Treatment Of Juvenile Idiopathic Arthritis Research Articles

THE PHENOMENON OF NEUTROPENIA DURING TOCILIZUMAB THERAPY IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Tocilizumab (TCZ) is one of the biological agents that are most commonly used in the treatment of juvenile idiopathic arthritis (JIA), especially its systemic variant. The development of neutropenia, which is associated with the use of TCZ and its mechanism of action, requires a detailed study. Based on the analysis of their own results and comparison of the latter with the data available in the literature, the authors analyze the aspects of development of neutropenia during TCZ therapy. Objective: to analyze all cases of neutropenia with the use of TCZ in polyarticular (pJIA) and systemic (sJIA) variants of the disease. Subjects and methods. The open-label prospective study enrolled 27 patients with pJIA and 83 patients with sJIA, who were resistant to prior standard therapy. The treatment duration was 4 to 84 months (median, 22 months for pJIA; 34 months for sJIA). The frequency and timing of neutropenia and the relationship to infection and concomitant/previous therapy were examined. Results and discussion. 22 and 62 patients with pJIA and sJIA, respectively, continued treatment; its median duration was 27.4 [9; 72] months. 7 patients with pJIA and 21 with sJIA, discontinued TCZ due to severe adverse events (n=2 and n=11, respectively) and organizational reasons (n=5 and n=7); in sJIA, therapy was discontinued for sustained remission in two patients and for secondary inefficiency in one patient. At least one episode of neutropenia was observed in 63% of patients with pJIA and in 48.2% of those with sJIA; among them, there was grade 1 neutropenia in 5 and 15 patients, respectively; grade 2 in 6 and 15, grade 3 in 4 and 10, and grade 4 in two patients with pJIA. Neutropenia was more frequently observed in the first months of therapy for pJIA; that was seen in patients with sJIA when the latter reached its inactive status. In 5 patients with sJIA, neutropenia was recorded as a manifestation of macrophage activation syndrome (MAS); no correlation with TCZ infusions was found. Neutropenia was not associated with an increased rate of infections. The use of methotrexate was not significantly related to the low level of neutrophils, whereas the earlier age was associated with the degree and frequency of neutropenia. All cases of neutropenia were recorded in patients with a therapeutic response rate of >50% according to the American College of Rheumatology Pediatric (ACR Pedi) criteria. The findings suggest that there are different mechanisms and periods of neutropenia during TCZ therapy for JIA: 1) benign, transient neutropenia, a predictor of the high efficiency of therapy, develops primarily in the first few days after infusion; 2) neutropenia as a phenomenon of «redundancy» of therapy (more resistant) develops more often in the inactive phase of the disease; 3) neutropenia as a component of MAS, which is associated with its other markers. No relationship was found between neutropenia and an increased risk of infections. TCZ-treated patients need careful clinical and laboratory monitoring, including consideration of a risk for neutropenia and subsequent individual treatment when this condition is identified.

Психоемоційний стан у молодих дорослих з ювенільним ідіопатичним артритом

Aim. To determine emotional state in adults with juvenile idiopathic arthritis (JIA) using questionnaires/ Material and Methods. Patients diagnosed with JIA (N=106) aged over 18 years were examined on the basis of the Alexander Municipal Clinical Hospital, Kyiv, Ukraine. The diagnosis was verified according to the classification criteria of the International League of the Association of Rheumatologists. The study did not include patients with organic pathology of the brain, encephalopathy associated with hypertension, diabetes mellitus, and chronic renal failure. Clinical examination included count of swollen and painful joints; count of joints requiring prosthetics in consequence of destructive changes; assessment of disease activity with regard to administered anti-rheumatic drugs; assessment of quality of life and health with the questionnaires SF-36, HAQ, PHQ-9; evaluation of anxiety by Beck and Hamilton (HAM-A) questionnaires; evaluation of depression by Beck questionnaire surveys and Chaban questionnaire on self-evaluation of anxiety and depression; and determining the social factors that appear to affect health. Results and Discussion. All patients were divided into two groups, depending on the need for prosthetic joints regardless of JIA clinical variants. Group I included 20 patients aged 24,20±8,7 years, with the need of one or more prosthetics joints as a result of JIA. The second group included 86 patients who did not require prosthetic joints, with mean age 23,18±6,18 years. In group I, a longer disease duration (p=0.025), more deformed joints (p<0.001), more frequent cervical spine damage (p=0.015), arthritis of hands joints (p=0.008), lesions of tendons (p=0.037), more systemic manifestations of JIA (p=0.003), higher ESR (p=0.001) and DAS 28 (p<0,0001) were found;  they also received more aggressive therapy, including longer course of glucocorticoids (GC) (81.74 months) than the patients in group II (15.34 months) (p<0.0001) and a higher cumulative dose of GC (p = 0.001). The patients' physical condition according to the SF-36 was 33,92±14,0 in  group I vs 43,74±13,62 in group II, indicating a lower level of physical health (p<0.001) and poorer functional status by HAQ (p=0.034). However, the patients' psychological health by the SF-36 did not differ in two groups (p=0.832), although the PHQ-9 questionnaire showed that the patients in group I revealed moderate severity depression (11,17±6,19) vs light ("subclinical") depression (6,4±6,02) in group II (p=0.019), which is also confirmed by the self-evaluation scale for depression, where a tendency towards depression was found in group I (9,0±6,39) compared to no signs of depression (4,5±3,98) in group II (p=0.018). According to the questionnaire on psychosomatic disorders, higher need for medical psychologist's consultation (8,5±6,35) was found in  group I (p=0.013) than in group II (4,08±3,56). However, in anxiety assessment, the difference was not detected by any questionnaires in both groups of patients, although the anxiety level was higher in group I. Conclusions. Patients with JIA with destructive changes in the joints have higher tendency towards psycho-emotional disorders that require medical consultations of a psychologist or a  psychosomatic medicine professional. Active and early treatment of JIA using modern methods, including biological therapy, allow to prevent destructive changes in the joints, that in its turn reduces psycho-emotional disorders in adult patients with JIA. Patients with aggressive destructive course of JIA need higher social adjustment, which causes a need to include medical psychologists in the team of doctors (along with rheumatologists, podiatrists, rehabilitation professionals, and ophthalmologists) who treat adults with JIA.&nbsp

Drug Compliance in Children with Juvenile Idiopathic Arthritis and Reasons for Poor Compliance

Children with chronic disorders are at risk for a higher medication non-adherence. Juvenile idiopathic arthritis (JIA) is a chronic childhood disorder where often medication non-adherence is an issue. The purpose of this study was to assess drug compliance of JIA patients,to find out the proportion of patients having poor drug compliance and to find out possible reasons of poor drug compliance. This was a retrospective study conducted in the Pediatric Rheumatology follow up clinic, Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. All JIA patients attending pediatric rheumatology follow up clinic during the study period was included. Data were collected using a structured questionnaire. Among the total 900 registered JIA cases, 116(12.9%) patients had poor compliance. Among 116 poor compliant patients, systemic onset JIA cases were the highest (34.5%), followed by enthesitis related arthritis (30.2%). Among the poor compliant patients, 6.9% patients had regular follow up and 93.1% had irregular follow up. Major reasons of poor compliance were financial crisis, lack of awareness and difficulty in transportation. Poor compliance to treatment of JIA in our setting was common. The most important reason for poor compliance was financial crisis.

Chitinase 3-like-1 is produced by human Th17 cells and correlates with the level of inflammation in juvenile idiopathic arthritis patients.

BackgroundCHI3L1 is a chitinase-like protein without enzymatic activity, produced by activated macrophages, chondrocytes, neutrophils. Recent studies on arthritis, asthma, and inflammatory bowel diseases suggest that chitinases are important in inflammatory processes and tissue remodeling, but their production by human T cells, has never been reported.MethodsA microarray analysis of gene expression profile was performed on Th17 and classic Th1 cell clones and CHI3L1 was found among the up-regulated genes on Th17 cells. Different types of helper T cell clones (TCCs) were then evaluated by Real Time PCR (RT-PCR) for CHI3L1 mRNA expression; protein expression was investigated in cell lysates by western blotting and in cultures supernatants by ELISA. ELISA was also used to measure CHI3L1 in the serum and in the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients.ResultsAt mRNA level CHI3L1 was highly expressed by Th17, Th17/Th1, non classic Th1 and even in Th17/Th2 cell clones, whereas it was virtually absent in CD161− classic Th1 and Th2 TCCs. CHI3L1 was also detected in cell culture supernatants of Th17 and Th17-derived cells but not of classic Th1. Moreover CHI3L1 was higher in the SF than in serum of JIA patients, and it positively correlated with the frequency of Th17 and non-classic Th1 cells in SF. CHI3L1 in SF also positively correlated with the C reactive protein (CRP) serum levels, and with the levels of some proinflammatory cytokines, such as IL-6 and p40, which is the common subunit of IL12 and IL23.ConclusionsHere we describe for the first time CHI3L1 production by T cells owing the Th17 family. Moreover the positive correlation found between the frequency of Th17 and Th17-derived cell subsets and CHI3L1 levels in SF of JIA patients, in agreement with the suggested role of these cells in inflammatory process, candidates CHI3L1 as a possible biological target in JIA treatment.

Immunosuppressive Activity of Abatacept on Circulating T Helper Lymphocytes from Juvenile Idiopathic Arthritis Patients

Background: Abatacept is used in the treatment of juvenile idiopathic arthritis (JIA) patients, but the activity of the drug on T helper cell function is not yet fully known. Methods: The ability of abatacept to affect cytokine production in vitro and the proliferative response to both recall antigens and polyclonal stimulation was firstly assessed in healthy donors. Then, 10 JIA patients who were due to start abatacept treatment were recruited and longitudinally evaluated during the first 90 days of therapy. Both their clinical response to the treatment and in vitro analysis aimed to assess the proliferative response to recall antigens and the proportions of circulating T helper subsets. Results: Abatacept reduced the proliferative response to recall antigens and the production of proinflammatory cytokines such as IFN-γ and TNF-α in healthy donors in vitro. It was also efficient in improving symptoms and reducing parameters of inflammation in JIA patients. Abatacept reduced the proliferative response to recall antigens, and this effect was significant soon after drug infusion (2 days). Regarding the proportions of circulating CD4+ T lymphocytes, only a reduction in the frequencies of circulating Treg cells was observed. Conclusions: Abatacept in vitro inhibits proliferation and cytokine production in healthy donors, and reduces parameters of inflammation in vivo in JIA patients. The reduction of the proliferative response to recall antigens induced by abatacept was evident only soon after drug administration, suggesting that its immunosuppressive activity is maintained only for a short time.

The risk of hospitalized infection following initiation of biologic agents versus methotrexate in the treatment of juvenile idiopathic arthritis.

BackgroundIn the present study, we compared the incidence of hospitalized infection among children with juvenile idiopathic arthritis (JIA) following initiation of treatment with biologic agents versus methotrexate (MTX).MethodsWe used national Medicaid claims data from 2000 through 2010 to create cohorts of children with JIA who were new users of tumor necrosis factor inhibitors (TNFi), anakinra, and MTX (without concurrent biologic agent use) as defined by a 6-month baseline period of nonuse. Because most anakinra users have systemic juvenile idiopathic arthritis (SJIA), we used claims to identify MTX users who likely had SJIA. Among TNFi users, concurrent MTX use was a time-varying covariate. The study outcome was a primary hospital discharge diagnosis of infection. We calculated adjusted hazard ratios (aHRs) to compare infection rates between biologic agents and MTX.ResultsWe identified 3075 new MTX users (160 with SJIA), 2713 new TNFi users, and 247 new anakinra users. There was no increased risk of infection associated with TNFi monotherapy versus MTX (aHR 1.19, 95 % CI 0.72–1.94) or with TNFi + MTX combination therapy versus MTX (aHR 1.23, 95 % CI 0.69–2.17). Baseline high-dose oral glucocorticoid use (≥10 mg/day of prednisone) was associated with infection (aHR 2.03 [95 % CI 1.21–3.39] versus no oral glucocorticoid). Anakinra was associated with infection versus MTX (aHR 3.53 95 % CI 1.83–6.82), but less so compared with MTX users with SJIA (aHR 2.69, 95 % CI 0.82–8.82).ConclusionsNeither TNFi monotherapy nor TNFi + MTX combination therapy was significantly associated with hospitalized infection compared with MTX. Anakinra was significantly associated with infection, but there was likely residual confounding by disease phenotype.

Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype.

The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how-through continuous dialogue between bench and bedside-immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL-1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin-18 are already used daily in clinic as markers for active sJIA. For non-sJIA subtypes, HLA-B27, antinuclear-antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA.

The many shades of enhancement: timing of post-gadolinium images strongly influences the scoring of juvenile idiopathic arthritis wrist involvement on MRI.

Potential long-term side effects of treatment for juvenile idiopathic arthritis are concerning. This has necessitated accurate tools, such as MRI, to monitor treatment response and allow for personalized therapy. To examine the extent to which timing of post-contrast MR images influences the scoring of inflammatory change in the wrist in children with juvenile idiopathic arthritis. We studied two sets of post-contrast 3-D gradient echo MRI series of the wrist in 34 children with juvenile idiopathic arthritis. These images were obtained immediately after administration of intravenous contrast material and again after approximately 10min. The dataset was drawn from a prospective multicenter project conducted 2006-2010. We assessed five wrist locations for synovial enhancement, effusion and overall inflammation. Examinations were scored by one radiologist in two sessions - the first was based on the early post-contrast images, and the later session, for which the previous findings were masked, was based on the later post-contrast images. Fifty-two of the 170 locations (30.6%) received a higher synovial enhancement score based on the late post-contrast images as compared to the early images. Sixty of the 170 (35%) locations received a higher total inflammation score. The mean scores of synovial enhancement and total inflammation were significantly higher when based on the late post-contrast images as compared to the early post-contrast images. An MRI-based scoring system for the presence and degree of synovitis should be based on a standardized MR-protocol with a fixed interval between intravenous contrast injection and post-contrast images.

Treatment prescribing patterns in patients with juvenile idiopathic arthritis (JIA): Analysis from the UK Childhood Arthritis Prospective Study (CAPS).

ObjectiveInitial treatment of juvenile idiopathic arthritis (JIA) is largely based on the extent of joint involvement, disease severity and ILAR category. The licensing of biologic therapies for JIA has expanded treatment options.The aims of the study are (1) to describe treatment prescribing patterns in JIA over the first 3 years following first presentation to paediatric rheumatology and (2) to determine whether patterns of treatment have changed as biologics have become more widely available.MethodsChildren with at least 3 years of follow-up within the Childhood Arthritis Prospective Study (CAPS) were included.For analysis, children were placed into one of five groups according to their initial presentation to paediatric rheumatology: oligoarthritis (oJIA), polyarthritis (pJIA), systemic (sJIA), enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Treatment patterns over 3 years were described.ResultsOf 1051 children, 58% received synthetic disease-modifying anti-rheumatic drugs (sDMARD) and 20% received biologics over the 3 years. Use of sDMARDs and biologics was higher in more severe disease presentations (sJIA and pJIA); however, 35% and 10% who presented with oJIA were also treated with sDMARDs and biologics, respectively. The number of children receiving sDMARD after 2006 was higher (p = 0.02); however, there was no difference in biologic prescribing before and after 2006 (p = 0.4).ConclusionsA high proportion of children presenting with JIA received sDMARDs plus/minus biologics during 3 years of follow-up. This was most common for patients with severe JIA but was also prescribed for patients with oligoarticular disease, despite the lack of evidence for effectiveness in this category.

Contemporary management of TMJ involvement in JIA patients and its orofacial consequences.

Juvenile idiopathic arthritis is the most common chronic rheumatic condition during childhood. Temporomandibular joint arthritis is frequently asymptomatic. When it takes place during childhood, it may affect condylar growth; therefore, these children are at risk of unfavorable long-term outcomes from the associated joint damage. The etiology is not completely understood, but it is considered as multifactorial with both genetic and environmental factors involved.The standardized examination and imaging protocols serve important purpose to diagnose temporomandibular joint (TMJ) arthritis not only to establish an early interventional strategy but also to assess craniofacial growth and the progression of signs and symptoms in those patients. Although the treatment of juvenile idiopathic arthritis (JIA) has changed dramatically over the last decades due to new therapeutic options, TMJ arthritis still can develop during the course of the disease. In clinical experience, TMJs appear to respond less well to the standard of care used to treat other joints. More individualized approach to the patient’s treatment serves as the main goal of personalized medicine. It could be achieved by adopting new methods of medical imaging such as conebeam computer tomography as well as developing reliable biomarkers which may assist with predicting disease type, course, or severity and predicting response to medication.This article provides an overview of current information on orofacial complications in JIA and its management. Based on information provided in this review, more precise diagnosis, proper tools for recognizing people at risk, and more efficient treatment approaches could be implemented. This may lead to more personalized treatment management strategies of TMJ complications of JIA patients.

Monitoring of Epstein–Barr virus load and killer T cells in patients with juvenile idiopathic arthritis treated with methotrexate or tocilizumab

Objectives: Methotrexate (MTX) is used for the treatment of polyarticular juvenile idiopathic arthritis (JIA), and an anti-interleukin-6 receptor monoclonal antibody (tocilizumab: TCZ) is also used and added for the treatment of intractable JIA. It has been reported that MTX might induce Epstein–Barr virus (EBV)-associated lymphoma, but the discussion about the effect of MTX and/or TCZ against reactivation of EBV in pediatric patients has been incomplete.Methods: The EBV loads in four polyarticular JIA and three systemic arthritis JIA patients treated with MTX and/or TCZ, and the percentage of EBV-specific killer T cells (EBV-CTLs) in some patients were prospectively monitored.Results: No patients had EBV-associated symptoms during the observation period. EBV loads in all patients were not significantly increased, and the levels of EBV loads were the same as EBV-seropositive healthy children following the administration of MTX and/or TCZ. EBV-CTLs were detectable during the observation period, but some patients had slightly low levels of EBV-CTLs.Conclusion: Treatment with MTX and/or TCZ did not severely affect EBV load and prevent induction of EBV-CTLs in JIA patients.

Nicotinamide Phosphoribosyltransferase Attenuates Methotrexate Response in Juvenile Idiopathic Arthritis and In Vitro

Variability in response to methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) remains unpredictable and poorly understood. Based on previous studies implicating an interaction between nicotinamide phosphoribosyltransferase (NAMPT) expression and MTX therapy in inflammatory arthritis, we hypothesized that increased NAMPT expression would be associated with reduced therapeutic response to MTX in patients with JIA. A significant association was found between increased plasma concentrations of NAMPT and reduced therapeutic response in patients with JIA treated with MTX. Inhibition of NAMPT in cell culture by either siRNA‐based gene silencing or pharmacological inhibition with FK‐866 was found to result in a fourfold increase in the pharmacological activity of MTX. Collectively, these findings provide evidence that NAMPT inhibits the pharmacological activity of MTX and may represent a predictive biomarker of response, as well as a therapeutic target, in the treatment of JIA with MTX.

Evaluation of efficacy and safety of TNF-α antagonists for treatment of juvenile idiopathic arthritis

Evaluation of efficacy and safety of TNF-α antagonists for treatment of juvenile idiopathic arthritis

Treatment of juvenile idiopathic arthritis combined with atopy by using Chinese traditional and Western medicine

Objective To confirm the therapeutic effect of traditional Chinese medicine (TCM) on juvenile idiopathic arthritis (JIA). Methods Patients who were newly diagnosed as JIA between December 2012 and December 2013 in Renji Hospital, School of Medicine, Shanghai Jiaotong University were enrolled in this study.All patients were divided into 3 groups. Group one was briefed as atopy-TCM group, which had 14 patients with both JIA and atopy, and was treated with TCM integrated medicine; group two was briefed as atopy-Western medicine group, which had 15 patients with both JIA and atopy, and was treated with Western medicine alone; and group three was briefed as non-atopy-Western medicine group, which had 36 patients with JIA, and was treated by Western medicine alone. And 25 healthy children were enrolled as healthy control group. First the effect of atopy on JIA patients who received Western medicine were compared, and then the effects of TCM on patients with JIA and atopy. The clinical effect was evaluated by using ACR 30 method which was made by American College of Rheumatology and the serum level of interleukin(IL)-1β, IL-6, IL-17 were studied by way of enzyme-linked immunosorbent assay. Results All the patients were followed up for at least 6 months among whom 55 completed the follow-up, and 10 withdrew. (1)When enrolled, atopy-TCM group and atopy-Western medicine group had higher levels of erythrocyte sediment rates (ESR) than non-atopy-Western medicine group respectively [(33.89±20.11) mm/1 h vs (17.35±10.71) mm/1 h, t=2.13, P 0.05). Atopy-TCM group had 4 patients (33.3%) achieving ACR30, 7 patients (58.3%) achieving ACR50 with an obvious difference from atopy-Western medicine group(u=40.5, P<0.05). (4) After 6 months′ follow-up, atopy-Western group had obviously higher level of IL-17 than that of atopy-TCM group [(0.75±0.33)ng/L vs (0.37±0.44) ng/L, t=2.43, P<0.05]. Conclusions Atopy will obviously improve inflammation cytokines level of patients with JIA.And TCM-integrated therapy can get better effects through suppression of cytokine level, especially IL-17. Key words: Juvenile idiopathic arthritis; Atopy; Synergistic therapy of Chinese traditional medicine and Western medicine; Cytokine

The lived experience of juvenile idiopathic arthritis in young people receiving etanercept.

BackgroundThis study explores young people’s daily experiences of living with Juvenile Idiopathic Arthritis (JIA) and their thoughts, beliefs and feelings related to the biological drug Etanercept, prescribed as part of their treatment.MethodsAn Interpretive Phenomenological approach was used to allow in-depth examinations of the young people’s personal accounts of their lived experiences. Data were obtained from 6 young people between the ages of 10–13 years, from one tertiary institution’s Paediatric Rheumatology department using audio-taped open-ended interviews.ResultsThe transcripts yielded seven thousand words of data and two hundred significant statements, which were reduced to five themes; 1) Who understands me, 2) Medicines and injections, 3) Challenges of schooling and friendships, 4) Being different, and 5) Exclusion from sports. There were marked similarities between the young people’s statements; however, there were also some striking differences. The theme ‘Who understands me’ yielded the biggest section of data, but also produced the biggest disparity between the young people. Two patients were very clear that they thought everyone ‘understands’, whilst two other patients held the belief that ‘no one understood’. This paper explores these statements in further detail.ConclusionsThe findings from this study can give healthcare professionals novel insight into the likely reactions to-treatment for JIA and, through this, enable them to offer improved support, education and early intervention before these issues become a concern. This study also provides insight into the emotional resilience of young people with JIA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-016-0083-7) contains supplementary material, which is available to authorized users.

The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation.

Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and a limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated. To assess the clinical effectiveness and cost-effectiveness of four biologic DMARDs [etanercept (Enbrel(®), Pfizer), abatacept (Orencia(®), Bristol-Myers Squibb), adalimumab (Humira(®), AbbVie) and tocilizumab (RoActemra(®), Roche) - with or without methotrexate where indicated] for the treatment of JIA (systemic or oligoarticular JIA are excluded). Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and the Database of Abstracts of Reviews of Effects were searched for published studies from inception to May 2015 for English-language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence. Systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision-analytic model was developed to compare the estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base-case time horizon was 30 years and the model took a NHS perspective, with costs and benefits discounted at 3.5%. Four placebo-controlled randomised controlled trials (RCTs) met the inclusion criteria for the clinical effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi)-30 response to open-label lead-in treatment in order to be randomised. An exploratory adjusted indirect comparison suggests that the four biologic DMARDs are similar, with fewer disease flares and greater proportions of ACR Pedi-50 and -70 responses among participants randomised to continued biologic DMARDs. However, confidence intervals were wide, the number of trials was low and there was clinical heterogeneity between trials. Open-label extensions of the trials showed that, generally, ACR responses remained constant or even increased after the double-blind phase. The proportions of adverse events and serious adverse events were generally similar between the treatment and placebo groups. Four economic evaluations of biologic DMARDs for patients with JIA were identified but all had limitations. Two quality-of-life studies were included, one of which informed the cost-utility model. The incremental cost-effectiveness ratios (ICERs) for adalimumab, etanercept and tocilizumab versus methotrexate were £38,127, £32,526 and £38,656 per quality-adjusted life year (QALY), respectively. The ICER for abatacept versus methotrexate as a second-line biologic was £39,536 per QALY. The model does not incorporate the natural history of JIA in terms of long-term disease progression, as the current evidence is limited. There are no head-to-head trials of biologic DMARDs, and clinical evidence for specific JIA subtypes is limited. Biologic DMARDs are superior to placebo (with methotrexate where permitted) in children with (predominantly) polyarticular course JIA who have had an insufficient response to previous treatment. Randomised comparisons of biologic DMARDs with long-term efficacy and safety follow-up are needed to establish comparative effectiveness. RCTs for JIA subtypes for which evidence is lacking are also required. This study is registered as PROSPERO CRD42015016459. The National Institute for Health Research Health Technology Assessment programme.

Current therapy of polyarticular forms of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in infancy and childhood. Approximately 20 % of patients with JIA suffer from the polyarticular form of the disease, which causes a substantial disease burden and long-term sequelae. Therapeutic approaches have used steroids and conventional disease modifying antirheumatic drugs (DMARD) but over the last decade new drugs have become available for the treatment of JIA, in particular biologic DMARD. This article summarizes the current therapy options for polyarticular JIA.

Difficult-To-Treat Juvenile Idiopathic Arthritis: Current and Future Options

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood and is usually treated with non-steroidal anti-inflammatory drugs or disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate or sulfasalazine. However, not all patients respond to these treatments, and toxicities may limit long-term use or diminish compliance. With advances in pharmacotherapy and the development of new therapeutic agents, there have been improvements in treatment of both systemic and non-systemic JIA, particularly with biologic agents such as anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-1, and anti-IL6. Anti-cell therapies, such as co-stimulator blockers or anti-CD20, small molecules, and biosimilars represent new areas of interest, and, while many are not yet currently commercially available for use in children, preliminary studies appear to be promising. In the present article, the authors review therapeutic strategies for the different JIA subtypes, mainly according to guidelines and recommendations. Newer and possible future treatments for arthritis, already approved in adults but currently under study in children, are also discussed. Drugs currently in development plans for rheumatoid arthritis, which hopefully will also be useful for JIA patients in the future, are also mentioned in this paper.

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis.

BackgroundMethotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX.MethodsConsecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics.Results196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation.ConclusionMutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-016-0071-y) contains supplementary material, which is available to authorized users.

Tocilizumab for treating juvenile idiopathic arthritis

ABSTRACTIntroduction: Based on the known relevance of IL-6 in juvenile idiopathic arthritis (JIA) pathophysiology, tocilizumab has been investigated and approved for use in the treatment of systemic and polyarticular JIA. Tocilizumab is a humanized monoclonal antibody that inhibits signaling through both membrane bound and soluble IL-6R.Areas Covered: The purpose of this article is to summarize the available clinical data on the efficacy and safety of tocilizumab in JIA and to provide our opinion on the place of tocilizumab in current treatment regimens. A literature search for all relevant clinical trials and studies with regards to tocilizumab, JIA and IL-6 was performed through PubMed, in addition to a review of recent conference abstracts.Expert Opinion: Tocilizumab has an important and evolving role in controlling disease activity in patients with JIA. It has proven useful even in patients whose JIA has previously been refractory to other biologic disease modifying anti-rheumatic drugs (DMARDs) and also appears quite effective as monotherapy. Tocilizumab is relatively well tolerated amongst JIA patients, with systemic JIA patients experiencing more serious adverse events overall.