-ILD died 2 years post-transplantation secondary to chronic allograft rejection.

Conclusion: COPA syndrome is a rare entity and gaps exist in its recognition, diagnosis and management. We found that mutations in the COPA gene underlie some cases of severe pulmonary fibrosis labeled as other forms of adult-onset ILD. Identification and characterization of patients with such mutations will better define this rare disorder and serves as a step toward devising effective therapeutic strategies for patients with COPA syndrome.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/copa-syndrome-associated-mutations-in-lung-transplant-recipients-for-interstitial-lung-disease/