Polyarticular Juvenile Arthritis Research Articles

Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment

BackgroundA better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls.MethodsBlood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann–Whitney U and Wilcoxon matched-pairs signed rank tests.ResultsTreatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients’ post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound.ConclusionsPatients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

Golimumab for Polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis: Pharmacologic and Clinical Considerations.

Psoriatic arthritis is a chronic debilitating autoimmune condition, and when diagnosed in patients before the age of eighteen, it is considered pediatric polyarticular juvenile idiopathic arthritis. Monoarticular or polyarticular psoriatic arthritis can be distinguished from other arthropathies by its unique cutaneous manifestations. With numerous treatments already in clinical practice, there are numerous options for treatment. The current literature indicates an elevated level of tumor necrosis factor is present in the epidermis of patients with psoriatic arthritis when compared with the general population. For this reason, anti-tumor necrosis factor therapies have become a hallmark option for psoriatic arthritis patients. Golimumab, a human monoclonal antibody tumor necrosis factor-alpha (TNF-a) receptor antagonist, was chosen as the focus therapy for this investigation. The mechanism of action behind anti-tumor necrosis factor-alpha blockers involves the binding of human TNF-a soluble and transmembrane proteins to competitively inhibit TNF-a from binding to its cellular receptors. The present investigation evaluated current treatment options available for both juvenile- and adult-onset psoriatic arthritis and compared them with the efficacy seen with golimumab use. Pediatric patients included children ages 2-17, while adult populations included adults 18-83 years old. The Food and Drug Administration has approved golimumab for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis. The results of four different studies reporting on the therapeutic effects and adverse events of golimumab use in psoriatic arthritis, juvenile psoriatic arthritis, juvenile idiopathic arthritis, and juvenile polyarticular arthritis were used for comparison. The meta-analysis referenced studies including children ages 2-17 with no reference mentioning children less than age 2. Based on the results of each study, it can be concluded that golimumab, a human monoclonal antibody that prevents the activation of cellular inflammatory reactions when it binds to the TNF-a receptor, is an effective option for patients with active psoriatic arthritis and psoriatic juvenile idiopathic arthritis and for patients who are no longer responding to their current treatment with adalimumab. Each study also reported minimal adverse events associated with golimumab use, and the drug can be safely used in the pediatric population.

Interrogation of STAT3 activation in patients with polyarticular juvenile arthritis

Abstract Juvenile idiopathic arthritis (JIA) can cause pain and disability, but early disease control improves outcomes. The polyarticular JIA (polyJIA) subset is clinically similar to adult rheumatoid arthritis (RA), yet its pathogenesis remains incompletely understood. A pathway of interest in polyJIA is STAT3 signaling. STAT3 is a transcription factor critical to development of inflammatory Th17 cells and modulation of regulatory T cells. Elevated Th17s and activated STAT3 have been shown in RA. We aimed to profile T cell subsets and STAT3 activation in polyJIA. Blood from 13 patients with polyJIA was collected at initial diagnosis and serially until remission. Peripheral blood mononuclear cells were isolated and T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Regulatory T cells from patients with polyJIA were found at similar levels as pediatric controls. However, treatment naïve polyJIA patients had increased Th17s compared to pediatric controls (0.15% v 0.44%, p=0.037). We identified IL-17 and IFN-γ dual+ helper T cells (non-classical Th1s) appearing in post-treatment samples from polyJIA patients. After stimulation (IL-6, IL-27 or IFN-α), a subset of polyJIA patients had highly activated STAT3, but not STAT1 or STAT5, in CD3+CD4+ T cells. A better understanding of the mechanisms underlying polyJIA is needed for more efficient and effective clinical care. Although multiple therapeutics to treat JIA exist, a biomarker-driven approach to treatment does not. Patients with polyJIA have increased Th17s and a subset have highly activated STAT3. These immunologic features may help identify patients that would benefit from upfront, tailored treatment with therapeutics targeting this pathway.

Interleukin-6-Blockade als potenzielles therapeutisches Target bei entzündlich-rheumatischen Erkrankungen

As a pro-inflammatory cytokine, the 21-kDa glycoprotein interleukin-6 (IL-6) plays a crucial role in the initiation of acute inflammation, as well in the perpetuation of a chronic inflammatory immune response. Thus, IL-6 might be involved in the pathogenesis of various autoimmune diseases. So far, the IL-6-rezeptor-antibody tocilizumab (TCZ, RoActemtra®) is the only approved drug for the treatment of IL-6-mediated disease, including rheumatoid arthritis (RA), systemic juvenile idiopathic (sJIA) and polyarticular juvenile arthritis (pJiA), as well as Castleman's disease (in Japan only). In recent years, an emerging number of case reports and small uncontrolled case series have reported on the successful treatment of various other chronic inflammatory diseases, which has resulted in the idea of a broad therapeutic potential for IL-6 blockade. Numerous IL-6 targets are currently in phase II/III study programs for RA as well as for other indications. This review focuses on the development of tocilizumab and other IL-6 targets as a therapeutic option for various diseases in rheumatology.

Stressful Life Events Antedating Chronic Childhood Arthritis

To investigate associations between antecedent stressful life events and occurrence of juvenile arthritis (JA). The study population comprised patients with JA referred to a pediatric rheumatology clinic between 1981 and 2010. A questionnaire, which was developed as a screening tool by the clinic, was completed at the first clinic visit by patients' parents and, for comparison, by parents of unrelated age, sex, geographically, and temporally matched healthy controls. The entire questionnaire captured a broad array of clinical, demographic, psychosocial, and environmental data, including questions about stressful life events from 686 patients with JA and from 1042 controls. Patients were more likely to have experienced a serious upset (OR 4.81; p < 0.0001), a currently ill family member (OR 2.29; p < 0.0001), separated parents (OR 1.96; p < 0.0001), or difficulties with interpersonal relationships (OR 2.54; p < 0.0001) prior to first clinic presentation compared to controls. Children with oligoarticular JA were more likely than controls to have experienced a serious upset (OR 3.46; p = 0.008), an ill family member (OR 3.79; CI 2.02, 7.11; p < 0.0001), or problems with interpersonal interactions (OR 3.32; p < 0.0001). Children with polyarticular JA were more likely to have experienced a serious upset (OR 5.68; p < 0.0001), separated parents (OR 2.66; p = 0.001), a deceased parent (OR 6.75, p = 0.017), or problems with interpersonal relationships (OR 2.39; p = 0.009). No significant differences were observed when comparing systemic JA patients to controls. Strong associations between stressful life events antedating the first clinic visit of patients with JA indicate that life event stresses should be identified and addressed when first encountering and managing children with JA.

Daily sleep quality and mood as predictors of pain in children with juvenile polyarticular arthritis.

Children with arthritis experience frequent pain, but the predictors of daily pain variations are largely unidentified. The goal of this study was to examine sleep quality as a predictor of pain in children with arthritis and to determine whether mood moderates this relationship. In this prospective, longitudinal study children with polyarticular arthritis (n = 51, ages 8-16 years) tracked daily symptoms, including sleep quality over 2 months. Self-reported daily pain intensity, as indicated on a visual analog scale, was used as the primary outcome measure in multilevel models. Poorer sleep quality was associated with higher next-day pain ratings (p < .01). Mood moderated this relationship such that as positive mood increased, the relationship between poor sleep quality and high pain weakened (p < .01). Daily pain did not predict nightly sleep quality (p > .05). Sleep quality is an important predictor of pain in children with arthritis. These findings add to the growing body of literature on the use of daily diaries for analyzing patterns of pain, sleep, and mood in children with chronic painful conditions.

Daily sleep quality and mood as predictors of pain in children with juvenile polyarticular arthritis.

Daily sleep quality and mood as predictors of pain in children with juvenile polyarticular arthritis.

Daily sleep quality and mood as predictors of pain in children with juvenile polyarticular arthritis

Daily sleep quality and mood as predictors of pain in children with juvenile polyarticular arthritis

Decreased levels of sCD21 and sCD23 in blood of patients with systemic-juvenile arthritis, polyarticular-juvenile arthritis, and pauciarticular-juvenile arthritis

A soluble form of CD21 (sCD21) and CD23 (sCD23) is released from the surface of human white blood cells upon shedding of the extracellular domain. sCD21 circulates in a complex with cleavage fragments of C3 and sCD23, which were previously identified as ligands of membrane and soluble CD21. sCD21 seems to be a marker of chronic inflammatory disease. To assess the sCD21 and sCD23 status in patients with subsets of juvenile arthritis (JA), we determined plasma levels sCD21 and sCD23. Plasma sCD21 levels were significantly decreased in all JA subtypes (O-JA P<0.0068; P- and S-JA P<0.0001) compared to healthy controls. Plasma sCD23 levels were significantly decreased in P-JA and S-JA (both P<0.0001), but not in O-JA (P<0.3843) in comparison with healthy controls, and data statistically analyzed. Our results suggest that pathological mechanisms relevant to autoimmune disorders interfere with the regulation of both CD21 and CD23 shedding.

THE CLINICAL AND DIAGNOSTIC VALUE OF ANTI-CYCLIC CITRULLINATED PEPTIDE ANTIBODIES IN EARLY JUVENILEARTHRITIS

Objective: to estimate the concentration of anti-cyclic citrullinated peptide antibodies (CCPA), the frequency of their increase, and their diagnostic value in children with early juvenile arthritis (JA). Subjects and methods. Sera from 80 patients (36 girls and 44 boys) aged 1,5 to 16 years (mean age 8,5+5,03 years) who had early JA were tested for CCPA. The diagnosis of juvenile rheumatoid arthritis (JRA) and juvenile chronic arthritis (JCA) was made in 19 and 57 patients, respectively; the duration of JA being &lt; 3 months in 4. The systemic type of JA was present in 8 (10%) children; the polyarticular and oligoar-ticular types in 37 (46,2%) and 35 (43,8%) children, respectively. The duration of the disease in all children did not exceed 6 months. A comparison group comprised 54 adult patients with early rheumatoid arthritis (RA), 27 with undifferentiated arthritis (UDA), and 37 apparently healthy children. The concentration of CCPA was measured by immunoassay using the commercial оAxis Shield Diagnosticsп kits (United Kingdom), the upper normal range being 5 U/ml. Results. The higher levels of CCPA were revealed in 7 (8,8%) children with early JA. Their frequency was higher than that in healthy children; however, it was lower than that in adult patients with RA and comparable with UDA. CCPAs were detected more frequently in JCA and rheumatoid factor (RF)-positive patients. Higher concentrations were observed in patients with RF-positive polyarticular JA. There were correlations of CCPA with the number of swollen and tender joints, RF. Conclusion. In patients with early JA, the detection rate of CCPA is significantly higher than that in healthy children and comparable with that of RF. CCPAs have a high specificity for the diagnosis of JRA (an independent nosological entity within JA) are a risk factor of polyarthritis. The early detection of CCPA alone or in combination with RF in JA patients may serve the basis for the early use of active, frequently aggressive therapy.

Frequency and diagnostic significance of anti-cyclic citrullinated peptide antibodies (ACCP) and anti-modified citrullinated vimentin antibodies (AMCV) in children with early juvenile arthritis

Система комплексной поддержки и сопровождения научного журнала Elpub позволяет запустить двуязычный сайт журнала со встроенной системой электронной редакции в соответствии с лучшими издательскими практиками, а так же предусматривает техническую и методическую поддержку со стороны специалистов НЭИКОН.

Biological therapy of arthritis and systemic autoimmune diseases

The concept of biological therapy arises from the specific targeting of a factor, e.g. a cytokine, involved in the inflammatory cascade. Thus, biologicals disrupt the complex network of autoimmune-inflammatory events. Today, rheumatoid arthritis is a prototype disease in this context as most compounds have been tried in this disease. Recently, biological therapy has been introduced to the treatment of other diseases including various forms of arthritis, such as ankylosing spondylitis and psoriatic arthritis, as well as systemic autoimmune disorders, such as systemic lupus erythematosus, scleroderma, inflammatory myopathies and Sjogren's syndrome. Anti-tumor necrosis factor-alpha (TNF-alpha) agents play a central role in biological therapy as these agents have been successfully tried in most of these diseases. When seeking for specific targets for biologicals, pathogenic factors of the disease, such as Th1 or Th2 type responses, should be evaluated. Some mostly T-cell mediated diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, polymyositis, polyarticular juvenile arthritis respond well to anti-TNF agents and T cell targeting, while others, such as lupus, Sjogren's syndrome, dermatomyositis may rather respond to anti-B cell biologicals. In this review, authors discuss the most recent advances in the biological therapy of arthritis and systemic autoimmune diseases including issues of efficacy and safety.

Sustained Benefit from Treatment of Polyarticular Juvenile Arthritis with a Biologic Agent

Sustained Benefit from Treatment of Polyarticular Juvenile Arthritis with a Biologic Agent

Pain, stiffness, and fatigue in juvenile polyarticular arthritis: Contemporaneous stressful events and mood as predictors

To analyze patterns of stress, mood, disease symptoms, and activity reduction in children with polyarticular arthritis, using a prospective daily diary method. For a 2-month period, 51 children with polyarticular arthritis (mean age 12.4 years, 65% female) completed daily diaries that included measures of symptoms of pain, stiffness, and fatigue, as well as stress, mood, and activity reduction. Functional status and disease activity were assessed at the initial and followup evaluations with use of the Childhood Health Assessment Questionnaire, physician global assessment, joint count, and laboratory testing. Children reported having pain, stiffness, and fatigue on >70% of days, with significant variability in symptom levels. Results revealed significant same-day relationships between stress, mood, and disease symptoms, after controlling for covariates. Specifically, daily fluctuations in both stress and mood were predictive of increased pain, stiffness, and fatigue. Increases in daily stress, mood, and disease symptoms were also significantly related to decreased participation in social activities on a day-to-day basis. Only mood and stiffness were predictors of a cutback in school attendance. Stress and mood are important predictors of daily disease symptoms in children with polyarticular arthritis. Moreover, daily fluctuations in stress, mood, and disease symptoms are predictive of aspects of daily function, including participation in school and social activities. Thus, health care providers should solicit daily symptom reports when making decisions regarding clinical management. Nonpharmacologic interventions such as cognitive-behavioral therapy and stress management may be useful adjuvant therapy when treating the disease symptoms of children with polyarticular arthritis.

Pediatric rheumatology: What does the future hold? 1,2

Emery H. Pediatric rheumatology: what does the future hold? Arch Phys Med Rehabil 2004;85:1382–4. Effectiveness of the traditional rehabilitation approaches used in pediatric rheumatology has been difficult to prove and, in times of cost containment, this lack of evidence may lead to undertreatment with physical and occupational therapies. Quantitative methods such as those described in this issue by Broström and colleagues can be used to validate those approaches and to reinforce the need for careful attention to the effects of even minor loss of range and strength in children with juvenile arthritis. Historically, up to half of the children affected by polyarticular juvenile arthritis became disabled. Some factors that have led to improved outcomes for childhood rheumatic diseases are discussed, including medications (use of weekly low-dose methotrexate, intra-articular steroid injections, new biologic agents that specifically block mediators of inflammation, for example, tumor necrosis factor and interleukin-1), surgery (joint replacements), and psychosocial interventions (with schools and families). The importance of maintaining range of movement, strength, weight bearing, and ambulation, in an effort to prevent sequelae such as osteoporosis and wheelchair dependence, is emphasized. Early identification of children with rheumatic diseases and aggressive intervention, with a combined medical, rehabilitation, psychosocial, and, rarely, surgical approach, should now allow most affected children to reach adulthood with little or no disability.

Daily pain and symptoms in children with polyarticular arthritis.

To analyze patterns of daily pain, stiffness, and fatigue related to juvenile arthritis; to examine the relationships of demographics, disease severity, and psychological adjustment to daily disease symptoms; and to examine daily disease symptoms as predictors of reduced participation in school and social activity. For a 2-month period, 41 children with polyarticular juvenile arthritis completed daily diaries that included measures of symptoms and function. Children also underwent an initial evaluation and 4 followup evaluations that included a joint count, laboratory testing, and completion of questionnaires assessing physical and psychosocial functioning. Children reported having pain an average of 73% of days, with the majority of children (76%) reporting pain on >60% of all days. On average, children described the intensity of their daily pain as being in the mild to moderate range; however, a significant subgroup (31%) reported pain in the severe range. Higher physician global assessment ratings, increased functional disability, and increased anxiety were significantly associated with increased daily pain and other daily symptoms. Multilevel random-effects analyses indicated that increased daily symptoms of pain, stiffness, and fatigue were significant predictors of reduced participation in school and social activities. Physicians should consider treating pain more aggressively in children with arthritis, in order to preserve function in school and social domains, as well as physical function. Moreover, optimal pain management in children with arthritis should include therapeutic regimens addressing anxiety as well as standard pharmacologic interventions.

Maternal Stressors, Maternal Wellbeing and Children's Wellbeing in the Context of Juvenile Idiopathic Arthritis

The purpose of the present study was to examine the level of maternal stressors associated with Juvenile Idiopathic Arthritis (JIA) and to explore the relationship between maternal wellbeing and children's wellbeing in the context of JIA. The sample (n=60) comprised 30 children with JIA and their mothers. Children and mothers completed self-administered questionnaires independently in outpatient clinics. Mothers had a mean age of 37.73 (SD=5.50), 73% were married, all were White/European. Child participants (20 female and 10 male) had a mean age of 11.46 (SD=2.93), 61% had oligoarticular idiopathic arthritis, 26% had polyarticular juvenile arthritis and 13% systemic onset juvenile idiopathic arthritis. Compared to normative data, mothers were at risk of anxious and depressed mood, respectively. The highest rated stressors concerned the side effects of medication, the child's future and becoming over-protective of the child. There was a robust association between maternal wellbeing and children's physical functioning that was partially mediated by maternal self-efficacy. In contrast, maternal wellbeing appeared to be independent of children's ratings of pain, anxiety, depression and self-esteem. Maternal stress regarding JIA warrants further investigation, particularly in terms of mother's concern about children's physical functioning, the side effects of medication, visibility of the child's condition, and becoming over-protective.

Arthrite chronique juvénile et spondylarthropathie à début juvénile. Étude des déficiences, incapacités et handicaps dans les formes polyarticulaires

Introduction The authors use the international classification of impairments, disabilities and handicaps for study the disablement in polyarticular juvenile arthritis or spondylarthopathies. Patients and method Thirty-two patients (18 women, 14 men) with a minimum of five years course (an average of 9.5 years) were assessed. The main deficiencies were pain, limited joint motion (hips, shoulders, ankles), and a decrease in the pinch strength. Results — Conclusion The functional independencescore (FIS) was slightly decreased in 39% of remission and stabilized patients and lowered in all exacerbation periods (average 115). The juvenile arthritis functional assessment report (Jafar) specific scales, assess disability in 50% of remission and stabilized patients. In exacerbation periods, the average value is 18.5. Nine percent of patients attended a specialized school. Social integration posed problems in 29%. This methodical analysis is imperative in the delivery of comprehensive physical treatments and appliances or modified physical and occupational environments.

3 Juvenile arthritis: genetic update

Juvenile arthritis (JA) is a term that covers a number of different disease entities, of which only three present with significant Human Leukocyte Antigen (HLA) associations. (1) Pauciarticular JA with late onset and a strong male proponderance is associated with HLA-B27 and represents the group of juvenile spondyloarthropathies related to adult ankylosing spondylitis. (2) Early onset pauciarticular JA with a preponderance of females and a frequent occurance of chronic iridocyclitis and the frequent presence of anti-nuclear antibodies is associated with alleles from three different regions of the HLA system: HLA-A2, which shows a very strong correlation with early age of onset; DR8, DR11 and DR12 as well as DQA1*0401, *0501, *0601 and finally DPB1*0201. These alleles show no linkage disequilibrium in the control population. (3) Rheumatoid factor positive polyarticular JA is associated, as is adult rheumatoid arthritis, with DR4. Concerning the possible mechanisms of the immunopathogenesis, it is speculated that the normal function of HLA molecules, namely the presentation of antigenic peptides, plays a major role. Data collected on HLA associations in early onset pauciarticular JA have been interpreted as indicating that alleles of the DQA1 locus (*0401, *0501, *0601) are probably responsible for presenting the hypothetical arthritogenic peptides. It is speculated that the pathogenic process includes the presentation of HLA-A2 or HLA-DPB1*0201 derived peptides presented by DQ molecules. It is clearly stated that typing for HLA alleles has very little or no importance for clinical diagnosis and prognosis.

Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: Report of five cases

OBJECTIVES: To evaluate the efficacy of cyclosporine A in the treatment of macrophage activation syndrome (MAS) occurring in children with juvenile arthritis. STUDY DESIGN: MAS developed in two boys and three girls with systemic juvenile arthritis (four) and polyarticular juvenile arthritis (one). In three children whose condition was life-threatening, increased parenteral administration of corticosteroids failed to improve their condition; therefore cyclosporine A (2 to 5 mg/kg per day) was added. In two other patients with less severe clinical manifestations, cyclosporine A alone (2 to 8 mg/kg per day) was given. RESULTS: After the introduction of cyclosporine A, rapid improvement was obtained in all patients and apyrexia occurred within 24 to 48 hours. The biologic abnormalities disappeared more slowly (up to 5 weeks for liver enzymes). CONCLUSIONS: These observations underline the usefulness of cyclosporine A in this complication. The use of this drug may circumvent the need for increased doses of corticosteroids in some patients. The mechanism of action of cyclosporine A remains speculative, but these results indicate indirectly that T-helper lymphocytes may play a role in the pathogenesis of MAS. (J Pediatr 1996;129:750-4)