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Background: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease that is typically well managed with colchicine. However, some adults develop late-onset disease destabilization with atypical or severe manifestations. Clonal hematopoiesis (CH), characterized by age-related somatic mutations in myeloid genes, is associated with chronic inflammation and late-onset autoinflammatory syndromes. This may suggest a potential role for CH as a disease-modifying factor in FMF.
Objectives: The aim is to explore whether clonal hematopoiesis may be present in adult FMF patients presenting with unusual or atypical inflammatory manifestations, and to describe the associated clinical and biological features.
Methods: Between 2017 and 2025, 51 adult FMF patients over the age of 40 were screened for CH using routine, targeted, myeloid NGS panels. The inclusion criteria were: (i) new inflammatory manifestations; (ii) disease-related complications; or (iii) sudden destabilization of previously stable FMF, despite confirmed adherence to treatment. CH was defined as the presence of somatic mutations with a variant allele fraction (VAF) of at least 1%. The clinical features, laboratory parameters and outcomes were then compared between patients with CH-positive FMF (CH+FMF) and patients with CH-negative FMF (CH–FMF).
Results: CH was identified in 23 out of 51 patients (45%), which exceeds the expected prevalence in age-matched populations (10–20%). The detected mutations primarily affected DNMT3A and TET2 , with VAFs ranging from 1% to 43%. Patients with CH+FMF more frequently developed atypical or novel manifestations than those with CH–FMF (52.2% vs 14.3%, p=0.006 ). Cardiac involvement, including pericarditis and cardiac tamponade, occurred exclusively in CH+FMF patients (26%, p=0.006 ), which is a rare complication in well-controlled FMF. Conversely, cryptogenic liver disease ( p=0.039 ) and new-onset cytopenia ( p=0.03 ) were associated with CH-FMF patients. Inflammatory markers (CRP and SAA) at the time of CH screening were comparable between the two groups (see table 1). The youngest CH+FMF patient developed recurrent pericarditis at the age of 42, despite having had long-standing disease control, which suggests that CH may arise earlier in FMF patients due to chronic inflammatory selective pressure.
Conclusions: Clonal hematopoiesis is highly prevalent in adult FMF patients with atypical or destabilized disease, and is strongly associated with severe manifestations, particularly cardiac involvement. These findings support the ‘second-hit’ model, in which CH amplifies autoinflammatory pathways in FMF. Screening for CH should be considered for FMF patients over 40 years of age who present with unexplained disease worsening, as early identification could facilitate closer monitoring and adaptation of therapy.
Main clinical and biological features of adult FMF patients with and without clonal hematopoiesis (CH)
| Characteristics | CH-FMF | CH+FMF | p-value |
|---|---|---|---|
| Demographics | |||
| Number of patients | 28 | 23 | - |
| Female n (%) | 17 (60.7) | 10 (43.5) | 0.345 |
| Age at the screening for CH (years)
| 64.8
| 64.8
| 0.325 |
| Death, N (%) | 6/28 (21.4) | 2/23 (8.7) | - |
| Medical history | |||
| History of hemopathy | 1/28 (3.6) | 2/23 (8.7) | 0.583 |
| History of cancer | 2/28 (7.1) | 2/23 (8.7) | > 0.999 |
| Clinical features | |||
| Atypical or novel symptoms* | 4/28 (14.3) | 12/23 (52.2) | 0.006 |
| Neutrophilic dermatosis | 0 | 1/23 (4.3) | 0.451 |
| Pericarditis/ tamponade* | 0 | 6/23 (26.09) | 0.006 |
| Periarteritis nodosa | 1/28 (3.6) | 1/23 (4.3) | > 0.99 |
| Ulcerative digestive disease | 1/28 (3.6) | 2/23 (8.7) | 0.583 |
| Immunonegative arthritis | 1/28 (3.6) | 2/23 (8.7) | 0.583 |
| Cryptogenic liver disease* | 13/28 (46.4) | 4/23 (17.4) | 0.039 |
| AA amyloidosis | 4/28 (14.3) | 1/23 (4.3) | 0.362 |
| Inflammatory markers | |||
| New-onset persistent inflammation despite adequate treatment, N (%) | 16/23 (69.6) | 14/17 (82.35) | 0.471 |
| CRP at time of CH suspicion (mg/L) | 12 [0 - 30.5] [27/28] | 12 [4 - 29.5] [22/23] | 0.602 |
| SAA at time of CH suspicion (mg/L) | 12 [0 - 45.75] [22/28] | 17 [6 - 60] [21/23] | 0.357 |
| Hematologic parameters | |||
| New onset cytopenia* | 12/28 (42.9) | 3/23 (13) | 0.03 |
| Anemia (< 11 g/dL) | 10/28 (35.7) | 3/23 (13) | 0.11 |
| Hb (g/dL) in anemic patients | 12 [11 - 13.5] [10/10] | 12.6 [12 - 14] [3/3] | - |
| MCV (fl) in anemic patients | 84 [82 - 88] [10/10] | 84 [81 - 88.5] [3/3] | - |
| Reticulocytes (10 9 ) in anemic patients | 66 [53.5 - 94.5] [6/10] | 48 [40 - 63] [2/3] | - |
| Thrombocytopenia (< 100 10 9 ) | 3/28 (10.7) | 1/23 (4.3) | 0.62 |
| Platelets (10 9 ) in thrombocytopenia patients | 197 [124 - 267] [3/3] | 225 [207.5 - 253.5] [1/1] | - |
| Presence of monoclonal Ig at time of CH suspicion | 2/13 (15.4) [13/28] | 1/8 (12.5) [8/23] | > 0.99 |
Variables in bold and indicated with * are statistically significant. Values are expressed as median [IQR25-75] or n (%) with the [Numbers of patients for which data is available] if relevant. p values in bold indicate statistical significance. CH, clonal hematopoiesis; FMF, familial Mediterranean fever.
REFERENCES: NIL.
Acknowledgments: NIL.
Disclosure of Interests: None declared.