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.

Familial Mediterranean Fever (FMF) and the Mediterranean diet: what impact on the severity of the disease?

Title in English: Association of Mediterranean diet adherence with Familial Mediterranean Fever severity in a Lebanese cohort.

First author: R. Hammoud.

Journal: Pediatric Rheumatology

Reference: Pediatr Rheumatol Online J. 2025 Nov 21;23(1):122.

Link to PubMed: https://pubmed.ncbi.nlm.nih.gov/41272709/

Summary author: Dr Catherine Grandpeix-Guyodo

Introduction:

Familial Mediterranean Fever (FMF) is the most common autoinflammatory disease worldwide. It is associated with pathogenic variants, classically in exon 10 of the MEFV gene. The variable expressivity of this disease is linked to the type of MEFV variant (particularly M694V), but epigenetic and environmental factors probably also play a role. Previous studies have suggested that a diet rich in fat and salt may worsen FMF symptoms, whereas a diet rich in antioxidants and vitamins may improve inflammation and quality of life. The Mediterranean diet, which is recommended for the prevention of other diseases, could therefore be of interest in FMF.

This study aimed to explore the relationship between adherence to the Mediterranean diet (MD) and the severity of familial Mediterranean fever (FMF) in a Lebanese cohort. It also took into account the influence of genetic background, lifestyle, and comorbidities on FMF severity.

Patients and methods:

This was a cross‑sectional questionnaire‑based study of 101 patients with confirmed FMF in Lebanon, conducted between January 2023 and January 2024. Patients were required to be between 18 and 65 years old and to have FMF. Data were collected using a structured questionnaire on demographic information, socioeconomic status, disease manifestations, comorbidities, treatments, and lifestyle habits. The questionnaire was pre‑tested and offered in Arabic or English.

FMF severity, adherence to the Mediterranean diet, and physical activity were assessed using scores.

Results:

A total of 101 patients, 58% of whom were women, were included, with a mean age of 35.7 years, and 55% were smokers. No significant sociodemographic differences were observed according to the different levels of adherence to the Mediterranean diet.

Genotype data were available for only 51/101 patients, of whom 17.6% were M694V homozygotes, and 64.6% were other homozygotes or compound heterozygotes.

Analysis of patients diets showed low adherence to the Mediterranean diet in 34%, moderate adherence in 48%, and good adherence in 19%. Overall, consumption of fish, fruit, and vegetables was below recommendations, whereas intake of cereals, pastries, and red meat was too high.

The only significant difference observed according to Mediterranean‑diet adherence was diarrhea, which was reported almost twice as often in patients with low adherence. Other symptoms, attack frequency, and FMF severity did not differ significantly.

Obesity and the presence of comorbidities (rheumatologic, IBD, cardiovascular) were significantly associated with more severe FMF.

Patients with severe FMF had a longer smoking history and smoked more cigarettes per day. High physical activity levels were more frequent in severe forms (73%), whereas moderate activity predominated in mild (82%) and intermediate (88%) forms.

Discussion:

A potentially beneficial effect of the Mediterranean diet on the digestive tract was observed, with less diarrhea among patients adhering to this diet. This is consistent with the expected effects on the digestive mucosa, microbiota, and the reduction of pro‑inflammatory interleukin secretion.

However, no significant association was found between FMF severity and adherence to the Mediterranean diet.

The association between more severe forms of FMF and intense physical activity should be taken into account: it is advisable to recommend adapted physical activity in order to avoid mechanical stress that could trigger attacks.

The limitations of this study include the cohort size and its specific characteristics, with generally lower adherence to the Mediterranean diet than would be expected.

In conclusion:

This study, the first conducted in Lebanon on this topic, does not demonstrate a direct association between adherence to the Mediterranean diet and FMF severity, but it does suggest a potential protective effect of the Mediterranean diet against FMF‑related diarrhea. It highlights the high prevalence of poor adherence to this diet and the failure to meet nutritional recommendations for most of its components. The multifactorial nature of FMF supports a comprehensive management approach that integrates targeted dietary and lifestyle strategies alongside treatments, with personalized nutrition and behavioral interventions aimed at improving prognosis and patients quality of life.

Colchicine-resistant Familial Mediterranean Fever: triggering factors are highly prevalent and reduced under IL-1 inhibition

Article title: Do we consider enough the presence of triggering factors in the evaluation of patients with FMF? Triggering factors are highly prevalent in colchicine-resistant FMF patients.

First author: Bayram Farisogullari

Journal: Internal and Emergency Medicine

Link to the article: https://pubmed.ncbi.nlm.nih.gov/38103114/

Introduction

The objective of this study was to investigate the frequency of triggering factors in patients with Familial Mediterranean Fever (FMF) who are resistant to colchicine and in those who are responsive to colchicine, and to assess the impact of interleukin-1 (IL-1) antagonist therapy on triggering factors in colchicine-resistant patients.

Patients and Methods

Colchicine-resistant FMF patients treated with IL-1 antagonists and colchicine-responsive patients treated with colchicine and experiencing ≤ 3 attacks in the previous year were questioned about the presence of 12 different triggering factors: cold exposure, emotional stress, fatigue, intense physical activity, menstruation (for women), sleep deprivation, prolonged standing, long-distance travel, high-fat diet, prolonged fasting, infections, and trauma.

Colchicine-resistant patients were questioned for two periods: before and after initiation of IL-1 antagonist therapy.

Results

A total of 63 patients were included, comprising 28 colchicine-resistant patients (19 treated with anakinra and 9 with canakinumab) and 35 colchicine-responsive patients. Only half carried two pathogenic mutations in exon 10 of the MEFV gene (Table 1). Overall, 77.8% of patients reported at least one triggering factor, with a mean number of 2.6 per patient.

The most common triggering factors, in decreasing order of frequency, were emotional stress, menstruation, cold exposure, prolonged standing, and long-distance travel. Triggering factors accounted for approximately one-third of attacks, and 57.1% of patients reported using avoidance strategies. The frequency of triggering factors was higher in colchicine-resistant patients than in colchicine-responsive patients (89.3% vs 68.6%; p = 0.04).

Among colchicine-resistant patients, the frequency of triggering factors decreased from 89.3% to 32.1% under IL-1 antagonist therapy, and the proportion of attacks initiated by a triggering factor decreased from 27.8% to 14.4% (p < 0.001) (Table 2).

Discussion

Triggering factors were more frequent in colchicine-resistant patients than in colchicine-responsive patients. Treatment with IL-1 antagonists appeared to reduce both the number of triggering factors and the proportion of attacks induced by these factors.

Conclusion

Triggering factors are common in FMF and should be systematically assessed, particularly when colchicine resistance develops. IL-1 antagonists reduce their impact and may be useful as long-term therapy or as preventive treatment during predictable exposures.