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.

Performance of serum interleukin-18 (IL-18) levels for the follow-up of patients with Familial Mediterranean Fever

French title: Performance du taux d'interleukine 18 (IL-18) sérique pour la surveillance des patients atteints de fièvre méditerranéenne familiale.

First author: Inès Elhani

Journal: The Journal of Allergy and Clinical Immunology: In Practice (JACIP)

Author of the abstract: https://pubmed.ncbi.nlm.nih.gov/39667435/

Article traduit par le Dr Catherine Grandpeix-Guyodo

Introduction:

Inflammasome activation in Familial Mediterranean Fever (FMF) leads to increased secretion of interleukin (IL)-1β and IL-18. Monitoring FMF activity is essential due to the risk of AA amyloidosis in cases of prolonged inflammation and is classically done using CRP and SAA (serum amyloid A protein), whose values may be dissociated. This study investigated the possibility of monitoring FMF activity through total blood IL-18 assay.

Patients and methods:

This monocentric, retrospective study involved adult FMF patients who had at least one total blood IL-18 assay during their follow-up between 2022 and 2024. The data collected included the mutational status of the MEFV gene, CRP and SAA values, disease activity (considered controlled if fewer than 2 flares per year / uncontrolled if 2 or more flares per year), and finally the total IL-18 assay(s) performed during follow-up consultations (routine care).

Results:

Among 208 sampled patients, half had controlled FMF, and a total of 308 IL-18 assays were analyzable with a median measurement of 922.25 pg/mL (N < 350 pg/mL). Among patients with controlled FMF, IL-18 levels were significantly higher in homozygous patients compared to compound heterozygotes and heterozygotes.

Some patients had IL-18 assays when FMF was inactive and active, and levels showed no significant difference.

IL-18 levels were not significantly different in patients treated with anti-IL-1.

Assays > 7,000 pg/mL concerned 16 patients who had adherence issues with their colchicine treatment and rather low dosages (< 2 mg).

Discussion:

Total blood IL-18 levels appear to be correlated with genotype but not with disease activity. The persistence of high IL-18 levels in asymptomatic patients could suggest low-grade activity of the pyrin inflammasome. Very high levels may show that patients are undertreated, but the significance of IL-18 levels in terms of amyloidosis risk remains to be determined if the SAA level is normal.

The limitations of this study are the few samples per patient (generally 1), the retrospective nature, and the absence of evaluation by a disease activity score at the time of sampling.

Conclusion:

The monitoring of total blood IL-18 levels has a role that remains to be defined since it does not seem to reflect either the patient's immediate inflammatory state or FMF activity. Its interest could lie in detecting subclinical inflammatory activity and evaluating treatment adherence. Prospective studies on large cohorts will be necessary to deepen its utility in FMF.