IDH1/2 mutations linked to inflammatory and rheumatological disorders

Somatic IDH1/2 mutations, well known in haematological malignancies, have now been associated with rheumatological conditions and cytopenia, even in the absence of overt malignancy, according to a report by Dr Flore Castellan (New York University School of Medicine, NY, USA) [1]. 

Using data from 3 large biobanks, including the UK Biobank, All of Us, and a Mayo Clinic cohort of clonal cytopenia of uncertain significance (CCUS), researchers performed an unbiased mutation enrichment analysis in 265 UBA1-negative adults with VEXAS-like systemic autoinflammatory disease versus matched controls to identify novel genes involved in the development of systemic autoinflammatory disease.  

Most participants had no haematological malignancy (72.8%), while 15.5% had myelodysplastic syndrome, 7.5% a myeloid neoplasm, and 4.2% a lymphoid neoplasm. Hotspot IDH1/2 mutations were among the most frequent and biologically significant, detected in 5.7% of participants with VEXAS-like disease. Notably, about 25% of participants with IDH1/2 mutations lacked any haematological malignancy and exhibited fewer co-mutations than those with haematological malignancy.  

Across all 3 biobanks, IDH1/2 mutations without concurrent haematological malignancy were significantly associated with rheumatologic conditions, elevated C-reactive protein (CRP) levels, and cytopenias. 

“All in all, we observed that IDH1/2 clonal haematopoiesis/CCUS co-occur with systemic inflammation with or without haematological malignancy,” concluded Dr Castellan. “These mutations are associated with rheumatological conditions in large biobanks. We suggest that IDH1/2 hotspot mutations are driving a treatable pre-malignant inflammatory condition, suggesting that screening for somatic IDH1/2 mutations in patients with unexplained systemic inflammation could inform targeted treatment strategies.” 

1. Castellan F, et al. IDH1/2 somatic hotspot mutations as independent drivers of autoinflammation. ACR Convergence, 24–29 October 2025, Chicago, IL, USA. 

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Posted on 27 November 20251 December 2025