New FMF Recommendations Tackle Drug Resistance and Fertility

A multidisciplinary team has released new evidence-based recommendations for the management of familial Mediterranean fever (FMF).

Jointly endorsed by the European Alliance of Associations for Rheumatology (EULAR) and the Pediatric Rheumatology European Society, the recommendations are the first update to the 2016 EULAR guidelines.

Although rare, FMF is the most common monogenic autoinflammatory disease and is most prevalent in people of Mediterranean or Middle Eastern descent.

The recommendations reflect recent developments around the treatment and management of FMF, including interleukin (IL)-1–targeting treatments for patients who are colchicine-resistant and safety data on colchicine use during pregnancy.

“It’s been almost a decade, and certainly we’ve learned a lot,” said Jonathan Hausmann, MD, director of the autoinflammatory disease program at Massachusetts General Hospital, Boston, and co-director of the autoinflammatory clinic at Boston Children’s Hospital, Boston. He was not involved with the work.

The recommendations were published online in Annals of the Rheumatic Diseases on April 8, 2025, and presented April 10 at the annual meeting for the International Society of Systemic Auto-Inflammatory Diseases in Paris, France.

Defining and Treating Colchicine-Resistant FMF

The new recommendations provide a formal definition of colchicine resistance and intolerance and emphasize adherence as the “cornerstone of FMF management,” according to the document.

“You can’t be colchicine-resistant if you don’t take your colchicine every day,” Hausmann said.

The experts referenced the 2020 EULAR guidelines on preventing, screening, and assessing nonadherence in patients, including providing equitable access to treatment and individualizing interventions based on patient needs and preferences.

Colchicine resistance was defined as, in adherent patients:

• More than three attacks every 6 months,
• More than one attack per month in the last 3 months, or
• Elevated C-reactive protein (CRP)/erythrocyte sedimentation rate/serum amyloid A (SAA) during an attack-free period.

The 2024 update provides more robust evidence for biologic disease-modifying antirheumatic drugs (DMARDs) for patients with FMF and colchicine resistance, including results from six randomized controlled trials with IL-1 blockers.

Canakinumab is the only biologic approved by the US Food and Drug Administration for FMF in both pediatric and adult patients, but other options include anakinra and rilonacept.

“We do not recommend a specific regimen or time,” senior author Loreto Carmona, MD, PhD, wrote in an email. She is a rheumatologist-epidemiologist and the scientific director at the Institute for Musculoskeletal Health (InMusc) in Madrid, Spain. “However, we do recommend tapering the DMARD after remission is achieved unless the patient has a poor prognostic genetic background.”

Improved Data on Colchicine and Reproductive Health

While the 2016 recommendations also supported continuing colchicine during conception, pregnancy, and breastfeeding, the 2024 update includes evidence such as a “ dedicated systematic review with meta-analysis specifically evaluating colchicine’s safety in these reproductive contexts, providing a more robust evidence base for the recommendations regarding its continued use,” Carmona said.

“This allows for more informed reassurance to patients about the safety of their medication during these important life stages.”

The literature review did find a trend of preterm births, but this trend is likely more related to continued inflammation from FMF than colchicine, the authors wrote. Current data and expert opinion support men continuing to use the recommended dosages of colchicine, but more research is needed on its effect on sperm count and fertility outcomes in men.

A ‘Patient-Centered’ Approach

The updated recommendations also established an overarching principle emphasizing the importance of quality of life and the need to support health and wellbeing in patients living with FMF.

“Even though attacks are the main concern in individuals with FMF, recent studies have shown the negative effects of the disease on exercise capacity, fatigue, physical activity levels, and emotional status,” the authors wrote.

Integrating nonpharmacologic interventions is a key component in managing the disease, they added, including physical activity to reduce inflammation and maintain functional capacity. Focusing on sleep hygiene and cognitive behavioral approaches can also address fatigue.

These concepts “weren’t specifically addressed in the previous guidelines,” Hausmann said, so this update is “a welcome change.”

While there are data supporting approaches such as physiotherapy, occupational therapy, and cognitive behavioral therapy in rheumatic diseases in general, he said, the effects of these nonpharmacologic interventions in managing FMF are not yet known.

Unanswered Questions

The recommendations also highlighted other areas for future research, including a need for a concrete definition for minimal disease activity for FMF. The expert panel that compiled these recommendations agreed that a definition should include:

• Measures of clinical disease activity (attack frequency per 3 months, physician assessment)
• Patient-reported outcome measures and patient-reported experience measures
• Biochemical markers, such as CRP or SAA

Outside of the management and treatment of FMF, the etiology of the disease is still not clear, the authors wrote. Mutations in the MEFV gene are known to cause the disease, but environmental factors may play a role in disease severity.

For example, a 1974 analysis of 100 Armenian patients with FMF in California observed that these patients in the United States had a much lower incidence of amyloidosis than a previous study of patients with FMF in Israel. Another study from 2009 found that Turkish children with FMF living in Turkey experienced higher disease severity than Turkish children with FMF born and raised in Germany.

While some environments seem to protect individuals from severe disease, others may worsen symptoms, Hausmann said, but it’s still not clear what drives these differences. 

“It’s a genetic disease, but it’s not all about the genes,” he said.

EULAR provided financial support for this work. Carmona reported no conflicts of interest for the topic but noted that InMusc delivers services for many stakeholders, including pharmaceutical companies that produce drugs listed in the recommendations, such as Roche or Novartis. Hausmann had no relevant disclosures.