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.
Objectives:To examine the change in health-related quality of life (HRQOL) and its determinants in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX).Methods:Patients ...were extracted from the PRINTO clinical trial which aimed to evaluate the efficacy and safety profile of MTX administered in standard, intermediate or higher doses (10, 15 and 30 mg/m2/week respectively). Children with polyarticular-course JIA, who were less than 18 years and had a complete HRQOL assessment were included.Results:A total of 521 children were included. At baseline, patients with JIA showed poorer HRQOL (p<0.01) than healthy children. In 207/412 (50%) and 63 (15%) children, HRQOL values were 2 standard deviations below the mean of healthy controls in the physical and psychosocial summary scale, respectively. After 6 months of treatment with standard dose MTX, there was a statistically significant improvement in all HRQOL health concepts, particularly the physical ones. Similar improvements were observed in those who did not respond to a standard dose of MTX and were subsequently randomised to a higher dose. The presence of marked disability at baseline was associated with a fivefold increased risk of retaining poor physical health after 6 months of active treatment with standard dose MTX. Other less important determinants of retaining poor physical well-being were the baseline level of systemic inflammation, pain intensity and an antinuclear-antibody-negative status.Conclusions:MTX treatment produces a significant improvement across a wide range of HRQOL components, particularly in the physical domains, in patients with JIA.
BackgroundIntravenous (IV) tocilizumab (TCZ) was approved in the, US (2011), EU (2013) and other countries for the treatment of systemic juvenile idiopathic arthritis (sJIA) patients (pts)≥2 years of ...age, based on a phase 3 study WA18221.1 US Food and Drug Administration approval resulted in postmarketing requirement to investigate TCZ in pts with sJIA <2 years of age (study NP25737; ClinicalTrials.gov, NCT01455701). Results from the 12 week main evaluation period (MEP) have been reported.2 ObjectivesReport safety results after completion of the optional extension period (OEP) of NP25737 (until 52 weeks from baseline or 2 years of age, whichever was longer).MethodsNP25737 was a multicenter, open-label, single-arm study to evaluate the pharmacokinetics and safety of IV TCZ, 12 mg/kg every 2 weeks, for 12 weeks in pts aged <2 years with active sJIA for ≥1 month who failed corticosteroid and nonsteroidal anti-inflammatory drug treatment and received stable background therapy during the MEP. After the 12 week MEP, pts could participate in the OEP and continue TCZ treatment (without requirement for stable background therapy). Cumulative adverse events (AEs) over the entire study period are reported.ResultsSeven of 11 pts enrolled in the MEP continued to the OEP and received ≥1 dose of TCZ. Over the entire study period (n=11), the median number of TCZ doses was 11 (range, 2–26) and the median duration of TCZ exposure was 22 weeks (range, 4–58). Most pts (10/11; 91%) had ≥1 AE; most were mild or moderate in intensity and unrelated to study drug. The most common AEs were upper respiratory tract infection (6/11 pts, 55%), hypersensitivity, neutropenia, rash, viral upper respiratory tract infection, and vomiting (each in 3/11 pts; 27%). Seven serious AEs occurred in 5 of 11 pts (46%): 2 in the OEP (transaminases increased and histiocytosis hematophagic), 3 in the MEP (3 hypersensitivity events), and 2 in the safety follow-up of the MEP (sJIA flare and hand-foot-and-mouth disease). AEs leading to dose modification occurred in 5 of 11 pts (1 in the MEP, 4 in the OEP) mostly because of infections, neutropenia, and elevated liver enzymes, all mild or moderate in intensity. AEs leading to withdrawal occurred in 5 of 11 pts (46%): 1 in the OEP because of serious increased transaminases, 3 in the MEP because of serious hypersensitivity reactions to TCZ, and 1 in the MEP because of thrombocytopenia. No deaths were reported during the study. AE rates per 100 pt-years of exposure are reported in the table 1.Abstract THU0598 – Table 1Rates of AEsConclusionsDuring the OEP of the study, long-term treatment with TCZ was well tolerated in sJIA pts aged <2 years, and no additional safety signals were reported in the OEP beyond those reported in the MEP or observed previously for pts with sJIA aged ≥2 years.References1 De Benedetti F, et al. N Engl J Med2012;367:2385–2395.2 Mallalieu NL, et al. Arthritis Rheumatol2017;69(suppl 10):abstract 2856.AcknowledgementsThis study was sponsored by F. Hoffmann-La Roche Ltd.Disclosure of InterestS. Wimalasundera Employee of: Roche, I. Calvo Penades: None declared, R. Cuttica Consultant for: Roche, Novartis, Lilly, GlaxoSmithKline, BMS, Janssen, Speakers bureau: Roche, Novartis, Lilly, GlaxoSmithKline, BMS, Janssen, H.-I. Huppertz: None declared, R. Joos: None declared, D. Milojevic: None declared, M. Rosenkranz: None declared, K. Schikler: None declared, T. Constantin: None declared, W. Douglass Employee of: Roche, C. Wells Shareholder of: Roche, Employee of: Roche, Y. Kimura Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, C. Wouters: None declared
Calcinosis is a frequent finding in up to 40% of children with juvenile dermatomyositis (JDM). Different treatments (aluminum hydroxide, diltiazem, probenecid, alendronate, etc.) have been used in an ...attempt to clear calcinosis and to avoid the onset of new calcium deposition, but none has been clearly effective. Pamidronate is a nitrogen-containing bisphosphonate with a potent inhibiting bone resorption effect that has been used to treat osteoporosis in children. We report three children with JDM who developed calcinosis and who received intravenous pamidronate with good results.
All three patients met the Bohan and Peter diagnostic criteria for JDM. Intravenous pamidronate was given at 1 mg/kg/day on three consecutive days every three months according to the protocol established by Glorieux et al. for osteoporosis treatment in osteogenesis imperfecta.
The calcinosis which developed in all three patients improved. No important adverse events were observed.
In all three cases, calcinosis significantly decreased, and even totally cleared in patient 1. Total clearance of pre-existing calcinosis in JDM with pamidronate therapy has not been previously described with any of the aforementioned treatments. The advantage of treatment with pamidronate compared to treatment with alendronate is that intravenous administration does not produce esophagitis, the most frequent adverse event when orally administering bisphosphonates. Our results strongly suggest that therapy with intravenous pamidronate in conjunction with good disease control with DMARD therapy is an apparently safe and effective treatment for calcinosis management in JDM.
The anti–interleukin-1 antibody canakinumab was effective at controlling and preventing recurrence of flares in autoimmune inflammatory diseases: familial Mediterranean fever, mevalonate kinase ...deficiency, and the TNF receptor–associated periodic syndrome.
Summary Background Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis ...factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. Methods We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6–17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. Findings Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0·0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0·0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0·31, 95% CI 0·16–0·95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0·47); only two serious adverse events were reported, both in controls (p=0·50). Interpretation Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. Funding Bristol-Myers Squibb.
BackgroundTocilizumab (TCZ) is approved for the treatment of systemic juvenile idiopathic arthritis (sJIA) based on clinical trials in patients (pts) ≥2 years of age. This study (NP25737) is the ...first for a biologic in sJIA pts <2 years of age.ObjectivesTo evaluate the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of TCZ in sJIA pts <2 years of age in a phase 1 trial.MethodsPts with uncontrolled sJIA and symptoms for ≥1 month prescreening who failed treatment with corticosteroids and NSAIDs and had no history of allergy to TCZ or other biologics received open-label TCZ 12 mg/kg intravenously (IV) every 2 weeks (dose calculated at each visit based on body weight). Pts were treated up to week 12 and could continue until the age of 2 years or were treated for 1 year from baseline. End points included PK (primary) at week 12, PD and efficacy (exploratory), and safety. Comparison was made to exposures from a previous trial in sJIA pts ≥2 years of age (WA18221) that was the basis for approval of TCZ in sJIA.ResultsEleven pts were enrolled; median (range) age was 16 (10–22) months and weight was 10.40 (6.8–11.5) kg. Serum TCZ concentrations, estimated using population PK analysis, peaked immediately after infusion; median (range) maximum concentration was 282 (195–347) μg/mL (steady state reached by week 12), and median (range) trough concentration was 34.3 (19.2–59.7) μg/mL. Peak and trough exposures were within the exposure range in older children (244 109–382 to 54.3 10.9–117 μg/mL; Figure). Observed mean±SD soluble IL-6 receptor levels were 47.65±16.40 ng/mL at baseline and 927.83±148.07 ng/mL at day 71. CRP levels were 250.81±425.11 mg/L and 2.80±3.56 mg/L, respectively. ESR levels were 59.40±27.47 mm/h and 2.00±1.00 mm/h, respectively. Mean±SD Juvenile Arthritis Disease Activity Score-71 improved from 22.27±10.09 at baseline to 3.66±4.66 at day 71. By week 12, 10 pts had 32 adverse events (AEs) and 4 withdrew due to AEs. Infections or infestations were the most frequently reported AEs (10 events, 9 pts). Five serious AEs (SAEs) occurred; 3 pts had SAEs of hypersensitivity that led to withdrawal; 1 of these pts then experienced SAEs of foot and mouth disease and sJIA flare after study withdrawal. No actual cases of MAS were reported, but 2 pts had laboratory abnormalities indicative of MAS according to 2016 criteria.1 No deaths occurred during the study.ConclusionsTCZ exposures achieved in this study fell within the range of the previous trial in sJIA pts ≥2 years of age. This study provides evidence that TCZ is effective in sJIA pts <2 years of age, achieves PK and efficacy similar to those demonstrated previously in older pts, and has a similar AE safety profile, but there was a higher incidence of serious hypersensitivity events and suspected MAS.References Ravelli A et al. Ann Rheum Dis. 2016;75:481–9. Disclosure of InterestN. Mallalieu Shareholder of: Roche, Employee of: Roche, J. Hsu Employee of: Roche, K. Wang Employee of: Roche, S. Wimalasundera Employee of: Roche Products Ltd., C. Wells Employee of: Roche Products Ltd., I. Calvo Penades: None declared, R. Cuttica Consultant for: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, Speakers bureau: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, H. Huppertz: None declared, R. Joos: None declared, Y. Kimura Consultant for: Novartis, SOBI, D. Milojevic: None declared, M. Rosenkranz: None declared, K. Schikler: None declared, T. Constantin: None declared, C. Wouters: None declared
Background The efficacy and safety of etanercept (ETN) has been demonstrated in patients with juvenile idiopathic arthritis (JIA) from 4 years, although more data are needed regarding the population ...under 4 years old. Objectives The aim is to evaluate the efficacy and safety of etanercept in patients under 4 years old diagnosed with polyarticular JIA and to assess the adherence to drug treatment in this population. Methods We analyzed retrospectively, from medical records of patients, the following variables: epidemiologic data, number of active and limited joints at baseline and at 6 months; we also registered laboratory parameters including CRP, ESR, iron and hemoglobin. Other variables recorded were CHAQ punctuation; physician and parents global assessment at baseline and 6 months of treatment. Continuous variables are presented as means±SD. Results From a total of 25 patients with JIA younger than 4 years old treated with ETN only 21 were analyzed. There were 14 girls and 7 boys with a mean age at diagnosis of 23±19.4 months. All patients had received methotrexate (MTX), corticosteroids (prednisolone) and ETN (0.8mg/kg/wk) as initial therapy. The mean duration of treatment with etanercept was 36.6±22 months.Iron laboratory values at baseline were low (49.89±25.6μg/dl) but normalized at 6 months of treatment (70.76±31.2μg/dl). Number of active and limited joints at baseline were 12±4.3/3.5±5.1 respectively; at six months of treatment were 1.44±1.77/1±1.33.CHAQ punctuation at baseline was 1.2±0.3 and 0.4±0.2 at six months. Physician and parents’global assessment at baseline were 71.5±11.5/70±14.1 respectively and 11.6±11.2/12.9±12.4 at 6 months of treatment. CRP and ESR parameters at baseline were 40.8±24.1 mg/l/51.9±19.4 mm/h respectively and 3±4.9 mg/l/14.1±8.3mm/h at six months of treatment. All patients achieved clinical remission at 6 months of treatment. Furthermore, in all patients discontinuation of therapy with corticosteroids was performed and 60% achieved discontinuation of MTX after 6 months of treatment. ETN was discontinued in 2 patients (9.5%) due to remission of the disease: one outbreak must be restarted on therapy after 3 months and the other remains in remission without treatment a year later. Four patients (19%) remained at doses below 0.8mg/kg/wk. Any patient had serious adverse effects secondary to treatment. Conclusions Although important joint involvement and alteration of analytical parameters at baseline a high percentage of patients achieved remission at 6 months of treatment with etanercept. All patients could reduce concomitant medication and dose reduction or withdrawal of etanercept was possible in some patients. Treatment with etanerceptin patients under 4 years old is shown as safe and effective in our patient group after 6 months of treatment. Disclosure of Interest None Declared
Background Many young people with rheumatic childhood-onset diseases continue to require medical care into adult life. There are many differences between pediatric and adult care. Although there is ...an extensive evidence base for the need of transitional care, there is a paucity of robust outcome data and a great variability on the models of transitional care. Objectives To develop recommendations on the transition from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood-onset based on the best evidence and experience. Methods Recommendations were generated following nominal group methodology and Delphi technique. A panel of experts was established (8 pediatricians, 8 rheumatologists). A systematic literature review (on) and a narrative review (websites, clinical guidelines and other relevant documentation) were performed and presented to the panel in the 1st panel meeting to be discussed and to help define recommendations. A first draft of recommendations was generated and circulated for comments and wording refinements. Focal groups with adolescents, young adults and parents were separately. In a 2nd panel meeting the focus group results along with the input from invited nurses and psychologists were used to established definitive recommendations. A Delphi process (2 rounds) was carried out. A large group of pediatricians and rheumatologits took part. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70% voted ≥7. The level of evidence and grade or recommendation was assessed using the Oxford Centre for Evidence-based Medicine Levels of Evidence. Results Transition care was defined as a purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic inflammatory rheumatic diseases with childhood-onset as they move from child-centred to adult-oriented health care systems. The consensus covers: transition needs, barriers and facilitators, transitional issues (objectives, participants, content, phases, timing, plans, documentation, and responsibilities), physicians and other health professionals knowledge and skills requirements, models/programs, strategies and guideline for implementation. Conclusions These recommendations are intended to provide pediatricians, rheumatologists, patients, families and other stakeholders with a consensus on the transition process from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood-onset. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5689
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