Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
...This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 29% of 72 patients) than with placebo (37 53% of 70 patients; hazard ratio 0·46, 95% CI 0·27–0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Pfizer.
In this randomized, placebo-controlled trial of 133 children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal ...antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn. Fourteen patients had serious adverse events, including seven patients with serious infections.
In children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn.
Juvenile rheumatoid arthritis is the most common rheumatic disease of childhood and is an important cause of disability among children.
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Weekly methotrexate (oral or parenteral), at dosages of up to 15 mg per square meter of body-surface area per week for parenteral administration, has been established as an effective therapy in polyarticular juvenile rheumatoid arthritis.
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During the past decade, the use of tumor necrosis factor (TNF) antagonists in adult rheumatoid arthritis has shifted the paradigm of care.
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More recently, TNF blockade has been shown to be an efficacious treatment option for polyarticular juvenile rheumatoid arthritis.
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Adalimumab (Humira, Abbott . . .
BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesReport the pharmacokinetics (PK), safety and taste acceptability of tofacitinib ...following multiple oral doses in patients (pts) 2-<18 years (yrs) old with active juvenile idiopathic arthritis (JIA).MethodsData were obtained from an open-label, non-randomised, multicentre, Phase I study (NCT01513902) where JIA pts were given 5 mg adult equivalent (based on body weight) of tofacitinib (tablet or solution) twice daily (BID) for 5 days (Table). There were 3 cohorts (COH) based on pt age, COH1: 12-<18 yrs, COH2: 6-<12 yrs, and COH3: 2-<6 yrs, with a target enrolment per group of ≥8 JIA pts for N=≥24 evaluable pts completing the study. Pts were enrolled in a step-wise approach beginning with the older age COH first. Subsequent younger age COH were enrolled following confirmation of safety and PK from the previous COH. PK parameters of tofacitinib were calculated using non-compartmental analysis of plasma concentration (conc)-time data. Taste acceptability of the solution formulation was listed and categorically summarised (frequency and %).Results26 pts (COH1 N=8, COH2 N=9 and COH3 N=9) were included in this analysis. Pts' age ranged from 2–17 years; all were white race except for one; there were 17 females and 9 males. Baseline disease characteristics were similar across all COH. All exposure metrics including geometric mean (GM) area under the conc-time curves (AUCtau), maximum (Cmax), minimum (Cmin) and predose (Ctrough) conc were lower in COH2 relative to those in COH1; however, due to higher doses in COH3 (modified after interim analysis of COH1 and 2), the mean AUCtau in COH3 was comparable to COH1. GM apparent volume of distribution (Vz/F) decreased with age (COH1=104.9L, COH2=71.0L, COH3=51.4L). Average terminal half-life (t1/2) were COH1=2.62h, COH2=1.95h and COH3=1.77h. GM tofacitinib CL/F were 53%, 39% and 11% higher in COH1, COH2 and COH3 pts, respectively, vs adult RA pts (18.4L/h) receiving tofacitinib 5 mg BID. GM CL/F and V/F parameters were similar between males and females. Tofacitinib, administered over 5 days as multiple dose tablets or solution formulation, was well tolerated and taste for the solution formulation was found acceptable in children with active JIA. No serious adverse events or new safety signals were identified.ConclusionsPK results from this study established dosing regimens for pts aged ≥2 years to be used in the upcoming efficacy and safety studies of tofacitinib in JIA pts. Tofacitinib was well tolerated in this study in JIA pts. Overall, pts found the taste of the tofacitinib solution formulation to be acceptable.AcknowledgementStudy sponsored by Pfizer Inc. Editorial support provided by CMC (funded by Pfizer Inc).Disclosure of InterestN. Ruperto Consultant for: Abbott, AbbVie, Amgen, Astellas Pharma, Alter, AstraZeneca, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer Inc, Roche, Sanofi Aventis, Servier, Takeda, Vertex, Speakers bureau: Abbott, AbbVie, Amgen, Astellas Pharma, Alter, AstraZeneca, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer Inc, Roche, Sanofi Aventis, Servier, Takeda, Vertex, H. Brunner Consultant for: Novartis, Roche, Pfizer Inc, UCB, Celgene, Regeneron, Amgen, AstraZeneca, GlaxoSmithKline, Speakers bureau: Novartis, Roche, A. Hazra Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Mebus Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Alvey Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Lamba Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, U. Conte Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Tzaribachev Grant/research support from: Pfizer Inc, UCB, Roche, I. Foeldvari: None declared, G. Horneff Grant/research support from: AbbVie, Chuigai, Pfizer Inc, Roche, D. Kingsbury Grant/research support from: Pfizer Inc, E. Koskova: None declared, E. Smolewska: None declared, R. Vehe Grant/research support from: Bristol-Myers Squibb, Z. Zuber: None declared, A. Martini Consultant for: Abbott, AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, Speakers bureau: Abbott, AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, D. Lovell Consultant for: AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer Inc, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen Idec, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen, Speakers bureau: Genentech, Roche, Novartis
Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care ...of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient's individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.
The American College of Rheumatology is an independent, professional, medical and scientific society which does not guarantee, warrant, or endorse any commercial product or service.
The relationship between rheumatoid factor positive (RF+) and rheumatoid factor negative (RF-) rheumatoid arthritis (RA) is controversial. We sought to determine whether the HLA genes conferring ...susceptibility for erosive RF+RA are also prevalent in patients with erosive RF-RA.
DNA-based HLA typing for DRB1, DQB1, and DPB1 was performed on 16 consistently RF--patients with erosive RA.
Thirteen of 16 (81%) RF-RA patients had the HLA susceptibility genes DRB1 *0401, *0404, or *0101, which are associated with RF+RA, as compared to 46% of normal controls (p = 0.017). By contrast, no associations with HLA-DQB1 and HLA-DPB1 alleles were apparent.
Specific HLA susceptibility alleles are prevalent in patients with erosive RA, regardless of RF status, suggesting a similar immunogenetic basis for RA in these patients.
Rheumatoid factor positive (seropositive) juvenile rheumatoid arthritis (JRA) is a relatively uncommon but severe form of JRA which shares clinical features with classical adult onset rheumatoid ...arthritis. Immunogenetic analysis of these patients supports the concept that this likely represents childhood onset of the same disease process. In this report, we review the clinical features as well as previous HLA studies of this disease. We report complete DNA based HLA typing of a small group of these patients, and discuss mechanistic implications of the results.
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