Colchicine-resistant Familial Mediterranean Fever Research Articles

An “On Demand” canakinumab regimen for treating children with Colchicine-Resistant familial Mediterranean fever – A multicentre study

ObjectivesCanakinumab, a human monoclonal antibody targeted at interleukin-1 beta, has demonstrated safety and efficacy in preventing familial Mediterranean fever (FMF) attacks among individuals with colchicine-resistant (crFMF). The manufacturer orders prescribe monthly subcutaneous injections. However, a subset of our patients is treated with an “canakinumab on demand ” (COD) strategy, with wider intervals between drug administrations. Therefore, we aimed to compare disease activity and drug safety between COD and “canakinumab fixed frequency” (CFF) policies. MethodsThis retrospective study collected data from three Israeli paediatric rheumatology centres, of children with crFMF who were treated with canakinumab. Epidemiological and clinical parameters, cumulative drug dosages, and adverse events were compared between children treated by both policies. ResultsTwenty-five (49 %) children were treated according to COD policy and 26 according to CFF policy. Demographic parameters and most of the disease features did not differ significantly between the groups. Both groups showed significant reduction in attacks after canakinumab introduction. The median number (interquartile range) of attacks per month did not differ significantly between the COD and CFF groups (0.33 (0.08, 0.58) and 0.13 (0, 0.5), respectively, p = 0.485 (even though, per definition, COD patients presumably had an attack before receiving the second canakinumab dose). The mean monthly dose was lower for the COD than the CFF group (1.13 ± 1.13 vs. 3.16 ± 1.46 mg/kg, p < 0.001). Adverse events were similar between the groups. ConclusionFor individuals with crFMF, COD compared to CFF policy can achieve similar efficacy and safety, with a lower accumulated canakinumab dose, rendering it less immunosuppressive and less expensive.

The possible anti-inflammatory effect of extra virgin olive oil with colchicine in treatment of resistant cases of familial Mediterranean fever in a cohort of pediatric Egyptian patients

BackgroundPeople of Mediterranean descent are primarily affected by the autoinflammatory genetic condition known as familial Mediterranean fever (FMF). The disease is resistant to colchicine therapy in 10–20% of patients. Numerous recent animal studies showed promising results of extra virgin olive oil (EVOO) to control inflammation. The objective of this study was to assess the effectiveness of combining EVOO with colchicine in the treatment of colchicine-resistant familial Mediterranean fever (CRFMF) patients.ResultsBoth the frequency of episodes and inflammatory indicators significantly decreased after a three-month course of daily EVOO treatment with colchicine. The average erythrocyte sedimentation rate (ESR) of patients was 78.6 mm/h before the EVOO administration, and it dropped to 27.8 mm/h, after that. Additionally, after taking EVOO, the mean serum amyloid A (SAA) decreased from 123.82 mg/dl to 59.78 mg/L. Also, the average C-reactive protein (CRP) decreased from 34.22 to 7.84 mg/dl following its administration; the mean nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) level decreased from 134.92 to 64.23 pg/ml. The mean caspase-1 level decreased from 7.8 to 4.98 ng/ml; and the mean levels of cytokines, interleukin 6 (IL-6), interleukin 1 beta (IL-1 β), and tumor necrosis factor-alpha (TNF-α) decreased from 9.8, 18.14, and 52.7 pg/ml, respectively, to 5.95, 12.51, and 29.39 pg/ml. Finally following the administration of EVOO, there was a notable overall improvement in the quality of life of (CRFMF) patients.ConclusionEVOO demonstrated a significant positive impact when paired with the tolerated dosage of colchicine in the management of CRFMF. Improvements were observed in both clinical and laboratory settings, including a reduction in the attack frequency and serum levels of inflammatory markers, such as NLRP3, caspase-1, ESR, CRP, IL-1β, IL-6, and TNF-α without any negative side effects.

Do we consider enough the presence of triggering factors in the evaluation of patients with FMF? Triggering factors are highly prevalent in colchicine-resistant FMF patients.

The aim of the study is to investigate the frequency of triggering factors in colchicine-resistant and -responsive Familial Mediterranean Fever (FMF) patients as well as the effect of interleukin (IL)-1 antagonist treatment on the triggering factors. Both colchicine-resistant (patients on IL-1 antagonist treatment) and colchicine-responsive (patients on colchicine who had ≤ 3 attacks in the last year) patients were questioned for the presence of12 different triggering factors, including exposure to cold, emotional stress, fatigue, physical activity, menstruation (for females), sleeplessness, prolonged standing, long-duration travel, high-fat diet intake, starvation, infection, and trauma. Colchicine-resistant patients were questioned for the presence of triggering factors for two time periods, before and after treatment with IL-1 antagonists. We studied 28 colchicine-resistant and 35 colchicine-responsive patients. Overall 77.8% of patients had at least one triggering factor. Triggering factors were associated with 28.5% of the total number of attacks. More than half of the patients (57.1%) declared that they hadavoided these conditions. The frequency of triggering factors was higher in the colchicine-resistant group as compared to the colchicine-responsive group (89.3% vs 68.6%; p = 0.04). In colchicine-resistant FMF patients, the frequency of triggering factors (89.3% vs 32.1%) and the percentage of attacks initiated by triggering factors (27.8 vs 14.4%; p < 0.001) were decreased after treatment with IL-1 antagonists. In this study, triggering factors were more frequent in colchicine-resistant patients as compared to colchicine-responsive patients. Treatment with IL-1 antagonists seems to increase the endurance of colchicine-resistant patients in stressful conditions.

Is it possible to extend the dose interval of canakinumab treatment in children with familial Mediterranean fever? PeRA group experience

BackgroundThere is no clear data on the optimal duration of treatment with anti-interleukin-1 drugs in colchicine-resistant familial Mediterranean fever patients, as well as on the dose interval. This study aimed to assess patients whose canakinumab dose interval was adjusted according to a specific protocol, with the objective of evaluating the effectiveness of implementing this protocol for the patient care.MethodsThe files of 45 patients whose canakinumab treatment interval was opened with a standard protocol previously determined by the Delphi method were retrospectively reviewed.ResultsCanakinumab treatment was initiated once a month for all patients. In the sixth month of canakinumab treatment, a dose interval extension was introduced; however, 7 patients (15.5%) experienced an attack, and consequently, no further interval extension was administered to them. For 29 patients, the dose interval was successfully extended to once every three months, as they remained attack-free for a year after the first interval extension. Nine patients continued receiving the drug every 2 months, as they had not yet completed one year since the first extension. The study found no significant correlation between experiencing an attack during the dose interval extension protocol and the number, duration of attacks, or autoinflammatory diseases activity index score.ConclusionExtending treatment intervals with canakinumab in colchicine-resistant familial Mediterranean fever shows promise for favorable outcomes.

Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients

ObjectiveColchicine is the primary treatment for familial Mediterranean fever (FMF). Although colchicine is safe and effective in FMF patients, around 5–10% of patients show resistance to the drug. This study investigates the possibility of a link between colchicine resistance and the distinct miRNA profiles in colchicine resistant FMF patients. MethodsDifferentially expressed miRNAs in colchicine resistant FMF patients were detected by Affymetrix 4.0 miRNA array analysis. These miRNAs were then categorized based on the role of their target genes in drug metabolism and inflammation related pathways. qRT-PCR was used to validate candidate miRNAs selected by Enrichr, a gene enrichment analysis system based on the relevance of possible target genes in drug metabolism pathways. Expression levels of these miRNAs’ potential target genes were investigated by qRT-PCR. Then, a colchicine resistant hepatoblastoma cell line (HEPG2) was established, and the differentially expressed miRNAs and genes identified in patients were also analyzed in this colchicine-resistant cell line. Results25 differentially expressed miRNAs were detected in colchicine resistant FMF patients. miR-183-5p, miR-15b-5p, miR-505-5p, and miR-125a-5p were identified to be associated with drug resistance and inflammatory pathways and thus chosen for further validation. miR-183-5p, miR-15b-5p, miR-505-5p miRNAs showed significantly differential expression in qRT-PCR.NFKB1, NR3C1, PPARα – drug absorption, distribution, metabolism, and excretion (ADME) genes were predicted to be targeted by these miRNAs. Among these targets, NFKB1 and NR3C1 were differentially over expressed in colchicine resistant FMF patients. These findings were validated in the colchicine resistant hepatoblastoma cell line (HEPG2). ConclusionThis is the first study evaluating the role of miRNAs in colchicine resistant patients with FMF. Their differential expression may result in resistance to standard colchicine treatment by affecting the expression of genes that take place in drug absorption, distribution, metabolism, and excretion (ADME) or nuclear receptors that regulate ADME genes, thus potentially playing a role in both drug metabolism and inflammation.

Effectiveness of Colchicine or Canakinumab in Japanese Patients with Familial Mediterranean Fever: A Single-Center Study.

Background: To investigate the clinical features of Japanese patients with Familial Mediterranean Fever (FMF), we evaluated the frequency of attacks, treatment responses, and adverse effects in 27 patients with FMF treated with colchicine or canakinumab in a real-world clinical setting. Methods: We retrospectively reviewed 27 Japanese patients with FMF treated at our institute between April 2012 and June 2023. All patients were diagnosed with FMF according to the Tel-Hashomer criteria. We performed genetic analyses of the MEFV gene using targeted next-generation sequencing. The clinical response was monitored through the number of attacks, and inflammatory markers were monitored through the C-reactive protein (CRP), and serum amyloid A (SAA) concentrations. Colchicine resistance was defined as the presence of at least one attack/month despite administration of the maximum tolerated dose of colchicine for at least 6 months, and C-reactive protein and serum amyloid A levels above the normal range between attacks. Results: A total of 27 patients diagnosed with FMF were enrolled in this study and the median follow-up period was 36.4 months. The median attack frequency was 1.0 (interquartile range: 0.33-1.0) every 3 months before treatment initiation. All the patients (n = 27) were treated with colchicine. Among the 27 patients, 20 (71.8%) showed a clinical response and 7 (25.9%) showed an incomplete response with sufficient doses of colchicine (n = 5) and non-sufficient doses (n = 2). Two patients on non-sufficient doses were unable to increase colchicine to the maximum dose due to diarrhea and liver dysfunction. All seven patients achieved a reduction in attack frequency after the initiation of canakinumab. No serious adverse events associated with canakinumab treatment were observed. In these seven patients with colchicine-resistant FMF (crFMF), the MEFV exon 10 variant was not detected, and the absence ratio of the MEFV variant was significantly higher compared to those without crFMF. Conclusions: Colchicine was effective in 71.8% (20/27) of Japanese patients with FMF; however, the remaining patients (7/27) had crFMF. Canakinumab effectively controlled febrile attacks in crFMF, even in the absence of pathogenic MEFV exon 10 variants.

Adherence to colchicine prophylaxis among patients with familial Mediterranean fever treated with interleukin-1 inhibitors

ObjectiveInterleukin-1 (IL-1) inhibitors are approved for treating familial Mediterranean fever (FMF) that is resistant to colchicine. However, continued concomitant treatment with colchicine is imperative, as it is the only drug proven to prevent secondary amyloidosis. We aimed to compare the adherence to colchicine between patients with colchicine-resistant FMF (crFMF) who were treated with IL-1 inhibitors and patients with colchicine-sensitive FMF (csFMF) who were treated only with colchicine. MethodsThe databases of Maccabi Health Services, a 2.6-million-member state-mandated health provider in Israel were searched for patients with FMF diagnosis. The medication possession ratio (MPR), calculated from the day of the first colchicine purchase (index date) until the last colchicine purchase was the main outcome measure. Patients with crFMF were matched in a 1:4 ratio to patients with csFMF. ResultsThe final cohort included 4526 patients. Of them, 108 (2.4%) were with crFMF, and were matched to 432 with csFMF. The total mean MPR in each of the matched groups was similar (78.9 ± 41.4 and 82.5 ± 80.6, respectively, P = 0.5). Statistically significant differences in MPR were not found between the groups according to age or duration of colchicine use. However, adherence to colchicine was insufficient (MPR<80%) among more than 50% of the patients in both groups. ConclusionIn contrast to initial concerns, adherence to colchicine was similar between patients with crFMF and csFMF. However, in both groups, adherence to colchicine was poor. Education of both caregivers and patients is essential to increase adherence.

Feasibility of canakinumab withdrawal in colchicine-resistant familial Mediterranean fever.

There is no consensus on canakinumab treatment tapering and discontinuation strategies in colchicine-resistant familial Mediterranean fever (FMF) patients. In this study, we aimed to establish a treatment management and discontinuation protocol in pediatric FMF patients treated with canakinumab. Fifty-eight FMF patients treated with canakinumab were included. Since 2020, we have applied a protocol based on our experience that canakinumab is administered monthly at first six months, followed by bimonthly for six months, and a final period of every three months (for six months). The patients were divided into two groups as 2012-2019 (group A) and 2020-2022 (group B). In group A (n = 33), the median duration of canakinumab treatment was 2.5(1.9-3.7) years. Twenty-five out of 33 patients discontinued canakinumab after a median of 2.1 (1.8-3.4) years. In two patients, canakinumab was restarted because of relapse.In group B (n = 25), canakinumab was discontinued in 18 patients at the end of 18 months. After a median follow-up of 0.8 (0.6-1.1) years, two patients of them had a relapse and canakinumab treatment was re-initiated. The remaining 16 patients still have clinically inactive disease and are receiving only colchicine. When we compared the characteristics between groups A and B, there were no significant differences regarding demographic, clinical features, and outcomes. This is the largest study in the literature suggesting a protocol for discontinuing canakinumab in pediatric FMF patients. It was possible to discontinue canakinumab successfully in more than half of the patients in 18 months. Thus, we suggest that this protocol can be used in pediatric FMF patients.

Familial Mediterranean Fever and Transverse Myelitis: A Causal Relation?

Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder characterized mainly by recurrent self-limited episodes of fever and polyserositis. FMF-related neurologic complication is an old debate, and the correlation between FMF and demyelinating disorders has been a matter of dispute for a long time. Few reports demonstrated a relationship between FMF and multiple sclerosis; however, the existence of a causal relationship between FMF and demyelinating disorders is still a puzzle. This report presents the first case of transverse myelitis following FMF attacks in which neurologic manifestations were resolved using colchicine treatment. Due to relapses of FMF, which were accompanied by transverse myelitis, rituximab was administered, which resulted in stabilizing disease activity. Accordingly, in the case of colchicine-resistant FMF and FMF-related demyelinating conditions, rituximab could be considered as a potential therapeutic option to alleviate both polyserositis and demyelinating manifestations.

Effect of interleukin-1 antagonist on growth of children with colchicine resistant or intolerant FMF

IntroductionFamilial Mediterranean Fever (FMF) is the most common monogentic autoinflammatory disease. FMF results from mutations in MEFV, which lead to a pro-inflammatory state and increased production of Interleukin 1 beta subunit (IL-1b) by myeloid cells. Despite the overall positive results obtained with anti-IL-1 agents in FMF patients, little is known about the long-term growth impact of these drugs in the pediatric population.ObjectivesTo assess the long-term body weight and height trajectories in children with FMF treated with anti-IL-1 agents.MethodsWe conducted a retrospective analysis of 646 pediatric FMF patients followed in our center, of whom 22 were treated with either anakinra (36.3%) and/or canakinumab (90.9%). Patients were assessed for demographic, clinical and genetic characteristics and were followed for a mean of 3.05 ± 1.75 years. Data of height and weight percentiles were recorded before and after treatment.ResultsThe most common indication for IL-1 blockers treatment was colchicine resistance (66.6%). Ninety percent of those patients had a moderate or severe disease according to the Pras score and had higher proportion of M694V homozygosity compared with patients who did not require anti IL-1 agents (95.2% vs. 30.5%, p < 0.001). Overall, anakinra and canakinumab resulted in a complete response in 80% of patients and exhibited low rates of adverse effects. We found a significant increase in height and body weight percentiles following treatment (19.6 ± 16% vs. 30.8 ± 23%, p = 0.007, and 29.5 ± 30% vs. 39.1 ± 36%, p = 0.043, respectively).ConclusionTreatment with anti-IL-1 agents in children with FMF is effective and safe and may potentiate long-term growth.

Efficacy and safety of anti-interleukin-1 in children with colchicine-resistant familial Mediterranean fever.

The aim of this study was to evaluate the efficacy and safety of anti-interleukin-1 (IL-1) therapies in colchicine-resistant pediatric patients with familial Mediterranean fever (FMF). In this study, we retrospectively evaluated 656 children with FMF and 27 patients who had been treated with anti-IL-1 therapies (anakinra/canakinumab) . Clinical and laboratory features, MEFV gene mutations, treatment responses were investigated. Twenty of the patients were treated with anakinra (the treatment of 6 patients who initially used anakinra was switched to canakinumab in the follow-up period), and 13 patients were treated with canakinumab. Clinical symptom and severity scores decreased in all patients A decrease in acute phase reactants was also observed in patients. A total of 18 (66%) patients had a M694V homozygous mutation, while 24 (89%) patients had a M694V mutation, at least in one allele. FMF patients with colchicine resistance may progress to amyloidosis. IL-1 antagonist treatment could be used safely with a favorable outcome in pediatric patients with FMF resistance to colchicine therapy and/or who have renal amyloidosis.

Live-attenuated measles, mumps, and rubella booster vaccine in children diagnosed with rheumatic disease: A single-center study.

To evaluate the safety profile of measles, mumps and rubella (MMR) booster in children diagnosed with rheumatic diseases receiving biological agents. The study included retrospective safety data of children administered MMR booster dose receiving biologics or biologics with methotrexate. The files of 182 patients were accessed from the pediatric rheumatology biological therapy archive, and the vaccination status of these children was obtained by accessing electronic records. Of 182 patients, 14 patients were vaccinated with MMR booster dose. Thirteen of the patients were followed up with a diagnosis of juvenile idiopathic arthritis and one with colchicine-resistant familial Mediterranean fever. None of the patients had disease exacerbation after vaccination, and three patients had mild side effects consisting of rash, angioedema, joint pain, and fatigue. Conclusion: This study supports the data regarding evidence of the safety of MMR booster dose administration in children with rheumatic diseases receiving bDMARDs. What is Known: •MMR booster is avoided in immunocompromised pediatric patients receiving bDMARDs except in specific conditions. What is New: •The MMR booster dose may be safe in children with PedRD receiving bDMARDs or bDMARDs with MTX. These bullets can be added to the manuscript.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.

The feasibility of withdrawing canakinumab in paediatric colchicine-resistant familial Mediterranean fever patients.

To determine the feasibility of withdrawing canakinumab (CAN) in a large cohort of paediatric patients with colchicine-resistant familial Mediterranean fever (crFMF). This retrospective observational cohort study included paediatric crFMF patients that received CAN treatment for ≥6 months. Patient data were recorded at treatment onset (baseline), and at 1, 3, 6, 12, 18, and 24 months after initiation of treatment. The study included 114 patients that were followed-up for 2736 person-months. During the 24-month follow-up period, the CAN dose interval remained unchanged in 44 patients. The dose interval was extended in 58 patients within a median 6 months (range: 3-18 months) of treatment initiation. In all, 4 of these 58 patients had a new attack of crFMF after the dose interval was extended. CAN was withdrawn in 12 patients (in 5 at month 12 month and in 7 at month 18), of which 2 had a new attack within 3 months of withdrawal. In these 2 patients CAN was re-initiated with a dose interval of 8 weeks. The remaining 10 patients in which CAN was withdrawn did not report any symptoms throughout the remainder of the 24-month follow-up period. The median attack-free period in those treated with CAN was 669 d (95% CI: 644-696). The present findings show that it may be feasible to withdraw CAN or extend its dose interval in paediatric crFMF patients. Based on the present findings, we think that as the quantity of real-life data increases, standard CAN protocols may be developed.

Effect of interleukin-1 inhibition in a cohort of patients with colchicine-resistant familial Mediterranean fever treated consecutively with anakinra and canakinumab

To evaluate the efficacy of IL-1 blockers in a cohort of patients with colchicine-resistant familial Mediterranean fever (crFMF) treated consecutively with anakinra and canakinumab. Patients with crFMF treated with anakinra and canakinumab in any order were identified using the computerised database of Sheba Medical Centre. Background characteristics of the patients, reason for switching IL-1 inhibitor, and frequency of attacks under colchicine only, anakinra, and canakinumab were extracted from the computerised patient files. Patients were then interviewed for patient-reported outcomes. A total of 46 patients in our clinic were prescribed canakinumab for crFMF after previous anakinra treatment, whereas no patients who switched treatment from canakinumab to anakinra were identified. Of those, 23/46 patients (50%) discontinued anakinra due to inadequate response (11 of them with secondary failure after a good initial response). Frequency of flares was significantly decreased following switch to canakinumab from anakinra treatment (p<0.01). After the switch to canakinumab, the median duration of flares, the severity of pain during a flare, and the patient's global assessment of disease activity were all significantly decreased (p≤0.01), according to the reports from the patients. Canakinumab is an effective treatment for FMF after failure of anakinra due to any cause.

Canakinumab improves patient-reported outcomes in children and adults with autoinflammatory recurrent fever syndromes: results from the CLUSTER trial.

To evaluate the effect of canakinumab on health-related quality of life (HRQoL), work/school and social life of patients with autoinflammatory recurrent fever syndromes, including colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and tumour necrosis factor receptor-associated periodic syndrome, in the CLUSTER trial. HRQoL of patients who received canakinumab 150 mg or 300 mg every four weeks in the CLUSTER trial (n=173) was assessed at baseline and Weeks 17 and 41. For children we used the Child Health Questionnaire - Parent Form 50 (CHQ-PF50), including psychosocial (PsS) and physical (PhS) component summary scores. For adults, the Short-Form-12 (SF-12) Health Survey was used, including physical (PFS) and mental (PCS) component summary scores. The Sheehan Disability Scale (SDS) was used to determine the impact of treatment on work/school, social and family life. The results obtained were remarkably consistent in both paediatric and adult patients across the three disease cohorts. At baseline, median scores for physical components were relatively low (26-29 for PhS and 34-38 for PFS); they improved to values similar to those expected in the general population by Week 17, and this improvement was sustained at Week 41, when median PhS scores were 47-50 and PFS 44-54. Psychosocial and mental scores also improved from baseline to Week 17 and 41, with scores comparable to the general population. Notable improvements were also observed in the SDS scale. Patients with three inherited autoinflammatory syndromes experienced sustained improvements on their HRQoL, work/school, and social life on treatment with canakinumab.

Effectiveness of Canakinumab Treatment in Colchicine Resistant Familial Mediterranean Fever Cases.

Anti-interleukin 1 agents are used successfully in colchicine-resistant or intolerant Familial Mediterranean Fever (FMF) patients. Sixty-five patients with FMF who received canakinumab treatment for at least 6 months due to colchicine resistance or intolerance between 2016 and 2020 in our department were retrospectively analyzed. Canakinumab treatment was given subcutaneously every 4 weeks. After completing monthly canakinumab therapy over 12 months, in patients with complete remission, the dosing interval was extended to every 1.5 months for 6 months, then every 2 months for 6 months, and finally every 3 months for a year. In patients without disease activation, canakinumab treatment was discontinued at the end of 3 years and followed up with colchicine treatment. Patients who had a flare switched to the previous dosing interval. In patients with renal amyloidosis, monthly canakinumab treatment was continued without extending the dose intervals. The mean duration of canakinumab use in our patients was 31.4 ± 10.57 months (6–52 months). The mean age at onset of symptoms was 4.65 ± 3.84 (range, 1–18) years, and the mean age at diagnosis was 5.59 ± 3.9 (range, 4–19) years. Complete remission was achieved in 57 (87.6%) and partial remission in seven (10.7%) patients. One patient was unresponsive to treatment. Canakinumab treatment was discontinued in three patients with complete remission and one patient with drug resistance. Erythrocyte sedimentation rate (ESR) (51.85 ± 15.7 vs. 27.80 ± 13.73 mm/h) and C-reactive protein (CRP) [26 (3-73) vs. 5 (1–48) mg/L] values were compared before and after canakinumab treatment in attack-free periods, a significant decrease was found after canakinumab treatment (p < 0.001, p < 0.001, respectively). Bodyweight Z-scores (respectively −0.80 ± 0.86 vs. −0.49 ± 0.92) were compared, similarly, a statistically significant increase after canakinumab treatment (p < 0.001), but no significant increase in height Z scores (−1.00 ± 0.88 vs. −0.96 ± 0.94) (p = 0.445) was detected. Four patients had FMF-related renal amyloidosis. The decrease in proteinuria with canakinumab treatment was not statistically significant (p = 0.068). Cervical lymphadenitis developed in one and local reactions in two patients. No severe adverse effects requiring discontinuation of canakinumab treatment were observed. Our study showed that canakinumab treatment was highly effective, well-tolerated in pediatric FMF patients, and controlled extension of the canakinumab dose interval was safe.

Biological disease-modifying antirheumatic drugs in the main monogenic autoinflammatory diseases treatment. Experience of application in rheumatological practice

Objective: to assess the frequency of prescription, efficacy and tolerability of biological disease-modifying antirheumatic drugs (bDMARDs) therapy in patients with major monogenic autoinflammatory diseases (mAID) according to the Federal Rheumatology Center clinical practice. Patients and methods. From 2008 to 2020 years, 158 patients with mAID were included in the study, 53 of whom were prescribed bDMARDs: 12 patients had Familial Mediterranean Fever (FMF); 26 – Cryopyrin-Associated Periodic Syndromes (CAPS), including 21 patients with MuckleWells Syndrome (MWS) and 5 – with Chronic Infantile Onset Neurologic Cutaneous Articular / Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID), 12 patients had Tumor necrosis factor (TNF) receptor-Associated Periodic Fever Syndrome (TRAPS) and 3 – Hyper-Immunoglobulinemia D-syndrome (HIDS/MKD). Among all these patients 25 were male and 28 female, aged 1.5 to 44 years, 45 were children (under 18) and 8 adults. Interleukin 1 inhibitors (iIL1) were prescribed in accordance with the following scheme: canakinumab – subcutaneously 2–5 mg/kg or 150 mg per injection, every 4–8 weeks; anakinra – subcutaneously 1–5 mg/kg or 100 mg/day, daily. Etanercept (ETC) was injected subcutaneously 0.4–0.8 mg/kg 1–2 times a week, and adalimumab (ADA) was injected subcutaneously 20–40 mg once every 2 weeks. Tocilizumab (TCZ) was administered intravenously, 8–12 mg/kg once every 2–4 weeks. The duration of the disease at the time of treatment initiation ranged from 1 to 44 years. The duration of bDMARDs therapy in patients with mAID ranged from 1 month to 12 years.Results and discussion. From 158 patients with mAID, in 53 (33.5%) bDMARDs were administered. They were used more often in patients with CAPS (56.6%), and less often – in TRAPS (26.4%), FMF (28.3%) and HIDS/MKD (5.7%). iIL1 were the most frequently prescribed bDMARDs (90.6%): canakinumab (in 38 patients) and anakinra (in 10), they were mainly used in patients with CAPS, in 2/3 of patients with TRAPS, HIDS/MKD and colchicine-resistant FMF. During the first days of iIL1 treatment, all patients with mAID showed a statistically significant clinical improvement: normalization of general condition, emotional recovery, relief of fever, disappearance of rash, decrease in the severity of lymphadenopathy and hepatosplenomegaly, relief or significant positive dynamics of eye symptoms, subjective improvement in hearing and audiogram (with dynamic control in patients with CAPS), decrease in the level of acute phase markers (in all cases). In 7 patients with CAPS, who received anakinra, after a positive response was achieved, switching to canakinumab was performed, which maintained the full effectiveness of therapy. TCZ (in 7 patients) and inhibitors of tumor necrosis factor α (iTNFα) – ADA (in 3) and ETC (in 4), – were used less frequently. iTNFα were more often prescribed to FMF patients with a complete response to treatment. Tolerability of bDMARD therapy was satisfactory in all patients.Conclusion. Currently, iIL1 are the first line of therapy among biological agents for mAID, especially in patients with CAPS. If they are ineffective or intolerant in certain situations, alternative bDMARDs (iTNFα and IL6 inhibitors) can also be used, but this issue needs further study.

Efficacy and safety of canakinumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: A single-centre observational study.

To evaluate the efficacy and safety of canakinumab in Japanese patients with colchicine-resistant or colchicine-intolerant familial Mediterranean fever (FMF) in a real-world clinical setting. We reviewed 13 Japanese FMF patients to whom canakinumab was introduced during the period of October 2017 to December 2020. All patients were diagnosed as FMF according to Tel-Hashomer criteria. We performed genetic analyses for Mediterranean fever or MEFV by targeted next-generation sequencing. Efficacy was assessed by attack frequency and the percentage of patients who achieved attack improvement at 24 weeks. Safety was assessed by adverse events observed during canakinumab treatment. The median duration and follow-up of canakinumab treatment were 13 and 16 months, respectively. The median attack frequency was 0.50 [0.30-1.00] at 24 weeks, which was a significant decrease from 2.00 [0.85-2.88] at the time of induction (p = .019). There were three patients (23%) with complete resolution of attacks at 24 weeks. No serious adverse events were observed. However, one patient had small intestinal ulceration which led to the discontinuation of canakinumab. Although the number of cases is small, this study suggests that canakinumab is efficacious and safe for use in Japanese patients with colchicine-resistant or colchicine-intolerant FMF in a real-world clinical setting in Japan.

Familial Mediterranean fever (FMF)-response to TNF-blockers used for treatment of FMF patients with concurrent inflammatory diseases.

Familial Mediterranean fever (FMF) is the most common interleukin 1 (IL-1)-driven monogenic autoinflammatory disease. Yet published data also suggest that tumor necrosis factor (TNF) may have a role in the pathogenesis of FMF and may serve as a target for treatment. In the present study we evaluate this hypothesis. To this goal, we studied the incidental effect on FMF of TNF-directed treatment, administered to colchicine-refractory FMF patients for the management of a concurrent inflammatory disease. The rates of FMF patients and of treatments with complete or nearly complete FMF response were determined, based on the number of FMF attacks during TNF-blocker exposures. The possible effect of various FMF and non-FMF features on the outcome was determined using comparative analysis. Patients were identified and data were retrieved using electronic files from the FMF clinic. Twenty-six patients were identified, each receiving ≥1 of four TNF-blockers for a mean duration of 27.6±16.4months. The TNF-blockers were found to induce complete or nearly complete FMF response in 10 (38.5%) of the patients, and in 13 of 50 (26%) exposures. No clinical, genetic, demographic, or therapeutic feature could predict which FMF patient would respond favorably to TNF-blocker therapy. This study suggests that TNF-blockers may be beneficial for a small proportion of colchicine-resistant FMF patients.