Background/Purpose: Recently, somatic mutations in hematopoietic stem and progenitor cells (HSPCs) have been proposed as a novel mechanism driving systemic inflammation. UBA1 somatic variants in HSPCs cause VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, a late onset, systemic autoinflammatory disease (SAID) with elevated morbidity and mortality. We hypothesized that additional somatic variants may underlie inflammation in undiagnosed SAID.

Methods: We performed unbiased mutation enrichment analysis in 265 UBA1-negative adults with VEXAS-like SAID versus matched controls. Associations between identified genes with autoimmune phenotypes were assessed in UK Biobank (N&#3f454,218), All of Us (N&#3f414,830), and a Mayo Clinic cohort of clonal cytopenia of uncertain significance (CCUS, N&#3f275). Finally, inflammatory outcomes in carriers were evaluated in a clinical trial of targeted treatment.

Results: Unbiased gene burden analysis identified IDH1/2 and SRSF2, frequently co-mutated, as significantly enriched in the SAID cohort. IDH1/2 hotspot mutations were observed in 5.7% of patients overall, and were the most recurrent impactful variants among patients without hematologic malignancy (N&#3f193, 2.1%). All of these individuals (N&#3f4) exhibited recurrent fevers, skin inflammation and cytopenia, with most (N&#3f3) having inflammatory arthritis requiring multiple DMARDs, supporting a role for IDH1/2 in driving inflammation outside of the established role of inflammation in overt malignancy.To explore the association between IDH-mutant clonal hematopoiesis (CH) or CCUS and autoimmune disease, we analyzed two large cohorts, identifying 264 individuals with IDH1/2-mutant CH without hematologic malignancy. IDH1/2 CH was associated with autoimmune disease (OR=1.8, p=4e-3), with the strongest associations for polymyalgia rheumatica (OR=4.0, p=1e-3) and giant cell arteritis (OR=8.1, p=1e-6). Carriers had elevated CRP versus other CH-carriers (p=1e-2) and altered myeloid counts. Findings were corroborated in the Mayo clinic CCUS cohort, where 8/275 patients (2.9%) carried IDH1 mutations, half of which exhibited autoimmune manifestations—including seronegative rheumatoid arthritis and Sweet syndrome – highlighting the clinical relevance of IDH mutations in the context of cytopenia.We then evaluated the effect of IDH1 inhibition on inflammation in a clinical trial of ivosidenib in IDH1 carriers with CCUS. Most (58%, 11/19) had elevated hsCRP ( >=5; range 6.91–46.2 mg/L) including 4 with autoimmune disorders—all with episodic joint pain and half with skin manifestations. Most patients with elevated hsCRP at baseline normalized ( < 5 mg/L) on treatment (7/9). All four individuals with autoimmune disorders had subjective improvement in symptoms with ivosidenib.

Conclusion: Together, our results point to IDH1/2 CH as a driver of autoinflammation, particularly in patients with cytopenia. Their presence in SAID cases without hematologic malignancy supports their role as drivers of inflammation. The efficacy of IDH1 inhibition in improving inflammatory manifestations in the ongoing IDH1-carrier trial underscores the potential for a therapeutic approach.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/idh1-2-somatic-hotspot-mutations-as-independent-drivers-of-autoinflammation/