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.

Premenstrual syndrome and inflammatory activity in adolescent Familial Mediterranean Fever

• English title: Premenstrual syndrome and inflammatory activity in adolescent familial Mediterranean fever

• First author: Nigar Aliyeva

• Journal: Rheumatology

• Reference: Rheumatology (Oxford). 2026:keag169. doi: 10.1093/rheumatology/keag169. Online ahead of print.

• PubMed link: https://pubmed.ncbi.nlm.nih.gov/41936095/

• Abstracted by: Dr. Catherine Grandpeix-Guyodo

Key points - Premenstrual syndrome and inflammatory activity in adolescent familial Mediterranean fever

1. Premenstrual syndrome (PMS) is less frequent in FMF patients treated with colchicine than in healthy controls.

2. In FMF patients, PMS is associated with higher disease activity, systemic inflammation, and poorer treatment adherence. PMS severity appears to be proportional to the level of inflammation.

3. Colchicine may prevent PMS by reducing inflammation, which could explain the lower prevalence of PMS in colchicine-treated FMF patients compared with controls.

Introduction

PMS is linked to hormonal fluctuations, but immunological and inflammatory mechanisms also seem to contribute to symptom expression. Cytokine fluctuations during the menstrual cycle and the direct activation of the pyrin inflammasome by steroid catabolites support a direct link between reproductive physiology and inflammatory pathways.

However, there are limited clinical data on PMS in adolescents with FMF, and on its association with disease activity or adherence to colchicine treatment.

Patients and methods

This was a prospective, single-center Turkish study comparing adolescents aged 12 to 18 years with and without FMF, focusing on PMS. Menarche had to have occurred at least 6 months earlier; cycles had to be regular and bleeding last fewer than 7 days. FMF patients were required to have two pathogenic MEFV variants. Disease activity score (AIDAI), number of attacks per month (1 versus several), and biological inflammatory markers were collected, along with an assessment of PMS severity (PMSS).

Results

Mean age in both groups was 16 years. Mean height was significantly lower in the FMF group, while weight did not differ. Half of the FMF patients had not experienced a flare in the previous 6 months. Among 40 adolescents with FMF treated with colchicine, only 45% had PMS, compared with 75% among 40 controls. The difference in dysmenorrhea prevalence was not statistically significant, but longer menstruation and heavier bleeding were reported in FMF patients (p<0.05). PMS was more frequent and more severe in controls than in FMF patients.

Among FMF patients, those with PMS had higher AIDAI scores and more frequent FMF attacks. Blood inflammatory markers were also higher in this group. A clear correlation was observed between attack frequency and PMS severity.

There was also an association between PMS frequency and poor adherence to colchicine treatment.

Discussion

PMS appears less frequent in FMF, but PMS symptoms increase with inflammation. This suggests that colchicine, by modulating inflammation, could reduce hormonal symptoms and thus decrease PMS frequency. PMS is also more common in FMF patients with poor adherence to colchicine.

During the menstrual phase, decreased estrogen and increased IL-6 have been shown to intensify inflammation, which aligns with the observation that menstruation can trigger FMF attacks. Colchicine could therefore attenuate inflammatory fluctuations and modulate PMS.

Regarding the higher frequency of heavy bleeding during menstruation in FMF patients, one hypothesis is repeated use of anti-inflammatory drugs.

This study has limitations, including the small cohort size and its single-center design.

Conclusion

PMS is less frequent in FMF patients treated with colchicine than in healthy controls. In FMF patients, PMS is associated with higher disease activity, systemic inflammation, and poorer treatment adherence. Colchicine may prevent PMS by reducing inflammation, which could explain the lower frequency of PMS compared with the control population.

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.