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.

The usefulness and reliability of English-language YouTube videos as a source of knowledge for patients with familial Mediterranean fever.

Background/Objectives: YouTube is increasingly being used as an educational tool and is a substantial source of information. This study aimed to assess the quality of the most viewed YouTube videos pertaining to familial Mediterranean fever (FMF). Methods: A search on YouTube was conducted on January 13, 2022, using the keywords: "familial Mediterranean fever treatment," "familial Mediterranean fever colchicine," and "familial Mediterranean fever colchicine opacalcium." Two rheumatologists independently evaluated the relevance and accuracy of the videos. Redundant or irrelevant videos were excluded. The educational value of YouTube videos was assessed using the Global Quality Scale (GQS). Comparative analyses of video parameters across different cohorts were performed. To assess the reliability and quality of the videos, a modified version of the DISCERN scale and the GQS were employed. Results: Out of the 59 videos reviewed, 43 (72.9%) were of high quality, 10 (16.9%) were of medium quality, and 6 (10.2%) were of low quality. Upon comparing parameters among groups, no significant disparities were observed in terms of daily views, daily favorites, daily dislikes, or daily comments (p > 0.05). GQS scores for usefulness and modified DISCERN scores showed significant differences among groups (p < 0.001). Additionally, both GQS and modified DISCERN scores exhibited moderately negative correlations (r =  - .450 and r =  - .474, respectively) and high statistical significance (p < 0.001 for both) with utility assessment. Conclusion: YouTube is a valuable repository of high-quality videos for FMF patients. Healthcare providers should guide their patients to high-quality video sources to supplement their educational material.

Pyrin Inflammasome Activation Defines Colchicine-Responsive SURF Patients from FMF and Other Recurrent Fevers.

Syndrome of undifferentiated recurrent fever (SURF) is characterized by recurrent fevers, a lack of confirmed molecular diagnosis, and a complete or partial response to colchicine. Despite the clinical similarities to familial Mediterranean fever (FMF), the underlying inflammatory mechanisms of SURF are not yet understood. We here analyzed the in vitro activation of the pyrin inflammasome in a cohort of SURF patients compared to FMF and PFAPA patients. Peripheral blood mononuclear cells (PBMC) were collected from SURF (both colchicine-treated and untreated), FMF, PFAPA patients, and healthy donors. PBMC were stimulated ex vivo with Clostridium difficile toxin A (TcdA) and a PKC inhibitor (UCN-01), in the presence or absence of colchicine. The assembly of the pyrin inflammasome was evaluated by measuring the presence of apoptosis-associated Speck-like protein containing caspase recruitment domain (ASC) specks in monocytes using flow cytometry. IL-1ß secretion was quantified using an ELISA assay. No differences in TcdA-induced activation of pyrin inflammasome were observed among FMF, PFAPA, and healthy donors. Untreated SURF patients showed a reduced response to TcdA, which was normalized after colchicine treatment. In contrast to FMF, SURF patients, similar to PFAPA patients and healthy donors, did not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. These data demonstrate that in vitro functional analysis of pyrin inflammasome activation can differentiate SURF from FMF and PFAPA patients, suggesting the involvement of the pyrin inflammasome in the pathophysiology of SURF.

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.

A score for predicting colchicine resistance at the time of diagnosis in familial Mediterranean fever: data from the TURPAID registry.

OBJECTIVES: Colchicine forms the mainstay of treatment in FMF. Approximately 5-10% of FMF patients are colchicine resistant and require anti-IL-1 drugs. We aimed to compare the characteristics of colchicine-resistant and colchicine-responsive patients and to develop a score for predicting colchicine resistance at the time of FMF diagnosis. METHODS: FMF patients (0-18 years) enrolled in the Turkish Paediatric Autoinflammatory Diseases (TURPAID) registry were included. The predictive score for colchicine resistance was developed by using univariate/multivariate regression and receiver operating characteristics analyses. RESULTS: A total of 3445 FMF patients [256 (7.4%) colchicine-resistant and 3189 colchicine-responsive) were included (female:male ratio 1.02; median age at diagnosis 67.4 months). Colchicine-resistant patients had longer, more frequent attacks and were younger at symptom onset and diagnosis (P < 0.05). Fever, erysipelas-like erythema, arthralgia, arthritis, myalgia, abdominal pain, diarrhoea, chest pain, comorbidities, parental consanguinity and homozygosity/compound heterozygosity for exon 10 MEFV mutations were significantly more prevalent among colchicine-resistant than colchicine-responsive patients (P < 0.05). Multivariate logistic regression analysis in the training cohort (n = 2684) showed that age at symptom onset, attack frequency, arthritis, chest pain and having two exon 10 mutations were the strongest predictors of colchicine resistance. The score including these items had a sensitivity of 81.3% and a specificity of 49.1%. In the validation cohort (n = 671), its sensitivity was 93.5% and specificity was 53.8%. CONCLUSION: We developed a clinician-friendly and practical predictive score that could help us identify FMF patients with a greater risk of colchicine resistance and tailor disease management individually at the time of diagnosis.

Is compressed colchicine tablet superior to other colchicine preparations in patients with familial Mediterranean fever?

AIMS: The aim of our study is to evaluate the differences in effectiveness, dosage, and side effect profiles in the use of colchicine preparations and evaluate the superiority of compressed colchicine tablets in familial Mediterranean fever (FMF) patients with resistance or intolerance to coated colchicine tablets. MATERIALS AND METHODS: Patients who were diagnosed with FMF according to the Tel Hashomer criteria, aged 18 years and older, and switched from compressed colchicine to coated colchicine tablets in the rheumatology clinic of Gazi University were identified. The daily colchicine dose and FMF attack frequency before and after switching from coated colchicine tablets to compressed colchicine tablets were compared. RESULTS: The study included 43 female (72.9%) and 16 male patients (27.1%), and the mean age was 34.54 ± 8.3 years. The number of attacks per year was significantly reduced after switching to compressed colchicine tablets, and daily colchicine doses were lower after switching to compressed colchicine tablets (1.97 ± 0.23 vs 1.78 ± 0.39 mg, p < 0.001). CONCLUSION: Compressed colchicine tablets were shown to be superior to other colchicine preparations and compressed colchicine tablets to be a useful treatment option before initiating biological agents in patients who were unresponsive to coated colchicine.

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.

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.

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.

Assessment of quality of life, school performance, and physical activity in adolescents with Familial Mediterranean fever.

OBJECTIVES: The aim of this study is to evaluate differences in school performance, school attendance, quality of life, and physical activity in adolescents with Familial Mediterranean fever (FMF) compared to healthy controls. METHODS: One hundred and twenty-nine patients with FMF and 154 healthy controls between 13 and 18 years were included in the study. Demographic, school performance (according to grade point average), school absenteeism, and type and frequency of exercise were recorded. Quality of life was evaluated with the Pediatric Quality of Life Inventory (PedsQL) 4.0. RESULTS: The mean age of FMF patients was 15.1 ± 2.7 years, and 69 patients (53.5%) were female. School performance was significantly higher in the control group compared to FMF patients (P < 0.001). In the control group, there were significantly higher participants who engaged in professional sports (P < 0.001). Patients with FMF had significantly lower self-reported PedsQL scores in school functioning, physical, and psychosocial health domains compared to those in the control group (P = 0.001, P < 0.001, and P = 0.028, respectively). CONCLUSIONS: FMF patients demonstrated lower school performance and quality-of-life scores compared to healthy controls. In addition to improving symptoms in chronic diseases, it is important to evaluate and improve the quality of life of patients in routine practice and to ensure psychosocial well-being.

Anxiety and depression among patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is a systemic autoinflammatory disease that requires lifelong treatment and is associated with several comorbidities, including mental health disorders such as anxiety and depression. FMF and mental health necessitate further research; hence, this study aims to observe anxiety and depression and their relationship with several variables in patients with FMF. METHODS: As the study population, 360 FMF patients were surveyed between June and October 2022. Surveys included inventories assessing anxiety and depression, i.e., the Beck's Depression Inventory (BDI), the Beck's Anxiety Inventory (BAI), and the State-Trait Anxiety Inventory (STAI). RESULTS: Mean scores for STAI-Y1 (state), STAI-Y2 (trait), BAI, and BDI were 42.2 ± 12.0, 45.9 ± 10.6, 24.0 ± 13.9, and 13.1 ± 8.99, respectively. Medication-adherent patients had significantly lower scores on STAI-Y1 (41.5 ± 11.4 vs. 45.2 ± 14.0; p-value: 0.04). M694V homozygous patients exhibited significantly lower scores in the BDI (12.4 ± 9.37 vs. 13.2 ± 8.93; p-value: < 0.001) and BAI (17.0 ± 12.1 vs. 25.1 ± 13.9; p-value: 0.001). The patients with an exon-10 mutation demonstrated significantly lower scores compared to patients with an exon­2 mutation (17.9 ± 12.3, 29.6 ± 13.3; p-value: < 0.001). CONCLUSION: The patients with FMF had mild depression and moderate anxiety scores. A higher level of education and medication adherence were associated with lower levels of anxiety. Likewise, the patients with genotypes associated with severe disease courses had lower levels of anxiety. We suggest that physicians should be more attentive to patients with a milder disease course and ensure that these patients are provided with sufficient treatment and knowledge about their disease.

Old paradigms and new concepts in familial Mediterranean fever (FMF): an update 2023.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent attacks of fever and polyserositis. Its first description as a new entity was published by Siegal in 1945. Colchicine has been the treatment of choice for this disease since 1972. Significant progress has been made over the years in understanding FMF's clinical features, diagnosis, mode of inheritance, pathogenesis and therapeutic approach. However, many old paradigms related to FMF have proven inaccurate, leading to the emergence of new concepts that provide more precise insights. The term 'FMF' is no longer appropriate as the disease is found beyond the Mediterranean basin. The concept of diagnosis based only upon clinical ground proved to be wrong. The paradigm that MEFV mutations in FMF lead to loss of function of the encoded peptide pyrin turned out to be a gain of function mutation. Finally, the concept that as a genetic disease FMF should be treated for life was found to be inaccurate for the subpopulation of the heterozygote patients. Thus, the breakthroughs of identifying the gene associated with the disease (MEFV) and the deciphering of its pathogenesis revolutionized our old paradigms and replaced them with new and more precise insights.

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.

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.

The effect of canakinumab treatment on growth parameters in children with familial Mediterranean fever.

INTRODUCTION/OBJECTIVES: This study aimed to evaluate the effect of canakinumab on growth parameters in children with familial Mediterranean fever (FMF). METHOD: We conducted a retrospective analysis of 946 pediatric FMF patients followed in our center, of whom 37 were treated with canakinumab for at least three doses. Patients were assessed for demographic, clinical, and genetic characteristics. Data of height and weight percentiles and Z scores were recorded before and after canakinumab treatment and compared. RESULTS: The study group comprised 37 FMF patients with treated canakinumab. The median age (IQR) at diagnosis and canakinumab initiation was 3.0 (2.0-4.3) years and 7.0 (3.6-10.1) years, respectively. The median weight scores and mean body mass index (BMI) values significantly increased after canakinumab treatment. There was no change in height scores following canakinumab treatment. CONCLUSION: Canakinumab treatment has improved off body weight and BMI parameters of FMF patients by controlling disease activity and inflammation. Key Points • To our knowledge, few studies in the literature evaluate the growth parameters of canakinumab treatment in FMF children. • Canakinumab treatment has been shown to affect body weight and BMI positively. • Long-term studies are needed for its effects on height.

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.