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.

Familial Mediterranean Fever: a single dose of anakinra to stop an acute attack

Article title: A single dose of anakinra for arresting Familial Mediterranean Fever attacks: a proof-of-concept study

First author: E. Giat

Journal: Clinical and Experimental Rheumatology

Link to the article: https://pubmed.ncbi.nlm.nih.gov/41133353/

Author of the abstract: Dr Catherine Grandpeix-Guyodo

Introduction

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is characterized by recurrent febrile attacks of serositis (peritonitis, pleuritis, arthritis) and may, in the long term, be complicated by AA amyloidosis in cases of uncontrolled chronic inflammation. Colchicine is the standard long-term treatment; however, some patients experience incomplete response or intolerance, leading to the continuous use of IL-1 inhibitors (anakinra or canakinumab). Nevertheless, acute attacks may still occur despite treatment, and their management remains largely symptomatic, with limited efficacy of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs).

Patients and Methods

The objective of this prospective study was to evaluate the efficacy of a single dose of anakinra (100 mg subcutaneously) administered at the onset of an attack to interrupt its progression. The study included patients with typical FMF according to Tel Hashomer criteria, carrying one or two pathogenic MEFV mutations, treated with colchicine, and having experienced at least two serositis attacks in the previous year. Patients receiving continuous anti–IL-1 therapy were excluded, as were those with atypical attacks or chronic inflammatory states.

Patients were provided with a prefilled syringe of anakinra and received training in self-injection and early recognition of attack symptoms. The duration of treated attacks was compared with each patient’s usual attack duration.

Results

Thirty-five patients agreed to participate: five were excluded due to persistent inflammation; four experienced no attacks during the study period; two did not ultimately use anakinra during an attack; and one discontinued due to an adverse event. A total of 23 patients were analyzed, including 13 with two pathogenic MEFV mutations (considered to have “classical” FMF) and 10 with a single pathogenic MEFV mutation (considered “heterozygous” FMF).

The mean duration of treated attacks was 8.3 ± 6.8 hours, compared with 56.3 ± 16.8 hours under usual conditions. When anakinra was injected within the first 4 hours of attack onset, 85% of attacks were interrupted within 4 hours after injection. Later injections resulted in a less pronounced but still significant reduction compared with usual attack duration. Overall, 91% of treated attacks lasted less than 24 hours. Only one adverse event was reported (local injection-site reaction), highlighting the good tolerability of this strategy.

Six patients continued to use self-purchased anakinra to treat 43 additional attacks, with similar results, confirming the reproducibility and feasibility of this approach in real-life conditions.

Discussion

The authors emphasize that this strategy is not an alternative to continuous treatment in colchicine-resistant or -intolerant patients. Rather, it should be considered a “rescue” therapy, allowing rapid interruption of occasional acute attacks, reduction of pain, avoidance of emergency department visits, decreased absenteeism, and improved quality of life.

Conclusion

This prospective study demonstrates the efficacy and safety of a single, early injection of anakinra to significantly shorten FMF attacks (both classical and heterozygous forms) in adults. A randomized controlled trial is currently underway to confirm these findings and to better define the optimal role of this strategy within the therapeutic armamentarium.

Genetic and clinical features of Familial Mediterranean Fever in a cohort of patients with kidney failure

First author: Ahmed Sheyyab

Journal: Journal of Nephrology

Link to the article: doi.org/10.1007/s40620-025-02272-y

Author of the abstract: Rim BOURGUIBA

Introduction

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. In its classic form, it is mainly associated with mutations in exon 10 of the MEFV gene. AA amyloidosis is the most severe complication of FMF.

The aim of this study was to compare the frequency of MEFV variants in hemodialysis patients versus healthy controls in a Mediterranean country, Jordan.

Methods

This was a cross‑sectional study including 78 patients with end‑stage kidney disease on hemodialysis and 201 healthy controls in Jordan. All patients underwent Sanger sequencing for the main MEFV variants. The following variants were tested: p.E148Q, p.P369S, p.F479L, p.M680I (G/C), p.M680I (G/A), p.I692del, p.M694V, p.M694I, p.K695R, p.V726A, p.A744S, and p.R761H.

Patients carrying a variant were then clinically assessed according to the Tel‑Hashomer criteria. Five underwent rectal biopsy to detect amyloidosis.

Results

Among dialysis patients, 16% had at least one MEFV variant versus 12.9% in the control group (not significant). The two most frequent mutations in the hemodialysis group were M694V (p = 0.035) and V726A (p = 0.009). The variants detected in both groups are summarized in Table 1. In the control group without renal failure, 22 individuals were heterozygous for the E148Q variant. Three patients met diagnostic criteria for FMF, and one case of AA amyloidosis was confirmed by biopsy.

Conclusion

FMF is the most common autoinflammatory disease in Mediterranean countries, yet it remains underdiagnosed even in high‑risk populations. This diagnostic delay leads to complications, notably AA amyloidosis. This study shows that 4% of hemodialysis patients were diagnosed with FMF. It also confirms the non‑pathogenic nature of the E148Q variant, which was detected in 22 healthy, asymptomatic individuals.

Overall, these findings underscore the importance of testing for MEFV mutations in patients with AA amyloidosis in countries where FMF is highly prevalent, in order to offer appropriate treatment to prevent AA amyloidosis and progression to renal failure.

Genetic and clinical features of familial Mediterranean fever in a cohort of patients with.

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