Efficacy, pharmacokinetics, and safety of adalimumab in pediatric patients with juvenile idiopathic arthritis in Japan Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Anti-adalimumab antibodies in a cohort of patients with juvenile idiopathic arthritis: incidence and clinical correlations Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. Two-year Efficacy and Safety of Etanercept in Pediatric Patients with Extended Oligoarthritis, Enthesitis-related Arthritis, or Psoriatic Arthritis Long‐Term Safety, Efficacy, and Quality of Life in Patients With Juvenile Idiopathic Arthritis Treated With Intravenous Abatacept for Up to Seven Years Longterm Safety and Effectiveness of the Anti-interleukin 6 Receptor Monoclonal Antibody Tocilizumab in Patients with Systemic Juvenile Idiopathic Arthritis in Japan A Randomized, Double‐Blind, Placebo‐Controlled Multicenter Study of Adalimumab in Pediatric Patients With Enthesitis‐Related Arthritis Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study Comparing ELISA and Surface Plasmon Resonance for Assessing Clinical Immunogenicity of Panitumumab A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Pharmacokinetics and Pharmacodynamics of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis. 2.3 Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular course juvenile rheumatoid arthritis (JRA): Findings from an open-label treatment extension Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.
The objective of this study was to evaluate the efficacy , pharmacokinetics , and safety of adalimumab in patients with polyarticular juvenile idiopathic arthritis ( JIA ) in Japan . Patients aged 4 to 17 years were enrolled in a single-arm , open-label , multicentre study of adalimumab .  Patients weighing < 30 kg received 20 mg every other week ( eow ) , and those ≥30 kg received 40 mg eow . Concomitant methotrexate ( MTX ) was allowed ( ≤10 mg/m2 per week ) . The primary efficacy outcome was the percent of patients with American College of Rheumatology Pediatric 30 response  ( ACR Pedi 30 ) at week 16 . JIA core variables , serum adalimumab concentrations , and anti-adalimumab antibodies ( AAAs ) were analysed . Patients were monitored for adverse events ( AEs ) . Twenty-five patients ( 20 with concomitant MTX at baseline and 5 without ) were enrolled : 24 patients completed 16 weeks of therapy and 22 patients completed 60 weeks . At week 16 , 90 % of patients with MTX and 100 % without MTX  achieved ACR Pedi 30 ; response rates were maintained through week 60 in 94 and 80 % of patients , respectively . Each JIA core variable improved over time . Six patients became AAA positive ( two each at weeks 8 , 16 , and 60 ) , some of which were transient . All six AAA-positive patients achieved ACR Pedi 30 at week 16 , and four maintained that response at week 60 . Six patients ( all with MTX ) experienced nine serious AEs ( JIA , pyrexia , arthralgia , pneumonia , hepatitis B infection , pharyngitis , dehydration , pharyngeal pain , and pneumonia ) . In pediatric patients with polyarticular JIA in Japan , adalimumab was safe and effective for reducing disease activity for up to 60 weeks Objective To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis ( pcJIA ) . Methods This three-part , r and omised , placebo-controlled , double-blind withdrawal study ( NCT00988221 ) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate .  During part 1 , patients received open-label tocilizumab every 4 weeks ( 8 or 10 mg/kg for body weight ( BW ) < 30 kg ; 8 mg/kg for BW ≥30 kg ) . At week 16 , patients with ≥JIA-American College of Rheumatology ( ACR ) 30 improvement entered the 24-week , double-blind part 2 after r and omisation 1:1 to placebo or tocilizumab ( stratified by methotrexate and steroid background therapy ) for evaluation of the primary end point : JIA flare , compared with week 16 . Patients flaring or completing part 2 received open-label tocilizumab . Results In part 1 , 188 patients received tocilizumab  ( < 30 kg : 10 mg/kg ( n=35 ) or 8 mg/kg ( n=34 ) ; ≥30 kg : n=119 ) . In part 2 , 163 patients  received tocilizumab ( n=82 ) or placebo ( n=81 ) . JIA flare occurred in 48.1 % of patients on placebo versus 25.6 % continuing tocilizumab ( difference in means adjusted for stratification : −0.21 ; 95 % CI −0.35 to −0.08 ; p=0.0024 ) . At the end of part 2 , 64.6 % and 45.1 % of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses , respectively . Rates/100 patient-years ( PY ) of adverse events ( AEs ) and serious AEs ( SAEs ) were 480 and 12.5 , respectively ; infections were the most common SAE ( 4.9/100 PY ) . Conclusions Tocilizumab treatment results in significant improvement , maintained over time , of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis . Trial registration number : NCT00988221 OBJECTIVE To determine the long-term safety and efficacy of rilonacept , an anti-interleukin-1 fusion protein , in patients with active systemic juvenile idiopathic arthritis ( JIA ) . METHODS In patients with systemic JIA , ages 4 - 20 years , the efficacy of rilonacept was evaluated using 30 % , 50 % , and 70 % levels of improvement according to the adapted American College of Rheumatology ( ACR ) Pediatric 30 , 50 , and 70 response criteria , respectively . Efficacy and safety were evaluated during 23 months of open-label treatment ( 3 phases ) after a 4-week , double-blind , placebo-controlled phase . Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept , patients were eligible to receive open-label treatment at their prior dose , with adjustments . Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity ( i.e. , decreased levels of D-dimer and myeloid-related proteins [ MRPs ] ) were also evaluated . RESULTS Twenty-four patients entered the double-blind study and 23 entered the open-label period . Patients were predominantly white and female , and had a median age of 14.0 years at baseline . No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase , but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur . Adapted ACR Pediatric 30 , 50 , and 70 response rates at 3 months from the start of the study were 78.3 % , 60.9 % , and 34.8 % , respectively ; these responses were generally maintained over the study duration . Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study , and in 22 of 23 patients , the prednisone dose was decreased or prednisone therapy was discontinued . No serious treatment-related adverse events were observed . CONCLUSION Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in > 50 % of rilonacept-treated patients over 2 years . Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated Adalimumab is a TNF-α blocker antibody similar in structure and function to natural human IgG1 . Even if adalimumab is fully humanized , the development of anti-drug antibodies has been reported in several inflammatory conditions . The objective of our study was to assess the presence of  anti-adalimumab antibodies ( AAA ) and their clinical relevance in a cohort of juvenile idiopathic arthritis ( JIA ) patients on adalimumab . This is a prospect i ve observational cohort study recruiting JIA children . Experiments were performed using a vali date d surface plasmon resonance (SPR)-based optical assay ( Biacore ® T100 ) . Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score with 10 joint count ( JADAS-10 ) . The Mann – Whitney U test , Wilcoxon signed-rank test for paired sample s , chi-square , and Fisher exact test were used to compare data . Pearson ’s and Spearman ’s correlation tests were used to determine correlation coefficients for entered variables : demographic , clinical , and serological data . Ten ( 37 % ) out of 27 patients included in the study had at least one AAA-positive sample . Patients developed AAA between 3 and 38 months after starting adalimumab . Seven ( 70 % ) out of 10 children with AAA positivity experienced at least a relapse compared to 4 ( 23.5 % ) out of 17 AAA-negative children ( rs 0.45 , p < 0.017 ) . In conclusion , using an innovative and accurate assay method , we found a high incidence of anti-drug antibodies in a cohort of adalimumab-treated JIA patients observed over a mean period of 40 weeks ; the presence of anti-adalimumab antibodies seemed to be related to the number of relapses BACKGROUND We evaluated the safety and efficacy of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein , in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate . METHODS Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial , open-label part of a multicenter trial . Those who responded to treatment then entered a double-blind study and were r and omly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred . A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity , with no more than one indicator worsening by more than 30 percent . RESULTS At the end of the open-label study , 51 of the 69 patients ( 74 percent ) had had responses to etanercept treatment . In the double-blind study , 21 of the 26 patients who received placebo ( 81 percent ) withdrew because of disease flare , as compared with 7 of the 25 patients who received etanercept ( 28 percent ) ( P=0.003 ) . The median time to disease flare with placebo was 28 days , as compared with more than 116 days with etanercept ( P<0.001 ) . In the double-blind study , there were no significant differences between the two treatment groups in the frequency of adverse events . CONCLUSIONS Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis .  Etanercept is well tolerated by pediatric patients Objective . The main objective was to determine the 2-year clinical benefit and safety of  etanercept ( ETN ) in children with the juvenile idiopathic arthritis ( JIA ) categories of extended oligoarthritis ( eoJIA ) , enthesitis-related arthritis ( ERA ) , or psoriatic arthritis ( PsA ) . Methods . CLIPPER was a 96-week , phase IIIb , open-label , multicenter study . Patients with eoJIA , ERA , or PsA received ETN 0.8 mg/kg once weekly ( 50 mg max ) for up to 96 weeks . The proportions of patients reaching the JIA American College of Rheumatology ( ACR ) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated . Adverse events ( AE ) were collected throughout the study ( intention-to-treat sample ) . Results . There were 127 patients ( eoJIA n = 60 , ERA n = 38 , PsA n = 29 ) who received ≥ 1 dose of ETN .  The mean disease duration was 31.6 ( eoJIA ) , 23.0 ( ERA ) , and 21.8 ( PsA ) months . At Week 96 , JIA ACR 30/50/70/90/100/inactive disease responses ( 95 % CI ) were achieved by 84.3 % ( 76.7 , 90.1 ) , 83.5 % ( 75.8 , 89.5 ) , 78.7 % ( 70.6 , 85.5 ) , 55.1 % ( 46.0 , 63.9 ) , 45.7 % ( 36.8 , 54.7 ) , and 27.6 % ( 20.0 , 36.2 ) of patients , respectively . The most common AE ( no. events , events per 100 patient-yrs ) overall were headache ( 23 , 10.7 ) , pyrexia ( 12 , 5.6 ) , and diarrhea ( 10 , 4.6 ) . The most common infections were upper respiratory tract infection ( 83 , 38.6 ) , pharyngitis ( 50 , 23.2 ) , gastroenteritis ( 22 , 10.2 ) , bronchitis ( 19 , 8.8 ) , and rhinitis ( 17 , 7.9 ) . No cases of malignancy , active tuberculosis , demyelinating disorders , or death were reported . Conclusion . Over 96 weeks of therapy , ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories , with no major safety issues The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis ( JIA ) who experienced an inadequate response to disease‐modifying antirheumatic drugs were previously established in a phase III study that included a 4‐month open‐label lead‐in period , a 6‐month double‐blind withdrawal period , and a long‐term extension ( LTE ) phase . The aim of this study was to present the safety , efficacy , and patient‐reported outcomes  of abatacept treatment ( 10 mg/kg every 4 weeks ) during the LTE phase , for up to 7 years of followup Objective . To assess the longterm safety and effectiveness of tocilizumab ( TCZ ) in systemic-onset juvenile idiopathic arthritis ( sJIA ) . Methods . The longterm extension phase of 2 pivotal studies ( phase II with 11 patients and phase III with 56 patients ) in patients with active sJIA was analyzed . Patients received open-label TCZ ( 8 mg/kg , every 2 weeks ) without concomitant use of disease-modifying antirheumatic drugs . Results . In total , 67 patients were enrolled . All patients received corticosteroid at baseline . Median duration of exposure to TCZ was 3.4 years . Nine patients withdrew from the study [ 4 because of adverse events ( AE ) , 4 because of the development of anti-TCZ antibodies , and 1 because of inadequate response ]  . Rates of AE and serious AE were 803.7/100 patient-years ( PY ) and 34.7/100 PY , respectively . The most common serious AE were infections ( 13.2/100 PY ) . No cases of malignancy or death were reported . Two serious infusion reactions were reported in patients testing negative for anti-TCZ antibodies . One definite macrophage activation syndrome ( MAS ) case and 1 potential MAS case were identified . American College of Rheumatology ( ACR ) response rates attained early in the TCZ treatment period were maintained throughout the study : at Week 168 , JIA ACR 30 , 50 , 70 , 90 , and 100 response rates were 80.3 % , 80.3 % , 75.4 % , 60.7 % , and 18.0 % , respectively . In total , 22 of 67 patients ( 32.8 % ) completely discontinued corticosteroids without flare . Conclusion . TCZ has demonstrated durability of effectiveness in the longterm treatment of children with sJIA and has shown good tolerability and a low discontinuation rate associated with AE , development of anti-TCZ antibodies , or inadequate response . ( Clinical Trials.gov NCT00144599 and NCT00144612 ) . ( First Release March 15 2014 ; J Rheumatol 2014;41:759 - 67 ; doi:10.3899/jrheum.130690 Enthesitis‐related arthritis ( ERA ) is a juvenile idiopathic arthritis ( JIA ) category , primarily affecting entheses and peripheral joints . This study evaluated efficacy , safety , and pharmacokinetics of adalimumab versus placebo in patients with ERA The objective of this study was to assess the safety of adalimumab in patients aged 2 to < 4 years old or ≥4 years old weighing < 15 kg with moderately to severely active polyarticular juvenile idiopathic arthritis ( JIA ) .  Clinical effectiveness and pharmacokinetics ( PK ) of adalimumab were also evaluated . This was an international , multicenter , open-label , phase 3b study in 32 patients with active JIA that were treated with adalimumab 24 mg/m2 ( maximum = 20 mg/dose ) every other week up to 120 weeks , with or without concomitant methotrexate . Adverse events ( AEs ) were summarized for completed visits . Efficacy endpoints included American College of Rheumatology pediatric ( PedACR ) 30/50/70/90 responses and JIA core components .  Adalimumab serum trough concentrations were measured in a subset of patients . Among the patients , 88 % were female . Baseline mean age , weight , and JIA duration were 3 years , 13 kg , and 12 months , respectively ; 39 % had elevated C-reactive protein . AE incidence rates included any AEs ( 29/32 , 91 % ) , serious AEs ( 5/32 , 16 % ) , infectious AEs ( 25/32 , 78 % ) , and serious infections ( 3/32 , 9 % ) . No deaths , malignancies , or opportunistic infections were reported . Growth was not adversely impacted . At week 96 , 92 % of patients achieved PedACR30 , and 77 % achieved PedACR70 . Improvements in JIA core components were observed . Mean steady-state serum adalimumab trough concentrations were 7–8 μg/mL at weeks 12 and 24 . Adalimumab  was well tolerated in JIA patients aged 2 to < 4 years old or ≥4 years old weighing < 15 kg .  The efficacy and PK of adalimumab were comparable to those seen in older JIA patients Objective This report aims to determine the safety , pharmacokinetics ( PK ) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis ( polyJIA ) . Methods In this three-part r and omised double-blinded placebo-controlled withdrawal trial , all patients received open-label  golimumab ( 30 mg/m2 of body surface area ; maximum : 50 mg/dose ) every 4 weeks together with weekly methotrexate during Part 1 ( weeks 0–16 ) . Patients with at least 30 % improvement per American College of Rheumatology Criteria for JIA ( JIA ACR30 ) in Part 1 entered the double-blinded Part 2 ( weeks 16–48 ) after 1:1 r and omisation to continue golimumab or start placebo . In Part 3 , golimumab was continued or could be restarted as in Part 1 . The primary outcome was JIA flares in Part 2 ; secondary outcomes included JIA ACR50/70/90 responses , clinical remission , PK and safety . Results Among 173 patients with polyJIA enrolled , 89.0 % ( 154/173 ) had a JIA ACR30 response and 79.2%/65.9%/36.4 % demonstrated JIA ACR50/70/90 responses  in Part 1 . At week 48 , the primary endpoint was not met as treatment groups had comparable JIA flare rates  ( golimumab vs placebo : 32/78=41 % vs 36/76=47 % ; p=0.41 ) , and rates of clinical remission were comparable ( golimumab vs placebo : 10/78=12.8 % vs 9/76=11.8 % ) . Adverse event and serious adverse event rates were similar in the treatment groups during Part 2 . Injection site reactions occurred with < 1 % of all injections . PK analysis confirmed adequate golimumab dosing for polyJIA . Conclusion Although the primary endpoint was not met , golimumab result ed in rapid , clinical ly meaningful , improvement in children with active polyJIA . Golimumab was well tolerated , and no unexpected safety events occurred . Clinical Trial Registration NCT01230827 ; Results 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 , r and omized , 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 > or=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 clinical ly 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 This study assessed the safety and preliminary efficacy of the interleukin-1 receptor antagonist anakinra in patients with polyarticular-course juvenile rheumatoid arthritis ( JRA ) . Eighty-six patients entered a 12-week open-label run-in phase ( 1 mg/kg anakinra daily , ≤100 mg/day ) . Fifty responders were r and omized to anakinra or placebo in a 16-week blinded phase , followed by a 12-month open-label extension ( N = 44 ) . Due to low enrollment , the primary endpoint was changed from efficacy to safety . The incidence and nature of adverse events were similar across all study phases , with the exception of injection site reactions , which were mild to moderate and decreased with time . Anakinra produced a nonsignificant ( P = 0.11 ) reduction in disease flares  compared with placebo . When normalized to 1 mg/kg dose , anakinra plasma concentrations were similar to values in adult patients with rheumatoid arthritis . These results indicate that anakinra 1 mg/kg once daily ( ≤100 mg/day ) is safe and well tolerated in patients with JRA Evaluation of the immunogenicity of panitumumab , a fully human anti-epidermal growth factor receptor mAb approved for use in colorectal cancer patients , led to the development of two separate immunoassays for the detection of anti-panitumumab Abs . The first immunoassay used a bridging ELISA capable of detecting 10 ng/ml positive control anti-panitumumab Ab . The ELISA incorporated an acid dissociation step to reduce drug interference and tolerated the presence of ∼100-fold molar excess of drug . During eight clinical trials , the ELISA detected developing Ab responses in 2 of 612 ( 0.3 % ) subjects . In one of the ELISA positive subjects , neutralizing Abs were detected using an epidermal growth factor receptor phosphorylation bioassay . The second immunoassay used a Biacore biosensor immunoassay format capable of detecting 1 μg/ml positive control Ab while tolerating the presence of equal molar amounts of drug . Although less sensitive and less tolerant to competing drug in the assay , the Biacore assay detected developing Ab responses in 25 of the 604 ( 4.1 % ) subjects . Additionally , the Biacore assay identified eight subjects who developed neutralizing Abs . Mouse mAbs with affinities ranging from 1.1 × 10−6 to 8.4 × 10−10 M were used to characterize both assay types . The ELISA was more sensitive for the detection of higher affinity mAbs and detected high-affinity mAbs in the presence of higher molar ratio of drug to mAb . The Biacore assay was more sensitive for detection of lower affinity mAbs and detected low affinity Abs in the presence of higher molar ratios of drug to mAb OBJECTIVE To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis ( JRA ) . METHODS This was an international , multicenter , r and omized , placebo-controlled , double-blind study . One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate ( MTX ) therapy were r and omized to receive infliximab or placebo for 14 weeks , after which all children received infliximab through week 44 . Patients received MTX plus infliximab 3 mg/kg through week 44 , or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44 . RESULTS Although a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology ( ACR ) Pediatric 30 ( Pedi 30 ) criteria for improvement at week 14 ( 63.8 % and 49.2 % , respectively ) , the between-group difference in this primary efficacy end point was not statistically significant ( P = 0.12 ) . By week 16 , after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab , an ACR Pedi 30 response was achieved in 73.2 % of all patients . By week 52 , ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6 % and 51.8 % , respectively , of patients . Infliximab was generally well tolerated , but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg , with more frequent occurrences of serious adverse events , infusion reactions , antibodies to infliximab , and newly induced antinuclear antibodies and antibodies to double-str and ed DNA observed with the 3 mg/kg dose . CONCLUSION While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year , achievement of the primary efficacy end point at 3 months did not differ significantly between  infliximab-treated  and  placebo-treated  patients . Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile . These results warrant further investigation in children with JRA We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis ( pJIA ) with polyarticular or oligoarticular onset . Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies : initial study ( to week 12 ) and then an extension study ( at least 48 weeks ) . Nineteen patients intractable to conventional methotrexate therapy were enrolled . Seventeen patients had polyarticular-onset pJIA ; two had oligoarticular-onset pJIA . Mean age was 11.6 years ; mean disease duration 5.3 years .  American College of Rheumatology Pediatric ( ACR Pedi ) 30 , 50 , 70 , and 90 response rates , respectively , were 94.7 % , 94.7 % , 57.9 % , and 10.5 % at week 12 , and 100 % , 94.1 % , 88.2 % , and 64.7 % at week 48 . Mean disease activity score ( DAS28 ) remained below the remission level ( 2.6 ) from week 24 . Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient ( one patient ) and antitocilizumab antibodies developed ( one patient ) . Adverse events were generally mild , and the four serious adverse events resolved spontaneously or with treatment . In conclusion , tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA , which suggests that it is a promising new treatment for this disease OBJECTIVE To assess dosing , preliminary safety , and efficacy of canakinumab , a fully human anti-interleukin-1β ( anti-IL-1β ) antibody , in children with systemic juvenile idiopathic arthritis ( JIA ) and active systemic features . METHODS In this phase II , multicenter , open-label , dosage-escalation study , children with systemic JIA who were ≥4 years of age , had fever , and were receiving ≤0.4 mg/kg/day of corticosteroids  were administered a single subcutaneous dose of canakinumab , 0.5 - 9 mg/kg of body weight , and were redosed upon relapse . Response to treatment was assessed according to an adaptation of the American College of Rheumatology ( ACR ) pediatric criteria for improvement . RESULTS A total of 23 children ages 4 - 19 years with active disease were enrolled . Of these , 1 patient was excluded from analysis , and 3 of the reenrolled patients were included twice in the efficacy analysis . By day 15 of the first treatment cycle , 15 of 25 patients ( 60 % ) had achieved an adapted ACR Pediatric 50 response , with 4 of them achieving inactive disease status . Response was sustained over time , with 11 of 13 patients able to maintain their response throughout the study . In 8 of the 11 responders who had been receiving steroids at baseline , the steroid dosage was decreased from a mean of 0.38 mg/kg/day to 0.13 mg/kg/day over the first 5 months , and 4 of them were able to discontinue steroids . At a dose of 4 mg/kg of canakinumab given subcutaneously every 4 weeks , the median percentage of patients predicted to relapse within 4 weeks was estimated to be 6 % ( 95 % confidence interval 1 - 21 ) . Therapy was generally well tolerated and few patients experienced injection-site reactions . CONCLUSION Canakinumab  has a promising preliminary safety and efficacy profile in this limited cohort . Based on the findings of this trial , further studies in a larger population of children with systemic JIA are warranted The characterization of the pharmacokinetic ( PK ) and pharmacodynamic ( PD ) properties in pediatric patients is essential in supporting the recommended dosage of canakinumab in the relevant population . Here the PK and PD properties of canakinumab-a monoclonal antibody-in  pediatric patients with systemic juvenile idiopathic arthritis ( SJIA ) are presented . Blood sample s were obtained from 4 phase 2/3 clinical studies in patients with SJIA .  Canakinumab PK properties and total interleukin (IL)-1β kinetic properties were characterized by a population -based PK-binding model . On administration , canakinumab increased total IL-1β complex in SJIA patients . Canakinumab clearance and volume of distribution were not impacted by age in pediatric patients after correction for the patient 's body weight . The estimated serum clearance of canakinumab was 0.106 ± 0.00689 L/day , with a corresponding volume of distribution at steady state of 3.2 L and an estimated half-life of 22 days , based on a model typical body weight of 33 kg . Body-weight-based dosing provided comparable canakinumab exposure across the age groups in patients 2 to < 20 years with SJIA . In younger children , a modest increase in the turnover rate of IL-1β was observed . Compared to other indications , IL-1β production rate was higher and clearance was slower in patients with SJIA . Low immunogenicity incidence of 3.1 % was observed , and none of the patients had neutralizing antibodies . In conclusion , the PK/PD findings further support dose selection of canakinumab in patients with SJIA We report long-term safety & efficacy of infliximab (IFX)+ methotrexate ( MTX ) treatment in JRA patients . In an international , multicenter , r and omized , double-blind study , 122 children w/active polyarticular JRA despite prior MTX therapy  received MTX plus a 3-dose induction ( wks 0 , 2 , 6 ) of IFX 3 mg/kg through wk 44 , or placebo ( PBO ) for 14 wks followed by IFX 6 mg/kg ( wks 14 , 16 , 20 , & then q8 wks ) through wk 44 . Patients completing treatment through wk 44 were eligible to enter an open-label extension ( OLE ) of IFX 3 mg/kg , beginning at wk 52 & continuing q8 wks through wk 196 . All patients continued with concomitant MTX . Physicians could increase or decrease the IFX dose by ≤1.5 mg/kg/infusion q8 wks , up to 6 mg/kg or down to 3 mg/kg , based on clinical response . Primary endpoint was the proportion of patients meeting ACR-Pedi-30 , defined as improvement of ≥30 % in ≥3 of 6 core variables , & ≤1 of the remaining variables worsened by > 30 % . Remission was defined as 0 joints with active arthritis , normal ESR , & physician 's global assessment ≤10 mm on a 10-cm visual analog scale . 78/122(63.9 % ) children entered the OLE . The mean(SD ) IFX  dose at wk 196 was 4.4(1.6)mg/kg . IFX  was well-tolerated;14.1 % of patients discontinued due to adverse events ( AE ) from wks 52–204 . The distribution/types of AE were similar to those in the first 52 wks & no new safety issues were reported . Among the 36 study patients by wk 204 , ACR-Pedi-30/50/70/90 responses were 91.7%(33/36 ) , 83.3%(30/36 ) , 69.4%(25/36 ) , & 50%(18/36 ) , respectively . 39%(14/36 ) of patients achieved remission . From wk 52 through wk 216 , 36.6%(26/71 ) of patients were positive for IFXantibodies ; 57.7%(15/26 ) of these had an infusion reaction . Continuous IFX+MTX administered up to 4 yrs was safe & effective in JRA patients , although accompanied by a high rate of patient discontinuation , which included subjects in remission BACKGROUND Systemic juvenile idiopathic arthritis ( JIA ) is the most severe subtype of JIA ; treatment options are limited . Interleukin-6 plays a pathogenic role in systemic JIA . METHODS We r and omly assigned 112 children , 2 to 17 years of age , with active systemic JIA ( duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids ) to the anti-interleukin-6 receptor antibody tocilizumab  ( at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was < 30 kg ) or placebo given intravenously every 2 weeks during the 12-week , double-blind phase . Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab . All patients could enter an open-label extension . RESULTS At week 12 , the primary end point ( an absence of fever and an improvement of 30 % or more on at least three of the six variables in the American College of Rheumatology [ ACR ] core set for JIA , with no more than one variable worsening by more than 30 % ) was met in significantly more patients in the tocilizumab group than in the placebo group ( 64 of 75 [ 85 % ] vs. 9 of 37 [ 24 % ] , P<0.001 ) . At week 52 , 80 % of the patients who received tocilizumab had at least 70 % improvement with no fever , including 59 % who had 90 % improvement ; in addition , 48 % of the patients had no joints with active arthritis , and 52 % had discontinued oral glucocorticoids . In the double-blind phase , 159 adverse events , including 60 infections ( 2 serious ) , occurred in the tocilizumab group , as compared with 38 , including 15 infections , in the placebo group . In the double-blind and extension periods combined , 39 serious adverse events ( 0.25 per patient-year ) , including 18 serious infections ( 0.11 per patient-year ) , occurred in patients who received tocilizumab . Neutropenia developed in 19 patients ( 17 patients with grade 3 and 2 patients with grade 4 ) , and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range . CONCLUSIONS Tocilizumab was efficacious in severe , persistent systemic JIA . Adverse events were common and included infection , neutropenia , and increased aminotransferase levels . ( Funded by Hoffmann-La Roche ; Clinical Trials.gov number , NCT00642460 . ) BACKGROUND Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis ( JIA ) . We assessed the efficacy and safety of canakinumab , a selective , fully human , anti-interleukin-1β monoclonal antibody , in two trials . METHODS In trial 1 , we r and omly assigned patients , 2 to 19 years of age , with systemic JIA and active systemic features ( fever ; ≥2 active joints ; C-reactive protein , > 30 mg per liter ; and glucocorticoid dose , ≤1.0 mg per kilogram of body weight per day ) , in a double-blind fashion , to a single subcutaneous dose of canakinumab ( 4 mg per kilogram ) or placebo . The primary outcome , termed adapted JIA ACR 30 response , was defined as improvement of 30 % or more in at least three of the six core criteria for JIA , worsening of more than 30 % in no more than one of the criteria , and resolution of fever . In trial 2 , after 32 weeks of open-label treatment with canakinumab , patients who had a response and underwent glucocorticoid tapering were r and omly assigned to continued treatment with canakinumab or to placebo . The primary outcome was time to flare of systemic JIA . RESULTS At day 15 in trial 1 , more patients in the canakinumab group had an adapted JIA ACR 30 response ( 36 of 43 [ 84 % ] , vs. 4 of 41 [ 10 % ] in the placebo group ; P<0.001 ) . In trial 2 , among the 100 patients ( of 177 in the open-label phase ) who underwent r and omization in the withdrawal phase , the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo ( 74 % of patients in the canakinumab group had no flare , vs. 25 % in the placebo group , according to Kaplan-Meier estimates ; hazard ratio , 0.36 ; P=0.003 ) . The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day , and glucocorticoids were discontinued in 42 of 128 patients ( 33 % ) . The macrophage activation syndrome occurred in 7 patients ; infections were more frequent with canakinumab than with placebo . CONCLUSIONS These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features . ( Funded by Novartis Pharma ; Clinical Trials.gov numbers , NCT00889863 and NCT00886769 . )
OBJECTIVE The clinical impact of anti-drug antibodies ( ADAbs ) in paediatric patients with JIA remains unknown .
This systematic review and meta- analysis aim ed to summarize the prevalence of ADAbs in JIA studies ; investigate the effect of ADAbs on treatment efficacy and adverse events ; and explore the effect of immunosuppressive therapy on antibody formation .