Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee

Background To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies

Subcutaneous abatacept in patients with polyarticular-course juvenile idiopathic arthritis : results from a phase III open-label study

OBJECTIVE : To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular‐course juvenile idiopathic arthritis (JIA). METHODS: In this phase III, open‐label, international, multicenter, single‐arm study, patients with polyarticular JIA (cohort 1, ages 6–17 years and cohort 2, ages 2–5 years) in whom treatment with ≥1 disease‐modifying antirheumatic drug was unsuccessful received weight‐tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA–American College of Rheumatology 30% improvement criteria (achieved a JIA‐ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady‐state serum trough concentration (Cminss) in cohort 1 at month 4. Other outcome measures included JIA‐ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C‐reactive protein level (JADAS‐71–CRP) over time, safety, and immunogenicity. RESULTS : The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 μg/ml) in both cohorts. The percentage of patients who had achieved JIA‐ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent‐to‐treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS‐71–CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS‐71–CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti‐abatacept antibodies, with no clinical effects. CONCLUSION : Weight‐stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.Results From a Phase III Open‐Label StudyWriting assistance was funded by Bristol‐Myers Squibb.https://onlinelibrary.wiley.com/journal/23265205am2018Internal Medicin

Clinical and immunological aspects and treatment of juvenile systemic sclerosis

Цель. На основании изучения иммунного статуса и цитокинового профиля разработать систему ранней диагностики и лечения больных ЮСД. Материал и методы. За период 2000 по 2003 гг наблюдались 70 детей, больных ЮСД (32 мальчика и 38 девочек), в возрасте от 12до 17 лет. Исследовалось содержание Т- и В-лимфоцитов, CD4, CD8, CD 16, CD20, CD95, соотношение CD4/CD8 (иммунно-регуляторный индекс), иммуноглобулинов G,A,M (IgA, IgM, IgG), циркулирующих иммунных комплексов (ЦИК), РФ, интерферона-у (ИФ-у), интерлейкинов-4,8 (ИЛ-4, ИЛ- 8),ФНО-а в сыворотке крови при поступлении больных и через 6 мес после выписки из стационара. Результаты. Иммунные реакции зависели от клинической формы ЮСД, связанной с полом больных детей. При длительности заболевания более года уровни CD4, CD95, ФНО-а, ИЛ-4 и ИФ-у были высокими, свидетельствуя о прогрессировании процесса и являясь показателем активности. Сравнительный анализ двух базисных препаратов - делагила и ауранофина показал, что последний положительно влияет не только на клиническую картину ЮСД, но и на иммунологические параметры. Заключение. Пик заболеваемости обследованных больных ЮСД приходился на пубертатный период. Для девочек более характерной была бляшечная, для мальчиков - линейная форма. Различные формы ЮСД имели общие иммунологические механизмы. Соли золота (ауранофин) в качестве базисного препарата положительно влияли не только клиническую картину заболевания, но и на динамику иммунологических показателей ЮСД

Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial

Objectives: This ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE). Methods: Patients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and ’30 alternative’ definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing. Results: Ninety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL. Conclusion: The belimumab intravenous pharmacokinetics and benefit–risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/ kg every 4 weeks dose is appropriat

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.

To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA).status: publishe

Subcutaneous Abatacept in Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: Results From a Phase III Open-Label Study

none59Objective: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). Methods: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6–17 years and cohort 2, ages 2–5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to &lt;25 kg (50 mg), 25 to &lt;50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA–American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71–CRP) over time, safety, and immunogenicity. Results: The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 μg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n&nbsp;=&nbsp;173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n&nbsp;= 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71–CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71–CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. Conclusion: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.noneBrunner H.I.; Tzaribachev N.; Vega-Cornejo G.; Louw I.; Berman A.; Calvo Penades I.; Anton J.; Avila-Zapata F.; Cuttica R.; Horneff G.; Foeldvari I.; Keltsev V.; Kingsbury D.J.; Viola D.O.; Joos R.; Lauwerys B.; Paz Gastanaga M.E.; Rama M.E.; Wouters C.; Bohnsack J.; Breedt J.; Fischbach M.; Lutz T.; Minden K.; Miraval T.; Ally M.M.T.M.; Rubio-Perez N.; Solau Gervais E.; van Zyl R.; Li X.; Nys M.; Wong R.; Banerjee S.; Lovell D.J.; Martini A.; Ruperto N.; Becker M.L.; Ilowite N.T.; Dare J.A.; Morris P.K.; Beukelman T.G.; Wagner-Weiner L.; Zemel L.; Quartier P.; Kone-Paut I.; Belot A.; Gerloni V.; Ferrandiz M.; Van Rensburg D.J.; Scheibel I.M.; Goldstein-Schainberg C.; Silva C.; Terreri M.T.S.E.L.A.; Gamir M.; Burgos Vargas R.; Faugier Fuentes E.; Cimaz R.; Alessio M.; Espada G.Brunner, H. I.; Tzaribachev, N.; Vega-Cornejo, G.; Louw, I.; Berman, A.; Calvo Penades, I.; Anton, J.; Avila-Zapata, F.; Cuttica, R.; Horneff, G.; Foeldvari, I.; Keltsev, V.; Kingsbury, D. J.; Viola, D. O.; Joos, R.; Lauwerys, B.; Paz Gastanaga, M. E.; Rama, M. E.; Wouters, C.; Bohnsack, J.; Breedt, J.; Fischbach, M.; Lutz, T.; Minden, K.; Miraval, T.; Ally, M. M. T. M.; Rubio-Perez, N.; Solau Gervais, E.; van Zyl, R.; Li, X.; Nys, M.; Wong, R.; Banerjee, S.; Lovell, D. J.; Martini, A.; Ruperto, N.; Becker, M. L.; Ilowite, N. T.; Dare, J. A.; Morris, P. K.; Beukelman, T. G.; Wagner-Weiner, L.; Zemel, L.; Quartier, P.; Kone-Paut, I.; Belot, A.; Gerloni, V.; Ferrandiz, M.; Van Rensburg, D. J.; Scheibel, I. M.; Goldstein-Schainberg, C.; Silva, C.; Terreri, M. T. S. E. L. A.; Gamir, M.; Burgos Vargas, R.; Faugier Fuentes, E.; Cimaz, R.; Alessio, M.; Espada, G