Colchicine-resistant Patients Research Articles

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.

Arterial Stiffness and Ambulatory Blood Pressure Measurements in Children With Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disease which may cause endothelial dysfunction and arterial stiffness. In this study, we evaluated patients with FMF in terms of arterial stiffness indicators and investigated whether there was any difference according to colchicine response. This is a single-center, prospective, case-control study conducted on pediatric patients with FMF. Patients were categorized into 2 groups: patients on colchicine monotherapy (group 1) and patients who used anti-interleukin-1 (IL-1) plus colchicine (group 2). Patient age, mutations in the MEFV gene, overall duration of treatments, and general characteristics of symptoms were recorded. Laboratory values in an attack-free period were noted. Pulse wave velocity (PWV) was measured in all patients. Erythrocyte sedimentation rate and C-reactive protein, nocturnal hypertension, and PWV were higher in group 2. Arterial stiffness develops due to subclinical inflammation in patients with FMF. It is more pronounced in colchicine-resistant patients.

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.

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

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. 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. 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. 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.

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

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. 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. 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%. 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.

Colchicine resistance: Associated factors and its effect on health-related quality of life in patients with familial Mediterranean fever.

To determine the factors associated with colchicine resistance and the effect of colchicine resistance on health-related quality of life (QoL) in patients with familial Mediterranean fever (FMF). Demographic and clinical features, MEFV gene mutations, and Pras disease severity scores were recorded. QoL was assessed using the Short Form-36 (SF-36) and FMF-QoL scales. Colchicine resistance was defined as at least 1 attack per month for 6months at the maximum tolerated dose of colchicine in fully compliant patients. The mean age of 118 patients (90 female, 28 male) with FMF was 38.4 ± 12.5 years. The percentage of colchicine-resistant patients was 19.5%. In univariable analysis, smoking (odds ratio [OR]=2.885; 95% confidence interval [CI]=1.104-7.539; P=0.031), attack duration (OR=1.955; 95% CI=1.137-3.360; P=0.015), presence of arthritis (OR=5.235; 95% CI=1.508-18.179; P=0.009), and disease severity score (OR=1.790; 95% CI=1.334-2.402; P < 0.001) were associated with colchicine resistance. The FMF-QoL and subscales of SF-36 except for role emotional and vitality, were different between colchicine-resistant and non-resistant patients (P < 0.05). Smoking, attack duration, presence of arthritis, and disease severity were associated with colchicine resistance in fully compliant FMF patients. Colchicine-resistant patients had poorer health-related QoL.

Canakinumab is effective in patients with familial Mediterranean fever resistant and intolerant to the colchicine and/or anakinra treatment.

As an autosomal recessive autoinflammatory disease, treatment of Familial Mediterranean fever (FMF) has still gaps. Clinical studies are proving the safety and efficacy of colchicine in patients with FMF. However, there are very limited data on colchicine-resistant patients treated with canakinumab. This study presents the real-life experience of two rheumatology clinics choosing canakinumab in adult patients with FMF resistant to standard therapy. Treatment-resistant FMF patients with validated diagnoses enrolled from two rheumatology clinics. A special database was generated for the study and patients' demographic characteristics, FMF attack characteristics, adverse events seen during treatment, family history, MediterraneanFeVer (MEFV) mutations, and laboratory results recorded. Patients with missing dates were excluded from the analysis. PRAS score is used to assess the disease activity. A total of thirty colchicine and/or anakinra-resistant patients were enrolled to study. Twenty-one patients were female (70%) and the average disease duration was 21years. The time from colchicine to anakinra was 4.27years and the time to canakinumab was 1.52years. Abdominal pain (100%), fever (93.3%), chest pain (56.7%) were the most prevailed findings. Morning stiffness, myalgia, low back pain, chest pain was the predominant musculoskeletal findings. Median colchicine dose was 2mg/day (min-max 0.5-3mg/day). The most common side effect during anakinra treatment, apart from treatment unresponsiveness, was injection site reactions. Before canakinumab treatment, the mean number of attacks was 8.3 in the 24weeks, 4.33 in the third month of canakinumab treatment, and 1.56 at the last visit (p < 0.001). Also, the mean duration of attacks was 67.20h before canakinumab treatment, this period decreased to 18.27h after six months of canakinumab treatment (p < 0.001). Canakinumab is effective and tolerable to reduce attacks in resistant patients with FMF. Laboratory findings and clinical observation reveals that canakinumab can be another treatment option for colchicine and/or anakinra non-responders. Further studies with larger patients are required to validate recent findings with canakinumab.

Is the performance of the international severity scoring system for familial mediterranean fever in children better than other scoring systems?

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterised by recurrent episodes of fever and serosal inflammation with elevated acute phase reactants. Assessing the severity of the disease may be useful in identifying colchicine-resistant patients. The aim of this study is to determine the disease severity of FMF patients according to the Pras, Mor, and International Severity Scoring System for Familial Mediterranean Fever (ISSF) scoring systems and to evaluate the consistency of these three systems. The medical records of patients with FMF were retrospectively reviewed. Demographic features, family history of FMF, clinical characteristics at disease onset, laboratory features, Mediterranean fever genetic mutations, treatment regimens, and disease courses were recorded. A total of 205 patients (116 girls) were included in the study. The mean age of the patients was 13.3±4.0years. The Pras, Mor, and ISSF scores were inconsistent with each other, and there was poor fit between them (generalised Kappa: 0.140±0.029; P<.001). In the receiver operating characteristic (ROC) analysis performed by accepting the clinician's opinion as the gold standard, the ISSF was found to be more sensitive and specific than the other two systems. Evaluation of disease severity according to the ISSF in paediatric patients is more sensitive and specific than the Pras and Mor scoring systems.

The remarkable characteristics of the children with colchicine-resistant familial Mediterranean fever in Turkey.

Colchicine is the fundamental treatment of familial Mediterranean fever (FMF). Still, 5-10% of patients are not in remission with colchicine treatment. A consensus could not be established for the definition of colchicine resistance in FMF. This study aimed to determine factors that help to predict colchicine resistance in pediatric FMF patients. Patients with FMF that age of diagnosis was under 18 years old were included in our study. Fifty colchicine responsive and 33 colchicine-resistant patients were stratified as groups 1 and 2, respectively. Patients' clinical and laboratory findings were evaluated. Logistic regression analysis was used to determine the risk factors of colchicine-resistant FMF. Receiver operating characteristic (ROC) curve analysis was used to identify and compare the predictive performances of colchicine-resistant FMF models. Homozygous exon 10 MEFV mutations were frequent in group 2 (Group 1: 34 (68%), group 2: 32 (97%), p = .013). Univariate analysis showed that the age of onset of symptoms, age of diagnosis, chronic arthritis, myalgia and diarrhea during attacks, and the number of attacks, high ISSF and Pras score, high C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values under colchicine treatment were risk factors for colchicine-resistant FMF. With multivariate analysis, the number of attacks (OR 1.418, CI (95%) 1.149-1.750, p = .001) and high ESR values (OR 1.129, CI (95%) 1.059-1.204, p<.001) were detected as independent risk factors for colchicine-resistant FMF. The predictive factors were determined for pediatric colchicine-resistant FMF in our study. The results will help to early diagnosis and treatment of chronic inflammation in FMF.

Anakinra treatment in patients with familial Mediterranean fever: a single-centre experience.

Anakinra is proven to be effective in controlled trials in terms of attack frequency and subclinical inflammation in colchicine-resistant patients. The objective of this study was to review the patients followed in our single centre with FMF who received anakinra because of insufficient colchicine response. The study was conducted at a tertiary rheumatology centre experienced in autoinflammatory diseases. The patients were treated for at least 1 month with anakinra. Patients with amyloidosis and pregnancy were not included. Attack frequency, patient global assessment scales of disease severity and acute phase reactants were recorded before and throughout anakinra treatment. Criteria of treatment termination were side effects, disease remission, inadequate response, pregnancy plan and non-compliance. One hundred and six patients diagnosed with FMF were treated with anakinra; 45.92% of the patients had a homozygous M694V mutation; 83 of the 98 patients tested for MEFV carried at least one copy of M694V. Attack frequency decreased while on anakinra treatment; in fact, no attacks were observed in 75 patients. Visual analogue scale score decreased from 7.49 (2.03) to 3.08 (2.82) (P = 0.001). Currently, 71 patients are still on anakinra treatment. Treatment of 34 patients was discontinued (32%). Insufficient response and side effects were the most common reasons for treatment discontinuation. All of the side effects observed were reversible and the patients alleviated after treatment cessation. In four patients, leukopenia was observed. In patients who were refractory to colchicine, anti-IL-1 agent anakinra was shown to be effective and safe. The effectiveness of anakinra stems from preventing attacks and increasing the quality of life.

Effect of anti-interleukin-1 treatment on quality of life in children with colchicine-resistant familial Mediterranean fever: A single-center experience.

The aim of this study is to evaluate the clinical parameters, acute-phase reactants, side effects, genetic mutations among colchicine-resistant Familial Mediterranean fever (FMF) patients who received anti-interleukin-1 (anti-IL-1) treatment. We also evaluate the quality of life and school attendance among colchicine-resistant FMF patients, in relation to treatment with anti-IL-1. Familial Mediterranean fever is the most common inherited autoinflammatory disorder. Although the main treatment of FMF is colchicine, a small group of patients are resistant to colchicine treatment. Anti-IL-1 treatment is promising in colchicine-resistant patients due to excessive IL-1β production in pathogenesis. The aim of this study is to evaluate the quality of life and school attendance rates among colchicine-resistant FMF patients after anti-IL-1 treatment. This is a single center retrospective study of 25 pediatric colchicine-resistant FMF patients treated with anti-IL-1 treatment. Autoinflammatory Disease Activity Index (AIDAI) was used for disease activity assessment. School attendance rates were evaluated before and after treatment. There were 25 patients with FMF (11M/14 F) who were treated with anakinra or canakinumab for various indications (colchicine-resistant recurrent febrile attacks in 20, colchicine-related side effects in 2, subclinical inflammation in 3 patients). Only 3 patients developed side effects with anakinra (2 headache, 1 urticarial rash). There was a significant decrease in the frequency of attacks, acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein), AIDAI and physician's and patient's global assessment scores and improvement in school attendance rates. At the last follow-up, all patients were in remission, and only 3 had subclinical inflammation. Anti-IL-1 treatment is quite effective in children with colchicine-resistant FMF patients, proven with improved AIDAI scores and school attendance rates. In the long term by lowering disease activation even development of amyloidosis may be prevented.

Comorbidities and phenotype-genotype correlation in children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting with phenotypic heterogeneity. The phenotype-genotype correlation is not established clearly yet. Furthermore, some comorbidities such as vasculitis and inflammatory arthritis may accompany FMF. Herein, we aimed to define phenotype-genotype correlation and comorbid diseases of children with FMF. The medical records of 1687 children diagnosed and followed up as FMF were reviewed retrospectively. Disease severity was assessed by PRAS score. A total of 1687 children (841 girls, 846 boys) were involved in the study. The mean ± standard deviation of current age, age at symptom onset, and age at diagnosis were 13.1 ± 5.4, 5.4 ± 4, and 8 ± 4.2years, respectively. Median (min-max) follow-up period was 3 (0.5-18) years. Among them, 118 (7%) patients had at least one concomitant disease and 72% of them were carrying at least one M694V mutation. Patients with a concomitant disease expressed a more severe course of disease when compared to ones without a concomitant disease (23.7% vs 8.8%, p < 0.001). Children carrying homozygous M694V mutation had significantly earlier age of disease onset and severe disease course (p < 0.001). Forty-four patients (2.6%) were colchicine resistant and most of them were carrying homozygous M694V mutation. Sixteen colchicine-resistant patients were treated with anakinra while 28 received canakinumab. Juvenile idiopathic arthritis (JIA) and immunoglobulin A vasculitis were the most commonly seen associated diseases and the patients with a concomitant disease demonstrated more severe course. This is the largest pediatric cohort studied and presented since now. We confirmed that carrying M694V mutation is associated both with a severe disease course and a predisposition to comorbidities.

Two Sisters with Colchicine-Resistant form of Familial Mediterranean Fever on the Canakinumab Therapy: Clinical Case

Background. Colchicine-resistant cases of familial Mediterranean fever (FMF) are associated with high risk of kidney amyloidosis and severe episodes of the disease with pyretic fever, arthritis, pleurisies, pericarditis. It is difficult to achieve disease control in colchicine-resistant patients and it is required to use genetically engineered biologic drugs. Clinical Case Description. The observation of the family with severe course of FFL is presented. The successful use of canakinumab (monoclonal antibody to interleukin-1) in sisters with colchicine-resistant form of disease is described. Fever, articular and abdominal syndromes were completely reversed after 4 weeks of treatment as well as normalisation of laboratory tests was noted. Laboratory indexes of disease activity (erythrocyte sedimentation rate and C-reactive protein level) have stayed in reference ranges after 32 weeks of therapy, no new episodes of the disease were recorded. There were no adverse effect on the canakinumab therapy during the observation period (32 weeks). Conclusion. The high canakinumab efficacy in patients with severe colchicine-resistant forms of FMF is shown.

In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism.

Starting from 1972, colchicine is known as the most useful drug for prevention of familial Mediterranean fever attacks. However, some patients do not respond to colchicine treatment, even taken in high doses. Despite the fact, that different hypotheses have been proposed, the molecular mechanisms of colchicine resistance are not completely clear. It is generally known, that colchicine binds β-tubulin and inhibits microtubules polymerization. The β-tubulin gene has SNPs, which lead to amino acid substitutions, and some of them are located in colchicine binding site (CBS). We have assumed, that this SNPs can affect tubulin-colchicine interaction and might be the reason for colchicine resistance. With this in mind, we modeled 7 amino acid substitutions in CBS, performed molecular dynamics simulations of tubulin-colchicine complex and calculated binding energies for every amino acid substitution. Thus, our study shows, that two amino acid substitutions in the β-tubulin, namely A248T and M257V, reduce binding energy for approximately 2-fold. Based on this, we assume, that these amino acid substitutions could be the reason for colchicine resistance. Thus, our study gives a new insight into colchicine resistance mechanism and provides information for designing colchicine alternatives, that could be effective for colchicine resistant patients.

S100A12 and vascular endothelial growth factor can differentiate Blau syndrome and familial Mediterranean fever from systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) has recently become regarded as one of the autoinflammatory syndromes (AIS). However, other AIS, such as familial Mediterranean fever (FMF) and Blau syndrome, have been initially misdiagnosed as sJIA because of the clinical similarities. Making the correct diagnosis in the early stage of these AIS is desirable. Therefore, we evaluated serum S100A12 and vascular endothelial growth factor (VEGF) levels to determine if they could be biomarkers for differentiating these AIS. Serum S100A12 and VEGF levels were examined in patients with Blau syndrome (n = 4), FMF (n = 4), and sJIA (n = 11) in the active and inactive phases. In the active phase, S100A12 levels were significantly higher in patients with sJIA and FMF compared with those with Blau syndrome (p < 0.001). VEGF levels of patients with sJIA were significantly higher than those of patients with others (p = 0.001). In the inactive phase, there was no significant difference in VEGF levels. However, colchicine-resistant patients or patients without treatment with FMF showed high levels of S100A12 compared with others. Measuring both serum S100A12 and VEGF levels may be useful for differentiating patients with Blau syndrome and FMF from those with sJIA at the early stage.

Association between colchicine resistance and vitamin D in familial Mediterranean fever

Although colchicines are the only effective treatment of familial Mediterranean fever (FMF), resistance to colchicines (CR) which is observed in up to 30% of the patients is still a problem. Clinically, resistance to colchicine is defined as three or more attacks within the last 6 months period while using ≥2 mg/day colchicine. Previous studies have shown decreased vitamin D levels in FMF patients compared with healthy controls. The aim of this study is to evaluate whether vitamin D levels differ between CR and non-CR FMF patients. This study included 64 FMF patients who were being followed in Nephrology Clinic of Samsun Research and Education Hospital for at least 1 year. FMF was diagnosed according to the criteria defined by Livneh et al. Serum 25-hydroxy vitamin D (25-OHD) concentration (ng/mL) was detected in all FMF patients who were not in an acute attack period. From 64 patients 29 were accepted as CR. Mean 25-OHD level was 9.39 ± 1.00 ng/mL in CR patients and 18.48 ± 1.09 ng/mL in colchicine responsive patients (p < 0.001). Plasma vitamin D levels were significantly lower in colchicine resistant patients. Vitamin D deficiency may be a factor in etiopathogenesis of CR. Studies in larger patient samples that particularly evaluate the response to vitamin D replacement in CR FMF patients are needed.

Biological agents in familial Mediterranean fever focusing on colchicine resistance and amyloidosis.

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome. FMF is caused by mutations in the MEFV gene which encodes the pyrin protein. FMF is characterized by sporadic, paroxysmal attacks of fever and serosal inflammation, lasting 1-3 days. Patients may develop renal amyloidosis. Colchicine prevents attacks and renal amyloidosis.5% to 10% of the patients with FMF are resistant or intolerant to colchicine. Colchicine resistant patients may receive biological therapies. Anti-interleukin-1 drugs are the most important agents of biological treatments. In this review, colchicine resistance and treatment options will be evaluated.

Identification of Disease-Promoting HLA Class I and Protective Class II Modifiers in Japanese Patients with Familial Mediterranean Fever.

ObjectivesThe genotype-phenotype correlation of MEFV remains unclear for the familial Mediterranean fever (FMF) patients, especially without canonical MEFV mutations in exon 10. The risk of FMF appeared to be under the influence of other factors in this case. The contribution of HLA polymorphisms to the risk of FMF was examined as strong candidates of modifier genes.MethodsGenotypes of HLA-B and -DRB1 loci were determined for 258 mutually unrelated Japanese FMF patients, who satisfied modified Tel-Hashomer criteria, and 299 healthy controls. The effects of carrier status were evaluated for the risk of FMF by odds ratio (OR). The HLA effects were also assessed for clinical forms of FMF, subsets of FMF with certain MEFV genotypes and responsiveness to colchicine treatment.ResultsThe carriers of B*39:01 were increased in the patients (OR = 3.25, p = 0.0012), whereas those of DRB1*15:02 were decreased (OR = 0.45, p = 0.00050), satisfying Bonferroni’s correction for multiple statistical tests (n = 28, p<0.00179). The protective effect of DRB1*15:02 was completely disappeared in the co-existence of B*40:01. The HLA effects were generally augmented in the patients without a canonical MEFV variant allele M694I, in accordance with the notion that the lower penetrance of the mutations is owing to the larger contribution of modifier genes in the pathogenesis, with a few exceptions. Further, 42.9% of 14 colchicine-resistant patients and 13.5% of 156 colchicine-responders possessed B*35:01 allele, giving OR of 4.82 (p = 0.0041).ConclusionsThe differential effects of HLA class I and class II polymorphisms were identified for Japanese FMF even in those with high-penetrance MEFV mutations.

Опыт применения ингибитора интерлейкина 1 канакинумаба у пациентов с аутовоспалительными заболеваниями

Interleukin 1 (IL 1) is the main mediator for many auto inflammatory diseases (AID). Cryopyrin-associated periodic syndromes (CAPS) became the first diseases, for which the efficacy of IL 1 inhibitors was shown with a high degree of evidence. Canacinumb (totally human monoclonal antibodies to IL 1 is registered in Russia since 2011 for treating CAPS. At the moment research is being conducted to evaluate the efficacy and tolerance to IL 1 inhibitors in patients with other AIDs. The accumulated experience and scarce randomized controlled studies demonstrate a successful usage of IL 1 inhibitors in colchicine-resistant patients with family Mediterranean fever with the cupping of inflammation attacks, reducing the acute phase activity and also in patients with other monogenic (TRAPS, HIDS and others) and multifactorial pathologies (systemic juvenile arthritis, Stilk disease in adults, gout etc.). Using the IL 1 inhibitors, especially canacinumab, in patients with different AIDs has shown good tolerance and a high efficacy in all patients with no correlation to the age, according to Russian and world research. Thus, canacinumab, thanks to its therapeutic abilities, has broad perspectives in terms of lightening the disease course, improving survival, life quality and the overall prognosis.

Interleukin-1 targeting treatment in familial Mediterranean fever: an experience of pediatric patients

Objectives. The aim of this report was to evaluate and discuss treatment of pediatric familial Mediterranean fever (FMF) patients with anti-interleukin1 (IL-1) agents.Methods. Refractory or colchicine unresponsive FMF was described as severe and frequent attacks and/or having high acute phase reactance levels despite having a maximum dose of colchicine (2 mg/day). Disease course, adverse effects, duration of follow-up, treatment protocols, responses to the therapies were discussed.Results. Eight patients (6 male, 2 female) having refractory FMF were identified. Mediterranean fever (MEFV) gene analyses revealed homozygous M694V mutations in six patients and heterozygote M694V mutations in one patient and no mutation in one patient. They were all treated with anakinra and/or canakinumab. The use of anti-IL-1 drugs was beneficial to all patients. None of them had any severe adverse effects due to the therapy.Conclusions. Anakinra and canakinumab were effective in patient refractory to colchicine treatment as shown both in our series and in the literature. Therefore, controlled trials are needed to evaluate the safety and long-term efficacy of IL-1 targeting agents in colchicine resistant patients.