Generation of iPSCs from a Patient with the M694V Mutation in the MEFV Gene Associated with Familial Mediterranean Fever and Their Differentiation into Macrophages.

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene, located on chromosome 16 (16p13.3) and encoding the pyrin protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of the pathological processes leading to the spontaneous and recurrent autoinflammatory attacks observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool to study the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs from an Armenian patient with FMF carrying the M694V, p.(Met694Val) (c.2080A>G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. We found that the morphology of macrophages derived from iPSCs of a patient with the MEFV mutation significantly differed from that of macrophages derived from iPSCs of a healthy donor carrying the wild-type MEFV gene.

Health conditions of first-degree relatives of children with familial Mediterranean fever.

BACKGROUND: Given the strong genetic background of familial Mediterranean fever (FMF), the frequently reported co-existing diseases in children with FMF should also be investigated in other family members. Therefore, we aimed to examine the medical conditions of first-degree relatives (FDRs) of our pediatric patients with FMF in the present study. METHODS: Chronic diseases of FDRs of pediatric 449 FMF, 147 juvenile idiopathic arthritis (JIA) patients and 93 healthy controls (HC) were questioned during their routine clinical visits for 9 consecutive months. RESULTS: A total of 1975 FDRs of 449 FMF, 690 FDRs of 147 JIA patients, and 406 FDRs of 93 HC were included into the study. The most common medical conditions were non-atopic asthma (n=71, 3.6%), type 2 DM (n=14, 2%), and tonsillectomy history (n=12, 2.95%) in the FMF, JIA, and HC groups, respectively. Atopic diseases (FMF vs. JIA: p=0.013; FMF vs. HC: p=0.014), rheumatic diseases (FMF vs. JIA: p=0.030; FMF vs. HC: p=0.017), and surgical histories (FMF vs. JIA: p<0.01; FMF vs. HC: p=0.026), including adenoidectomy, tonsillectomy, and appendectomy, were significantly more common in the FMF group than in other groups. CONCLUSIONS: Our novel findings may contribute to understanding the hereditary burden of co-existing diseases in children with FMF and encourage further studies involving genetic screenings.

Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (ß1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (ß1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (ß1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (ß1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (ß1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (ß1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing?

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.

Canakinumab treatment real world evidence in 3 monogenic periodic fever syndromes in 2009-2022: an interim analysis using the French JIR cohort database.

BACKGROUND: Our study aimed to provide real-world evidence on the treatment patterns, effectiveness and safety of canakinumab in France in Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD), and Tumor necrosis factor Receptor Associated Periodic Syndrome (TRAPS). METHODS: This study used the JIR cohort, a multicentre international registry created in 2013 to collect data on patients with juvenile inflammatory rheumatic diseases. French patients diagnosed with FMF, MKD or TRAPS and treated with canakinumab were included in this study. RESULTS: 31 FMF, 26 MKD and 7 TRAPS patients received canakinumab during the study period. Most of them initiated canakinumab at the recommended dose of 2 mg/kg or 150 mg, but less than half of FMF and MKD patients initiated it at the recommended frequency (every 4 weeks). Two years after initiation, the rate of patients still on treatment was 78.1% in FMF, 73.7% in MKD, and 85.7% in TRAPS patients. While the dose per injection remained globally the same over the course of the treatment, some adjustments of the dose intervals were observed. Six patients had a severe adverse event reported. Of those, three were possibly related to canakinumab. CONCLUSION: This interim analysis showed a good maintenance of canakinumab treatment 2 years after initiation and confirmed its safety profile in real-life practice in France in patients diagnosed with FMF, MKD and TRAPS. The high variety of dose and interval combinations observed in canakinumab treated patients let suppose that physicians adapt the posology to individual situations rather than a fixed treatment plan.

Predicting genetic risk factors for AA amyloidosis in Algerian patients with familial Mediterranean fever.

Renal amyloid-associated (AA) amyloidosis is a harmful complication of familial Mediterranean fever (FMF). Its occurrence involves polymorphisms and mutations in the Serum Amyloid A1 (SAA1) and Mediterranean Fever (MEFV) genes, respectively. In Algeria, the association between SAA1 variants and FMF-related amyloidosis was not investigated, hence the aim of this case-control study. It included 60 healthy controls and 60 unrelated FMF patients (39 with amyloidosis, and 21 without amyloidosis). All were genotyped for the SAA1 alleles (SAA1.1, SAA1.5, and SAA1.3), and a subset of them for the - 13 C/T polymorphism by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comparisons between genotype and allele frequencies were performed using Chi-square and Fisher tests. The SAA1.1/1.1 genotype was predominant in amyloid FMF patients, compared to non-amyloid FMF patients (p = 0.001) and controls (p < 0.0001). SAA1.1/1.5 was higher in non-amyloid patients (p = 0.0069) and in controls (p = 0.0082) than in patients with amyloidosis. Bivariate logistic regression revealed an increased risk of AA amyloidosis with three genotypes, SAA1.1/1.1 [odds ratio 7.589 (OR); 95% confidence interval (CI): 2.130-27.041] (p = 0.0018), SAA1.1/1.3 [OR 5.700; 95% CI: 1.435-22.644] (p = 0.0134), and M694I/M694I [OR 4.6; 95% CI: 1.400-15.117] (p = 0.0119). The SAA1.1/1.5 genotype [OR 0.152; 95% CI: 0.040-0.587] (p = 0.0062) was protective against amyloidosis. In all groups, the - 13 C/C genotype predominated, and was not related to renal complication [OR 0.88; 95% CI: 0.07-10.43] (p = 0.915). In conclusion, in contrast to the - 13 C/T polymorphism, the SAA1.1/1.1, SAA1.1/1.3 and M694I/M694I genotypes may increase the risk of developing renal AA amyloidosis in the Algerian population.

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry.

OBJECTIVE: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). METHODS: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. RESULTS: At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. CONCLUSION: Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.

Unraveling the genome: Familial Mediterranean fever.

ABSTRACT: Familial Mediterranean fever (FMF) is an inherited, autoinflammatory disease with a high prevalence in Middle Eastern and Mediterranean populations including Turks, Iranian, Spanish, Sephardic Jews, Arabs, and other Mediterranean ethnic groups. Autoinflammatory diseases are genetically predetermined disorders with multisystem effects primarily caused by defects in innate immunity. Although primarily known for an autosomal recessive mode of inheritance, there are increasing case reports associated with single Mediterranean fever (MEFV) mutation or dominant transmission. There have been over 300 variants identified in the MEFV gene; however, roughly 9-11 variants are responsible for the phenotypical expression seen with FMF. Symptoms include recurrent episodes of fever of unknown origin, abdominal, chest, or joint pain because of serosal inflammation. Persistent elevations in serum amyloid A can lead to complications like renal amyloidosis, kidney dysfunction, and end-stage kidney disease. Familial Mediterranean fever is diagnosed clinically using the Tel-Hashomer criteria and confirmed through genetic testing. Treatment includes initiation of colchicine with the goal of stopping attacks and preventing renal dysfunction and end-stage kidney disease. Genetic testing helps to identify the specific mutation allowing the provider to create a patient-specific treatment plan, monitor for complications such as renal amyloidosis, and enhance knowledge on the genetic heterogeneity and possible epigenetic factors.

Malignant Peritoneal Mesothelioma Complicating Familial Mediterranean Fever on 18 F-FDG PET/CT.

ABSTRACT: A 77-year-old man with a personal history of familial Mediterranean fever presented with a slowly enlarging tumefaction of the left abdominal wall and persistent inflammatory syndrome despite good adherence to colchicine. 18 F-FDG PET/CT showed a hypermetabolic muscular mass of the abdominal wall along with other hypermetabolic lesions including a peritoneal mass and several subcutaneous soft tissue nodules. CT-guided needle biopsy led to the diagnosis of a muscular localization of a malignant peritoneal mesothelioma, which is an extremely rare complication of familial Mediterranean fever. Six courses of chemotherapy with carboplatin and pemetrexed allowed an almost complete response.

Evaluation of the Inflammatory Response After Eradication of Helicobacter pylori in Patients With Familial Mediterranean Fever.

PURPOSE: Evaluation of the inflammatory response after Helicobacter pylori (Hp) eradication in patients with Familial Mediterranean Fever (FMF) during the non-attack period and determining whether there is a change in the ongoing inflammation during the non-attack period. MATERIALS AND METHODS: Sixty-four patients, who have not been eradicated for Hp in the last 2 years, diagnosed with FMF, and evaluated in the non-attack period, were included in the study. Hp eradication therapy was administered to patients who were found to be Hp-positive. C-reactive protein (CRP), high-sensitive C-reactive protein (hs-CRP), interleukin-6, interleukin-8, tumor necrosis factor-alpha, and serum amyloid A values were compared between the groups before and after eradication. RESULTS: CRP and hs-CRP levels were found to be statistically higher in the FMF group than in the control group. A statistically significant decrease was found in the values of CRP and hs-CRP, in the number of patients with attacks, and in attack frequency after eradication in the Infected Patients compared to the values before eradication. CONCLUSIONS: We determined a decrease in CRP and hs-CRP values, the number of patients with attacks, and attack frequency with the eradication of Infected Patients. In patients with FMF, in whom it has been proven by different studies that the inflammation continues during the non-attack period, it may be recommended to investigate the presence of Hp infection, which is thought to contribute to this inflammation and to give Hp eradication therapy to patients who are found positive to reduce the development of secondary complications caused by chronic inflammation.

Cleavage-resistant RIPK1-induced autoinflammatory syndrome-A report of three generations with periodic fever and clinical response to colchicine.

The clinical syndrome caused by cleavage-resistant RIPK1 is known as CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome. We present a family with three generations affected by CRIA syndrome. Our index patient (P1), a boy born of a non-consanguineous marriage, developed recurrent episodes of fever after 5 months of age, with variable periodicity. His father (P2) and paternal grandmother also had periodic fever. At 23 months of age, P1 was diagnosed with renal biopsy-proven steroid-responsive nephrotic syndrome. His first visit to our center was at 2 years of age. At presentation, he had failure to thrive, microcytic hypochromic anemia, and elevated inflammatory markers and interleukin-6 levels. Amyloid A protein was elevated, serum creatinine was normal, and proteinuria resolved after addition of steroids. Next-generation sequencing showed heterozygous mutation (c.970G>A, p.Asp324His) in RIPK1. This mutation has been reported to cause CRIA syndrome. P2 and P1's asymptomatic younger brother had the same mutation. All the affected members showed variability with respect to frequency and duration of periodic fever as well as the age of onset. Both P1 and P2 had elevated amyloid A, with no evidence of renal dysfunction. P1 and P2 showed improvement in the intensity of fever spikes with colchicine treatment; however, both continue to have periodic fever.

Gut microbiota alterations are associated with phenotype and genotype in familial Mediterranean fever.

OBJECTIVE: FMF is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another, despite similar genotype, suggesting the role of environmental factors. The objective of this study was to analyse the gut microbiota of a large cohort of FMF patients in relation to disease characteristics. METHODS: The gut microbiotas of 119 FMF patients and 61 healthy controls were analysed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics, and genotypes were evaluated using multivariable association with linear models (MaAslin2), adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily faeces. Bacterial network structures were also analysed. RESULTS: The gut microbiotas of FMF patients differ from those of controls in having increased pro-inflammatory bacteria, such as the Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with expansion of the Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure, with decreased intertaxa connectivity. CONCLUSION: The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment.

Cutaneous vasculitis in autoinflammatory diseases.

Autoinflammatory diseases (AIDs) characterized by recurrent episodes of localized or systemic inflammation are disorders of the innate immune system. Skin lesions are commonly found in AIDs and cutaneous vasculitis can coexist with AIDs and even present as the most striking feature. This review aims to focus on the frequent cutaneous vasculitis association in three monogenic AIDs including familial Mediterranean fever (FMF), deficiency of adenosine deaminase type 2 (DADA2), and the recently identified adult-onset VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Cutaneous vasculitis in FMF is characterized by: (1) small-vessel vasculitis similar to IgA vasculitis with palpable purpura but increased intussusception complication and less vascular IgA deposit, and (2) cutaneous arteritis-like vasculitis presenting as subcutaneous nodules most often with higher glomerular involvement. DADA2 has a wide spectrum of clinical presentations ranging from fatal systemic vasculitis with multiple strokes, especially in pediatric patients, to limited cutaneous disease in middle-aged patients. DADA2 shares similar clinical and histopathological features with polyarteritis nodosa (PAN). As a result, DADA2 is commonly initially misdiagnosed as childhood PAN. Livedo racemosa reveals the most common cutaneous manifestation of cutaneous vasculitis in patients with DADA2. VEXAS syndrome is a life-threatening disease. A diagnosis of VEXAS syndrome should be strongly considered or could be made in patients with skin lesions characterized by Sweet syndrome-like eruption, livedo racemosa, concomitant relapsing polychondritis, deep venous thrombosis, pulmonary involvement, and progressive hematologic abnormalities such as myelodysplastic syndrome with a unique finding of cytoplasmic vacuoles in myeloid and erythroid precursor cells from bone marrow aspirate smear. As skin involvement is common in AIDs and may present as the most frequent manifestation, especially in DADA2 (70% to 90%) and VEXAS syndrome (83% to 91%), dermatologists play a crucial role in contributing to the early diagnosis of these AIDs with early initiation of the appropriate therapy to avoid progressing fatal outcomes.

Characteristics and course of patients with AA amyloidosis: single centre experience with 174 patients from Turkey.

OBJECTIVES: This study aimed to evaluate the clinical, laboratory and genetic characteristics and outcomes of patients with AA amyloidosis. METHODS: Patients followed up in a tertiary referral centre in Turkey with the diagnosis of inflammatory rheumatic diseases and immunohistologically proven AA amyloidosis were included in the study and retrospectively analysed. RESULTS: Among 184 patients with the diagnosis of AA amyloidosis, 174 (83 female, 91 male) were included in the analysis. The most common cause of AA amyloidosis was FMF (78.7%), and 91% of FMF-AA amyloidosis patients were carrying the p.M694V variant (74.1% homozygous). AA amyloidosis was identified earlier in patients with homozygous or compound heterozygous MEFV exon 10 variants compared with the heterozygous patients (27, 30 and 41 years, respectively). Patients with an estimated glomerular filtration rate <60 ml/min at admission had a higher frequency of progression to end-stage renal disease (P < 0.001). The overall mortality rate was 15.3% and it increased gradually in association with the amyloid burden (10% in patients with renal, 15% in renal + gastrointestinal and 43% in those with additional cardiac involvement). Renal findings responded completely to treatment in 31% of the patients, a partial response was observed in 4%, a stable course in 23.6% and progression in 38.5%. Amyloid storm was identified in nine patients and was found to be associated with increased mortality within 1 year. CONCLUSION: FMF patients still constitute the majority of AA amyloidosis patients in Turkey. The MEFV genotype and associated inflammatory load may affect the age of onset of AA amyloidosis, and earlier diagnosis and stricter follow-up and treatment may delay progression of the disease.

Lipids in inflammasome activation and autoinflammatory disorders.

Autoinflammatory diseases (AIDs) are a group of rare monogenetic disorders characterized by recurrent episodes of fever and systemic inflammation. A major pathologic hallmark of AIDs is excessive inflammasome assembly and activation, often the result of gain-of-function mutations in genes encoding core inflammasome components, including pyrin and cryopyrin. Recent advances in lipidomics have revealed that dysregulated metabolism of lipids such as cholesterol and fatty acids, especially in innate immune cells, exerts complex effects on inflammasome activation and the pathogenesis of AIDs. In this review, we summarize and discuss the impact of lipids and their metabolism on inflammasome activation and the disease pathogenesis of the most common AIDs, including familial Mediterranean fever, cryopyrin-associated periodic syndromes, and mevalonate kinase deficiency. We postulate that lipids hold diagnostic value in AIDs and that dietary and pharmacologic intervention studies could represent a promising approach to attenuate inflammasome activation and AID progression.

Colchicine: the good, the bad, the ugly and how to minimize the risks.

Colchicine has an important role in managing various conditions, including gout, familial Mediterranean fever, amyloidosis, Behçet's syndrome, recurrent pericarditis and calcium pyrophosphate deposition disease. The adverse effect profile of colchicine is well understood. However, due to its narrow therapeutic index, colchicine has been associated with overdose and fatalities. When ingested in toxic amounts, the mainstay of management is supportive care. Strategies to minimize the risk of colchicine poisoning can focus on three broad causes: unauthorized access, intentional overdose and inappropriate dosing. Culturally safe and appropriate education about storage and appropriate use of colchicine is essential to minimize the risk of overdose.

Adhesive small-bowel obstruction as a challenging complication of familial Mediterranean fever: A case-based review.

Familial Mediterranean fever (FMF) is the most common inherited autoinflammatory disorder, characterized by recurrent and self-limiting episodes of fever and serosal inflammation. Recurrent serositis may rarely lead to the formation of adhesions in the peritoneum, which may result in mechanical bowel obstruction. The symptoms, such as abdominal pain and vomiting, may mimic typical FMF attacks, resulting in misdiagnosis and severe morbidity, including strangulation and intestinal necrosis. Physicians are generally aware of other complications associated with FMF but reports on peritoneal adhesions and intestinal obstruction in English-language literature are inadequate to increase clinicians' awareness. Therefore, it is crucial to meticulously evaluate FMF patients presenting with abdominal pain and ileus because these symptoms could be due to adhesive small-bowel obstruction (ASBO). Furthermore, patients presenting with ASBO without a history of abdominal surgery should also be thoroughly evaluated, especially as it could be an initial presentation for an autoinflammatory disease. Herein, we present a pediatric case of FMF with the M694V homozygous mutation, complicated by ASBO while under colchicine treatment. Additionally, we provide a comprehensive review of the available literature on ASBO in FMF.

Long-term efficacy of canakinumab in hyperimmunoglobulin D syndrome.

Hyperimmunoglobulin D syndrome (HIDS) is a rare autoinflammatory disorder with autosomal recessive inheritance. It is caused by specific mutations in the mevalonate kinase gene (MVK). No treatment specific to HIDS has been approved to date; however, nonsteroidal anti-inflammatory drugs, steroids, colchicine, tumor necrosis factor-α inhibitors, and anti-interleukin-1 treatments are used, based on case reports and observational studies. Herein, we report a case with recurrent fever and arthritis attacks who did not respond to anakinra and was successfully treated with canakinumab. Long-term remission was achieved without any side effects with 300 mg canakinumab treatment every 4 weeks for 5 years.

Inflammatory comorbidities in the largest pediatric Familial Mediterranean fever cohort: a multicenter retrospective study of Pediatric Rheumatology Academy (PeRA)-Research Group (RG).

AIM: The aim of this study was to investigate the frequency and type of FMF-associated inflammatory diseases in a large FMF pediatric patients and to compare them to those FMF patients without concomitant inflammatory diseases. MATERIALS AND METHODS: Familial Mediterranean fever patients enrolled in the Pediatric Rheumatology Academy (PeRA)-Research Group (RG) were included. The patients were divided into two groups according to concomitant inflammatory disease as FMF patients who had a concomitant inflammatory disease (group 1) and FMF patients who did not have a concomitant inflammatory disease (group 1). The clinical findings and treatments were compared between the two groups. RESULTS: The study group comprised 3475 patients with FMF. There were 294 patients (8.5%) in group 1 and 3181 patients (91.5%) in group 2. Juvenile idiopathic arthritis (n = 136) was the most common accompanying inflammatory disease. Arthritis, M694V homozygosity, and the need for biological therapy were more frequently observed in Group 1 (p < 0.05). Fever and abdominal pain were more frequently detected in Group 2 (p < 0.05). FMF patients with concomitant inflammatory diseas more frequently demonstrated colchicine resistance. There were no significant differences in the median attack frequency, chest pain, amyloidosis, erysipelas-like erythema, or family history of FMF between the two patient groups. CONCLUSION: To the best of our knowledge, this is the largest pediatric cohort reviewed to date. FMF patients may have different clinical profiles and colchicine responses if they have with concomitant inflammatory diseases. Key points • FMF is associated with some inflammatory comorbidities diseases. • To the best of our knowledge, this is the largest cohort evlauated pediatric FMF associated inflammatory comorbidities diseases reviewed to date.

Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry.

To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.