Familial Mediterranean Fever and infertility: a possible role of inflammation

Article title: Novel use of interleukin-1 antagonists in male familial Mediterranean

fever patients with infertility: Case series

First author: Bugra Egeli

Journal: Archives of rheumatology

Link to the article: https://pubmed.ncbi.nlm.nih.gov/39507831/

Author of the abstract: Dr. Catherine Grandpeix-Guyodo

Introduction:

The main treatment for familial Mediterranean fever (FMF) is colchicine. Interleukin-1 (IL-1) inhibitors are used in cases of colchicine resistance in FMF.

Fertility disorders with azoospermia or oligospermia have been described in FMF; colchicine is often held responsible but this could be related to chronic inflammation induced by FMF.

Patients and methods: This article reports the cases of 2 men followed for FMF and suffering from infertility who successfully conceived embryos in vitro after stopping colchicine and starting treatment with IL-1 inhibitors.

Results:

Case N°1: A 38-year-old man with FMF, with homozygous M69V mutation of MEFV, treated with 2 mg colchicine/day had failed to conceive for 15 years despite 5 IVF attempts and stopping colchicine after the first 2 IVF. Semen analysis was macroscopically normal, with normal sperm count but decreased motility. Treatment with anakinra (IL-1 RA) was started, resulting in satisfactory semen analysis after 4 months and the obtaining of 2 genetically normal embryos compatible with transfer.

• Case N°2: A 33-year-old man suffering from FMF, with a heterozygous M694V mutation of MEFV, treated with colchicine for 14 years, presented with infertility with azoospermia. The failure of a first IVF under colchicine motivated its discontinuation and the prescription of Canakinumab. Successive sperm analyses showed progressive improvement in sperm motility which allowed, during the 5th IVF, the conception of a child.

Discussion:

These two cases show reversibility of Infertility under IL-1 inhibitors in FMF in 2 men: The introduction of anti-IL1 instead of colchicine allowed improvement in sperm quality in both cases.

Colchicine resistance is suggested as a predictive factor for infertility in FMF patients, suggesting that better control of inflammation may improve it.

Conclusion:

Infertility in men with FMF could be reversible and anti-IL1 could become the treatment of choice in FMF men with fertility disorders.

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.