Systemic juvenile idiopathic arthritis-associated lung disease: A retrospective cohort study.

BACKGROUND: Lung damage in systemic juvenile arthritis (sJIA) is one of the contemporary topics in pediatric rheumatology. Several previous studies showed the severe course and fatal outcomes in some patients. The information about interstitial lung disease (ILD) in the sJIA is scarce and limited to a total of 100 cases. AIM: To describe the features of sJIA patients with ILD in detail. METHODS: In the present retrospective cohort study, information about 5 patients less than 18-years-old with sJIA and ILD were included. The diagnosis of sJIA was made according to the current 2004 and new provisional International League of Associations for Rheumatology criteria 2019. ILD was diagnosed with chest computed tomography with the exclusion of other possible reasons for concurrent lung involvement. Macrophage activation syndrome (MAS) was diagnosed with HLH-2004 and 2016 EULAR/ACR/PRINTO Classification Criteria and hScores were calculated during the lung involvement. RESULTS: The onset age of sJIA ranged from 1 year to 10 years. The time interval before ILD ranged from 1 mo to 3 years. The disease course was characterized by the prevalence of the systemic features above articular involvement, intensive rash (100%), persistent and very active MAS (hScore range: 194-220) with transaminitis (100%), and respiratory symptoms (100%). Only 3 patients (60%) developed a clubbing phenomenon. All patients (100%) had pleural effusion and 4 patients (80%) had pericardial effusion at the disease onset. Two patients (40%) developed pulmonary arterial hypertension. Infusion-related reactions to tocilizumab were observed in 3 (60%) of the patients. One patient with trisomy 21 had a fatal disease course. Half of the remaining patients had sJIA remission and 2 patients had improvement. Lung disease improved in 3 patients (75%), but 1 of them had initial deterioration of lung involvement. One patient who has not achieved the sJIA remission had the progressed course of ILD. No cases of hyper-eosinophilia were noted. Four patients (80%) received canakinumab and one (20%) tocilizumab at the last follow-up visit. CONCLUSION: ILD is a severe life-threatening complication of sJIA that may affect children of different ages with different time intervals since the disease onset. Extensive rash, serositis (especially pleuritis), full-blown MAS with transaminitis, lymphopenia, trisomy 21, eosinophilia, and biologic infusion reaction are the main predictors of ILD. The following studies are needed to find the predictors, pathogenesis, and treatment options, for preventing and treating the ILD in sJIA patients.

Defining criteria for disease activity states in systemic juvenile idiopathic arthritis based on the systemic Juvenile Arthritis Disease Activity Score.

OBJECTIVE: To develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis (sJIA), based on subjective disease state assessment by the treating pediatric rheumatologist. METHODS: The cutoffs definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, 6 methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, Youden index, 90% specificity, maximum agreement, and ROC curve analysis. Sixty percent of the patients were assigned to the definition cohort and 40% to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. RESULTS: The sJADAS10 cutoffs that separated ID from MiDA, MiDA from MoDA, and MoDA from HDA were ≤ 2.9, ≤ 10, and > 20.6. The cutoffs discriminated strongly among different levels of pain, between patients with or without morning stiffness, and between patients whose parents judged their disease status as remission or persistent activity/flare or were satisfied or not satisfied with current illness outcome. CONCLUSION: The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts, and are therefore suitable for use in clinical trials and routine practice.

BCD020 rituximab bioanalog compared to standard treatment in juvenile systemic lupus erythematosus: The data of 12 months case-control study.

BACKGROUND: Systemic lupus erythematosus (SLE) is the most frequent and serious systemic connective tissue disease. Nowadays there is no clear guidance on its treatment in childhood. There are a lot of negative effects of standard-of-care treatment (SOCT), including steroid toxicity. Rituximab (RTX) is the biological B-lymphocyte-depleting agent suggested as a basic therapy in pediatric SLE. AIM: To compare the benefits of RTX above SOCT. METHODS: The data from case histories of 79 children from the Saint-Petersburg State Pediatric Medical University from 2012 to 2022 years, were analyzed. The diagnosis of SLE was established with SLICC criteria. We compared the outcomes of treatment of SLE in children treated with and without RTX. Laboratory data, doses of glucocorticosteroids, disease activity measured with SELENA-SLEDAI, and organ damage were assessed at the time of initiation of therapy and one year later. RESULTS: Patients, treated with RTX initially had a higher degree of disease activity with prevalence of central nervous system and kidney involvement, compared to patients with SOCT. One year later the disease characteristics became similar between groups with a more marked reduction of disease activity (SELENA-SLEDAI activity index) in the children who received RTX [-19 points (17; 23) since baseline] compared to children with SOCT [-10 (5; 15.5) points since baseline, P = 0.001], the number of patients with active lupus nephritis, and daily proteinuria. During RTX therapy, infectious diseases had three patients; one patient developed a bi-cytopenia. CONCLUSION: RTX can be considered as the option in the treatment of severe forms of SLE, due to its ability to arrest disease activity compared to SOCT.

Using HScore for Evaluation of Hemophagocytosis in Multisystem Inflammatory Syndrome Associated with COVID-19 in Children.

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.

Interferon type I signature associated with skin disease in juvenile dermatomyositis.

Background: Interferon type I (IFN-I) signaling system hyperactivation plays an important role in the pathogenesis of juvenile dermatomyositis (JDM). Aim of the study: To analyze IFN-I score with disease activity in patients with JDM. Materials and methods: Clinical manifestations laboratory data, and treatment options were analyzed in 15 children with JDM. Disease activity was assessed by CMAS (childhood myositis assessment tool) and CAT (cutaneous assessment tool) scores. IFN I-score was assessed by RT-PCR quantitation of 5 IFN I-regulated transcripts (IFI44L, IFI44, IFIT3, LY6E, MXA1). Results: All patients had skin and muscle involvement, some had a fever (n = 8), swallowing disorders (n = 4), arthritis (n = 5), calcinosis (n = 3), lipodystrophy (n = 2), and interstitial lung disease (n = 5). Twelve patients had elevated IFN I-score and it was correlated with skin disease activity. Ten patients had clinically active disease and the level of IFN I-score and its components were higher than in patients with inactive disease (8.8 vs. 4.2, p = 0.011). IFN I-score was evaluated in nine patients during follow-up. The simultaneous reduction of IFN I-score and its components, CMAS and CAT scores was observed. Conclusion: Skin involvement in refractory JDM is a challenging problem requiring the use of additional medications. Serum IFN I-score might be suggested as the promising biomarker of skin disease activity in JDM patients. Further investigations on patients with JDM and recurrent disease activity are needed, especially concerning biomarkers that determine the response to JAK inhibitors and treatment options for patients who don't respond to them.

Specific Features of Juvenile Idiopathic Arthritis Patients' Cytokine Profile.

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, 1ß, 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.

Safety and efficacy of canakinumab treatment for undifferentiated autoinflammatory diseases: the data of a retrospective cohort two-centered study.

Introduction: The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinaemia D syndrome, and cryopyrin-associated periodic syndrome, but this treatment has not been assessed for patients with undifferentiated AIDs (uAIDs). Our study aimed to assess the safety and efficacy of canakinumab for patients with uAIDs. Methods: Information on 32 patients with uAIDs was retrospectively collected and analyzed. Next-generation sequencing and Federici criteria were used for the exclusion of the known monogenic AID. Results: The median age of the first episode was 2.5 years (IQR: 1.3; 5.5), that of the disease diagnosis was 5.7 years (IQR: 2.5;12.7), and that of diagnostic delay was 1.1 years (IQR: 0.4; 6.1). Patients had variations in the following genes: IL10, NLRP12, STAT2, C8B, LPIN2, NLRC4, PSMB8, PRF1, CARD14, IFIH1, LYST, NFAT5, PLCG2, COPA, IL23R, STXBP2, IL36RN, JAK1, DDX58, LACC1, LRBA, TNFRSF11A, PTHR1, STAT4, TNFRSF1B, TNFAIP3, TREX1, and SLC7A7. The main clinical features were fever (100%), rash (91%; maculopapular predominantly), joint involvement (72%), splenomegaly (66%), hepatomegaly (59%), lymphadenopathy (50%), myalgia (28%), heart involvement (31%), intestinal involvement (19%); eye involvement (9%), pleuritis (16%), ascites (6%), deafness, hydrocephalia (3%), and failure to thrive (25%). Initial treatment before canakinumab consisted of non-biologic therapies: non-steroidal anti-inflammatory drugs (NSAID) (91%), corticosteroids (88%), methotrexate (38%), intravenous immunoglobulin (IVIG) (34%), cyclosporine A (25%), colchicine (6%) cyclophosphamide (6%), sulfasalazine (3%), mycophenolate mofetil (3%), hydroxychloroquine (3%), and biologic drugs: tocilizumab (62%), sarilumab, etanercept, adalimumab, rituximab, and infliximab (all 3%). Canakinumab induced complete remission in 27 patients (84%) and partial remission in one patient (3%). Two patients (6%) were primary non-responders, and two patients (6%) further developed secondary inefficacy. All patients with partial efficacy or inefficacy were switched to tocilizumab (n = 4) and sarilumab (n = 1). The total duration of canakinumab treatment was 3.6 (0.1; 8.7) years. During the study, there were no reported Serious Adverse Events (SAEs). The patients experienced non-frequent mild respiratory infections at a rate that is similar as before canakinumab is administered. Additionally, one patient developed leucopenia, but it was not necessary to stop canakinumab for this patient. Conclusion: The treatment of patients with uAIDs using canakinumab was safe and effective. Further randomized clinical trials are required to confirm the efficacy and safety.

Application and performance of disease activity indices proposed for patients with systemic sclerosis in an international cohort of patients with juvenile systemic sclerosis.

Objectives: Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis. Methods: The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians' and the patients' global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models. Results: Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity. Conclusion: Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.

Thrombosis in Multisystem Inflammatory Syndrome Associated with COVID-19 in Children: Retrospective Cohort Study Analysis and Review of the Literature.

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.

Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva.

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.

Determination of Risk Factors for Severe Life-Threatening Course of Multisystem Inflammatory Syndrome Associated with COVID-19 in Children.

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.

Juvenile idiopathic arthritis with systemic onset with inflammatory bone lesions: two case reports of patients successfully treated with canakinumab and experience gained from literature.

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-1ß antibodies) caused remission. Case descriptions: Patient 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. Conclusion: This 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.

IFIH1 and DDX58 gene variants in pediatric rheumatic diseases.

BACKGROUND: The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor. Both proteins are parts of the interferon (IFN) I signaling pathway and are responsible for antiviral defense and innate immune response. IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases. Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome, while DDX58 mutation can cause atypical Singleton-Merten syndrome. AIM: To characterize children with pediatric rheumatic diseases (PRD) carrying DDX58 or IFIH1 variants. METHODS: Clinical exome sequencing was performed on 92 children with different PRD. IFIH1 and DDX58 variants have been detected in 14 children. IFN-I score has been analyzed and the clinical characteristics of patients have been studied. RESULTS: A total of seven patients with systemic lupus erythematosus (SLE) (n = 2), myelodysplastic syndrome with SLE features at the onset of the disease (n = 1), mixed connective tissue disease (MCTD) (n = 1), undifferentiated systemic autoinflammatory disease (uSAID) (n = 3) have 5 different variants of the DDX58 gene. A common non-pathogenic variant p.D580E has been found in five children. A rare variant of uncertain significance (VUS) p.N354S was found in one patient with uSAID, a rare likely non-pathogenic variant p.E37K in one patient with uSAID, and a rare likely pathogenic variant p.Cys864fs in a patient with SLE. Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants. Seven patients had six different IFIH1 variants. They were presented with uSAID (n = 2), juvenile dermatomyositis (JDM) (n = 1), SLE-like disease (n = 1), Periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome (n = 1), and systemic onset juvenile idiopathic arthritis (n = 1). Three patients have VUS p.E627X, one patient has benign variant p.I923V. Rare VUS p.R595H was detected in the JDM patient. Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID. One patient with uSAID has rare VUS p.T520A. All patients had elevated IFN-I scores. CONCLUSION: Rare compound-heterozygous IFIH1 variant (p.L679Ifs*2 and p.V599Ffs*5), heterozygous IFIH1 variant (p.T520A) and heterozygous DDX58 variant (p.Cys864fs) are probably disease causative for uSAID and SLE. The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.

Gender differences in juvenile systemic sclerosis patients: Results from the international juvenile scleroderma inception cohort.

Objective: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. Methods: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. Results: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. Conclusion: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.

Juvenile Dermatomyositis and Infantile Cerebral Palsy: Aicardi-Gouteres Syndrome, Type 5, with a Novel Mutation in SAMHD1-A Case Report.

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.

Case report: Sulfasalazine-induced hypersensitivity.

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.

Rituximab Biosimilar BCD020 Shows Superior Efficacy above Conventional Non-Biologics Treatment in Pediatric Lupus Nephritis: The Data of Retrospective Cohort Study.

BACKGROUND: Pediatric lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) in children, determining the outcomes of the disease. There are no standardized treatment protocols for pediatric LN, and the role of biologics has not yet been conclusively defined. OBJECTIVES: analyze the safety and efficacy of rituximab biosimilar BCD020 in pediatric patients with lupus nephritis. METHODS: in a retrospective cohort study, the data from the case histories of 25 patients with LN (10 boys and 15 girls) with an onset age of 13 (9-16) years, who failed conventional non-biologic treatment or developed corticosteroid dependence/toxicity, were included. The diagnosis was made using Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Rituximab biosimilar BCD020 was prescribed in a dosage of 375 mg/m2 every week (2-4 infusions) with repeated courses every 6-12 months (2-4 infusions) according to disease activity, B-cell depletion, and IgG levels. The dynamics of clinical and laboratory data, the activity of the disease by SLEDAI, and corticosteroid doses were assessed at the onset and during the rituximab trial. RESULTS: The main patient's characteristics were: Pre-rituximab non-biologic conventional treatment included: cyclophosphamide 15 (60%), MMF 8 (32%), azathioprine 3 (12%), hydroxychloroquine 12 (48%), and pulse therapy of methylprednisolone followed by oral methylprednisolone 25 (100%). The time before rituximab was 7.0 (3.0-24.0) months, and the whole observation period was 7.0 (0; 24) months. The initial pre-rituximab treatment slightly reduced SLEDAI levels and the proportion of patients with LN. A significant reduction of SLEDAI, the anti-dsDNA level, proteinuria, hematuria, C4 complement, ESR, and the median corticosteroid dose by 80% from the initial value, as well as the proportion of patients without corticosteroids, was observed after rituximab administration. Two deaths were observed due to catastrophic SLE with macrophage activation syndrome, accompanied by a severe infection (invasive aspergillosis, n = 2). Three patients developed serious adverse events: pneumonia (n = 2), transient agranulocytosis (n = 1) after the third rituximab infusion, and meningitis, caused by Listeria monocytosis, after the first rituximab infusion. Eight patients received antibacterial treatment for different respiratory infections without hospital admissions. CONCLUSIONS: Rituximab biosimilar BCD020 showed effectiveness in LN, whereas previous non-biologic treatment was insufficiently effective. Randomized controlled trials are required to evaluate the efficacy and safety of rituximab and evaluate the benefits when compared with conventional SLE treatment.

Temporomandibular Joint Involvement in Juvenile Idiopathic Arthritis: The Results from a Retrospective Cohort Tertial Center Study.

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.

Nonbacterial and bacterial osteomyelitis in children: a case-control retrospective study.

Purpose: Osteomyelitis 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). Methods: The 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. Results: The 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%. Conclusion: The diagnostic criteria may help discriminate NBO and BO and avoid excessive antibacterial treatment and surgery.

Vaccination coverage in children with juvenile idiopathic arthritis, inflammatory bowel diseases, and healthy peers: Cross-sectional electronic survey data.

BACKGROUND: Patients with immune-mediated diseases, such as juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD) are at increased risk of developing infections, due to disease-related immune dysfunction and applying of immunosuppressive drugs. AIM: To evaluate vaccine coverage in patients with IBD and JIA, and compare it with healthy children. METHODS: In the cross-sectional study we included the data from a questionnaire survey of 190 Legal representatives of children with JIA (n = 81), IBD (n = 51), and healthy children (HC, n = 58). An electronic online questionnaire was created for the survey. RESULTS: There were female predominance in JIA patients and younger onset age. Parents of JIA had higher education levels. Employment level and family status were similar in the three studied groups. Patients with JIA and IBD had lower vaccine coverage, without parental rejection of vaccinations in IBD, compare to JIA and healthy controls. The main reason for incomplete vaccination was medical conditions in IBD and JIA. IBD patients had a lower rate of normal vaccine-associated reactions compared to JIA and HC. The encouraging role of physicians for vaccinations was the lowest in JIA patients. IBD patients had more possibilities to check antibodies before immune-suppressive therapy and had more supplementary vaccinations compared to JIA and HC. CONCLUSION: JIA and IBD patients had lower vaccine coverage compared to HC. Physicians' encouragement of vaccination and the impossibility of discus about future vaccinations and their outcomes seemed the main factors for patients with immune-mediated diseases, influencing vaccine coverage. Further investigations are required to understand the reasons for incomplete vaccinations and improve vaccine coverage in both groups, especially in rheumatic disease patients. The approaches that stimulate vaccination in healthy children are not always optimal in children with immune-mediated diseases. It is necessary to provide personalized vaccine-encouraging strategies for parents of chronically ill children with the following validation of these technics.