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Drug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially fatal systemic reaction characterized by multiorgan damage involving the liver, hematopoietic system and skin, and heterogeneous manifestations of fever, rash, lymphadenopathy and eosinophilia with unpredictable course.We describe a 41-year-old female patient who developed DRESS syndrome after taking sulfasalazine prescribed for non-radiographic axial spondyloarthritis. Treatment with intravenous and then oral glucocorticoids was effective. A review of the literature on this topic is presented.

Introduction: Interferon I (IFN I) signaling hyperactivation is considered one of the most important pathogenetic mechanisms in systemic lupus erythematosus (SLE). Early manifestation and more severe SLE courses in children suggest a stronger genetic influence in childhood-onset SLE (cSLE). Aim: To evaluate IFN-I score and SLE-associated genetic variants in cSLE. Material and Methods: 80 patients with cSLE were included in the study. IFN I-score was assessed by real-time PCR quantitation of 5 IFN I-regulated transcripts (IFI44L, IFI44, IFIT3, LY6E, MXA1) in 60 patients. Clinical exome sequencing (CES) was performed in 51 patients. Whole-exome sequencing was performed in 32 patients with negative results of CES. Results: 46/60 patients (77%) had elevated IFN-I scores. Leucopenia and skin involvement were associated with over-expression of IFI44 and IFI44L, while hypocomplementemia—with hyperactivation of IFIT3, LY6E, and MX1. No correlation of IFN-I score with disease activity was found. At least one rare genetic variant, potentially associated with SLE, was found in 29 (56.9%) patients. The frequency of any SLE-genetic variants in patients with increased IFN scores was 84%, in patients with normal IFN scores—33%, and in the group whose IFN score was not assessed was 65% (p = 0.040). The majority of genetic variants (74%) are functionally related to nucleic acid sensing and IFN-signaling. The highest frequency of genetic variants was observed in Sakha patients (9/14; 64.3%); three and two unrelated patients had identical variants in PTPN22 and TREX1 genes, respectively. Conclusions: More than half of patients with childhood-onset SLE have rare variants in SLE-associated genes. The IFN-I score could be considered a tool for the selection of patients for further genetic assessment in whom monogenic lupus is suspected.

Hypophosphatasia is rare genetic disease caused by tissue-nonspecific alkaline phosphatase deficiency due to the mutation in the ALPL gene. Disease can manifest in utero, in childhood or in adults depending on its form and severity. This article presents modern data on the epidemiology, etiology, and clinical signs of hypophosphatasia in children, covers in details differential diagnostic search, and gives guidelines for its evidence-based treatment. Without timely treatment the prognosis of the disease is unfavorable in most cases. Such patients require follow-up by multidisciplinary team of physicians. The only effective method of treatment is enzyme replacement therapy with asfotase alfa. Symptomatic therapy is also crucial as well as physiotherapeutic procedures and therapeutic exercise programs (at rehabilitation stage).

Abstract 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.

Hemophagocytic lymphohistiocytosis (hemophagocytic syndrome, HLH, HPS) is the group of severe life-threatening and hardly diagnosing conditions caused by the immune dysregulation because of systemic inflammatory response with non-controlled proliferation and activation of T-cells, monocytes and macrophages with accumulation in target organs and the development of multiple organ failure. HLH are includes primary (monogenic) and secondary forms associated with various conditions, such as infections, immunopathological, oncohematological diseases. The severity of the condition, association with infections makes these diseases potentially lethal and requiring intensive care. In many critically ill patients in the intensive care unit, the presence of hemophagocytic syndrome remains unrecognized and is often interpreted as generalized infection, sepsis, systemic inflammatory response syndrome, multiple organ failure. Such patients require special attention, timely diagnosis and treatment. Nowadays, we have got a big group of drugs, which can pointwise block one or another pathogenesis pathway, but for a quick and correct choice, we need clear algorithms for deciding on the use of this group of targeted therapy. The article presents the history of the study of the issue and modern approaches to the diagnosis and treatment of these conditions in critically ill patients.

Background. In this article, we would like to describe the atypical clinical picture and course of 22q11 microdeletion syndrome in a patient without specific phenotypic signs and symptoms typical for this disease.Clinical case description. Male patient, 13 years old, was hospitalized for the first time with seizure and multiple spinal fractures caused by hypocalcemia. He was referred to rheumatologist and clinical geneticist after hospital stay. Differential diagnosis included not only various bones metabolic diseases, but also 22q11 deletion syndrome. Later it was confirmed via FISH test.Conclusion. This clinical case proves once again the uniqueness of every single case, as well as the importance of comprehensive approach to the diagnosis and management of such patients.

SummaryA 12-year-old girl with mucopolysaccharidosis (MPS) type I (Gurler-Scheie syndrome, Q70X/del C683 of the IDUA gene in the compound heterozygous state) regularly received enzyme replacement therapy (laronidase) since the preclinical stage (6 months old) due to positive family history, and started etanercept treatment due to progression of joint pain and decreasing capability to walk. The patient had a significant reduction of pain in the joints and an expansion of daily physical activity without adverse events. A decrease in bone marrow edema without foci progression compared to baseline assessment was observed in the whole-body MRI.During the treatment (baseline/6 months/12 months) the following was observed: childhood health assessment questionnaire (CHAQ) index of 1.88/2.13/1.63 points; patient’s pediatric quality of life inventory (PedsQL) of 37/30/31 points; parental PedsQL of 26/27/34 points; and patient’s pain visual-analog scale (VAS) of 75/45/40, with no VAS recorded for the mother. Juvenile arthritis functional assessment report (JAFAR) scores of 35/34/8 points were observed. A significant reduction in the taking of NSAIDs was observed. In the second half of the year, the nasal breathing became normal, and remission in chronic rhinitis and adenoiditis was achieved (no infection episodes) without otitis episodes.ConclusionEtanercept in mucopolysaccharidosis type 1 is safe and well tolerated. The reduction of joint pain and increased walking capacity were observed. A decreased number of respiratory infection episodes and nasal breathing improvement were noted during the treatment. The observation shows the role of inflammation in the different aspects of MPS. Further investigations on immune system dysregulation in patients with MPS I are needed. Additional studies on the efficacy and safety of anti-rheumatic biological drugs in patients with MPSI are required.

Introduction The complex treatment of osteoarticular tuberculosis is based on combination of anti-tuberculosis therapy, complete (radical) removal of involved bone and restoration of the supporting and motor function of the affected musculoskeletal segment. Inhibited activity of osteoclasts involved in osteoresorption as one of the mechanisms of reparative osteoregeneration can be involved in regulation of bone formation after radical reconstructive surgery. The objective was to explore CT signs of osteoregeneration due to multimodal treatment of experimental tuberculous osteitis with use of bisphosphonates as targeted inhibitors of osteoclasts. Material and methods An experimental study was carried out on 21 mature male Chinchilla rabbits. The first stage included bone tuberculosis simulated in the medial condyle of the right femur using invasive local infection with M. tuberculosis strains H37Rv, a virulent reference laboratory strain. Pathological focus was resected and bone graft used at the second stage. Animals receiving antituberculosis therapy (ATT), ATT and bisphosphonates (BP) and BP only were divided into three groups at the third stage. Animals were sacrificed at 3 and 6 months of surgical treatment at the fourth stage. Autopsy implantation zone, bone of the contralateral condyle and intact femur were quantitatively and qualitatively assessed using micro-CT imaging. Results Positive dynamics in bone restoration was seen in the groups. ATT group showed complete lysis of the implant with bone cavities identified and no bone restoration in half of the cases seen at 6 months. Rabbits treated with BP demonstrated absence of complete lysis of the implant and CT signs of ingrowth of bone trabeculae. CT signs of maximum osteoregeneration were noted in the group of isolated BP therapy. Discussion The use of bisphosphonates can prevent lysis of grafts preserving the osteoconductive properties and facilitating formation of new bone. Conclusion Targeted osteoclast inhibitors can be safety and efficaciously used in the complex treatment of focal infectious skeletal lesions and be recommended as a potential component of pathogenetic therapy in the postoperative treatment of infectious (tuberculous) skeletal lesions.

Background. Differential diagnosis of attenuated forms of mucopolysaccharidosis (MPS) and juvenile idiopathic arthritis (JIA) can be challenging due to their similarities.Objective. The aim of the study is to create simple diagnostic criteria (DScore) that would allow to differentiate MPS from JIA for earlier MPS diagnosis.Methods. The retrospective multicenter study included analysis of clinical (joint, heart, eye involvement, hearing loss, hernias, psychomotor delay, noisy breathing, posture disorders, macrocephaly, hepatomegaly, splenomegaly, and growth delay) and laboratory data (ESR, CRP, hemoglobin, WBC, and platelets) from MPS patients (n = 41) and from rheumatoid factor-negative polyarticular category of JIA patients (n = 255). These variables allowed to differentiate both conditions and were used to create DScore.Results. Patients with MPS had younger onset age, male predominance, height and weight delay, lower inflammation markers (WBC, platelets, and ESR), and usually involved joints, especially cervical spine, upper limbs joints, hip, and small foot joints. The prevalence of eye involvement was similar for both diseases, however, the type of involvement was different. JIA patients had uveitis and its’ complications and MPS patients — corneal opacity and cataract. No differences in CRP levels were revealed in most cases. The major diagnostic criterion of MPS was the presence of more than one extra-articular manifestation associated with polyarticular involvement. DScore has included 5 following criteria: ESR ≤ 11 mm/h (38 points), height ≤ -2.0 SD (20 points), onset age of articular manifestations ≤ 1.1 year (24 points), male gender (15 points), and symmetrical limitation of movements in elbow joints (29 points). The sum > 38 points allowed us to differentiate MPS and JIA with sensitivity of 92.7% and specificity of 91.0%.Conclusion. This DScore can be used for differential diagnosis of mild MPS and JIA alongside with routine diagnostic procedures. DScore allows us to identify a group of patients with joint involvement who require MPS exclusion.

Hemophagocytic syndrome is a key point in the pathogenesis of severe forms of multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C). The factors associated with hemophagocytosis in patients with MIS-C were assessed in the present study of 94 boys and 64 girls ranging in age from 4 months to 17 years, each of whose HScore was calculated. In accordance with a previous analysis, patients with HScore ≤ 91 (n = 79) and HScore > 91 (n = 79) were compared. Patients with HScore > 91 had a higher frequency of symptoms such as cervical lymphadenopathy, dry cracked lips, bright mucous, erythema/swelling of hands and feet, peeling of fingers, edematous syndrome, hepatomegaly, splenomegaly, and hypotension/shock. They also had a higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and D-dimer levels, and a tendency to anemia, thrombocytopenia, and hypofibrinogenemia. They more often needed acetylsalicylic acid and biological treatment and were admitted to ICU in 70.9% of cases. Conclusion: The following signs of severe MIS-C were associated with HScore > 91: myocardial involvement, pericarditis, hypotension/shock, and ICU admission.

Juvenile idiopathic arthritis (JIA) is a systemic autoimmune disease that affects the joints, leading to disability. Cytokines and signaling molecules expressed by the immune system cells play a key role in JIA pathogenesis. Understanding how their content changes during pathology development can open up new opportunities for its diagnosis and treatment. The blood plasma of 30 patients with JIA (14 males and 16 females with a mean age of 12.2 ± 4.1) and 20 relatively healthy individuals (10 males and 10 females with a mean age of 10.20 ± 5.85) was analyzed to determine the levels of cytokines using the MILLIPLEX® kit. An increase in interleukins (IL)-1α, 1β, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 17F, 22, and 27 and a decrease in IL-3 levels have been shown in patients with JIA. Levels of cytokines, which are important for B-cell activation and proliferation, are increased, while levels of T-cell activating factors remained similar to the control group. Based on our results, it can be assumed that the use of combination therapy aimed at inhibiting both nonspecific interleukins and cytokines that activate B-cells will be more effective for the treatment of JIA.

Progeria, or Hutchinson-Gilford Syndrome is a rare disease from the group of laminopathies characterized by premature aging with skin, bones and cardiovascular system lesions. Pathogenesis is based on pathogenic variants in the LMNA gene leading to anomalies in the nuclear membrane morphology, gene expression disruption, chromatin structure changes, mitochondrial dysfunction, DNA repair and alternative splicing defects, and telomere shortening acceleration. Major manifestations of the disease are: skin lesions (scleroderma-like syndrome and pigmented lesions), lipodystrophy, late teeth eruption, teeth crowding, alopecia, nail dystrophy, osteolysis of distal phalanges, hip joints valgus deformation, joints contractures, atherosclerosis, hearing loss, early heart attacks and strokes. Scleroderma-like skin changes, osteoporosis, flexion contractures of hands’ interphalangeal joints, and hip joints osteoarthritis require differential diagnosis with rheumatic diseases. The basic strategy in management of patients with progeria is the prevention and treatment of its cardiovascular manifestations (early strokes and heart attacks, arterial hypertension, and atherosclerosis), as well as the increase of patients’ quality of life and daily activity. The efficacy of therapy in patients with progeria via the use of farnesyltransferase inhibitors (monotherapy; combination with bisphosphonates or statins), retinoids, and 1,25(OH)2 — vitamin D3 is studied. This literature review is updated with clinical case description of a girl with progeria. The diagnosis was confirmed by sequencing of the LMNA gene (Sanger), and previously described pathogenic variant in exon 11 (c.1824C>T, rs58596362) in the heterozygous state (p.Gly608Gly, NM_170707.3) was revealed.

Non-bacterial osteomyelitis (NBO) is a rare chronic inflammatory bone disease related to immune system dysregulation. This disease belongs to a family of autoinflammatory diseases. It often coexists with other TNF-α-mediated immune-mediated diseases such as juvenile idiopathic arthritis (JIA) and inflammatory bowel diseases. Previously, interleukin-1-driven inflammation was described predominantly in monogenic cases of NBO, such as DIRA syndrome or Majeed syndrome. However, the association between NBO and JIA with systemic onset (soJIA) has not been described yet.Herein, we describe the cases of two patients with soJIA with inflammatory bone lesions wherein canakinumab (anti-interleukin-1β antibodies) caused remission. Case descriptionsPatient 1–A 6-month-old boy with typical soJIA suffered a destruction of the 7th to 9th ribs and the left pubic bone. Antibiotics, IVIG, and cyclosporine proved ineffective. Corticosteroids were effective, but due to the factor of corticosteroid dependence, which has some disadvantages, canakinumab with a dosage of 4 mg/kg was initiated every 4 weeks, which completely controlled the disease and allowed to taper corticosteroids.Patient 2—A 2-year-old girl developed chronic non-bacterial osteomyelitis of the 5th rib 2 months after taking corticosteroids prescribed for typical soJIA. She underwent surgical debridement removal, and several courses of antibiotics proved ineffective. She developed macrophage activation syndrome, following which anakinra was prescribed, which resulted in only temporary improvement. Therefore, this drug was switched to canakinumab, which caused corticosteroid-free remission.ConclusionThis is the first description of a rare association of soJIA with inflammatory bone lesions with the proven efficacy of IL-1 blockade. The association of two autoinflammatory conditions should indicate IL-1-driven mechanisms and a possible genetic basis. Follow-up genetic and functional studies are required to better understand the pathogenesis of such overlapping diseases.

Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a systemic inflammatory condition that is characterized by multisystemic involvement (liver, blood, and skin), heterogeneous manifestations (fever, rash, lymphadenopathy, and eosinophilia), and an unpredictable course; cases of DiHS/DRESS caused by sulfasalazine are rare in children compared to adults. We report a case of a 12-year-old girl with juvenile idiopathic arthritis (JIA) and sulfasalazine-related hypersensitivity who developed fever, rash, blood abnormalities, and hepatitis complicated with hypocoagulation. The treatment with intravenous and then oral glucocorticosteroids was effective. We also reviewed 15 cases (67% male patients) of childhood-onset sulfasalazine-related DiHS/DRESS from the MEDLINE/PubMed and Scopus online databases. All reviewed cases had a fever, lymphadenopathy, and liver involvement. Eosinophilia was reported in 60% of patients. All patients were treated with systemic corticosteroids, and one patient required emergency liver transplantation. Two patients (13%) died. A total of 40.0% of patients satisfied RegiSCAR definite criteria, 53.3% were probable, and 80.0% satisfied Bocquet's criteria. Only 13.3% satisfied typical and 20.0% atypical DIHS criteria from the Japanese group. Pediatric rheumatologists should be aware of DiHS/DRESS due to its similarities to other systemic inflammatory syndromes (especially systemic JIA, macrophage activation syndrome, and secondary hemophagocytic lymphohistiocytosis). Further studies of DiHS/DRESS syndrome in children are needed to improve its recognition and differential diagnostic and therapeutic options.

PurposeOsteomyelitis is a group of bone infectious (bacterial osteomyeilitis—BO) and noninfectious inflammatory diseases (nonbacterial osteomyelitis—NBO) with similar clinical, radiology, and laboratory features. Many patients with NBO are misdiagnosed as BO and receive unnecessary antibiotics and surgery. Our study aimed to compare clinical and laboratory features of NBO and BO in children, to define key discriminative criteria, and to create an NBO diagnostic score (NBODS).MethodsThe retrospective multicenter cohort study included clinical, laboratory, and instrumental information about histologically confirmed NBO (n = 91) and BO (n = 31). The variables allowed us to differentiate both conditions used to construct and validate the NBO DS.ResultsThe main differences between NBO and BO are as follows: onset age—7.3 (2.5; 10.6) vs. 10.5 (6.5; 12.7) years (p = 0.03), frequency of fever (34.1% vs. 90.6%, p = 0.0000001), symptomatic arthritis (67% vs. 28.1%, p = 0.0001), monofocal involvement (28.6% vs. 100%, p = 0.0000001), spine (32% vs. 6%, p = 0.004), femur (41% vs. 13%, p = 0.004), foot bones (40% vs. 13%, p = 0.005), clavicula (11% vs. 0%, p = 0.05), and sternum (11% vs. 0%, p = 0.039) involvement. The following four criteria are included in the NBO DS: CRP ≤ 55 mg/l (56 points), multifocal involvement (27 points), femur involvement (17 points), and neutrophil bands ≤ 220 cell/μl (15 points). The sum > 17 points allowed to differentiate NBO from BO with a sensitivity of 89.0% and a specificity of 96.9%.ConclusionThe diagnostic criteria may help discriminate NBO and BO and avoid excessive antibacterial treatment and surgery.

Systemic corticosteroids are continued to be administered in juvenile idiopathic arthritis (JIA) patients, especially in systemic JIA (sJIA), despite the ability of biologic therapy. One of the complications of long-term CS treatment is delayed hip arthritis development with risk of secondary hip osteoarthritis formation and total hip arthroplasty (THA).We compared different types of hip joint lesions in JIA, especially, secondary hip osteoarthritis development and THA rates in systemic and non-systemic JIA, and evaluate systemic corticosteroids contribution to those complications.The study included 753 JIA patients. They were divided into 2 groups: patients with sJIA and non-systemic JIA (nsJIA). Clinical and demographic characteristics, CS treatment regimens were compared.Results. Hip arthritis was found equally often in both groups, but both secondary hip osteoarthritis (19% vs 5,3%) and THA (8.6% vs 1.6%) prevailed in the sJIA. Patients with sJIA had delayed hip involvement (57.9% vs 30.6%; p=0.019), earlier secondary hip osteoarthritis development (4.5 vs 5.1 years after the JIA onset) with younger age of secondary hip osteoarthritis achievement (13.7 vs 15.2 years; р=0.045), they also had higher inflammatory activity, greater systemic corticosteroids administration (94.8% vs 56.1%; р=0.0000001) and higher cumulative systemic corticosteroids dose (3085 mg vs 2000 mg; p=0,005). More than half patients (56.1%) with nsJIA had systemic corticosteroids treatment and impaired calcium-phosphorus metabolism.Conclusion. Systemic corticosteroid treatment and delayed hip involvement are independent predictors of secondary hip osteoarthritis in all JIA categories. Calcium and phosphate metabolism disturbances are additional predictor for secondary hip osteoarthritis in non-systemic JIA categories

Background. Mucopolysaccharidosis type I is disease from the group of lysosomal storage disease developing due to mutations in the IDUA gene. It leads to the accumulation of glycosaminoglycans (GAGs) in organs and tissues. Joints damage in this disease is systemic and progressive.Objective. The aim of the study. Nowadays, relevant issue is to investigate the effects of various types of pathogenetic therapy on the state of the osteoarticular system in patients with severe and mild phenotypes of MPS I to prevent further progression of joint pathology.Methods. The study included 46 patients diagnosed with “mucopolysaccharidosis type I”. 35 children had severe phenotype (Hurler syndrome) and 11 — with mild phenotypes (Hurler-Scheie and Scheie syndromes). The onset age of clinical manifestations in osteoarticular system, the state of large and small joints, and the presence of cervical stenosis according to the therapy were evaluated in these patients.Results. The osteoarticular system pathology can be usually revealed in all patients with MPS I, in both mild and severe phenotypes. The contractures of shoulder, ulnar, wrist, and small hand joints have been revealed in most patients with Hurler syndrome, regardless of the administered therapy. Hip joints pathology was observed in children who was administered with: enzyme replacement therapy (ERT) — in 46.7% of cases, hematopoietic stem cell transplantation (HSCT) in combination with ERT — in 34.4% of cases. Patients with Hurler syndrome administered with HSCT in combination with ERT had cervical stenosis statistically significantly more rarely (p = 0.018) compared to patients treated with ERT only. Patients with Hurler syndrome who were on ERT had statistically significantly lower growth rates than patients after HSCT in combination with ERT. Lesions in ulnar, wrist, knee and small hand joints were the most common in children with mild phenotypes (in 90% of cases).Conclusion. Combined therapy (HSCT and ERT) in patients with Hurler syndrome reduces severe manifestations in osteoarticular system, including children with a pathogenic nucleotide variant c.208C>T in a homozygous state.

Background. Vaccination is the most effective method for reducing morbidity, disability, mortality from of various infections. However, there was a view for a long time that vaccines are ineffective and unsafe to use in people with rheumatological diseases, including juvenile idiopathic arthritis (JIA). Objective.The aim of the study is to analyze literature data on safety and efficacy of vaccination for JIA patients with live and non-live vaccines.Methods: literature analysis was based on data from medical databases PubMed and Google Scholar.Results. Both live and non-live vaccines are safe and immunogenic enough for children with JIA. Most studies confirm vaccination efficacy in patients with JIA when using glucocorticosteroids (GCS) and methotrexate, while therapy with disease-modifying antirheumatic drugs (DMARD) can reduce antibody titers over time. In general, antibodies levels preservation in previously vaccinated children with JIA is less than in global population. This indicates the need to administer booster doses for such patients. No adverse effects on the course of primary disease after vaccination and no post-vaccine complications were revealed.Conclusion. Vaccination of patients with JIA should be performed with reference to the therapy that the patient already receives, under the control of antibodies level. Booster doses should be implemented in case of titers decrease below the protective levels.

Multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) is a life-threatening condition that often requires intensive care unit (ICU) admission. The aim of this study was to determine risk factors for severe/life-threatening course of MIS-C. The study included 166 patients (99 boys, 67 girls) aged 4 months–17 years (median 8.2 years). The criterion of severity was the fact of ICU admission. To conduct a comparative analysis, MIS-C patients were divided into two groups: patients hospitalized in the ICU (n = 84, 50.6%) and those who did not need ICU admission (n = 82, 49.4%). Patients with a more severe course of MIS-C were significantly older. They had a higher frequency of signs such as rash, swelling, hepatomegaly, splenomegaly, and neurological and respiratory symptoms. Hypotension/shock and myocardial involvement were much more common in patients with severe MIS-C. These patients had a more significant increase in CRP, creatinine, troponin, and D-dimer levels. Additionally, the presence of macrophage activation syndrome was higher in patients admitted to the ICU. Conclusion: Nineteen predictors of severe course of MIS-C were found, out of which hepatomegaly, splenomegaly, D-dimer > 2568 ng/mL, troponin > 10 pg/mL were mainly associated with the probability of being classified as early predictors of severe MIS-C requiring ICU admission.

Background: The causative agent of the new coronavirus infection SARS-CoV-2 has unique properties causing hyperinflammatory syndrome and cytokine storm, as well as widespread endotheliitis and thrombotic microangiopathy, initially detected in the lungs of adult patients who died from a severe form of the disease. Venous and arterial thrombosis in adults were identified as common causes of severe complications and deaths in new coronavirus infections. There are very few reports of thrombotic events in children with COVID-19 in the literature. Methods: We conducted a retrospective analysis of the histories of 60 patients in the Irkutsk Regional Children’s Clinical Hospital from November 2020 to November 2022 with a MIS-C diagnosis established according to WHO criteria, of which 8 (13.3%) were diagnosed with venous and/or arterial thrombosis, confirmed by laboratory and ultrasound and/or X-ray methods. Results: The average age of children with thrombosis (Me) was 7.5 years (min 4 months, max 17 years), with a M:F ratio of 3.0. Venous thrombosis was detected in six of the eight patients, including in the deep veins of the lower extremities in four. Pulmonary embolism occurred in two (one of them was fatal), and cerebral venous sinus thrombosis and thrombosis of the branches of the upper and lower vena cava were found in one patient. Extensive bilateral stroke due to thrombosis of the large cerebral arteries occurred in two patients, including one in combination with distal gangrene. Secondary thrombotic renal microangiopathy took place in three of the eight patients. Among these three, atypical HUS was diagnosed in one case. Multiple thrombosis involving the venous and arterial bed was detected in four of the eight patients. High levels of D-dimer, thrombocytopenia, increased NT-proBNP, cerebral coma, and aseptic meningitis were the events most often associated with thrombosis. All patients received immunomodulatory therapy (immunoglobulin, dexamethasone/methylprednisolone), pathogenetic therapy for multiorgan failure, anticoagulant therapy with heparin/LMWH, and acetylsalicylic acid. Biologics were used in two patients. Conclusions: The main predictors of thrombosis in children with MIS-C were increased D-dimer, thrombocytopenia, hospitalization in the ICU, and noncardiogenic pulmonary edema. Thrombosis of the deep veins of the lower extremities, large cerebral arteries, and secondary thrombotic microangiopathy was common. There was a single death (12.5% of the eight patients), associated with PE.

Introduction: Aicardi-Gouteres syndrome (AGS) is a monogenic interferonopathy characterized by early onset, dysregulation of skin (chilblain lesions), brain, and immune systems (fever, hepatomegaly, glaucoma, arthritis, myositis, and autoimmune activity). The disease looks like TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes) infection with early-onset encephalopathy resulting in severe neuropsychological disability. Case description: A six-year-old girl has been suffering from generalized seizures, fever episodes, severe psychomotor development delay, and spastic tetraparesis since the first year of her life. Her two elder brothers died at a young age from suspected infantile cerebral palsy (ICP). Other siblings (younger brother and two elder sisters) are as healthy as their parents. The girl was diagnosed with juvenile dermatomyositis at 5.5 years. Basal ganglia, periventricular, and cerebellum calcifications; hypoplasia of the corpus callosum; and leukodystrophy were detected on CT. The IFN-I score was 12 times higher than normal. The previously not described nucleotide variant c.434G > C (chr 20:36935104C > G; NM_015474) was detected in exon 4 of the SAMHD1 gene in the homozygous state, leading to amino acid substitution p.R145P. Aicardi-Goutières syndrome 5 was diagnosed. Her treatment included corticosteroids, methotrexate, and tofacitinib 5 mg twice a day and it contributed to health improvements. The following brain CT depicted the previously discovered changes without the sign of calcification spreading. Conclusions: Early diagnosis of AGS is highly important as it allows starting treatment in a timely manner. Timely treatment, in return, can help avoid the development/progression of end-organ damage, including severe neurological complications and early death. It is necessary to spread information about AGS among neurologists, neonatologists, infectious disease specialists, and pediatricians. A multidisciplinary team approach is required.

Abstract Background Immunosuppressive drugs, incomplete vaccine coverage, immune system dysregulation might be factors of a low level of anti-vaccine antibodies in JIA patients. The study aimed to evaluate vaccine coverage, post-vaccine immunity, and risk factors of non-protective levels of antibodies against measles, mumps, rubella, hepatitis B, and diphtheria in JIA patients. Methods A cross-sectional study included 170 children diagnosed with JIA aged 2 to 17 years who received routine vaccinations against measles, rubella, mumps (MMR), diphtheria, and hepatitis B national vaccine schedule. In all patients, the levels of post-vaccination antibodies (IgG) for measles, rubella, mumps, hepatitis B, and diphtheria were measured with ELISA. Results Protective level of antibodies were 50% against hepatitis B, 52% - diphtheria, 58% - measles, 80% - mumps, 98% rubella. MMR’s best coverage had patients with enthesitis-related arthritis-85%, compared to oligoarthritis-70%, polyarthritis-69%, systemic arthritis-63%. Diphtheria coverage was 50, 51, 46, 63%, respectively. Incomplete MMR vaccination had 39% patients, treated with biologics, 22% with methotrexate and 14% with NSAID (p = 0.025), and 61, 46, 36% for diphtheria (p = 0.021). Incomplete vaccination was a risk factor of non-protective level of antibodies against measles (HR = 2.03 [95%CI: 1.02; 4.0], p = 0.042), mumps (HR = 6.25 [95%CI: 2.13; 17.9], p = 0.0008) and diphtheria (HR = 2.39 [95%CI: 1.18; 4.85], p = 0.016) vaccines, as well as JIA category, biologics, corticosteroids and long-term methotrexate treatment for distinct vaccines. One-third part of JIA patients continued vaccination against MMR and diphtheria without serious adverse events and JIA flare. There were no differences between patients who continued MMR vaccination or denied in the means of JIA category and treatment options. Patients, continued diphtheria vaccination rare received methotrexate (p = 0.02), biologics (p = 0.004), but had higher levels of anti-diphtheria antibodies (p = 0.024) compare who omitted vaccination. Methotrexate (OR = 9.5 [95%CI: 1.004; 90.3]) and biologics (OR = 4.4 [95%CI: 1.6; 12.1]) were predictors of omitted diphtheria revaccination. Conclusion Children with JIA may have lower anti-vaccine antibody levels and required routine checks, especially in children with incomplete vaccination, biologics, systemic arthritis, and long-term methotrexate treatment. Revaccination of JIA patients was safe and effective.

Introduction. The issue of protection against vaccinepreventable diseases has acquired new urgency in connection with the decrease in the vaccination rate established by WHO against the background of the COVID-19 pandemic. This creates the conditions for outbreaks and puts patients with immunopathological diseases at particular risk, who are most often not vaccinated from the moment of diagnosis Purpose of the study – to assess the safety of specific antibodies to measles, mumps, rubella and diphtheria in children with JIA, depending on the duration of vaccination, the duration of the disease and the therapy received.Materials and methods. The vaccination rate of 171 children with juvenile idiopathic arthritis (JIA) aged (11,31±0,31 years) with the duration of the disease at the time of examination was 4,69±0,29 years, who had previously received 1-2 vaccinations against measles, mumps, rubella and 3-6 vaccinations against diphtheria. Antibodies to these infections were determined by ELISA.Results. 42.1% of children had no protective titers of antibodies to measles, 19,9% – to mumps, 9,4% – to rubella and 16,4% – to diphtheria. Among 93 vaccinated and revaccinated patients, there were no protective titers of antibodies to measles – 40,9% (38 children), mumps – 13,9% (13 people), rubella – 5,4% (5 children), and among 78 vaccinated once, respectively: measles – 43.6% (34 children), mumps – 25.6% (20 children), rubella – 14,1% (11). The level of protection against diphtheria was comparable for those who received 3-5 vaccinations. Depending on the therapy, 3 groups were identified: group 1-71 children received metatrexate and glucocorticosteroids, 2-82 children received modifying anti-rheumatic drugs (DMARD) and 18 children without this therapy (Group 3). Children of the 2nd group were on average older (12,48±0,42 years) than in the 1st and 3rd groups (10,04±0,48 and 10,96±0,96 years, respectively), they had significantly more frequent systemic variant and polyarthritis (64,6% compared to 36,6% and 16,7%, px2˂0,001). The number of vaccine doses received by children in all groups before the onset of the disease did not significantly differ. The average level of antibodies to measles in children of group 2 (0,32±0,07 IU/ml) was 2,8 times less than in group 3 and significantly less than in group 1 (0,78±0,16, Pt=0.009), the average value of antibodies to rubella was also significantly less in group 2 (84,48±7,34 IU/ml) than in group 1 (109,73±8,09, Pt=0,022) and in group 3 (120,01±15,42, Pt=0,042). The analysis showed that the safety of antibodies to antigens of live vaccines, especially against measles, is negatively affected by the duration of the disease and the nature of therapy. Children who received combined therapy with anti-TNF, anti-IL-6 and anti-CD-80 drugs had a longer duration of the disease (7,5±0,97 years)=0,00082 compared to those who received only anti-IL-6 (2,9±0,7 years) and antiTNF therapy (6,1±0,5 years) and with a comparable number of vaccine doses received, significantly lower average values of antibodies and a larger number of unprotected ones.Conclusions. The duration of the disease, the lack of timely age-related revaccinations, as well as the presence of combination therapy aimed at suppressing various mechanisms of the immune response in children with JIA are factors that lead to an increase in the number of unprotected from controlled infections. Immunity to measles suffers the most – 40.9% of revaccinated people are unprotected.

Background. Patients with juvenile idiopathic arthritis (JIA) may have incomplete vaccination againts different vaccines leads to lower protective levels of anti-vaccine antibodies.The aim of the study – to evaluate the rate and the main factors of incomplete vaccination against measels, parotitis, rubella (MMR), and diphtheria in JIA patients.Methods. In the present study were included data 170 JIA (55 boys and 115 girls) aged from 2 to 17 years, who received scheduled vaccination before the age of 2 years and before JIA onset against measles, parotitis, diphtheria and rubella. Incomplete vaccination means the reduced number of vaccine to age. In all patients the IgG anti-vaccine antibodies levels were detected with ELISA. Data presented with odds ratio ()OR) with 95 confidence interval (CI).Results. Incomplete vaccination against MMR was in 50 (32.5%) of children less than 6 years. Incomplete vaccination against diphtheria was in 6/16 (37.5%) of children less than 6 year, in 53/110 (48.2%) of children aged 6–14 years and in 26/44 (59.1%) of the JIA patients more than 14 years. The main predictors in logistic regression for incomplete vaccination for MMR were: onset age 3.1 years (OR=4.4 [95% CI: 2.0–9.9]; p=0.0002), methotrexate duration >3 years (OR=5.7 [95% CI 2.7–12.0]; p=0.0000012); biologic treatment (OR=2.5 [95% CI: 1.3–4.9]; p=0.008) and treatment >1 biologic (OR=3.3 [95% CI: 1.1–10.4]; p=0.002); for diphtheria were: JIA duration >3.1 years (OR=3.4 [95% CI: 1.8–6.5]; p=0.0002), methotrexate duration >2.8 years (OR=4.1 [95% CI: 2.1–8.1]; p=0.00004), biologic treatment (OR=2.4 [95% CI: 1.3–4.4]; p=0.006). In the multiple regression only JIA onset age (p=0.00001) and duration of methotrexate (p=0.003) were predictors of incomplete vaccination against MMR. Methotrexate duration (p=0.005) and biologics treatment (p=0.05) were predictors of incomplete vaccination against diphtheria.Conclusion. The main predictor of incomplete vaccination was younger onset age of JIA. Children received more intensive immunosupression usually have scheduled vaccination rarely which leads to increased number of patients without protective antibody levels. These facts indicate the attitude of physicians parents to vaccination in immunocompromised children. Further investigations required for assessment of safety of vaccinations in children with rheumatic diseases may be a factor for changing this prejudice.

ObjectiveMacrophage activation syndrome (MAS) is a life-threatening, potentially fatal condition associated with systemic juvenile idiopathic arthritis (sJIA). Interleukin-1 (IL-1) is a key cytokine in the pathogenesis of sJIA MAS. Many cases of MAS are medically refractory to traditional doses of biologic cytokine inhibitors and may require increased dosing. When MAS occurs in the setting of sJIA treated with the IL-1 receptor antagonist (IL-1Ra), anakinra, increased anakinra dosing may be beneficial. Increased dosing of another IL-1 inhibitor, canakinumab, a monoclonal antibody to IL-1β, has not been reported to treat refractory MAS in the setting of sJIA.MethodsRetrospective data collection extracted from the electronic medical record focused on canakinumab usage and dosing in 8 children with sJIA who developed MAS at a single academic center from 2011 to 2020.ResultsEight sJIA children (five girls) with median age 8.5 years (range, 0.9–14.2 years) were included in the present study. Five children developed MAS at disease onset and three during ongoing canakinumab therapy. MAS resolved in all eight children with canakinumab treatment. When the canakinumab dosing was insufficient or MAS developed during canakinumab therapy, the dosing was temporally up-titrated (four patients, maximum 300 mg per dose) without observed side effects.ConclusionThis report provides evidence for the efficacy and safety of short-term increased doses (2–3-times normal) of canakinumab in treating sJIA associated MAS. Further study of the efficacy and safety of increased doses of canakinumab for treatment of MAS in children with sJIA is warranted.

Since March 2020, the first reports have appeared about the increasing, almost everywhere, number of children who have undergone a new coronovirus infection caused by SARS-Cov-2 with a symptom complex resembling the manifestations of Kawasaki disease. A special feature of the clinical manifestations of this syndrome, which is called “Pediatric multisystem inflammatory syndrome associated with COVID-19”, is the high incidence of life-threatening conditions caused by the sharp development of arterial hypotension against the background of cardiogenic or vasogenic shock.In St. Petersburg, since the end of November 2020, there has been a sharp surge in admissions of children to the ICU of various hospitals with the clinic of Pediatric multisystem inflammatory syndrome, who have laboratory confirmation of the transferred COVID-19.The purpose of this article is to attract the attention of doctors of various profiles, to combine efforts to study this pathology, to determine the criteria for verifying the diagnosis, optimal treatment regimens and dispensary monitoring of patients who have been ill.

Our study aimed to evaluate the clinical and laboratory features of juvenile idiopathic arthritis (JIA) children with temporomandibular joint (TMJ) arthritis. In the retrospective cohort study, we analyzed data of 753 patients with JIA aged 2–17 years, depending on TMJ arthritis or not. TMJ arthritis can to be diagnosed in the presence of at least two of the following clinical signs of inflammation: pain in TMJ, jaw opening limitation, jaw opening deviation, and micrognathia. We compared clinical, laboratory, and treatment features in JIA patients depending on the involvement of TMJ. TMJ arthritis was detected in 43 (5.7%) of our patients and associated with a longer course of the disease, polyarticular JIA category, treatment with systemic corticosteroids, and longer achievement of the remission and involvement of cervical spine, hip, and shoulder. Active joints >8 (OR = 14.9, p = 0.0000001), delayed remission >7 years (OR = 3.1; p = 0.0004), delayed hip involvement (OR = 4.6; p = 0.041), hip osteoarthritis (OR = 4.0; p = 0.014), cervical spine arthritis (OR = 10.3, p = 0.000001), and corticosteroid treatment (OR = 2.3, p = 0.0007) were associated with TMJ involvement. Patients with TMJ arthritis require more biologics (OR = 3.2, p = 0.0006, HR = 2.4, p = 0.005) and have decreased probability of remission achievement (p = 0.014). Consequently, TMJ arthritis was associated with a severe disease course. Early biologic treatment and corticosteroid avoidance might decrease TMJ involvement.

Background: Several cases of skin and central nervous system vasculopathy associated with COVID-19 in children have been published, but the information is rather limited. Our study aimed to describe these cases of vasculitis associated with COVID-19 in children. Methods: In the retrospective-prospective case series study we included information regarding four children with COVID-19-associated vasculitis. In every case, we had a morphological description and the etiology was confirmed via real-time polymerase chain reaction during a tissue biopsy. Results: The most involved systems were skin (4/4), respiratory (3/4), cardiovascular (2/4), nervous (1/4), eye (1/4), kidney (1/4), and inner year (1/4). All patients had increased inflammatory markers and thrombotic parameters (D-dimer). No patient met the criteria for multisystem inflammatory syndrome in children. Two patients met polyarteritis nodosa criteria, one met Henoch–Schonlein purpura criteria, and one met unclassified vasculitis criteria. All patients were treated with systemic glucocorticosteroids (two-pulse therapy). Non-biologic DMARDs were prescribed in all cases; 1/4 patients (25%) was treated with intravenous immunoglobuline, and 3/4 (75%) were treated with biologics (etanercept, tocilizumab, and adalimumab). Conclusions: Vasculitis associated with COVID-19 could be a life-threatening condition; SARS-CoV-2 might be a new trigger or etiological agent for vasculitis and other immune-mediated diseases. Further research and collection of similar cases are required.

Introduction. In children with rheumatic diseases, severe fungal infections (invasive mycoses – IM) are not well understood.Objectives. To analyze risk factors, disease course of IM in children with systemic rheumatic diseases.Materials and methods. For diagnosis of IM were used criteria EORTC/MSGERC, 2019. We reviewed the literature over the past 15 years on IM in children with rheumatic diseases from the international databases Pubmed and Web of Science.Results. In retrospective multicenter study were included 8 children with IM and systemic rheumatic diseases: ANCA-associated vasculitis (n=4), systemic lupus erythematosus (n=3), juvenile rheumatoid arthritis (n=1). Median age was 13,5 (8-17) y., boys – 67%. Invasive aspergillosis was diagnosed in 5 patients and invasive candidiasis – 3. The risk factors of invasive mycoses were high rheumatic disease activity (100%), corticosteroids (prednisolone ≥ 0,3 mg/kg/d) use for ≥21 d (87,5%), immunosuppressive therapy (87,5%), recent (≤ 2 weeks) pulse steroid therapy (75%), hemophagocytic lymphohistiocytosis (62,5%), prolonged (≥ 10 days) severe neutropenia (≤ 0,5х109/l) (62,5%), and prolonged (≥10 days lymphopenia (≤ 1,0х109/l) (37,5%). In patients with invasive aspergillosis the involved organ was the lung, in patients with invasive candidiasis a candidemia was diagnoses. All patients received antifungal therapy. The overall 30 days survival rate was 37,5%.Сonclusions. Children with high rheumatic diseases activity and intensive treatment with immunosuppressive agents should be considered as patients with a high risk of invasive mycoses with a high mortality.

he authors present the latest data on the hypophosphatasia (HPP) management in children. Hypophosphatasia is a rare genetic disease caused by deficiency of tissue-specific alkaline phosphatase due to mutation in the ALPL gene. The article covers all the features of epidemiology, etiology and pathogenesis, detailed stages of differential diagnostics. Treatment guidelines for pediatric patients are provided, they are based on the principles of evidence-based medicine. Special attention was given to the only effective method of hypophosphatasia management —enzyme replacement therapy (ERT). This material is the clinical guideline draft for the management of patients with hypophosphatasia prepared by the Union of Pediatricians of Russia and the Association of Medical Geneticists.

ObjectivesHeart involvement in multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) is a new challenging problem, requiring fast and reliable diagnostics and appropriate treatment. The aim of this study is to describe heart involvement in patients with MIS-C.Study DesignIn this retrospective, multicenter cohort study, data of 122 patients were included. All patients met WHO and CDC criteria of MIS-C.ResultsVarious types of heart involvement in MIS-C patients were observed. Patients with solely coronary artery lesions (CAL, n = 10, 8.2%) had typical features of Kawasaki disease: younger age, thrombocytosis and normal ferritin level, without giant CA aneurysms, thrombosis, myocardial infarction, shock, and ICU admission. Patients with solely myocardial involvement (MI, n = 30, 24.6%) had an older onset age, elevated ferritin, LDH, the highest D-dimer, H score, and thrombocytopenia level. The following clinical signs were associated with MI: gastrointestinal and central nervous system disorder, sore throat, swelling face, splenomegaly, shock, and treatment in the intensive care unit required. Patients with a combination of CAL and MI (n = 10, 8.2%) had symptoms similar to patients with solely MI, except for impressive thrombocytopenia. Shock and ICU admission were found in 34.7% of patients without heart involvement (n = 72, 59%). One major criterion [troponin > 32 pg/ml (52 points)] or at least two minor criteria [face swelling (32 points) and D-Dimer > 1,300 ng/ml (29 points)] were associated with MI (>32 points) with a sensitivity of 67.5% and a specificity of 88.9%.ConclusionThe above-suggested criteria can be added to routine diagnostic procedures to confirm MI in MIS-C patients.

The risk of a severe course of new coronavirus infection (COVID-19) due to the development of acute respiratory distress syndrome is extremely high, which is especially true for patients with comorbidities. The aim of the study is to demonstrate the peculiarities of the course and intensive care measures in new coronavirus infection COVID-19 in children with comorbidities. Patients and methods: On the example of clinical cases, the characteristics of the course of a new coronavirus infection of COVID-19 in children with systemic lupus erythematosus and bronchopulmonary dysplasia are considered. Results: The main data from the history and clinical laboratory examination are reflected, which made it possible to identify a cytokine storm in a timely manner, a high risk of adverse course and begin timely specific pathogenetic therapy, including immunoglobulins for intravenous administration, hydroxychloroquine, ritonavir in combination with lopinavir, azithromycin and dexamethasone. Particular attention is paid to the need to limit infusion therapy, maintain a negative water balance and optimal blood oxygen capacity, ambiguity of opinions on the need for routine use of albumin and dexamethasone solutions in patients with COVID-19 has been demonstrated. Conclusion: Children with comorbidities are characterized by a severe course of a new coronavirus infection COVID-19, which requires timely pathogenetic therapy taking into account the individual characteristics of the patient.

Juvenile localized scleroderma (JLS) is a group of childhood diseases with the main symptom — skin and subcutaneous structures lesions, without any organ involvement. There is active (inflammatory) and fibrotic phase in development of JLS. The JLS treatment during active phase (when skin lesions are reversible) is the most effective. The management is determined by the area and depth of skin lesions, appearance and spread of new lesions, presence of extracutaneous signs of the disease. Topical and systemic immunosuppressants are the basic therapy for JLS. The use of antibiotics is not suggested. Clinical scores (LoSCAT), ultrasound, thermography and magnetic resonance imaging are recommended to estimate the treatment efficacy.

Background. Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. It is more typical among Turks, Jews, Armenians, Arabs and nationalities permanently living in the Mediterranean area. Crimean Tatars were not considered as the population where FMF may occur until 2016. Objective. The aim of the study was to describe the clinical course and outcomes of familial Mediterranean fever in Crimean Tatar children. Methods. We have studied data from medical records of children under the age of 18 with the diagnosis of FMF verified according to the Eurofever/PRINTO 2019 criteria. The illness onset characteristics were estimated on the last admission to the hospital, as well as aspects of management. Results. The median age of FMF diagnosis was 9.5 (4; 14) years, time from the first clinical manifestations to diagnosis establishment was 5.5 (2; 9) years. The primary clinical manifestations of SSL were fever and arthritis (n = 16), erysipelas rashes (n = 9/16), peritonitis (n = 8/16), pleurisy (n = 1/17). All patients had knee arthritis, and 4/16 had hip arthritis. 12 children with FMF at debut were diagnosed as acute respiratory infection, 2 — as teething, 2 — as juvenile arthritis. The M694V variant of MEFV gene were revealed in 14/16 patients (3 in homozygous state), M680I and V726A variants were revealed once each. Parents of 8/16 patients were near related (cousins and second cousins). Colchicine intolerance was diagnosed in 2/16 patients, resistance — in 4/16 patients. Genetically engineered biologic drugs (GEBD) were prescribed for 6 patients (canakinumab in 4 cases, tocilizumab in 2 cases). Colchicine and/or GEBD therapy was effective in all patients (lesser frequency, duration and severity of episodes; improvement of laboratory signs of disease activity). Conclusion. Heterozygous pathological variant M694V of MEFV gene is the most common among Crimean Tatar patients with FMF, when the most frequent clinical signs are fever and arthritis. Every third patient has received GEBD therapy. This therapy was effective in all cases.

The localized scleroderma (morphea) is the clinical option of the juvenile scleroderma, the third in prevalence rheumatic condition in pediatrics. The article summarizes all the data on the classification, diagnostics, and differential diagnosis of juvenile localized scleroderma. The recent international guidelines on the localized scleroderma in pediatrics (the European consensus of pediatric rheumatologists, the German and Japanese national guidelines) are presented in the article.

The paper presents data on the pathogenesis of systemic lupus erythematosus (SLE), and depicts various molecular mechanisms for the development of SLE and lupus-like syndromes. It describes groups of diseases, such as apoptotic defects; NETosis; interferonopathies; complement deficiency; autotolerance disorders associated with mutations in the RAG1/RAG2 genes; hereditary metabolic diseases (prolidase deficiency, deficiency of adenosine deaminase 2; lysinuric protein intolerance; and α-mannosidase deficiency). The table summarizes clinical data on most of the known lupus-like syndromes and their molecular mechanisms.The pathogenesis of many forms of monogenic lupus-like diseases is being studied. The main sign suggesting in favor of the possible monogenic disease in a patient with SLE is its onset in infancy, especially in males. Attention should be also paid to a compromised family history, including to the marriage between close relatives, the resistance of disease to standard therapy, as well as atypical symptoms.

Background. Hypophosphatasia is rare hereditary disease caused by deficiency of the tissue-nonspecific alkaline phosphatase isozyme. It manifests with bone and teeth mineralisation defects, electrolyte imbalance, respiratory disorders, convulsive syndrome, physical developmental delay, nephrocalcinosis. The rarity of this disease, clinical polymorphism, non-specificity of complains and signs are the major reasons of hypophosphatasia late diagnosis. The enzyme replacement therapy with recombinant alkaline phosphatase (asfotase alfa) can be used for treatment of severe forms of disease.Clinical Case Description. The girl (1 y 4 m) was routinely admitted with complains of physical developmental delay and psychomotor retardation, deformation of lower limbs, chest, gait abnormality, teeth loss and with diagnosis «protein-calorie malnutrition». Rickets-like changes in skeleton, myopathic syndrome, early normal teeth loss, hepatomegaly were revealed. Reduced activity of alkaline phosphatase in blood serum (33 u/l; reference range 156–369 u/l) was revealed. The infantile hypophosphatasia has been diagnosed. Due to molecular genetic testing of ALPL gene we revealed pathogenic variants c.526G>A (p.Ala176Thr) and c.1375G>A (p.Val459Met) in compound heterozygous state. The asphotase alpha therapy was initiated at the age of 1 y 10 m, the dose was 2 mg/kg subcutaneously 3 times a week. The results of 6 months of the therapy are the following: significant increase in the activity of alkaline phosphatase (maximum 4400 u/l), body weight (+ 2 kg), growth (+ 6 cm), reduction of bone deformation, normalisation of muscle tone and gait, exercise tolerance. The patient tolerated the drug administration well. Rarely there were hyperemia zones up to 4 cm in diameter with moderate induration at the injection site but they spontaneous disappeared in 2–3 days though.Conclusion. Patients with rickets-like diseases and low alkaline phosphatase activity requires performing of molecular genetic testing to confirm hypophosphatasia. Timely diagnosis and early initiation of enzyme replacement therapy can significantly improve the quality of life of children with hypophosphatasia.

Background. Patients with juvenile idiopathic arthritis (JIA) can have low levels of antibodies to vaccine antigens due to immunologic features of the main disease, disruptions in vaccination schedule and immunosuppressive drugs administrationObjective. The aim of the study was to examine the status of postvaccinal immunity and determine the factors associated with preservation of protective level of antibodies in patients with JIA.Methods. This cross-sectional study included patients with JIA at the age from 2 to 17 years old vaccinated under the age of two (before JIA) against measles, rubella, parotitis, hepatitis B and diphtheria. Levels of IgG to vaccine antigens were measured by enzyme immunoassay. The minimum protective level of anti-measles IgG was esteemed as 0.18 IU/ml, antibodies to rubella — 10 IU/ml, for parotitis — COI > 1.0, for hepatitis B — 10 mIU/ml, antibodies to diphtheria — 0.09 IU/ml.Results. The study included 90 patients with JIA (71% of girls) at the age (median) 11.3 (7.5; 14.9) years. The age of JIA manifestation was 6.0 (4.0; 8.0) years, disease duration — 4.0 (2.0; 7.3) years. Glucocorticosteroids administration in anamnesis or at study entry was recorded in 24/88 (27%) patients, methotrexate — 81/88 (92%), genetically engineered biologic drugs — 54/89 (61%). Protective level of antibodies to measles virus was revealed in 45 (50%) children with JIA, to rubella virus — in 88 (98%), to parotitis — in 68 (76%), to hepatitis B — in 49 (54%), to diphtherial anatoxin — in 45 (50%). The decrease of postvaccinal immunity level was associated with JIA duration and glucocorticosteroids administration (against diphtheria) duration, as well as drop-out immunization (against measles).Conclusion. Major part of children with JIA have no protection against measles, parotitis, hepatitis B or diphtheria. High risk of progression of such vaccine-preventable diseases in these children demands development of individual programs of immunization.

Background. Gravitational erythema is rare pathologic condition that is characterized by abnormal vascular response on venous pressure changes. It is benign disease, and it is included in differential diagnosis of vasculitis, vasculopathies, neuropathies and does not require treatment. Compression garments may be required in some cases.Clinical Case Description. The case of gravitational erythema in 13 years old patient of is presented. The disease was presented with erythematous mosaic rash on the lower limbs skin. It has appeared in 4-6 minutes after verticalisation and mostly on the lower legs. The rash was accompanied with some bluish spots disappearing after pressure. The elements of rush were itchy, there was pain in distal parts of the feet. The rash was reversed after walking and changing of limb position. Positive compression test was mentioned.Conclusion. Differential diagnosis of gravitational erythema with other clinically similar conditions remains relevant. The rare diagnosis of gravitational erythema and low awareness of doctors about it cause misdiagnosis, costly continuous examination and ineffective treatment.

PANS, or Pediatric Acute-onset Neuropsychiatric Syndrome, is characterized by the sudden onset of obsessive-compulsive syndrome and accompanied by anxiety, emotional lability and other symptoms. PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections, is a subtype of PANS. Modern data on PANS/PANDAS etiology, pathogenesis, diagnostics and management is presented in this article. Therapeutic decisions on using anti-inflammatory and immunotropic therapy including non-steroidal anti-inflammatory drugs, glucocorticoids, intravenous immunoglobulin, plasmapheresis, rituximab and mycophenolate mofetil are analysed.

JAK-inhibitors are small molecules blocking the JAK-STAT pathway that have proven effective in the treatment of different immune-mediated diseases in adults and juvenile idiopathic arthritis (JIA).Aim of StudyTo evaluate the safety and efficacy of tofacitinib in children with different rheumatic diseases.Material and MethodsWe extracted information from 24 children with the following diagnosis: JIA (n = 15), undifferentiated systemic autoinflammatory diseases (SAIDs) (n = 7), and juvenile dermatomyositis (JDM) (n = 2) who have been treated with tofacitinib for a period of longer than 6 months. The treatment outcomes were classified according to the opinion of the attending physicians as having a complete response (CR), i.e., the absence of disease activity, or a partial response (PR)—a significant improvement of symptoms and disease activity, or no response (NR)—no changes in disease activity.ResultsCR was achieved in 10/24 patients; 7/15 among JIA patients, 1/2 among JDM patients, 4/7 among SAID patients, and PR in 5/15 of JIA, 1/2 of JDM, and 3/7 of SAID patients. Three non-responders with JIA discontinued tofacitinib. Corticosteroids were successfully tapered off in 11/14 patients and discontinued in 2/14 patients. Four patients had side effects not requiring treatment discontinuation: liver enzyme elevation (n = 2), hypercholesterolemia (n = 1), lymphadenitis (n = 1).ConclusionJAK-inhibitors are effective new therapies for the treatment of multiple immune-mediated diseases. Our experience has shown the best results in patients with JIA and JIA-associated alopecia, and type I interferonopathies. More data from randomized controlled clinical trials are needed to use JAK-inhibitors safely in pediatric rheumatic diseases.

Objectives: To describe the clinical characteristics of hip involvement in juvenile idiopathic arthritis (JIA) from arthritis to hip osteoarthritis (HOA) and total hip arthroplasty (THA).Study Design: Seven hundred fifty-three patients aged 2–17 years with JIA were included in the study. The comparison analysis was performed between the following subgroups: (i) JIA without hip involvement (n = 600; 79.7%) vs. JIA with hip involvement without HOA (n = 105; 13.9%), (ii) JIA with hip involvement with HOA, but without THA (n = 32; 4.3%) and JIA with hip involvement with HOA and with THA (n = 16; 2.1%). Clinical, laboratory characteristics and treatment regimens compared.Results: Hip involvement was present in 20.3% of patients. HOA was present in 6.4% (12*1,000 patient-years) of the entire JIA group and 31.4% of patients with hip involvement. Sixteen patients (2.1%; 4.0*1,000 patient-years) required THA. The following factors were associated with HOA: sJIA (OR = 3.6, p = 0.008; HR = 3.0, p = 0.002), delayed remission (OR = 4.2, p = 0.004; HR = 1.4, p = 0.538), delay in biologic therapy initiation (OR = 7.5, p = 0.00001; HR = 6.7, p = 0.002), alkaline phosphatase 2,700 mg (OR = 4.3, p = 0.032; HR = 1.4, p = 0.527). The following factors were associated with THA: delay in biologic treatment initiation (OR = 1.04, p = 0.0001; HR = 9.1, p = 0.034), delayed hip involvement (OR = 5.2, p = 0.002; HR = 3.0, p = 0.044), and methylprednisolone pulse therapy (OR = 10.8, p = 0.0000001; HR = 5.6, p = 0.002).Conclusion: Both sJIA and systemic CS, impaired calcium-phosphorus metabolism, and delayed hip arthritis are associated with HOA development in JIA. HOA is considered to be a severe adverse event of CS treatment, especially delayed hip involvement.

Objectives: Diagnostic between multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) and Kawasaki disease (KD) can make difficulties due to many similarities. Our study aimed to create a Kawasaki/MIS-C differentiation score (KMDscore) allowing discrimination of MIS-C and KD.Study design: The retrospective multicenter cohort study included clinical, laboratory, and instrumental information about MIS-C (n = 72) and KD (n = 147). The variables allowed to discriminate both conditions used to construct and validate the diagnostic score called the KMDscore.Results: Patients with MIS-C were older, had earlier admission to the hospital, had a shorter time before fever resolution, two times frequently had signs of GI and CNS involvement observed, and had more impressive thrombocytopenia, higher level of CRP, ferritin, ALT, AST, LDH, creatinine, triglycerides, troponin, and D-dimer compared to KD patients. Respiratory signs in MIS-C were presented with pleuritis, acute respiratory distress syndrome, oxygen dependency, lung infiltration, and ground-glass opacities in CT. The heart involvement with fast progression of myocarditis provided the severity of MIS-C and ICU admission due to 12 times higher arterial hypotension or shock and required cardiotonic. No differences in the frequency of CA lesions were seen in the majority of cases. Five criteria, CRP >11 mg/dl (18 points), D-dimer >607 ng/ml (27 points), age >5 years (30 points), thrombocytopenia (25 points), and GI involvement (28 points), were included in the KMDscore. The summa >55 points allowed to discriminate MIS-C from KD with a sensitivity of 87.5% and specificity of 89.1%.Conclusion: The KMDscore can be used to differentiate the diagnostic of MIS-C from KD.

The paper presents a clinical case series that includes 12 children with pelvic bone neoplasms mimicking sacroiliitis, which led to the initial misdiagnosis of enthesitis-related arthritis. It discusses the features of the clinical manifestations and radiation imaging of the tumors and characterizes osteoid osteoma and Hodgkin’s lymphoma, which are located in the sacroiliac joints.

Homocystinuria is rare autosomal-recessive monogenic disorder associated with disturbance of methionine metabolism due to liver enzyme cystathionine--synthetase (CBS) deficit. That in turn causes elevated concentration of homocystein and its metabolites in blood and urine. The main clinical manifestations of homocystinuria are: myopia, ectopia lentis, psychomotor retardation, learning difficulties, mental retardation, mental illnesses, behaviour problems, paroxysms, extrapyramidal symptoms, skeletal anomalies (body height), long limbs — dolichostenomelia and arachnodactylia (Marfan Phenotype), pectus carinatum, valgus lower limbs, scoliosis, osteoporosis, thromboembolic disorders. Diagnostics of homocystinuria is based on clinical findings and laboratory changes (increase of methionine and homocysteine levels in serum). There is prenatal and DNA-diagnostics (genetic variants in CBS gene). Revealing of homocystinuria demands examination of first-degree relatives. Therapy of patients with homocystinuria includes not only diet therapy but also pyridoxine, folic acid, betaine administration. Syndromic concomitant therapy is also used. The description of the patient with severe B6-resistant form of homocystinuria is given in this article.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease with a high prevalence in some countries. The carriers of the MEFV gene causing FML are Jews, Armenians, Turks, Arabs and other nationalities of Mediterranean origin. Crimean Tatars are one of the nations that inhabit the Crimean peninsula, who do not formally belong to Mediterranean populations. Until 2016, there were no data on FMF in Crimea among the Crimean Tatar population; however, 15 new cases of FMF have been diagnosed in the Republic of Crimea in the past 2 years. The paper provides data on FML patients and information about the ethnic origin of the Crimean Tatars, explaining the possible origin of mutant alleles in the population.

Background. Patients with haematogenous and non-bacterial osteomyelitis have similar clinical symptoms (pain in the nidus area, soft tissue swelling, fever) and laboratory signs (increased erythrocyte sedimentation rate, leukocyte count, C-reactive protein concentration). The criteria for distinguishing these two states are not determined. Objective. Our aim was to determine diagnostic criteria to differentiate haematogenous and non-bacterial osteomyelitis. Methods. The study included data of patients under the age of 18 years with non-bacterial or haematogenous osteomyelitis hospitalised to two clinical centres from 2009 to 2016. The diagnosis was established and re-verified according to archival data (medical history) and after two years of observation (at least once a year). Clinical, anamnestic and laboratory data (haemoglobin, leukocytes, leukocyte formula, platelets, ESR and C-reactive protein, CRP) as well as the results of radiation diagnostics (X-ray, CT scan, MRI or osteosyntigraphy) obtained at the disease onset were taken into account as potential diagnostic criteria. Results. Out of 145 patients with non-bacterial or haematogenous osteomyelitis, the diagnosis was re-verified in 138, of them non-bacterial osteomyelitis — in 91, haematogenous osteomyelitis — in 47. The following criteria had the highest diagnostic value for establishing cases of non-bacterial osteomyelitis: detection of bone destruction foci surrounded by osteosclerosis area [sensitivity (Se) 1.0; specificity (Sp) 0.79]; absence of fever (Se 0.66; Sp 0.92); the number of bone destruction foci > 1 (Se 0.73; Sp 1.0); CRP 55 mg/L (Se 0.94; Sp 0.73); negative results of bacteriological examination of the material from the bone destruction focus (Se 1.0; Sp 0.67). Conclusion. Diagnostic criteria for differentiation of non-bacterial and haematogenous osteomyelitis have been described. Further research on the efficacy of using these criteria to reduce the risk of diagnostic errors, decrease the diagnostic pause, reduce the risk of non-bacterial osteomyelitis complications is needed.

Mucopolysaccharidosis type I (MPS I) is a hereditary metabolic disease that manifests itself in childhood by systemic damage to tissues and organs, a constantly progressive course leading to disability. Diagnosis of mild forms of the disease is particularly difficult due to the absence of specific symptoms. A specific symptom of the mild forms of MPS I (as for other types of MPS) is joint stiffness in children combined with hernia, frequent infections, or valvular defects. Stiffness in MPS I is often interpreted as a manifestation of rheumatological diseases (arthrogriposis, juvenile idiopathic arthritis). The article offers a simple algorithm for diagnosing MPS I, which helps to eliminate the disease using a simple test for determining the activity of an enzyme called alpha-L-iduronidase in a dried blood spot.

Familial Mediterranean fever is a typical monogenic disease with an autosomal recessive inheritance pattern; caused by mutations in the MEFV gene, which encodes the pyrin protein. It is a relatively rare pathology in the practice of paediatricians and rheumatologists of the Russian Federation. The article provides up-to-date data on the disease prevalence, presents a complete clinical picture of the auto-inflammatory syndrome, discusses diagnostic criteria and methods for treating patients with familial Mediterranean fever.