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Genetic and clinical features of Familial Mediterranean Fever in a cohort of patients with kidney failure

First author: Ahmed Sheyyab

Journal: Journal of Nephrology

Author of the abstract: Rim BOURGUIBA

Graphical abstract de l'article

Introduction

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. In its classic form, it is mainly associated with mutations in exon 10 of the MEFV gene. AA amyloidosis is the most severe complication of FMF.


The aim of this study was to compare the frequency of MEFV variants in hemodialysis patients versus healthy controls in a Mediterranean country, Jordan.


Methods

This was a cross‑sectional study including 78 patients with end‑stage kidney disease on hemodialysis and 201 healthy controls in Jordan. All patients underwent Sanger sequencing for the main MEFV variants. The following variants were tested: p.E148Q, p.P369S, p.F479L, p.M680I (G/C), p.M680I (G/A), p.I692del, p.M694V, p.M694I, p.K695R, p.V726A, p.A744S, and p.R761H.


Patients carrying a variant were then clinically assessed according to the Tel‑Hashomer criteria. Five underwent rectal biopsy to detect amyloidosis.


Results

Among dialysis patients, 16% had at least one MEFV variant versus 12.9% in the control group (not significant). The two most frequent mutations in the hemodialysis group were M694V (p = 0.035) and V726A (p = 0.009). The variants detected in both groups are summarized in Table 1. In the control group without renal failure, 22 individuals were heterozygous for the E148Q variant. Three patients met diagnostic criteria for FMF, and one case of AA amyloidosis was confirmed by biopsy.


Conclusion

FMF is the most common autoinflammatory disease in Mediterranean countries, yet it remains underdiagnosed even in high‑risk populations. This diagnostic delay leads to complications, notably AA amyloidosis. This study shows that 4% of hemodialysis patients were diagnosed with FMF. It also confirms the non‑pathogenic nature of the E148Q variant, which was detected in 22 healthy, asymptomatic individuals.


Overall, these findings underscore the importance of testing for MEFV mutations in patients with AA amyloidosis in countries where FMF is highly prevalent, in order to offer appropriate treatment to prevent AA amyloidosis and progression to renal failure.


Résultats du dépistage génétique du gène MEFV montrant le taux de fréquence des variants détectés dans les groupes souffrant d'insuffisance rénale et dans les groupes témoins

 
 
 

Could tocilizumab be used in familial Mediterranean fever? A systematic review

Updated: Jan 22

First author : P. Mertz

Review: Rheumatology



Could tocilizumab be used in Familial Mediterranean Fever?
Could tocilizumab be used in Familial Mediterranean Fever ?

Abstract:


Introduction:

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent fever and serosal inflammation. Although colchicine is the primary treatment, around 10% of FMF patients do not respond to it, necessitating alternative therapies. Biologic treatments, such as IL-1β, TNF-α and IL-6 inhibitors, have been considered. However, the accessibility and cost of IL-1β inhibitors may limit their use in certain regions. Tocilizumab (TCZ), an IL-6 receptor inhibitor, offers an alternative, but its efficacy in FMF is not well-documented.


Results:

After selection, 14 articles were included: two double-blind RCTs, two retrospective studies and 10 case reports. Multicentre double-blind RCTs reported mixed results in FMF patients without AA amyloidosis due to genetic/classification heterogeneity of the available studies, possible misdiagnosed FMF patients and study design. Retrospective studies suggest that TCZ may benefit FMF patients with established renal AA amyloidosis, potentially preventing progression and managing flares more effectively. TCZ showed a safe profile with no specific adverse events, but data on its use during pregnancy or breastfeeding are lacking. There was no available data on the use of TCZ in paediatric FMF.


Conclusion:

This review summarizes the current state of research, safety and efficacy of TCZ in FMF. While IL1β inhibitors remain the first choice for colchicine-resistant or intolerant FMF patients, TCZ might be of interest in some selected FMF patients with established AA amyloidosis and resistance to colchicine and interleukin 1 inhibitors.




 
 
 

Waldenstrom macroglobulinaemia with AA amyloidosis reveals a B-cell-restricted NLRP2 variant

First author: Terré et al.

Link to article: DOI: 10.1111/bjh.19383


Waldenstrom macroglobulinaemia with AA amyloidosis

Summary

Waldenström macroglobulinemia (WM) is a rare malignant hematopathy characterized by lymphoplasmacytic lymphoma (LPL) secreting IgM. Some patients with WM exhibit chronic inflammation, sometimes complicated by AA amyloidosis, which involves the deposition of insoluble fibrils derived from serum amyloid A (SAA) protein. However, the underlying mechanism of this inflammation remains poorly understood.


We report the case of an 86-year-old female patient with WM complicated by AA amyloidosis. Whole-exome sequencing (WES) revealed a somatic mutation in NLRP2 restricted to B cells. We investigated the functional consequences of this mutation.


The analyses showed that the NLRP2 p.Asp121Gly mutation leads to a reduction in ASC aggregation, a marker of inflammasome activation. In a WM model, the loss of NLRP2 resulted in an increased secretion of CCL-5, a cytokine promoting IL-6 production by stromal cells. IL-6 is a key factor in the induction of SAA, and our results suggest that the NLRP2 mutation may have contributed to the development of AA amyloidosis in this patient.


These findings highlight the importance of somatic mutations in inflammatory regulation and the need for further studies to clarify the role of NLRP2 in the pathophysiology of inflammatory WM (IWM).





 
 
 
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