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.

Renal amyloidosis in Norway: how the disease has evolved over 30 years

English title: Epidemiology and clinical presentation of kidney amyloidosis have changed over the past three decades: a nationwide population-based study

First author: Hilde J. Vasstrand

Journal : BMC Nephrology

Reference : BMC Nephrol. 2025 Jun 2;26(1):272.

PubMed link : https://pubmed.ncbi.nlm.nih.gov/40457206/

Article summarized by: Dr Catherine Grandpeix-Guyodo

Introduction:

Amyloidoses are diseases related to protein deposits in the form of amyloid fibrils. Protein typing helps understand the presentation of the disease, its progression, prognosis, and allows treatment adaptation. Early diagnosis of kidney amyloidosis is essential for treatment optimization and prognosis improvement. This Norwegian nationwide study conducted over 30 years explores changes in the epidemiology and clinical presentation of kidney amyloidosis to raise awareness about these conditions.

Patients and methods: Over a 30-year period, 479 patients with amyloidosis on kidney biopsy were identified in the registries, including 209 AA amyloidoses (SAA protein deposits) and 270 non-AA amyloidoses (mainly AL amyloidoses from immunoglobulin light chain deposits). Patient records were studied and cases were separated into AA amyloidosis and non-AA amyloidosis.

Results:

The frequency of renal amyloidosis was stable over time (4% of kidney biopsies), but AL amyloidosis became the predominant form of non-AA amyloidoses with a frequency increasing from 1.9% to 2.8% of kidney biopsies (p = 0.014). In parallel, the proportion of AA amyloidosis decreased from 2.6% to 1.3% (p < 0.001), due to the reduction in amyloidoses secondary to inflammatory rheumatic diseases, partly offset by AA amyloidoses secondary to drug injections.

Advances in typing amyloid deposits significantly reduced undetermined amyloidoses (p < 0.001) and led to more precise diagnoses. Clinical presentations were varied, but proteinuria was present in 94% of patients. Nephrotic syndrome was noted more frequently in patients with non-AA amyloidosis (70%) than in those with AA amyloidosis (51%). Kidney function was better preserved in non-AA amyloidoses (median GFR 53 ml/min/1.73 m²) than in AA amyloidoses (median GFR 27 ml/min/1.73 m²). Patients with AA amyloidosis were younger (p < 0.001) and more often hypertensive (53% versus 38%, p < 0.001).

Regarding patients developing AA amyloidosis following drug injection, they were younger, more often male, and presented more advanced kidney disease with half in end-stage kidney disease.

Recently, the authors noted that patients with non-AA amyloidosis had better albumin, hemoglobin, and ESR levels (p < 0.05). Additionally, the proportion of non-AA amyloidosis with end-stage kidney disease dropped from 26.8% to 8.7% (p = 0.005), which could indicate earlier diagnoses.

Conclusion:

There have been changes in the epidemiology of kidney amyloidosis in Norway over the past 30 years. The rate of non-AA amyloidosis in biopsies has increased, and certain indicators suggest that diagnosis is made earlier. Amyloid typing has improved, which is reflected in more precise diagnoses with a decrease in undetermined forms. AA amyloidoses related to inflammatory rheumatic diseases have significantly decreased, but the increase in AA amyloidoses in patients who inject drugs is becoming a growing problem.

Awareness of amyloidoses remains necessary, especially during this period when epidemiology is changing with, as a consequence, the possibility of changes in clinical presentation and therapeutic needs.

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.