Background/Purpose: Myeloidmutations commonly associated to neoplasia in patients who do not meet the diagnostic criteria for myelodysplastic syndrome are coined as clonal hematopoiesis of indeterminate potential (CHIP). CHIP-related mutations are somatic DNA mutations accumulating with aging, being found in approximately 10% of over 65. Chronic inflammation, mirrored by TNF-aexposure, has been reported to favor the expansion of CHIP-mutant clones, such as TET2- and JAK2-, but recent evidence suggests that CHIP-mutated clones contribute to chronic inflammation, as TET2-mutated myeloid clones manifest a hyper-inflammatory M1 status. We hypothesize that chronic inflammation concurs with age to CHIP-mutation appearance, i.e. they should be more precocious and frequent in rheumatic patients; moreover, CHIP-mutations are associated to more active rheumatic diseases.

Methods: We investigated the peripheral blood and synovial fluid myeloid cells from 4 rheumatoid arthritis (RA), 4 psoriatic arthritis (PsA), and 4 knee osteoarthritis (OA) patients (female 5, median age 73,5 years, range 53-91, median disease duration 10 years, range 7-20). To detect the presence of CHIP-mutations we used a high-throughput sequencing platform (Illumina NextSeq platform) for mutation screening of 78 genes known to be relevant in myelodysplastic diseases. We evaluated only variants known as pathogenic in COSMIC database, with a population frequency (MAF) < 0.1% described in dbSNP and in 1000 Genome Project.

Results: We found somatic mutations of JAK2, TP53, and TET2in 2/4 RA patients, GATA2-mutation in 1/4 PsA patients, and a small clone of SF3B1 in 1/4 OA cases. Mutated clones were found both in peripheral blood and synovial fluid of the patients. The patients with CHIP-mutations did not have a more active disease (DAS28-CRP 4.2±0.6 vs 5.1±1.2; p>0.05), but 1 RA patient with JAK2-mutation and 1 PsA patient had < 65years.

Conclusion: Our data suggests that CHIP-mutations are frequent in patients with chronic arthritis, also before 65 years. Understanding the mechanisms connecting somatic mutation-driven clonal hematopoiesis and chronic inflammation will be of great interest not only from a pathogenic point of view, but also in considering possible therapeutic options, such as JAK-inhibitors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mutations-associated-with-clonal-hematopoiesis-of-indeterminate-potential-are-found-in-peripheral-blood-and-synovial-fluid-macrophages-from-patients-with-rheumatoid-and-psoriatic-arthritis/