Long‐term safety and efficacy of abatacept in children with juvenile idiopathic arthritis

Objective

We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease‐modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long‐term extension (LTE) phase of that study.

Methods

This report describes the long‐term, open‐label extension phase of a double‐blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6–17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open‐label LTE phase and reflect ≥21 months (589 days) of treatment. Safety results include all available open‐label data as of May 7, 2008.

Results

Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double‐blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open‐label lead‐in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient.

Conclusion

Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4‐month open‐label lead‐in phase.

     

Long‐term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis

Objective

This study was undertaken to evaluate the long‐term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA).

Methods

Patients ages 2–18 years with rheumatoid factor (RF)–positive or RF‐negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (≥10 mg/m²/week [∼0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open‐label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment.

Results

A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure‐adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient‐years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient‐years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study.

Conclusion

These data confirm the findings of other long‐term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

     

Long-term outcome in patients with juvenile idiopathic arthritis

OBJECTIVE: To describe the long-term outcome of juvenile idiopathic arthritis (JIA). METHODS: All patients with JIA referred to a pediatric rheumatology center between 1978 and 1988 were identified and invited to undergo an assessment. Patients with JIA from a population-based cohort from East Berlin were included. The outcome assessment considered changes in body function and structure (e.g., mortality, joint abnormalities, disease activity), activities at the individual level (Health Assessment Questionnaire), and participation in society (e.g., mobility, educational and vocational background). RESULTS: Of 260 eligible patients, 215 (83%) were evaluated. Subtypes of JIA at disease onset included oligoarthritis (40%), polyarthritis (14%), systemic arthritis (14%), psoriatic arthritis (1%), enthesitis-related arthritis (15%), and other arthritis (16%). Followup was conducted after a median of 16.5 years. No deaths occurred in this cohort. At followup, approximately half of the patients had active disease and/or changes in body structures to a variable extent. Approximately one-third of patients rated themselves as being functionally limited. Patients demonstrated good social integration: few mobility problems were reported, and the educational achievements of patients were higher and their rate of unemployment was lower compared with the age-matched population. No significant differences in outcome were found between the population-based and the referral-based cohorts. CONCLUSION: Even though approximately half of the JIA patients had more or less distinctive changes in body function and/or structure after a disease duration of >15 years, fewer than 10% were severely disabled or handicapped. Because JIA often persists into adulthood, long-term followup and care are necessary.     

Frequency of osteopenia in adolescents with early‐onset juvenile idiopathic arthritis: A long‐term outcome study of one hundred five patients

Objective

To determine the frequency of low bone mineral content (BMC) and low bone mineral density (BMD) as long‐term complications in adolescents with early‐onset juvenile idiopathic arthritis (JIA), and to identify disease variables, patient characteristics, and biochemical bone markers related to low bone mass.

Methods

One hundred five (87%) of 121 adolescent patients with early‐onset JIA (ages 13–19 years, 80 girls and 25 boys, mean age at onset of JIA 2.8 years), from a cohort first admitted to the hospital between 1980 and 1985, were assessed after a mean disease duration of 14.2 years. BMC and BMD of the total body, the lumbar spine at L2–L4, and the femoral neck were measured by dual‐energy x‐ray absorptiometry. Age‐ and sex‐specific reference values from a pooled, healthy reference population were used to calculate Z scores. Low bone mass was defined as a Z score less than −1 SD.

Results

Among the 103 adolescent JIA patients who underwent total‐body imaging, 41% had low total‐body BMC and 34% had low total‐body BMD. Compared with adolescent JIA patients who had normal total‐body BMC, those with low BMC had lower mean weight (P < 0.001), height (P < 0.001), lean mass (P < 0.001), and remission rates (P = 0.016), had longer duration of active disease (P = 0.013), had higher numbers of active and mobility‐restricted joints (P < 0.001 and P = 0.001, respectively), had more disability (P = 0.011), had higher frequencies of joint erosions (P < 0.001), and had higher erythrocyte sedimentation rates (P = 0.033). In multiple linear regression analyses of total‐body BMC, 88% of the variance was explained by the duration of active disease, the number of joints with restricted mobility, the bone area, urinary deoxypyridinoline values, age, weight, and height.

Conclusion

Forty‐one percent of the adolescents with early‐onset JIA had low bone mass >11 years after disease onset. The development of low total‐body BMC was related to the duration of active disease, disease severity, measures of bone resorption, weight, and height.

     

Long‐term safety and efficacy of etanercept in children with polyarticular‐course juvenile rheumatoid arthritis

Objective

Previous studies showed that etanercept treatment in patients with polyarticular‐course juvenile rheumatoid arthritis (JRA) provided rapid clinical improvement that was sustained for up to 2 years. The goal of our study was to provide data on safety and efficacy after 4 years of etanercept treatment in patients with JRA.

Methods

Patients with active polyarticular‐course JRA who participated in an efficacy study continued etanercept treatment in an open‐label extension. Safety was assessed by measuring rates of serious adverse events (SAEs) and serious infections. Efficacy was assessed using the American College of Rheumatology (ACR) Pediatric 30 criteria for improvement and standard measures of disease activity. (The ACR Pediatric 30 criteria are defined as improvement of ≥30% in at least 3 of 6 core response variables used to assess disease activity, with no more than 1 variable worsening by ≥30%.)

Results

Of the 69 patients who enrolled in the original efficacy study, 58 patients (84%) enrolled in the extension, 34 patients received etanercept treatment for ≥4 years, and 32 of these received complete efficacy assessments. The rate of SAEs was 0.13 per patient‐year, and the rate of serious infections was 0.04 per patient‐year, in a total etanercept exposure of 225 patient‐years. Eighty‐two percent of patients who received corticosteroids at any time during the extension were able to decrease their dosage to ≤5 mg/day prednisone equivalent. Of the 32 patients with complete efficacy data who received etanercept for ≥4 years, 94% achieved an ACR Pediatric 30 response and 78% achieved an ACR Pediatric 70 response at the last study visit.

Conclusion

Etanercept offers an acceptable safety profile in children with polyarticular‐course JRA and provides significant improvement in disease manifestations that are sustained for ≥4 years.

     

Long‐term impact of delay in assessment of patients with early arthritis

Objective

During the last decade, rheumatologists have learned to initiate disease‐modifying antirheumatic drugs (DMARDs) early to improve the outcome of rheumatoid arthritis (RA). However, the effect of delay in assessment by a rheumatologist on the outcome of RA has scarcely been explored. The purpose of this study was to examine the association between delay in assessment by a rheumatologist, rates of joint destruction, and probability of achieving DMARD‐free remission in patients with RA. Patient characteristics associated with components of delay (by the patient, by the general practitioner [GP], and overall) were assessed.

Methods

A total of 1,674 early arthritis patients from the Leiden Early Arthritis Clinic cohort were evaluated for patient delay, GP delay, and total delay in assessment by a rheumatologist. Among 598 RA patients, associations between total delay, achievement of sustained DMARD‐free remission, and the rate of joint destruction over 6 years followup were determined.

Results

The median patient, GP, and total delays in seeing a rheumatologist among patients with early arthritis were 2.4 weeks, 8.0 weeks, and 13.7 weeks, respectively. Among all diagnoses, those diagnosed as having RA or spondylarthritis had the longest total delay (18 weeks). Among the RA patients, 69% were assessed in ≥12 weeks; this was associated with a hazard ratio of 1.87 for not achieving DMARD‐free remission and a 1.3 times higher rate of joint destruction over 6 years, as compared with assessment in <12 weeks. Older age, female sex, gradual symptom onset, involvement of the small joints, lower levels of C‐reactive protein, and the presence of autoantibodies were associated with longer total delay.

Conclusion

Only 31% of the RA patients were assessed in <12 weeks of symptom onset. Assessment in <12 weeks is associated with less joint destruction and a higher chance of achieving DMARD‐free remission as compared with a longer delay in assessment. These results imply that attempts to diminish the delay in seeing a rheumatologist will improve disease outcome in patients with RA.

     

Long‐term open‐label preliminary study of the safety and efficacy of leflunomide in patients with polyarticular‐course juvenile rheumatoid arthritis

Objective

To obtain preliminary data regarding the efficacy and long‐term safety of leflunomide in patients with refractory polyarticular‐course juvenile rheumatoid arthritis (JRA).

Methods

Twenty‐seven patients were entered into the initial 26‐week open‐label study of leflunomide therapy; 17 entered the extension phase (maximum 107 weeks). Mean disease duration at study entry was 7.0 years. All patients had ≥5 joints with active arthritis and had received methotrexate for a mean of 36.0 months. Following a loading dose, patients initially received leflunomide at a dosage of 10 mg/1.73 m²/day, which could be increased to 20 mg/1.73 m²/day (maximum 20 mg/day) beginning at week 8. The primary efficacy outcome was the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement. Last observation carried forward (LOCF) analysis was used, and all patients were entered into an intent‐to‐treat analysis. Intraarticular corticosteroids (maximum of 2 in the initial 26 weeks) were allowed, but no new disease‐modifying antirheumatic drug or change in nonsteroidal antiinflammatory drug was allowed throughout the study.

Results

Seventeen of the 27 patients (63%) completed the initial 26‐week study. Fourteen patients (52%) met the ACR Pedi 30 response criteria at week 26. Seventeen patients entered into the extension phase (13 who met response criteria and 4 who failed to meet response criteria but decided to continue). Nine of the 17 patients (53%) who entered the extension phase either completed all 30 months of study or the study ended prior to the month 30 visit. Five patients withdrew because of failure to maintain efficacy, 2 withdrew their consent, and 1 withdrew because of an adverse event. Using LOCF analysis, 65% of patients met ACR Pedi 30 response criteria at 1 year and 2 years (weeks 50 and 106, respectively) and 53% at the end of the study. Good response rates were also seen using ACR Pedi 50 and ACR Pedi 70 criteria (47% and 24% at week 106, respectively).

Conclusion

In this open‐label study of JRA patients who either failed to respond to, or were intolerant of, methotrexate, the majority met the ACR Pedi 30 response criteria at week 26. The response was durable, since 53% of patients who entered into the extension phase (maximum 30 months) responded at the end of this phase. Our findings support the further study of the role of leflunomide in the treatment of polyarticular‐course JRA.

     

Effects of adherence to treatment on short‐term outcomes in children with juvenile idiopathic arthritis

Objective

To determine the impact of adherence to treatment (medication and prescribed exercise) on outcomes in children with juvenile idiopathic arthritis (JIA).

Methods

In this longitudinal study, we studied parents of patients with JIA at the Montreal Children's Hospital and British Columbia Children's Hospital in Vancouver. Adherence was evaluated on a visual analog scale in the Parent Adherence Report Questionnaire. Outcomes of interest were active joint count, pain, child functional score on the Child Health Assessment Questionnaire, quality of life score on the Juvenile Arthritis Quality of Life Questionnaire, and parental global impression of overall well‐being. The association between adherence to treatment and subsequent outcomes was evaluated using generalized estimating equations and logistic regression.

Results

Mean age and disease duration of our sample of 175 children were 10.2 and 4.1 years, respectively. Moderate adherence to medication was associated with lower active joint count (odds ratio [OR] 0.47, 95% confidence interval [95% CI] 0.22–0.99). Moderate adherence to exercise was associated with better functional score (OR 0.13, 95% CI 0.03–0.54), and lower pain during the last week (OR 0.14, 95% CI 0.04–0.50). Both high and moderate adherence to exercise were associated with parental perception of global improvement.

Conclusion

Improved outcomes in patients who adhered to treatment underscores the need for clinicians to address adherence issues with their patients. Sustaining adherence, particularly to the more time‐consuming treatment of exercise, is a challenge.     

Prevalence,risk factors,and outcome of uveitis in juvenile idiopathic arthritis: A long‐term followup study

Objective

To assess the prevalence, risk factors, and long‐term outcome of uveitis in patients with juvenile idiopathic arthritis (JIA).

Methods

An inception cohort of all 1,081 patients diagnosed as having JIA at a single tertiary care center was established. A questionnaire and followup telephone calls were used to confirm the diagnosis of uveitis. Ophthalmologists' records of patients with uveitis were collected. Kaplan‐Meier and Cox regression analyses were used to assess risk factors for developing uveitis and for complications of uveitis.

Results

After a mean followup time of 6.9 years, 142 of 1,081 patients (13.1%) had developed uveitis. Risk factors were young age at diagnosis, female sex, antinuclear antibody positivity, and the subtype of JIA. The relative contribution of these risk factors was different for the different subtypes of JIA. Until the end of the study, uveitis complications had developed in 53 of 142 patients with uveitis (37.3%; 4.9% of the total cohort). Only 16 of 175 involved eyes (9.1%) in 14 of 108 patients (13%; 1.3% of the total cohort) for whom ophthalmology reports were available had best corrected visual acuity less than 20/40 (mean followup time for uveitis of 6.3 years). Abnormal vision was associated with synechiae or cataract.

Conclusion

Risk factors for developing uveitis were different among subtypes of JIA. The long‐term outcome of JIA‐associated uveitis in our cohort was excellent despite the high rate of complications.

     

Longterm outcome of amyloidosis associated with juvenile idiopathic arthritis

OBJECTIVE: To determine the outcome of amyloidosis associated with juvenile idiopathic arthritis (JIA) in a hospital-based series. METHODS: Patient registers and amyloidosis biopsy files of the Department of Pediatrics of Rheumatism Foundation Hospital, the main tertiary center for inflammatory joint disorders in children in Finland, were scrutinized from 1976 to the end of 2003 to look for amyloidosis in patients under age 19 years. Medical records were reviewed and patients were interviewed by telephone. The causes of any deaths were obtained from death certificates. RESULTS: Twenty-four patients under age 19 years with biopsy-proven amyloidosis were found. As a sign of renal disease at the time of diagnosis of amyloidosis, 16 patients (67%) had proteinuria, but none had renal insufficiency. The 5-year survival rate of the series was 87.5% (95% CI 75% to 100%), and 10-year survival was 75% (54% to 92%). Ten patients (42%) out of the 24 died during a mean followup of 15.4 (range 1.5-27.6) years. The main cause of death was related to JIA in all patients but one. Patients treated with prednisolone alone from the diagnosis of amyloidosis onward had a mortality rate significantly higher than those taking disease modifying antirheumatic drugs and/or cytostatics (p = 0.001). At the end of followup, 14 patients (58%) were alive, 12 with normal renal function (3 of them had undergone renal transplantation), one had renal insufficiency, and one proteinuria. Proteinuria disappeared in 4 patients who were proteinuric (2 with nephrotic syndrome) at baseline, and their renal function remained normal. All the live patients had completed at least the 9 years of compulsory education, and 4 had academic degrees. Two female patients had delivered healthy children. CONCLUSION:The outcome of JIA-associated amyloidosis is poor. However, renal disease regressed in some patients under vigorous treatment. Successful treatment makes an active life possible for these patients.     

Long‐term cardiovascular outcome of Williams syndrome

Objective: Cardiovascular lesions are the leading cause of morbidity and mortality in patients with Williams syndrome. Recent studies have rebutted conventional reports about the natural course of cardiovascular anomalies in Williams syndrome.
Design: Retrospective study.
Setting: Single tertiary center.
Patients: Eighty patients with Williams syndrome followed up for more than 5 years.
Interventions: Not applicable.
Outcome Measures: Long‐term outcome of cardiovascular lesions, peak velocity change in obstructive cardiovascular lesions over time, post‐interventional courses of disease‐specific intervention, and intervention‐free survival of obstructive cardio‐ vascular lesions.
Results: The median follow‐up duration was 11.0 (5.1‐28.3) years. Among 80 pa‐ tients, supravalvular aortic stenosis (87.5%) was the most common cardiovascular lesion, followed by branch pulmonary stenosis (53.8%), mitral valve prolapse (22.5%), and aortic arch hypoplasia/coarctation (5.0%). During the follow‐up period, the peak flow velocity of supravalvular aortic stenosis did not change on peak Doppler echo‐ cardiography. Initially, severe supravalvular aortic stenosis was aggravated (P < .027). Conversely, the peak velocity of branch pulmonary stenosis decreased (from 3.08 to 1.65 m/s; P < .001) within age 3.2 (0.4‐6.9) years. Even the group with severe branch PS improved over time. Twenty‐two patients (27.5%) with Williams syndrome under‐ went disease‐specific interventions without mortality, mostly for supravalvular aortic stenosis or mitral valve prolapse. No patient in the late‐onset and initially mild sup‐ ravalvular aortic stenosis group needed intervention and 37.5%, 48.4%, and 65.1% in initially moderate and severe supravalvular aortic stenosis groups needed inter‐ vention at age 5, 10, and 20 years, respectively. Unlike the conventional therapeutic concept, the intervention for branch pulmonary stenosis was almost unnecessary.
Conclusions: In Williams syndrome, initially severe supravalvular aortic stenosis worsened over time and most branch pulmonary stenoses, including those in the severe group, improved spontaneously. Most patients with branch pulmonary ste‐ nosis did not require disease‐specific intervention. Surgical repairs for cardiovascular abnormalities in Williams syndrome showed favorable results.     

Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: Long‐term followup of a prospective clinical trial

Objective

To assess the safety and efficacy of intensive immunosuppression followed by T cell–depleted autologous hematopoietic stem cell transplantation (ASCT) for induction of disease remission in children with refractory progressive juvenile idiopathic arthritis (JIA).

Methods

Twenty‐two patients with progressive refractory JIA were followed up over a median period of 80 months after pretreatment with intensive immunosuppression followed by ASCT in a multicenter, prospective, phase II clinical trial. Hematopoietic stem cells were harvested from the patients' bone marrow, depleted of T cells, and kept frozen until used for ASCT. Pretreatment of patients consisted of a combination of antithymocyte globulin, cyclophosphamide, and low‐dose total body irradiation. Patients were followed up for ASCT‐related complications, recovery of hematologic and immune system parameters, and disease outcomes.

Results

Reconstitution of hematologic values to normal range was rapid. Recovery of immune system parameters, especially normalization of CD4+, CD45RA+ naive T cells, was delayed, occurring at ≥6 months after ASCT. The prolonged period of immune deficiency resulted in a large number of viral infections and may have contributed to the development of macrophage activation syndrome (MAS), leading to death, in 2 patients. After ASCT, 8 of the 20 evaluable patients reached complete clinical remission of their JIA, 7 were partial responders, and 5 experienced a relapse of their disease (occurring 7 years after ASCT in 1 patient). Later during followup, 2 of the patients whose disease relapsed died from infections that developed after restarting immunosuppressive medication.

Conclusion

Intensive immunosuppression followed by ASCT resulted in sustained complete remission or marked improvement in 15 of 22 patients with progressive refractory JIA. The procedure, however, is associated with significant morbidity and risk of mortality due to prolonged and severe depression of T cell immunity. After fatal complications due to MAS were observed in some patients, the protocol was amended in 1999, to ensure less profound depletion of T cells, better control of systemic disease before transplantation, antiviral prophylaxis after transplantation, and slow tapering of corticosteroids. Following these protocol modifications, no additional ASCT‐related deaths were observed among the 11 patients who received the modified treatment.

     

Anti-keratin antibodies in patients with juvenile idiopathic arthritis

OBJECTIVE: We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA). METHODS: An indirect immunofluorescence test with rat oesophagus substrate was used for the detection and quantification of AKA antibodies in patients'sera. RESULTS: Overall 30/60 patients with JIA had sera positiveforAKA (50%, p=0.0005) ranging from 1:20 to 1:160 dilutions. Using the classification criteria for childhood idiopathic arthritis, AKA occurred in 2/7 patients with systemic disease (28.6%), in 13/30 patients with RF negative polyarthritis (43.3%, p=0.008) and in 12/18 RF positive polyarthritis (66.7%, p=0.002). AKA were also found in a small cohort of patients with oligoarthritis (1/3) and psoriatic arthritis (2/2). AKA positivity occurred in 3/26 healthy controls at a 1:20 dilution. The presence ofAKA was correlated as well as with the severity of the disease. Our study revealed that AKA was present overall in 16/29 patients (55.2%) with severe JIA and in 11/26 patients (42.3%) with non-severe disease. We also observed that AKA remained positive regardless of disease activity. AKA were detectable in 44.4% patients with active JIA and in 45.9% patients in the complete or near remission. CONCLUSION: Our data suggest that AKA are present in patients with JIA. However no correlation with severity or disease activity was observed.