Background/Purpose: Familial Mediterranean fever (FMF) is an autoinflammatory disease associated with biallelic pathogenic variants in the MEFV gene encoding the myeloid-restricted inflammasome sensor pyrin. The majority of FMF-associated missense variants reside in exon 10 of MEFV within the B30.2/SPRY domain, with M680I, M694V, and V726A being the most common disease-associated variants in Eastern Mediterranean populations. The Ile692del (rs104895093) variant has been reported in Arab patients with recessively inherited FMF, Patients who are compound heterozygous for the I692del and V726A variants presented with a severe inflammatory phenotype including transfusion-dependent anemia and neutrophilic dermatoses. Several patients had a history of cytokine storm, which is not reported in patients with classical FMF. To study the impact of the Ile692del variant, we analyzed the clinical histories, biomarker testing, and response to therapy of 53 individuals who have at least one copy of the Ile692del variant. We then examined the inflammatory signature associated with this phenotype in the primary cells of patients who are compound heterozygotes for I692del/Val726Ala. We have designated this condition as CHIVE-18 syndrome.

Methods: We designed analogous panels to measure the response to cytokine stimulation in whole blood and cryopreserved PBMCs. Phospho-STAT staining was carried out on whole blood (n=2) or frozen PBMCs (n=2) of compound heterozygotes for I692del/Val726Ala with controls. Samples were stained with fluorochrome-conjugated antibodies for myeloid and lymphoid markers, stimulated with IFN-a, IFN-g, or IL-10 and then stained with intracellular antibodies for pSTAT1 and pSTAT3. Stained cells were acquired on a 5-laser Cytek® Aurora Spectral Cytometer.

Results: All patients with CHIVE-18 had significantly elevated levels of serum total IL-18, IL-18 BP, and free IL-18. Given high serum levels of the IL-18 cytokine, a known inducer of IFN-g, we measured phosphorylation of STAT1 and STAT3 in stimulated patients’ cells. CHIVE-18 patients had enhanced STAT1 phosphorylation after stimulation with IFN-g compared to age-matched controls, while pSTAT3 was not higher. Interferon-induced STAT1 phosphorylation was more pronounced in cellular populations from the myeloid lineage, confirming the role of these cells in mediating FMF pathology.

Conclusion: CHIVE-18 syndrome is a severe inflammatory disease distinct from classic FMF. Our data show that IFN-induced pSTAT1 was more pronounced in cellular populations from the myeloid lineage, consistent with observations in patients with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, another pyrin-related autoinflammatory disease, and confirms the role of these cells in mediating FMF pathology. Although IFN-γ is not a major driver of a pyrin-mediated inflammatory disease, it is a contributing factor to disease pathophysiology and could make patients with high-impact mutations prone to episodes of cytokine storm. Such hyperinflammatory episodes increase mortality risk and should be treated aggressively. Affected patients usually require treatment with high-dose of IL-1 inhibitors or with combination of cytokine inhibitors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/compound-heterozygosity-for-the-ile692del-and-val726ala-pathogenic-mefv-variants-and-elevated-il-18-chive-18-syndrome-is-distinct-from-familial-mediterranean-fever-fmf-and-includes-a-pronounced-re/