Colchicine-resistant Familial Mediterranean Fever: triggering factors are highly prevalent and reduced under IL-1 inhibition

Article title: Do we consider enough the presence of triggering factors in the evaluation of patients with FMF? Triggering factors are highly prevalent in colchicine-resistant FMF patients.

First author: Bayram Farisogullari

Journal: Internal and Emergency Medicine

Link to the article: https://pubmed.ncbi.nlm.nih.gov/38103114/

Introduction

The objective of this study was to investigate the frequency of triggering factors in patients with Familial Mediterranean Fever (FMF) who are resistant to colchicine and in those who are responsive to colchicine, and to assess the impact of interleukin-1 (IL-1) antagonist therapy on triggering factors in colchicine-resistant patients.

Patients and Methods

Colchicine-resistant FMF patients treated with IL-1 antagonists and colchicine-responsive patients treated with colchicine and experiencing ≤ 3 attacks in the previous year were questioned about the presence of 12 different triggering factors: cold exposure, emotional stress, fatigue, intense physical activity, menstruation (for women), sleep deprivation, prolonged standing, long-distance travel, high-fat diet, prolonged fasting, infections, and trauma.

Colchicine-resistant patients were questioned for two periods: before and after initiation of IL-1 antagonist therapy.

Results

A total of 63 patients were included, comprising 28 colchicine-resistant patients (19 treated with anakinra and 9 with canakinumab) and 35 colchicine-responsive patients. Only half carried two pathogenic mutations in exon 10 of the MEFV gene (Table 1). Overall, 77.8% of patients reported at least one triggering factor, with a mean number of 2.6 per patient.

The most common triggering factors, in decreasing order of frequency, were emotional stress, menstruation, cold exposure, prolonged standing, and long-distance travel. Triggering factors accounted for approximately one-third of attacks, and 57.1% of patients reported using avoidance strategies. The frequency of triggering factors was higher in colchicine-resistant patients than in colchicine-responsive patients (89.3% vs 68.6%; p = 0.04).

Among colchicine-resistant patients, the frequency of triggering factors decreased from 89.3% to 32.1% under IL-1 antagonist therapy, and the proportion of attacks initiated by a triggering factor decreased from 27.8% to 14.4% (p < 0.001) (Table 2).

Discussion

Triggering factors were more frequent in colchicine-resistant patients than in colchicine-responsive patients. Treatment with IL-1 antagonists appeared to reduce both the number of triggering factors and the proportion of attacks induced by these factors.

Conclusion

Triggering factors are common in FMF and should be systematically assessed, particularly when colchicine resistance develops. IL-1 antagonists reduce their impact and may be useful as long-term therapy or as preventive treatment during predictable exposures.

Familial Mediterranean Fever: a single dose of anakinra to stop an acute attack

Article title: A single dose of anakinra for arresting Familial Mediterranean Fever attacks: a proof-of-concept study

First author: E. Giat

Journal: Clinical and Experimental Rheumatology

Link to the article: https://pubmed.ncbi.nlm.nih.gov/41133353/

Author of the abstract: Dr Catherine Grandpeix-Guyodo

Introduction

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is characterized by recurrent febrile attacks of serositis (peritonitis, pleuritis, arthritis) and may, in the long term, be complicated by AA amyloidosis in cases of uncontrolled chronic inflammation. Colchicine is the standard long-term treatment; however, some patients experience incomplete response or intolerance, leading to the continuous use of IL-1 inhibitors (anakinra or canakinumab). Nevertheless, acute attacks may still occur despite treatment, and their management remains largely symptomatic, with limited efficacy of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs).

Patients and Methods

The objective of this prospective study was to evaluate the efficacy of a single dose of anakinra (100 mg subcutaneously) administered at the onset of an attack to interrupt its progression. The study included patients with typical FMF according to Tel Hashomer criteria, carrying one or two pathogenic MEFV mutations, treated with colchicine, and having experienced at least two serositis attacks in the previous year. Patients receiving continuous anti–IL-1 therapy were excluded, as were those with atypical attacks or chronic inflammatory states.

Patients were provided with a prefilled syringe of anakinra and received training in self-injection and early recognition of attack symptoms. The duration of treated attacks was compared with each patient’s usual attack duration.

Results

Thirty-five patients agreed to participate: five were excluded due to persistent inflammation; four experienced no attacks during the study period; two did not ultimately use anakinra during an attack; and one discontinued due to an adverse event. A total of 23 patients were analyzed, including 13 with two pathogenic MEFV mutations (considered to have “classical” FMF) and 10 with a single pathogenic MEFV mutation (considered “heterozygous” FMF).

The mean duration of treated attacks was 8.3 ± 6.8 hours, compared with 56.3 ± 16.8 hours under usual conditions. When anakinra was injected within the first 4 hours of attack onset, 85% of attacks were interrupted within 4 hours after injection. Later injections resulted in a less pronounced but still significant reduction compared with usual attack duration. Overall, 91% of treated attacks lasted less than 24 hours. Only one adverse event was reported (local injection-site reaction), highlighting the good tolerability of this strategy.

Six patients continued to use self-purchased anakinra to treat 43 additional attacks, with similar results, confirming the reproducibility and feasibility of this approach in real-life conditions.

Discussion

The authors emphasize that this strategy is not an alternative to continuous treatment in colchicine-resistant or -intolerant patients. Rather, it should be considered a “rescue” therapy, allowing rapid interruption of occasional acute attacks, reduction of pain, avoidance of emergency department visits, decreased absenteeism, and improved quality of life.

Conclusion

This prospective study demonstrates the efficacy and safety of a single, early injection of anakinra to significantly shorten FMF attacks (both classical and heterozygous forms) in adults. A randomized controlled trial is currently underway to confirm these findings and to better define the optimal role of this strategy within the therapeutic armamentarium.

Dysimmune Actinopathies: Better Understanding These Rare Diseases in the Middle East and North Africa

Article title: Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry

First author: Zahra Chavoshzadeh

Journal: Front Genet.

Link to the article: https://pubmed.ncbi.nlm.nih.gov/40860338/

Author of the abstract: Philippe Mertz

Actinopathies are an emerging group of primary immunodeficiencies linked to abnormalities in the genes that regulate the actin cytoskeleton. These proteins control essential immune functions such as cell migration, tissue infiltration, and immunological synapse formation. Clinically, they are associated with severe and recurrent infections, allergic manifestations, cytopenias (particularly thrombocytopenia and/or abnormal mean platelet volume), autoimmunity, and sometimes malignancies.

The MENA (Middle East and North Africa) region has a high prevalence of these diseases, due in particular to a high frequency of consanguineous marriages. The aim of this retrospective multicenter study was to describe the clinical, immunological, and genetic characteristics and therapeutic approaches used in patients with actinopathy.

The authors proposed a classification of actinopathies into three main groups, according to the mechanisms affected (see Figure 1A extracted from the article). For the record, actin polymerization is essential for the formation of cell protrusions and depends mainly on two pathways associated with the RHO GTPases RAC2 and CDC42:

The group of RAC2 pathway regulators (in blue), which activates the ARP2/3 complex and induces lamellipodia formation;

The group of CDC42 pathway regulators (in red), which activates the WAVE complex and generates filopodia;

A third group mainly includes abnormalities in actin transcription factors or their regulators (in green), such as CEBPE, WDR1, or MKL1.

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A total of 503 patients from 17 countries were included. The median age at symptom onset was 4 months, and the median time to diagnosis was 19 months. Overall mortality was 23%, mainly due to infectious complications and cancers.

The most common initial presentations were allergic manifestations (33.7%), infections (32%), and hemorrhages (16.8%). Throughout life, infections predominated (90%), especially respiratory (72%) and skin (48%) infections. Eczema was the most common allergic manifestation (67.9%). Cytopenias (42.7%), lymphoproliferative disorders (19.1%), and lymphomas (5.9%) completed the spectrum.

Among the 391 patients who received a genetic diagnosis, the genes most commonly involved were DOCK8 (53.8%), WAS (n=24.6%), and CARMIL2 (4.3%). It should be noted that no patients with CDC42 mutations were included in the CDC42 pathway regulator group.

Hematopoietic stem cell transplantation (HSCT) was performed in 24% of patients, significantly improving survival in WAS, DOCK8, and DOCK2 deficiencies. Immunoglobulin replacement (89.4%) and antibiotic prophylaxis (93%) were almost systematic.

The authors then looked at the differences in presentation between the different groups. The main differences are shown in the figure opposite.

VPM : volume plaquettaire moyen

Key messages

1. Actinopathies are most often revealed in early childhood through severe infections (respiratory +++) and allergies (eczema, atopic dermatitis), with an overall mortality rate of around 25%. Platelet counts may be normal in the vast majority of patients (48–94% depending on the group).

   
   

2. Variants affecting the CDC42 pathway are associated with earlier onset, a more severe phenotype, and higher mortality than those affecting the RAC2 pathway, which have a later onset, often marked by lymphoproliferation.

   
   

3. Hematopoietic stem cell transplantation (HSCT) is a key therapeutic option, particularly beneficial for DOCK8, WAS, and DOCK2 deficiencies, highlighting the importance of early diagnosis and rapid referral to a center of expertise.

Clinical and molecular findings in actin-related inborn errors of immunity: the middle Eas.

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