Co-occurrence of autoimmune diseases and metabolic disorders in familial mediterranean fever patients: review of literature and case reports

Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease predominantly affecting populations from the Mediterranean region, with a high prevalence reported among Armenians, Turks, Arabs, and Jews. The condition results from mutations in the MEFV gene, which encodes pyrin, a key regulator of inflammation. Both genetic and epigenetic factors contribute to the diverse clinical manifestations of FMF, which are characterized by recurrent episodes of fever, abdominal pain, chest pain, arthritis, and erysipelas-like erythema. In addition to these symptoms, individuals with FMF patients appear to have an increased risk of developing autoimmune and metabolic disorders, likely due to shared inflammatory pathways. In fact, FMF exemplifies a monogenic autoinflammatory disorder arising from mutations in genes related to the innate immune system, unlike autoimmune diseases that stem from defects in the adaptive immune system. Despite differences in their underlying mechanisms, both autoinflammatory and autoimmune diseases involve the production of interleukin-1β, a key cytokine that influences effector cells of the adaptive immune system, including B and T lymphocytes. Accordingly, numerous studies have investigated the increased prevalence of autoimmune and metabolic disorders among FMF patients, seeking to understand whether these comorbidities exacerbate FMF symptoms, increase the risk of complications, or affect treatment responses. This review examines the coexistence of FMF with autoimmune diseases and metabolic disorders and explores potential correlations with MEFV mutations.

1 Autoinflammatory vs. autoimmune diseases

Autoinflammatory diseases (AIDs) are clinical disorders that arise from dysregulation of the innate immune system. These conditions are characterized by recurrent or persistent episodes of inflammation, with little to no involvement of the adaptive immune system in disease pathogenesis (1). In fact, AIDs often involve mutations in genes related to cytokines and inflammasomes, protein complexes that activate the innate immune system, and may present with recurrent episodes of fever among other systemic inflammatory symptoms (2). In contrast, autoimmune diseases (ADs) are primarily mediated by autoantibodies or autoreactive B and T cells, leading to chronic inflammation and localized tissue destruction (3). Despite their distinct pathophysiology, AIDs and ADs exhibit overlapping features in their genetic background, inflammatory manifestations, and clinical presentations (3). Both diseases can cause persistent inflammation throughout the body in the absence of an infectious trigger, leading to a range of symptoms such as pain, swelling, fever, and fatigue, ultimately resulting in a chronic condition that necessitates ongoing medical management (3). AIDs comprise a broad and continuously expanding spectrum of disorders (1). Within this spectrum, one category consists of polygenic AIDs, which include complex multifactorial disorders of unknown etiology, with no clearly identified genetic mutations (2). Another category, monogenic autoinflammatory diseases (mAIDs), consists of rare genetic immune disorders arising from mutations in genes linked to innate immune pathways. Among them, inflammasomopathies, or inflammasome-mediated AIDs, are caused by inherited defects in proteins that form inflammasome complexes.

Figure 1 illustrates the spectrum of immune-mediated diseases based on the degree of genetic contribution—ranging from monogenic to polygenic—and the type of immune response involved, from innate to adaptive immunity.

Figure 1

Figure 1. The spectrum of immune-mediated diseases based on the degree of genetic contribution—ranging from monogenic to polygenic—and the type of immune response involved, from innate to adaptive immunity. On the left, monogenic autoinflammatory diseases are primarily driven by innate immune dysregulation. Moving rightward, the spectrum includes polygenic autoinflammatory diseases and disorders with mixed immune mechanisms, reflecting increasing complexity in both genetic and immunological factors. Further along the continuum are monogenic autoimmune diseases, predominantly mediated by adaptive immune responses involving autoantibodies and/or autoreactive B and T cells, with polygenic autoimmune diseases positioned at the far right. Monogenic autoinflammatory diseases are categorized based on their underlying mechanisms, including inflammasomopathies and other IL-1 family-related conditions (red), NF-κB pathway abnormalities and/or excessive TNF activity (green), type I interferonopathies (blue), and other mechanisms (brown). FMF, Familial Mediterranean Fever; CAPS (FCAS, MWS, NOMID), Cryopyrin-Associated Periodic Syndromes (Familial Cold Autoinflammatory Syndrome, Muckle–Wells Syndrome, Neonatal-Onset Multisystem Inflammatory Disease); PAPA, Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne syndrome; CRMO, Chronic Recurrent Multifocal Osteomyelitis (Majeed syndrome); PAAND, Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis; MKD, Mevalonate Kinase Deficiency; TRAPS, TNF Receptor-Associated Periodic Syndrome; Blau syndrome, Granulomatous arthritis/uveitis/dermatitis due to NOD2 mutation; HA20, Haploinsufficiency of A20; RELA haploinsufficiency, NF-κB p65 haploinsufficiency; CRIA, Cleavage-Resistant RIPK1-Induced Autoinflammatory syndrome; PFIT, Periodic Fever, Immunodeficiency, and Thrombocytopenia; Hz/Hc, Hypozincemia/Hypercalprotectinemia; AIEFC, Autoinflammation with Episodic Fever and Colitis; NAIAD, NF-κB Activation Impairment with Dysregulated Cytokine production syndrome; DIRA, Deficiency of the Interleukin-1 Receptor Antagonist; ORAS, Otulipenia/ORAS (OTULIN-Related Autoinflammatory Syndrome); LUBAC deficiency, Linear Ubiquitin Chain Assembly Complex deficiency; DADA2, Deficiency of Adenosine Deaminase 2; DTRA, Deficiency of TNF Receptor Antagonist; Aicardi–Goutières syndrome (AGS), Type I interferonopathy; Monogenic SLE, Monogenic Systemic Lupus Erythematosus; CANDLE, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature; SMS, Singleton–Merten syndrome; SAVI, STING-Associated Vasculopathy with Onset in Infancy; SPENCD, Spondyloenchondrodysplasia with Immune Dysregulation; COPA, COPA syndrome (autoimmune interstitial lung disease/arthritis); VEO-IBD, Very Early Onset Inflammatory Bowel Disease; PLAID, PLCγ2-Associated Antibody Deficiency and Immune Dysregulation; APLAID, Autoinflammation and PLCγ2-Associated Antibody Deficiency; SIFD, Sideroblastic Anemia with Immunodeficiency, Fevers, and Developmental Delay; LACC1 deficiency, Laccase Domain-Containing 1 deficiency; ARPC1B deficiency, Actin-Related Protein 2/3 Complex Subunit 1B deficiency; CDC42 deficiency, Cell Division Control Protein 42 deficiency; IBD (UC, Crohn’s disease), Inflammatory Bowel Disease (Ulcerative Colitis, Crohn’s disease); JIA, Juvenile Idiopathic Arthritis; PFAPA, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis syndrome; SLE, Systemic Lupus Erythematosus; SSc, Systemic Sclerosis; RA, Rheumatoid Arthritis; T1DM, Type 1 Diabetes Mellitus; PBS, Primary Biliary Sclerosis; IPEX, Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome; ALPS, Autoimmune Lymphoproliferative Syndrome; APECED, Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy; ATD, Autoimmune Thyroid Disease; PM, Polymyositis; DM, Dermatomyositis; AAV, ANCA-Associated Vasculitis; Anti-GBM disease, Anti–Glomerular Basement Membrane disease.

2 Familial mediterranean fever

2.1 History and prevalence

Familial Mediterranean Fever (FMF) is the most recognized and prevalent AID worldwide (4). It was first described in 1945 by allergist Siegal (5). Initially identified as ‘benign paroxysmal peritonitis,’ it was later referred to as periodic peritonitis, familial recurrent polyserositis, and periodic disease. The modern universally accepted name, ‘Familial Mediterranean Fever,’ was coined by Heller in 1958 (6). While populations from the Eastern Mediterranean, including Turks, Jews, Arabs, and Armenians, are particularly susceptible to FMF, numerous cases have been documented in Europe, North America, and Japan due to migration from endemic regions (7). The prevalence of FMF ranges from 1 in 500 to 1 in 1,000 in endemic regions, with Central Anatolia reporting the highest recorded prevalence of 1 in 395 (8).

2.2 Genetics and pathophysiology

FMF is an autosomal recessive disease caused by mutations in the MEFV (MEditerranean FeVer) gene, which is located on the short arm of chromosome 16 (16p13.3). The gene consists of 10 exons, with over 404 variants recorded to date (9). The majority of the variants classified as pathogenic or likely pathogenic are found in exon 10. The most prevalent variants in FMF-endemic regions are the M694V, M694I, V726A, and M680I, located in exon 10, along with the E148Q variant in exon 2, collectively accounting for 85% of cases (8, 10). Genotype-phenotype correlation studies indicate that M694V mutation is associated with the most severe phenotype of the disease while the clinical significance of E148Q — whether as a pathogenic variant with low penetrance or a benign polymorphism — remains under investigation (11).

The MEFV gene encodes a 781 amino acid protein called pyrin, also known as marenostrin, which is mainly expressed in granulocytes, eosinophils, monocytes, and dendritic cells. Pyrin consists of five domains: the N-terminal Pyrin domain (PYD), bZIP transcription factor domain, B-box zinc finger, α-helix coiled-coil domain, and the C-terminal B30.2/SPRY domain (12). MEFV mutations, predominantly clustered in the B30.2 domain, activate pyrin which associates with pro-caspase-1 and apoptosis-associated speck-like protein (ASC) to form a multiprotein complex known as inflammasome. The assembly of the pyrin inflammasome leads to the autocatalytic activation of caspase-1, which subsequently converts pro-interleukin-1beta (IL-1β) and pro-IL-18 into their active forms, IL-1β and IL-18. Caspase-1 also mediates pyroptosis through the gasdermin D pathway leading to the formation of membrane pores and the release of pro-inflammatory cytokines, thereby amplifying ongoing subclinical inflammation (12, 13).

2.3 Clinical manifestations

FMF typically manifests before the age of 20, with the majority of cases reported during childhood (4). A less common adult-onset presentation of FMF is reported in some patients, who tend to have milder clinical manifestations (14). FMF is characterized by recurrent bouts of fever and inflammation, frequently affecting the joints and serosal membranes. In fact, increased IL-1β production results in subclinical inflammation persisting between attacks in patients with FMF (15, 16). The frequency of episodes varies among individuals, occurring as often as once a week or as infrequently as every few months. Several factors were reported to trigger FMF attacks, including, stressful situations, exposure to cold, and hormonal changes in women during menstrual cycles (17). Nearly half of patients with FMF experience a prodrome, which precedes the attacks and is marked by discomfort, malaise, and occasional neurological symptoms such as headaches (17).

During an attack, fever typically lasts 12 to 72 hours and reaches temperatures of 38 °C to 40 °C. One of the most common symptoms of FMF is intense joint pain, with monoarthritis being the most frequent manifestation (4). Although arthritis usually resolves within 24 to 48 hours, it can occasionally cause severe joint damage (4). Abdominal pain is another common symptom, often severe enough to mimic an acute abdomen. It may be associated with diarrhea or constipation due to sterile peritoneal inflammation (18). Furthermore, pericardial and pleural inflammation may result in dyspnea, pleural effusion, and chest pain (19). Although rare, pericarditis occurs more frequently in patients with FMF than in the general population (4). Other reported FMF manifestations include erysipelas-like erythema, recurrent oral ulceration, myalgia, and orchitis (17, 20). Finally, the most serious complication of untreated or improperly managed FMF is amyloidosis, characterized by the buildup of amyloid proteins in organs, including the kidneys, resulting in renal failure (21). In this regard, monitoring and controlling inflammation are crucial to avoid long-term consequences (21). The clinical presentation of FMF varies significantly among patients. In addition to MEFV allelic heterogeneity, modifying genes such as IL-1β (22) and SAA1 (Serum Amyloid A1) (23), as well as environmental factors, contribute to the variable expressivity of the disease through epigenetic mechanisms, primarily DNA methylation and microRNAs (miRNAs) (24). Nonetheless, few characteristic traits remain usually evident, aiding in diagnosis and treatment.

2.4 Treatment

Colchicine, extracted from the plant Colchicum autumnale, is the oldest known medication still used today to treat patients with FMF (25). It is effective in reducing the frequency and severity of attacks and in preventing the development of amyloidosis. Although its capacity to bind microtubules and prevent mitosis was first established, current studies support the existence of additional mechanisms of action of colchicine in FMF treatment. Indeed, studies have shown that colchicine impairs neutrophil chemotaxis, lowers leukocyte function, and attenuates inflammation through suppression of pyrin and NLRP3 inflammasomes (26). Colchicine is generally safe, but it has a limited therapeutic index and is associated with gastrointestinal symptoms such as cramps, diarrhea, and vomiting, all of which are common adverse effects (27). Notably, 5-10% of patients exhibit partial or no response to colchicine treatment (28). Classified as colchicine-resistant, this category of patients can benefit from alternative treatments including the administration of IL-1β inhibitors, namely, anakinra (an IL-1 receptor antagonist) and canakinumab (a human monoclonal anti-IL-1β antibody) (29).

3 Comorbidities in FMF

The presence of comorbidities in FMF may contribute to the heterogeneity of clinical manifestations, influence disease severity, and affect patients’ responses to treatment (30). This may explain why some individuals require specialized management and face therapeutic challenges. Supporting this, a large cross-sectional study of 686 pediatric FMF patients reported that around one-fifth of the patients had coexisting inflammatory conditions—such as juvenile idiopathic arthritis, asthma, Henoch–Schönlein purpura, uveitis, and inflammatory bowel disease— highlighting the frequent overlap between FMF and other immune-mediated disorders (31). Therefore, to improve the quality of life and long-term health outcomes for FMF patients, researchers aim to unravel the complex interactions between FMF and coexisting comorbidities, with the goal of developing more targeted therapeutic strategies.

Consequently, the objective of this review is to comprehensively examine the relationship between FMF and its co-occurring disorders—specifically, autoimmune and metabolic diseases — focusing on MEFV variants, underlying shared pathogenic mechanisms, and clinical presentation. To achieve this aim, a thorough literature search was conducted using databases such as PubMed, Google Scholar, Scopus, and Medline. Relevant studies published in English within the last 10–15 years were identified using the following keywords: “Familial Mediterranean Fever”, “FMF”, “MEFV”, “autoimmune diseases/disorders”, “metabolic diseases/disorders”, “Inflammatory Bowel Disease”, “IBD”, “Systemic Lupus Erythematosus”, “SLE”, “Multiple Sclerosis”, “MS”, “Rheumatoid Arthritis”, “RA”, “Sjögren’s Syndrome”, “SS”, “Celiac Disease”, “CD”, “Hashimoto’s Thyroiditis”, “HT”, “Type 1 Diabetes”, “T1D”, “Metabolic Syndrome”, “MetS”, “Non-Alcoholic Fatty Liver Disease”, and “NAFLD”. Studies assessed included original research articles, review articles, case reports, and letters to the editor. After initial screening of titles and abstracts, full texts were reviewed to confirm relevance. Data on study design, population characteristics, and key findings were extracted, synthesized, and interpreted, and existing gaps were identified to help guide future research directions.

3.1 FMF and autoimmune diseases

3.1.1 FMF and inflammatory bowel disease

Inflammatory bowel disease (IBD) is a complex immune-mediated disease characterized by chronic inflammation, damage to the epithelium of the gastrointestinal tract, abnormalities in innate immune responses, and dysregulation of the adaptive immune system (32). Typically, IBD arises in early childhood and adulthood and manifests in three forms: Crohn’s disease (CD), ulcerative colitis (UC), and inflammatory bowel disease unclassified (IBDU), previously referred to as indeterminate colitis (IC) (32).

FMF and IBD share several clinical and pathogenic features, which have been extensively explored in the literature. First, both conditions are associated with inflammasome pathway dysregulation, though through different mechanisms. While FMF is associated with mutations in the MEFV gene and the activation of the pyrin inflammasome, IBD is a more complex disorder linked to mutations in NLRP3, which encodes the cryopyrin protein involved in inflammasome-mediated IL-1β processing (33). Interestingly, wild type pyrin was found to negatively modulate the NLRP3 inflammasome by interacting with several components of the inflammasome, mainly ASC, to inhibit pro-IL-1β processing (34, 35). Beyond its role in inflammasome regulation, pyrin also contributes to autophagy by facilitating the degradation of inflammasome components such as NLRP3 and pro-caspase 1. Dysfunction in this autophagic process has been strongly linked to the development of IBD (36, 37). Furthermore, the caspase activation recruitment domain family member 15 (CARD15) gene, which encodes the nucleotide-binding oligomerization domain-containing protein 2 (NOD2), plays a key role in cellular protection against invasive bacteria via the activation of the NF-kB (nuclear factor-kappa B) pathway. In CD, NOD2 acts as a susceptibility gene; abnormal responses to bacterial components can disrupt innate immune signaling, resulting in persistent intestinal inflammation (38, 39). Remarkably, pyrin also regulates neutrophil activity through its CARD domain, supporting the idea that pyrin and the NOD2/CARD15 gene product belong to the same death domain superfamily involved in cytokine processing and inflammatory signaling (39). These genetic and molecular parallels have encouraged researchers to explore the connection between FMF and IBD, particularly the role of MEFV mutations in IBD pathogenesis.

A recent large-scale, population-based study from Israel using the epi-IIRN cohort and covering 98% of the national population showed a significantly higher prevalence of FMF among patients with IBD compared to matched non-IBD controls (40). Specifically, FMF was more common in CD patients (0.6%) than in those with UC (0.3%). Notably, in 83% of cases, FMF was diagnosed prior to IBD onset. The study also found that FMF was associated with increased disease severity at diagnosis in UC but not in CD. UC patients with FMF also required biologic therapy earlier, whereas disease outcomes in CD appeared unaffected by FMF status (40).

Studies on MEFV variants in IBD have yielded variable results. Some have reported that MEFV gene mutations are more frequent in IBD patients compared to control groups, though these findings lack consistency (41, 42). For example, Yurtcu et al. (2009) compared 47 Turkish IBD patients with 25 controls and found MEFV mutation frequencies of 19.1% in IBD patients versus 12% in controls, implying that MEFV variants may not play a significant role in IBD susceptibility (39). Similarly, Karban et al. (2005) reported that MEFV mutations are not considered major risk factors for CD (38). Additionally, no significant differences in MEFV mutation prevalence were observed among CD patients with varying NOD2/CARD15 genotypes, and no clinical differences were reported between carriers and noncarriers of MEFV mutations (38). Nevertheless, specific MEFV variants have been implicated in IBD pathogenesis. One notable variant, E148Q, has been associated with perianal disease, commonly found in CD patients. In fact, it was shown that 21.2% of CD patients with perianal disease were E148Q carriers, compared to only 6.7% of those without perianal disease, suggesting a potential role for E148Q in CD pathogenesis independent of NOD2/CARD15 mutations (38). Another significant MEFV variant reported in the literature is the M694V variant. While a recent study identified E148Q as the most common variants among patients with UC and CD, and M694V as the most prevalent among patients with IC (43), other numerous studies seem to agree that M694V variant is the most frequent mutation among IBD patients (44–46). For instance, the screening of FMF-associated MEFV variants in Turkish children with IBD revealed that 70% of patients with coexisting FMF and IBD carried the M694V mutation, making it the most common mutation in this group (46). Similarly, another study showed that, among 53 Turkish children suffering from IBD, FMF was diagnosed in 14 patients, predominately carrying the homozygous M694V mutation (45). Notably, FMF was more prevalent in UC patients (78.6%) than in CD patients (21.4%) (45). The same group of researchers found that MEFV gene variants were present in all 12 IBD patients studied, with variant frequencies of 41.7% for M694V, 25% for M680I, 25% for K695R, and 8.3% for E148Q (44). This was the first study to establish an association between the K695R mutation and IBD (44). Comparable findings have been reported by other researchers from Turkey and Armenia (47, 48).

The impact of MEFV variants on IBD severity remains controversial. Some studies suggest that FMF-associated MEFV mutations are linked to a more aggressive IBD phenotype, while others refute this association. For instance, Sahin et al. (2021) reported that UC patients carrying M694V or E148Q variants required surgery more frequently and experienced more severe disease than CD patients (49). However, these findings may be biased, as CD patients in the study had less severe inflammatory profiles, did not require surgery, and mostly lacked MEFV mutations (49). Similar observations have been reported in studies and case reports from Israel (40), Armenia (48), and Turkey (50). These reports highlight that IBD patients with concomitant FMF tend to experience a more severe disease course, and their symptoms often persist despite standard IBD treatments. Notably, treatment with colchicine has been shown to induce remission of both conditions, underscoring the importance of early screening for MEFV variants to facilitate appropriate disease management (48, 50). Conversely, other studies from Turkey and Israel suggest that disease activity indices are independent of MEFV mutations (43, 51, 52). Nonetheless, these studies report that extraintestinal manifestations, including arthritis, arthralgia, edema, myalgia, sacroiliitis, and pyoderma gangrenosum, were more frequent in individuals with MEFV mutations (43, 51, 52). Furthermore, some manifestations, like amyloidosis, may worsen as a result of the synergistic relationship between FMF and IBD (52). Even such findings remain debated, with certain Turkish studies failing to establish a clear association between MEFV mutations and these manifestations (39, 49).

In summary, studies investigating the association between FMF and IBD suggest that M694V and E148Q are the most common MEFV variants in IBD patients. However, whether these variants significantly influence IBD severity and extraintestinal manifestations remains controversial. Due to the inconsistent findings, large, multiethnic studies are needed to better understand the role of MEFV mutations in IBD pathogenesis and clinical outcomes.

3.1.2 FMF and systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by the production of autoantibodies directed against multiple organ systems, including the skin, kidneys, joints, and central nervous system (CNS), leading to tissue damage (53). Although its pathogenesis is not yet fully elucidated, SLE is thought to arise from a complex interplay of genetic predisposition, environmental triggers, hormonal influences, and immunological mechanisms (54). The main features of SLE include polyserositis which manifests as pericarditis, pleuritis, and peritonitis, dysregulation of both the innate and adaptive immune systems, and the generation of abnormal autoantibodies such as anti-double-stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-ribonucleoprotein (anti-RNP), anti-Sjögren’s syndrome antigen A (anti-Ro/SSA), anti-Sjögren’s syndrome antigen B (anti-La/SSB), and anti-phospholipid antibodies (55, 56). These autoantibodies lead to the formation of immune complexes that deposit in tissues. These deposits activate the immune system, triggering the recruitment of monocytes and macrophages and leading to the production of pro-inflammatory cytokines such as TNF (tumor necrosis factor), IL-1, IL-6, and IL-18. Additionally, type I interferons and immunoregulatory cytokines like IL-10 and B-cell activating factor (BAFF) — a member of the TNF family — are involved (57). These cytokines promote B-cell activation and sustained autoantibody production, thereby perpetuating the autoimmune response and contributing to ongoing tissue damage (57).

SLE shares numerous overlapping symptoms with FMF, including fever, fatigue, arthritis, pericarditis, pleuritis, peritonitis, rash, and both musculoskeletal and renal involvement (58, 59). Case studies of patients with both SLE and FMF have shown that fever, abdominal pain, and joint pain are the most frequent FMF symptoms, and these are often successfully managed with colchicine treatment (60–65).

Given the shared clinical features and the involvement of inflammasomes and inflammatory pathways in both diseases, researchers have explored the potential link between FMF and SLE. For instance, a study conducted in South Asia found that SLE patients had a higher prevalence of FMF compared to the non-SLE control group (1.29% vs. 0.79%) (66). Similarly, an Israeli cohort study reported a 0.68% prevalence of FMF among SLE patients, compared to only 0.21% in individuals without SLE (67). However, conflicting findings have emerged from studies in Turkey and Israel, where the frequency of MEFV variants in SLE patients was reported to be similar to or even lower than that in healthy controls (58, 68, 69). Additionally, in the study by Ozen and Bakkaloglu (2005), many of the FMF patients included had other inflammatory diseases, but none had SLE. To explain these findings, several researchers from Turkey and Israel proposed a notable concept: a “protective” association between FMF and SLE, suggesting that the presence of FMF-related mutations might actually confer some resistance to developing SLE (70, 71). This association may be attributed to the lack of anti-serum amyloid P (SAP) antibodies. SAP is a protein that belongs to the pentraxin family and is involved in removing nuclear ligands from necrotic and apoptotic cells (72). It has been demonstrated recently that elevated levels of anti-SAP antibodies are linked to active SLE; nevertheless they are not detected in patients with FMF or in patients who have both SLE and FMF (73). Therefore, it is hypothesized that the lack of anti-SAP antibodies in patients with FMF and SLE allows SAP to function normally, leading to a quicker clearance of chromatin and other apoptotic products, thereby promoting a milder SLE phenotype (70). Another molecule that may contribute to this protective association is C-reactive protein (CRP), a member of the pentraxin family and a commonly measured acute phase reactant (71). These molecules are known to bind accessible small nuclear ribonucleoprotein (snRNP) particles and play a significant role in the clearance of apoptotic debris (71). While research suggests that decreased basal CRP expression contributes to the development of SLE (74), CRP concentrations are elevated in FMF patients (71). Therefore, both SAP and CRP may exert protective effects against SLE susceptibility in individuals with FMF.

To investigate the role of MEFV variants in organ involvement among SLE patients, Shinar et al. (2012) compared the clinical phenotypes of SLE patients with and without MEFV mutations. Their findings suggested that the presence of an MEFV variant may influence the SLE phenotype, with carriers displaying a higher prevalence of inflammatory manifestations but a reduced risk of developing renal disease, potentially due to the protective effects of CRP and SAP. This distinction underscores the difference between autoinflammation, which underlies FMF, and autoimmunity, which plays a central role in the development of SLE nephritis (58).

Regarding FMF attacks in SLE patients, studies have found that they tend to be milder, shorter in duration, and associated with lower fever spikes compared to FMF patients without SLE (75, 76). However, in terms of frequency, controversial findings were noted, with some reports indicating a higher FMF attacks prevalence in SLE patients, while others stating that FMF attacks in SLE patients are less common than FMF patients without SLE (75, 76).

In conclusion, although a few studies indicate a higher prevalence of MEFV mutations among SLE patients, FMF may confer a protective effect against SLE via mechanisms involving CRP and SAP, which could account for the milder SLE symptoms observed in patients with both conditions. This hypothesis warrants further investigation.

3.1.3 FMF and multiple sclerosis

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease, affecting the CNS. It is characterized by episodes of neurological impairment that can be fully or partially reversible, typically lasting from a few days to several weeks (77). The most common clinical manifestations include ataxia resulting from cerebellar lesions, diplopia caused by brainstem involvement, limb weakness or sensory deficits due to transverse myelitis, and monocular visual loss associated with optic neuritis (77). Many affected individuals experience a progressive clinical course after approximately 10–20 years, ultimately leading to cognitive and mobility impairments (77). A central element in MS pathophysiology is the immune system, involving both innate and adaptive responses. Notably, the disease heavily depends on the adaptive immune system, primarily involving T cells and B cells (78). Furthermore, several genetic factors, particularly within the Human Leukocyte Antigen (HLA) class II region, are associated with an increased risk of developing MS, although no single gene has been identified as the definitive cause (79). Additionally, environmental factors such as viral infections, vitamin D deficiency, and alterations in gut microbiota may interact with genetic predispositions, contributing to the development of MS (80–82). Interestingly, both FMF and MS share common underlying mechanisms, including dysregulation of the innate immune system and a genetic predisposition. Specifically, HLA-related polymorphisms—well-known risk factors for MS—have also been linked to an increased risk of FMF and are considered potential modifier genes for these conditions (83). In fact, numerous case studies have reported the co-occurrence of FMF and MS symptoms, which has sparked further interest in exploring the potential connection between these two diseases (84–91).

At the molecular level, the frequency of MEFV variants was found to be higher in MS patients compared to healthy individuals. Several studies conducted in Turkey have identified the M694V mutation as the most common among MS patients relative to controls (86, 92–94). Similar findings have been reported in Israeli and northern European Caucasian MS populations, where the presence of MEFV variants, particularly M694V and E148Q, suggests that these mutations may act as potential modifier genes or risk factors for MS (95, 96). Moreover, research on pediatric MS patients indicated that 37.9% carried at least one heterozygous mutation in the TNFRSF1A gene, associated with TNF receptor-associated periodic fever syndrome, TRAPS, and/or MEFV gene. This rate was significantly higher than that observed in adult MS patients, suggesting a potential role in the pathogenesis of MS during childhood (97). However, such as finding was not observed in other studies from Turkey, which reported no significant difference in MEFV mutation frequencies between MS patients and healthy controls (98, 99).

Several theories have been proposed to elucidate the relationship between FMF and MS. The prevailing hypothesis suggests that mutations in the MEFV gene along with the production of proinflammatory cytokines, such as IL-1, IFN-γ, and TNF-α, may overwhelm monocytes, impairing their ability to suppress the inflammatory response. This could result in increased secretion of oligotoxic and neurotoxic compounds and in decreased activity of microglial cells in MS lesions (58, 99, 100). However, in the study by Elhani et al. (2021), patients receiving colchicine exhibited higher MS incidences in the absence of peripheral inflammation, which challenges the prevailing theory proposing that the link between FMF and MS is mainly driven by inflammation (98). An alternative hypothesis proposes a potential role of non-inflammatory factors in FMF patients presenting with MS. In fact, rather than being solely driven by inflammation, demyelination in MS is thought to occur prior to T cell infiltration into tissues (101). Consequently, it is suggested that additional mechanisms, such as endothelial dysfunction and vasculitis in FMF, may contribute to disruption of the blood brain barrier, thereby initiating MS lesion formation (101). Furthermore, the elevated body temperature experienced during FMF attacks might impair the function of myelin and mitochondrial proteins, potentially promoting disease progression (101).

The influence of MEFV mutations on MS disease progression has been investigated in many studies yielding inconsistent results. Shinar et al. (2003) reported similar frequencies of MEFV mutations among primary progressive (PP) and relapsing–remitting (RR) MS patients within European Jewish (Ashkenazi), Iraqi Jewish, and North-African Jewish populations. These patients also experienced increased disability, higher relapse rate, and lower attack rate. However, the researchers found that these disease progression characteristics varied between different ethnicities. For example, Iraqi and Jewish M694V carriers demonstrated rapid disease deterioration as opposed to Ashkenazi carriers that showed no significant variation (102). In fact, gene variants, namely, delta 32 CCR5, prevalent among Ashkenazi Jews, may inhibit the expression of MEFV mutations, accounting for a milder MS course (103). Moreover, in the Ashkenazi group, the consensus HLA type II haplotype for individuals with MS, DRB1*1501, DQA1*0102, and DQB1*0602, is more common than in the Iraqi Jewish cohort, further increasing the genetic heterogeneity between the two cohorts and potentially affecting the rate of MS progression (102, 104). In accordance with Shinar et al.’s (2003) findings, Unal and colleagues found that the annual relapse rate was slightly higher among RR MS patients carrying MEFV mutations as compared to non-carrier RR MS patients, suggesting that MEFV mutations may confer a more progressive disease course. Nevertheless, these findings were contradicted by recent studies showing that MS patients with MEFV mutations had similar disease course, clinical features, severity, response to therapy, and progression to patients with no MEFV mutations (95, 96, 99). The only exception was observed in patients with K695R mutations who exhibited a more severe disease course with higher progression rates, leading to brain atrophy and cognitive deficits in some severe cases (95). Besides K695R mutation carriers, another study reported that patients homozygous for M694V mutation experienced a more progressive MS course (96).

To summarize, the relationship between MS and FMF appears to be mediated by both inflammatory and non-inflammatory mechanisms, with different MEFV variants exerting distinct effects on MS disease progression. While some mutations may exacerbate MS severity, the overall impact remains inconsistent across studies, highlighting the need for further research to elucidate the precise role of MEFV variations in MS pathogenesis and progression.

3.1.4 FMF and rheumatoid arthritis

Arthritis can be defined as an acute or persistent inflammation of the joints (105). Several symptoms, including pain, stiffness, reduced range of motion, and joint abnormalities, can be attributed to this disease (105). Arthritis can exist in various forms; the most prevalent type is osteoarthritis, known as degenerative non-inflammatory arthritis (105). However, inflammation-related arthritis is also common and can arise from various causes, including autoimmune conditions such as rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis; infectious etiologies like septic arthritis and Lyme’s arthritis; and crystal deposition diseases such as gout, pseudogout, and basic calcium phosphate disease (105).

Several key factors contribute to the pathogenesis of RA. They include environmental factors (such as infections, smoking, and obesity), genetic predispositions (notably HLA alleles like HLA-DRB1 and HLA-DR4), and autoimmune responses (106, 107). The autoimmune nature of RA results in the overactivity of both T and B cells in affected patients. This process involves cytokine release, such as IL-12 and IL-18, and intercellular communication that activates T cells near macrophages, thereby amplifying B-cell cytokine production even in the absence of direct cell contact (108).

The MEFV gene is located within a susceptibility region for RA on chromosome 16p13-q12.2, prompting researchers to explore the potential relationship between FMF and RA (109). Indeed, several case studies have reported the co-occurrence of FMF and RA (110–114). For example, in Turkey, Israel, and Japan the frequency of MEFV variants in RA patients was shown to be comparable to that in the general population, with E148Q being the most prevalent variant in RA patients (115–118). On the other hand, an Israeli study involving 98 RA patients and 100 healthy controls found that carriers of MEFV mutations tend to have a later disease onset, suggesting that these variants may have a minimal or potentially protective role in predisposing individuals to RA (118). Similar findings were reported in Turkish and Japanese cohorts (115–117): in the Japanese research, no significant association was noted between MEFV variants and either RA onset or RA-related amyloidosis (117). Similarly, studies conducted by Inanir et al. (2013) and Koca et al. (2010) in Turkey identified only a statistically significant difference in the number of deformed joints among patients, but these findings were insufficient to conclusively determine whether RA patients with MEFV variants experience more severe clinical outcomes (115, 116). Interestingly, a recent Moroccan study revealed contrasting results, showing a higher MEFV mutation rate of 24% in RA patients compared to 2% in the control group (119). These findings align with those reported by Kalyoncu and colleagues, who demonstrated that the incidence of RA is significantly higher in asymptomatic variant carrier parents of FMF patients compared to healthy subjects (120).

Regardless of whether MEFV variants are considered predisposing factors for the development of RA, evidence suggests that they may influence disease severity (116, 118–120). For example, compared to healthy subjects, asymptomatic RA patients carrying MEFV mutations have been observed to experience a minimum of four febrile episodes per year, along with increased incidences of arthralgia, acute rheumatic fever, and more severe RA symptoms (120). This might be attributed to the elevated baseline levels of inflammation in patients carrying MEFV variants, which potentially increases their susceptibility to complications (120–122).

In an attempt to understand how MEFV mutations affect RA severity, several theories emerged. On one hand, some authors attributed this association to the formerly reported relationship between some HLA-DR/DQ alleles that are directly linked to RA severity and MEFV variants in FMF patients (123, 124). Notably, the HLA-DR4 allele was found at a higher frequency in FMF patients compared to their family members and healthy controls. Additionally, specific mutations such as M694V were associated with HLA DR3, HLA DR11/5, HLA DR 13/6, HLA DQ6/1, HLA DQ7/3, and HLA DQ8/3 alleles; M680I with HLA DR7 and HLA DQ2 alleles; and V726A HLA DQ6/1 (123). On the other hand, other researchers relate this association to the role of the MEFV gene in the deregulated inflammatory process of RA. Particularly, the increased IL-1β production in MEFV carriers may contribute to the severity of RA symptoms in these patients (118, 119).

In conclusion, MEFV mutations appear to influence the severity and progression of RA rather than being directly involved in the development of the disease in individuals.

3.1.5 FMF and Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease, characterized by the infiltration of inflammatory CD4⁺ T cells and cytokines into exocrine glands, including salivary and lacrimal glands, leading to neurological symptoms, joint discomfort, fever, and dry eyes and mouth, termed the sicca syndrome (125). Particularly in its early phase, SS may affect other organs and systems, resulting in a variety of clinical manifestations, namely, exocrine glandular and extra-glandular presentations (126). SS can either appear as a primary disease that is unrelated to other illnesses or secondary to other inflammatory diseases such as SLE, RA, systemic sclerosis, polymyositis, and FMF (126). The coexistence of SS and FMF is of particular interest because both diseases were reported to be together associated with other diseases including hepatitis, ankylosing spondylitis, and mixed connective tissue disease (125, 127, 128).

Previous case studies have documented patients diagnosed with both FMF and SS. The first reported case was a 42-year-old man who had a 20-year history of FMF and complained of dry mouth and eyes, which was later associated with SS (129). Analysis of his genetic profile revealed a compound heterozygosity for the M694V mutation (129). However, the authors suggested that this association is likely coincidental and does not necessarily indicate a true relationship between SS and FMF; therefore, further studies are needed to better elucidate the nature of this potential link (129). Similarly, another case study described a 42-year-old Japanese woman suffering from SS (130). Due to her recurrent attacks and homozygosity for the M694I mutation, she was diagnosed with FMF and immediately started colchicine treatment (130). Her previously elevated IL-18 levels were efficiently reduced upon colchicine administration, suggesting that the FMF-related dysregulated IL-18 production and chronic inflammation may be attributed to the occurrence of SS (130).

In conclusion, the coexistence of FMF and SS appears to be rare and underreported, and its underlying mechanisms remain poorly understood, warranting further research.

3.1.6 FMF and celiac disease

Celiac disease (CD) is a life-long gluten-sensitive autoimmune disease of the small intestine affecting genetically susceptible individuals worldwide (131). The disease is characterized by gastrointestinal-related symptoms such as diarrhea, steatorrhea, and weight loss due to malabsorption (131). The variable clinical picture of CD is attributed to genetic and immunological factors, with the age of onset, extent of mucosal injury, dietary habits, and gender influencing the clinical presentation of the disease (131). CD diagnosis is based on the presence of a predisposing genetic factor, HLA DQ2/8, along with positive biopsy and serological antibodies upon the consumption of a gluten-containing diet (131). CD is triggered by the ingestion of gliadin and other related prolamins. Gliadin, a major component of gluten, is a 30 kDa alcohol-soluble protein rich in glutamine and proline and resistant to gastrointestinal enzymes (132). Upon ingestion, gliadin peptides are transported from the lumen of the gut to the lamina propria of the small intestine where tissue transglutaminase 2 catalyzes their deamidation, converting glutamine residues to negatively charged glutamic acid (132). Subsequently, modified gliadin peptides are recognized by antigen-presenting cells (APC) and presented on their surface in association with HLA-DQ2 or HLA-DQ8 which, unlike other HLA-DQ molecules, have a high binding affinity to the deaminated form of gliadin (132, 133). In fact, patients homozygous for HLA-DQ2/8 are more susceptible to develop CD than their heterozygous counterparts (134). Following gliadin-HLA complex presentation, CD4+ T cells recognize this complex leading to T cell activation, inflammatory response stimulation, and cytokine release, all of which cause intestinal mucosa damage and villous atrophy (133).

CD and FMF share a common inflammatory etiology, prompting several case studies to investigate their co-existence (135–137). However, diagnosing CD in FMF patients (or vice versa) is challenging due to their overlapping clinical features such as abdominal pain and diarrhea (138). Although the exact nature of the association remains unclear, it is believed that the amplified ongoing inflammation in FMF activates intestinal mucosal immune cells, leading to intestinal lesions and contributing to CD pathogenesis (139, 140).

The prevalence of CD was evaluated in two separate studies involving children with FMF and children with CD. In the first study, 50 FMF children were tested for anti-gliadin antibodies (AGA) (IgA/IgG) and anti-endomysium antibodies (EMA) (IgA/IgG), while 17 children with CD were assessed for MEFV variants, clinical features, and laboratory findings (141). None of the FMF patients were diagnosed with CD and none of the CD children showed consistent FMF clinical manifestations despite three CD children being heterozygous for the E148Q and one child heterozygous for M680I (141). The researchers concluded that MEFV variants were similarly prevalent in CD patients and the general population, indicating no association between CD and FMF (141). In a second study, Işikay et al. (2015) evaluated 112 FMF patients and 32 healthy controls by measuring serum tissue transglutaminase IgA (tTG IgA). Four participants—three FMF patients and one control—had positive tTG IgA levels and underwent gastroscopy, which confirmed CD diagnosis. HLA typing revealed HLA-DQ8 positivity in one FMF patient and HLA-DQ2 positivity in the other three confirmed CD cases, further suggesting no significant link between CD and FMF (142). However, both studies faced limitations, including small sample sizes and the absence of the ESPGHAN (European Society for Paediatric Gastroenterology Hepatology and Nutrition) criteria for accurate CD diagnosis. To address these issues, Sahin et al. (2017) conducted a larger longitudinal study from October 2015 to March 2016, involving 303 FMF children, using ESPGHAN criteria for diagnosis. Among them, nine tested positive for tTG IgA, but only one exhibited high EMA IgA levels. Gastro-duodenoscopy in these patients showed no evidence of CD, leading the researchers to conclude that CD is not prevalent among children with FMF and that there is no significant association between the two conditions (138). Overall, these studies suggest that CD is unlikely to be a common complication in pediatric FMF.

In summary, existing research does not support a strong clinical relationship between CD and FMF. The main limitations of previous studies include small sample sizes and inconsistent application of diagnostic criteria. Future research should aim for larger, more standardized investigations to explore potential genetic or inflammatory links that may exist between CD and FMF.

3.1.7 FMF and psoriasis

Psoriasis is an autoimmune disease characterized by immune cell infiltration into the dermis, epidermal hyperplasia, and a complex pathogenesis involving interactions between immune cells, keratinocytes, and other skin-resident cells (143). Over the past two decades, research has identified immune cells as the primary drivers of psoriasis, with keratinocytes acting as mediators of immune dysregulation in the disease process. The IL-23/IL-17 pathogenic axis plays a central role in psoriasis pathogenesis (143). Once T helper 1(Th1) and Th17 cells are activated, plasmacytoid dendritic cells stimulate the maturation of myeloid dendritic cells, leading to the production of inflammatory cytokines such as TNF-α, IL-12, and IL-23, which are crucial in orchestrating the skin’s immune response (143). Particularly, TNF-α, IL-17, IL-21, and IL-22 stimulate keratinocytes, which in turn amplify inflammation. Among these, IL-17 is particularly significant for its role in promoting the production of antimicrobial peptides, cytokines, and chemokines by keratinocytes (143). This keratinocyte activation creates a feedback loop that sustains chronic inflammation, leading to hallmark features of psoriasis, such as epidermal thickening and plaque formation.

Both FMF and psoriasis exhibit cutaneous manifestations and share underlying pathogenic features, such as dysregulated proinflammatory cytokine release and amplified systemic inflammation. The frequency of psoriasis among patients with FMF has been assessed in a cohort of 351 FMF patients (177 adults and 174 children) (144). Interestingly, among the 351 patients, psoriasis was identified in 13 FMF patients, consisting of 11 adults and 2 children. Moreover, 12.4% of adult FMF patients and 5.2% of juvenile patients had psoriasis (144). Therefore, researchers concluded that psoriasis may be occurring at a higher rate in FMF patients as compared to the general population, with adult patients being at greater risk than juvenile patients since the onset of psoriasis typically peaks around age 20, with a second peak observed between ages 50 and 60 (144, 145). The increased prevalence of psoriasis in FMF patients is thought to be linked to the elevated levels of active IL-1, which promotes Th17 cell activation and stimulates keratinocytes, contributing to psoriatic pathology (144). Supporting this, Ashida et al. (2016) reported an abundance of Th17 cells in the upper dermis of psoriasis-like lesions in a patient with FMF (146). Similarly, the occurrence of psoriasis among FMF patients has been examined by Barut et al. (2014) in a group of 202 FMF patients. In accordance with Erden et al. (2018) findings, psoriasis was observed in 41 patients, accounting for 20.3% of the cohort (147). Given these findings, it is important for clinicians to thoroughly evaluate psoriasis lesions and inquire about family history in FMF patients. However, further research, particularly prospective multicenter studies, is necessary to better understand the incidence and underlying mechanisms of psoriasis in the FMF population (144).

3.1.8 FMF and Hashimoto’s thyroiditis

Hashimoto’s thyroiditis (HT) is an autoimmune thyroid disease characterized by the destruction of thyroid cells through both cell- and antibody-mediated immune mechanisms (148). It has been proposed that shared inflammatory pathways, particularly cytokine dysregulation in FMF, may provoke autoimmune responses and predispose to thyroid autoimmunity. Case reports support this possible link; for instance, Gulcan et al. (2009) described a 21-year-old woman with coexisting FMF and HT, suggesting that cytokine expression in FMF may act as a trigger for thyroid autoimmunity (149, 150). Similarly, a case of a 10-year-old girl with FMF carrying a heterozygous E148Q MEFV mutation who later developed HT has been reported. Her thyroiditis was confirmed by high anti-thyroid antibody titers and ultrasound results, and treatment with levothyroxine led to resolution of symptoms, further supporting a potential association between FMF and autoimmune thyroid disease (149). Moreover, Dikbas et al. (2013) found that, although not statistically significant in his small cohort, thyroid autoimmunity was more common in FMF patients compared to healthy controls, with significantly higher levels of thyroid autoantibodies observed in the FMF group (151).

However, more recent data have challenged this association. In a Turkish cohort of 133 pediatric FMF patients and 70 healthy controls, serum levels of thyroid-stimulating hormone, free thyroxine, and thyroid autoantibodies were comparable between groups, suggesting no increased prevalence of thyroid dysfunction or autoimmunity in FMF (152). In agreement with the study by Turan et al. (2021), a retrospective analysis of 421 French adult FMF patients documented a prevalence of HT of 1.6%, which is within the estimated range in the general population (1.35–8.4%) (153). These findings imply that regular screening of thyroid function and autoantibody levels may be not necessary in FMF patients in the absence of clinical symptoms or family history (152). Overall, the available data about the association between FMF and HT are limited in literature, mostly observational, and sometimes inconsistent, which underscores the need for further investigation.

3.2 FMF and metabolic diseases

3.2.1 FMF and Type 1 diabetes mellitus

Autoimmune diabetes, or type 1 diabetes mellitus (T1DM), is a chronic inflammatory disease characterized by an autoimmune reaction against pancreatic beta cells, hence leading to insufficient insulin production and hyperglycemia. Th17 cells are central to T1DM pathogenesis, with proinflammatory cytokines such as IL-1 and IL-6 promoting their differentiation (154). In fact, elevated serum levels of TNF-α, IL-1, and IL-6 have been observed in diabetic patients compared to healthy controls, further supporting their role in disease development (155, 156). Moreover, recent studies on mice have also implicated NLRP3 inflammasome activation and excessive IL-1 production in the development of T1DM (157). Considering that FMF is characterized by increased IL-1 levels, it is hypothesized that this proinflammatory milieu may contribute to the development of T1DM in genetically susceptible individuals. Thus, the immune dysregulation seen in FMF could potentially predispose individuals to autoimmune mechanisms underlying T1DM.

While T1DM is frequently associated with other autoimmune disorders such as Addison’s disease, autoimmune thyroid disease (ATD), and celiac disease, the co-occurrence with FMF is rare (158). Only a few reports have documented this association, making it a relatively novel observation in the medical literature. For instance, Atabek et al. (2006) described a 9-year-old girl who had T1Dm and experienced recurrent stomach pain since childhood (159). Her symptoms persisted inexplicably despite a thorough medical evaluation until a family history of FMF prompted genetic testing, which revealed that she and her parents carried the M680I mutation (159). Although the patient was only heterozygous, colchicine medication greatly reduced her symptoms. Thereby, the patient’s persistent stomach pain, which was previously attributed to unknown reasons, may have been caused by undiagnosed FMF, which raises the possibility of a connection between FMF and T1DM (159). Similarly, Baş et al. (2009) reported a case of a 10.5-year-old boy who initially presented with T1DM, autoimmune thyroid disease, and celiac disease, and subsequently developed recurrent febrile attacks accompanied by abdominal and chest pain (135). Molecular analysis confirmed an M694I/V726A compound heterozygous genotype, and colchicine therapy alleviated the symptoms significantly. In another case, Gicchino and colleagues reported a 13-year-old boy who had been diagnosed with T1DM at age four and later presented with recurrent fever, abdominal pain, chest pain, and arthralgia. Genetic analysis revealed a homozygous E148Q variation, confirming FMF, and treatment with colchicine resulted in significant symptom relief (158). Collectively, these cases highlight the need to consider FMF in the differential diagnosis of unexplained febrile or inflammatory symptoms in patients with T1DM.

To investigate the potential association between T1DM and FMF, Anwar et al. (2015) conducted a study involving 45 Egyptian children with T1DM and 41 healthy controls to screen for MEFV mutations. The results showed an MEFV variant frequency of 42.2% in diabetic patients and 34.1% in healthy subjects, with no statistically significant difference. Notably, heterozygosity was observed in 31.1% of diabetic patients, most commonly for E148Q, followed by A744S, V726A, M680I (G/C), and P369S, with 11.1% being compound heterozygotes. The elevated variant carrier rate in both groups is likely reflective of the high consanguinity within the studied population (160). Although no significant difference in MEFV mutation frequency was found between diabetic and non-diabetic children, these findings emphasize the importance of ongoing clinical monitoring. FMF should be considered in T1DM patients presenting with recurrent, self-limiting febrile episodes, abdominal or chest pain, or arthritis. Moreover, the shared proinflammatory cytokine pathways between FMF and T1DM suggest potential mechanistic links and may provide opportunities for targeted therapeutic approaches.

3.2.2 FMF and metabolic syndrome

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including insulin resistance (IR), hypertension, dyslipidemia, and Type 2 diabetes mellitus (T2DM), which is five times more likely to occur in MetS patients compared to healthy individuals (161). The role of chronic inflammation in MetS pathogenesis has been well established, with early studies identifying TNF-α as a key driver of IR and human T2DM through suppression of the insulin receptor substrate-1 (IRS-1) signaling pathway. TNF-α also activates NF-κB and activator protein 1 (AP-1), amplifying the inflammatory cascade and further disrupting glucose metabolism (162, 163). Alongside TNF-α, IL-6 plays a critical role in promoting systemic inflammation and insulin resistance, as demonstrated by Stenlöf et al. (2003) and Xu et al. (2017) (164, 165). Additionally, the infiltration of immune cells, particularly macrophages, into adipose tissue fosters a chronic low-grade inflammatory state that exacerbates metabolic dysfunction (166).

Given the central role of inflammation in MetS, researchers have explored whether genetic predispositions, specifically MEFV gene mutations, contribute to metabolic dysfunction (167). Balkarli et al. (2016) reported a significantly higher prevalence of the R202Q MEFV mutation in 50 MetS patients compared to 50 healthy controls; however, this mutation did not appear to directly influence clinical markers of MetS severity (168). Likewise, a cross-sectional study involving 154 FMF patients (66 males and 88 females) and 154 age- and sex-matched controls showed that the frequency of MetS among FMF patients was higher (42.90%) compared to controls (28.57%) (169). Additionally, serum uric acid levels were elevated in FMF patients, leading researchers to suggest that hyperuricemia could serve as a reliable biochemical marker for MetS in FMF patients, aiding in early diagnosis and intervention (169). More recently, a 2024 case-control study investigated metabolic syndrome components in Egyptian children with FMF during attack-free periods (170). Although none of the children met the full criteria for MetS, they exhibited significantly higher insulin resistance levels compared to healthy controls, indicating that chronic subclinical inflammation may predispose these children to develop MetS later in life (170).

Collectively, these findings underscore the intricate interplay between genetic susceptibility, inflammation, and metabolic disturbances in FMF patients. While MEFV mutations and inflammatory cytokines such as IL-1β may create a proinflammatory environment that promotes insulin resistance, additional factors such as adipose tissue dysfunction and hyperuricemia likely contribute to metabolic deterioration. Given these insights, further research is essential to elucidate the precise mechanisms underlying the FMF-MetS connection, which may lead to targeted therapeutic strategies to mitigate metabolic risk in FMF patients.

3.2.3 FMF, amyloidosis, and goiter

Amyloidosis is a disorder characterized by the accumulation of proteins into amyloid fibrils and formation of a β-pleated sheet structure in various human tissues and organs (171). The key mechanism that underlies amyloid pathology is the protein’s capacity to acquire many conformations, which makes it amyloidogenic (172). In fact, aberrant proteolysis, point mutations, and post-translational modifications such as phosphorylation, oxidation, and glycation may cause proteins to lose or be unable to acquire their physiologic and active fold, leading to the formation of amyloid fibrils which eventually settle in the target organs’ interstitial spaces (172). These extracellular deposits may either precipitate where they were generated, which would cause a localized form of amyloidosis similar to Alzheimer’s disease, or cause systemic amyloidosis (173). Among the systemic amyloidosis is the secondary AA amyloidosis caused by any long-term inflammatory disease through the accumulation of SAA protein. SAA is an acute phase reactant produced by hepatocytes as well as other cells such as macrophages, endothelial cells, and smooth muscle cells and is regulated transcriptionally by proinflammatory cytokines, specifically TNF- α, IL-1β, and IL-6 (174). In addition, SAA has been shown to participate in immunity regulation and inflammation by activating immune cells at the site of inflammation and promoting the release of proinflammatory cytokines and chemokines (175). Thereby, AA amyloidosis may exacerbate a number of chronic inflammatory disorders, including cancer, autoinflammatory diseases, chronic infections, and idiopathic inflammatory diseases (176). FMF, among other diseases, is one of the primary causes of amyloidosis (171). Given the life-threatening nature of FMF, its connection with amyloidosis, more specifically, AA-type amyloidosis, is crucial. While colchicine successfully prevents FMF incidents and amyloidosis from developing, it is still difficult to anticipate the onset of amyloidosis purely from clinical and demographic factors (177). Therefore, previous studies and case reports have examined the correlation between FMF and AA amyloidosis to grasp a better understanding of their relationship.

In 2004, Atagunduz et al. examined the frequencies of three common MEFV mutations (M694V, M680I, and V726A) in 37 Turkish FMF patients with amyloidosis (AA-FMF), 35 FMF patients without amyloidosis (non-AA-FMF), 19 patients with secondary amyloidosis unrelated to inflammatory diseases (S-AA), and 185 healthy controls (178). They found that MEFV mutations were significantly more prevalent in both AA-FMF (81%) and non-AA-FMF (62.7%) patients compared to healthy controls (4.2%), and in AA-FMF compared to non-AA-FMF patients (178). M694V was the most frequent mutation in both FMF groups (63.5% vs. 51.4%), although allele frequency and homozygosity rates did not differ significantly between them (178). Interestingly, S-AA patients also had a higher rate of MEFV mutations than controls, and M694V was the only mutation detected in this group. Overall, these findings indicate that MEFV mutations are increased in both FMF and non-FMF-associated secondary amyloidosis, but no clear association exists between M694V and amyloidosis development in FMF (178). In agreement, Tekin et al. (2000) showed that FMF patients lacking M694V are still at risk for amyloidosis and that genetic mutations alone cannot fully account for its development, suggesting the involvement of additional genetic or environmental factors (179).

In contrast, a study from Algeria involving 28 FMF patients with biopsy-confirmed renal AA amyloidosis and 20 matched FMF patients without amyloidosis found a strong genotype–phenotype correlation (180). Sequencing of exon 10 revealed that 87.5% of affected patients carried mutant alleles, with M694I being the most common variant (62.5%), followed by M694V (17.85%), M680I (5.35%), and I692Del (1.78%) (180). Notably, M694I/M694I homozygosity was present in 52% of patients with amyloidosis and was significantly associated with the development of amyloidosis compared to controls (180). Although M694V/M694V was detected only in patients with amyloidosis (11%), this finding was not statistically significant (180). The discrepancies between studies suggest that the contribution of specific MEFV variants to amyloidosis risk may vary across populations, potentially reflecting differences in ethnic or regional genetic backgrounds, environmental exposures, or gene-environment interactions.

Another important type of amyloidosis is amyloid goiter, characterized by a gradually growing enlarging thyroid gland that is often asymptomatic initially. Generally, about 30–80% of individuals with secondary amyloidosis and 50% of those with original amyloidosis experience amyloid deposition in the thyroid (181). In FMF, amyloid goiter has been documented in several studies. Özdemir et al. (2001) reported pathological amyloid goiter in 10 of 22 FMF patients, confirmed by biopsy and histological examination. The majority of patients had non-tender thyroid enlargement, with varying degrees of severity, and hypoactive nodules were commonly observed (182). Additional case reports have further supported the association of FMF with amyloid goiter (181, 183–185) Interestingly, some cases of amyloid goiter in FMF have been linked to the E148Q variant (186), which is generally regarded as either a low-penetrance pathogenic variant or a benign polymorphism. While E148Q is usually associated with less severe disease and lower risk of systemic amyloidosis, these findings suggest that even mild MEFV variants can contribute to localized amyloid deposition in the thyroid, highlighting the variable phenotypic expression of FMF (186). These cases show the importance of considering amyloid infiltration of the thyroid in FMF patients, even in those with mild MEFV variants, to ensure early detection and appropriate management.

3.2.4 FMF and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver conditions, ranging from simple steatosis (fatty infiltration of the liver) to nonalcoholic steatohepatitis (NASH), characterized by steatosis with inflammation and hepatocyte necrosis, and eventually cirrhosis (187). The onset of fatty liver can be attributed to multiple factors, including lipid metabolism abnormalities, lipoatrophy, insulin resistance, metabolic syndromes such as obesity and diabetes, certain drugs like steroids, severe weight loss, total parenteral nutrition, and exposure to toxins such as organic solvents (187).

It has been suggested that the development of NASH occurs through a two-step process (188). The first step involves hepatic fat deposition, which exacerbates insulin resistance, while the second involves oxidative stress and fatty acid oxidation in the liver, driven by cytokine-mediated injury, hyperinsulinemia, extracellular matrix alterations, energy imbalance, and immune system changes (188). The pathological progression of NAFLD may follow three interrelated pathways: steatosis, lipotoxicity, and inflammation. Steatosis activates the transcription factor NF-κB, increasing the production of proinflammatory mediators such as IL-6, TNF-α, and IL-1β (189). These cytokines recruit and activate resident hepatic macrophages (Kupffer cells), further mediating inflammation in NASH (189). Additionally, TNF-α and IL-6 contribute to hepatic insulin resistance through upregulation of Suppressor of Cytokine Signaling 3 (SOCS3) (190). The resulting imbalance between pro- and anti-inflammatory cytokines, favoring proinflammatory signaling, promotes recurring or chronic inflammation and lipid accumulation. Given this central role of systemic inflammation and cytokine dysregulation, a co-occurrence between FMF and NAFLD may be expected.

To explore the potential association between FMF and NAFLD, Rimar et al. (2011) examined 27 FMF patients who were referred to a liver clinic because of hepatic function abnormalities persisting for more than 6 months (191). The liver biopsy revealed the presence of NAFLD in 15 patients: 5 with simple steatosis, 3 with NASH, and 7 with NASH-cirrhosis. These findings suggest a potentially underrecognized link between FMF and NAFLD (191). At the molecular level, researchers reported that the homozygous M694V mutation, which was prevalent among the FMF participants (70%), exacerbated the chronic inflammatory state characteristic of FMF, thereby influencing the clinical presentation of NAFLD and promoting its progression to NASH (191). Collectively, these observations suggest that persistent systemic inflammation in FMF may predispose patients to a higher risk of developing severe NAFLD (191). However, Sarkis et al. (2012) documented contrasting results in a cohort of 52 FMF patients and 30 healthy controls, finding that NAFLD was equally frequent in both groups (192). Likewise, a more recent study assessing the prevalence of NAFLD in 54 FMF patients and 54 matched controls detected no significant difference in NAFLD prevalence between the groups (193). Additionally, NAFLD presence was not associated with disease severity, duration, or colchicine dose (193). Overall, the study suggests that FMF patients do not have an increased risk of NAFLD, despite ongoing subclinical inflammation (193).

In summary, although studies on the association between FMF and NAFLD have yielded inconsistent results, chronic or recurrent inflammation in FMF seems to contribute to liver injury in some patients. Therefore, regular monitoring of liver function and colchicine intake are recommended to help prevent hepatic complications.

3.3 Synthesis of key interactions between FMF and autoimmune and metabolic diseases

The associations between FMF and its comorbidities highlight its role as a broad immunoinflammatory mediator, bridging innate and adaptive immune dysregulation. Through pyrin inflammasome activation, FMF creates a proinflammatory environment that can predispose to, exacerbate, or mimic other disorders (Figure 2). Autoimmune conditions such as IBD, RA, MS, and psoriasis demonstrate a bidirectional interaction with FMF: FMF amplifies systemic inflammation, while these diseases, in turn, intensify FMF-related immune activation, resulting in more severe symptoms and disease manifestations. Interestingly, the coexistence of FMF and SLE appears to be protective, as the heightened inflammatory state in FMF mitigates SLE symptoms rather than worsening them. On the other hand, conditions such as SS, CD, and HT show no consistent clinical association with FMF. Amyloidosis represents the most direct and causal complication of FMF, arising from chronic SAA-driven inflammatory deposition, whereas metabolic comorbidities, including T1DM, NAFLD, and MetS, may result from sustained cytokine imbalance, insulin resistance, and inflammasome-mediated tissue inflammation. Collectively, these observations indicate that FMF functions as a systemic inflammatory state capable of influencing the onset, course, and clinical expression of a variety of autoimmune and metabolic disorders, with the magnitude and direction of these interactions dependent on disease-specific pathophysiology.

Figure 2

Figure 2. Potential links between FMF and autoimmune and metabolic diseases. FMF exhibits diverse interactions with several immune-mediated and metabolic conditions. Diseases shown in red (inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, type 1 diabetes mellitus (T1DM), metabolic syndrome (MetS), and nonalcoholic fatty liver disease (NAFLD)) represent conditions in which FMF has been associated with exacerbation or increased risk, likely through persistent pyrin inflammasome activation and downstream inflammatory signaling. In green, the association with systemic lupus erythematosus (SLE) is rather protective, where the inflammatory environment in FMF reduce lupus susceptibility. Amyloidosis, shown in orange, represents a causal complication directly resulting from chronic inflammation in FMF. Conditions shown in blue (sjögren’s syndrome (SS), celiac disease (CD), and Hashimoto's thyroiditis (HT)) indicate no significant association, based on available evidence.

Table 1 summarizes the relationship between FMF and co-occurring disorders, namely, autoimmune and metabolic diseases.

Table 1

Table 1. Overview of autoimmune and metabolic diseases associated with FMF: underlying mechanisms, genetic and epidemiological patterns, and clinical outcomes.

4 Conclusion

FMF is not considered a typical autoinflammatory disease, as increasing evidence highlights its frequent coexistence with both autoimmune and metabolic disorders. While some studies have demonstrated strong associations, others have yielded inconsistent results, reflecting the complex interplay between MEFV genetic variants, epigenetic factors, and environmental influences. Nonetheless, these co-occurrences suggest shared underlying mechanisms, such as innate immune dysregulation, inflammasome activation, and chronic metabolic inflammation.

Clinically, this underscores the importance of vigilant monitoring in both directions: healthcare providers should consider the possibility of FMF in patients presenting with autoimmune or metabolic conditions, and conversely, remain alert to potential comorbidities when diagnosing FMF. Incorporating genetic testing for key MEFV variants (such as M694V, E148Q), especially in patients with atypical presentations or overlapping inflammatory features, can help identify high-risk individuals and guide early and tailored interventions. Furthermore, integrating metabolic and autoimmune screening into FMF management may improve long-term outcomes and prevent secondary complications.

Despite recent advances, significant gaps remain. Future research should include longitudinal cohort studies to clarify the impact of MEFV variants on comorbidity development, functional studies to link specific mutations to pathogenic mechanisms, and multi-omics approaches combining genetic, epigenetic, transcriptomic, and metabolomic data, to uncover shared inflammatory pathways. Additionally, efforts to identify novel biomarkers could enable earlier detection of comorbidities and refine risk stratification.

Ultimately, viewing FMF within the broader context of inflammation not only enhances our understanding of its pathogenesis but also paves the way for more precise and effective patient care.

Author contributions

AC: Writing – original draft, Formal analysis, Methodology, Investigation. NB: Methodology, Writing – original draft, Investigation. RN: Methodology, Writing – original draft, Investigation. EE: Formal analysis, Writing – review & editing. PK: Formal analysis, Supervision, Writing – review & editing, Data curation. JI: Formal analysis, Supervision, Writing – review & editing, Data curation.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Acknowledgments

The authors thank Ms. Razane Chaaban for her assistance with designing the figures.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Glossary

AID: Autoinflammatory disease

AD: Autoimmune disease

mAID: Monogenic autoinflammatory disease

FMF: Familial Mediterranean Fever

MEFV: Mediterranean Fever gene

PYD: Pyrin domain

ASC: Apoptosis-associated speck-like protein

IL: Interleukin

bZIP: Basic leucine zipper

miRNA: MicroRNA

CD: Crohn’s disease

UC: Ulcerative colitis

IBD: Inflammatory bowel disease

IBDU: Inflammatory bowel disease unclassified

IC: Indeterminate colitis

NLRP3: NOD-like receptor family pyrin domain-containing 3

CARD15: Caspase activation and recruitment domain family member 15

NOD2: Nucleotide-binding oligomerization domain-containing protein 2

NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells

TNF: Tumor necrosis factor

SLE: Systemic lupus erythematosus

CNS: Central nervous system

anti-dsDNA: Anti–double-stranded DNA antibody

anti-Sm: Anti-Smith antibody

anti-RNP: Anti–ribonucleoprotein antibody

anti-Ro/SSA: Anti–Sjögren’s syndrome antigen A antibody

anti-La/SSB: Anti–Sjögren’s syndrome antigen B antibody

BAFF: B-cell activating factor

SAP: Serum amyloid P component

CRP: C-reactive protein

snRNP: Small nuclear ribonucleoprotein

HLA: Human leukocyte antigen

MS: Multiple sclerosis

TNFRSF1A: Tumor necrosis factor receptor superfamily member 1A

TRAPS: TNF receptor–associated periodic fever syndrome

IFN-γ: Interferon gamma

PP: Primary progressive (multiple sclerosis subtype)

RR: Relapsing–remitting (multiple sclerosis subtype)

CCR5: C-C chemokine receptor type 5

RA: Rheumatoid Arthritis

HLA: Human Leukocyte Antigen

SS: Sjögren’s Syndrome

CD: Celiac Disease

AGA: Anti-Gliadin Antibodies

EMA IgA: Anti-Endomysium Antibodies Immunoglobulin A

tTG IgA: Tissue Transglutaminase Immunoglobulin A

ESPGHAN: European Society for Paediatric Gastroenterology Hepatology and Nutrition

Th: T helper

T1DM: Type 1 Diabetes Mellitus

ATD: Autoimmune Thyroid Disease

MetS: Metabolic Syndrome

IR: Insulin Resistance

T2DM: Type 2 Diabetes Mellitus

IRS-1: Insulin Receptor Substrate-1

AP-1: Activator Protein 1

AA: Amyloid A

SAA: Serum Amyloid A

S-AA: Secondary Amyloidosis (non-FMF related)

AA-FMF: Amyloidosis-associated FMF2

NAFLD: Nonalcoholic Fatty Liver Disease

NASH: Nonalcoholic Steatohepatitis

SOCS3: Suppressor of Cytokine Signaling

References

1. Yıldız M, Haşlak F, Adrovic A, Barut K, and Kasapçopur Ö. Autoinflammatory diseases in childhood. Balkan Med J. (2020) 37:236–46. doi: 10.4274/balkanmedj.galenos.2020.2020.4.82

PubMed Abstract | Crossref Full Text | Google Scholar

2. Zen M, Gatto M, Domeneghetti M, Palma L, Borella E, Iaccarino L, et al. Clinical guidelines and definitions of autoinflammatory diseases: contrasts and comparisons with autoimmunity-a comprehensive review. Clin Rev Allergy Immunol. (2013) 45:227–35. doi: 10.1007/s12016-013-8355-1

PubMed Abstract | Crossref Full Text | Google Scholar

3. El-Shebiny EM, Zahran ES, Shoeib SA, and Habib ES. Bridging autoinflammatory and autoimmune diseases. Egypt J Intern Med. (2021) 33:11. doi: 10.1186/s43162-021-00040-5

Crossref Full Text | Google Scholar

4. Bhatt H and Cascella M. Familial mediterranean fever. In: StatPearls. StatPearls Publishing, Treasure Island (FL (2025). Available online at: http://www.ncbi.nlm.nih.gov/books/NBK560754/ (Accessed January 10, 2025).

PubMed Abstract | Google Scholar

5. Adwan MH. A brief history of familial Mediterranean fever. Saudi Med J. (2015) 36:1126–7. doi: 10.15537/smj.2015.9.12219

PubMed Abstract | Crossref Full Text | Google Scholar

6. Heller H, Sohar E, and Sherf L. Familial mediterranean fever. AMA Arch Intern Med. (1958) 102:50–71. doi: 10.1001/archinte.1958.00260190052007

PubMed Abstract | Crossref Full Text | Google Scholar

7. Ben-Chetrit E and Touitou I. Familial mediterranean Fever in the world. Arthritis Rheumatol. (2009) 61:1447–53. doi: 10.1002/art.24458

PubMed Abstract | Crossref Full Text | Google Scholar

8. Tufan A and Lachmann HJ. Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turk J Med Sci. (2020) 50:1591–610. doi: 10.3906/sag-2008-11

PubMed Abstract | Crossref Full Text | Google Scholar

9. Infevers. Infevers - Tabular list (2025). Available online at: https://infevers.umai-montpellier.fr/web/search.php?n=1 (Accessed July 1, 2025).

Google Scholar

10. El Roz A, Ghssein G, Khalaf B, Fardoun T, and Ibrahim JN. Spectrum of MEFV variants and genotypes among clinically diagnosed FMF patients from southern Lebanon. Med Sci (Basel). (2020) 8:35. doi: 10.3390/medsci8030035

PubMed Abstract | Crossref Full Text | Google Scholar

11. Feghali R, Ibrahim JN, Salem N, Moussallem R, Hijazi G, Attieh C, et al. Updates on the molecular spectrum of MEFV variants in lebanese patients with Familial Mediterranean Fever. Front Genet. (2024) 15:1506656. doi: 10.3389/fgene.2024.1506656

PubMed Abstract | Crossref Full Text | Google Scholar

12. Schnappauf O, Chae JJ, Kastner DL, and Aksentijevich I. The pyrin inflammasome in health and disease. Front Immunol. (2019) 10:1745. doi: 10.3389/fimmu.2019.01745

PubMed Abstract | Crossref Full Text | Google Scholar

13. Ibrahim JN, Jéru I, Lecron JC, and Medlej-Hashim M. Cytokine signatures in hereditary fever syndromes (HFS). Cytokine Growth Factor Rev. (2017) 33:19–34. doi: 10.1016/j.cytogfr.2016.11.001

PubMed Abstract | Crossref Full Text | Google Scholar

14. Hernández-Rodríguez J, Ruíz-Ortiz E, Tomé A, Espinosa G, González-Roca E, Mensa-Vilaró A, et al. Clinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center. Autoimmun Rev. (2016) 15:9–15. doi: 10.1016/j.autrev.2015.08.008

PubMed Abstract | Crossref Full Text | Google Scholar

15. Ibrahim J, Jounblat R, Jalkh N, Abou Ghoch J, Al Hageh C, Chouery E, et al. RAC1 expression and role in IL-1β production and oxidative stress generation in familial Mediterranean fever (FMF) patients. Eur Cytokine Netw. (2018) 29:127–35. doi: 10.1684/ecn.2018.0416

PubMed Abstract | Crossref Full Text | Google Scholar

16. Ibrahim JN, Jounblat R, Delwail A, Abou-Ghoch J, Salem N, Chouery E, et al. Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: Involvement of IL-1β, IL-1α and Th17-associated cytokines and decrease of Th1 and Th2 cytokines. Cytokine. (2014) 69:248–54. doi: 10.1016/j.cyto.2014.06.012

PubMed Abstract | Crossref Full Text | Google Scholar

17. Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R, et al. An update on familial mediterranean fever. Int J Mol Sci. (2023) 24:9584. doi: 10.3390/ijms24119584

PubMed Abstract | Crossref Full Text | Google Scholar

18. Group TFS. Familial mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Med (Baltimore). (2005) 84:1. doi: 10.1097/01.md.0000152370.84628.0c

PubMed Abstract | Crossref Full Text | Google Scholar

19. Zadeh N, Getzug T, and Grody WW. Diagnosis and management of familial Mediterranean fever: integrating medical genetics in a dedicated interdisciplinary clinic. Genet Med. (2011) 13:263–9. doi: 10.1097/GIM.0b013e31820e27b1

PubMed Abstract | Crossref Full Text | Google Scholar

20. Kushnir T, Eshed I, Heled Y, Livneh A, Langevitz P, Ben Zvi I, et al. Exertional muscle pain in familial Mediterranean fever patients evaluated by MRI and 31P magnetic resonance spectroscopy. Clin Radiol. (2013) 68:371–5. doi: 10.1016/j.crad.2012.08.030

PubMed Abstract | Crossref Full Text | Google Scholar

21. Varan O, Kucuk H, Babaoglu H, Tecer D, Atas N, Bilici Salman R, et al. Chronic inflammation in adult familial Mediterranean fever patients: underlying causes and association with amyloidosis. Scand J Rheumatol. (2019) 48:315–9. doi: 10.1080/03009742.2018.1558282

PubMed Abstract | Crossref Full Text | Google Scholar

22. Ibrahim JN, Chouery E, Lecron JC, Mégarbané A, and Medlej-Hashim M. Study of the association of IL-1β and IL-1RA gene polymorphisms with occurrence and severity of Familial Mediterranean fever. Eur J Med Genet. (2015) 58:668–73. doi: 10.1016/j.ejmg.2015.11.007

PubMed Abstract | Crossref Full Text | Google Scholar

23. Cazeneuve C, Ajrapetyan H, Papin S, Roudot-Thoraval F, Geneviève D, Mndjoyan E, et al. Identification of MEFV-independent modifying genetic factors for familial mediterranean fever. Am J Hum Genet. (2000) 67:1136–43. doi: 10.1016/S0002-9297(07)62944-9

PubMed Abstract | Crossref Full Text | Google Scholar

24. Chaaban A, Salman Z, Karam L, Kobeissy PH, and Ibrahim JN. Updates on the role of epigenetics in familial mediterranean fever (FMF). Orphanet J Rare Dis. (2024) 19:90. doi: 10.1186/s13023-024-03098-w

PubMed Abstract | Crossref Full Text | Google Scholar

25. Liantinioti G, Argyris AA, Protogerou AD, and Vlachoyiannopoulos P. The role of colchicine in the treatment of autoinflammatory diseases. Curr Pharm Des. (2018) 24:690–4. doi: 10.2174/1381612824666180116095658

PubMed Abstract | Crossref Full Text | Google Scholar

26. Dalbeth N, Lauterio TJ, and Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther. (2014) 36:1465–79. doi: 10.1016/j.clinthera.2014.07.017

PubMed Abstract | Crossref Full Text | Google Scholar

27. Slobodnick A, Shah B, Pillinger MH, and Krasnokutsky S. Colchicine: old and new. Am J Med. (2015) 128:461–70. doi: 10.1016/j.amjmed.2014.12.010

PubMed Abstract | Crossref Full Text | Google Scholar

28. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. (2016) 75:644–51. doi: 10.1136/annrheumdis-2015-208690

PubMed Abstract | Crossref Full Text | Google Scholar

29. Chaaban A, Yassine H, Hammoud R, Kanaan R, Karam L, and Ibrahim JN. A narrative review on the role of cytokines in the pathogenesis and treatment of familial Mediterranean fever: an emphasis on pediatric cases. Front Pediatr. (2024) 12:1421353. doi: 10.3389/fped.2024.1421353

PubMed Abstract | Crossref Full Text | Google Scholar

30. Kisla Ekinci RM, Kilic Konte E, Akay N, and Gul U. Familial mediterranean fever in childhood. Turk Arch Pediatr. (2024) 59:527–34. doi: 10.5152/TurkArchPediatr.2024.24188

PubMed Abstract | Crossref Full Text | Google Scholar

31. Yildiz M, Adrovic A, Tasdemir E, Baba-Zada K, Aydin M, Koker O, et al. Evaluation of co-existing diseases in children with familial Mediterranean fever. Rheumatol Int. (2020) 40:57–64. doi: 10.1007/s00296-019-04391-9

PubMed Abstract | Crossref Full Text | Google Scholar

32. Wehkamp J, Götz M, Herrlinger K, Steurer W, and Stange EF. Inflammatory bowel disease. Dtsch Arztebl Int. (2016) 113:72–82. doi: 10.3238/arztebl.2016.0072

PubMed Abstract | Crossref Full Text | Google Scholar

33. Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C, et al. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat Genet. (2009) 41:71–6. doi: 10.1038/ng.285

PubMed Abstract | Crossref Full Text | Google Scholar

34. de Torre-Minguela C, Mesa Del Castillo P, and Pelegrín P. The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases. Front Immunol. (2017) 8:43. doi: 10.3389/fimmu.2017.00043

PubMed Abstract | Crossref Full Text | Google Scholar

35. Omenetti A, Carta S, Delfino L, Martini A, Gattorno M, and Rubartelli A. Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann Rheum Dis. (2014) 73:462–9. doi: 10.1136/annrheumdis-2012-202774

PubMed Abstract | Crossref Full Text | Google Scholar

36. Angelidou I, Chrysanthopoulou A, Mitsios A, Arelaki S, Arampatzioglou A, Kambas K, et al. REDD1/autophagy pathway is associated with neutrophil-driven IL-1β Inflammatory response in active ulcerative colitis. J Immunol. (2018) 200:3950–61. doi: 10.4049/jimmunol.1701643

PubMed Abstract | Crossref Full Text | Google Scholar

37. Kimura T, Jain A, Choi SW, Mandell MA, Schroder K, Johansen T, et al. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol. (2015) 210:973–89. doi: 10.1083/jcb.201503023

PubMed Abstract | Crossref Full Text | Google Scholar

38. Karban A, Dagan E, Eliakim R, Herman A, Nesher S, Weiss B, et al. Prevalence and significance of mutations in the familial Mediterranean fever gene in patients with Crohn’s disease. Genes Immun. (2005) 6:134–9. doi: 10.1038/sj.gene.6364156

PubMed Abstract | Crossref Full Text | Google Scholar

39. Yurtcu E, Gokcan H, Yilmaz U, and Sahin FI. Detection of MEFV gene mutations in patients with inflammatory bowel disease. Genet Test Mol Biomarkers. (2009) 13:87–90. doi: 10.1089/gtmb.2008.0094

PubMed Abstract | Crossref Full Text | Google Scholar

40. Kori M, Buchuk R, Goldzweig O, Weisband YL, Tal N, Ben-Tov A, et al. Familial Mediterranean fever in patients with inflammatory bowel diseases: a nationwide study from the epi-IIRN. Rheumatol (Oxford). (2025) 64:1347–54. doi: 10.1093/rheumatology/keae303

PubMed Abstract | Crossref Full Text | Google Scholar

41. Akyuz F, Besisik F, Ustek D, Ekmekçi C, Uyar A, Pinarbasi B, et al. Association of the MEFV gene variations with inflammatory bowel disease in Turkey. J Clin Gastroenterol. (2013) 47:e23–27. doi: 10.1097/MCG.0b013e3182597992

PubMed Abstract | Crossref Full Text | Google Scholar

42. Salah S, El-Shabrawi M, Lotfy HM, Shiba HF, Abou-Zekri M, and Farag Y. Detection of Mediterranean fever gene mutations in Egyptian children with inflammatory bowel disease. Int J Rheum Dis. (2016) 19:806–13. doi: 10.1111/1756-185X.12482

PubMed Abstract | Crossref Full Text | Google Scholar

43. Urgancı N, Ozgenc F, Kuloğlu Z, Yüksekkaya H, Sarı S, Erkan T, et al. Familial mediterranean fever mutation analysis in pediatric patients with inflammatory bowel disease: A multicenter study. Turk J Gastroenterol. (2021) 32:248–60. doi: 10.5152/tjg.2021.20057

PubMed Abstract | Crossref Full Text | Google Scholar

44. Beşer OF, Kasapçopur O, Cokuğraş FC, Kutlu T, Arsoy N, and Erkan T. Association of inflammatory bowel disease with familial Mediterranean fever in Turkish children. J Pediatr Gastroenterol Nutr. (2013) 56:498–502. doi: 10.1097/MPG.0b013e31827dd763

PubMed Abstract | Crossref Full Text | Google Scholar

45. Beşer ÖF, Çokuğraş FÇ, Kutlu T, Erginöz E, Gülcü D, Kasapçopur Ö, et al. Association of familial Mediterranean fever in Turkish children with inflammatory bowel disease. Turkish Arch Pediatrics/Türk Pediatri Arşivi. (2014) 49:198. doi: 10.5152/tpa.2014.1998

PubMed Abstract | Crossref Full Text | Google Scholar

46. Uslu N, Yüce A, Demir H, Saltik-Temizel IN, Usta Y, Yilmaz E, et al. The association of inflammatory bowel disease and Mediterranean fever gene (MEFV) mutations in Turkish children. Dig Dis Sci. (2010) 55:3488–94. doi: 10.1007/s10620-010-1178-5

PubMed Abstract | Crossref Full Text | Google Scholar

47. Agin M, Bisgin A, Yilmaz M, Ozhan AK, Mammadov F, and Tumgor G. The cumulative effects of MEFV gene polymorphisms and mutations in patients with inflammatory bowel diseases. J Pak Med Assoc. (2021) 71:479–83. doi: 10.47391/JPMA.762

PubMed Abstract | Crossref Full Text | Google Scholar

48. Amaryan G, Sarkisian T, Tadevosyan A, and Braegger C. Familial Mediterranean fever in Armenian children with inflammatory bowel disease. Front Pediatr. (2024) 11:1288523. doi: 10.3389/fped.2023.1288523

PubMed Abstract | Crossref Full Text | Google Scholar

49. Sahin S, Gulec D, Günay S, and Cekic C. Evaluation of the clinical effects and frequency of MEFV gene mutation in patients with inflammatory bowel disease. Gastroenterol Res Pract. (2021) 2021:5538150. doi: 10.1155/2021/5538150

PubMed Abstract | Crossref Full Text | Google Scholar

50. Sari S, Egritas O, and Dalgic B. The familial Mediterranean fever (MEFV) gene may be a modifier factor of inflammatory bowel disease in infancy. Eur J Pediatr. (2008) 167:391–3. doi: 10.1007/s00431-007-0508-x

PubMed Abstract | Crossref Full Text | Google Scholar

51. Fidder H, Chowers Y, Ackerman Z, Pollak RD, Crusius JBA, Livneh A, et al. The familial Mediterranean fever (MEVF) gene as a modifier of Crohn’s disease. Am J Gastroenterol. (2005) 100:338–43. doi: 10.1111/j.1572-0241.2005.40810.x

PubMed Abstract | Crossref Full Text | Google Scholar

52. Fidder HH, Chowers Y, Lidar M, Sternberg M, Langevitz P, and Livneh A. Crohn disease in patients with familial Mediterranean fever. Med (Baltimore). (2002) 81:411–6. doi: 10.1097/00005792-200211000-00001

PubMed Abstract | Crossref Full Text | Google Scholar

53. Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, et al. Systemic lupus erythematosus. Nat Rev Dis Primers. (2016) 2:16039. doi: 10.1038/nrdp.2016.39

PubMed Abstract | Crossref Full Text | Google Scholar

54. Accapezzato D, Caccavale R, Paroli MP, Gioia C, Nguyen BL, Spadea L, et al. Advances in the pathogenesis and treatment of systemic lupus erythematosus. Int J Mol Sci. (2023) 24:6578. doi: 10.3390/ijms24076578

PubMed Abstract | Crossref Full Text | Google Scholar

55. Dema B and Charles N. Autoantibodies in SLE: specificities, isotypes and receptors. Antibodies (Basel). (2016) 5:2. doi: 10.3390/antib5010002

PubMed Abstract | Crossref Full Text | Google Scholar

56. Zampeli E, Skopouli FN, and Moutsopoulos HM. Polyserositis in a patient with active systemic lupus erythematosus: A case of pseudo-pseudo meigs syndrome. J Rheumatol. (2018) 45:877–8. doi: 10.3899/jrheum.171296

PubMed Abstract | Crossref Full Text | Google Scholar

57. Aringer M. Inflammatory markers in systemic lupus erythematosus. J Autoimmun. (2020) 110:102374. doi: 10.1016/j.jaut.2019.102374

PubMed Abstract | Crossref Full Text | Google Scholar

58. Shinar Y, Kosach E, Langevitz P, Zandman-Goddard G, Pauzner R, Rabinovich E, et al. Familial Mediterranean FeVer gene (MEFV) mutations as a modifier of systemic lupus erythematosus. Lupus. (2012) 21:993–8. doi: 10.1177/0961203312441048

PubMed Abstract | Crossref Full Text | Google Scholar

59. Yildiz G, Kayatas M, Uygun Y, Timuçin M, and Candan F. Coexistence of systemic lupus erythematosus and familial mediterranean fever. Intern Med. (2010) 49:767–9. doi: 10.2169/internalmedicine.49.3102

PubMed Abstract | Crossref Full Text | Google Scholar

60. Bakir F and Saaed B. Systemic lupus erythematosus and periodic peritonitis (FMF). Br J Rheumatol. (1989) 28:81–2. doi: 10.1093/rheumatology/28.1.81

PubMed Abstract | Crossref Full Text | Google Scholar

61. Erten S, Taskaldiran I, and Yakut ZI. Are systemic lupus erythematosus patients carrying MEFV gene less prone to renal involvement? Report of three cases and review of the literature. Ren Fail. (2013) 35:1013–6. doi: 10.3109/0886022X.2013.809096

PubMed Abstract | Crossref Full Text | Google Scholar

62. Kiyani A, Parperis K, and Parperis K. Familial mediterranean fever imitating lupus flare: A rare coexistence of an autoimmune disease with an autoinflammatory disease. J Clin Rheumatol. (2018) 24:104–6. doi: 10.1097/RHU.0000000000000636

PubMed Abstract | Crossref Full Text | Google Scholar

63. Kokubu H, Ida H, Tanaka T, and Fujimoto N. Systemic lupus erythematosus with familial mediterranean fever: case report and review of literature. Acta Derm Venereol. (2019) 99:822–3. doi: 10.2340/00015555-3197

PubMed Abstract | Crossref Full Text | Google Scholar

64. Matsuda M, Kishida D, Tsuchiya-Suzuki A, Fukushima K, Shimojima Y, Yazaki M, et al. Periodic peritonitis due to familial Mediterranean fever in a patient with systemic lupus erythematosus. Intern Med. (2010) 49:2259–62. doi: 10.2169/internalmedicine.49.4043

PubMed Abstract | Crossref Full Text | Google Scholar

65. Schreiber BE, Lachmann HJ, and Mackworth-Young CG. Possible familial Mediterranean fever in a Caucasian patient with systemic lupus erythematosus. Lupus. (2008) 17:752–3. doi: 10.1177/0961203308089449

PubMed Abstract | Crossref Full Text | Google Scholar

66. Farooq MU, Sohail H, Mohsin M, Iqbal R, Malik J, and Ishaq U. Co-occurrence of familial Mediterranean fever with systemic lupus erythematosus in South Asian population. Reumatol Clin (Engl Ed). (2023) 19:130–5. doi: 10.1016/j.reumae.2023.02.001

PubMed Abstract | Crossref Full Text | Google Scholar

67. Klein TL, Tiosano S, Gilboa Y, Shoenfeld Y, Cohen A, and Amital H. The coexistence of familial Mediterranean fever (FMF) in systemic lupus erythematosus (SLE) patients - A cross sectional study. Lupus. (2021) 30:1094–9. doi: 10.1177/09612033211004726

PubMed Abstract | Crossref Full Text | Google Scholar

68. Deniz R, Ozen G, Yilmaz-Oner S, Alibaz-Oner F, Erzik C, Aydin SZ, et al. Familial Mediterranean fever gene (MEFV) mutations and disease severity in systemic lupus erythematosus (SLE): implications for the role of the E148Q MEFV allele in inflammation. Lupus. (2015) 24:705–11. doi: 10.1177/0961203314560203

PubMed Abstract | Crossref Full Text | Google Scholar

69. Tanatar A, Çakan M, Karadağ ŞG, Kısaarslan AP, Sözeri B, and Ayaz NA. The influence of carrying MEFV gene variants on juvenile systemic lupus erythematosus. Rheumatol Int. (2021) 41:157–61. doi: 10.1007/s00296-019-04420-7

PubMed Abstract | Crossref Full Text | Google Scholar

70. Lidar M, Zandman-Goddard G, Shinar Y, Zaks N, Livneh A, and Langevitz P. Systemic lupus erythematosus and familial Mediterranean fever: a possible negative association between the two disease entities–report of four cases and review of the literature. Lupus. (2008) 17:663–9. doi: 10.1177/0961203308089403

PubMed Abstract | Crossref Full Text | Google Scholar

71. Ozen S and Bakkaloglu A. C reactive protein: protecting from lupus in familial Mediterranean fever. Ann Rheum Dis. (2005) 64:786–7. doi: 10.1136/ard.2004.027037

PubMed Abstract | Crossref Full Text | Google Scholar

72. Emsley J, White HE, O’Hara BP, Oliva G, Srinivasan N, Tickle IJ, et al. Structure of pentameric human serum amyloid P component. Nature. (1994) 367:338–45. doi: 10.1038/367338a0

PubMed Abstract | Crossref Full Text | Google Scholar

73. Lidar M, Doron A, Kedem R, Yosepovich A, Langevitz P, and Livneh A. Appendectomy in familial Mediterranean fever: clinical, genetic and pathological findings. Clin Exp Rheumatol. (2008) 26:568–73.

PubMed Abstract | Google Scholar

74. Russell AI, Cunninghame Graham DS, Shepherd C, Roberton CA, Whittaker J, Meeks J, et al. Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet. (2004) 13:137–47. doi: 10.1093/hmg/ddh021

PubMed Abstract | Crossref Full Text | Google Scholar

75. Efraimidou M, Osipyan M, Sevoyan L, Bazeyan S, Vardanyan V, and Ginosyan K. AB1472 THE PECULIARITIES OF THE CLINICAL MANIFESTATIONS OF FAMILIAL MEDITERRANEAN FEVER ACCOMPANIED WITH LUPUS-LIKE SYNDROME. Ann Rheum Dis. (2023) 82:1965. doi: 10.1136/annrheumdis-2023-eular.6158

Crossref Full Text | Google Scholar

76. Ginosyan K, Vardanyan V, Beglaryan A, and Ayvazyan A. FRI0414 systemic lupus erythematosus with coexisting familial mediterranean fever. Ann Rheum Dis. (2014) 73:537. doi: 10.1136/annrheumdis-2014-eular.3549

Crossref Full Text | Google Scholar

77. Brownlee WJ, Hardy TA, Fazekas F, and Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet. (2017) 389:1336–46. doi: 10.1016/S0140-6736(16)30959-X

PubMed Abstract | Crossref Full Text | Google Scholar

78. Tian J, Jiang L, Chen Z, Yuan Q, Liu C, He L, et al. Tissue-resident immune cells in the pathogenesis of multiple sclerosis. Inflammation Res. (2023) 72:363–72. doi: 10.1007/s00011-022-01677-w

PubMed Abstract | Crossref Full Text | Google Scholar

79. Attfield KE, Jensen LT, Kaufmann M, Friese MA, and Fugger L. The immunology of multiple sclerosis. Nat Rev Immunol. (2022) 22:734–50. doi: 10.1038/s41577-022-00718-z

PubMed Abstract | Crossref Full Text | Google Scholar

80. Ghasemi N, Razavi S, and Nikzad E. Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy. Cell J. (2017) 19:1–10. doi: 10.22074/cellj.2016.4867

PubMed Abstract | Crossref Full Text | Google Scholar

81. Nourbakhsh B and Mowry EM. Multiple sclerosis risk factors and pathogenesis. Continuum (Minneap Minn). (2019) 25:596–610. doi: 10.1212/CON.0000000000000725

PubMed Abstract | Crossref Full Text | Google Scholar

82. Rodríguez Murúa S, Farez MF, and Quintana FJ. The immune response in multiple sclerosis. Annu Rev Pathol. (2022) 17:121–39. doi: 10.1146/annurev-pathol-052920-040318

PubMed Abstract | Crossref Full Text | Google Scholar

83. Yasunami M, Nakamura H, Agematsu K, Nakamura A, Yazaki M, Kishida D, et al. Identification of disease-promoting HLA class I and protective class II modifiers in Japanese patients with familial mediterranean fever. PloS One. (2015) 10:e0125938. doi: 10.1371/journal.pone.0125938

PubMed Abstract | Crossref Full Text | Google Scholar

84. Gershoni-Baruch R, Brik R, Shinawi M, and Livneh A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet. (2002) 10:145–9. doi: 10.1038/sj.ejhg.5200776

PubMed Abstract | Crossref Full Text | Google Scholar

85. Guinet A, Grateau G, Nifle C, Rozier A, and Pico F. Multiple sclerosis and familial Mediterranean fever: a case report. Rev Neurol (Paris). (2008) 164:943–7. doi: 10.1016/j.neurol.2008.04.004

PubMed Abstract | Crossref Full Text | Google Scholar

86. Kalyoncu U, Eker A, Oguz KK, Kurne A, Kalan I, Topcuoglu AM, et al. Familial Mediterranean fever and central nervous system involvement: a case series. Med (Baltimore). (2010) 89:75–84. doi: 10.1097/MD.0b013e3181d5dca7

PubMed Abstract | Crossref Full Text | Google Scholar

87. Sayin R, Alpayci M, and Soyoral YU. A case with multiple sclerosis and familial Mediterranean fever. Genet Couns. (2011) 22:309–12.

PubMed Abstract | Google Scholar

88. Topçuogˇlu MA and Karabudak R. Familial Mediterranean fever and multiple sclerosis. J Neurol. (1997) 244:510–4. doi: 10.1007/s004150050134

PubMed Abstract | Crossref Full Text | Google Scholar

89. Ugurlu S, Bolayir E, Candan F, and Gumus C. Familial mediterranean fever and multiple sclerosis–a case report. Acta Reumatol Port. (2009) 34:117–9.

PubMed Abstract | Google Scholar

90. Unal A, Emre U, Dursun A, and Aydemir S. The co-incidence of multiple sclerosis in a patient with familial Mediterranean fever. Neurol India. (2009) 57:672–3. doi: 10.4103/0028-3886.57790

PubMed Abstract | Crossref Full Text | Google Scholar

91. Yücesan C, Canyiğit A, and Türkçapar N. The coexistence of familial Mediterranean fever with multiple sclerosis. Eur J Neurol. (2004) 11:716–7. doi: 10.1111/j.1468-1331.2004.00877.x

PubMed Abstract | Crossref Full Text | Google Scholar

92. Akman-Demir G, Gul A, Gurol E, Ozdogan H, Bahar S, Oge AE, et al. Inflammatory/demyelinating central nervous system involvement in familial Mediterranean fever (FMF): coincidence or association? J Neurol. (2006) 253:928–34. doi: 10.1007/s00415-006-0137-8

PubMed Abstract | Crossref Full Text | Google Scholar

93. Unal A, Dursun A, Emre U, Tascilar NF, and Ankarali H. Evaluation of common mutations in the Mediterranean fever gene in Multiple Sclerosis patients: is it a susceptibility gene? J Neurol Sci. (2010) 294:38–42. doi: 10.1016/j.jns.2010.04.008

PubMed Abstract | Crossref Full Text | Google Scholar

94. Yigit S, Karakus N, Kurt SG, and Ates O. Association of missense mutations of Mediterranean fever (MEFV) gene with multiple sclerosis in Turkish population. J Mol Neurosci. (2013) 50:275–9. doi: 10.1007/s12031-012-9947-6

PubMed Abstract | Crossref Full Text | Google Scholar

95. Kümpfel T, Gerdes LA, Wacker T, Blaschek A, Havla J, Krumbholz M, et al. Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis. Mult Scler. (2012) 18:1229–38. doi: 10.1177/1352458512437813

PubMed Abstract | Crossref Full Text | Google Scholar

96. Yahalom G, Kivity S, Lidar M, Vaknin-Dembinsky A, Karussis D, Flechter S, et al. Familial Mediterranean fever (FMF) and multiple sclerosis: an association study in one of the world’s largest FMF cohorts. Eur J Neurol. (2011) 18:1146–50. doi: 10.1111/j.1468-1331.2011.03356.x

PubMed Abstract | Crossref Full Text | Google Scholar

97. Blaschek A, Kries R V, Lohse P, Huss K, Vill K, Belohradsky BH, et al. TNFRSF1A and MEFV mutations in childhood onset multiple sclerosis. Eur J Paediatr Neurol. (2018) 22:72–81. doi: 10.1016/j.ejpn.2017.08.007

PubMed Abstract | Crossref Full Text | Google Scholar

98. Elhani I, Dumont A, Vergneault H, Ardois S, Le Besnerais M, Levesque H, et al. Association between familial Mediterranean fever and multiple sclerosis: A case series from the JIR cohort and systematic literature review. Mult Scler Relat Disord. (2021) 50:102834. doi: 10.1016/j.msard.2021.102834

PubMed Abstract | Crossref Full Text | Google Scholar

99. Terzi M, Taskın E, Unal Akdemir N, Bagcı H, and Onar M. The relationship between familial Mediterranean fever gene (MEFV) mutations and clinical and radiologic parameters in multiple sclerosis patients. Int J Neurosci. (2015) 125:116–22. doi: 10.3109/00207454.2014.913170

PubMed Abstract | Crossref Full Text | Google Scholar

100. Lin CC and Edelson BT. New insights into the role of IL-1β in experimental autoimmune encephalomyelitis and multiple sclerosis. J Immunol. (2017) 198:4553–60. doi: 10.4049/jimmunol.1700263

PubMed Abstract | Crossref Full Text | Google Scholar

101. Alpayci M, Bozan N, Erdem S, Gunes M, and Erden M. The possible underlying pathophysiological mechanisms for development of multiple sclerosis in familial Mediterranean fever. Med Hypotheses. (2012) 78:717–20. doi: 10.1016/j.mehy.2012.02.017

PubMed Abstract | Crossref Full Text | Google Scholar

102. Shinar Y, Livneh A, Villa Y, Pinhasov A, Zeitoun I, Kogan A, et al. Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun. (2003) 4:197–203. doi: 10.1038/sj.gene.6363967

PubMed Abstract | Crossref Full Text | Google Scholar

103. Maayan S, Zhang L, Shinar E, Ho J, He T, Manni N, et al. Evidence for recent selection of the CCR5-Δ32 deletion from differences in its frequency between Ashkenazi and Sephardi Jews. Genes Immun. (2000) 1:358–61. doi: 10.1038/sj.gene.6363690

PubMed Abstract | Crossref Full Text | Google Scholar

104. Weatherby SJM, Thomson W, Pepper L, Donn R, Worthington J, Mann CLA, et al. HLA-DRB1 and disease outcome in multiple sclerosis. J Neurol. (2001) 248:304–10. doi: 10.1007/s004150170205

PubMed Abstract | Crossref Full Text | Google Scholar

105. Senthelal S, Li J, Ardeshirzadeh S, and Thomas MA. Arthritis. In: StatPearls. StatPearls Publishing, Treasure Island (FL (2025). Available online at: http://www.ncbi.nlm.nih.gov/books/NBK518992/ (Accessed February 1, 2025).

PubMed Abstract | Google Scholar

106. Weyand CM, Goronzy JJ, and Association of MHC and rheumatoid arthritis. HLA polymorphisms in phenotypic variants of rheumatoid arthritis. Arthritis Res. (2000) 2:212–6. doi: 10.1186/ar90

PubMed Abstract | Crossref Full Text | Google Scholar

107. Zaccardelli A, Friedlander HM, Ford JA, and Sparks JA. Potential of lifestyle changes for reducing the risk of developing rheumatoid arthritis: is an ounce of prevention worth a pound of cure? Clin Ther. (2019) 41:1323–45. doi: 10.1016/j.clinthera.2019.04.021

PubMed Abstract | Crossref Full Text | Google Scholar

108. Mitra S. ARTHRITIS: CLASSIFICATION, NATURE & CAUSE - A REVIEW. Am J Biopharmacology Biochem Life Sci. (2013) 02:1–19.

Google Scholar

109. Fisher SA, Lanchbury JS, and Lewis CM. Meta-analysis of four rheumatoid arthritis genome-wide linkage studies: confirmation of a susceptibility locus on chromosome 16. Arthritis Rheumatol. (2003) 48:1200–6. doi: 10.1002/art.10945

PubMed Abstract | Crossref Full Text | Google Scholar

110. Matsuoka N, Iwanaga J, Ichinose Y, Fujiyama K, Tsuboi M, Kawakami A, et al. Two elderly cases of familial mediterranean fever with rheumatoid arthritis. Int J Rheum Dis. (2018) 21:1873–7. doi: 10.1111/1756-185X.12354

PubMed Abstract | Crossref Full Text | Google Scholar

111. Migita K, Abiru S, Sasaki O, Miyashita T, Izumi Y, Nishino A, et al. Coexistence of familial Mediterranean fever and rheumatoid arthritis. Mod Rheumatol. (2014) 24:212–6. doi: 10.3109/14397595.2013.852843

PubMed Abstract | Crossref Full Text | Google Scholar

112. Mori S, Yonemura K, and Migita K. Familial Mediterranean fever occurring in an elderly Japanese woman with recent-onset rheumatoid arthritis. Intern Med. (2013) 52:385–8. doi: 10.2169/internalmedicine.52.9102

PubMed Abstract | Crossref Full Text | Google Scholar

113. Nureki SI, Ishii K, Fujisaki H, Torigoe M, Maeshima K, Shibata H, et al. Familial mediterranean fever with rheumatoid arthritis complicated by pulmonary paragonimiasis. Intern Med. (2016) 55:2889–92. doi: 10.2169/internalmedicine.55.6999

PubMed Abstract | Crossref Full Text | Google Scholar

114. Yago T, Asano T, Fujita Y, and Migita K. Familial Mediterranean fever phenotype progression into anti-cyclic citrullinated peptide antibody-positive rheumatoid arthritis: a case report. Fukushima J Med Sci. (2020) 66:160–6. doi: 10.5387/fms.2020-07

PubMed Abstract | Crossref Full Text | Google Scholar

115. Inanir A, Yigit S, Karakus N, Tekin S, and Rustemoglu A. Association of MEFV gene mutations with rheumatoid factor levels in patients with rheumatoid arthritis. J Investig Med. (2013) 61:593–6. doi: 10.2310/JIM.0b013e318280a96e

PubMed Abstract | Crossref Full Text | Google Scholar

116. Koca SS, Etem EO, Isik B, Yuce H, Ozgen M, Dag MS, et al. Prevalence and significance of MEFV gene mutations in a cohort of patients with rheumatoid arthritis. Joint Bone Spine. (2010) 77:32–5. doi: 10.1016/j.jbspin.2009.08.006

PubMed Abstract | Crossref Full Text | Google Scholar

117. Migita K, Nakamura T, Maeda Y, Miyashita T, Koga T, Tanaka M, et al. MEFV mutations in Japanese rheumatoid arthritis patients. Clin Exp Rheumatol. (2008) 26:1091–4.

Google Scholar

118. Rabinovich E, Livneh A, Langevitz P, Brezniak N, Shinar E, Pras M, et al. Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene. Ann Rheum Dis. (2005) 64:1009–14. doi: 10.1136/ard.2004.029447

PubMed Abstract | Crossref Full Text | Google Scholar

119. Missoum H, Adadi N, Alami M, Toufik H, Bouyahya A, Laarabi FZ, et al. Correlation genotype-phenotype: MEFV gene mutations and Moroccan patients with rheumatoid arthritis. Pan Afr Med J. (2022) 41:121. doi: 10.11604/pamj.2022.41.121.30368

PubMed Abstract | Crossref Full Text | Google Scholar

120. Kalyoncu M, Acar BC, Cakar N, Bakkaloglu A, Ozturk S, Dereli E, et al. Are carriers for MEFV mutations “healthy”? Clin Exp Rheumatol. (2006) 24:S120–122.

Google Scholar

121. Kogan A, Shinar Y, Lidar M, Revivo A, Langevitz P, Padeh S, et al. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet. (2001) 102:272–6. doi: 10.1002/ajmg.1438

PubMed Abstract | Crossref Full Text | Google Scholar

122. Lachmann HJ, Sengül B, Yavuzşen TU, Booth DR, Booth SE, Bybee A, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatol (Oxford). (2006) 45:746–50. doi: 10.1093/rheumatology/kei279

PubMed Abstract | Crossref Full Text | Google Scholar

123. Kinikli G, Bektaş M, Misirlioğlu M, Ateş A, Turgay M, Tuncer S, et al. HLA-DQ alleles and MEFV gene mutations in familial Mediterranean fever (FMF) patients. Turk J Gastroenterol. (2005) 16:143–6.

PubMed Abstract | Google Scholar

124. Zsilák S, Gál J, Hodinka L, Rajczy K, Balog A, Sipka S, et al. HLA-DR genotypes in familial rheumatoid arthritis: increased frequency of protective and neutral alleles in a multicase family. J Rheumatol. (2005) 32:2299–302.

PubMed Abstract | Google Scholar

125. Migita K, Abiru S, Tanaka M, Ito M, Miyashita T, Maeda Y, et al. Acute hepatitis in a patient with familial Mediterranean fever. Liver Int. (2008) 28:140–2. doi: 10.1111/j.1478-3231.2007.01598.x

PubMed Abstract | Crossref Full Text | Google Scholar

126. Barsottini OGP, de Moraes MPM, PHA F, Marussi VHR, de Souza AWS, Braga Neto P, et al. Sjogren’s syndrome: a neurological perspective. Arq Neuropsiquiatr. (2023) 81:1077–83. doi: 10.1055/s-0043-1777105

PubMed Abstract | Crossref Full Text | Google Scholar

127. Dörtbaş F, Garip Y, Güler T, and Karci AA. Coexistence of familial mediterranean fever with ankylosing spondylitis and sjogren’s syndrome: A rare occurrence. Arch Rheumatol. (2016) 31:087–90. doi: 10.5606/ArchRheumatol.2016.5671

PubMed Abstract | Crossref Full Text | Google Scholar

128. Fujita Y, Asano T, Sato S, Furuya MY, Temmoku J, Matsuoka N, et al. Coexistence of mixed connective tissue disease and familial mediterranean fever in a Japanese patient. Intern Med. (2019) 58:2235–40. doi: 10.2169/internalmedicine.2376-18

PubMed Abstract | Crossref Full Text | Google Scholar

129. Kobak S, Kobak AC, Aksu K, Keser G, and Oksel F. Coexistance of Sjogren’s syndrome and familial Mediterranean fever. Int J Rheum Dis. (2007) 10:244–5. doi: 10.1111/j.1479-8077.2007.00296.x

Crossref Full Text | Google Scholar

130. Tanaka M, Migita K, Miyashita T, Maeda Y, Nakamura M, Komori A, et al. Coexistence of familial Mediterranean fever and Sjögren’s syndrome in a Japanese patient. Clin Exp Rheumatol. (2007) 25:792.

PubMed Abstract | Google Scholar

131. Gujral N, Freeman HJ, and Thomson AB. Celiac disease: Prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol. (2012) 18:6036–59. doi: 10.3748/wjg.v18.i42.6036

PubMed Abstract | Crossref Full Text | Google Scholar

132. De Re V, Caggiari L, Tabuso M, and Cannizzaro R. The versatile role of gliadin peptides in celiac disease. Clin Biochem. (2013) 46:552–60. doi: 10.1016/j.clinbiochem.2012.10.038

PubMed Abstract | Crossref Full Text | Google Scholar

133. Christophersen A, Risnes LF, Dahal-Koirala S, and Sollid LM. Therapeutic and diagnostic implications of T cell scarring in celiac disease and beyond. Trends Mol Med. (2019) 25:836–52. doi: 10.1016/j.molmed.2019.05.009

PubMed Abstract | Crossref Full Text | Google Scholar

134. Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci U S A. (2003) 100:12390–5. doi: 10.1073/pnas.2135229100

PubMed Abstract | Crossref Full Text | Google Scholar

135. Baş F, Kabataş-Eryilmaz S, Günöz H, Darendeliler F, Küçükemre B, Bundak R, et al. Type 1 diabetes mellitus associated with autoimmune thyroid disease, celiac disease and familial Mediterranean fever: case report. Turk J Pediatr. (2009) 51:183–6.

PubMed Abstract | Google Scholar

136. Kuloğlu Z, Kansu A, Tutar E, Yalçinkaya F, Ensari A, and Girgin N. Association of familial Mediterranean fever and celiac disease in a 14-year-old girl with recurrent arthritis. Clin Exp Rheumatol. (2008) 26:S131.

PubMed Abstract | Google Scholar

137. Yilmaz Y, Baran B, Seniz NB, and Dolar E. Familial Mediterranean Fever coexisting with celiac disease: is there a link with long-term colchicine treatment? J Gastrointestin Liver Dis. (2009) 18:119–20.

PubMed Abstract | Google Scholar

138. Sahin Y, Adrovic A, Barut K, Kutlu T, Cullu-Cokugras F, Sahin S, et al. The frequency of the celiac disease among children with familial Mediterranean fever. Modern Rheumatol. (2017) 27:1036–9. doi: 10.1080/14397595.2016.1270497

PubMed Abstract | Crossref Full Text | Google Scholar

139. Di Sabatino A, Ciccocioppo R, Cupelli F, Cinque B, Millimaggi D, Clarkson MM, et al. Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut. (2006) 55:469–77. doi: 10.1136/gut.2005.068684

PubMed Abstract | Crossref Full Text | Google Scholar

140. Kagnoff MF. Celiac disease: pathogenesis of a model immunogenetic disease. J Clin Invest. (2007) 117:41–9. doi: 10.1172/JCI30253

PubMed Abstract | Crossref Full Text | Google Scholar

141. Kuloğlu Z, Ozçakar ZB, Kirsaçlioğlu C, Yüksel S, Kansu A, Girgin N, et al. Is there an association between familial Mediterranean fever and celiac disease? Clin Rheumatol. (2008) 27:1135–9. doi: 10.1007/s10067-008-0879-z

PubMed Abstract | Crossref Full Text | Google Scholar

142. Işikay S, Işikay N, and Kocamaz H. The prevalence of celiac disease among patients with familial mediterranean Fever. Arq Gastroenterol. (2015) 52:55–8. doi: 10.1590/S0004-28032015000100012

PubMed Abstract | Crossref Full Text | Google Scholar

143. Lowes MA, Bowcock AM, and Krueger JG. Pathogenesis and therapy of psoriasis. Nature. (2007) 445:866–73. doi: 10.1038/nature05663

PubMed Abstract | Crossref Full Text | Google Scholar

144. Erden A, Batu ED, Seyhoğlu E, Sari A, Sönmez HE, Armagan B, et al. Increased psoriasis frequency in patients with familial Mediterranean fever. Ups J Med Sci. (2018) 123:57–61. doi: 10.1080/03009734.2017.1423425

PubMed Abstract | Crossref Full Text | Google Scholar

145. Langley RGB, Krueger GG, and Griffiths CEM. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. (2005) 64 Suppl 2:ii18–23. doi: 10.1136/ard.2004.033217

PubMed Abstract | Crossref Full Text | Google Scholar

146. Ashida M, Koike Y, Kuwatsuka S, Ichinose K, Migita K, Sano S, et al. Psoriasis-like lesions in a patient with familial Mediterranean fever. J Dermatol. (2016) 43:314–7. doi: 10.1111/1346-8138.13068

PubMed Abstract | Crossref Full Text | Google Scholar

147. Barut K, Guler M, Erener-Ercan T, Sezen M, and Kasapcopur O. Increased frequency of psoriasis in the families of subjects with childhood Familial Mediterranean Fever. Pediatr Rheumatol. (2014) 12:P258. doi: 10.1186/1546-0096-12-S1-P258

Crossref Full Text | Google Scholar

148. Caturegli P, Kimura H, Rocchi R, and Rose NR. Autoimmune thyroid diseases. Curr Opin Rheumatol. (2007) 19:44–8. doi: 10.1097/BOR.0b013e3280113d1a

PubMed Abstract | Crossref Full Text | Google Scholar

149. Ergul AB, Dursun I, and Torun YA. Hashimoto’s thyroiditis in a child with familial mediterranean fever: a case report. Iran J Pediatr. (2013) 23:489–90.

PubMed Abstract | Google Scholar

150. Gulcan E, Gulcan A, Koplay M, Alcelik A, and Korkmaz U. Co-existence of Hashimoto’s thyroiditis with familial Mediterranean fever: is there a pathophysiological association between the two diseases? Clin Exp Immunol. (2009) 156:373–6. doi: 10.1111/j.1365-2249.2009.03891.x

PubMed Abstract | Crossref Full Text | Google Scholar

151. Dikbas O, Soy M, Bes C, Ankaralı H, Bugdayci G, and Zeyrek A. Thyroid autoimmunity in patients with Familial Mediterranean Fever: preliminary results. Eur Rev Med Pharmacol Sci. (2013) 17:3024–30.

PubMed Abstract | Google Scholar

152. Turan H, Yildiz M, Civan O, Cakir AD, Tarcin G, Ozer Y, et al. Evaluation of the thyroid disorders in children with familial Mediterranean fever. Clin Rheumatol. (2021) 40:1473–8. doi: 10.1007/s10067-020-05430-8

PubMed Abstract | Crossref Full Text | Google Scholar

153. Vergneault H, Bourguiba R, Ardois S, Dumont A, Savey L, Grateau G, et al. Thyroid disorders in familial Mediterranean fever: think about AA amyloidosis! Clin Rheumatol. (2021) 40:3381–2. doi: 10.1007/s10067-021-05852-y

PubMed Abstract | Crossref Full Text | Google Scholar

154. Kumar P and Subramaniyam G. Molecular underpinnings of Th17 immune-regulation and their implications in autoimmune diabetes. Cytokine. (2015) 71:366–76. doi: 10.1016/j.cyto.2014.10.010

PubMed Abstract | Crossref Full Text | Google Scholar

155. Bradshaw EM, Raddassi K, Elyaman W, Orban T, Gottlieb PA, Kent SC, et al. Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells. J Immunol. (2009) 183:4432–9. doi: 10.4049/jimmunol.0900576

PubMed Abstract | Crossref Full Text | Google Scholar

156. Dogan Y, Akarsu S, Ustundag B, Yilmaz E, and Gurgoze MK. Serum IL-1beta, IL-2, and IL-6 in insulin-dependent diabetic children. Mediators Inflamm. (2006) 2006:59206. doi: 10.1155/MI/2006/59206

PubMed Abstract | Crossref Full Text | Google Scholar

157. Hu C, Ding H, Li Y, Pearson JA, Zhang X, Flavell RA, et al. NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets. Proc Natl Acad Sci U S A. (2015) 112:11318–23. doi: 10.1073/pnas.1513509112

PubMed Abstract | Crossref Full Text | Google Scholar

158. Gicchino MF, Iafusco D, Zanfardino A, del Giudice EM, and Olivieri AN. A case report of a boy suffering from type 1 diabetes mellitus and familial Mediterranean fever. Ital J Pediatr. (2021) 47:127. doi: 10.1186/s13052-021-01077-6

PubMed Abstract | Crossref Full Text | Google Scholar

159. Atabek M, Pirgon O, Sert A, and Arslan U. Familial mediterranean fever associated with type 1 diabetes. Endocrinologist. (2006) 16:133–5. doi: 10.1097/01.ten.0000217875.07954.6e

Crossref Full Text | Google Scholar

160. Anwar GM, Fouad HM, Abd El-Hamid A, Mahmoud F, Musa N, Lotfi H, et al. A study of familial Mediterranean Fever (MEFV) gene mutations in Egyptian children with type 1 diabetes mellitus. Eur J Med Genet. (2015) 58:31–4. doi: 10.1016/j.ejmg.2014.10.005

PubMed Abstract | Crossref Full Text | Google Scholar

161. Bovolini A, Garcia J, Andrade MA, and Duarte JA. Metabolic syndrome pathophysiology and predisposing factors. Int J Sports Med. (2021) 42:199–214. doi: 10.1055/a-1263-0898

PubMed Abstract | Crossref Full Text | Google Scholar

162. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, and Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. (1996) 271:665–8. doi: 10.1126/science.271.5249.665

PubMed Abstract | Crossref Full Text | Google Scholar

163. Wang S, Leonard SS, Castranova V, Vallyathan V, and Shi X. The role of superoxide radical in TNF-alpha induced NF-kappaB activation. Ann Clin Lab Sci. (1999) 29:192–9.

Google Scholar

164. Stenlöf K, Wernstedt I, Fjällman T, Wallenius V, Wallenius K, and Jansson JO. Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects. J Clin Endocrinol Metab. (2003) 88:4379–83. doi: 10.1210/jc.2002-021733

PubMed Abstract | Crossref Full Text | Google Scholar

165. Xu E, Pereira MMA, Karakasilioti I, Theurich S, Al-Maarri M, Rappl G, et al. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nat Commun. (2017) 8:14803. doi: 10.1038/ncomms14803

PubMed Abstract | Crossref Full Text | Google Scholar

166. Lackey DE and Olefsky JM. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol. (2016) 12:15–28. doi: 10.1038/nrendo.2015.189

PubMed Abstract | Crossref Full Text | Google Scholar

167. McDermott MF. A common pathway in periodic fever syndromes. Trends Immunol. (2004) 25:457–60. doi: 10.1016/j.it.2004.07.007

PubMed Abstract | Crossref Full Text | Google Scholar

168. Balkarli A, Akyol M, Tepeli E, Elmas L, and Cobankara V. MEFV gene variation R202Q is associated with metabolic syndrome. Eur Rev Med Pharmacol Sci. (2016) 20:3255–61.

PubMed Abstract | Google Scholar

169. Gögebakan H, Akkececi NS, and Cetin GY. Relationship between metabolic syndrome and uric acid levels in patients with familial mediterranean fever. Arch Iran Med. (2019) 22:566–73.

PubMed Abstract | Google Scholar

170. Atef S, Marzouk H, El-khity MM, and Abu Shady HM. Metabolic syndrome among Egyptian children with Familial Mediterranean Fever: a case–control study. Egypt Pediatr Assoc Gaz. (2024) 72:56. doi: 10.1186/s43054-024-00297-9

Crossref Full Text | Google Scholar

171. Wisniowski B and Wechalekar A. Confirming the diagnosis of amyloidosis. Acta Haematol. (2020) 143:312–21. doi: 10.1159/000508022

PubMed Abstract | Crossref Full Text | Google Scholar

172. Griffin JM, Rosenblum H, and Maurer MS. Pathophysiology and therapeutic approaches to cardiac amyloidosis. Circ Res. (2021) 128:1554–75. doi: 10.1161/CIRCRESAHA.121.318187

PubMed Abstract | Crossref Full Text | Google Scholar

173. Benson MD, Buxbaum JN, Eisenberg DS, Merlini G, Saraiva MJM, Sekijima Y, et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid. (2018) 25:215–9. doi: 10.1080/13506129.2018.1549825

PubMed Abstract | Crossref Full Text | Google Scholar

174. Quinton LJ, Blahna MT, Jones MR, Allen E, Ferrari JD, Hilliard KL, et al. Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice. J Clin Invest. (2012) 122:1758–63. doi: 10.1172/JCI59408

PubMed Abstract | Crossref Full Text | Google Scholar

175. Ji YR, Kim HJ, Bae KB, Lee S, Kim MO, and Ryoo ZY. Hepatic serum amyloid A1 aggravates T cell-mediated hepatitis by inducing chemokines via Toll-like receptor 2 in mice. J Biol Chem. (2015) 290:12804–11. doi: 10.1074/jbc.M114.635763

PubMed Abstract | Crossref Full Text | Google Scholar

176. Papa R and Lachmann HJ. Secondary AA. Amyloidosis. Rheum Dis Clin North Am. (2018) 44:585–603. doi: 10.1016/j.rdc.2018.06.004

PubMed Abstract | Crossref Full Text | Google Scholar

177. Unverdi S, Inal S, Ceri M, Unverdi H, Batgi H, Tuna R, et al. Is colchicine therapy effective in all patients with secondary amyloidosis? Ren Fail. (2013) 35:1071–4. doi: 10.3109/0886022X.2013.811345

PubMed Abstract | Crossref Full Text | Google Scholar

178. Atagunduz MP, Tuglular S, Kantarci G, Akoglu E, and Direskeneli H. Association of FMF-related (MEFV) point mutations with secondary and FMF amyloidosis. Nephron Clin Pract. (2004) 96:c131–135. doi: 10.1159/000077375

PubMed Abstract | Crossref Full Text | Google Scholar

179. Tekin M, Yalçinkaya F, Cakar N, Akar N, Misirlioğlu M, Taştan H, et al. MEFV mutations in multiplex families with familial Mediterranean fever: is a particular genotype necessary for amyloidosis? Clin Genet. (2000) 57:430–4. doi: 10.1034/j.1399-0004.2000.570605.x

PubMed Abstract | Crossref Full Text | Google Scholar

180. Ait-Idir D, Djerdjouri B, Bouldjennet F, Taha RZ, El-Shanti H, Sari-Hamidou R, et al. The M694I/M694I genotype: A genetic risk factor of AA-amyloidosis in a group of Algerian patients with familial Mediterranean fever. Eur J Med Genet. (2017) 60:149–53. doi: 10.1016/j.ejmg.2016.12.003

PubMed Abstract | Crossref Full Text | Google Scholar

181. Altıparmak MR, Pamuk ÖN, Pamuk GE, Apaydın S, Ataman R, and Serdengeçti K. Amyloid goitre in familial mediterranean fever: report on three patients and review of the literature. Clin Rheumatol. (2002) 21:497–500. doi: 10.1007/s100670200122

PubMed Abstract | Crossref Full Text | Google Scholar

182. Ozdemir BH, Akman B, and Ozdemir FN. Amyloid goiter in Familial Mediterranean Fever (FMF): a clinicopathologic study of 10 cases. Ren Fail. (2001) 23:659–67. doi: 10.1081/jdi-100107362

PubMed Abstract | Crossref Full Text | Google Scholar

183. Abukhalaf SA, Dandis BW, Za’tari T, Amro AM, Alzughayyar TZ, and Rajabi YA. Familial mediterranean fever complicated by a triad of adrenal crisis: amyloid goiter and cardiac amyloidosis. Case Rep Rheumatol. (2020) 2020:7865291. doi: 10.1155/2020/7865291

PubMed Abstract | Crossref Full Text | Google Scholar

184. Turhan İyidir Ö, Altay M, Konca Degertekin C, Altınova A, Karakoç A, Ayvaz G, et al. Diffuse amyloid deposition in thyroid gland: a cause for concern in familial Mediterranean fever. Amyloid. (2012) 19:161–2. doi: 10.3109/13506129.2012.687701

PubMed Abstract | Crossref Full Text | Google Scholar

185. Vergneault H, Terré A, Buob D, Buffet C, Dumont A, Ardois S, et al. Amyloid goiter in familial mediterranean fever: description of 42 cases from a french cohort and from literature review. J Clin Med. (2021) 10:1983. doi: 10.3390/jcm10091983

PubMed Abstract | Crossref Full Text | Google Scholar

186. Moreno JCA, Eyzaguirre E, and Qiu S. Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case. Chronic Dis Transl Med. (2023) 9:266–8. doi: 10.1002/cdt3.79

PubMed Abstract | Crossref Full Text | Google Scholar

187. Bayard M, Holt J, and Boroughs E. Nonalcoholic fatty liver disease. Am Fam Physician. (2006) 73:1961–8.

PubMed Abstract | Google Scholar

188. Edmison J and McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis. (2007) 11:75–104. doi: 10.1016/j.cld.2007.02.011

PubMed Abstract | Crossref Full Text | Google Scholar

189. Anderson N and Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev. (2008) 60:311–57. doi: 10.1124/pr.108.00001

PubMed Abstract | Crossref Full Text | Google Scholar

190. Persico M, Capasso M, Persico E, Svelto M, Russo R, Spano D, et al. Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy. Hepatology. (2007) 46:1009–15. doi: 10.1002/hep.21782

PubMed Abstract | Crossref Full Text | Google Scholar

191. Rimar D, Rosner I, Rozenbaum M, and Zuckerman E. Familial Mediterranean fever: an association with non-alcoholic fatty liver disease. Clin Rheumatol. (2011) 30:987–91. doi: 10.1007/s10067-011-1718-1

PubMed Abstract | Crossref Full Text | Google Scholar

192. Sarkis C, Caglar E, Ugurlu S, Cetinkaya E, Tekin N, Arslan M, et al. Nonalcoholic fatty liver disease and familial Mediterranean fever: are they related? Srp Arh Celok Lek. (2012) 140:589–94. doi: 10.2298/sarh1210589s

PubMed Abstract | Crossref Full Text | Google Scholar

193. Tasliyurt T, Gokce E, Sahin S, Aslan AB, Demir AK, Uzun S, et al. Prevalence of nonalcoholic fatty liver disease in familial mediterranean fever. Endocr Metab Immune Disord Drug Targets. (2020) 20:952–8. doi: 10.2174/1871530320666200220125829

PubMed Abstract | Crossref Full Text | Google Scholar