Current management of juvenile idiopathic arthritis

The goal of juvenile idiopathic arthritis (JIA) treatment is to achieve remission of disease. The absence of a full understanding of the disease pathogenesis for JIA hinders the development of truly effective treatment approaches. Further, the lack of clear knowledge regarding the mechanisms of action of rheumatologic medications and the existence of few randomized controlled trials leaves clinicians with very little evidence upon which to base decisions regarding the best timing, dosages or combinations of medications to be used for fully effective treatment of JIA. There is now a shift in treatment focus from that of chasing failure (gradual add-on approach to the use of medications) to one of early aggressive combination treatment. This chapter will discuss the current approaches to medical management of JIA and the medications currently available for use. JIA treatment is a vast, rich area in need of research.     

Proposal for juvenile idiopathic arthritis guidance on diagnosis and treatment for primary care pediatricians and nonpediatric rheumatologists (2007)

The Pediatric Standing Committee of the Japan College of Rheumatology, in collaboration with the Pediatric Rheumatology Association of Japan, produced guidance on the diagnosis and treatment for juvenile idiopathic arthritis (JIA) for primary care pediatricians and nonpediatric rheumatologists in Japan. This guidance aims to achieve early diagnosis and treatment for JIA, which is similar to adult rheumatoid arthritis (RA), based on recent progress in rheumatology, and to resolve arthritis at an early stage and improve the prognosis of the affected inflammatory joints. It describes clinical symptoms and laboratory findings characteristic to JIA in order to make early diagnosis and treatment possible, and also serves as a triage of patients who are refractory to the treatment protocol described here and need more aggressive interventions. However, because JIA is a complicated and heterogeneous disease and the optimal treatment approach can be diverse and different patient by patient, these guidelines should be viewed as recommendations and be individualized according to the condition of the patient. Finally, we hope that this guidance will trigger exploration for further information by referring to the textbooks and literature listed at the end of these guidelines. All authors are members of the Pediatric Standing Committee of the Japan College of Rheumatology.     

Proposal for juvenile idiopathic arthritis guidance on diagnosis and treatment for primary care pediatricians and nonpediatric rheumatologists (2007)

Abstract

The Pediatric Standing Committee of the Japan College of Rheumatology, in collaboration with the Pediatric Rheumatology Association of Japan, produced guidance on the diagnosis and treatment for juvenile idiopathic arthritis (JIA) for primary care pediatricians and nonpediatric rheumatologists in Japan. This guidance aims to achieve early diagnosis and treatment for JIA, which is similar to adult rheumatoid arthritis (RA), based on recent progress in rheumatology, and to resolve arthritis at an early stage and improve the prognosis of the affected inflammatory joints. It describes clinical symptoms and laboratory findings characteristic to JIA in order to make early diagnosis and treatment possible, and also serves as a triage of patients who are refractory to the treatment protocol described here and need more aggressive interventions. However, because JIA is a complicated and heterogeneous disease and the optimal treatment approach can be diverse and different patient by patient, these guidelines should be viewed as recommendations and be individualized according to the condition of the patient. Finally, we hope that this guidance will trigger exploration for further information by referring to the textbooks and literature listed at the end of these guidelines.     

Juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatologic disease in childhood, which represents a nonhomogeneous group of disorders that share the clinical manifestation of arthritis lasting at least 6 wk under the age of 16. The exact diagnosis requires exclusion of other diseases that cause arthritis. The exact etiopathogenesis of JIA is still unknown. The interactions between genetic factors, environmental exposures and immune mechanisms are thought to contribute to pathogenesis of the disease. The “International League Against Rheumatism” classification divides JIA into 7 subtypes: oligoarticular JIA, rheumatoid factor (RF) positive polyarticular JIA, RF negative polyarticular JIA, systemic-onset JIA, enthesitis-related arthritis, juvenile psoriatic arthritis and undifferentiated JIA. Each subgroup of JIA is characterized by a different mode of presentation, disease course and outcome. The improvements in treatment of JIA in the last 2 decades, such as the early introduction of intraarticular corticosteroids, methotrexate and biologic agents, have dramatically upgraded the prognosis of the disease. If untreated, JIA may cause devastating results, such as disability from joint destruction, growth retardation, blindness from chronic iridocyclitis, and even multiple organ failure and death in systemic-onset JIA. The aim of treatment is the induction of remission and control the disease activity to minimize the pain and loss of function, and to maximize quality of life. JIA is a disease having a chronic course, which involves active and inactive cycles over the course of years. Recent studies showed that nearly half of the patients with JIA enter adulthood with their ongoing active disease. This review elucidates how recent advances have impacted diagnosis, pathogenesis and current treatment.     

Update on the medical treatment of juvenile idiopathic arthritis

Many exciting developments in the treatment of juvenile idiopathic arthritis (JIA) have emerged recently, including new tools to assess the results of clinical trials (eg, the definition of remission and a radiologic scoring tool). New controlled studies examined the equivalence of meloxicam to naproxen, the efficacy of leflunomide but the superiority of methotrexate, and the use of infliximab in polyarthritis JIA. Initial studies have shown the potential of anti-interleukin (IL)-1 and anti-IL-6 receptor antibody therapy for systemic JIA. Corticosteroid-sparing medications including the use of "biologic modifiers" for JIA-associated uveitis have been described. Evidence-based guidelines for the main subtypes of JIA have been published. However, good evidence on the treatment of several disease subtypes is still lacking. Studies of new medications and the use of combination therapy, including aggressive induction therapy early in the disease course, are necessary to continue improving the outcome of JIA patients.     

Growth abnormalities in children and adolescents with juvenile idiopathic arthritis

In patients with juvenile idiopathic arthritis (JIA) growth impairment and variance in body composition are well-known long-term complications. In the active phases of the disease, particular patients with systemic and polyarticular JIA reveal growth impairment. Some experience “catch-up” growth following reduction in disease activity and lower glucocorticoid doses. Although new therapeutic options are available, there are still 10–20 % of patients with severe forms of the disease who show continuous growth disturbance. Only few studies have specifically addressed body composition in JIA. Bone mass deficits in part could be related to the deficits of muscle mass. Study data on growth hormone treatment in short children with JIA are promising in respect of growth development, final height and body composition. The major goal for physicians is optimal disease control while maintaining normal growth and body composition. Early recognition of patients who develop prolonged growth and body composition disturbances is important as these abnormalities contribute to long-term morbidity and need to be addressed both diagnostically and therapeutically.     

Rheumatoid factors and anticyclic citrullinated peptide antibodies in pediatric rheumatology

Juvenile idiopathic arthritis (JIA) is a heterogenous childhood disease without reliable biomarkers for monitoring disease progression. Immunoglobulin (Ig) M rheumatoid factor (RF) is used to define a subset of JIA patients, but its significance in JIA is dependent on the method of measurement. In addition to IgM RF, IgA RF has been implicated in determining disease severity in JIA, including functional disability and joint damage. Anticyclic citrullinated peptide (anti-CCP) antibodies have been a valuable diagnostic tool in rheumatoid arthritis, with varied results in their significance in JIA patients. Recent studies have demonstrated the possible usefulness of isotypes of anti-CCP antibodies in monitoring JIA patients to determine disease outcome. Overall, RF isotypes and anti-CCP isotypic antibodies have demonstrated increasing importance in the evaluation of JIA patients to determine which patients may have more aggressive or severe disease and to aid in possible treatment plans to prevent joint damage and disability.     

Biologic therapies in juvenile idiopathic arthritis: why and for whom?

With greater understanding of pathophysiological, genetic and environmental influences on juvenile arthritis, there is an opportunity to develop new targets for therapy and greater control of disease. Early, aggressive control of arthritis is essential in order to prevent long-term disability. For those children that are resistant to standard therapy, new and exciting alternative medications are emerging. However, continued research is needed to gain a greater understanding of immunological and genetic profiles of the disease. Pharmaco-vigilance is essential to establish efficacy and side effect profiles. Physiotherapy, occupational therapy, nursing issues, and psychology remain integral to the management of JIA, along with liaison with ophthalmology, orthopaedic and dental colleagues. This article reviews the current biologic treatment options available for children with arthritis and the evidence base that supports their use.     

Current Developments in the Use of Biomarkers for Juvenile Idiopathic Arthritis

Use of biomarkers in clinical practice has proved extremely valuable and is a rapidly expanding field. However, despite the huge potential of biomarkers, for juvenile idiopathic arthritis (JIA) there are currently no validated paediatric biomarkers available to help with setting up a more tailored approach on which drug choice could be based, to achieve remission early in the course of disease. Early remission reduces burden of disease, limits side effects from toxic and unnecessary medication, and, most importantly, enhances quality of life. Several studies have suggested promising biomarkers: these may be a protein, cellular component, mRNA, or genetic component, for example a single nucleotide polymorphism (SNP). Here we describe recent developments in the use of biomarkers for JIA and their potential to assist in management of disease by predicting disease phenotype, severity, progression, and response to treatment, and determining when patients have reached stable remission and can safely discontinue treatment.     

Long-term outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis

OBJECTIVE: To describe the long-term outcome and determine predictors of severity among patients with oligoarticular-onset juvenile idiopathic arthritis (JIA). METHODS: In a longitudinal study, 207 patients with oligoarticular-onset JIA who were referred between 1988 and 1998 were evaluated. At disease onset, selected clinical and laboratory data were collected as independent variables. A polyarticular disease course, joint erosion, uveitis, and remission were assessed as dependent variables. Longitudinal analyses were performed with the Kaplan-Meier method, and multivariate analysis with the Cox model. RESULTS: After 6 years of followup, the probability of a polyarticular course of disease was 50%, joint erosion was 35%, uveitis was 30%, and remission was 23% in these patients. Joint erosion was strongly associated with a polyarticular course. A high erythrocyte sedimentation rate (ESR) as well as involvement of more than 1 joint or involvement of an upper limb at disease onset were predictors of disease extension. A high ESR was also a strong predictor of a destructive course, and a family history of psoriasis was predictive of uveitis occurrence. No predictive factor for remission could be identified. CONCLUSION: Oligoarticular-onset JIA is a severe disease with frequent complications. Factors predictive of severity in oligoarticular-onset JIA were identified. This could allow early identification of high-risk patient subgroups, warranting a more aggressive therapeutic approach.     

Appropriate and effective management of rheumatoid arthritis

Early referral (at <3 months) and early DMARD treatment enable the course of RA to be changed. Once the disease has become aggressive it is much harder to treat and improvements will not be as great as they would have been with earlier treatment. The latest strategies and treatments enable remission to be achieved in many more patients than formerly.     

Correlation between juvenile idiopathic arthritis activity and damage measures in early, advanced, and longstanding disease

OBJECTIVE: To compare the correlation between juvenile idiopathic arthritis (JIA) measures of disease activity and damage in patients with early and late disease. METHODS: Three cohorts of patients with JIA disease duration < or =1 year (early disease, n = 70), 5-9.9 years (advanced disease, n = 114), and > or =10 years (longstanding disease, n = 39) were studied. Measures included physician's global assessment of overall disease activity (MD global), parent's global assessment of the child's well-being (parent global) and pain (parent pain), joint counts, Childhood Health Assessment Questionnaire (CHAQ), erythrocyte sedimentation rate, C-reactive protein level, and Poznanski score of radiographic damage. RESULTS: In all cohorts, the MD global assessment was generally well correlated with the other variables, except the Poznanski score. The parent global assessment was correlated strongly with the parent pain assessment and moderately with the CHAQ irrespective of disease duration. Correlations between the CHAQ and the joint counts were low in early disease, moderate in advanced disease, and high to moderate in longstanding disease. Correlation between the CHAQ and the Poznanski score was low in early and advanced disease and moderate in longstanding disease. The Poznanski score was highly correlated with the number of joints with restricted motion in longstanding disease. CONCLUSION: We found important differences in the level of correlation between JIA measures of activity and damage in patients with different lengths of disease duration. These findings have important implications for clinical trials because they indicate that the responsiveness of some variables and their correlation with other variables change as disease duration changes.     

Assessment of the clinical significance of gelatinase activity in patients with juvenile idiopathic arthritis using quantitative protein substrate zymography

OBJECTIVE: To measure gelatinase activities in paired synovial fluid (SF) and serum of patients with juvenile idiopathic arthritis (JIA), and to assess how these activities relate to clinical and laboratory measures of disease activity. METHODS: A quantitative protein substrate zymography method was adapted and validated for use with serum and SF. Bands of activity were measured by densitometry and correlated with standard laboratory indicators of inflammation: erythrocyte sedimentation rate and platelet count. RESULTS: Gelatinase activity was found consistently in patients with JIA, with reproducible, quantified bands of activity corresponding to pro-matrix metalloproteinase-9 (pro-MMP-9), including the neutrophil associated lipocalin complex, and pro- and active forms of MMP-2. Both active MMP-2 and pro-MMP-9 were higher in JIA serum than in controls, though no differences were seen between patients grouped according to age, disease duration, or JIA subtype. However, SF MMP-9 correlated significantly with the laboratory indicators of inflammation, as did the relative level of active MMP-2. CONCLUSIONS: Both MMP-2 and MMP-9 gelatinolytic activities are raised during active JIA and associated with inflammatory activity regardless of age and disease duration, supporting a role for MMPs in the breakdown of joint components from early in disease. These MMPs may be specific markers of active joint destruction linked to inflammatory JIA, MMP-9 as a product of infiltrating cells, and the activation of MMP-2 produced within the joint.     

Imaging in paediatric rheumatology: Is it time for imaging?

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritides characterized by chronic synovial inflammation that can lead to structural damage. The main objective of JIA therapies is to induce disease control to avoid disability in childhood. The advances in therapeutic effectiveness have created a need to search for imaging tools that describe more precisely disease activity in children with JIA. Musculoskeletal ultrasound and magnetic resonance imaging have demonstrated to be more sensitive than clinical examination in early detection of synovitis. These modalities can detect both inflammatory and destructive changes. The unique characteristics of the growing skeleton and a scarce validation of imaging in children result in important challenges in evaluating paediatric population. This review describes indications and limitations of these imaging techniques and suggests some advices for a rational use in the management of JIA in clinical practice.     

Laryngeal involvement in juvenile idiopathic arthritis patients

Juvenile idiopathic arthritis (JIA) is an autoimmune diseases characterized by chronic arthritis and systemic manifestations. Autoimmune diseases can affect the upper airways including the larynx. The aim of this study was to investigate laryngeal involvement in JIA patients and its possible association with JIA disease parameters. Fifty consecutive JIA patients were screened for laryngeal abnormalities using flexible fiberoptic laryngoscope and laryngeal computerized tomography. Laryngeal abnormalities were detected in nine (18%) of our cases, with cricoarytenoiditis in six cases (12%) and a rheumatoid nodule in the pyriform fossa in only one case (2%). Diffuse congestion and edema of the posterior part of the larynx with normal vocal cord mobility was detected in two cases (4%). In our study, laryngeal abnormalities were significantly higher in patients with polyarticular seropositive disease subtype and also were significantly higher in patients with longer disease duration, higher disease activity scores, and those with erosive disease. JIA may affect the larynx. Laryngeal involvement in JIA patients is more in polyarticular seropositive cases. JIA patients have to be subjected to thorough otolaryngologic examination for early diagnosis and prompt management.     

Remission in Juvenile Idiopathic Arthritis: Current Facts

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthritic disease affecting children. Despite the availability of potent disease-modifying antirheumatic medications, most children still experience a chronic course with long periods of active disease. Goals of treatment should include achievement of disease remission with optimal physical functioning that allows children to lead normal lives with no structural joint damage. The term remission implies a complete lack of disease activity. This article focuses on recently developed preliminary criteria for inactive disease and remission in JIA. Recent studies using these new definitions demonstrate only modest rates of achievement of remission favoring children with persistent oligoarticular JIA. Children with rheumatoid factor-positive polyarticular JIA are least likely to achieve remission. Therapeutic strategies to achieve remission are also discussed.     

Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis

Objective

To explore biologic correlates to age at onset in patients with juvenile idiopathic arthritis (JIA) using peripheral blood mononuclear cell (PBMC) gene expression analysis.

Methods

PBMCs were isolated from 56 healthy controls and 104 patients with recent‐onset JIA (39 with persistent oligoarticular JIA, 45 with rheumatoid factor–negative polyarticular JIA, and 20 with systemic JIA). RNA was amplified and labeled using NuGEN Ovation, and gene expression was assessed with Affymetrix HG‐U133 Plus 2.0 GeneChips.

Results

A total of 832 probe sets revealed gene expression differences (false discovery rate 5%) in PBMCs from children with oligoarticular JIA whose disease began before age 6 years (early‐onset disease) compared with those whose disease began at or after age 6 years (late‐onset disease). In patients with early‐onset disease, there was greater expression of genes related to B cells and less expression of genes related to cells of the myeloid lineage. Support vector machine analyses identified samples from patients with early‐ or late‐onset oligoarticular JIA (with 97% accuracy) or from patients with early‐ or late‐onset polyarticular JIA (with 89% accuracy), but not from patients with systemic JIA or healthy controls. Principal components analysis showed that age at onset was the major classifier of samples from patients with oligoarticular JIA and patients with polyarticular JIA.

Conclusion

PBMC gene expression analysis reveals biologic differences between patients with early‐and late‐onset JIA, independent of classification based on the number of joints involved. These data suggest that age at onset may be an important parameter to consider in JIA classification. Furthermore, pathologic mechanisms may vary with age at onset, and understanding these processes may lead to improved treatment of JIA.

     

Biological therapy with TNF-inhibitors in pediatric rheumatology. Review of the literature and personal experience

The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some autoinflammatory diseases). TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established.     

Evaluation of the association between Hispanic ethnicity and disease activity and severity in a large cohort of patients with juvenile idiopathic arthritis

To examine the association between ethnicity and disease activity in patients with juvenile idiopathic arthritis (JIA), and to determine the association of ethnicity with disease severity and disability in this population. CARRAnet, a US database containing information (collected between May 2010 and June 2011) on almost 3,000 subjects with JIA, was used. Demographic variables were compared between Hispanic patients and non-Hispanic patients. Mann–Whitney and chi-square tests were used to compare indicators of disease activity, as well as imaging evidence of joint damage, and Childhood Health Assessment Questionnaire (CHAQ) scores between ethnicities. Two linear regression models were used to determine the association of ethnicity with number of active joints in JIA, and the association between ethnicity and disability (CHAQ scores). A total of 2,704 patients with JIA (277 Hispanic; 2,427 non-Hispanic) were included. Income and health insurance coverage were higher in non-Hispanics. RF-positive polyarticular JIA, positive RF and anti-CCP, as well as use of systemic steroids were more frequent in Hispanics. Imaging evidence of joint damage was present in 32 % of the Hispanic patients compared to 24 % of the non-Hispanic patients (p = 0.008). In multivariate linear regression analyses, the number of active joints was significantly higher in Hispanics than in non-Hispanics (p = 0.03), as well as CHAQ scores (p = 0.003), after adjusting for confounders. Hispanic patients with JIA had higher disease activity than non-Hispanic patients, as well as higher disease severity and disability. Since ethnicity influences disease activity, severity, and disability, different management and treatment plans should be planned accordingly.     

Temporomandibular joint arthritis in juvenile idiopathic arthritis: prevalence, clinical and radiological signs, and relation to dentofacial morphology

OBJECTIVE: To perform a prospective, comprehensive, clinical, and radiological evaluation of temporomandibular joint (TMJ) involvement and its influence on craniofacial growth, in a cohort of patients with juvenile idiopathic arthritis (JIA), representing all JIA subtypes. METHODS: Clinical rheumatologic and orthodontic evaluations were performed in 100 patients with JIA [12 systemic arthritis, 24 rheumatoid factor (RF)-negative polyarthritis, 1 RF-positive polyarthritis, 39 oligoarthritis, 22 enthesitis-related arthritis, 2 psoriatic arthritis]. An orthopantomogram and lateral cephalogram were performed in 46 patients. The prevalence of TMJ arthritis was studied in relation to JIA subtype and disease characteristics; cephalometric measurements were compared to those from age- and sex-matched healthy controls. RESULTS: Whereas 55% of patients with JIA had at least one symptom/sign of TMJ arthritis, 78% of the radiographed group exhibited condylar lesions. The presence of condylar damage was not related to clinical orthodontic findings or to JIA subtype, disease activity, severity, or duration. Patients with JIA exhibited larger mandibular plane and A-nasion-B angles, larger total anterior facial height, smaller interincisal and sella-nasion-B angles, and shorter mandibular ramus lengths than their age- and sex-matched controls. Craniofacial alterations were clearly related to the presence of condylar damage, even when present at a minimal degree. CONCLUSION: Our data show that TMJ condylar damage occurs very frequently in JIA, and irrespective of JIA subtype; condylar lesions can present early, progress insidiously, and -- even at a minimal degree -- can severely alter the craniofacial profile. We propose that the followup of patients with JIA should include early and regular evaluation by an orthodontist, supplemented with radiographic TMJ imaging.