Juvenile Idiopathic Arthritis (JIA) is a condition which affects children, causing stiff, inflamed, and painful joints. There are many different classifications of JIA, which include systemic arthritis (in which the immune system attacks the joints), polyarthritis (which affects more than 4 joints for at least 6 months), oligoarthritis (which affects fewer than 5 joints for at least 6 months), enthesitis-related arthritis (which affects the leg and back joints), and psoriatic arthritis (which affects many joints, as well as causing skin rash and nail changes)1. Epidemiologically, it is less common in African American and Asian populations, and the female-to-male ratio is between 2:1 and 3:1. JIA’s peak incidence is in children one to three years old, but varies depending on patients’ gender, and classification of the disease. The pathogenesis is ambiguous, but similar to other autoimmune disorders, and contributing factors include genetic factors, immune mechanisms and environmental exposures2.
There is lack of standard diagnostic criteria for JIA, and may be difficult to diagnose because children do not always complain of pain when it begins. Children with JIA also usually have a negative rheumatoid factor blood test, therefore diagnosis is dependent on physical findings, and the exclusion of other diagnoses3. In patients with JIA, osteoclasts are activated when enzymes are released by inflammatory cells within the synovial fluid, which produce cytokines and cause bone demineralization and bone erosions2. This manifests as joint swelling, resulting from the accumulation of synovial fluid and synovial thickening. This tumor-like swelling causes stretching of ligaments and tendons, further causing joint deformities. Other symptoms include limping, reduced activity level, and fever3.
The goals of therapy are to minimize symptoms, prevent irreversible joint damage and maintain function. Injectable and oral steroids may be used, however oral steroids should only be used for a short time at the lowest dose possible, because they can be associated with serious and long-term side effects. Disease modifying drugs (DMARDs), such as methotrexate (Rheumatrex), leflunamide (Arava), etanercept (Enbrel), infliximab (remicade), and rituximab (Rituxan) are used as second-line therapy when JIA involves multiple joints, or is unresponsive to injectable steroids3. Another treatment being studied is abatacept (Orencia). Abatacept is a selective T-cell costimulation modulator, and is being investigated in children with JIA who have failed previous treatments2.
Activated T-lymphocytes are found in the synovial fluid of JIA patients, and the mechanism of action of abatacept is inhibiting their activation by binding to CD80 and CD86 on antigen presenting cells (APC), blocking the interaction between APC and T-cells2.
A double-blind, randomized, placebo-controlled withdrawal trial conducted February 2004 to June 2006 studied whether abatacept was safe and effective in in children with juvenile idiopathic arthritis who had failed previous treatments. This study included patients aged 6-17 years old (intent to treat, n=190). These children were required to have a history of active juvenile idiopathic arthritis, at least five active joints (those with swelling, limited range of motion, accompanied by either pain or tenderness), and an inadequate response to, or intolerance to at least one disease-modifying antirheumatic drug (DMARD), including biological agents such as etanercept, infliximab, and adalimumab. Screening excluded children who had active uveitis, major concurrent medical conditions, or were pregnant or lactating4.
The primary endpoint was to determine the effect of abatacept versus placebo in terms of the time to flare of juvenile idiopathic arthritis. A flare was defined as worsening of 30% or more in at least three of the six American College of Rheumatology (ACR) core-response variables for JIA, which were number of active joints, number of joints with limited range of motion, physicians’ global assessment of disease severity, parents’ global assessment of patient’s overall wellbeing, functional ability with the Childhood Health Assessment Questionnaire (CHAQ) disability index, and the erythrocyte sedimentation rate; and at least 30% improvement in one variable during the double-blind period. Secondary objectives were assessed at the end of the 6-month double blind period, and included changes from baseline in each of the six ACR core variables, and assessment of safety and tolerability. To make the assessment of endpoints consistent, each participating center had two certified joint assessors who underwent standardized training mandated by the US FDA. The participants were all initially given abatacept by 30-minute IV infusion on days 1, 15, 29, 57 and 85 of a 4-month open-label period. On day 113, patients who had improved by 30% according to the ACR pediatric definition were randomly assigned 1:1 to receive either abatacept or placebo. During the double-blind period, abatacept and placebo were given at doses of 10 mg/kg at random, at 28 day intervals for 6 months, or until a flare of arthritis4.
The response to treatment was determined by the percentage improvement in the six ACR core-response variables. Assessments were collected at screening, baseline, and at each dosing visit in the 4 month open-label lead-in period (days 1, 15, 29, 57, 85, and 113) and the 6-month double-blind period (days 29, 57, 85, 113, 141, and 169). In the intent-to-treat population, median time to flare was 6 months for patients given placebo, and insufficient events had occurred in the abatacept group for median time of flare to be assessed (p=0.0002). Arthritis flare occurred in 33 (53%) of 62 patients in the placebo group during the double-blind period, and 12 (20%) of 60 patients given abatacept (p=0.0003), both of which were statistically significant. Few serious adverse events were reported, with no serious infections, opportunistic infections, or serious autoimmune disorders. Although data cannot be directly compared with those reported for the adult rheumatoid arthritis population, few serious ADE and discontinuations have been reported in either the JIA or adult rheumatoid arthritis populations after abatacept treatment. Of the 133 (70%) patients in which ADE did occur; 25 had headache, 19 had nausea, 17 had cough, 17 had diarrhea, 14 had upper respiratory tract infections, and 12 had pyrexia4.
Overall, the authors concluded that abatacept treatment induced improvement and was well-tolerated by patients with active juvenile idiopathic arthritis. However, further research will be needed to compare abatacept to other biological agents and to address functional outcomes such as joint erosion and structural damage.
The results from this trial were statistically significant, therefore I agree with the authors’ conclusions and believe it would be appropriate to recommend abatacept in children ages 6-17 years of age with JIA who have failed or not been able to tolerate current standard therapy. STUDY STRENGTHS AND WEAKNESSES?
Another open-label, single-arm trial studied the pharmacokinetics, effectiveness and safety of subcutaneous (SC) abatacept over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (pJIA). Children included were ages 2-17 and categorized into two cohorts (cohort 1: 6-17 years; cohort 2: 2-5 years) (intent to treat, n = 187). These patients also had a history of at least 5 joints with active disease, currently had active disease with ≥ 2 active joints and ≥ 2 joints with limitation of motion and insufficient therapeutic response or intolerance to at least one non-biologic DMARD or Tumor Necrosis Factor (TNFα) antagonists for at least 3 months. Children excluded were those with other rheumatic diseases, or major chronic inflammatory/ immunologic diseases, active uveitis, systemic JIA with active systemic features, persistent oligoarthritis JIA, or failed 3 or more TNFα antagonists or other biologic DMARDs.
The exposure-response relationship in JIA demonstrates that Cminss is a good predictor of efficacy, therefore, the primary endpoint was abatacept Cminss in cohort 1 at month 4 of the study, and secondary objectives included the proportion of patients achieving JIA-ACR30 (≥ 30% improvement in at least 3 of the 6 JIA core set variables) at the end of month 4, proportion of patients experiencing serious adverse events, adverse events, adverse events leading to discontinuation, death, laboratory marked abnormalities and a positive immunogenic response. SC abatacept was administered by prefilled syringe once weekly. Patients 10-25 kg received 50 mg, 25-50 kg received 87.5 mg, and 50 kg received 125 mg. Trough concentration was reported as geometric mean of Cmin and the desired therapeutic target was ≥ 10 µg/mL.
This study did not have any formal statistical analysis because the purpose was to assess the pharmacokinetics of SC abatacept and not powered for hypothesis testing. However, in both cohorts, JIA-ACR responses were observed. At month 1, response rates were 83% and 89% in cohorts 1 (n=173) and 2 (n=46), respectively; at month 21, they were 75% and 96%, and at month 24, they were 58% and 100% respectively. Inactive disease status was achieved by month 4 by 30% and 50% of patients in cohorts 1 and 2 respectively. This study did not show any significant effect from treatment on adverse events caused by the study drug. Local injection-site reactions were of mild to moerate intensity and none led to discontinuation. All laboratory marked abnormalities were mild to moderate and no deaths occurred during the study.
The results of the trial, although not statistically analyzed, showed that weekly SC abatacept was effective in patients with pJIA, with no safety concerns identify. The authors concluded that SC abatacept provides an effective and well-tolerated treatment for patients with pJIA with more convenience than IV administration. PK data confirmed that SC abatacept treatment values were within the ranges of exposure found for IV abatacept. Cminss values at month 4 and 24 were comparable, which demonstrated that target therapeutic exposure is maintained with continued dosing.
Because the results were not statistically analyzed, several things need to be taken into consideration. It is not clear exactly how each outcome performed because the study just states a percentage of patients who improved. This causes decreased precision in estimating the effects of abatacept. Additionally, it is difficult to determine if any new studies are required to further investigate certain issues, what those studies may be, and generating new hypotheses for future studies. However, the trial was conducted across 48 centers worldwide, so it has good external validity.
Both of the trials encompass the preliminary research needed to determine the benefit of abatacept in children with a history of active JIA, and an inadequate response or intolerance to DMARDs. More studies need to be done in order to establish the proper role of this medication in comparison with other biological agents, and do address functional outcomes such as joint erosions and structural damage. Because of the statistical significance in the first trial, and the minimal adverse events seen, it can be recommended to use abatacept in the treatment of juvenile idiopathic arthritis in children who had an inadequate response, or intolerance to DMARDs. For children < 75 kg, recommended dose is 10 mg/kg, and for children ≥ 75 kg, recommended dose is 750 mg, with a max dose of 1,000 mg. Dose should be repeated at 2 weeks and 4 weeks after initial dose, then every 4 weeks thereafter. No dosage adjustments are required for renal or hepatic impairment. Patients must be monitored for signs and symptoms of infection, hypersensitivity reaction, hepatitis and be screened for TB prior to therapy initiation5.