RARE DISEASE
Familial Mediterranean fever
Familial Mediterranean fever
Familial Mediterranean fever
Synonyms: Benign paroxysmal peritonitis, Benign recurrent polyserositis, FMF, Familial paroxysmal polyserositis, Periodic disease
Synonyms: Benign paroxysmal peritonitis, Benign recurrent polyserositis, FMF, Familial paroxysmal polyserositis, Periodic disease
Synonyms: Benign paroxysmal peritonitis, Benign recurrent polyserositis, FMF, Familial paroxysmal polyserositis, Periodic disease
Drug discovery
4
drugs
With orphan designations
Overview
Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder caused by MEFV gene mutations, leading to dysregulated pyrin-mediated inflammation. It manifests as recurrent self-limiting episodes of fever, serositis (peritonitis, pleuritis), synovitis, and erysipelas-like rashes. Untreated, chronic inflammation predisposes to AA amyloidosis, particularly nephropathy. Diagnosis combines clinical criteria (Tel HaShomer), genetic testing (detecting ~80% of mutations), and exclusion of mimics. Lifelong colchicine remains first-line prophylaxis, reducing attacks and amyloidosis risk [1][3][8][13]. IL-1 inhibitors (anakinra, canakinumab) are reserved for colchicine-resistant cases [8][13].
Burden
Recurrent attacks impair quality of life; 25–48% of untreated patients develop amyloidosis in endemic regions [4][9][13].
Chronic kidney disease occurs in 60% of amyloidosis cases without prophylaxis [6][13].
Subclinical inflammation persists in 30% despite treatment, necessitating lifelong monitoring [13][16].
Therapies
Categories: rare genetic diseases, rare immunological diseases, rare renal diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood, rare transplant-related disorders
Research Papers
1,252 drug discovery papers about Familial Mediterranean fever, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,252 drug discovery papers about Familial Mediterranean fever, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | LLM-supported self-diagnosis and self-treatment of familial Mediterranean fever: a case report
Large language models (LLMs) are increasingly being used by patients to seek explanations for persistent or unexplained symptoms. However, their impact on real-world diagnostic pathways and patient behavior remains poorly understood. We report the case of a 34-year-old male of Egyptian origin with recurrent episodes of fever, severe migratory abdominal pain, arthralgia, myalgia, and intermittent erythematous skin lesions since early childhood. Despite almost 3 decades of extensive investigations, no unifying diagnosis had been established. During an iterative dialogue with the LLM DeepSeek in June 2025, the differential diagnosis was progressively refined toward familial Mediterranean fever (FMF). Although the model repeatedly recommended specialist assessment, it also provided specific information regarding genetic testing and colchicine treatment. The patient subsequently arranged genetic testing independently and obtained colchicine in Egypt, initiating treatment without prior specialist assessment at 0.5 mg twice daily. His inflammatory attacks ceased completely. However, liver enzymes increased, prompting temporary treatment discontinuation and dose reduction. FMF was thereafter confirmed by specialist assessment based on the characteristic clinical phenotype, family history, genotype, and response to colchicine. This case illustrates how patient-facing LLMs may facilitate recognition of rare autoinflammatory diseases. However, confident diagnostic language combined with actionable treatment advice may also encourage unsupervised testing and self-medication, underscoring the need for clear safety boundaries and specialist confirmation.
2026-09-29 | A Pilot Study on the Ocular Effects of Colchicine in Children with Familial Mediterranean Fever
Background and Objectives: Myopia is a worldwide healthcare problem, particularly in the young population. Inflammation, alongside genetic and environmental factors, may contribute to the onset and progression of myopia. This pilot study explored whether long-term colchicine therapy is associated with ocular biometric and refractive differences in pediatric patients with Familial Mediterranean Fever (FMF). Materials and Methods: In this cross-sectional study, ocular biometric and refractive parameters were compared between FMF patients receiving colchicine for at least one year and age-matched healthy controls, including refraction, keratometry, anterior chamber depth (ACD), axial length (AL), and ganglion cell complex (GCC). Results: Compared with controls, the colchicine group showed a smaller refractive error (−0.46 ± 1.06 vs. −1.48 ± 1.93 D) and shallower ACD (3.29 ± 0.35 vs. 3.73 ± 0.31 mm); both remained significant after Holm-Bonferroni correction (corrected p = 0.041 and p < 0.001). Keratometry was also lower in the colchicine group but did not remain significant after correction (corrected p = 0.194). AL and GCC did not differ significantly between groups. Conclusions: Colchicine-treated FMF patients showed a less myopic profile and shallower anterior chamber depth than controls. Given the cross-sectional design and the inseparability of FMF status from colchicine treatment, these findings should be considered preliminary and hypothetical rather than evidence of a plausible protective effect, highlighting the need for longitudinal studies to clarify this potential association.
2026-09-28 | Real-world safety of concomitant colchicine and statin therapy.
This study aimed to evaluate the risk of clinically meaningful muscle- and liver-related outcomes associated with concomitant colchicine-statin therapy in a real-world setting, and to determine whether concomitant therapy increases the incidence of toxicity compared with either agent alone. A retrospective cohort study using the national Clalit Health Services database (≈5.4 million insured individuals). Adults with gout or familial Mediterranean fever between 2010 and 2024 were categorized into four exposure groups: no treatment, colchicine only, statin only, or concomitant therapy. Propensity-score matching was used to balance baseline characteristics. The primary outcome was creatine kinase (CK) elevation >3× the upper limit of normal (ULN), while secondary outcomes included alanine transaminase (ALT) elevation >5× the ULN, myopathy, liver disease, and hospitalizations related to these conditions. Eligible participants before and after propensity-score matching were 104,066 and 31,839, respectively (no treatment n=7,146; colchicine only n=7,146; statin only n=9,030; concomitant therapy n=8,517). Compared with no treatment, CK elevations >3× ULN were observed with statin therapy (HR 1.64, 95% CI 1.39-1.93) and concomitant colchicine-statin therapy (HR 1.74, 95% CI 1.44-2.09), but not with colchicine therapy alone (HR 1.08, 95% CI 0.89-1.31). Clinically diagnosed myopathy was infrequent and showed a graded increase across exposure groups, with the highest risk observed in the concomitant treatment group (HR 1.50, 95% CI 1.31-1.72). Although colchicine-statin concomitant therapy was associated with higher rates of laboratory and clinical adverse events, the additional risk beyond statin monotherapy was small, supporting their use when clinically indicated.
2026-09-18 | JAK Inhibitors in Colchicine Resistant FMF Patients: A Case-Based Review.
Familial Mediterranean Fever (FMF) is an autoinflammatory disorder typically controlled with colchicine; however, 5-10% of patients exhibit colchicine resistance or intolerance. Although biologic therapies targeting IL-1 may be effective, their cost and limited accessibility create a need for alternative oral treatments. Janus kinase (JAK) inhibitors have emerged as potential modulators of multiple inflammatory pathways implicated in FMF pathogenesis. We conducted a retrospective case series of three adults with colchicine-resistant FMF who had previously demonstrated partial but inadequate responses to colchicine and dapsone combination therapy. All patients-initiated treatment with an oral JAK inhibitor at 5 mg twice daily. None of the patients had received IL-1 or IL-6 inhibitors prior to JAK inhibitor therapy. Clinical outcomes, including attack frequency, remission status, and adverse events, were documented over 9-12 months of follow-up. All three patients achieved complete remission, defined as the absence of any FMF attacks throughout the follow-up period. No infectious, hematologic, thrombotic, or hepatic adverse events were observed. JAK inhibitor therapy was associated with rapid, complete, and sustained remission in adults with colchicine-resistant FMF. These findings support the growing evidence that JAK inhibition may offer an effective oral alternative to biologics in refractory FMF.
2026-09-11 | P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.
Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.
antibodies
2026-07-20 | Axial Spondyloarthritis in Familial Mediterranean Fever: Bridging the Gap Between Autoinflammation and Autoimmunity
The clinical and pathogenetic intersection of Familial Mediterranean Fever (FMF) and axial spondyloarthritis (axSpA) represents a compelling frontier in modern rheumatology, challenging the traditional binary classification of inflammatory diseases. FMF is a monogenic autoinflammatory disorder caused by mutations in the MEFV gene, characterized by dysregulation of the pyrin inflammasome and surges in interleukin-1β (IL-1β), while axSpA is an immune-mediated condition linked to the HLA-B27 antigen and the IL-23/IL-17 axis. Following a structured search of PubMed/MEDLINE and Scopus, this review integrates PRISMA-informed screening of epidemiological data with a comprehensive narrative synthesis of the molecular pathogenesis and clinical management of this association. The analysis demonstrates a substantially elevated prevalence of spondyloarthritis among FMF patients compared to the general population. It explores the molecular “bridge” where innate immune activation provides the requisite cytokine milieu for the expansion of Th17 cells that drive spinal inflammation. Clinical evidence defines a distinct FMF-associated spondyloarthritis phenotype, characterized by a balanced sex distribution, early onset, and high risk of destructive hip involvement and AA amyloidosis, particularly in M694V carriers. Management strategies focus on dual biologic blockade in refractory cases, targeting both the upstream IL-1 pathway and downstream TNF or IL-17 effectors. This report identifies critical knowledge gaps, emphasizing the need for large-scale clinical trials to optimize outcomes for this complex patient population.
2026-03-18 | Familial Mediterranean Fever Associated with Anti-PLA2R-Positive Membranous Nephropathy: A Case-Based Review
Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease in which renal involvement is a major determinant of prognosis and is classically dominated by amyloid A (AA) amyloidosis. Non-amyloid renal manifestations are uncommon and poorly characterized. We report a case of clinically overt FMF associated with anti-phospholipase A2 receptor (PLA2R) antibody-positive membranous nephropathy (MN). A 46-year-old man with recurrent febrile episodes fulfilling Tel Hashomer criteria for FMF developed progressive proteinuria with detectable anti-PLA2R antibodies. Genetic testing identified a heterozygous missense MEFV variant in exon 10 (p.Lys695Arg), a mutation with variable penetrance and conflicting pathogenic classification. Kidney biopsy demonstrated PLA2R-positive MN, excluding amyloidosis. After initial conservative management, the patient progressed to nephrotic syndrome complicated by renal vein thrombosis, requiring immunosuppressive therapy according to the Ponticelli regimen in addition to colchicine and anticoagulation, resulting in clinical and immunological remission. In parallel, we performed a systematic review of the literature, identifying only isolated reports of biopsy-proven MN in FMF patients. This case highlights the diagnostic importance of kidney biopsy in FMF patients with proteinuria and illustrates that immune-mediated glomerular disease may occur even in association with non-founder or variably penetrant MEFV mutations, requiring disease-specific management beyond standard autoinflammatory control.
2026-03-14 | γδ T Cells in Autoinflammatory Diseases.
Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries by linking innate immune activation to tissue-specific inflammatory pathology. Here, we review evidence that in both monogenic and multifactorial autoinflammatory diseases-including, for example, familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, gout, Behçet's disease, Still's disease, atherosclerosis, and neurodegenerative disorders-γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g., Behcet's disease, IFNγ and tumor necrosis factor (TNF)α producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases.
2026-03-05 | Clinical, genetic, and therapeutic differences in pediatric versus adult colchicine-resistant FMF patients.
Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent febrile episodes and serositis. Colchicine-resistant FMF represents a challenging subset of patients with more severe clinical manifestations, limited treatment options, and increased risk of long-term complications. This study aimed to compare clinical manifestations, genetic mutations, comorbidities, and treatment approaches between pediatric and adult patients diagnosed with colchicine-resistant FMF. This retrospective cross-sectional study included 107 colchicine-resistant FMF patients who received biologic treatment at Ankara Bilkent City Hospital between 2018 and 2023. Demographic, clinical, and genetic data were collected and compared between the groups. Treatment response was evaluated using the International Severity Score for FMF (ISSF). A total of 107 patients with colchicine-resistant FMF were included, comprising 38 pediatric and 69 adult individuals. Female predominance was noted in both groups, more prominently in pediatric patients (68.4% vs. 53.6%). Classical FMF symptoms; abdominal pain (100% vs. 89.9%, p = 0.042), fever (97.4% vs. 82.6%, p = 0.025), chest pain (57.9% vs. 24.6%, p = 0.001), and arthritis (50.0% vs. 26.1%, p = 0.013) were significantly more prevalent in pediatric patients. In contrast, adult patients more frequently presented with inflammatory back pain (40.6% vs. 10.5%, p = 0.001), persistent inflammation (24.6% vs. 7.9%, p = 0.039), and amyloidosis (36.2% vs. 2.6%, p = 0.001). Following biological treatment, median ISSF scores decreased significantly in both groups (5.0 to 0.0, p < 0.001). Although overall MEFV mutation distribution was similar between groups (p = 0.574). This study highlights significant age-related differences in clinical presentation and treatment patterns among crFMF patients. Pediatric cases tend to present with a more typical and severe phenotype, while adults exhibit higher rates of complications such as amyloidosis. These findings underscore the need for age-tailored diagnostic and therapeutic approaches in colchicine-resistant FMF.
2025-12-05 | Efficacy and safety of anti-interleukin-6 treatment in familial Mediterranean fever: a systematic literature review.
Biological treatments are indicated in familial Mediterranean fever (FMF) patients with colchicine resistance or intolerance. Interleukin-1 (IL-1) inhibitors may not yield sufficient efficacy and safety. Interleukin-6 inhibitors (tocilizumab - TCZ) have been suggested to be potentially beneficial. This systematic literature review aimed to evaluate the existing data on the efficacy and safety of IL-6 inhibitors in the treatment of FMF. A systematic literature review was conducted using PubMed, Embase, Scopus, Web of Science, and the Cochrane Library to identify literature published until February 2024 on "Tocilizumab" OR "Interleukin-6 inhibitor" AND "Familial Mediterranean Fever". This study was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 11 studies were included, corresponding to 68 patients: 6 studies were case reports, 3 were case series, and 2 were randomized control trials. Tocilizumab was indicated mainly for amyloid A (AA) amyloidosis and resistance/intolerance to other drugs. Tocilizumab showed efficacy in controlling FMF attacks and disease symptoms including fever, abdominal pain, arthritis and arthralgia. Inflammatory markers including C-reactive protein and serum amyloid A protein decreased. A decrease in proteinuria levels was reported in 20 patients. Adverse events were recorded in one-third of patients and led to TCZ discontinuation in 5 patients. No deaths associated with anti-IL-6 treatment were documented within a median follow-up period of 13 months. Although the duration of follow-up of TCZ was short, we concluded that TCZ might present an acceptable profile regarding efficacy and safety in adult FMF patients. Our data suggest that TCZ could be a good treatment option after IL-1 inhibitors and warrants further investigation.
oligonucleotides
2025-01-09 | miR-21 and cathepsin B in familial Mediterranean fever: novel findings regarding their impact on disease severity.
The limited predictive effect of genotype on familial Mediterranean fever (FMF) phenotype suggests that epigenetic factors and alternative mechanisms that may cause IL-1β release could contribute to phenotypic heterogeneity. The objective of this study was to examine the role of IL-1β levels and miR-21-5p, cathepsin B and pyrin levels, which were identified as potential factors causing IL-1β release through the use of bioinformatics tools, in the pathogenesis of FMF and their relationship with disease severity. 50 paediatric patients with FMF and 40 healthy children were enrolled in this study. Patients were divided into subgroups according to Pras disease severity score. Serum miR-21-5p expression levels were assessed by qRT-PCR, while serum pyrin, IL-1β and cathepsin B levels were determined by ELISA. Serum miR-21-5p was significantly downregulated in FMF patients compared with the control group (p<0.001), while serum pyrin, IL-1β and cathepsin B levels were markedly elevated (p<0.001 for each). Only miR-21-5p was negatively correlated with IL-1β (r=-0.855; p<0.001). In moderately severe FMF patients, miR-21-5p exhibited a statistically significant downregulation (p<0.001), whereas IL-1β and cathepsin B showed a statistically significant increase (p<0.001 and p<0.05, respectively). Furthermore, the Pras score showed a strong negative correlation (r=-0.738; p<0.001) with miR-21-5p levels. Multivariate logistic regression showed that in FMF, a one-unit decrease in miR-21 increased disease severity risk 6.76-fold, while a one-unit increase in cathepsin B raised it 1.71-fold. This might be considered one of the mechanisms for subclinical inflammation in paediatric FMF patients through increased activation of cytokines via the downregulation of miR-21-5p. Our findings suggest that miR-21-5p and IL-1β play key roles in subclinical inflammation, and these molecules might be a potential therapeutic target.
2024-05-09 | Characterization of serum extracellular vesicles and their differential level of miR-197-3p in familial Mediterranean fever patients.
The aim of this study was to analyze the existence of miRNAs derived from serum extracellular vesicles (EVs) in familial Mediterranean fever (FMF) patients. Our group has previously shown the association of certain miRNAs with FMF. Serum samples of adult and pediatric FMF patients and their age matched controls were used in the study. Serum EVs were characterized by transmission electron microscopy (TEM) and flow cytometry. RNAs were isolated from EVs and levels of miR-197-3p and miR-20a-5p were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). EV characterization using TEM demonstrated fraction of 30-120 nm-sized particles with cup-shaped morphology. Flow cytometry results revealed the CD63 and CD81 positive populations as 53.3% in serum EVs. We showed that miR-197-3p and miR-20a-5p were "circulating miRNAs" and carried in EVs of FMF patients and controls. In FMF patients, level of miR-197-3p was significantly decreased. There was no significant alteration in the level for miR-20a-5p between patients and controls. We showed the differential level of miR-197-3p in serum EVs of the FMF patients. miR-197-3p's potential as a biomarker and therapeutic target in FMF pathogenesis warrants further investigation. EVs and EV-miRNAs can be identified in FMF patients’ sera.Serum EV-miR-197-3p is dysregulated in FMF patients.Serum EV-miR-197-3p might have both diagnostic and therapeutic potentials.
2023-11-01 | Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients.
Colchicine is the primary treatment for familial Mediterranean fever (FMF). Although colchicine is safe and effective in FMF patients, around 5-10% of patients show resistance to the drug. This study investigates the possibility of a link between colchicine resistance and the distinct miRNA profiles in colchicine resistant FMF patients. Differentially expressed miRNAs in colchicine resistant FMF patients were detected by Affymetrix 4.0 miRNA array analysis. These miRNAs were then categorized based on the role of their target genes in drug metabolism and inflammation related pathways. qRT-PCR was used to validate candidate miRNAs selected by Enrichr, a gene enrichment analysis system based on the relevance of possible target genes in drug metabolism pathways. Expression levels of these miRNAs' potential target genes were investigated by qRT-PCR. Then, a colchicine resistant hepatoblastoma cell line (HEPG2) was established, and the differentially expressed miRNAs and genes identified in patients were also analyzed in this colchicine-resistant cell line. 25 differentially expressed miRNAs were detected in colchicine resistant FMF patients. miR-183-5p, miR-15b-5p, miR-505-5p, and miR-125a-5p were identified to be associated with drug resistance and inflammatory pathways and thus chosen for further validation. miR-183-5p, miR-15b-5p, miR-505-5p miRNAs showed significantly differential expression in qRT-PCR. NFKB1, NR3C1, PPARα - drug absorption, distribution, metabolism, and excretion (ADME) genes were predicted to be targeted by these miRNAs. Among these targets, NFKB1 and NR3C1 were differentially over expressed in colchicine resistant FMF patients. These findings were validated in the colchicine resistant hepatoblastoma cell line (HEPG2). This is the first study evaluating the role of miRNAs in colchicine resistant patients with FMF. Their differential expression may result in resistance to standard colchicine treatment by affecting the expression of genes that take place in drug absorption, distribution, metabolism, and excretion (ADME) or nuclear receptors that regulate ADME genes, thus potentially playing a role in both drug metabolism and inflammation.
2023-01-10 | Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases
Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against Streptococcus pneumoniae, specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.
2021-10-13 | The Assessment of Selected miRNA Profile in Familial Mediterranean Fever
Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the MEFV gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators' production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to SNORD61. Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment.
proteins
2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-07-19 | Anakinra treatment practices in colchicine-resistant familial Mediterranean fever: a survey of pediatric rheumatologists conducted through the PReS AID-WP and the Turkish pediatric rheumatology associations.
Colchicine-resistant familial Mediterranean fever (cr-FMF) represents a therapeutic challenge, and anakinra, a recombinant interleukin-1 receptor antagonist, is widely used in clinical practice. Our aim was to describe real-world practices of pediatric rheumatologists regarding anakinra use in patients with cr-FMF, with a focus on treatment initiation, tapering strategies, and discontinuation approaches. This survey-based study included pediatric rheumatologists with at least one year of clinical experience in managing cr-FMF. The survey assessed physician characteristics, treatment practices including initiation, tapering, and discontinuation strategies. Data were collected via an online survey platform between September and November 2025. A total of 81 pediatric rheumatologists participated, mostly practicing in Türkiye (92.6%). Most respondents preferred once-daily anakinra at 1-2 mg/kg/day and assessed response within the first month. Among tapering strategies, 90.1% favored interval extension, most commonly every 3 days or weekly. 79.0% considered discontinuation after sustained remission (median 6 months). During tapering-related flares, clinicians preferred interval shortening (43.2%) or dose escalation (37.0%), while 19.8% switched to an alternative biologic. After discontinuation-related relapse, 81.5% restarted anakinra at the previous effective dose. While anakinra initiation and relapse management appear relatively consistent, tapering and discontinuation strategies remain highly variable, underscoring the need for evidence-based guidance.
2026-05-18 | Evidence of the role of Midkine and Pleiotrophin in the pathogenesis of Familial Mediterranean Fever.
Familial Mediterranean Fever (FMF) is a chronic autoinflammatory illness that follows a pattern of periodic attacks; however, the majority of cases experience ongoing subclinical inflammation during the attack-free periods that could lead to the development of anemia, splenomegaly, heart disease, and the major complication, amyloidosis. Midkine/Pleiotrophin (MDK/PTN) are heparin-binding cytokines, with upregulated expression in various inflammatory and malignant diseases. Thus, the present research aims to identify the role of MDK and PTN in the pathogenesis of chronic inflammation and to explore the potential of both cytokines as new markers of subclinical inflammation in FMF. Blood samples from 30 FMF patients and 30 controls were collected to assess gene expression and protein levels of MDK and PTN by qRT-PCR and ELISA, respectively. Statistical correlation between different parameters and bioinformatic analysis to link the MEFV gene to the relevant genes was also performed. The expression of MDK and PTN genes was significantly higher in FMF children than in healthy subjects. Additionally, the serum level of MDK showed a fourfold increase in patients compared to controls (p < 0.001). The levels of PTN were also higher in cases, but without reaching the significance level (p = 0.096). MDK gene expression was inversely related to ESR level and positively correlated to serum level of MDK and anemia occurrence. Conclusion: Collectively, our results disclosed that Midkine could be identified as a useful clinical tool in diagnosing and managing systemic and subclinical inflammation in FMF cases, while Pleiotrophin might provide additional information on acute inflammatory processes.
2026-02-21 | Real-World Efficacy, Safety, and Drug Retention of Anakinra and Canakinumab in Pediatric Colchicine-Resistant Familial Mediterranean Fever: Insights from a Single-Center Cohort.
This study evaluated the efficacy, safety, and drug retention of anakinra and canakinumab in pediatric patients with colchicine-resistant familial Mediterranean fever (cr-FMF) within a real-world cohort. This retrospective cohort study was conducted from June 2016 to April 2024, including 86 patients diagnosed with cr-FMF. Clinical and laboratory parameters, including attack frequency, C-reactive protein (CRP), serum amyloid A (SAA), and autoinflammatory disease activity index (AIDAI) scores, were recorded at baseline and during follow-up. A total of 86 patients (50 females, 36 males) were included in the study. All carried exon 10 MEFV mutations, with 69 patients (80.2%) having the M694V/M694V genotype. Anakinra was initiated in36 patients (41.9%), and canakinumab in 50 patients (58.1%). The median treatment duration was significantly longer for canakinumab (48 months) compared to anakinra (7 months) (p<0.001). Both treatments significantly reduced attack frequency, AIDAI scores, CRP, and SAA levels compared to baseline (p<0.001). While the reduction in attack frequency was comparable between the groups, patients treated with canakinumab achieved significantly lower mean AIDAI scores at 12 months compared to the anakinra group (p = 0.021). Anakinra provided a more rapid onset of symptom control but was commonly discontinued due to injection site reactions (44.4%). Canakinumab was associated with sustained long-term disease control with fewer local side effects. However, rare serious events, including acute myeloid leukemia and inflammatory bowel disease, were observed, though causality with treatment could not be established. In this pediatric cohort of cr-FMF patients, both anakinra and canakinumab were effective in reducing disease activity and inflammation. Anakinra offered rapid symptom relief but had frequent injection site reactions. Canakinumab provided sustained control with fewer local side effects but required monitoring for rare complications.
2025-10-29 | Successful multimodal intensive care management including early plasmapheresis and granulocyte colony stimulating factor in severe colchicine poisoning: A case report.
Colchicine is a narrow therapeutic index drug widely used in the treatment of inflammatory diseases such as acute gout attacks and Familial Mediterranean Fever (FMF). In case of overdose, the risk of toxicity is high and can rapidly lead to multiple organ failure. The lack of an antidote for colchicine toxicity continues the search for a definitive treatment. We present a case of severe colchicine toxicity managed successfully with early initiation of therapeutic plasma exchange (TPE), intensive supportive care including noninvasive ventilation, hemodynamic stabilization, electrolyte management, and granulocyte colony- stimulating factor (G-CSF) therapy. This multimodal intensive care approach resulted in complete recovery.
other
2025-08-26 | Vasculitis in autoinflammatory diseases.
This review aims to explore the relationship between autoinflammatory diseases (AIDs) and vasculitis, with a focus on recently identified syndromes and newly published data since 2016. While the connection between innate immune dysregulation and systemic inflammation is well established in AIDs, the occurrence of vasculitis in these disorders remains underrecognized and often misclassified.We discuss vasculitic manifestations in a wide range of AIDs, including familial Mediterranean fever, DADA2, HA20, VEXAS, CAPS, TRAPS, HIDS/MKD, Blau syndrome, and others. Each condition presents a unique pattern of vascular involvement, ranging from incidental cutaneous findings to life-threatening systemic vasculitis. The underlying mechanisms often involve overactivation of inflammatory pathways such as IL-1β, or NF-κB, and in some cases, novel genetic mutations affecting non-inflammatory pathways such as purine metabolism. The histologic, clinical, and genetic features often differ from classic vasculitic syndromes. Recognizing vasculitis in the context of AIDs is critical for early diagnosis, especially in pediatric patients or those with treatment-resistant or atypical presentations. Genetic testing should be considered in such cases. Understanding these distinct disease patterns allows physicians to tailor management strategies, including biologic therapies or hematopoietic stem cell transplantation, improving outcomes in these complex and often severe disorders.
2024-11-12 | New and future perspectives in familial Mediterranean fever and other autoinflammatory diseases.
Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations.
2024-10-13 | Cost-saving approach with screening of selected variants in genetic diagnosis in Turkish pediatric familial Mediterranean fever patients: a single center longitudinal study.
The aim of this study was to investigate whether a short exon screening consisting of selected variants could confirm the diagnosis in patients with a preliminary diagnosis of familial Mediterranean fever (FMF), thus providing a cost-saving alternative to a comprehensive MEditerranean FeVer (MEFV) gene sequence analysis test. This observational study on pediatric patients focused on clinically suspected FMF cases without prior genetic analysis. Participants met the Turkish pediatric FMF criteria. They underwent short exon screening for M694V, M680I, V726A, and E148Q variants. Those who were heterozygous or negative on short exon screening received further MEFV gene sequence analysis. The study involved 1557 patients. Pathogenic variants in both alleles of the MEFV gene were found in 611 patients (39.2%), and a high-penetrance variant in heterozygosity or an E148Q variant on the other allele was found in 643 patients (41.3%). A further 189 patients (12.1%) had one or two E148Q variants. Short-exon screening was negative in 114 patients (7.6%). Of the 876 patients who underwent MEFV gene sequence analysis, additional variants were found in 72 of the 762 initially heterozygous patients. Of the 114 initially negative patients, 34 had homozygous or compound heterozygous variants, and 74 had heterozygous variants. Ultimately, only 6 patients yielded negative results in the MEFV gene sequence analysis. The short exon screening for common MEFV mutations offers a practical and cost-saving alternative to comprehensive MEFV gene sequence analysis in populations with a high prevalence of FMF.
2024-02-26 | Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.
Outcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, the data are inconclusive and mostly based on studies from the early 2000s and earlier. Retrospective multicenter cohort study. We searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018. Age, cause of amyloidosis, use of biotherapies, and C-reactive protein levels. Outcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events. Kaplan-Meier estimator for mortality and cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively. 86 patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (IQR, 39.7-61.1). The main cause of amyloidosis was familial Mediterranean fever (37 cases; 43%). 16 (18.6%) patients received biotherapy after transplantation. Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation. Cumulative incidences of allograft loss were 10.5% (4.0-17.0) at 1 year and 13.0% (5.8-20.1) at 5 years after transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases, and there was a 27.9% incidence of acute allograft rejection. Multivariable analysis showed that C-reactive protein concentration at the time of transplantation was associated with patient survival (HR, 1.01; 95% CI, 1.00-1.02; P=0.01) and allograft survival (HR, 1.68; 95% CI, 1.10-2.57; P=0.02). The study lacked a control group, and the effect of biotherapies on transplantation outcomes could not be explored. This relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease. AA amyloidosis is a severe and rare disease. Kidney involvement is frequent and leads to end-stage kidney disease. Because of the involvement of other organs, these patients are often frail, which has raised concerns about their suitability for kidney transplantation. We reviewed all patients with AA amyloidosis nephropathy who underwent kidney transplantation in France in the recent era (2008-2018) and found that the outcomes after kidney transplantation were favorable, with 85.5% of patients still alive 5 years after transplantation, a survival rate that is comparable to the outcomes of patients receiving a transplant for other forms of kidney diseases. Recurrence of amyloidosis in the transplanted kidney was infrequent (5.8%). These data support the practice of kidney transplantation for patients with AA amyloidosis who experience kidney failure.
2017-01-18 | Allogeneic Transplant in ELANE and MEFV Mutation Positive Severe Cyclic Neutropenia: Review of Prognostic Factors for Secondary Severe Events
Objective and Importance. Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection. Case. A 25-year-old male diagnosed with CyN, on G-CSF but worsening quality of life. Pretransplant investigations revealed ELANE mutation positive severe CyN along with familial Mediterranean fever (MEFV) mutation. Intervention. Bone marrow transplantation as treatment for dual mutation (ELANE and MEFV mutation) positive severe CyN. Conclusion. BMT may be considered as an alternative treatment for severe CyN in patients who are refractory to G-CSF. It is postulated that in our patient the combined mutations (CyN and MEFV) may have contributed to the severity of this individual’s symptoms. We suggest CyN patients who present with severe symptoms have evaluation with ELANE mutation testing, Periodic Fever Syndromes Panel, and routine marrow assessment with FISH, conventional cytogenetics, and morphological evaluation for MDS/AML.
small molecules
2026-09-29 | LLM-supported self-diagnosis and self-treatment of familial Mediterranean fever: a case report
Large language models (LLMs) are increasingly being used by patients to seek explanations for persistent or unexplained symptoms. However, their impact on real-world diagnostic pathways and patient behavior remains poorly understood. We report the case of a 34-year-old male of Egyptian origin with recurrent episodes of fever, severe migratory abdominal pain, arthralgia, myalgia, and intermittent erythematous skin lesions since early childhood. Despite almost 3 decades of extensive investigations, no unifying diagnosis had been established. During an iterative dialogue with the LLM DeepSeek in June 2025, the differential diagnosis was progressively refined toward familial Mediterranean fever (FMF). Although the model repeatedly recommended specialist assessment, it also provided specific information regarding genetic testing and colchicine treatment. The patient subsequently arranged genetic testing independently and obtained colchicine in Egypt, initiating treatment without prior specialist assessment at 0.5 mg twice daily. His inflammatory attacks ceased completely. However, liver enzymes increased, prompting temporary treatment discontinuation and dose reduction. FMF was thereafter confirmed by specialist assessment based on the characteristic clinical phenotype, family history, genotype, and response to colchicine. This case illustrates how patient-facing LLMs may facilitate recognition of rare autoinflammatory diseases. However, confident diagnostic language combined with actionable treatment advice may also encourage unsupervised testing and self-medication, underscoring the need for clear safety boundaries and specialist confirmation.
2026-09-29 | A Pilot Study on the Ocular Effects of Colchicine in Children with Familial Mediterranean Fever
Background and Objectives: Myopia is a worldwide healthcare problem, particularly in the young population. Inflammation, alongside genetic and environmental factors, may contribute to the onset and progression of myopia. This pilot study explored whether long-term colchicine therapy is associated with ocular biometric and refractive differences in pediatric patients with Familial Mediterranean Fever (FMF). Materials and Methods: In this cross-sectional study, ocular biometric and refractive parameters were compared between FMF patients receiving colchicine for at least one year and age-matched healthy controls, including refraction, keratometry, anterior chamber depth (ACD), axial length (AL), and ganglion cell complex (GCC). Results: Compared with controls, the colchicine group showed a smaller refractive error (−0.46 ± 1.06 vs. −1.48 ± 1.93 D) and shallower ACD (3.29 ± 0.35 vs. 3.73 ± 0.31 mm); both remained significant after Holm-Bonferroni correction (corrected p = 0.041 and p < 0.001). Keratometry was also lower in the colchicine group but did not remain significant after correction (corrected p = 0.194). AL and GCC did not differ significantly between groups. Conclusions: Colchicine-treated FMF patients showed a less myopic profile and shallower anterior chamber depth than controls. Given the cross-sectional design and the inseparability of FMF status from colchicine treatment, these findings should be considered preliminary and hypothetical rather than evidence of a plausible protective effect, highlighting the need for longitudinal studies to clarify this potential association.
2026-09-28 | Real-world safety of concomitant colchicine and statin therapy.
This study aimed to evaluate the risk of clinically meaningful muscle- and liver-related outcomes associated with concomitant colchicine-statin therapy in a real-world setting, and to determine whether concomitant therapy increases the incidence of toxicity compared with either agent alone. A retrospective cohort study using the national Clalit Health Services database (≈5.4 million insured individuals). Adults with gout or familial Mediterranean fever between 2010 and 2024 were categorized into four exposure groups: no treatment, colchicine only, statin only, or concomitant therapy. Propensity-score matching was used to balance baseline characteristics. The primary outcome was creatine kinase (CK) elevation >3× the upper limit of normal (ULN), while secondary outcomes included alanine transaminase (ALT) elevation >5× the ULN, myopathy, liver disease, and hospitalizations related to these conditions. Eligible participants before and after propensity-score matching were 104,066 and 31,839, respectively (no treatment n=7,146; colchicine only n=7,146; statin only n=9,030; concomitant therapy n=8,517). Compared with no treatment, CK elevations >3× ULN were observed with statin therapy (HR 1.64, 95% CI 1.39-1.93) and concomitant colchicine-statin therapy (HR 1.74, 95% CI 1.44-2.09), but not with colchicine therapy alone (HR 1.08, 95% CI 0.89-1.31). Clinically diagnosed myopathy was infrequent and showed a graded increase across exposure groups, with the highest risk observed in the concomitant treatment group (HR 1.50, 95% CI 1.31-1.72). Although colchicine-statin concomitant therapy was associated with higher rates of laboratory and clinical adverse events, the additional risk beyond statin monotherapy was small, supporting their use when clinically indicated.
2026-09-18 | JAK Inhibitors in Colchicine Resistant FMF Patients: A Case-Based Review.
Familial Mediterranean Fever (FMF) is an autoinflammatory disorder typically controlled with colchicine; however, 5-10% of patients exhibit colchicine resistance or intolerance. Although biologic therapies targeting IL-1 may be effective, their cost and limited accessibility create a need for alternative oral treatments. Janus kinase (JAK) inhibitors have emerged as potential modulators of multiple inflammatory pathways implicated in FMF pathogenesis. We conducted a retrospective case series of three adults with colchicine-resistant FMF who had previously demonstrated partial but inadequate responses to colchicine and dapsone combination therapy. All patients-initiated treatment with an oral JAK inhibitor at 5 mg twice daily. None of the patients had received IL-1 or IL-6 inhibitors prior to JAK inhibitor therapy. Clinical outcomes, including attack frequency, remission status, and adverse events, were documented over 9-12 months of follow-up. All three patients achieved complete remission, defined as the absence of any FMF attacks throughout the follow-up period. No infectious, hematologic, thrombotic, or hepatic adverse events were observed. JAK inhibitor therapy was associated with rapid, complete, and sustained remission in adults with colchicine-resistant FMF. These findings support the growing evidence that JAK inhibition may offer an effective oral alternative to biologics in refractory FMF.
2026-09-11 | P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.
Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.
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2026-07-20 | Axial Spondyloarthritis in Familial Mediterranean Fever: Bridging the Gap Between Autoinflammation and Autoimmunity
The clinical and pathogenetic intersection of Familial Mediterranean Fever (FMF) and axial spondyloarthritis (axSpA) represents a compelling frontier in modern rheumatology, challenging the traditional binary classification of inflammatory diseases. FMF is a monogenic autoinflammatory disorder caused by mutations in the MEFV gene, characterized by dysregulation of the pyrin inflammasome and surges in interleukin-1β (IL-1β), while axSpA is an immune-mediated condition linked to the HLA-B27 antigen and the IL-23/IL-17 axis. Following a structured search of PubMed/MEDLINE and Scopus, this review integrates PRISMA-informed screening of epidemiological data with a comprehensive narrative synthesis of the molecular pathogenesis and clinical management of this association. The analysis demonstrates a substantially elevated prevalence of spondyloarthritis among FMF patients compared to the general population. It explores the molecular “bridge” where innate immune activation provides the requisite cytokine milieu for the expansion of Th17 cells that drive spinal inflammation. Clinical evidence defines a distinct FMF-associated spondyloarthritis phenotype, characterized by a balanced sex distribution, early onset, and high risk of destructive hip involvement and AA amyloidosis, particularly in M694V carriers. Management strategies focus on dual biologic blockade in refractory cases, targeting both the upstream IL-1 pathway and downstream TNF or IL-17 effectors. This report identifies critical knowledge gaps, emphasizing the need for large-scale clinical trials to optimize outcomes for this complex patient population.
2026-03-18 | Familial Mediterranean Fever Associated with Anti-PLA2R-Positive Membranous Nephropathy: A Case-Based Review
Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease in which renal involvement is a major determinant of prognosis and is classically dominated by amyloid A (AA) amyloidosis. Non-amyloid renal manifestations are uncommon and poorly characterized. We report a case of clinically overt FMF associated with anti-phospholipase A2 receptor (PLA2R) antibody-positive membranous nephropathy (MN). A 46-year-old man with recurrent febrile episodes fulfilling Tel Hashomer criteria for FMF developed progressive proteinuria with detectable anti-PLA2R antibodies. Genetic testing identified a heterozygous missense MEFV variant in exon 10 (p.Lys695Arg), a mutation with variable penetrance and conflicting pathogenic classification. Kidney biopsy demonstrated PLA2R-positive MN, excluding amyloidosis. After initial conservative management, the patient progressed to nephrotic syndrome complicated by renal vein thrombosis, requiring immunosuppressive therapy according to the Ponticelli regimen in addition to colchicine and anticoagulation, resulting in clinical and immunological remission. In parallel, we performed a systematic review of the literature, identifying only isolated reports of biopsy-proven MN in FMF patients. This case highlights the diagnostic importance of kidney biopsy in FMF patients with proteinuria and illustrates that immune-mediated glomerular disease may occur even in association with non-founder or variably penetrant MEFV mutations, requiring disease-specific management beyond standard autoinflammatory control.
2026-03-14 | γδ T Cells in Autoinflammatory Diseases.
Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries by linking innate immune activation to tissue-specific inflammatory pathology. Here, we review evidence that in both monogenic and multifactorial autoinflammatory diseases-including, for example, familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, gout, Behçet's disease, Still's disease, atherosclerosis, and neurodegenerative disorders-γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g., Behcet's disease, IFNγ and tumor necrosis factor (TNF)α producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases.
2026-03-05 | Clinical, genetic, and therapeutic differences in pediatric versus adult colchicine-resistant FMF patients.
Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent febrile episodes and serositis. Colchicine-resistant FMF represents a challenging subset of patients with more severe clinical manifestations, limited treatment options, and increased risk of long-term complications. This study aimed to compare clinical manifestations, genetic mutations, comorbidities, and treatment approaches between pediatric and adult patients diagnosed with colchicine-resistant FMF. This retrospective cross-sectional study included 107 colchicine-resistant FMF patients who received biologic treatment at Ankara Bilkent City Hospital between 2018 and 2023. Demographic, clinical, and genetic data were collected and compared between the groups. Treatment response was evaluated using the International Severity Score for FMF (ISSF). A total of 107 patients with colchicine-resistant FMF were included, comprising 38 pediatric and 69 adult individuals. Female predominance was noted in both groups, more prominently in pediatric patients (68.4% vs. 53.6%). Classical FMF symptoms; abdominal pain (100% vs. 89.9%, p = 0.042), fever (97.4% vs. 82.6%, p = 0.025), chest pain (57.9% vs. 24.6%, p = 0.001), and arthritis (50.0% vs. 26.1%, p = 0.013) were significantly more prevalent in pediatric patients. In contrast, adult patients more frequently presented with inflammatory back pain (40.6% vs. 10.5%, p = 0.001), persistent inflammation (24.6% vs. 7.9%, p = 0.039), and amyloidosis (36.2% vs. 2.6%, p = 0.001). Following biological treatment, median ISSF scores decreased significantly in both groups (5.0 to 0.0, p < 0.001). Although overall MEFV mutation distribution was similar between groups (p = 0.574). This study highlights significant age-related differences in clinical presentation and treatment patterns among crFMF patients. Pediatric cases tend to present with a more typical and severe phenotype, while adults exhibit higher rates of complications such as amyloidosis. These findings underscore the need for age-tailored diagnostic and therapeutic approaches in colchicine-resistant FMF.
2025-12-05 | Efficacy and safety of anti-interleukin-6 treatment in familial Mediterranean fever: a systematic literature review.
Biological treatments are indicated in familial Mediterranean fever (FMF) patients with colchicine resistance or intolerance. Interleukin-1 (IL-1) inhibitors may not yield sufficient efficacy and safety. Interleukin-6 inhibitors (tocilizumab - TCZ) have been suggested to be potentially beneficial. This systematic literature review aimed to evaluate the existing data on the efficacy and safety of IL-6 inhibitors in the treatment of FMF. A systematic literature review was conducted using PubMed, Embase, Scopus, Web of Science, and the Cochrane Library to identify literature published until February 2024 on "Tocilizumab" OR "Interleukin-6 inhibitor" AND "Familial Mediterranean Fever". This study was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 11 studies were included, corresponding to 68 patients: 6 studies were case reports, 3 were case series, and 2 were randomized control trials. Tocilizumab was indicated mainly for amyloid A (AA) amyloidosis and resistance/intolerance to other drugs. Tocilizumab showed efficacy in controlling FMF attacks and disease symptoms including fever, abdominal pain, arthritis and arthralgia. Inflammatory markers including C-reactive protein and serum amyloid A protein decreased. A decrease in proteinuria levels was reported in 20 patients. Adverse events were recorded in one-third of patients and led to TCZ discontinuation in 5 patients. No deaths associated with anti-IL-6 treatment were documented within a median follow-up period of 13 months. Although the duration of follow-up of TCZ was short, we concluded that TCZ might present an acceptable profile regarding efficacy and safety in adult FMF patients. Our data suggest that TCZ could be a good treatment option after IL-1 inhibitors and warrants further investigation.
oligonucleotides
2025-01-09 | miR-21 and cathepsin B in familial Mediterranean fever: novel findings regarding their impact on disease severity.
The limited predictive effect of genotype on familial Mediterranean fever (FMF) phenotype suggests that epigenetic factors and alternative mechanisms that may cause IL-1β release could contribute to phenotypic heterogeneity. The objective of this study was to examine the role of IL-1β levels and miR-21-5p, cathepsin B and pyrin levels, which were identified as potential factors causing IL-1β release through the use of bioinformatics tools, in the pathogenesis of FMF and their relationship with disease severity. 50 paediatric patients with FMF and 40 healthy children were enrolled in this study. Patients were divided into subgroups according to Pras disease severity score. Serum miR-21-5p expression levels were assessed by qRT-PCR, while serum pyrin, IL-1β and cathepsin B levels were determined by ELISA. Serum miR-21-5p was significantly downregulated in FMF patients compared with the control group (p<0.001), while serum pyrin, IL-1β and cathepsin B levels were markedly elevated (p<0.001 for each). Only miR-21-5p was negatively correlated with IL-1β (r=-0.855; p<0.001). In moderately severe FMF patients, miR-21-5p exhibited a statistically significant downregulation (p<0.001), whereas IL-1β and cathepsin B showed a statistically significant increase (p<0.001 and p<0.05, respectively). Furthermore, the Pras score showed a strong negative correlation (r=-0.738; p<0.001) with miR-21-5p levels. Multivariate logistic regression showed that in FMF, a one-unit decrease in miR-21 increased disease severity risk 6.76-fold, while a one-unit increase in cathepsin B raised it 1.71-fold. This might be considered one of the mechanisms for subclinical inflammation in paediatric FMF patients through increased activation of cytokines via the downregulation of miR-21-5p. Our findings suggest that miR-21-5p and IL-1β play key roles in subclinical inflammation, and these molecules might be a potential therapeutic target.
2024-05-09 | Characterization of serum extracellular vesicles and their differential level of miR-197-3p in familial Mediterranean fever patients.
The aim of this study was to analyze the existence of miRNAs derived from serum extracellular vesicles (EVs) in familial Mediterranean fever (FMF) patients. Our group has previously shown the association of certain miRNAs with FMF. Serum samples of adult and pediatric FMF patients and their age matched controls were used in the study. Serum EVs were characterized by transmission electron microscopy (TEM) and flow cytometry. RNAs were isolated from EVs and levels of miR-197-3p and miR-20a-5p were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). EV characterization using TEM demonstrated fraction of 30-120 nm-sized particles with cup-shaped morphology. Flow cytometry results revealed the CD63 and CD81 positive populations as 53.3% in serum EVs. We showed that miR-197-3p and miR-20a-5p were "circulating miRNAs" and carried in EVs of FMF patients and controls. In FMF patients, level of miR-197-3p was significantly decreased. There was no significant alteration in the level for miR-20a-5p between patients and controls. We showed the differential level of miR-197-3p in serum EVs of the FMF patients. miR-197-3p's potential as a biomarker and therapeutic target in FMF pathogenesis warrants further investigation. EVs and EV-miRNAs can be identified in FMF patients’ sera.Serum EV-miR-197-3p is dysregulated in FMF patients.Serum EV-miR-197-3p might have both diagnostic and therapeutic potentials.
2023-11-01 | Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients.
Colchicine is the primary treatment for familial Mediterranean fever (FMF). Although colchicine is safe and effective in FMF patients, around 5-10% of patients show resistance to the drug. This study investigates the possibility of a link between colchicine resistance and the distinct miRNA profiles in colchicine resistant FMF patients. Differentially expressed miRNAs in colchicine resistant FMF patients were detected by Affymetrix 4.0 miRNA array analysis. These miRNAs were then categorized based on the role of their target genes in drug metabolism and inflammation related pathways. qRT-PCR was used to validate candidate miRNAs selected by Enrichr, a gene enrichment analysis system based on the relevance of possible target genes in drug metabolism pathways. Expression levels of these miRNAs' potential target genes were investigated by qRT-PCR. Then, a colchicine resistant hepatoblastoma cell line (HEPG2) was established, and the differentially expressed miRNAs and genes identified in patients were also analyzed in this colchicine-resistant cell line. 25 differentially expressed miRNAs were detected in colchicine resistant FMF patients. miR-183-5p, miR-15b-5p, miR-505-5p, and miR-125a-5p were identified to be associated with drug resistance and inflammatory pathways and thus chosen for further validation. miR-183-5p, miR-15b-5p, miR-505-5p miRNAs showed significantly differential expression in qRT-PCR. NFKB1, NR3C1, PPARα - drug absorption, distribution, metabolism, and excretion (ADME) genes were predicted to be targeted by these miRNAs. Among these targets, NFKB1 and NR3C1 were differentially over expressed in colchicine resistant FMF patients. These findings were validated in the colchicine resistant hepatoblastoma cell line (HEPG2). This is the first study evaluating the role of miRNAs in colchicine resistant patients with FMF. Their differential expression may result in resistance to standard colchicine treatment by affecting the expression of genes that take place in drug absorption, distribution, metabolism, and excretion (ADME) or nuclear receptors that regulate ADME genes, thus potentially playing a role in both drug metabolism and inflammation.
2023-01-10 | Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases
Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against Streptococcus pneumoniae, specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.
2021-10-13 | The Assessment of Selected miRNA Profile in Familial Mediterranean Fever
Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the MEFV gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators' production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to SNORD61. Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment.
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2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-07-19 | Anakinra treatment practices in colchicine-resistant familial Mediterranean fever: a survey of pediatric rheumatologists conducted through the PReS AID-WP and the Turkish pediatric rheumatology associations.
Colchicine-resistant familial Mediterranean fever (cr-FMF) represents a therapeutic challenge, and anakinra, a recombinant interleukin-1 receptor antagonist, is widely used in clinical practice. Our aim was to describe real-world practices of pediatric rheumatologists regarding anakinra use in patients with cr-FMF, with a focus on treatment initiation, tapering strategies, and discontinuation approaches. This survey-based study included pediatric rheumatologists with at least one year of clinical experience in managing cr-FMF. The survey assessed physician characteristics, treatment practices including initiation, tapering, and discontinuation strategies. Data were collected via an online survey platform between September and November 2025. A total of 81 pediatric rheumatologists participated, mostly practicing in Türkiye (92.6%). Most respondents preferred once-daily anakinra at 1-2 mg/kg/day and assessed response within the first month. Among tapering strategies, 90.1% favored interval extension, most commonly every 3 days or weekly. 79.0% considered discontinuation after sustained remission (median 6 months). During tapering-related flares, clinicians preferred interval shortening (43.2%) or dose escalation (37.0%), while 19.8% switched to an alternative biologic. After discontinuation-related relapse, 81.5% restarted anakinra at the previous effective dose. While anakinra initiation and relapse management appear relatively consistent, tapering and discontinuation strategies remain highly variable, underscoring the need for evidence-based guidance.
2026-05-18 | Evidence of the role of Midkine and Pleiotrophin in the pathogenesis of Familial Mediterranean Fever.
Familial Mediterranean Fever (FMF) is a chronic autoinflammatory illness that follows a pattern of periodic attacks; however, the majority of cases experience ongoing subclinical inflammation during the attack-free periods that could lead to the development of anemia, splenomegaly, heart disease, and the major complication, amyloidosis. Midkine/Pleiotrophin (MDK/PTN) are heparin-binding cytokines, with upregulated expression in various inflammatory and malignant diseases. Thus, the present research aims to identify the role of MDK and PTN in the pathogenesis of chronic inflammation and to explore the potential of both cytokines as new markers of subclinical inflammation in FMF. Blood samples from 30 FMF patients and 30 controls were collected to assess gene expression and protein levels of MDK and PTN by qRT-PCR and ELISA, respectively. Statistical correlation between different parameters and bioinformatic analysis to link the MEFV gene to the relevant genes was also performed. The expression of MDK and PTN genes was significantly higher in FMF children than in healthy subjects. Additionally, the serum level of MDK showed a fourfold increase in patients compared to controls (p < 0.001). The levels of PTN were also higher in cases, but without reaching the significance level (p = 0.096). MDK gene expression was inversely related to ESR level and positively correlated to serum level of MDK and anemia occurrence. Conclusion: Collectively, our results disclosed that Midkine could be identified as a useful clinical tool in diagnosing and managing systemic and subclinical inflammation in FMF cases, while Pleiotrophin might provide additional information on acute inflammatory processes.
2026-02-21 | Real-World Efficacy, Safety, and Drug Retention of Anakinra and Canakinumab in Pediatric Colchicine-Resistant Familial Mediterranean Fever: Insights from a Single-Center Cohort.
This study evaluated the efficacy, safety, and drug retention of anakinra and canakinumab in pediatric patients with colchicine-resistant familial Mediterranean fever (cr-FMF) within a real-world cohort. This retrospective cohort study was conducted from June 2016 to April 2024, including 86 patients diagnosed with cr-FMF. Clinical and laboratory parameters, including attack frequency, C-reactive protein (CRP), serum amyloid A (SAA), and autoinflammatory disease activity index (AIDAI) scores, were recorded at baseline and during follow-up. A total of 86 patients (50 females, 36 males) were included in the study. All carried exon 10 MEFV mutations, with 69 patients (80.2%) having the M694V/M694V genotype. Anakinra was initiated in36 patients (41.9%), and canakinumab in 50 patients (58.1%). The median treatment duration was significantly longer for canakinumab (48 months) compared to anakinra (7 months) (p<0.001). Both treatments significantly reduced attack frequency, AIDAI scores, CRP, and SAA levels compared to baseline (p<0.001). While the reduction in attack frequency was comparable between the groups, patients treated with canakinumab achieved significantly lower mean AIDAI scores at 12 months compared to the anakinra group (p = 0.021). Anakinra provided a more rapid onset of symptom control but was commonly discontinued due to injection site reactions (44.4%). Canakinumab was associated with sustained long-term disease control with fewer local side effects. However, rare serious events, including acute myeloid leukemia and inflammatory bowel disease, were observed, though causality with treatment could not be established. In this pediatric cohort of cr-FMF patients, both anakinra and canakinumab were effective in reducing disease activity and inflammation. Anakinra offered rapid symptom relief but had frequent injection site reactions. Canakinumab provided sustained control with fewer local side effects but required monitoring for rare complications.
2025-10-29 | Successful multimodal intensive care management including early plasmapheresis and granulocyte colony stimulating factor in severe colchicine poisoning: A case report.
Colchicine is a narrow therapeutic index drug widely used in the treatment of inflammatory diseases such as acute gout attacks and Familial Mediterranean Fever (FMF). In case of overdose, the risk of toxicity is high and can rapidly lead to multiple organ failure. The lack of an antidote for colchicine toxicity continues the search for a definitive treatment. We present a case of severe colchicine toxicity managed successfully with early initiation of therapeutic plasma exchange (TPE), intensive supportive care including noninvasive ventilation, hemodynamic stabilization, electrolyte management, and granulocyte colony- stimulating factor (G-CSF) therapy. This multimodal intensive care approach resulted in complete recovery.
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2025-08-26 | Vasculitis in autoinflammatory diseases.
This review aims to explore the relationship between autoinflammatory diseases (AIDs) and vasculitis, with a focus on recently identified syndromes and newly published data since 2016. While the connection between innate immune dysregulation and systemic inflammation is well established in AIDs, the occurrence of vasculitis in these disorders remains underrecognized and often misclassified.We discuss vasculitic manifestations in a wide range of AIDs, including familial Mediterranean fever, DADA2, HA20, VEXAS, CAPS, TRAPS, HIDS/MKD, Blau syndrome, and others. Each condition presents a unique pattern of vascular involvement, ranging from incidental cutaneous findings to life-threatening systemic vasculitis. The underlying mechanisms often involve overactivation of inflammatory pathways such as IL-1β, or NF-κB, and in some cases, novel genetic mutations affecting non-inflammatory pathways such as purine metabolism. The histologic, clinical, and genetic features often differ from classic vasculitic syndromes. Recognizing vasculitis in the context of AIDs is critical for early diagnosis, especially in pediatric patients or those with treatment-resistant or atypical presentations. Genetic testing should be considered in such cases. Understanding these distinct disease patterns allows physicians to tailor management strategies, including biologic therapies or hematopoietic stem cell transplantation, improving outcomes in these complex and often severe disorders.
2024-11-12 | New and future perspectives in familial Mediterranean fever and other autoinflammatory diseases.
Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations.
2024-10-13 | Cost-saving approach with screening of selected variants in genetic diagnosis in Turkish pediatric familial Mediterranean fever patients: a single center longitudinal study.
The aim of this study was to investigate whether a short exon screening consisting of selected variants could confirm the diagnosis in patients with a preliminary diagnosis of familial Mediterranean fever (FMF), thus providing a cost-saving alternative to a comprehensive MEditerranean FeVer (MEFV) gene sequence analysis test. This observational study on pediatric patients focused on clinically suspected FMF cases without prior genetic analysis. Participants met the Turkish pediatric FMF criteria. They underwent short exon screening for M694V, M680I, V726A, and E148Q variants. Those who were heterozygous or negative on short exon screening received further MEFV gene sequence analysis. The study involved 1557 patients. Pathogenic variants in both alleles of the MEFV gene were found in 611 patients (39.2%), and a high-penetrance variant in heterozygosity or an E148Q variant on the other allele was found in 643 patients (41.3%). A further 189 patients (12.1%) had one or two E148Q variants. Short-exon screening was negative in 114 patients (7.6%). Of the 876 patients who underwent MEFV gene sequence analysis, additional variants were found in 72 of the 762 initially heterozygous patients. Of the 114 initially negative patients, 34 had homozygous or compound heterozygous variants, and 74 had heterozygous variants. Ultimately, only 6 patients yielded negative results in the MEFV gene sequence analysis. The short exon screening for common MEFV mutations offers a practical and cost-saving alternative to comprehensive MEFV gene sequence analysis in populations with a high prevalence of FMF.
2024-02-26 | Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.
Outcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, the data are inconclusive and mostly based on studies from the early 2000s and earlier. Retrospective multicenter cohort study. We searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018. Age, cause of amyloidosis, use of biotherapies, and C-reactive protein levels. Outcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events. Kaplan-Meier estimator for mortality and cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively. 86 patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (IQR, 39.7-61.1). The main cause of amyloidosis was familial Mediterranean fever (37 cases; 43%). 16 (18.6%) patients received biotherapy after transplantation. Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation. Cumulative incidences of allograft loss were 10.5% (4.0-17.0) at 1 year and 13.0% (5.8-20.1) at 5 years after transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases, and there was a 27.9% incidence of acute allograft rejection. Multivariable analysis showed that C-reactive protein concentration at the time of transplantation was associated with patient survival (HR, 1.01; 95% CI, 1.00-1.02; P=0.01) and allograft survival (HR, 1.68; 95% CI, 1.10-2.57; P=0.02). The study lacked a control group, and the effect of biotherapies on transplantation outcomes could not be explored. This relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease. AA amyloidosis is a severe and rare disease. Kidney involvement is frequent and leads to end-stage kidney disease. Because of the involvement of other organs, these patients are often frail, which has raised concerns about their suitability for kidney transplantation. We reviewed all patients with AA amyloidosis nephropathy who underwent kidney transplantation in France in the recent era (2008-2018) and found that the outcomes after kidney transplantation were favorable, with 85.5% of patients still alive 5 years after transplantation, a survival rate that is comparable to the outcomes of patients receiving a transplant for other forms of kidney diseases. Recurrence of amyloidosis in the transplanted kidney was infrequent (5.8%). These data support the practice of kidney transplantation for patients with AA amyloidosis who experience kidney failure.
2017-01-18 | Allogeneic Transplant in ELANE and MEFV Mutation Positive Severe Cyclic Neutropenia: Review of Prognostic Factors for Secondary Severe Events
Objective and Importance. Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection. Case. A 25-year-old male diagnosed with CyN, on G-CSF but worsening quality of life. Pretransplant investigations revealed ELANE mutation positive severe CyN along with familial Mediterranean fever (MEFV) mutation. Intervention. Bone marrow transplantation as treatment for dual mutation (ELANE and MEFV mutation) positive severe CyN. Conclusion. BMT may be considered as an alternative treatment for severe CyN in patients who are refractory to G-CSF. It is postulated that in our patient the combined mutations (CyN and MEFV) may have contributed to the severity of this individual’s symptoms. We suggest CyN patients who present with severe symptoms have evaluation with ELANE mutation testing, Periodic Fever Syndromes Panel, and routine marrow assessment with FISH, conventional cytogenetics, and morphological evaluation for MDS/AML.
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Drug Discovery Landscape
4 orphan drug designations for Familial Mediterranean fever, including 2 approved therapies.
4 orphan drug designations for Familial Mediterranean fever, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
goflikicept | proteins | FDA | R-Pharm Overseas, Inc. | |
canakinumab [ILARIS] | antibodies | FDA | Approved | Novartis Pharmaceuticals Corporation |
rilonacept | proteins | FDA | Philip J Hashkes, MD, MSc. | |
colchicine [Colcrys] | small molecules | FDA | Approved | AR Holding Company, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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