Thrombotic Microangiopathy Associated with Macrophage Activation Syndrome: A Multinational Study of 23 Patients.

OBJECTIVE: To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). STUDY DESIGN: International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS. RESULTS: Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab. CONCLUSIONS: The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.

Cytokine profile in patients with chronic non-bacterial osteomyelitis, juvenile idiopathic arthritis, and insulin-dependent diabetes mellitus.

OBJECTIVES: Our study aimed to evaluate the cytokine levels in pediatric chronic non-bacterial osteomyelitis (CNO) patients and compare these with other immune-mediated diseases and healthy controls. METHODS: In this prospective study, we included 42 children with CNO, 28 patients with non-systemic juvenile idiopathic arthritis (JIA), 17 children with insulin-dependent diabetes mellitus (IDDM), and 30 healthy age-matched controls. In each of the CNO patients and comparison groups, the levels of 14-3-3-η protein, S100A8/A9 protein, interleukin-4 (IL-4), interleukin-17 (IL-17), interleukin-18 (IL-18), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) were measured by ELISA assay. RESULTS: All studied cytokines in the CNO patients were significantly higher than controls, and IDDM, 14-3-3-η protein, IL-18, IL-4, IL-17, IL-1ß, and TNF-α were less than in JIA patients. In the discriminant analysis, ESR, 14-3-3 protein, S100A8/A9, IL-18, IL-4, and TNF-α can discriminate CNO from JIA, and 14-3-3 protein, S100A8/A9, IL-18, IL-17, IL-4, and TNF-α can distinguish CNO from other diseases and HC. CONCLUSION: The increased level of pro-inflammatory cytokines confirms the role of monocyte-driven inflammation in CNO patients. Cytokines may prove valuable as biomarkers and potential therapeutic targets for CNO.

Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis.

OBJECTIVE: To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. METHODS: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. RESULTS: A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. CONCLUSION: The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively.

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity.

Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity-related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome-associated IEIs, 45/202 (22%) of nonsyndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome-associated SEMA3E c.2108C>T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, Х-linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C>T (p.R257*), NBN c.657del5, DCLRE1C c.103C>G (p.H35D), NLRP12 c.1054C>T (p.R352C) and c.910C>T (p.H304Y). NGS is a powerful tool for high-throughput examination of patients with malfunction of immunity.

The peculiarities and treatment outcomes of the spinal form of chronic non-bacterial osteomyelitis in children: a retrospective cohort study.

Chronic non-bacterial osteomyelitis (CNO) is a group of immune-mediated diseases which appears in bone inflammation, destruction and some orthopaedic consequences, especially in the cases of spinal involvement. This study is to compare characteristics and treatment outcomes of CNO patients with spinal involvement. The retrospective cohort study included data from 91 pediatric patients with CNO. The diagnosis is based on Jannson's criteria with morphological confirmation (nonspecific chronic inflammation). Spine involvement detected by X-ray, computed tomography, magnetic resonance imaging, and bone scan in 29 (31.9%) patients. No differences in the family history, concomitant immune-mediated diseases between spinal (SpCNO) and peripheral (pCNO) forms of CNO have been revealed. Only 5 (10.2%) SpCNO patients (10.2%) had monofocal monovertebral involvement. The main risk factors of spinal involvement were female sex: RR = 2.0 (1.1; 3.9), sensitivity (Se) = 0.66, specificity (Sp) = 0.6; multifocal involvement: RR = 2.1 (0.9; 5.0), Se = 0.83, Sp = 0.37; no foot bones involvement: RR = 3.1 (1.3; 7.5), Se = 0.83, Sp = 0.5; sternum involvement RR = 2.3 (1.3; 4.1), Se = 0.24, Sp = 0.94. In the linear regression analysis only female sex (p = 0.005), multifocal involvement (p = 0.000001) and absence of foot bones involvement (p = 0.000001) were independent risk factors of spinal involvement (p = 0.000001). The response rate on bisphosphonates and tumor necrosis factor-a inhibitors was 90.9% and 66.7%, consequently. Only 4/29 (13.8%) SpCNO patients underwent surgery due to severe spinal instability or deformities. The spinal involvement is frequent in CNO and could be crucial for choosing a treatment strategy. Bisphosphonates and TNFa-inhibitors could be effective treatment options for severe SpCNO.

Comparison of different treatment approaches of pediatric chronic non-bacterial osteomyelitis.

Chronic non-bacterial osteomyelitis (CNO) is a chronic inflammatory bone disease which usually manifests in children and adolescents. There are a few data about pathogenesis and treatment. The aim of the study to compare the efficacy of different treatment approaches in pediatric CNO cohort patient. Fifty two children (25 boys and 27 girls) with CNO with average age at the onset of the disease 8.4 years (5.4; 11.0), number of foci - 3.0 (2.0; 6.0, incl. multifocal cases in 80.8%). Non-steroid anti-inflammatory drugs (NSAID) was the first-line treatment for non-vertebral cases, as well as pamidronate (PAM) for vertebral involvement. Second-line treatment includes sulfasalazine (SSZ), methotrexate (MTX), PAM and tumor necrosis factor-α inhibitors (TNFα-inh). We evaluated the dynamics of pain, patient's and physician's (MDVAS) assessment with visual-analog scale (VAS) and ability to each medication to achieve remission of CNO activity. According to the NSAID, MTX, SSZ, PAM and TNFα-inh groups the following data were registered: patient's VAS: - 14.2% (p = 0.05), - 50.0% (p = 0.04), - 23.1 (p = 0.89), - 83.3% (p = 0.0001), - 73.6% (p = 0.0007); painVAS: - 21.9% (p = 0.01), - 18.6% (p = 0.13), + 36.4 (p = 0.89), - 79.7% (p = 0.00016), - 74.1%, (p = 0.0015); MDVAS: - 13.8% (p = 0.13); - 56.4% (p = 0.09), + 30.8% (p = 0.89), - 74.7%, (p = 0.0001), - 82.1 (p = 0.0015) respectively. The ability of each treatment strategy to achieve the CNO remission was 52.6%, 44.4%, 57,1%, 88.8% and 73.3%, respectively (log-rank test, p = 0.001). The efficacy of treatment approaches for CNO depended on the severity of the disease. NSAID, methotrexate, and sulfasalazine were effective in forms without spine involvement, but pamidronate and TNF-a inhibitors were useful in vertebral forms of CNO. Pamidronate and TNF-a inhibitors more extensively suppressed CNO activity. The randomized controlled trials for assessment of the efficacy and safety of these medications is mandatory to confirm these results.

Reasons for inactive disease and flare in systemic onset juvenile idiopathic arthritis patients during tocilizumab treatment.

OBJECTIVES: The aim of our study was to evaluate disease courses and outcomes of sJIA children undergoing tocilizumab (TCZ) treatment, and to establish the predictors which distinguish inactive disease and disease flares. METHODS: Our retrospective study included 48 active sJIA children who were refractory to different anti-rheumatic drugs and who were then started on TCZ. The effectiveness of TCZ was assessed by the changes of sJIA attributed signs and symptoms and the remission was judged according to the Wallace (2004) criteria. RESULTS: The main demographic parameters (Me; IQR) were shown; mean age: 9.9 (5-12.7) years and mean duration of TCZ administration: 27.0 (5.9-89.7) months. During the TCZ treatment 40 cases (83.3%) achieved remission in 138.5 (56.0; 255.0) days. Patients who achieved remission had milder disease course, and presented less frequent epatosplenomegaly, lung, heart involvement and MAS. They had higher Hb and lower WBC, granulocytes, ESR, CRP, LDH, ferritin. The main predictors of achievement of inactive disease, calculated with Cox-regression models, were CRP≤82.0 mg/l (OR=7.9, HR=1.17), ESR≤32 mm/h (OR=17.0, HR=0.85), ferritin ≤273 ng/ml (OR=56.5, HR=2.6), Hb>113 g/l (OR=17.0, HR=1.33), LDH≤676 U/l (OR=113.6, HR=3.2), PLT>335*109/l (OR=5.0, HR=2.5), and intensive depression of WBC in 2 weeks after the 1st TCZ infusion>11% (OR=13.0, HR=6.0) and granulocytes>12% (OR=14.0, HR=4.7). CONCLUSIONS: sJIA children with milder disease course have more posssibilty of achieving disease remission during TCZ treatment. Male sex, signs of high disease activity, previous CS treatment, the long time needed to achieve inactive disease and treatment protocol deviations increased the risk of sJIA flare.

Multigene sequencing reveals heterogeneity of NLRP12-related autoinflammatory disorders.

NLRP12-related autoinflammatory disease (NLRP12-AID) is an exceptionally rare autosomal dominant disorder caused by germline mutations in NLRP12 gene. Very few patients with NLRP12-AD have been identified worldwide; therefore, there is a scarcity of data on phenotypic presentation of this syndrome. Here we provide evidence that NLRP12-AID may have clinical manifestations characteristic for primary immune deficiencies (PID). 246 children with periodic fever (PF) of unknown origin were subjects to the next generation sequencing (NGS) analysis; 213 of these patients had signs of primary immunodeficiency (PID) manifested by recurrent infections, while 33 kids had isolated PF. The NGS panel was composed of 302 genes implicated in PID and/or AID. 15 patients (9 girls and 6 boys) with NLRP12-AID were identified. Median age of first AID-related fever episode was 12 months, ranging from 2 months to 13 years. Main clinical features of NLRP12-related AID were periodic fever (100%), abdominal pain and diarrhea (47%), arthralgia (20%), headache (20%) and failure to thrive (33%). Nine patients demonstrated increased susceptibility to infection and two children suffered from Crohn's disease. Administration of short courses of NSAID or corticosteroids resulted in resolution of the disease flare. In one severe case, canakinumab (anti-interleukin-1ß antibody) was successfully used. Significant number of patients with genetically assigned diagnosis of NLPR12-AID has clinical features which close resemble primary immune deficiency. This phenotypic overlap may result in underdiagnosis of NLPR12-AID among patients with PID.

Methotrexate treatment may prevent uveitis onset in patients with juvenile idiopathic arthritis: experiences and subgroup analysis in a cohort with frequent methotrexate use.

OBJECTIVES: To re-evaluate the ability of methotrexate (MTX) to prevent the onset of uveitis in Russian children with juvenile idiopathic arthritis (JIA). METHODS: The clinical charts for all consecutive patients who received a stable management for at least 2 years with or without MTX were reviewed. Patients who were given systemic medications other than MTX (except NSAID) and patients with systemic arthritis, rheumatoid factor-positive arthritis, or enthesitis-related arthritis were excluded. Each patient was examined after at least a 2-year follow-up period after the first visit to establish whether uveitis had occurred. RESULTS: A total of 281 patients with a median disease duration of 3.8 years were included. 191 patients (68%) were treated with MTX. During the observation period, 64 patients (22.8%) developed uveitis, a median of 1.6 year after disease onset. The frequency of uveitis was lower in MTX-treated than in MTX-untreated patients (11.5% vs. 46.7%, respectively, OR=6.7 (95%CI:3.7-12.3), p=0.0000001). Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis (HR=4.35, p=0.000001). In subgroup analysis it was shown that MTX was more preventive in boys than in girls, and in patients with JIA onset age of over 5 years compared to those with disease onset less than 5 years. The data of survival analysis of MTX prevention has shown that benefits do not depend on the number of active joints and ANA status. CONCLUSIONS: MTX therapy may prevent the onset of uveitis in children with JIA. Further randomised controlled trials are required to confirm our results.

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.

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.

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.

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.

IFN-I Score and Rare Genetic Variants in Children with Systemic Lupus Erythematosus.

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.

Initial Respiratory System Involvement in Juvenile Idiopathic Arthritis with Systemic Onset Is a Marker of Interstitial Lung Disease: The Results of Retrospective Cohort Study Analysis.

Background: Pulmonary involvement in systemic juvenile idiopathic arthritis (SJIA) is a rare but dangerous complication. The main risk factors are already known, such as macrophage activation syndrome, a refractory course of systemic juvenile arthritis, infusion reaction to interleukin 1 and/or interleukin 6 blockers, trisomy 21, and eosinophilia. However, information about respiratory system involvement (RSI) at the onset of SJIA is scarce. Our study aimed to evaluate the specific features of children with SJIA with RSI and their outcomes. Methods: In a single-center retrospective cohort study, we compared the information from the medical records of 200 children with SJIA according to ILAR criteria or SJIA-like disease (probable/possible SJIA) with and without signs of RSI (dyspnea, shortness of breath, pleurisy, acute respiratory distress syndrome, and interstitial lung disease (ILD)) at the disease onset and evaluated their outcomes (remission, development of chronic ILD, clubbing, and pulmonary arterial hypertension). Results: A quarter (25%) of the SJIA patients had signs of the RSI at onset and they more often had rash; hepato- and splenomegaly; heart (pericarditis, myocarditis), central nervous system, and kidney involvement; hemorrhagic syndrome; macrophage activation syndrome (MAS, 44.4% vs. 9.0%, p = 0.0000001); and, rarely, arthritis with fewer active joints, compared to patients without RSI. Five patients (10% from the group having RSI at the onset of SJIA and 2.5% from the whole SJIA cohort) developed fibrosing ILD. All of them had a severe relapsed/chronic course of MAS; 80% of them had a tocilizumab infusion reaction and further switched to canakinumab. Unfortunately, one patient with Down's syndrome had gone. Conclusion: Patients with any signs of RSI at the onset of the SJIA are required to be closely monitored due to the high risk of the following fibrosing ILD development. They required prompt control of MAS, monitoring eosinophilia, and routine checks of night oxygen saturation for the prevention/early detection of chronic ILD.

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.

Defining Criteria for Disease Activity States in Systemic Juvenile Idiopathic Arthritis Based on the Systemic Juvenile Arthritis Disease Activity Score.

OBJECTIVE: Our objective was 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 (MDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis, based on subjective disease state assessment by the treating pediatric rheumatologist. METHODS: The cutoff 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, six methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, the Youden index, 90% specificity, maximum agreement, and receiver operating characteristic curve analysis. Sixty percent of the patients were assigned to the definition cohort, and 40% were assigned to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. RESULTS: The sJADAS10 cutoffs that separated ID from MDA, MDA from MoDA, and MoDA from HDA were ≤2.9, ≤10, and >20.6, respectively. The cutoffs discriminated strongly among different levels of pain, between patients with and without morning stiffness, and among patients whose parents judged their disease status as remission or persistent activity or 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.

Interleukin(IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses.

BACKGROUND: After introducing interleukin(IL)-1/IL-6 inhibitors, some Still and Still-like patients developed unusual often fatal pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: We sought to facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not-stopping IL-1/IL-6-inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6-inhibitors to 37 cases not-stopping these drugs. RESULTS: Before reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease onset age for reaction cases with pre-existing cardiothoracic comorbidities. After reaction began, increased rates of pulmonary complications and macrophage activation syndrome (MAS), differentiated drug-reaction cases from drug-tolerant controls (p=4.7x10-35; p=1.1x10-24, respectively). Initial DReSS feature was typically reported 2-8 weeks after initiating IL-1/IL-6-inhibition. In drug-reaction cases stopping versus not-stopping IL-1/IL-6-inhibitor treatment, reaction related features were indistinguishable, including pulmonary complication rates [75%(39/52] versus [76%(28/37)]. Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of MAS, and improved survival (p=0.005, multivariate regression). Resolution of pulmonary complications occurred in 67%(26/39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6-inhibitors significantly improved outcomes.

Methotrexate therapy may prevent the onset of uveitis in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate whether early treatment with methotrexate (MTX) prevents the onset of uveitis in children with juvenile idiopathic arthritis. STUDY DESIGN: The clinical charts of all consecutive patients seen between January 2002 and February 2011 who had a disease duration <1 year at first visit and had received a stable management for at least 2 years with or without MTX were reviewed. Patients who were given systemic medications other than MTX (except nonsteroidal anti-inflammatory drugs) were excluded. Patients with systemic arthritis, rheumatoid factor-positive arthritis, or enthesitis-related arthritis were also excluded. In each patient, the 2-year follow-up period after first visit was examined to establish whether uveitis had occurred. RESULTS: A total of 254 patients with a median disease duration of 0.3 year were included. Eighty-six patients (33.9%) were treated with MTX, whereas 168 patients (66.1%) did not receive MTX. During the 2-year follow-up, 211 patients (83.1%) did not develop uveitis, whereas 43 patients (16.9%) had uveitis a median of 1.0 year after the first visit. The frequency of uveitis was lower in MTX-treated than in MTX-untreated patients (10.5% vs 20.2%, respectively, P = .049). Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis. CONCLUSION: Early MTX therapy may prevent the onset of uveitis in children with juvenile idiopathic arthritis. Because our study may be affected by confounding by indication, the potential of MTX to reduce the incidence of ocular disease should be investigated in a randomized controlled trial.