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.

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.