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
1,236 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:
1,236 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:
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.
2026-08-07 | Disentangling the hepatic risks of familial Mediterranean Fever and colchicine: A propensity score-matched analysis of 19,231 patients.
Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disease commonly treated with lifelong colchicine therapy. Although colchicine is considered safe, its long-term hepatic effects remain debated. Distinguishing liver injury attributable to FMF itself from that induced by colchicine is essential for guiding clinical management. To determine whether FMF or colchicine exposure are independently associated with liver cirrhosis and fatty liver disease. This retrospective cohort study utilized electronic medical records from a tertiary care centre in Israel. Patients diagnosed with FMF, gout, pseudogout, or pericarditis were included. Liver injury outcomes were assessed via ICD codes, imaging, and biopsy data. Propensity score matching was applied to isolate the effects of FMF diagnosis and colchicine treatment, and multivariate logistic regression models were constructed to adjust for relevant confounders. Among 19,231 patients, FMF diagnosis was significantly associated with increased risk of cirrhosis (OR = 4.00; 95% CI: 2.78-5.75) and fatty liver (OR = 2.03; 95% CI: 1.57-2.61), both in unmatched and matched cohorts. In contrast, colchicine treatment was not associated with elevated OR for either condition (Cirrhosis OR = 0.92 [95% CI: 0.69-1.22]; Fatty Liver OR = 1.01 [95% CI: 0.85-1.21]). FMF is independently associated with increased hepatic injury risk, while colchicine treatment does not appear to confer additional liver toxicity. These findings underscore the importance of controlling FMF-related inflammation to prevent hepatic complications, and support the continued use of colchicine as a safe therapeutic agent in this population.
2026-08-05 | Clinical spectrum of pediatric patients carrying heterozygous MEFV gene variants.
The MEditerranean FeVer (MEFV) gene is a critical regulator of the innate immune response. The prototypical disease related to the MEFV gene is familial Mediterranean fever (FMF). Heterozygous MEFV gene variants have increasingly been reported in association with a wide range of inflammatory disorders besides FMF. The aim of this study was to evaluate the diagnostic spectrum and clinical and demographic findings of patients carrying heterozygous MEFV variants. This retrospective study included pediatric patients carrying heterozygous MEFV variants who were followed up at our center between January 2012 and January 2025. Diagnosis, demographics, and clinical manifestations were reviewed. A total of 270 patients with a median age of 7 years were identified. The diagnoses of the study population included FMF (67%), IgA vasculitis (7%), PFAPA syndrome (6%), inflammatory bowel disease (3%), juvenile idiopathic arthritis (3%), chronic nonbacterial osteomyelitis (2%), Behçet's disease (1%), and other vasculitides (1%). Fourteen percent of the patients were asymptomatic carriers. During follow-up, 22 of the 74 patients (30%) initially diagnosed with other inflammatory conditions later developed clinical features consistent with FMF. Colchicine therapy was initiated not only for typical attacks of FMF but also for selected indications in other inflammatory diseases. Heterozygous MEFV variants have been reported to be associated with various inflammatory diseases besides FMF. Long-term follow-up is essential, as some patients may later develop FMF. MEFV gene testing should be considered in other inflammatory diseases with severe or atypical manifestations, particularly in populations where FMF is highly prevalent. • Heterozygous MEFV variants have been associated with FMF and several inflammatory diseases. • This large pediatric cohort demonstrates that heterozygous MEFV variants may be encountered across a broad spectrum of inflammatory diseases, and some patients initially diagnosed with other conditions may subsequently develop FMF during follow-up.
2026-07-30 | Diagnosis of fibrillary glomerulonephritis suggests possible atypical familial Mediterranean fever in a patient with ulcerative colitis.
Fibrillary glomerulonephritis (FGN) is a rare glomerular disease that typically presents in middle age, and reports in young adults are uncommon. Herein, we describe the case of a 22-year-old woman with ulcerative colitis who was referred for evaluation of persistent proteinuria and microscopic hematuria. Kidney biopsy showed mild mesangial hypercellularity with increased mesangial matrix on light microscopy. Electron microscopy revealed randomly oriented, nonbranching microfibrils measuring approximately 20 nm in diameter within the mesangial areas. Immunohistochemistry for DnaJ heat shock protein family member B9 (DNAJB9) was positive in the glomeruli, confirming the diagnosis of FGN. Given the unusually young onset, the clinical course, and the presence of intestinal inflammatory lesions, an autoinflammatory disorder, specifically atypical familial Mediterranean fever (FMF), was suspected. Therapy with an angiotensin II receptor blocker was initiated for proteinuria, and colchicine was subsequently added while mesalazine was tapered. After treatment, urinary protein excretion decreased, and endoscopic and histologic bowel inflammation improved. This case highlights three practical points: DNAJB9 immunostaining is useful to establish FGN when classic ultrastructural features are present, FGN can occur in young adults, prompting evaluation for underlying systemic or autoinflammatory conditions, and in patients with intestinal lesions resembling inflammatory bowel disease, consideration of FMF may lead to colchicine therapy that benefits renal and gastrointestinal manifestations.
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.
2026-08-12 | 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.
2026-08-07 | Disentangling the hepatic risks of familial Mediterranean Fever and colchicine: A propensity score-matched analysis of 19,231 patients.
Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disease commonly treated with lifelong colchicine therapy. Although colchicine is considered safe, its long-term hepatic effects remain debated. Distinguishing liver injury attributable to FMF itself from that induced by colchicine is essential for guiding clinical management. To determine whether FMF or colchicine exposure are independently associated with liver cirrhosis and fatty liver disease. This retrospective cohort study utilized electronic medical records from a tertiary care centre in Israel. Patients diagnosed with FMF, gout, pseudogout, or pericarditis were included. Liver injury outcomes were assessed via ICD codes, imaging, and biopsy data. Propensity score matching was applied to isolate the effects of FMF diagnosis and colchicine treatment, and multivariate logistic regression models were constructed to adjust for relevant confounders. Among 19,231 patients, FMF diagnosis was significantly associated with increased risk of cirrhosis (OR = 4.00; 95% CI: 2.78-5.75) and fatty liver (OR = 2.03; 95% CI: 1.57-2.61), both in unmatched and matched cohorts. In contrast, colchicine treatment was not associated with elevated OR for either condition (Cirrhosis OR = 0.92 [95% CI: 0.69-1.22]; Fatty Liver OR = 1.01 [95% CI: 0.85-1.21]). FMF is independently associated with increased hepatic injury risk, while colchicine treatment does not appear to confer additional liver toxicity. These findings underscore the importance of controlling FMF-related inflammation to prevent hepatic complications, and support the continued use of colchicine as a safe therapeutic agent in this population.
2026-08-05 | Clinical spectrum of pediatric patients carrying heterozygous MEFV gene variants.
The MEditerranean FeVer (MEFV) gene is a critical regulator of the innate immune response. The prototypical disease related to the MEFV gene is familial Mediterranean fever (FMF). Heterozygous MEFV gene variants have increasingly been reported in association with a wide range of inflammatory disorders besides FMF. The aim of this study was to evaluate the diagnostic spectrum and clinical and demographic findings of patients carrying heterozygous MEFV variants. This retrospective study included pediatric patients carrying heterozygous MEFV variants who were followed up at our center between January 2012 and January 2025. Diagnosis, demographics, and clinical manifestations were reviewed. A total of 270 patients with a median age of 7 years were identified. The diagnoses of the study population included FMF (67%), IgA vasculitis (7%), PFAPA syndrome (6%), inflammatory bowel disease (3%), juvenile idiopathic arthritis (3%), chronic nonbacterial osteomyelitis (2%), Behçet's disease (1%), and other vasculitides (1%). Fourteen percent of the patients were asymptomatic carriers. During follow-up, 22 of the 74 patients (30%) initially diagnosed with other inflammatory conditions later developed clinical features consistent with FMF. Colchicine therapy was initiated not only for typical attacks of FMF but also for selected indications in other inflammatory diseases. Heterozygous MEFV variants have been reported to be associated with various inflammatory diseases besides FMF. Long-term follow-up is essential, as some patients may later develop FMF. MEFV gene testing should be considered in other inflammatory diseases with severe or atypical manifestations, particularly in populations where FMF is highly prevalent. • Heterozygous MEFV variants have been associated with FMF and several inflammatory diseases. • This large pediatric cohort demonstrates that heterozygous MEFV variants may be encountered across a broad spectrum of inflammatory diseases, and some patients initially diagnosed with other conditions may subsequently develop FMF during follow-up.
2026-07-30 | Diagnosis of fibrillary glomerulonephritis suggests possible atypical familial Mediterranean fever in a patient with ulcerative colitis.
Fibrillary glomerulonephritis (FGN) is a rare glomerular disease that typically presents in middle age, and reports in young adults are uncommon. Herein, we describe the case of a 22-year-old woman with ulcerative colitis who was referred for evaluation of persistent proteinuria and microscopic hematuria. Kidney biopsy showed mild mesangial hypercellularity with increased mesangial matrix on light microscopy. Electron microscopy revealed randomly oriented, nonbranching microfibrils measuring approximately 20 nm in diameter within the mesangial areas. Immunohistochemistry for DnaJ heat shock protein family member B9 (DNAJB9) was positive in the glomeruli, confirming the diagnosis of FGN. Given the unusually young onset, the clinical course, and the presence of intestinal inflammatory lesions, an autoinflammatory disorder, specifically atypical familial Mediterranean fever (FMF), was suspected. Therapy with an angiotensin II receptor blocker was initiated for proteinuria, and colchicine was subsequently added while mesalazine was tapered. After treatment, urinary protein excretion decreased, and endoscopic and histologic bowel inflammation improved. This case highlights three practical points: DNAJB9 immunostaining is useful to establish FGN when classic ultrastructural features are present, FGN can occur in young adults, prompting evaluation for underlying systemic or autoinflammatory conditions, and in patients with intestinal lesions resembling inflammatory bowel disease, consideration of FMF may lead to colchicine therapy that benefits renal and gastrointestinal manifestations.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
goflikicept | proteins | FDA | 2024-10-07 | — | R-Pharm Overseas, Inc. |
canakinumab [ILARIS] | antibodies | FDA | 2013-12-05 | 2016-09-23 | Novartis Pharmaceuticals Corporation |
rilonacept | proteins | FDA | 2013-01-09 | — | Philip J Hashkes, MD, MSc. |
colchicine [Colcrys] | small molecules | FDA | 2007-09-25 | 2009-07-29 | AR Holding Company, Inc. |
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