The effect of IL-1 blockers on exertional leg pain in Familial Mediterranean Fever patients: an exploratory study

• First author: Amit Druyan1

• Journal: Rheumatology

• Reference: Rheumatology (Oxford). 2026;65:keag160

• PubMed link: https://pubmed.ncbi.nlm.nih.gov/42024667/

• Abstracted by: Dr. Catherine Grandpeix-Guyodo

Key points:

- Exertional/orthostatic leg pain is a frequent complaint in FMF patients with severe phenotypes.

- This lower-limb pain impacts quality of life.

- Interleukin‑1 inhibitors seem effective in at least about half of patients.

Introduction

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide and is associated with mutations in the MEFV gene. The classic presentation combines febrile attacks and serositis. Patients also frequently report leg pain typically triggered by walking or prolonged standing, lasting for several hours despite rest and often associated with swelling and sometimes redness. This symptom responds less well to colchicine than other manifestations and is associated with severe FMF phenotypes, persistent inflammation, homozygosity for the MEFV M694V variant, and an increased risk of AA amyloidosis. This study evaluated the efficacy of anti‑interleukin‑1 therapy (anti‑IL‑1) on leg pain in FMF.

Patients and methods

This retrospective, single‑center Turkish study included adult FMF patients resistant to colchicine, treated with anti‑IL‑1 for at least 3 months and with colchicine at the maximum tolerated dose, and who had leg pain that pre‑dated the start of anti‑IL‑1. The control group was a historical cohort of FMF patients with leg pain who had not received anti‑IL‑1. Variables assessed included demographics, homozygosity for the M694V variant, leg pain, and quality of life.

Results

A total of 27 long‑term anti‑IL‑1–treated patients with leg pain (23 canakinumab, 4 anakinra) were compared with 99 patients from the historical cohort. These anti‑IL‑1 patients had more severe disease, with more frequent attacks prior to anti‑IL‑1 (50/year), homozygous MEFV M694V in 55%, lower‑limb arthritis during FMF flares in 85%, a higher mean colchicine dose (2.6 mg/day), and AA amyloidosis in 11%. Leg pain was bilateral, triggered by prolonged standing or walking, and resolved after several hours of lying down. Under anti‑IL‑1, attack frequency decreased to a mean of 9/year and inter‑critical CRP normalized in 50% of patients. Improvement in leg pain was reported in 52% of patients. An association between quality of life and leg pain was observed only in anti‑IL‑1–treated patients, likely because the symptom had previously been masked by inflammatory attacks.

Discussion

Leg pain improved in only about half of patients, but the cohort had particularly severe FMF. In the literature, MRI studies have shown signs of spondyloarthritis or occult enthesitis in some patients with leg pain. The mediators of these conditions are TNF‑α and IL‑17 more than IL‑1, which may explain lack of efficacy in some. Limitations include the retrospective design, small sample size, and missing data. Canakinumab is very expensive and should not be prescribed as first‑line therapy.

Familial Mediterranean Fever: unexpected symptoms in some patients

Title in English: Non-canonical manifestations of FMF in homozygous M694V MEFV genotype: Insights from a large patient cohort

First author: Eitan Giat

Journal: Seminars in Arthritis and Rheumatism

Link to PubMed : https://pubmed.ncbi.nlm.nih.gov/40902213/

Summary by: Dr Catherine Grandpeix-Guyodo

Introduction:

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. Among the MEFV gene mutations associated with a classic FMF phenotype, homozygous M694V variants are classically associated with the most severe forms of the disease, with more frequent attacks, more frequent arthritis, lower limb pain during exercise, poorer quality of life, higher colchicine requirements, poorer treatment response, and increased risk of inflammatory amyloidosis, with half of AA amyloidosis cases in FMF patients being associated with a homozygous M694V genotype. This study examined clinical and biological manifestations other than those already known, associated with homozygous M694V mutations in a large cohort of patients in Israel.

Patients and methods:

This was a retrospective study of adults with FMF followed between 2010 and 2020 at an Israeli hospital center. Patients carrying the homozygous M694V mutation were compared to a control group of patients with a classic FMF phenotype and either homozygous MEFV mutations other than M694V, compound heterozygotes, or heterozygotes (known variants associated with classic FMF but also presence of variants of unknown significance (VUS) such as E148Q, K695R, P369S).

Results:

The cohort included 3,866 FMF patients, 47.6% male, and 517 (13.4%) homozygous M694V. Significant differences between the two groups were, in homozygous M694V: higher colchicine dosage (median 2 mg/day versus 1.5 mg/day) despite better compliance, greater number of colchicine failures requiring addition of biotherapy (anti-IL1 or anti-TNF) (30% versus 4.2%), higher number of associated pathologies (*ankylosing spondylitis (AS), Behçet's disease, congestive heart failure, deep vein thromboses, chronic renal failure, and hepatic dysfunctions*), more significant abnormalities in biological parameters (CRP, ESR, liver enzymes, bilirubin, creatinine, and uric acid), higher number of hospitalizations and emergency room visits, particularly due to FMF attacks.

The results are the same if patients with at least one M694V mutation are excluded from the control group. Moreover, comparison of a heterozygous M694V group to other controls shows no difference.

It should also be noted that homozygous M694V patients on biotherapies had more AS, Behçet's disease, chronic renal failure, hepatic cytolysis, hyperuricemia, emergency room visits, and hospitalizations. However, there was no difference in terms of cardiovascular pathologies between homozygotes on biotherapies and those on colchicine alone.

Discussion:

In addition to what is described in the literature (more severe phenotype, more attacks, specific locations of FMF flares, poorer response to colchicine, more associations with inflammatory diseases, more AA amyloidosis and chronic renal failure), this study shows in FMF patients with homozygous M694V mutation the use of higher colchicine dosages, more frequent use of biotherapies, no increase in ischemic cardiovascular pathologies despite greater inflammation (possibly due to the action of anti-IL1). The study did find a higher rate of congestive heart failure which could be attributed to greater systemic inflammation, as has been shown in rheumatoid arthritis, Crohn's disease, and ulcerative colitis. The same applies to the higher frequency of deep vein thromboses.

Hepatic dysfunctions and hepatic cytolysis were more frequent in homozygous M694V FMF patients and could also be attributed to systemic inflammation that would generate hepatic steatosis.

To better understand the pathophysiological mechanisms, more studies seem necessary.

Conclusion:

In addition to the more severe and complicated presentations of classic FMF associated with the homozygous M694V genotype of MEFV, higher colchicine requirements or even recourse to biotherapies are observed, more frequent associated pathologies such as inflammatory diseases (AS, Behçet), increased frequency of congestive heart failure, deep vein thromboses, chronic renal failure, and liver diseases. Increased biannual monitoring of homozygous M694V patients seems essential.

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.