Performance of serum interleukin-18 (IL-18) levels for the follow-up of patients with Familial Mediterranean Fever

French title: Performance du taux d'interleukine 18 (IL-18) sérique pour la surveillance des patients atteints de fièvre méditerranéenne familiale.

First author: Inès Elhani

Journal: The Journal of Allergy and Clinical Immunology: In Practice (JACIP)

Author of the abstract: https://pubmed.ncbi.nlm.nih.gov/39667435/

Article traduit par le Dr Catherine Grandpeix-Guyodo

Introduction:

Inflammasome activation in Familial Mediterranean Fever (FMF) leads to increased secretion of interleukin (IL)-1β and IL-18. Monitoring FMF activity is essential due to the risk of AA amyloidosis in cases of prolonged inflammation and is classically done using CRP and SAA (serum amyloid A protein), whose values may be dissociated. This study investigated the possibility of monitoring FMF activity through total blood IL-18 assay.

Patients and methods:

This monocentric, retrospective study involved adult FMF patients who had at least one total blood IL-18 assay during their follow-up between 2022 and 2024. The data collected included the mutational status of the MEFV gene, CRP and SAA values, disease activity (considered controlled if fewer than 2 flares per year / uncontrolled if 2 or more flares per year), and finally the total IL-18 assay(s) performed during follow-up consultations (routine care).

Results:

Among 208 sampled patients, half had controlled FMF, and a total of 308 IL-18 assays were analyzable with a median measurement of 922.25 pg/mL (N < 350 pg/mL). Among patients with controlled FMF, IL-18 levels were significantly higher in homozygous patients compared to compound heterozygotes and heterozygotes.

Some patients had IL-18 assays when FMF was inactive and active, and levels showed no significant difference.

IL-18 levels were not significantly different in patients treated with anti-IL-1.

Assays > 7,000 pg/mL concerned 16 patients who had adherence issues with their colchicine treatment and rather low dosages (< 2 mg).

Discussion:

Total blood IL-18 levels appear to be correlated with genotype but not with disease activity. The persistence of high IL-18 levels in asymptomatic patients could suggest low-grade activity of the pyrin inflammasome. Very high levels may show that patients are undertreated, but the significance of IL-18 levels in terms of amyloidosis risk remains to be determined if the SAA level is normal.

The limitations of this study are the few samples per patient (generally 1), the retrospective nature, and the absence of evaluation by a disease activity score at the time of sampling.

Conclusion:

The monitoring of total blood IL-18 levels has a role that remains to be defined since it does not seem to reflect either the patient's immediate inflammatory state or FMF activity. Its interest could lie in detecting subclinical inflammatory activity and evaluating treatment adherence. Prospective studies on large cohorts will be necessary to deepen its utility in FMF.

Anakinra treatment in colchicine-resistant or colchicine-intolerant Familial Mediterranean Fever: real-world experience

Summary by Dr Catherine Grandpeix-Guyodo

First author: Tuğba Ocak

Journal: Medicina

Reference: Medicina (Kaunas). 2025 Apr 25; 61: 792

Link to PubMed: https://pubmed.ncbi.nlm.nih.gov/40428750/

Introduction:

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is associated with MEFV gene mutations and is characterized by recurrent inflammatory attacks, particularly with abdominal pain. The most severe complication is AA amyloidosis. The recommended treatment is colchicine to prevent attacks and complications. In some patients, colchicine at the maximum tolerated dose is insufficient to prevent attacks, while others do not tolerate colchicine. Anti–interleukin‑1 agents are effective in cases of colchicine resistance or intolerance. This Turkish team investigated treatment with anakinra in colchicine‑resistant/intolerant FMF patients, focusing on their clinical characteristics, treatment duration, treatment response, possible extension of injection intervals, and long‑term outcomes.

Patients and methods:

This single‑center retrospective study included 68 FMF patients with colchicine resistance or intolerance who required initiation of anakinra at a dose of 100 mg/day. Colchicine resistance was defined as at least one attack per month despite the maximum tolerated daily dose of colchicine. Colchicine intolerance was defined as the inability to increase the colchicine dose because of digestive side effects.

Results:

Among these 68 patients, the median age was 40.2 years and 57.3% were women. Of the 60 patients who had undergone genetic testing, 32 patients (53%) had two pathogenic MEFV mutations, 26 (43%) were heterozygous for pathogenic mutations, and 2 had no identified mutation.

Fifteen patients had AA amyloidosis. All patients were treated with colchicine before starting anakinra, at a median dose of 2 mg/day, and 63 patients continued colchicine in parallel. Median follow‑up was 34 months.

Treatment was effective in the majority of patients, with significant reductions in the Pras score, ESR, CRP, SAA, and proteinuria when present.

In 21 patients, remission was achieved under treatment, allowing an increase in the interval between anakinra injections to every 2 days, then every 3 days. Eight of these patients were able to discontinue anakinra completely while continuing colchicine alone. Only 2 patients relapsed within the month following complete treatment withdrawal.

The main adverse events were injection‑site reactions.

Seventeen additional treatment discontinuations were reported, mostly due to insufficient response (7 patients) or adverse events (7 patients).

Four patients received anakinra during pregnancy without adverse effects in either the mother or the baby.

Six kidney‑transplant recipients were treated with anakinra, one of whom died from COVID‑19 pneumonia.

Discussion:

This study shows that treatment with anakinra in patients who are resistant or intolerant to colchicine leads to rapid and sustained improvement in clinical signs and inflammatory markers, with good tolerability. Injection intervals could be extended to every 2 or even 3 days while maintaining clinical and biological response. Proteinuria decreased in some patients, suggesting a potential benefit in those with AA amyloidosis. Treatment was also well tolerated, with no adverse effects reported in the 4 pregnant women.

In practice:

In this study of 68 Turkish adults with FMF, anakinra was rapidly effective and well tolerated in the long term in patients who were resistant or intolerant to colchicine.