PURPOSE OF REVIEW: Genetic autoinflammatory conditions constitute an increasing field. Among them, type I interferonopathies (IFNp-I) were conceptualized 15 years ago as inborn errors of immunity due to chronic activation of the type I interferon (IFN-I) signalling pathway. Here, we provide recent insights in genetic mechanisms, clinical phenotypes and therapeutic options for these severe and rare disorders. RECENT FINDINGS: We will cover the novel findings into disease mechanisms, particularly the role of PTP1B in STING and IFNAR signalling, as well as the contribution of endosomal TLR pathways. We will also discuss the expanding phenotypic spectrum highlighted by recent case reports and cohort studies, together with the topic of clinical expressivity, including clinical non-penetrance, and possible mechanistic explanations such as monoallelic expression, the STING HAQ haplotype, and innovative approaches to characterise disease variability. Finally, we discuss current targeted therapeutic approaches for these disabling conditions, as well as potential new treatments for the future. SUMMARY: Overall, these findings highlight the need to consider these rare diseases across a wide range of clinical phenotypes. Advances in next-generation sequencing have enabled a genetic diagnosis in suspected cases and the implementation of targeted treatments, thereby reducing diagnostic uncertainty and providing the possibility of genetic counselling.
The development and implementation of genetic testing has revolutionized the diagnostic landscape of autoinflammatory diseases, leading to an exponential increase in the identification of disease-associated genetic variants. Yet a substantial proportion of these are considered variants of uncertain significance (VUS), complicating both diagnosis and therapeutic decision-making. This challenge is relevant not only for monogenic systemic autoinflammatory diseases, but also in the context of genetically complex disorders that can involve multiple low-penetrance variants. Advances in protein structure prediction tools, machine learning and artificial intelligence provide powerful computational frameworks for the classification of variants; however, their predictive accuracy must be benchmarked against functional assays, particularly with respect to gain-of-function variants. Functional screening approaches benefit from both technological progress and expanding knowledge of the innate immune pathways underlying systemic autoinflammatory diseases. Large-scale analyses of variants including multiplexed functional assays and deep mutational scanning experiments have enabled the assessment of hundreds of variants, notably in NLRP3, MEFV and ADA2, generating datasets that improve variant interpretation and genetic diagnosis. Altogether, these advances increase the potential of accurately predicting in the near future the effects of missense VUS, although numerous challenges remain to be addressed, especially those concerning our understanding of the influence of non-coding VUS in systemic autoinflammatory diseases.
Objectives This study aimed to investigate whether growth differentiation factor-15 (GDF-15) can serve as a potential biomarker for assessing subclinical inflammation during the attack-free (intercritical) period in patients with familial Mediterranean fever (FMF). Methods In a single-center cross-sectional case–control study, 52 FMF patients in the attack-free period were compared with 52 age- and sex-matched healthy controls. ELISA measured serum GDF-15 levels; acute-phase reactants (CRP, ESR, SAA, fibrinogen) and various hematologic inflammation indices were evaluated. Statistical analyses included the Mann–Whitney U, chi-square, Kruskal–Wallis, Spearman correlation, and ROC curve methods. Results Serum GDF-15 levels were significantly higher in the FMF group than in controls (p 10 mg/L, was detected in 78.8% of FMF patients. GDF-15 correlated positively with CRP and SAA (p < 0.05). GDF-15 levels did not differ across MEFV mutation subgroups or by the presence of the M694V mutation. Patients with subclinical inflammation had significantly higher GDF-15 levels than those without. ROC analysis showed that GDF-15 had a statistically significant ability to distinguish FMF from controls (AUC = 0.78; p < 0.001) and to identify subclinical inflammation (AUC = 0.74; p = 0.014). Conclusion GDF-15 appears to be a potential biomarker reflecting ongoing subclinical inflammation during the attack-free period in FMF. Elevated GDF-15 levels in patients with SAA-defined subclinical inflammation suggest that GDF-15 may reflect low-grade inflammatory activity. Larger studies are needed to validate these findings. Key Points • Serum GDF-15 was significantly higher in the attack-free FMF patients than in controls, supporting its potential to reflect persistent low-grade (subclinical) inflammation. • GDF-15 showed moderate discriminative performance (AUC 0.783) and may complement conventional acute-phase reactants in assessing inflammatory burden during attack-free periods. • GDF-15 levels did not differ significantly across MEFV
Our study results show that acute scrotum and epididymo-orchitis were the most frequent urological manifestations in FMF, and testicular amyloidosis and fertility impairment were also notable. These findings highlight the importance of considering urological involvement as part of the FMF spectrum in clinical practice.
Inflammasome-mediated activation of interleukin (IL)-1β and IL-18 plays a key role in the pathogenesis of adult-onset Still's disease (AOSD), a systemic autoinflammatory disorder. The cleaved free active form of IL-18 may more accurately reflect inflammasome activity than total IL-18, which includes pro-IL-18, free active IL-18, and IL-18 bound to IL-18-binding protein. This study aimed to measure serum active IL-18 levels in patients with AOSD and evaluate their clinical and diagnostic significance. Serum samples were obtained from 47 untreated patients with AOSD, 42 patients with rheumatoid arthritis (RA), 9 patients with familial Mediterranean fever (FMF), and 26 healthy controls (HCs). Active IL-18 was quantified using a specific ELISA detecting cleaved, biologically active IL-18, and 69 cytokines were analyzed in patients with AOSD using a multiplex suspension array. Correlations between active IL-18 and other cytokines, clinical parameters, and the reactive hemophagocytic syndrome diagnostic score (HScore) were evaluated, and discriminative performance was assessed using receiver operating characteristic analysis. Serum levels of active IL-18 were significantly higher in patients with AOSD than in those with RA, FMF, and HCs (all p < 0.001). Active IL-18 levels positively correlated with the Pouchot score (p < 0.001), serum ferritin level (p = 0.004), and C-reactive protein level (p = 0.004) and decreased significantly after immunosuppressive therapy (p = 0.003). Active IL-18 significantly and positively correlated with total IL-18, macrophage colony-stimulating factor, basic fibroblast growth factor, leukemia inhibitory factor, chemokine (C-X-C motif) ligand 9, and IL-12 (p40), all of which were significantly correlated with the HScore. Elevated active IL-18 levels were associated with rashes and splenomegaly. Among the evaluated biomarkers, active IL-18 showed the highest diagnostic accuracy for AOSD (cutoff > 4,231.1 pg/mL; sensitivity, 89.4%; specificity, 92.9%;
Colchicine prophylaxis significantly reduces PFAPA attack frequency, with therapeutic benefits that are independent of FMF genetic status. These findings support colchicine as an effective first-line prophylactic treatment for PFAPA patients with frequent episodes or families concerned about frequent steroid use, representing a paradigm shift from reactive to preventive management.
Colchicine non-adherence is frequent in paediatric FMF and largely unrelated to patient factors. Objective tools such as MASIF reveal higher non-adherence rates than self-reports and are essential for accurate evaluation in clinical decision making.
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. Colchicine is the first-line treatment, yet 5-10% of patients are resistant, increasing the risk of complications like amyloidosis. In 2023, Batu et al proposed the Turkish Paediatric Autoinflammatory Diseases (TURPAID) score to predict colchicine resistance in paediatric FMF at diagnosis. Its utility in broader populations is unknown. We assessed its performance in paediatric and adult FMF patients from the international Juvenile Inflammatory Rheumatism (JIR) cohort. We retrospectively analysed 236 genetically confirmed FMF patients treated with colchicine for ≥6 months. Patients were classified as colchicine-sensitive (CoS) or colchicine-resistant (CoR) based on the initiation of biologic therapy, which served as an operational definition of resistance, and matched for age and sex. The TURPAID score (range 0-4; resistance threshold ≥2) was retrospectively applied. Receiver operating characteristic (ROC) curves were used to assess predictive value. A TURPAID score ≥2 was observed in 89% of paediatric and 76% of adult CoS patients. Mean scores were significantly higher in paediatric-onset FMF. ROC analysis showed poor discrimination in both paediatric and adult groups (area under the curve=0.6). Clinical features and attack patterns varied by age. The genetic component (1.5 points for MEFV exon 10 mutations) contributed to overclassification, reducing predictive accuracy. The TURPAID score did not effectively predict colchicine resistance in the JIR cohort. Its limited generalisability may stem from age-related differences, recall bias and excessive genetic weighting. Genetic results should be a prerequisite and not a determinant of colchicine resistance prediction scores in FMF.
To evaluate the diagnostic yield of whole-exome sequencing (WES) vs targeted gene panel (TGP) testing in patients evaluated for autoinflammation at the Great Ormond Street Hospital Autoinflammation Centre of Excellence. We retrospectively analysed 476 patients who underwent TGP testing between 2015 and 2022, and 210 patients who underwent WES between 2022 and 2025. Analysis of WES data combined: (i) a virtual gene panel of genes (germline and somatic) associated with inflammation; (ii) agnostic filtering according to ClinVar classification of pathogenicity; (iii) copy number variant analysis using ExomeDepth; and (iv) phenotype-driven prioritization using Exomiser. TGP testing identified molecular diagnoses in 71/476 patients (14.9%). WES increased the molecular diagnostic yield to 41/210 patients (19.5%). WES also enabled the discovery of novel genotype-phenotype associations. Significant incidental findings were identified in 29/210 (13.8%) of the cases, including variants predisposing to cancer or cardiomyopathy. In patients with suspected autoinflammation, WES increased diagnostic yield compared with TGP testing, while providing additional clinical value through novel gene discovery and capacity for future systematic reanalysis of unsolved cases. Incidental findings required careful and explicit a priori patient counselling and informed consent before offering WES. While there will be an inevitable shift from WES to whole-genome sequencing in the future, significant challenges remain for WGS, including costly large-data handling and storage, and uncertainty about the interpretation of variants in non-exonic regions. Our findings, therefore, demonstrate the significant clinical impact of WES for the work-up of autoinflammation, with pragmatic utility for timely return of results.
This study evaluated the efficacy, safety, and drug retention of anakinra and canakinumab in pediatric patients with colchicine-resistant familial Mediterranean fever (cr-FMF) within a real-world cohort. This retrospective cohort study was conducted from June 2016 to April 2024, including 86 patients diagnosed with cr-FMF. Clinical and laboratory parameters, including attack frequency, C-reactive protein (CRP), serum amyloid A (SAA), and autoinflammatory disease activity index (AIDAI) scores, were recorded at baseline and during follow-up. A total of 86 patients (50 females, 36 males) were included in the study. All carried exon 10 MEFV mutations, with 69 patients (80.2%) having the M694V/M694V genotype. Anakinra was initiated in36 patients (41.9%), and canakinumab in 50 patients (58.1%). The median treatment duration was significantly longer for canakinumab (48 months) compared to anakinra (7 months) (p<0.001). Both treatments significantly reduced attack frequency, AIDAI scores, CRP, and SAA levels compared to baseline (p<0.001). While the reduction in attack frequency was comparable between the groups, patients treated with canakinumab achieved significantly lower mean AIDAI scores at 12 months compared to the anakinra group (p = 0.021). Anakinra provided a more rapid onset of symptom control but was commonly discontinued due to injection site reactions (44.4%). Canakinumab was associated with sustained long-term disease control with fewer local side effects. However, rare serious events, including acute myeloid leukemia and inflammatory bowel disease, were observed, though causality with treatment could not be established. In this pediatric cohort of cr-FMF patients, both anakinra and canakinumab were effective in reducing disease activity and inflammation. Anakinra offered rapid symptom relief but had frequent injection site reactions. Canakinumab provided sustained control with fewer local side effects but required monitoring for rare complications.
Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent febrile attacks and serositis, with a high prevalence and carrier frequency of MEFV variants in eastern Mediterranean populations. In this setting, interpretation of MEFV variants of uncertain significance (VUS) is challenging, and their clinical relevance remains controversial. We aimed to describe the clinical characteristics of patients carrying mono- or biallelic MEFV VUS and to compare them with patients harbouring biallelic pathogenic MEFV variants, including assessment of FMF and PFAPA classification according to Eurofever/PRINTO criteria. This retrospective study included paediatric patients with recurrent autoinflammatory manifestations who underwent MEFV genetic analysis and were receiving colchicine. Patients were stratified by MEFV genotype, and clinical features, attack characteristics, treatment profiles and classification status were compared. Patients with MEFV VUS exhibited fewer classical FMF features, such as serositis-related chest pain and arthritis, but more frequent atypical manifestations, including diarrhoea, oral aphthae and lymphadenopathy, along with longer attack duration. Measures of disease burden, including age at onset and attack frequency, were similar between groups. FMF criteria were fulfilled by approximately half of patients with VUS. Patients with autoinflammatory disease carrying MEFV variants of uncertain significance may exhibit atypical clinical features. Alternative diagnoses should be considered, and further genetic evaluation may be required.
FMF is a monogenic autoinflammatory disease caused by MEFV mutations, with amyloidosis as its most severe complication. This study aimed to compare logistic regression, random forest, and gradient-boosting models to predict amyloidosis in FMF patients. Patients with FMF diagnosed between 1990 and 2022 at Cerrahpaşa Faculty of Medicine were retrospectively screened. Eligible patients with available clinical records were included. Clinical, genetic, and laboratory variables were extracted. Univariate analyses and pooled multivariate logistic regression were conducted. Logistic regression, random forest, and gradient-boosting machine-learning models were developed. Models were optimized by hyperparameter tuning and evaluated on a held-out test set. Of the 615 FMF patients included, 58 (9.4%) had amyloidosis. Patients with amyloidosis had earlier symptom onset, longer diagnostic delay and disease duration, were more often male, and more frequently carried M694V homozygosity. Comorbidities, parental consanguinity, frequent infections, erysipelas-like erythema, myalgia, arthritis, and higher median CRP levels were more prevalent in the amyloidosis group. In multivariate analysis, disease duration, M694V homozygosity, comorbidity, parental consanguinity, frequent infections, and erysipelas-like erythema were independently associated with amyloidosis. Random forest achieved the best performance on the test set (area under the receiver operating characteristic = 0.784), followed by logistic regression (0.766) and gradient boosting (0.749). SHAP analysis identified M694V homozygosity, myalgia, erysipelas-like erythema, disease duration, and arthritis as the strongest contributors to amyloidosis prediction. Amyloidosis, the most severe FMF complication, is driven by key clinical and genetic factors, with ensemble machine-learning models outperforming conventional regression for early risk prediction.
Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease with variable manifestations across Mediterranean regions. This study compares FMF cohorts from Italy (Apulia) and Lebanon. We analyzed a cohort of 443 FMF patients, 165 Italians (females: males = 90:75) and 278 Lebanese (females: males = 173:105). Clinical records/interviews provided data on demographics, MEFV genetic testing, and treatments. A 55-item questionnaire in 54 Italians and 42 Lebanese patients assessed disease knowledge, management, misdiagnoses, attack frequency (yearly), duration (days), body temperature, symptoms prevalence and frequency, and severity score before/after treatment. Italians were significantly older at disease onset, diagnosis, and had longer diagnostic delay than Lebanese patients (p < 0.00001). The most common MEFV variants were E148Q and R202Q in Italians, and M694V and E148Q in Lebanese, with fewer pathogenic and homozygous cases in Italians. Italian patients had lower prevalence of FMF symptoms (10-92% vs. 30-99%; p < 0.00001) and fewer attacks. All Italians received treatment compared to 88.5% of Lebanese. Colchicine was first-line treatment, while biological drug use was higher in Italians. In the subgroups study, Italians reported lower disease knowledge and were followed up mainly by internists, while Lebanese were followed up by gastroenterologists or pediatricians. Italians were misdiagnosed with appendicitis, whereas Lebanese were misdiagnosed with gastrointestinal diseases. Italians exhibited lower symptom frequency, lower severity scores, and a better response compared to Lebanese patients. In conclusion, FMF presentation differed by country, with Italians showing milder symptoms and better treatment response, while Lebanese showed severe symptoms linked to pathogenic MEFV variants. Gene-environment interactions require further studies.
Exertional leg pain (ELP) is an underrecognized manifestation of FMF with unclear pathophysiology. This study performed a comprehensive ultrasonographic evaluation of lower-extremity joints, tendons and entheses in paediatric FMF patients with ELP, comparing findings with non-ELP patients and matched healthy controls. Paediatric FMF patients carrying homozygous or compound heterozygous pathogenic MEFV variants were enrolled in this prospective study. Demographic, anthropometric and clinical data were collected, while a blinded operator performed standardized ultrasonographic evaluations. A total of 50 patients and 25 heathy controls were included (25 with ELP, 25 without). No differences were observed between the groups in demographic, anthropometric or FMF-related factors, including MEFV mutations and ISSF scores. Among the evaluated parameters, Achilles tendon thickness was significantly increased in children with ELP, independent of demographic or anthropometric factors, compared with both healthy and non-ELP group (P < 0.01). Nine patients exhibited grade 1 knee synovial effusions, predominantly in the ELP cohort, most with subclinical inflammation. One patient with ELP demonstrated enthesitis and was diagnosed with HLA-B27-negative ERA. Patellar tendon and plantar fascia thickness were comparable. Paediatric FMF patients with ELP demonstrated increased achilles tendon thickness. Although no standardized cut-off exists for tendinopathy, this may reflect tendon structural changes related to ELP. Moreover, FMF patients, particularly those with ELP, exhibited inter-attack knee effusions which may serve as a marker for subclinical inflammation. Larger longitudinal cohorts are needed to define ELP, elucidate its underlying pathways and clarify the clinical significance of Achilles tendon thickening.
To examine the demographic and clinical features of paediatric familial Mediterranean fever (FMF) patients with a heterozygous Mediterranean fever (MEFV) gene mutation, focusing on colchicine discontinuation and factors linked to sustained remission. This retrospective study included 2325 paediatric FMF patients followed at a tertiary rheumatology clinic between August 2016 and February 2024. Of these, 1246 carried a heterozygous MEFV mutation, and 87 had stopped colchicine. Discontinuation was either physician decision (PD) or initiated by family/patient decision (FD). Demographic data, clinical symptoms, colchicine use, and MEFV variants were recorded. Patients were monitored after discontinuation to assess remission and the need for retreatment. Of 87 patients, 47 (54%) were discontinued under PD and 40 (46%) under FD. The median discontinuation age was 10.8 years in PD and 11.7 years in FD. Colchicine was reinitiated in 25 patients (28.7%): 11 (4.0%) from PD and 14 (56.0%) from FD. Drug-free remission was maintained in 62 patients (71.3%), including 36 PD (58.1%) and 26 FD (41.9%) (p = 0.45). The pre-discontinuation asymptomatic period was significantly longer in PD (p < 0.01). PD patients also had a lower risk of reinitiating treatment than FD patients (p = 0.046). Older age at discontinuation was associated with sustained remission (p = 0.01). Colchicine withdrawal under physician supervision and at older ages is associated with a lower risk of relapse and greater likelihood of maintaining drug-free remission.
FMF is highly prevalent in Mediterranean countries and represents a substantial proportion of paediatric rheumatology patients. Colchicine, the mainstay of treatment, requires lifelong daily use, yet long-term adherence remains challenging, leading to recurrent attacks and increased healthcare burden. This study aimed to develop a freely downloadable mobile application to improve medication adherence by providing reminders and enabling direct communication with physicians. The application was designed as a structured medication-timing and monitoring tool, providing time-specific medication reminders, real-time intake confirmation ('taken/missed') and digital adherence tracking. The user interface was tailored to the needs of patients and parents, considering children's attention span, parental workload and health literacy. Following pilot testing in seven volunteer patients, the application was refined based on user feedback. Physicians used a web-based panel to register patients, define prescriptions and treatment schedules, and assign calendar-based appointments. Medication adherence was assessed using the MASIF scale, and disease activity was evaluated using the AIDAI score. A total of 93 patients with FMF were included in the study. Before application use, adherence was low, with a median MASIF score of 44 and most patients demonstrating poor adherence. After implementation, MASIF scores significantly improved at 3, 6 and 12 months, with a marked reduction in poorly adherent patients (P < 0.001). AIDAI scores and attack frequency significantly decreased, and no patient had an AIDAI score >9 during follow-up. Agreement between application-measured adherence and MASIF scores was excellent (ICC > 0.90). Mobile reminder applications are low-cost, accessible digital health tools with strong potential to enhance medication adherence in FMF patients.
To evaluate for the first time a combination of novel colour Doppler ultrasound (CDUS), greyscale (GSUS) and oscillometric indices of angiopathy in patients with autoinflammatory syndromes (AIS). Further, to explore the associations between these markers and patient- and disease-related characteristics, as well as traditional cardiovascular (CV) risk factors. CDUS was used to assess arterial compliance markers, such as resistance index, pulsatility index (PI) and flow-velocity integral (FVI) in the common carotid artery (CCA) of AIS patients and healthy controls. Additionally, GSUS was employed to measure carotid intima-media thickness (cIMT), detect plaques and quantify total calcification surface. Oscillometry was utilized to evaluate aortic stiffness by carotid-femoral pulse wave velocity (cfPWV). Thirty-one patients with AIS and 62-matched (1:2) healthy controls were recruited. AIS patients exhibited higher CCA-PI [1.89 (0.46) vs 1.59 (0.32), P = 0.024] and peak systolic velocity (80.15 vs 64.95 cm/s, P = 0.003), compared with controls. Moreover, AIS patients not receiving biologic therapy demonstrated significantly higher cfPWV [6.99 (1.71) vs 5.86 (0.81) m/s, P = 0.001]. cfPWV and cIMT were predicted by age (cfPWV: rho = 0.573, P < 0.001; cIMT: rho = 0.675, P = 0.002), systolic arterial pressure (SAP) (cfPWV: r = 0.464, P = 0.009; cIMT: rho = 0.514, P = 0.029) and lymphadenopathy (cfPWV: eta = 0.373, P = 0.039). PI associated with nicotine (rho = 0.691, P = 0.008) and FVI (inversely) with SAP (rho = -0.522, v0.026). In the first CV surrogate marker study in AIS combining oscillometry and arterial US, patients exhibited increased carotid pulsatility and altered flow dynamics vs controls. Aortic stiffness was lower in patients receiving biologics and mainly predicted by traditional CV factors and lymphadenopathy. Angiopathy markers may reveal significant vascular abnormalities in AIS patients, improving CV screening and risk classification.
Exertional leg pain (ELP) is a distinctive musculoskeletal manifestation of familial Mediterranean fever (FMF), associated with severe disease and chronic inflammation. Despite adequate control of disease activity with colchicine, ELP often persists and contributes to disability, creating a serious unmet therapeutic need. This exploratory study evaluated the efficacy of IL-1 blockers in alleviating ELP in colchicine-resistant FMF (CR-FMF) patients. Twenty-seven CR-FMF patients treated with IL-1 blockers (23 canakinumab, four anakinra) at the Sheba Medical Center FMF clinic were included. Patients retrospectively assessed ELP severity and quality of life (QOL), using a 0-10 visual analogue scale (VAS), before and during IL-1 blocker treatment. The primary end point was reduction in ELP severity, measured by change in VAS pain score. The cohort exhibited a severe phenotype (mean pre-treatment annual attack rate 50.69 ± 35.4; 55.5% M694V homozygous; 11% with amyloidosis). Following IL-1 blockade, 52% (14/27) of patients reported improvement in ELP. Mean pain scores decreased by 3.0 ± 3.68 points (P = 0.0003), and QOL scores improved by 3.07 ± 3.73 points (P = 0.0002). Residual ELP severity correlated strongly and negatively with QOL under biological treatment (r = -0.73, P < 0.0001). IL-1 blockers provide meaningful benefit in approximately half of patients with FMF-related ELP, supporting their role as a therapeutic option for this refractory manifestation. However, the persistence of ELP in a substantial proportion of patients underscores the need for additional therapeutic strategies to address this disabling manifestation.
To examine cross-national accessibility and reimbursement policies for IL-1 inhibitors in FMF treatment and compare national guidelines. As part of the Clinical Practice Strategies (CLiPS) project, data on biologic DMARD (bDMARD) access and reimbursement were collected through questionnaires distributed to paediatric and adult rheumatologists and national representatives of the project. CLiPS representatives from non-responding countries were contacted via email. National FMF treatment guidelines were retrieved from PubMed, MEDLINE, Scopus and Google Scholar searches without language restrictions. Analysis focused on colchicine resistance, intolerance, adverse events, biologic indications and IL-1 inhibitor availability. We examined 39 countries and obtained national guidelines from 11. Country representatives indicated the use of EULAR 2016 recommendations as their guidelines in seven further countries. Anakinra was available for colchicine-resistant FMF treatment in 29 of 39 countries and covered by national health insurance in 23 of these 29 (79.3%). Canakinumab was accessible in 23 of 39 countries, with reimbursement in 21 of 23 (91.3%). Eighteen countries imposed additional prescription and reimbursement restrictions for bDMARDs in FMF patients. Significant multi-country disparities exist for the prescription of IL-1 inhibitors in FMF, with variations in national guidelines, drug availability and reimbursement. Standardized treatment guidelines and equitable access to therapies are essential to improve patient care.