Good results from combining etanercept to prevailing DMARD therapy in refractory juvenile idiopathic arthritis

OBJECTIVE: To assess the effect of etanercept added to prevailing drug therapy in patients with juvenile idiopathic arthritis (JIA) whose disease was refractory to conventional disease-modifying antirheumatic drug (DMARD) treatment, including combinations of different DMARDs. METHODS: Data on 31 JIA patients with a disease resistant to conventional DMARD treatment were retrospectively collected from medical records and assessed for a one-year period after the introduction of etanercept or to the time of cessation of the drug due to a lack of efficacy or side effects. Efficacy was assessed based on the normal laboratory indexes of inflammation and changes in the following parametres: number of DMARDs used and intraarticular (i.a.) glucocorticoid injections. The numbers of inpatient days needed were also recorded. RESULTS: Etanercept was well tolerated. Only two patients stopped discontinued the treatment because of allergic rash, after 3 weeks of treatment in one case and after 4 months in another. In two cases the treatment was discontinued because of a lack of efficacy. During the treatment, there was a significant decrease in the number of DMARDs used and the i.a. glucocorticoid injections needed as well as in the dose of per oral glucocorticoids. The laboratory parameters also improved. In addition, there was a significant decrease in the number of inpatient days per 3-month period before and during the etanercept treatment. CONCLUSION: The addition of etanercept to conventional DMARD therapy in children with the most severe cases of JIA leads to an excellent clinical response during the first 12 months. The tolerability of the drug is good in combination therapy with various DMARDs.     

The German etanercept registry for treatment of juvenile idiopathic arthritis

OBJECTIVE: To describe a registry set up to monitor children treated with etanercept in Germany and Austria. METHODS: Giannini's criteria, duration of morning stiffness, number of swollen, tender and contracted joints, adverse events, and reasons for discontinuation were assessed. RESULTS: 322 patients with juvenile idiopathic arthritis (JIA) and 12 additional patients with non-JIA rheumatic diagnoses were included. Therapeutic efficacy was observed from one month after treatment was started. The number of patients with significant improvement and the degree of improvement increased during the first year. The mean (SD) number of tender and swollen joints decreased from 9 (9) and 8.4 (9) to 3.0 (6.5) and 4.5 (7) after one month, and to 2.2 (5.5) and 3.3 (5.5) after three months; morning stiffness decreased from 45 (65) minutes to 12 (30) and 7 (19) after one and three months (p<0.001 for all). Using Gianinni's criteria of 30%, 50%, and 70% improvement, a therapeutic response in JIA patients was achieved in, respectively, 66%, 54%, and 30% after one month, 78%, 61%, and 38% after three months, and 83%, 72%, and 52% after six months. Therapeutic efficacy was lower in patients with systemic onset arthritis. Overall tolerability was good: in 592 patient treatment-years there were 69 reports of adverse events in 56 patients, including one CNS demyelination. There were no opportunistic infections or lupus-like reactions. Treatment was discontinued in 53 JIA patients, in 25 because of lack of efficacy. CONCLUSION: Etanercept treatment was safe and led to a significant improvement in most JIA patients resistant to conventional treatment.     

Bone status over 1 yr of etanercept treatment in juvenile idiopathic arthritis

OBJECTIVE: To evaluate bone mineral status over 1 yr of etanercept treatment in juvenile idiopathic arthritis (JIA). METHODS: Twenty children (13 female, 7 male) aged 5.2-11.4 yr, with active polyarticular JIA were prospectively enrolled to receive etanercept (0.4 mg/kg, twice weekly). Responders were defined according to the American College of Rheumatology Pediatric 50 definition of improvement. Broadband ultrasound attenuation (BUA) by bone was determined at the left calcaneus to assess bone status at baseline and at 1-yr follow-up. RESULTS: After 12 months of treatment, 15 (75%) patients were considered as responders. At baseline, responders and non-responders did not differ with regard to age, disease duration, core-set variables or BUA and Z-score values (patient's value--age specific normal value/normal group's s.d.). At 6-month and 1-yr follow-up in the whole group, BUA and Z-score values were not significantly different compared with baseline. At 1-yr follow-up, but not at 6 months, all 15 responders, differently from non-responders, showed a significant increase in both BUA and Z-score values: BUA at 1 yr 55.2 +/- 3.3 vs baseline 43.5 +/- 3.2 dB/MHz, P<0.001; Z score at 1 yr -0.3 +/- 0.2 vs baseline 1.5 +/- 0.4, P<0.002. CONCLUSION: For the first time in childhood rheumatic disease this pilot prospective study, although in a small group, shows evidence that 1 yr of etanercept therapy by controlling the underlying disease activity induces a sustained benefit on JIA bone loss. Prospective studies in larger patient samples are needed to confirm these data.     

Safety and effectiveness of etanercept for treatment of juvenile idiopathic arthritis: Results from a postmarketing surveillance

Objectives: The objectives of this surveillance were to determine safety and effectiveness of etanercept in patients with juvenile idiopathic arthritis (JIA).

Methods: In this postmarketing surveillance, patients aged 5–16 years with active polyarthritis JIA were treated with etanercept at the doses approved in the Japanese package insert. The occurrence and seriousness of adverse events (AEs) were assessed using the Japanese Medical Dictionary for Regulatory Activities version 15.1. Effectiveness was determined as the improvement from baseline in disease activity score in 28 joints (DAS28)–erythrocyte sedimentation rate (ESR), remission, and physician’s assessment of overall improvement. The number of responders was expressed as a percentage. The last observation carried forward method was used to impute missing data.

Results: Safety analysis included 102 patients; 22 patients experienced 36 treatment-related AEs, three of which were unexpected. None of the AEs were deemed to need special safety warnings. Effectiveness analysis included 87 patients. At 24 weeks, 29/46 (63.0%) patients demonstrated either good or moderate response in DAS28-4/ESR and treatment was assessed to be markedly effective or effective by physicians in 79/83 (95.2%) patients.

Conclusions: These data are consistent with earlier reports showing that etanercept was effective and demonstrated no safety signals in patients with JIA.     

Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis

OBJECTIVE: To evaluate the efficacy of anti-tumour necrosis factor (anti-TNF) treatment in juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: 24 patients with uveitis taking etanercept and 21 taking infliximab were studied. The endpoint ophthalmological evaluation was at 24 months or at the termination of the first biological agent. The ocular inflammatory activity was graded on the basis of the number of anterior chamber cells. RESULTS: Of the 45 patients, uveitis improved in 14 (31%), no change was observed in 14 (31%) and the activity of uveitis increased in 17 (38%). Inflammatory activity improved more frequently (p=0.047) in the patients taking infliximab than in those taking etanercept. The number of uveitis flares/year was higher (p=0.015) in the patients taking etanercept (mean 1.4, range 0-3.2) than in those taking infliximab (mean 0.7, range 0-2). Uveitis developed for the first time while taking anti-TNF treatment in five patients-4 taking etanercept (2.2/100 patient-years) and 1 taking infliximab (1.1/100 patient-years). CONCLUSIONS: During anti-TNF treatment, the ophthalmological condition improved in one-third of the patients with uveitis. In chronic anterior uveitis, associated with refractory JIA, infliximab may be more effective than etanercept.     

TNF and LT binding capacities in the plasma of arthritis patients: effect of etanercept treatment in juvenile idiopathic arthritis

BACKGROUND: Etanercept (Enbrel) induces a rapid and sustained decline in disease activity in the majority of patients with refractory juvenile idiopathic arthritis (JIA). For unknown reasons, however, a number of JIA patients fail to respond to this therapy. During this treatment neutralisation of tumour necrosis factor (TNF, previously termed TNF alpha) and lymphotoxin (LT, previously termed TNF beta) may be mediated by etanercept itself as well as by naturally occurring soluble TNF receptors. In light of this, it was of interest to study the total TNF neutralizing capacity in plasma before and during treatment with etanercept. RESULTS: In initial experiments plasma samples from healthy individuals were incubated with etanercept, and spiked with TNF or LT to a final concentration of 1000 pg/mL. Detection of TNF and LT by ELISA was found to be reduced by approximately 50% and 80% respectively, at a concentration of etanercept of 5-500 ng/mL, which is close to the pharmacological plasma concentrations. Plasma samples (n = 80) were then collected from 12 JIA patients (5 with pauciarticular, 5 with polyarticular and 2 with the systemic onset type) during treatment with etanercept (0.4 mg/kg twice weekly) for a period of 20.8 (15.6-23.9) months (median, range). The plasma samples were spiked with LT, and the inhibition of LT detection in ELISA was measured. In samples obtained 3 months after the start of etanercept, the inhibition of LT detection was augmented [72% (60-85)] compared with pre-treatment samples [16% (0.32)] (p = 0.0039). These findings were confirmed in binding assays using radiolabelled TNF. Among patients who responded insufficiently to therapy, reduced LT binding capacity, coinciding with flares of disease activity, was observed. CONCLUSION: We have developed an assay by which LT binding capacity, reflecting the level of free, pharmacologically active etanercept, may be monitored in the blood of patients treated with etanercept. This assay may prove to be useful in guiding dose adjustments in patients with an incomplete response to etanercept.     

Clinical remission in juvenile idiopathic arthritis after termination of etanercept

Biologicals are very effective for inhibiting disease progression in active juvenile idiopathic arthritis (JIA). To date, there have been no recommendations on how and when to stop therapy with TNF inhibitors. Our objective was to analyze characteristics and the disease course of JIA patients who discontinued etanercept due to achievement of inactive disease. Data of 39 patients with JIA from two clinical pediatric rheumatology centers in Bydgoszcz and Lublin (Poland) were analyzed retrospectively. All patients discontinued etanercept due to a remission on treatment. Etanercept was started after a mean 33.7 ± 36 (range 3–137) months of disease. The mean duration of therapy with etanercept was 34.7 ± 16.7 (range 6–72) months, with a mean duration of remission on medication 21.3 ± 9.6 (range 4–42) months before withdrawal of etanercept. The mean duration of remission after etanercept discontinuation was 14.2 ± 12.1 (range of 1–60) months. Only 12/39 (30.8 %) patients did not develop a disease exacerbation until the end of the study. Early flares, that is less than 6 months after termination of etanercept, were observed in 15/39 (38.5 %) patients. Twelve (30.8 %) patients restarted etanercept after exacerbation—all patients responded satisfactorily. Our data show that etanercept discontinuation in a substantial proportion of JIA patients results in early disease exacerbation. In many cases, reintroduction of etanercept is needed. Patients, in whom etanercept was restarted, responded satisfactorily.     

Improvement of functional ability in children with juvenile idiopathic arthritis by treatment with etanercept

The objective of the study is to investigate the functional ability, i.e., the physical aspect of the health-related quality of life and its determining factors during therapy with etanercept in children with juvenile idiopathic arthritis (JIA). Assessment of the Child Health Assessment Questionnaire (CHAQ), the number of active joints, duration of morning stiffness, ESR, C-reactive protein, parent’s global assessment of the overall patient’s well-being, physician’s global assessment of the overall disease activity, concomitant treatment with methotrexat, number of aids/devices needed, and calculation of the PedACR-score. Data of 437 children were analyzed for disease severity and impact of the disease on functional abilities. Data of 114 children with a complete data set and a continuous treatment for at least 24 months were used for analysis of the impact of treatment on functional abilities. Before treatment with etanercept, patients with systemic arthritis and seropositive or seronegative polyarthritis were disabled more heavily than those with other subtypes of JIA. There was a correlation between high CHAQ scores and the number of active joints, aids/devices needed, parent’s global assessment of the overall patient’s well-being, morning stiffness, physician’s global assessment of the overall disease activity, and C-reactive protein (P < 0.005). Of the eight areas, “dressing and grooming”, “arising”, “eating”, “walking”, “hygiene”, “reach”, “grip” and “activities”, the latter was most severely affected. 96.5, 93.8, and 90.3% of the patients reached a PedACR-30, -50 and -70 score upon treatment with etanercept for 24 months. The areas of eating and walking were best before therapy and showed highest improvement with therapy. Under therapy with etanercept patients of all JIA subgroups significantly improved their functional ability (P < 0.0001), but patients with polyarthritis less frequently improved their physical functioning. Disease activity and the physical aspect of health-related quality of life including functional ability improved significantly during therapy with etanercept in children with JIA. Duties of everyday life were easier to accomplish.     

Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type

OBJECTIVE: To assess the efficacy of etanercept in patients with juvenile idiopathic arthritis (JIA), and to assess the tolerance of these patients to etanercept. METHODS: All JIA patients with active chronic polyarthritis, who were first treated with etanercept between November 1999 and June 2001 in 18 French centers because of poor response or intolerance to methotrexate, were included in this open-label, prospective, multicenter study. A standardized questionnaire was sent to the treating physicians. We assessed the validated international core-set score for JIA activity every 3 months and performed an intent-to-treat analysis. We also compared the risk of treatment failure in patients defined as having systemic-onset, oligoarticular-onset, or polyarticular-onset JIA. RESULTS: Sixty-one patients were enrolled and were followed up for a median of 13 months. Treatment had to be stopped in 1 patient who became pregnant and in 12 patients due to severe side effects, including neurologic or psychiatric disorders, retrobulbar optic neuropathy, major weight gain, severe infection, cutaneous vasculitis with systemic symptoms, hemorrhagic diarrhea, uveitis flare, and pancytopenia. All of these side effects disappeared after discontinuation of etanercept. Crohn's disease was subsequently diagnosed in 1 child. Scores improved by > or =30% in 73% of patients after 3 months, but this proportion decreased to 39% after 12 months. The response rate was significantly lower in patients with systemic-onset JIA than in those with oligoarticular- or polyarticular-onset JIA. CONCLUSION: Treatment of JIA with etanercept may be associated with a wide spectrum of severe side effects. Although most patients initially respond to etanercept, this initial response is not always followed by sustained improvement over longer periods of time. In addition, the higher rate of treatment failure in the group with systemic-onset JIA indicates that these patients in particular may require alternative treatments.     

Update upon efficacy and safety of etanercept for the treatment of spondyloarthritis and juvenile idiopathic arthritis

TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis (AS), psoriasis (Ps) and/or psoriatic arthritis (PsA) and may be administered off-label to treat disseminated granuloma annulare, systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. In this article, we discuss the efficacy and safety of etanercept in the treatment of spondyloarthritis and juvenile idiopathic arthritis (JIA). Etanercept is effective in the treatment of PsA, AS, JIA and uveitis. Independent predictors of achieving a sustained clinical improvement or MDA in children with JIA include shorter disease duration, no concurrent oral corticosteroid use, history of chronic anterior uveitis and age <9 years. IBD incidence was lower in patients receiving etanercept plus MTX. Intra-articular administration of etanercept seems to favor a prompt target joint improvement without serious adverse events. Etanercept improve endothelial function reducing the risk of acute cardiovascular and/or cerebrovascular events. The most commonly reported adverse events were nasopharyngitis, epidermal and dermal conditions, upper respiratory tract infection, cough, headache and fatigue.     

Guidelines on the use of etanercept for juvenile idiopathic arthritis in Japan

Etanercept is a dimeric fusion protein consisting of the extracellular domain of human tumor necrosis factor receptor II (TNFR II, molecular weight 75 kDa) coupled to the Fc region of human immunoglobulin (IgG1). It is produced by recombinant DNA technology by first introducing the gene into Chinese hamster ovarian cells and then purifying the protein from the culture supernatant. The mechanism of action of etanercept consists of binding to serum TNF-α and lymphotoxin (LT)-α (TNF-β), which prevents TNF-α and LT-α from binding to the TNF-α receptor on the plasma membrane of the target cell. Etanercept is currently approved for treating adult rheumatoid arthritis (RA) in more than 70 countries worldwide. In Japan, it was approved for this target group in January 2005. The USA and Europe were the first to approve entanercept for use in treating juvenile idiopathic arthritis (JIA), initially for the treatment of active polyarticular JIA in patients not responding to disease-modifying antirheumatic drugs (USA in May 1999, followed by the EU in February 2000). Thereafter, the drug received approval for the treatment of JIA in many other countries. In Japan, children who have been diagnosed and treated according to Yokota et al. (Mod Rheumatol 17:353–363, 2007), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adhesion to the indications and exclusion criteria and should be used, for the time being, only by physicians trained on how to use them. In Japan, etanercept was approved in July 2009 for use in children. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidelines presented here define the indications, exclusion criteria, usage, and evaluation criteria of etanercept for the treatment of polyarticular JIA.     

Safety and efficacy of long-term etanercept in the treatment of methotrexate-refractory polyarticular-course juvenile idiopathic arthritis in Japan

Objectives

Previous short-term trials found etanercept (0.2 or 0.4?mg/kg) to be effective and well tolerated in Japanese children with juvenile idiopathic arthritis (JIA) who were intolerant/resistant to methotrexate. The aim of this study was to evaluate the long-term safety and efficacy of etanercept in Japanese children with JIA.

Methods

Patients (4–19?years) who received etanercept in one of three short-term studies continued onto this long-term open-label study.

Results

Of the 32 patients enrolled, 18 (56.3%) completed 192?weeks of the study and 14 (43.8%) were discontinued; 7 (21.9%) for patient refusal, 2 (6.3%) for adverse events (AEs), and 5 (15.6%) for lack of efficacy. All patients reported AEs; 31 (96.9%) reported infections and 6 (18.8%) reported serious AEs. Main efficacy assessments included change from baseline in the American College of Rheumatology Pediatric core components, including mean improvements from baseline in the physician global assessment (90.7%), patient/guardian global assessments (54.1%), Childhood Health Assessment Questionnaire (84.6%), and median improvements in C-reactive protein levels (92.7%). No unexpected safety results were reported, and early efficacy responses were sustained in the long term.

Conclusions

This study provides further evidence that etanercept is an effective therapeutic option for Japanese children with polyarticular-course JIA.     

Safety and efficacy of long-term etanercept in the treatment of methotrexate-refractory polyarticular-course juvenile idiopathic arthritis in Japan

Abstract

Objectives Previous short-term trials found etanercept (0.2 or 0.4 mg/kg) to be effective and well tolerated in Japanese children with juvenile idiopathic arthritis (JIA) who were intolerant/resistant to methotrexate. The aim of this study was to evaluate the long-term safety and efficacy of etanercept in Japanese children with JIA.

Methods Patients (4–19 years) who received etanercept in one of three short-term studies continued onto this long-term open-label study.

Results Of the 32 patients enrolled, 18 (56.3%) completed 192 weeks of the study and 14 (43.8%) were discontinued; 7 (21.9%) for patient refusal, 2 (6.3%) for adverse events (AEs), and 5 (15.6%) for lack of efficacy. All patients reported AEs; 31 (96.9%) reported infections and 6 (18.8%) reported serious AEs. Main efficacy assessments included change from baseline in the American College of Rheumatology Pediatric core components, including mean improvements from baseline in the physician global assessment (90.7%), patient/guardian global assessments (54.1%), Childhood Health Assessment Questionnaire (84.6%), and median improvements in C-reactive protein levels (92.7%). No unexpected safety results were reported, and early efficacy responses were sustained in the long term.

Conclusions This study provides further evidence that etanercept is an effective therapeutic option for Japanese children with polyarticular-course JIA.     

Clinical trial of etanercept tapering in juvenile idiopathic arthritis during remission

To explore the possibility of step-down method and low dose of etanercept for long-term stable remission of patients with juvenile idiopathic arthritis (JIA). Patients with JIA were enrolled into this study between February 2008 and March 2010 and then followed up for 2 years. The inclusion criteria were clinical remission and use of etanercept for therapy. On the first year of the study, the dose of etanercept was kept at 0.4 mg/kg per week, the half dose of what those patients had been used. On the second year, the dose of etanercept was further lowered to 0.4 mg/kg per month. DMARDs were allowed in this study. MR images were performed to observe joint changes. The primary end point was disease flare defined according to clinical and/or radiological data. The flare rate curve was analyzed by Kaplan–Meier, and logistic regression model was used to find factors associating with disease flare. MRI was performed to prove no active changes or progressions of bone erosions on joints. Thirty-one patients were enrolled in this study. There were 4 patients experiencing disease flare during the first 12th month. During the second year, disease flare was not occurred. Thus, the cumulative flare rate was 12.9 % on 12th month and then unchanged on the second year. Logistic regression model indicates there are no differences in sex, age of disease initiation, disease duration, subtypes, DMARDs, HLA-B27, months of etanercept duration and scores on MRI between patients with remission and those experiencing flares. At the end of the study, MRI found no progressions of joints to the patients keeping stable remission. Step-down method can be used for etanercept tapering. Long-term remission and low flare rate can be got by this method.     

A combination of etanercept and methotrexate for the treatment of refractory juvenile idiopathic arthritis: a pilot study

OBJECTIVE: To study the efficacy of combination therapy with etanercept and methotrexate in patients with refractory juvenile idiopathic arthritis. METHODS: Seven children with active juvenile idiopathic arthritis refractory to at least combination therapy with methotrexate and sulfasalazine or cyclosporin A were studied. Concomitant treatment, consisting of non-steroidal drugs, corticosteroids, and methotrexate, remained unchanged. RESULTS: Six patients continued the treatment for at least 24 weeks. In the child with systemic arthritis, etanercept was stopped because of persisting spiking fever, joint pain, and rash. In the remaining children an immediate significant decrease in joint pain (p<0.05), disappearance of morning stiffness, and regression of joint swelling (p<0.05) were observed. Improvement was apparent after two injections. An immediate significant (p<0.05) decrease in erythrocyte sedimentation rate, C reactive protein, and interleukin 6 was observed. Side effects consisted of mild reactions at the injection site in two children. CONCLUSIONS: In this observational study, etanercept in combination with methotrexate was well tolerated and highly effective in treating juvenile polyarthritis but not in the patient with systemic arthritis. Combination treatment appears to be feasible in terms of toxicity and may enhance efficiency.     

Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study

OBJECTIVE: To study infliximab and etanercept in the treatment of refractory juvenile idiopathic arthritis (JIA). METHODS: In a non-randomised, prospective, open label study, 24 patients (mean age 10.2 years, range 3.3-16.3) with polyarticular JIA were treated with either infliximab (n=14) or etanercept (n=10). The patients had had active polyarthritis for at least one year and standard treatment had failed. Anti-tumour necrosis factor (TNF) treatment was added to the current drug treatment. Infliximab (3-4 mg/kg) was given intravenously at weeks 0, 2, and 6, and thereafter at 4 to 8 week intervals. Etanercept (0.4 mg/kg) was given subcutaneously twice a week. Improvement of the patients was assessed at 3, 6, and 12 months according to established JIA response criteria. RESULTS: In intention to treat analyses, patients in both treatment groups improved significantly. ACR Paediatric 50 was achieved at 3, 6, and 12 months by 9/10 (90%), 8/9 (89%), and 8/9 (89%) patients with etanercept and by 8/12 (67%), 10/12 (83%), and 7/9 (78%) with infliximab, respectively. At 12 months, ACR Paediatric 75 was achieved by 67% of patients in both treatment groups. Five withdrawals due to adverse effects or lack of efficacy occurred in the infliximab group and one due to lack of compliance in the etanercept group. CONCLUSION: In this open label clinical study of active JIA, both infliximab and etanercept provided a significant rapid and sustained reduction in disease activity. Adequately powered randomised controlled trials are needed to elucidate the long term safety and efficacy of TNF modulators in the treatment of JIA.