Switching the therapy from etanercept to infliximab in a child with rheumatoid factor positive polyarticular juvenile idiopathic arthritis

Abstract

Tumor necrosis factor α (TNFα)-blocking agents have been used increasingly in the treatment of severe refractory juvenile idiopathic arthritis (JIA). However, some patients have been forced to discontinue these agents because of the lack of efficacy or adverse events. In these situations, cases of switching from one TNF-blocking agent to another are reported in rheumatoid arthritis, but there are few cases in JIA. This report documents the case of a patient with JIA who improved following a switch from etanercept to infliximab.     

Use of adalimumab in patients with juvenile idiopathic arthritis refractory to etanercept and/or infliximab

To analyse the effectiveness and safety of adalimumab in a group of patients with juvenile idiopathic arthritis (JIA) who had failed treatment with etanercept and/or infliximab in a single paediatric rheumatology clinic. Patients with JIA with active polyarthritis refractory to metotrexate (MTX) (≥20 mg/m²/week) for at least 3 months and to etanercept (up to 1 mg/kg twice weekly) and/or infliximab (up to 10 mg/kg every 4 weeks) for at least 6 months were included. All patients received adalimumab 24 mg/m²/week concomitantly with MTX 7.5–10 mg/week. Evaluation of efficacy included improvement as defined by the ACR paediatric 30 criteria, 50% and 70% improvement and remission. Six patients were included. Three patients met improvement criteria; 50% and 70% improvement occurred in two children. Improvement was sustained for 12, 24 and 36 months, respectively. Remission occurred in one patient. Adalimumab was discontinued due to lack of efficacy in three patients. No side effects were observed. Adalimumab appears to be effective and safe in patients with JIA refractory to other anti-TNF agents. Further controlled studies are needed in order to assess efficacy of adalimumab in children with refractory JIA.     

Tumour necrosis factor alpha promoter polymorphisms and etanercept therapy in juvenile idiopathic arthritis

The objective of this study was to investigate the influence of TNF-α promoter alleles on clinical response to etanercept therapy in JIA. TNF-α promoter polymorphisms at positions −163, −238, −244, −308, −376 were determined in 137 JIA patients treated with etanercept for at least 3 months. A PCR fragment of about 500 bp of the TNF gene promoter was amplified. Polymorphisms were detected by a single sequencing procedure. Patients with the genotype −308GG achieved an ACR-JRA 30 response at month 6 more frequently than patients with the genotype −308GA or AA. This was already notable at month 3 of therapy. This difference in the total patient group is attributable to the JIA subgroup with rheumatoid factor negative polyarthritis. In this subgroup, patients with the −308GG genotype achieved an ACR-JRA 30 response more frequently than those with the −308GA or AA genotype (84 vs. 33% at months three, P < 0.01, 93 vs. 67% at months six, P < 0.05). There was no influence of the −238 TNF-α promoter alleles on clinical response. The rare alleles at position −376 or at positions −163 and −244 were too infrequent. There is an association between TNF gene promoter polymorphisms and response to etanercept in rheumatoid factor negative polyarticular JIA.     

Clinical impact of switching from infliximab to etanercept in patients with rheumatoid arthritis

We assessed the disease activity in patients with rheumatoid arthritis (RA) after switching from infliximab to etanercept according to the reason of infliximab discontinuation. At Helsinki University Central Hospital during the period 1999 to 2003, 49 patients with RA were switched from infliximab to etanercept. The reasons for infliximab discontinuation were: 42% for failure to respond by >American College of Rheumatology 50% criteria; 12% for adverse events; 46% responded to infliximab and were switched for non-medical reasons. Clinical outcome after the switch was compared between the groups according to the reason of infliximab discontinuation. Disease activity was measured with the 28-joint count Disease Activity Score (DAS28). In patients in the non-medical reasons group, the disease activity was suppressed effectively both during infliximab and etanercept. Furthermore, the one-year drug survival of etanercept in this group was the highest of 77% (95% confidence interval (CI), 62 to 97) among the three groups. In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. The 1-year drug survival of etanercept was 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. For RA patients who discontinued taking infliximab because of non-medical reasons experienced similar treatment efficacy during both biological agents. The treatment with etanercept provided sufficient disease control also for patients with infliximab failure or adverse event. Therefore, etanercept can be suggested when infliximab has failed or discontinued for other reasons.     

A case of planned pregnancy with an interruption in infliximab administration in a 27-year-old female patient with rheumatoid-factor-positive polyarthritis juvenile idiopathic arthritis which improved after restarting infliximab and methotrexate

We report a 27-year-old case of juvenile idiopathic arthritis (JIA) having been stopped infliximab during pregnancy. She was safely treated by infliximab therapy with premedications for preventing infusin reactions after her delivery, and then improved in the same manner as when she had been treated with infliximab therapy before pregnancy. As a result, it remains unclear whether or not we can use infliximab to control disease activities during pregnancy. In addition, it is also important to clarify whether or not premedications should be used when resuming infliximab treatment in such patients after pregnancy. These problems still remain controversial. More definitive data are needed in order to allow rheumatologists to better select the optimal TNF-alpha inhibitor therapy when treating pregnant JIA patients.     

Interleukin-33 as a marker of disease activity in rheumatoid factor positive polyarticular juvenile idiopathic arthritis

Objective: To investigate clinical usefulness of serum interleukin (IL)-33 levels as an indicator of disease activity in juvenile idiopathic arthritis (JIA).

Methods: We measured serum levels of IL-33 in 39 patients with JIA, including 7 patients with rheumatoid factor positive poly-JIA (RF?+?poly-JIA), 8 patients with RF negative poly-JIA (RF-poly-JIA), 20 patients with oligoarticular JIA (Oligo-JIA), 4 patients with enthesitis-related arthritis (ERA) and 30 age-matched healthy controls. Furthermore, we determined their correlation with measures of disease activity.

Results: Serum IL-33 levels in patients with RF?+?poly-JIA were significantly elevated compared to those in patients with RF-poly-JIA, oligo-JIA and HC. Serum IL-33 levels in patients with RF-poly-JIA, oligo-JIA and ERA were not elevated compared to those in HC. Serum IL-33 levels in RF?+?poly-JIA patients normalized in remission phase. Serum IL-33 levels correlated positively with RF in patients with RF?+?poly-JIA.

Conclusions: These results indicate that serum IL-33 levels in RF?+?poly-JIA patients correlated with disease activity, suggesting a potential role of IL-33 as a promising indicator of disease activity.     

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.     

Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept

We present a case of toxic hepatitis related to infliximab treatment in a 38-year-old woman with rheumatoid arthritis (RA). The patient had previously been treated with different disease-modifying drugs (DMARDs) alone or in combination but had never revealed signs of liver dysfunction. Due to high disease activity, treatment with infliximab (3 mg/kg i.v.) was initiated in combination with methotrexate (MTX) (25 mg/week) and folic acid (5 mg/week). The patient stopped MTX and folic acid on her own initiative after 3 weeks due to improvement of joint symptoms. After seven infusions, progressive elevations of the transaminases up to five times the upper normal limit were noted and treatment with infliximab was terminated. Serological tests for viral and autoimmune hepatitis and for ANA and anti-dsDNA were all negative. Specific infliximab antibodies could not be detected. Ultrasound of the liver was normal. Liver biopsy showed late signs of acute toxic hepatitis without MTX-related fibrosis. This is one the first cases that convincingly demonstrates that infliximab treatment may cause toxic hepatitis. Moreover, the case suggests a lack of hepatic cross-toxicity between infliximab and etanercept as the patient continued with etanercept without new episodes of liver dysfunction.     

Safety and efficacy of once-weekly application of Etanercept in children with juvenile idiopathic arthritis

Etanercept—a recombinant TNF receptor fusion protein—has been approved for the treatment of resistant polyarticular juvenile idiopathic arthritis. In children with JIA, 0.4 mg/kg is given subcutaneously twice weekly. In adult patients efficacy and safety of etanercept, 25 mg twice weekly was comparable to 50 mg once weekly. In the German paediatric Etanercept registry six patients with JIA were identified, who received Etanercept once weekly primarily and six patients who received Etanercept initially twice weekly and later once weekly with increased dose per injection. In both groups, treatment was efficacious and well tolerated. In patients switching from twice to once weekly administration, there was no loss of efficacy and no increase in toxicity. At last observation 10/12 patients achieved an ACR-JRA 30 and 8/12 achieved an ACR-JRA70 response. These data indicate that once weekly application of etanercept is safe and efficacous in children.     

Etanercept in the treatment of disease-modifying anti-rheumatic drug (DMARD)-refractory polyarticular course juvenile idiopathic arthritis: experience from Japanese clinical trials

Abstract

Efficacy, safety, and pharmacokinetics results from 4 studies—3 open-label (OL) and 1 randomized double-blind (DB)—have provided data for approval of etanercept for treatment of disease-modifying anti-rheumatic drug (DMARD)-refractory juvenile idiopathic arthritis (JIA) in Japan. Results from the 3 shorter-term (2 OL and 1 DB) studies are reported here. Subjects (4–17 years) enrolled in the OL studies had active JIA, i.e. ≥ 5 swollen joints and ≥ 3 joints with limitation of motion and pain or tenderness. Subjects enrolled in the primary OL study received etanercept 0.4 mg/kg subcutaneously twice weekly; in the lower-dose OL study subjects received etanercept 0.2 mg/kg. Subjects in the primary OL study who completed ≥ 48 weeks could continue into a 12-week DB dose-down extension study in which subjects received etanercept 0.4 or 0.2 mg/kg twice weekly. The primary endpoint in all 3 studies, i.e. 30% improvement in the American College of Rheumatology criteria for JIA (ACR Pedi 30) at 12 weeks, was achieved by ≥ 80% of subjects by week 2 and sustained to week 12. Common adverse events reported were injection site reactions, nasopharyngitis, and gastroenteritis. These results provide further evidence that etanercept is effective therapy for DMARD-refractory polyarticular JIA patients.     

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.     

HLA-DRB typing among polyarticular juvenile idiopathic arthritis and progressive pseudorheumatoid dysplasia patients

Juvenile Idiopathic Arthritis (JIA) is a multi-factorial disease influenced both by environmental and genetic factors. Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disorder affecting multiple joints, mimicking JIA. Aim of the work: to reveal the frequency of HLA-DR types among the studied patients and to correlate the different allele variations clinically. Patients and methods: Thirty JIA patients, in addition to 15 molecularly diagnosed PPD patients were subjected to full history taking and clinical examination. HLA-DRB1 typing was performed to 24/30 JIA and 12/15 PPD cases and thirty healthy age and sex matched children who were included as a control group. Results: The JIA patients were 22 females and 8 males with mean age of 15.8 ± 1.96 years and disease duration 5.3 ± 4.4 years. PPD patients were 8 males and 7 females with mean age of 8.7 ± 3.06 years and disease duration 3.95 ± 2.68 years. A significant frequency of HLA-DRB 04 (p = 0.049) among JIA patients was present in comparison to the controls (OR = 2.81, CI:1.02–7.75), other risky alleles were HLA-DRB 10, 13 and 15. However, HLA-DRB 01, 03, 07, 11 and 14 were found to be protective. HLA-DRB 01, 04, 10 and 13 were found to be risky alleles in PPD. However, HLA 03, 07, 11 and 15 were found to be protective alleles among PPD patients. Conclusion: HLA-DRB 04 was found in a higher frequency in JIA patients with a significant difference in comparison to the controls, denoting that it may play a role in the genetic pathogenesis of JIA.     

Influence of antibodies against infliximab and etanercept on the treatment effectiveness of these agents in Japanese patients with rheumatoid arthritis

Abstract

We investigated the influence of antibodies against infliximab and etanercept on the serum trough levels of these agents and the influence of these antibodies on the effectiveness of treatment in patients with rheumatoid arthritis treated with these agents. Forty patients treated with infliximab for 54 weeks and 40 patients treated with etanercept for 32 weeks were enrolled. They were divided into responder and non-responder groups. Serum trough levels of and antibodies against these agents were measured by enzyme-linked immunosorbent assay or radioimmunoassay. Of the 40 patients treated with infliximab, 14 (35%) had anti-infliximab antibodies. Serum trough levels were significantly lower in the non-responder group (14 patients) than in the responder group (26 patients) 6 weeks after initiation of infliximab (p < 0.05). Conversely, titers of anti-infliximab antibody were significantly higher in the non-responder group than in the responder group between 6 and 38 weeks after initiation of infliximab (p < 0.05). Anti-etanercept antibodies were not detected in any patients on etanercept. Serum trough levels of etanercept were not significantly different between the responder (31 patients) and non-responder groups (9 patients). It seems that the appearance of anti-infliximab antibodies might decrease infliximab serum concentrations and, thereby, reduce the agent’s effectiveness. The clinical efficacy of etanercept does not appear to be affected by the serum concentrations if it is administered at standard doses.     

Chitotriosidase activity in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is an inflammatory joint disease of unknown etiology. The pathogenesis is driven by T and B cells. The role of macrophages remains unclear. Chitotriosidase belongs to the chitinase protein family and is secreted by activated macrophages. The chitinases are able to catalyze the hydrolysis of chitin or chitin-like substrates such as 4-methylumbelliferyl chitotrioside. Chitotriosidase activity was determined using the substrate 4-methylumbelliferyl beta-DNN'N'-triacetylchitotrioside (4-MU-TCT, SIGMA Chemical Co.). The substrate and serum were incubated with the serum in a citrate/phosphate buffer. The reaction was stopped by adding a buffer (Na(2)CO(3)). The fluorescence of 4-methylumbelliferone was evaluated by fluorimeter at excitation 360 nm and emission 450 nm. We report about chitotriosidase measurements in patients with JIA. The chitotriosidase level in synovial fluid was up to approximately 1,000 nmol/(h ml) at disease onset before therapy. The level in the sera was below 600 nmol/(h ml). Serum chitotriosidase levels could represent the activity of macrophages in the synovial fluid in JIA.     

Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis

Abstract

Application of biological agents targeting tumor necrosis factor-α (TNF-α) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-α agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-α blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-α blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-α blocking agents and be alert to any adverse events for a better management of RA patients.     

Analysis of childhood reactive arthritis and comparison with juvenile idiopathic arthritis

There is currently no agreement on how to classify and diagnose reactive arthritis (ReA) and what kind of clinical and laboratory findings are specific for the diagnosis. This study retrospectively analyzed the initial clinical manifestations and laboratory findings in children diagnosed with ReA and juvenile idiopathic arthritis (JIA). A comparison was also made between these two groups to see if there were differences. A retrospective chart review was performed and 44 patients diagnosed with ReA and 80 patients with JIA were enrolled in this study. Their initial clinical manifestations and laboratory findings were also analyzed and compared. The initial clinical manifestations in ReA were analyzed including the demographic data, the preceding infection history, the duration of the infectious episode to the onset of arthritis, the duration of arthritic symptoms, and the involved joint pattern. Comparison of the initial laboratory findings between patients with ReA and JIA showed significant differences between erythrocyte sedimentation rates (ESR) in the first hour, platelet counts (p<0.05), and ESR in the second hour (p=0.052). Further, comparing ReA with the subtypes of JIA, significant differences were noted between ReA and the systemic type in terms of hemoglobin level, platelet counts, C-reactive protein, and first and second hour ESR (p<0.05). However, if compared with the polyarticular or pauciarticular type, only the platelet counts showed any significant statistical difference (p<0.05). This study summarizes clinical experiences in ReA. The differences in laboratory findings of ReA and JIA may provide a clue in making a differential diagnosis.     

Efficacy of treatment intensification with adalimumab,etanercept and infliximab in rheumatoid arthritis: A systematic review of cohort studies with focus on dose

Objectives

To summarize the empirical evidence regarding the effect of treatment intensification on clinical outcomes in patients with rheumatoid arthritis treated with one of the TNF-α-inhibitors, adalimumab, etanercept or infliximab.

Methods

A systematic search of the bibliographic databases Embase, Medline, Web of Science and Cochrane Central identifying articles concerning treatment with adalimumab, etanercept or infliximab in adult patients with rheumatoid arthritis exposed to dose increase or shortening of dosing intervals was performed. Longitudinal cohorts, both clinical trials and observational studies, were included. ACR and EULAR response criteria and DAS28 were the preferred outcome measures.

Results

Out of 1135 records, eleven studies were included in the final evidence synthesis. One article concerned all the three TNF-α-inhibitors, eight used infliximab, one adalimumab and one etanercept. According to GRADE, evidence was weakened in particular by the lack of control groups, and for treatment intensification with adalimumab and etanercept, no conclusions could be drawn. With infliximab, two trials of high quality revealed contradictory results, but six studies described an improved clinical outcome following intensified treatment strategies. Some studies (2/2) also indicated that for infliximab, frequency increase was superior to dose increase.

Conclusions

Available studies indicate that intensifying treatment with infliximab in rheumatoid arthritis patients, preferably by increasing the frequency of drug administration, may lead to improved clinical outcome in some patients, but the evidence is weak. There is an urgent need for prospectively designed cohort studies to be able to draw a final conclusion.     

Pulmonary function in children with juvenile idiopathic arthritis and effects of methotrexate therapy

Summary Objective To evaluate impairment of lung function as an adverse effect associated with methotrexate therapy in patients with juvenile idiopathic arthritis (JIA). Methods We performed pulmonary function testing including diffusion capacity for carbon monoxide as measured by the single breath method (DLCO-SB) in 89 children with juvenile idiopathic arthritis. Forty (45%) were treated with methotrexate for a median of 24 months (range 3 to 120 months). Except for the presence of asthma in two children, there was no clinical or radiological evidence of pulmonary disease. Results Pulmonary function testing demonstrated moderate airway obstruction in two children with known bronchial asthma. Neither obstructive nor restrictive alteration of ventilation was found in any other patient. Two juvenile idiopathic arthritis patients showed a reduced CO diffusion capacity of 64 and 67%. One of them was treated with methotrexate. Conclusions With regard to lung function impairment treatment with low dose methotrexate appears to be safe even when performed for several years reaching a total amount of up to 3.5 g. In contrast to studies performed in adult rheumatoid arthritis patients, in children with juvenile idiopathic arthritis impairment of lung function is a rare event. Received: 23 February 2001 Accepted: 16 May 2001     

Etanercept and infliximab induce the same serological autoimmune modifications in patients with rheumatoid arthritis

Etanercept and infliximab treatments are often associated with autoantibodies induction. Their reported prevalences vary among different studies and the conclusions are somehow conflicting, mainly regarding whether the two drugs induce the same modifications. In this small prospective study, specifically designed to identify transient phenomena, we assess the prevalence of different relevant rheumatologic autoantibodies during anti-TNF-α courses in patients with rheumatoid arthritis. We report that both etanercept and infliximab transiently induce anti-DNA antibodies in 50–78% of patients, respectively, and these antibodies seem to be different from the typical lupus associated ones. Antinuclear antibodies (ANA) increased their titres and were newly produced up to 100% of patients. No other relevant antibodies are affected. Finally, as also confirmed for the first time by the patients switched from one drug to the other, the two TNF-α blockers behave similarly.