Case report: Success of allogeneic hematopoietic stem cell transplantation for refractory systemic-onset juvenile idiopathic arthritis.

Objectives: This study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA. Methods: We present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient's disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience. Results: Two patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2-7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT. Conclusion: We report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk-benefit ratio of this procedure.

Disease evolution in systemic juvenile idiopathic arthritis: an international, observational cohort study through JIRcohort.

BACKGROUND: Systemic juvenile idiopathic arthritis (systemic JIA) is a severe disease with both systemic and joint inflammation. This study aims to identify predictors of disease evolution within the systemic JIA population enrolled in the Juvenile Inflammatory Rheumatism cohort (JIRcohort). METHODS: Observational patient cohort study with 201 recruited children from 4 countries (3 European, 1 North Africa) from 2005 until 2019, using retrospectively (2005-2015) and prospectively (2015-2019) routine care collected data. RESULTS: Sixty-five patients with complete follow-up data for 24 months after first diagnosis were classified as monophasic (n = 23), polyphasic (n = 6) or persistent group (n = 36) corresponding to their evolution (unique flare, recurrent flares, or persistent disease activity respectively). The patients of the persistent group were more likely to have an earlier disease onset, before the age of 6 (OR 2.57, 95%-CI 0.70-9.46), persistence of arthritis at 12-months post-diagnosis (OR 4.45, 95%-CI 0.58-34.20) and higher use of synthetic DMARD (sDMARD, OR 5.28, 95%-CI 1.39-20.01). Other variables like global assessment by physician and by patient and C Reactive Protein levels at 12-months post-diagnosis were assessed but without any predictive value after adjusting for confounding factors. CONCLUSIONS: Our results suggest that the earlier disease onset, the persistence of arthritis throughout the first year of disease evolution and the need of sDMARD might predict a persistent disease course.

Immune dysregulation.

The understanding of immune dysregulation in many different diseases continues to grow. There is increasing evidence that altered microbiome and gut barrier dysfunction contribute to systemic inflammation in patients with primary immunodeficiency and in patients with rheumatic disease. Recent research provides insight into the process of induction and maturation of pathogenic age-associated B cells and highlights the role of age-associated B cells in creating tissue inflammation. T follicular regulatory cells are shown to help maintain B-cell tolerance, and therapeutic approaches to increase or promote T follicular regulatory cells may help prevent or decrease immune dysregulation. Meanwhile, novel studies of systemic-onset juvenile idiopathic arthritis reveal a strong HLA association with interstitial lung disease and identify key aspects of the pathogenesis of macrophage activation syndrome. Studies of hyperinflammatory syndromes, including the recently described multisystem inflammatory syndrome of children, characterize similarities and differences in cytokine profiles and T-cell activation. This review focuses on recent advances in the understanding of immune dysregulation and describes potential key factors that may function as biomarkers for disease or targets for therapeutic interventions. Future trials are necessary to address the many remaining questions with regards to pathogenesis, diagnosis, and treatment of autoimmune, inflammatory, and immunodeficiency syndromes.

Enfermedad de Crohn en paciente con artritis idiopática juvenil de inicio sistémico: ¿asociación o complicación asociada al tratamiento? / Crohn's Disease in a Patient with Systemic Onset Juvenile Idiopathic Arthritis. Association or Associated Side Effect of Treatment?

La evolución de la artritis idiopática juvenil de inicio sistémico (AIJs) hacia las diferentes formas de presentación de enfermedad inflamatoria intestinal es extremadamente infrecuente. Presentamos la que, hasta ahora, es la primera comunicación de un paciente con AIJs con evolución a enfermedad de Crohn en el que se han detectado mutaciones en genes responsables de la adecuada regulación del sistema inmune innato.(AU)

The progression of systemic-onset juvenile idiopathic arthritis (JIAs) to the different forms of presentation of inflammatory bowel disease is extremely rare. We present the first report of a patient with SJIA that progressed to Crohn's disease in which mutations have been detected in genes responsible for the adequate regulation of the innate immune system.(AU)

Refractory systemic onset juvenile idiopathic arthritis: current challenges and future perspectives.

Systemic juvenile idiopathic arthritis (SJIA) is a rare disease with distinct features not seen in other categories of juvenile idiopathic arthritis. In recent years, advances in the understanding of disease immunopathogenesis have led to improved targeted therapies with significant improvement in patient outcomes. Despite these advances, there remain subsets of SJIA with refractory disease and severe disease-associated complications. This review highlights existing options for treatment of refractory SJIA and explores potential future therapeutics for refractory disease.Key Points:Despite targeted Interleukin IL-1 and IL-6 inhibitors a subset of SJIA remains refractory to therapy. About 1 in 7 SJIA patients will be refractory to targeted IL-1 or IL-6 therapy.There is no current agreed upon definition for refractory SJIA and we propose in this review that refractory SJIA is presence of active systemic or arthritic features despite treatment with anti-IL-1 or anti-IL-6 therapy or disease requiring glucocorticoids for control beyond 6 months.SJIA disease associated complications include presence of associated macrophage activation syndrome (MAS), interstitial lung disease (ILD) or amyloidosis and management of each differs.Refractory SJIA treatment options currently include additional conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS), biologic (bDMARDS), combination biologic therapy, targeted synthetic (tsDMARDS) or other immunomodulatory therapies.

A case of multisystem inflammatory syndrome in children presenting as systemic onset juvenile idiopathic arthritis.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and serious COVID-19 manifestation characterised by generalised inflammatory response including inflammation of the heart, blood vessels, lungs, kidneys, brain, skin, eyes and gastrointestinal system. Children usually present with fever lasting for 24 hours or more along with other symptoms such as abdominal pain, vomiting, diarrhoea, skin rash, red eyes, and swelling of the lips, tongue, hands and feet. Children with MIS-C usually have negative results for a current infection with COVID-19 but positive antibody results indicating that these children were infected with the COVID-19 virus in the past. We present the case of a 12-month-old girl with multisystem inflammatory syndrome presenting as systemic-onset juvenile idiopathic arthritis (SoJIA) and positive Covid-19 PCR. She was treated successfully with Dexamethasone and Naproxen.

Efficacy of anakinra treatment in pediatric rheumatic diseases: Our single-center experience.

Objectives: This study aims to present our experience on anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, and efficacy results in pediatric rheumatic diseases in our clinic. Patients and methods: Between July 1st, 2016 and July 1st, 2020, a total of 33 pediatric patients (18 males, 15 females; mean age: 6±3.4 years; range 4 to 13 years) with pediatric rheumatic diseases who were treated with anakinra were retrospectively analyzed. The patients with over one-month treatment period and followed for at least one year were included. Demographic and clinical findings, outcomes, adverse events, prior and/or additional treatments were collected at baseline, at 3 and 12 months of therapy. Results: There were 33 patients with different pediatric rheumatic diseases (11 with systemic juvenile idiopathic arthritis [sJIA] complicated by macrophage activation syndrome [MAS], six with hyperimmunoglobulin-D syndrome, five with cryopyrin-associated periodic syndrome, five with familial Mediterranean fever, four with idiopathic recurrent pericarditis, one with NLRP12-associated periodic fever syndrome and one with unclassified systemic autoinflammatory disease), in the study group. The complete response was observed 69.7% of patients, partial response in 24.2%, and no response in 6.1% at three months of treatment. Inactive disease status was achieved in 45.5% of the patients with remission-on medication and 18.2% of the patients with remission-off medication at the end of a year. Anakinra was switched to other biological treatments in 51.5% of patients (n=17). Biological switch to canakinumab and tocilizumab were observed in 70.6% and 29.4% of these patients. Except for local reactions (n=2), no adverse events were observed in any of the patients. Conclusion: Anakinra appears to be a promising treatment alternative owing to its rapid effect as a result of its short half-life in autoinflammatory conditions. While short-term therapy seems to be sufficient for the sJIA complicated by MAS, the patients with systemic autoinflammatory diseases maintenance a more anakinra-dependent course.

Crohn's disease in a patient with systemic onset juvenile idiopathic arthritis. Association or associated side effect of treatment?

The progression of systemic-onset juvenile idiopathic arthritis (JIAs) to the different forms of presentation of inflammatory bowel disease is extremely rare. We present the first report of a patient with SJIA that progressed to Crohn's disease in which mutations have been detected in genes responsible for the adequate regulation of the innate immune system.

Adult-onset Still's disease or systemic-onset juvenile idiopathic arthritis and spondyloarthritis: overlapping syndrome or phenotype shift?

OBJECTIVES: Systemic-onset JIA (SJIA) and adult-onset Still's disease (AOSD) are the same sporadic systemic auto-inflammatory disease. SpA is a group of inflammatory non-autoimmune disorders. We report the observations of eight patients with SJIA/AOSD who also presented features of SpA during their disease evolution and estimate the prevalence of SpA in SJIA/AOSD. METHODS: This was a retrospective national survey of departments of paediatric and adult rheumatology and internal medicine. To be included, SJIA patients had to fulfil the ILAR criteria, AOSD patients the Yamaguchi or Fautrel criteria, and all patients the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial or peripheral SpA, ESSG criteria for SpA or Classification Criteria for Psoriatic Arthritis (CASPAR) criteria for PsA. The data were collected with a standardized form. RESULTS: Eight patients (five adults) were identified in one paediatric and two adult departments. In all but one patient, SpA manifestations occurred several years after SJIA/AOSD onset [mean (s.d.) delay 6.2 (3.8) years]. Two patients had peripheral and three axial SpA, and four later exhibited PsA and one SAPHO syndrome. The prevalence of SpA in an adult cohort of 76 patients with AOSD was 6.58% (95% CI 2.17, 14.69), greater than the prevalence of SpA in the French general population (0.3%; 95% CI 0.17, 0.46). The prevalence of SpA in an SJIA cohort of 30 patients was 10% (95% CI 2.11, 26.53), more than that reported in the general population of industrialized countries, estimated at 0.016-0.15%. CONCLUSION: While the temporal disassociation between SpA and AOSD in most cases might suggest a coincidental finding, our work raises the possibility of an SpA/AOSD spectrum overlap that needs further study.

Still's Disease Mortality Trends in France, 1979-2016: A Multiple-Cause-of-Death Study.

Still's disease (SD) is often considered a benign disease, with low mortality rates. However, few studies have investigated SD mortality and its causes and most of these have been single-center cohort studies. We sought to examine mortality rates and causes of death among French decedents with SD. We performed a multiple-cause-of-death analysis on data collected between 1979 and 2016 by the French Epidemiological Center for the Medical Causes of Death. SD-related mortality rates were calculated and compared with the general population (observed/expected ratios, O/E). A total of 289 death certificates mentioned SD as the underlying cause of death (UCD) (n = 154) or as a non-underlying causes of death (NUCD) (n = 135). Over the study period, the mean age at death was 55.3 years (vs. 75.5 years in the general population), with differences depending on the period analyzed. The age-standardized mortality rate was 0.13/million person-years and was not different between men and women. When SD was the UCD, the most frequent associated causes were cardiovascular diseases (n = 29, 18.8%), infections (n = 25, 16.2%), and blood disorders (n = 11, 7.1%), including six cases (54%) with macrophage activation syndrome. As compared to the general population, SD decedents aged <45 years were more likely to die from a cardiovascular event (O/E = 3.41, p < 0.01); decedents at all ages were more likely to die from infection (O/E = 7.96-13.02, p < 0.001).

Clinical Phenotypes of Adult-Onset Still's Disease: New Insights from Pathophysiology and Literature Findings.

Adult-onset Still's disease (AOSD) is a non-familial, polygenic systemic autoinflammatory disorder. It is traditionally characterized by four cardinal manifestations-spiking fever, an evanescent salmon-pink maculopapular rash, arthralgia or arthritis and a white-blood-cell count (WBC) ≥ 10,000/mm3, mainly neutrophilic polymorphonuclear cells (PMNs)-but many other manifestations and complications can be associated, making clinical expression very heterogeneous and diagnosis sometimes difficult. The AOSD course can be diverse and is currently impossible to predict. Several clinical phenotypes have been described, either on the basis of the evolution of symptoms over time (monocyclic, polycyclic and chronic evolution) or according to dominant clinical evolution (systemic and arthritis subtypes). However, these patterns are mainly based on case series and not on robust epidemiological studies. Furthermore, they have mainly been established a long time ago, before the era of the biological treatments. Thus, based on our personal experience and on recent advances in the understanding of disease pathogenesis, it appears interesting to reshuffle AOSD phenotypes, emphasizing the continuum between AOSD profiles and other systemic autoinflammatory disorders, eventually proposing a research agenda.

Adult-Onset Still's Disease: Clinical Aspects and Therapeutic Approach.

Adult-onset Still's disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still's disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials.

Detection and Prediction of Macrophage Activation Syndrome in Still's Disease.

Distinguishing between macrophage activation syndrome (MAS) and a simple flare of Still's disease (SD) may be challenging. We sought to clarify the clinical features and outcome of MAS in SD and to explore predictive factors of MAS development. Demographic and clinical data, treatments, and outcomes were recorded in a cohort of 206 SD patients. SD patients with and without MAS were compared. To explore predictive factors for the development of MAS, patients were compared at the time of SD diagnosis. Twenty (9.7%) patients experienced MAS, which was inaugural in 12 cases. Patients with MAS were more likely to have hepatomegaly (OR, 3.71; 95% CI, 1.14-11.2; p = 0.03) and neurological symptoms (OR, 4.43; 95% CI, 1.08-15.3; p = 0.04) than patients without MAS. Cytopenias, abnormal liver tests, and coagulation disorders were significantly more frequent in patients with MAS; lactate dehydrogenase and serum ferritin levels were significantly higher. An optimized threshold of 3500 µg/L for serum ferritin yielded a sensitivity (Se) of 85% and a negative predictive value (NPV) of 97% for identifying patients with/without MAS. Survival analysis showed that a high ferritin level at the time of SD diagnosis was predictive of MAS development (p < 0.001). Specific factors, including neurological symptoms, cytopenias, elevated LDH, and coagulopathy, may contribute to the early detection of MAS. Extreme hyperferritinemia at the onset of SD is a prognostic factor for the development of MAS.

Severe Recurrent Fever Episodes With Clinical Diagnosis of Hemophagocytic Lymphohistiocytosis, Incomplete Kawasaki Disease and Systemic-Onset Juvenile Idiopathic Arthritis: A Case Report and Literature Review.

The pathogeneses of recurrent fever are quite complicated when excluding repeated infections. Recurrent fever is a common symptom for autoinflammatory diseases, relapse of Systemic-onset juvenile idiopathic arthritis (SoJIA) and recurrent Kawasaki disease (KD). There are no specific diagnostic laboratory tests for the diseases. Some studies showed that KD was the precursor of hemophagocytic lymphohistiocytosis (HLH). Macrophage activation syndrome (MAS) is another form of HLH in SoJIA. Cytokine disturbances are considered to be involved in the pathogenesis of the diseases. We describe a Chinese female toddler that developed three separate fever episodes with eventual diagnose of SoJIA within about 10 months. The first episode was diagnosed as IKD, immunoglobulin nonresponsive KD, and HLH. The second and third episodes were diagnosed as IKD and SoJIA, respectively. The fever was hard to be relieved by antipyretics, and the peak axillary temperature was above 40°C. For every fever episode, infections were excluded. For the first episode, trends over time of hemoglobin, platelets, fibrinogen, and triglycerides indicated HLH, which was finally diagnosed and treated according to the HLH-2004 protocol. For the second episode 6 months later, after excluding an HLH relapse and infections, IKD was finally diagnosed. Oral aspirin was administered, and the HLH treatment was ceased. The third episode occurred 3 months later, and SoJIA was finally diagnosed. For each episode, except for relative tests, we only tested for cytokines interleukin-1ß, interleukin-6, and interferon-γ, due to limited laboratory test availability. These cytokines were elevated during remission and rose much higher in the fever phases. The case showed the difficulty to differentiating the recurrent fever in clinical practice. Surveillance of routine laboratory parameters over time might reveal a trend that indicates possible disease, even when parameter values do not meet diagnostic criteria. Changes in cytokine profiles are promising markers for differentiating recurrent fever diseases in future. An unknown immunological defect for the case may contribute to the recurrent immunological insults, and we are following up the recurrence of fever episode.

Comparison of Early vs. Delayed Anakinra Treatment in Patients With Adult Onset Still's Disease and Effect on Clinical and Laboratory Outcomes.

Background: Aim of this study was to search for any difference in the outcome of patients with adult onset Still's disease (AOSD) treated with anakinra (ANK) in relation with the interval between disease onset and the start of anti-interleukin(IL)-1 treatment and according with the different lines of ANK treatment. Patients and Methods: One hundred and forty-one AOSD patients treated with ANK have been retrospectively assessed. Statistically significant differences (p < 0.05) were analyzed in the frequency of ANK effectiveness, primary or secondary inefficacy to ANK and rate of resolution of clinical and laboratory AOSD manifestations after 3, 6, and 12 months since ANK treatment according with different lines of treatment and different times between AOSD onset and start of ANK. Results: No significant differences were identified in the ANK effectiveness and frequency of primary or secondary inefficacy for patients starting ANK within 6 months (p = 0.19, p = 0.14, and p = 0.81, respectively) or 12 months (p = 0.37, p = 0.23, and p = 0.81, respectively) since AOSD onset compared with patients starting ANK thereafter; no significant differences were identified in ANK effectiveness and primary or secondary inefficacy according with different lines of ANK treatment (p = 0.06, p = 0.19, and p = 0.13, respectively). Patients starting ANK within 6 and 12 months since AOSD onset showed a significantly quicker decrease of erythrocyte sedimentation rate and C-reactive protein than observed among patients undergoing ANK treatment after 6 and 12 months. The number of swollen joints at the 3 month follow-up visit was significantly lower among patients undergoing ANK within 6 months since AOSD onset (p = 0.01), while no significance was identified at the 6 and 12 month assessments (p = 0.23 and p = 0.45, respectively). At the 3 and 6 month visits, the number of swollen joints was significantly higher among patients previously treated with conventional and biological disease modifying anti-rheumatic drugs (DMARDs) compared with those formerly treated only with conventional DMARDs (p < 0.017). Conclusions: Clinical and therapeutic outcomes are substantially independent of how early ANK treatment is started in AOSD patients. However, a faster ANK effectiveness in controlling systemic inflammation and resolving articular manifestations may be observed in patients benefiting from IL-1 inhibition as soon as after disease onset.

Autoinflammatory diseases in childhood, part 2: polygenic syndromes.

Autoinflammatory diseases are a family of disorders characterized by aberrant stimulation of inflammatory pathways without involvement of antigen-directed autoimmunity. They can be further divided in monogenic and polygenic types. Those without an identified genetic mutation are known as polygenic and include systemic-onset juvenile idiopathic arthritis, idiopathic recurrent acute pericarditis, Behçet syndrome, chronic recurrent multifocal osteomyelitis and inflammatory bowel disease among others. Autoinflammatory diseases are characterized by recurrent flares or persistent systemic inflammation and fever, as well as lymphadenopathy and cutaneous, abdominal, thoracic and articular symptoms. Although these syndromes can mimic infections clinically, the inflammatory lesions in autoinflammatory disorders are aseptic. However, because of their infrequency, varied and nonspecific presentation, and the new genetic identification, diagnosis is usually delayed. In this article, which is Part 2 of a two-part series, the authors review the main polygenic autoinflammatory diseases that can be seen in childhood, with special emphasis wherever applicable on imaging features that may help establish the correct diagnosis. However, the major role of imaging is to delineate organ involvement and disease extent.

The role of serum cytokine level in the evaluation of the efficacy of tocilizumab for the treatment of systemic-onset juvenile idiopathic arthritis / 中华检验医学杂志

Objective@#To evaluate the value of serum cytokine level in the efficacy of tocilizumab for the treatment of systemic-onset juvenile idiopathic arthritis.@*Methods@#30 cases with SoJIA hospitalized in Capital Institute of Paediatrics from June 2016 to October 2018 were treated with Interleukin-6 receptor antagonist(tocilizumab) injection. Among them, 20 were males(67%) and 10 were females(33%). The age at diagnosis was between 0.84 to 13years. Whiteblood cell, C-reactive protein, erythrocyte sedimentation rate, serum interleukin(IL-6, IL-2R, IL-8, IL-10, IL-1β) and tumor necrosis factor-alpha levels were observed before treatment, after the 2nd week, after the 6th week and after the 22nd week.Mann-Whitney nonparametric test and Chi-square test were used to analyze the data of cytokines pre and after-treatment.@*Results@#All of the 30 cases had fever before medication. The fever disappeared in 28 cases after using tocilizumab. One case stopped using tocilizumab because of allergic reaction and one case stopped because of poor efficacy. Among 28 cases with normal body temperature after medication, the arthritis and rash manifestations were significantly improved. WBC, AESR and CRP were all lower than those before medication. Within these 28 cases, the serum IL-6 level was168.50(67.40-589.25) pg/mL pre-treatment, 107.50(28.03-281.50) pg/mL after the 2nd week. There was no statistical difference between them(Z=-1.754, P>0.05). The serum IL-6 level was 64.05 (19.90-130.75) pg/mL after the 6th week and 24.80 (3.45-95.40) pg/mL after the 22nd week. Compared with pre-treatment, they were all lower than pre-treatment levels(Z=-2.942,-3.334,P<0.01,<0.01).Serum IL-2R level was 740.50(510.00-1 161.00)U/mL after the 2nd week, 796.50 (534.00-1 008.00) U/mL after the 6th week and 688.00 (527.00-889.50) U/mL after the 22nd week. Compared with pre-treatment [1 322.50(812.00-1 659.00)U/mL], they were all lower than pre-treatment levels (Z=-2.818,-3.130,-3.466, P<0.01, <0.01, <0.01). Serum TNF-alpha level was 23.70 (20.30-41.23) pg/ml after the 2nd week, 26.75(16.83-47.03) pg/ml after the 6th week,18.60(13.10-34.90) pg/ml after the 22nd week. Compared with pre-treatment [26.50(20.55-37.43) pg/ml], there were no statistical difference between after and pre-treatment(Z=0,-0.560,-1.954,P>0.05,>0.05,>0.05). Serum IL-8 level was 200.85(95.43-364.00)pg/ml after the 2nd week, 194.50(50.75-433.00)pg/ml after the 6th week, 161.50 (38.98-308.00)pg/ml after the 22nd week. Compared with pre-treatment [96.20(59.75-371.75) pg/ml], there were no statistical difference between after and pre-treatment(Z=-0.86,-0.131,-0.186,P>0.05,>0.05,>0.05). There was no statistical difference between after the 2nd week and pre-treatment in the IL-10 level(χ2=2.33, P>0.05). The IL-10 level after 6th week and after 22nd week were all lower than pre-treatment levels(χ2=4.08, 4.08, P<0.05, <0.05). There were no statistical difference between after and pre-treatment(χ2=0.084, 2.504,3.818,P>0.05,>0.05,>0.05)in IL-1β level.@*Conclusion@#After treatment with tocilizumab, the levels of serum IL-6 and IL-2R are helpful to assess the activity of SoJIA and the efficacy of therapy.

Population pharmacokinetics of tacrolimus in pediatric patients with systemic-onset juvenile idiopathic arthritis: Initial dosage recommendations.

Pediatric patients with systemic-onset juvenile idiopathic arthritis (SOJIA) may be treated with tacrolimus. However, the therapeutic range for tacrolimus is narrow with considerable inter- and intra-individual variability, making it difficult to formulate an ideal dosage regimen for personalized treatment. The purpose of the present study was to set up a population pharmacokinetics (PPK) model of tacrolimus treatment for SOJIA to determine the optimal initial dosage. Patients with SOJIA were analyzed using non-linear mixed-effects modeling. Different regimens were analyzed using Monte Carlo simulation with concentration profiles. A first-order absorption and elimination one-compartment model was selected as the most appropriate model for SOJIA. Based on initial dosage recommendations, the regimen of 0.5 mg every 24 h (q24h) appeared to be most suitable for subjects with a body weight of 5 kg, while the 0.5 mg q12h regimen was most suitable for subjects with a body weight of 15-25 kg, the 1/0.5 mg q24h regimen was appropriate for the 26-35 kg group and the 1 mg q12h regimen was suitable for the subjects with a body weight of 36-50 kg. To the best of our knowledge, the present study established the first PPK model of tacrolimus treatment that may be used for the selection of the initial dose based on body weight of pediatric patients with SOJIA.

Characterization of microbiota in systemic-onset juvenile idiopathic arthritis with different disease severities.

BACKGROUND: Systemic-onset juvenile idiopathic arthritis (SoJIA) is one of most serious subtypes of juvenile idiopathic arthritis. Although the pathogenesis of SoJIA remains unclear, several studies have suggested a correlation between gut dysbiosis and JIA. Further understanding of the intestinal microbiome may help to establish alternative ways to treat, or even prevent, the disease. AIM: To explore alterations in fecal microbiota profiles in SoJIA patients and to evaluate the correlations between microbiota and clinical parameters. METHODS: We conducted an observational single-center study at the Pediatric Department of Peking Union Medical College Hospital. Children who were diagnosed with SoJIA at our institution and followed for a minimum period of six months after diagnosis were recruited for the study. Healthy children were recruited as a control group (HS group) during the same period. Clinical data and stool samples were collected from SoJIA patients when they visited the hospital. RESULTS: The SoJIA group included 17 active and 15 inactive consecutively recruited children; the control group consisted of 32 children. Firmicutes and Bacteroidetes were the two most abundant phyla among the total sample of SoJIA children and controls. There was a significant difference among the three groups in observed species, which was the highest in the Active-SoJIA group, followed by the Inactive-SoJIA group and then HS group (Active-SoJIA vs HS: P = 0.000; and Inactive-SoJIA vs HS: P = 0.005). We observed a lower Firmicutes/Bacteroidetes ratio in SoJIA patients (3.28 ± 4.47 in Active-SoJIA, 5.36 ± 8.39 in Inactive-SoJIA, and 5.67 ± 3.92 in HS). We also observed decreased abundances of Ruminococcaceae (14.9% in Active-SoJIA, 17.3% in Inactive-SoJIA, and 22.8% in HS; Active-SoJIA vs HS: P = 0.005) and Faecalibacterium (5.1% in Active-SoJIA, 9.9% in Inactive-SoJIA, and 13.0% in HS; Active-SoJIA vs HS: P = 0.000) in SoJIA compared with HS. By contrast, the abundance of Bacteroidaceae was the highest in the Active-SoJIA group, followed by the Inactive-SoJIA and HS groups (16.5% in Active-SoJIA, 12.8% in Inactive-SoJIA, and 9.7% in HS; Active-SoJIA vs HS: P = 0.03). The Spearman correlation analysis revealed a negative correlation between Proteobacteria or Enterobacteriaceae and juvenile arthritis disease activity score on 27 joints (JADAS-27). CONCLUSION: The composition of the intestinal microbiota is different in SoJIA patients compared with healthy children. The dysbiosis presents partial restoration in inactive status patients.