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Background: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory periodic fever syndrome, characterized by attacks of fever, abdominal pain, chest pain, joint pain, and rash. A significant complication of the disease is systemic AA amyloidosis, which can cause renal damage. Studies suggest that patients in North America are more treatment responsive and get less complicated specifically with amyloidosis compared to patients in other Middle Eastern countries due to unclear reasons.
Objectives: The aim of this study was to describe the clinical and genetic information of two cohorts Children’s Hospital Los Angeles CHLA in the US and Dana Children’s Hospital in Israel, and to evaluate if there is a difference in disease severity and treatment response.
Methods: Medical records of pediatric patients who were diagnosed with FMF and routinely being followed in the 2 tertiary rheumatology centers experienced in autoinflammatory diseases, were analyzed retrospectively. Measurement tools were recorded from at least three time points: at time of diagnosis prior to any treatment, after one year of follow up and at the last charted follow-up visit.
Results: The US and Israel cohorts consisted of 63 and 32 patients. More than 75% of the US cohort had Armenian ancestry, whereas the Israel cohort had a variety of ancestries, mostly from Morocco (29%) and Iraq (27%). The onset of symptoms, time of diagnosis and colchicine initiation was earlier amongst patients from the Israel cohort compared to the US cohort, despite similar genetic mutations and family history. Table 1 summarizes the initial visit including symptoms, genetic information, and family history. Mean follow-up duration was 53.7 months (SD: 34.3) in US cohort and 9.9 months (SD: 18.2) in Israel. During follow-up, the attack frequency declined over time for US children from an average of 16.2/year to ~1/month (Table 2). Both cohorts did have elevated acute phase reactants during attack-free periods. At the last follow-up visit recorded, none of the patients in either cohort demonstrated kidney injury but seven (11.1%) patients in US, and one (3.1%) patient in Israel had new proteinuria (p= 0.2). Of the patients in the US cohort with proteinuria (n=7), 3 had a homozygous M694V mutation, 3 had compound heterozygous MEFV mutations, and 1 had a heterozygous M694V mutation. Of the patients with proteinuria, 1 patient was not on colchicine treatment. The other 6 started colchicine within 21.5 months of symptoms onset on average, similar to the rest of the cohort without renal involvement.
Disease characteristics on initial visit
| US (n=63) | Israel (n=32) | p | |
|---|---|---|---|
| Mean age of initial symptoms (mo) (SD) | 34.7 (32.7) | 6.0 (4.6) | <0.0001 |
| Mean age of diagnosis (mo) (SD) | 62 (41.6) | 8.4 (4.9) | <0.0001 |
| Mean delay in diagnosis (mo) | 17 (37.7) | 2.4 (4.8) | 0.03 |
| Mean age of colchicine treatment (mo)(SD) | 63.8 (41) | 6.9 (5.4) | <0.0001 |
| Family history of FMF | 31 (49%) | 16 (50%) | 0.94 |
| Homozygous MEFV mutation | 10 (17%) | 3 (9%) | 0.38 |
| Symptoms | |||
| fever | 57 (90%) | 25 (78%) | 0.98 |
| joint pain | 37 (59%) | 19 (59%) | 0.95 |
| chest pain | 8 (13%) | 6 (19%) | 0.43 |
| abdominal pain | 50 (79%) | 27 (84%) | 0.55 |
| rash | 6 (10%) | 0 (0%) | 0.26 |
| sore throat | 3 (5%) | 7 (22%) | 0.01 |
Attack frequency and inflammatory markers over time in two cohorts
| US | Israel | |||||
|---|---|---|---|---|---|---|
| Initial visit | One year follow up | End of follow up | Initial visit | One year follow up | End of follow up | |
| Number of attacks in one year, mean (SD) | 16.2 (15.2) | 1.5 (2.8) | 0.7 (2.3) | 0.96 (2.27) | 3.2 (5.5) | 3.1 (7.2) |
| Elevated CRP (%) | 4 (6.3) | 3 (4.8) | 2 (3.2) | 8 (25) | 3 (9.4) | 3 (9.4) |
| Elevated ESR (%) | 5 (7.9) | 7 (11.1) | 4 (6.3) | 5 (15.6) | 1 (3.1) | 1 (3.1) |
Conclusion: The US and Israel cohorts had similar disease characteristics despite the differences in their ethnic distribution. Patients in the Israel cohort both presented and diagnosed at an earlier age even though their presentation was not as severe. This may be due to the high prevalence of the condition in Israel with increased awareness or/and higher access to pediatric rheumatology for these patients. Despite delays in diagnosis and initiation of treatment of patients in the US, they still seemed to have favorable outcomes. The presence of proteinuria did not appear related with delay in diagnosis or treatment.
REFERENCES: NIL.
Acknowledgements: NIL.
Disclosure of Interests: None declared.