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.

2025: A Year Rich in Autoinflammation, FMF, and VEXAS

In 2025, together with the team of the CEREMAIA Reference Center (Tenon Hospital, AP-HP / Sorbonne University), within the FAI2R network and the European Reference Network ERN RITA, we carried out extensive work focused on:

Familial Mediterranean Fever (FMF) and pyrin-associated diseases,

VEXAS syndrome, a prototype of hemato-inflammatory diseases,

AA amyloidosis and other rarer autoinflammatory diseases.

🔬 FMF and pyrin

We contributed to the update of the international EULAR/PReS recommendations for FMF, which incorporate recent advances regarding colchicine resistance and the use of biologic therapies (published in Annals of the Rheumatic Diseases, 2025).

Several studies based on the adult cohort of our reference center explored the following aspects: iron deficiency, liver involvement, FMF onset after the age of 65, the optimal daily dose of colchicine, and patients’ and prescribers’ perceptions of colchicine treatment.

We also conducted biological and genetic research on variants of the MEFV gene and pyrin-associated diseases, as well as on the role of IL-18 as a monitoring biomarker and as a specific signature of diseases involving the pyrin inflammasome.

🧬 VEXAS syndrome

In collaboration with the French VEXAS group and the MINHEMON club:

international reviews and recommendations were developed to structure the diagnosis and management of VEXAS syndrome, including a consensual definition of “flares,” infectious risks, and therapeutic strategies;

studies focused on specific organ involvement (kidney, nervous system, erythroblastopenia), as well as a multicenter study on VEXAS in women and across different ethnic backgrounds.

🧩 AA amyloidosis and other rare autoinflammatory diseases

We participated in a systematic review on AA amyloidosis in inflammatory rheumatic diseases, highlighting the importance of long-term strict control of inflammation.

We authored literature reviews on autoinflammatory actinopathies, A20 haploinsufficiency, and undifferentiated autoinflammatory diseases.

We also published work on diagnostic delay and the clinical presentation of cryopyrin-associated periodic syndromes (CAPS) in adulthood.

🧠 Therapeutic patient education programs

We continued the deployment of our three therapeutic education programs dedicated to AA amyloidosis, cryopyrinopathies (CAPS), and FMF. These programs aim to help patients and their relatives better understand the disease, treatments, monitoring, and warning signs.

In 2025, we notably led a session dedicated to CAPS during the weekend organized in July by the Muckle-Wells / CINCA association, in close collaboration with patient associations.

🎥 Patient webinars and online information

We launched a series of informational webinars for patients and their relatives on FMF, as well as educational videos on rare autoinflammatory diseases (AA amyloidosis, VEXAS syndrome, etc.), freely available on the CEREMAIA Tenon YouTube channel: CEREMAIA Tenon – Patient Webinars. These formats allow us to translate research findings and recommendations into practical messages for patients’ daily lives.

• All of this work shares a common goal:

• to better characterize these rare diseases,

• to refine diagnostic and monitoring strategies,

and ultimately, to provide more personalized and safer care for patients.

We warmly thank the patients, healthcare teams, colleagues from rare disease networks, and international partners for their commitment.

For those who would like to access specific articles in more detail, please feel free to contact us via private message or by email at:

ceremaia-medecine-int.tenon@aphp.fr

Happy New Year 2026, A new year to advance autoinflammation, together

The entire CEREMAIA Tenon team sends you our best wishes for the new year.

The past year has been rich in exchanges, scientific progress, and collaborations around autoinflammatory diseases, Familial Mediterranean Fever (FMF), VEXAS syndrome, AA amyloidosis, and other rare diseases. Above all, it has been marked by a shared commitment: to better understand these complex diseases and improve patient care in a concrete way.

In 2026, we will continue this commitment by:

• Developing clinical, biological, and genetic research,

• Elaborating and sharing international recommendations,

• Strengthening patient education programs,

• Continuing accessible information initiatives for patients and their families.

• We warmly thank all patients, care teams, associations, and our national and international partners for their trust and collaboration throughout the year.

May this new year bring progress, hope, and shared projects for the benefit of rare diseases and autoinflammation.

Wishing you a wonderful year ahead.

The CEREMAIA Team – Tenon Hospital, AP-HP / Sorbonne University