New research identifies IDH1/2 mutations as drivers of treatable systemic autoinflammatory disease, offering hope for targeted therapies.
Breaking new research at ACR Convergence has shown – for the first time – what is being called ‘the new VEXAS’: a previously unrecognised link between certain genetic mutations in blood-forming stem cells and systemic inflammatory diseases, which might also have an existing targeted therapy.
The research included scientists from around the US, including New York University School of Medicine and Washington University School of Medicine, as well as Associate Professor Devendra Hiwase, a clinician‐scientist and consultant haematologist at the University of Adelaide’s Medical School, who also holds roles at the South Australian Health and Medical Research Institute and the haematology department at the Royal Adelaide Hospital.
The researchers have identified mutations in the IDH1 and IDH2 genes as potential drivers of inflammation in patients with systemic autoinflammatory disease (SAID) who test negative for UBA1 mutations – long known to cause the rare VEXAS syndrome.
Their findings were shared in a late breaking presentation at ACR Convergence last month, by Dr Flore Castellan, a postdoctoral fellow at the New York University Grossman School of Medicine.
“The impact of mutations in CH [clonal haematopoiesis] can vary widely from having no apparent clinical consequence to contributing to an increased risk of rheumatic and cardiovascular conditions to causing somatic monogenic diseases such as VEXAS syndrome,” she told delegates.
VEXAS syndrome is a rare autoinflammatory disease first described in 2020 by researchers at the US National Institutes of Health, with the acronym reflecting key features of the disorder, including vacuoles, E1 enzyme, X-chromosome linked, autoinflammatory and somatic mutations.
Because the mutation is on the X chromosome, the syndrome predominantly affects men aged over 40 years. Women are rarely affected, but cases have been reported in those with X-chromosome monosomy, such as Turner syndrome or mosaicism.
VEXAS syndrome manifests with a combination of systemic inflammatory and hematologic features including recurrent fevers, skin rashes (especially red, painful nodules or vasculitic lesions), chondritis, lung inflammation, arthritis, venous thromboembolism, fatigue and weight loss, low blood counts (including anaemia, low platelets or white cells) and bone marrow with vacuoles in precursor cells.
As part of their study, researchers analysed genetic data from 265 adults with VEXAS-like disease who did not carry UBA1 mutations, comparing them with matched controls. Investigators discovered that mutations in IDH1/2 and SRSF2 were significantly enriched in the patient group, suggesting a new molecular pathway linking CH to systemic inflammation.
IDH1/2 mutations, present in roughly 6% of patients, were the most frequent impactful variants among those without blood cancer, occurring in individuals with recurring fevers, skin inflammation, cytopenia and inflammatory arthritis resistant to multiple treatments.
To confirm these findings, the researchers turned to large population cohorts, including the UK Biobank and All of Us, encompassing more than 850,000 participants.
Across these datasets, 264 individuals with IDH1/2-mutant CH but no blood malignancy were identified. Carriers of these mutations had a significantly higher risk of autoimmune disease, especially polymyalgia rheumatica and giant cell arteritis, both inflammatory conditions that primarily affect older adults. They also showed elevated levels of C-reactive protein, a biomarker of inflammation, and changes in blood cell profiles compared with other CH carriers.
Further validation came from the Mayo Clinic cohort of patients with clonal cytopenia of uncertain significance (CCUS), where nearly 3% carried IDH1 mutations. Half of these individuals had autoimmune symptoms, including seronegative rheumatoid arthritis and Sweet syndrome, underscoring the clinical relevance of these mutations even in the absence of malignancy.
In a promising therapeutic development, treatment with the IDH1 mutant inhibitor ivosidenib appeared to reduce inflammation in patients with IDH1mutant CCUS.
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Dr Castellan detailed a phase 2 clinical trial of ivosidenib run by study collaborator Dr Kelly Bolton, a physician-scientist specialising in medical oncology and genetic epidemiology at Washington University School of Medicine. The trial included 20 patients, with the primary goal over a five-year treatment period to evaluate haematologic improvements in these patients.
“Notably, more than half of the patients had elevated C-reactive protein levels at study entry,” Dr Castellan told delegates.
“Among these five had autoimmune conditions, including polymyalgia rheumatica, Sjögren’s disease, Sweet syndrome and two cases of seronegative rheumatoid arthritis.
“Over the course of the treatment, we observed a decrease in CRP levels with normalisation in eight of the 11 patients for whom we have sufficient longitudinal data.”
All patients with autoimmune disorders reported symptomatic improvement, particularly in joint and skin inflammation.
Collectively, the findings suggest that IDH1 and IDH2 mutations in hematopoietic stem cells can directly promote autoinflammatory disease, expanding the paradigm of how somatic mutations influence immune regulation.
The observed anti-inflammatory effects of IDH1 inhibition also point to a potential precision-medicine approach for managing inflammatory conditions in patients with CH.
“All in all, we observed that IDH1 and [IDH]2 CHRC class co-occur with inflammation with or without hematologic malignancy,” Dr Castellan concluded in her presentation.
“IDH1 and [IDH]2 hotspot mutations are associated with rheumatologic conditions in large biobanks. Targeted treatment with IDH inhibition improves inflammatory manifestation.
“We suggest that IDH1 and [IDH]2 hot spot mutations to be driving a treatable pre-malignant inflammatory condition, and that screening of somatic IDH1 and [IDH]2 mutations in patients with undiagnosed systemic inflammatory disorders could inform targeted treatment.”
ACR Convergence 2025 was held in Chicago from 24-29 October.
