Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic ossification. Since flares of the disease are associated with inflammation, it is assumed that JAK inhibitors can control active FOP due to blocking multiple signaling pathways.

Juvenile idiopathic inflammatory myopathies (JIIM) are rare diseases in which the prognosis is largely determined by timely diagnosis, timing of prescription and effectiveness of therapy.Objective: to characterize the clinical phenotypes, the results of paraclinical examination methods, the spectrum of autoantibodies, as well as therapeutic options in patients with JIIM.Patients and methods. The retrospective study included 37 patients with JIIM hospitalized in the pediatric department of the V.A. Nasonova Research Institute of Rheumatology from 2016 to 2020. All patients underwent a standard clinical and laboratory-instrumental examination in accordance with the diagnosis and severity of the condition.Results and discussion. Twenty-three of the 37 JIIM patients had juvenile dermatomyositis (JDM), 1 had polymyositis, and 13 had overlap-myositis (OM). The ratio of boys and girls was 1:1.7. The median age of onset for JDM was 6.9 years, and OM was 11.3 years. All patients had skeletal muscles involvement, dysphagia was detected in 52.2% of cases of JDM and in 15.4% of cases of OM. An increase in the level of creatine phosphokinase at the time of diagnosis was observed in 72.9% of patients, of lactate dehydrogenase – in 81.1%, of alanine aminotransferase - in 67.6%, of aspartate aminotransferase – in 75.7%. Heliotrope rash and/or Gottron's syndrome were observed in 100% of patients with JDM and in 30.8% with OM. Lung involvement was found in 27% of children. The myopathic capillaroscopic changes were present in 95.2% of patients with JDM and 53.8% with OM. Myositis-specific autoantibodies were found in 10.8% of patients with JIIM.All patients received glucocorticoids, 81.0% methotrexate, 18.9% hydroxychloroquine, 8.1% cyclophosphamide, 8.1% cyclosporine, 2.7% mycophenolate mofetil, 2.7% azathioprine, 67.6% - intravenous immunoglobulin. Biologic disease modifying antirheumatic drugs (bDMARDs) were prescribed to 26% of patients with JDM and to all patients with OM (only in 51.3% of cases with JIIM). The median duration of illness before initiation of bDMARDs therapy was 2.25 years. 58.8% of patients were treated with rituximab (RTM), 41.2% with abatacept (ABA). In 1 patient with OM, represented by a combination of systemic lupus erythematosus and JDM, three bDMARDs were used sequentially: ABA, etanercept and RTM. All patients achieved inactive disease status.Conclusion. JDM is the most common phenotype of JIIM, which is characterized by an earlier age of onset, skin involvement that precedes the development of myopathy, and typical capillaroscopic changes. The conclusion was made about the high efficacy and acceptable safety profile of bDMARDs therapy in children with JIIM, with careful monitoring of its tolerability. bDMARDs can be prescribed even in the early stages of the disease in the presence of unfavorable prognostic factors.

Monogenic familial autoinflammatory Behçet-like syndrome/haploinsufficiency A20 syndrome is a hereditary autoinflammatory disease from the group of ubiquitinopathies which are caused by a mutation of the TNFAIP3 gene encoding the A20 protein with an autosomal dominant inheritance mechanism and clinical picture similar to Behçet’s disease. Pathogenesis is based on a 50% function decreasing of the nuclear factor inhibitor protein NFkB, what leads to overexpression of proinflammatory cytokines. The disease onset is usually in childhood. Clinical features are presented with recurrent aphthous stomatitis and genital aphthae in most patients and also inflammatory bowel damage is noted. Eye damage is noted rarely than in sporadic Behçet’s disease. In addition, the clinical picture may be presented with arthritis, skin rashes, lesions of the cardiovascular system (pericarditis), fever. Increasing of acute-phase markers is noticed, there is a high frequency of autoantibodies detection in contrast with “classic” autoinflammattory diseases. It can be combined with other autoimmune diseases (systemic lupus erythematosus (SLE), autoimmune thyroiditis, hepatitis, etc.). The description of two patients and comparison with another patient from Russia who was described earlier are presented. All patients had aphthous stomatitis and genital aphthaes, intestinal inflammation symptoms, which was dominanting in one of the patients. Another patient had severe polyarthritis in combination with immunological manifestations which were typical for SLE. The first patient had a good clinical response with the tumor necrosis factor inhibitor adalimumab, the second patient – the anti-B cell drug rituximab.

Background. Fibrodysplasia ossificans progressiva (FOP) — is an extremely rare genetic disorder with an autosomal dominant type of inheritance. FOP is associated with a genetically determined disorder caused by the presence of a specific mutation in the ACVR1/ALK2 gene encoding the bone morphogenetic protein receptor. FOP is clinically manifested by the unrestrained formation of heterotopic ossifications, leading to a gradual progression of disability up to complete immobility of the patient. At an early age, the disease can be recognized by the presence of characteristic phenotypic stigmas, mainly the characteristic malformation of the thumbs, confirming the diagnosis by molecular genetic analysis. Early diagnosis of FOP avoids unnecessary iatrogenic manipulations and slows down the progression of the disease. Up until recently, there was no therapy that had a pathogenetic effect, preventing the development of ossifications. The first and only drug that has proven its effectiveness as a result of clinical trials and is registered for use in patients with FOP in a number of countries is palovarotene.Case reports: The publication presents the first Russian experience of using palovarotene with a description of two clinical observations of patients with a genetically confirmed diagnosis of FOP. The clinical picture, the difficult path to diagnosis, and the encouraging experience of treating patients, including anti-inflammatory therapy using Janus kinase inhibitors (tofacitinib) and pathogenetic therapy with palovarotene, are described.Conclusion. The aggressive nature of the course of FOP, which inevitably leads to severe disability of patients, necessitates the widespread attention of practitioners to the early diagnosis of FOP, an in-depth study of the factors determining progression, and new opportunities for pathogenetic therapy allow us to count on improving the prognosis of this extremely serious disease.

Objective. To evaluate the pharmacokinetics (PK), efficacy, and safety of the direct interleukin-6 inhibitor olokizumab (OKZ) when used in adolescent patients with active juvenile idiopathic polyarthritis (JIA), with ineffectiveness or intolerance to methotrexate. Patients and methods. The results of OKZ therapy at a dose of 64 mg every 4 weeks during 24 weeks of the open-label study were analysed. The parameters of PK, efficacy, dynamics of serum concentration of C-reactive protein (CRP), adverse events (AEs) were evaluated. Results. Sixteen patients were included in the study, of whom 13 (81.2%) received OKZ therapy up to and including week 24. The PK profile was consistent with that of adults with rheumatoid arthritis. By week 16, 12 (80%) patients achieved an ACRpedi30 response, 11 (73.3%) achieved ACRpedi50, inactive disease was achieved by 2 (13.3%) patients. The response was maintained until week 24. There were no exacerbations of pJIA. Patients with baseline CRP values >10 mg/L and in the subgroup naive to biologic anti-rheumatic drugs had a trend towards a higher response (p > 0.05). Twenty-three AEs were reported in 12 (75.0%) patients, all of mild to moderate severity, with infections being the most frequent AE in 6 (37.5%) patients. No serious AEs or deaths were reported. Conclusion. Treatment with OKZ demonstrated a reduction in pJIA activity and good tolerability. The safety profile was consistent with that of interleukin-6 blockers, and the OKZ PK was consistent with that of adults with rheumatoid arthritis. Key words: juvenile idiopathic arthritis, genetically engineered biological drugs, interleukin-6 inhibitor, olokizumab, clinical

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare monogenic disease manifested by an uncontrolled process of generalized heterotopic ossification. The first and only drug that has demonstrated in clinical trials the ability to slow the growth of new ossifications is palovarotene (PVT), a selective agonist of the gamma subtype of the retinoic acid receptor (RARã), which has been approved for the treatment of FOP in certain age groups in several countries. Published real-world data on its use are limited. Objective: to analyze the experience of using PVT in FOP in real-world Russian clinical practice, with an emphasis on detailed patients’ characteristics description and assessment of treatment efficacy and safety. Material and methods. Nineteen patients with severe FOP (mean age 12.4 years; 14 patients younger than 14 years) who met the selection criteria were chosen for PVT therapy. Progression of the total volume of heterotopic ossifications (HO) was assessed using low-dose whole-body computed tomography (LDCT). The number of flare-ups before and during therapy was analyzed. Functional status was assessed using the CAJIS and CHAQ scales. Adverse events (AEs) occurring during treatment were recorded. Results and discussion. All 19 patients with FOP had the classic disease phenotype with a pathogenic variant of the ACVR1 gene. Of these, 15 are currently receiving PVT in the ongoing regimen in combination with the Janus kinase inhibitor tofacitinib (TOFA); in 8 of these patients, treatment duration exceeds 1 year (median 18 months). Another 4 patients are awaiting access to the drug. According to serial LDCT examinations with a 12-month interval, no substantial increase in the total HO volume was detected. No deterioration in functional status was observed during therapy. No serious AEs were recorded. In 14 of 15 patients, mucocutaneous AEs (dryness, pruritus, retinoid dermatitis) of varying severity were observed. Conclusion. Preliminary analysis of PVT use in patients with FOP showed no significant progression of HO and, at the same time, a favorable safety profile. Complementarity of the pathogenetic effects of PVT and TOFA may become a new therapeutic strategy for FOP.