Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial.

BACKGROUND: 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). METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Pfizer.

Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis.

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.

Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA. METHODS: This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated. RESULTS: Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUCtau) was 156.6 ng•h/mL in Cohort 1, 118.8 ng•h/mL in Cohort 2, and 142.5 ng•h/mL in Cohort 3; Cmax (ng/mL) was 47.0, 41.7, and 66.2, respectively. Ctrough, Cmin, and t1/2 were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to Cmax (Tmax) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed. CONCLUSIONS: PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01513902 .

Psoríase e comorbidades / Psoriasis and comorbidities

A psoríase é uma doença inflamatória crônica associada a comorbidades graves, incluindo artrite psoriásica, depressão, malignidade e complicações cardiovasculares. Esta revisão tem como foco uma série de comorbidades associadas à psoríase. A natureza crônica da psoríase tem sido sugerida como um fator de risco independente para o desenvolvimento destas comorbidades.

Terapia com agentes biológicos na criança e no adolescente: [revisão] / Treatment with biologic agents in child and adolescent: [review]

OBJETIVO: Revisar os mecanismos fisiopatológicos e novos alvos terapêuticos, os agentes biológicos disponíveis, principais indicações e a evidência científica atual para o uso de terapias biológicas na população pediátrica. FONTES DE DADOS: Pesquisa na base de dados Medline e SciELO, nas línguas inglesa e portuguesa, entre 2000 e 2009. As palavras-chave usadas foram "agentes biológicos", "crianças" e "adolescentes". SÍNTESE DOS DADOS: Os agentes biológicos são uma importante opção terapêutica para tratar as doenças autoimunes refratárias às terapias convencionais na infância e na adolescência. Com exceção da artrite idiopática juvenil, a maioria dos estudos em outras doenças autoimunes não é controlada. CONCLUSÕES: Os agentes biológicos têm demonstrado eficácia no tratamento de doenças autoimunes pediátricas como artrite idiopática juvenil, miopatias idiopáticas inflamatórias, lúpus eritematoso juvenil, vasculites, uveítes crônicas, doenças inflamatórias intestinais e púrpura trombocitopênica imune crônica, assim como no linfoma não-Hodgkin. Considerando-se o custo elevado e os potenciais eventos adversos, o uso desses agentes deve ser individualizado e acompanhado por especialista.

OBJECTIVE: To review the physiopathology and new therapeutical targets, the available biologic agents, the main indications and the current scientific evidence for the use of biological therapies in the pediatric population. DATA SOURCES: A bibliographical search was obtained from Medline and SciELO databases in English and Portuguese from 2000 to 2009. The key-words included were "biologic agent", "children" and "adolescent". DATA SYNTHESIS: Biologic agents are important therapeutic options to treat refractory autoimmune diseases to conventional therapies in childhood and adolescence. Excluding juvenile idiopathic arthritis, the majority of studies in other autoimmune diseases are uncontrolled trials. CONCLUSIONS: Biologic agents have shown efficacy in the treatment of pediatric autoimmune diseases such as juvenile idiopathic arthritis, idiopathic inflammatory myositis, juvenile systemic lupus erythematosus, vasculitis, chronic uveitis, inflammatory bowel diseases, and chronic immune thrombocytopenic purpura, as well as in non-Hodgkin lymphoma. Considering the high cost and the potential adverse events, the choice to use them must be individualized and followed by a specialist.

Effect of musculoskeletal pain on sexuality of male adolescents and adults with juvenile idiopathic arthritis.

OBJECTIVE: To develop a questionnaire for the evaluation of sexuality of male patients with juvenile idiopathic arthritis (JIA). METHODS: A cohort of male patients with rheumatoid factor (RF)-negative polyarticular JIA according to the 2004 revised ILAR criteria and inactive disease was studied. The Health Assessment Questionnaire (HAQ) was applied to all patients. As a control group, 120 age-matched males of the same socioeconomic status were evaluated. A self-administered structured instrument, the Male Sexual Evaluation Questionnaire (MSEQ), was developed by multiprofessional experts to assess sexual life, including satisfaction, practice, and related functional aspects. RESULTS: Thirty-two male patients with RF-negative polyarticular JIA [mean age 20.8+/-3.8 yrs (range 16-26), mean disease duration 15.4+/-3.6 yrs (range 13-20)] were studied. Mean HAQ score was 1.25+/-0.67 (range 0.1-2.1). Masturbation was practiced similarly by patients and controls (87.5% vs 91%; p>0.999), although joint pain was observed in only 2 (7%) patients. Regular sexual intercourse (>or=once/week) was reported by 78% of patients and 62% of controls (p=0.86). Joint pain during intercourse was more frequent in patients (48% vs 3% in controls; p<0.001). The mean HAQ score was higher in the 12 patients with joint pain (hips=3, knees=5, and hips+knees=4) during intercourse compared to the 13 patients without joint pain (1.82+/-0.27 vs 1.43+/-0.32; p<0.05). Preserved desire and satisfaction were universal findings for all JIA patients and controls. CONCLUSION: The MSEQ was applicable to this cohort of male patients with RF-negative polyarticular JIA and showed that sexual life is preserved despite longterm disease, morbidity/functional dysfunction, and joint pain.

Agentes biológicos na artrite reumatoide / Biologicals in the treatment of rheumatoid arthritis

A artrite reumatoide (AR) é uma doença crônica, caracterizada principalmente por poliartrite que pode levar a deformidades e destruição das articulações. Os objetivos principais do tratamento da AR são o controle da dor, a prevenção e o controle das lesões articulares, a prevenção da perda de função e a melhoria da qualidade de vida. Embora a causa da AR permaneça desconhecida, estudos realizados ao longo das duas últimas décadas possibilitaram maior compreensão da patogenia da doença. Dois principais componentes do processo inflamatório na AR são os linfócitos T e as citocinas pró-inflamatórias. O conhecimento a respeito da patogenia da AR vem permitindo o desenvolvimento dos agentes denominados biológicos, usados para tratar as formas mais graves da doença. Os principais biológicos aprovados para uso clínico são anticorpos monoclonais (infliximabe, adalimumabe e rituximabe) ou proteínas solúveis com estrutura semelhante à de receptores ou moléculas de superfície (etanercepte e abatacepte). Os biológicos apresentam grande especificidade contra alvos terapêuticos definidos e com papel conhecido na patogenia da AR. Os principais entre esses alvos são o fator de necrose tumoral, o mecanismo de coestimulação de linfócitos T e o antígeno CD-20. Neste artigo fazemos uma revisão a respeito do uso dos agentes biológicos nessa doença, que é importante causa de morbidade e também responsável por aumento de mortalidade e altos custos para a sociedade.

Avaliação da função das células de Sertoli testiculares em pacientes do sexo masculino com lúpus eritematoso sistêmico / Testicular Sertoli cell function evaluation in male systemic lupus erytemathosus patients

Objetivo: Avaliar a função das células testiculares de Sertoli em homens com lúpus eritematoso sistêmico (LES). Métodos: Trinta e quatro pacientes consecutivos foram prospectivamente selecionados para avaliar a função das células testiculares de Sertoli pelos níveis séricos da inibina B. Características clínicas, tratamento, análises dos espermatozóides, avaliação urológica, ultrasonografia testicular, hormônios e anticorpos anti-espermatozóides foram avaliados. Resultados: Os pacientes foram subdivididos em dois grupos: níveis séricos reduzidos (Grupo 1, n=8) e níveis séricos normais (Grupo 2, n=26) de inibina B. As medianas da concentração média de espermatozóides (p=0,024), da contagem total de espermatozóides (p=0,023) e da contagem total de espermatozóides móveis (p=0,025) foram menores no Grupo 1. Os níveis de inibina B foram positivamente correlacionados com a concentração de espermatozóides (r=0,343) e contagem total de espermatozóides móveis (r=0,357), e negativamente correlacionados com FSH (r=0,699) e LH (r=0,397). A mediana de inibina B sérica foi menor nos pacientes com LES tratados com pulsoterapia com ciclofosfamida endovenosa (CICIV) comparada aos não tratados com este medicamento (p=0,031). Avaliação dos 26 pacientes com LES e níveis normais de inibina B e FSH revelou que a mediana da relação inibina B/FSH foi menor nos pacientes lúpicos com oligozoospermia comparada aos pacientes com normozoospermia (p=0,004). Esta relação também foi menor nos pacientes com LES tratados com CICIV do que naqueles sem esta terapia (p=0,04). Conclusão: Este é o primeiro estudo que identificou uma alta freqüência de disfunção das células testiculares de Sertoli em homens com LES associada a anormalidades dos espermatozóides. Outros estudos prospectivos são necessários para determinar se os níveis séricos de inibina e a relação inibina B/FSH serão um marcador útil e precoce de toxicidade pela CICIV neste pacientes

Objective: To assess the testicular Sertoli cell function in male SLE patients. Methods: 34 consecutive patients were prospectively selected to evaluate the testicular Sertoli cell function by serum inhibin B levels. Clinical features, treatment, semen analysis, urologic evaluation, testicular ultrasound, hormones, and antisperm antibodies were determined. Results: Patients were subdivided into two Groups: low serum inhibin B (Group 1, n=8) and normal levels (Group 2, n=26). The medians of sperm concentration (p=0.024), total sperm count (p=0.023) and total motile sperm count (p=0.025) were lower in Group 1. Inhibin B levels were positively correlated with sperm concentration (r=0.343), total motile sperm count (r=0.357), and negatively correlated with FSH (r=0.699) and LH (r=0.397). The median serum inhibin B was lower in SLE patients treated with intravenous cyclophosphamide pulsetherapy (IVCYC) compared to those without this therapy (p=0.031). Further evaluation of the 26 SLE patients with normal inhibin B and FSH levels revealed that medians of inhibin B/FSH ratio were lower in SLE patients with oligozoospermia compared to normozoospermia (p=0.004). This ratio was also lower in SLE patients treated with IVCYC than those without this therapy (p=0.04). Conclusions: This is the first study to identify a high frequency of testicular Sertoli cell dysfunction in male SLE associated with sperm abnormalities. Further prospective studies are necessary to determine if inhibin levels and inhibin B/FSH ratio will be an earlier and useful marker of IVCYC toxicity in these patients

Acute hemorrhagic edema of childhood.

Acute hemorrhagic edema (AHE) of childhood, a variant of Henoch-Schönlein purpura (HSP), is a rare vasculitis with benign course, generally no systemic involvement and rare flares. From January 1983 to June 2004, 4,502 patients were followed at the Pediatric Rheumatology Unit, Hospital of Clinics. Diagnosis of HSP was made in 203 cases (4.5%), of which 5 (0.1%) had AHE. All patients with AHE were male and the mean age at onset was 18 months (range: 8 to 21 months). All five cases presented vasculitis with characteristic hemorrhagic and purpuric lesions in malar region of the face, associated with painless edema of the hands and feet. Laboratory exams were normal. Upper respiratory tract infection preceding clinical manifestations occurred in four and mononucleosis in one. Treatment with corticosteroids was necessary only in one patient with necrotic lesions on the face and ears.

Aspectos da sexualidade e gravidez em adolescentes com artrite idiopática juvenil ( AIJ ) / Sexuality aspects and pregnancy of adolescents with juvenile idiopathic arthritis ( JIA )

O presente trabalho tem como objetivo descrever aspectos da sexualidade, gravidez e pós-parto de três adolescentes com artrite idiopática juvenil (AIJ). No período entre 1983 e 2004, 4.638 pacientes foram acompanhados na Unidade de Reumatologia Pediátrica do Departamento de Pediatria da FMUSP, entre os quais 537 (11,5 por cento) apresentaram o diagnóstico de AIJ (critérios do ILAR). Entre os pacientes com AIJ, três engravidaram durante o seguimento ambulatorial. A idade da primeira atividade sexual variou de 16 a 18 anos. A paciente 1 apresentou uma gestacão gemelar a termo, permanecendo em atividade da doenca durante toda a gravidez, em uso de 15mg/dia de prednisona. As pacientes 2 e 3 encontravam-se em remissão da doenca, sem uso de medicamentos, apresentando gestacão a termo sem intercorrências. A paciente 2, porém, evoluiu com recidiva da doenca um ano após o parto. Todos os recém-nascidos foram adequados para idade gestacional e evoluíram adequadamente no período neonatal. Apenas a paciente 1 necessitou de prednisona, naproxeno e cloroquina na amamentacão. O aumento da gravidez na adolescência é uma realidade nos servicos de reumatologia pediátrica, o que impõe novos debates sobre os aspectos da sexualidade e contracepcão nessa populacão.

Uso de micofenolato mofetil em pacientes com lúpus eritematoso sistêmico juvenil e nefrite refratária / Use of mycophenolate mofetil in patients with juvenile systemic lupus erythematosus and refractory nephritis

O micofenolato mofetil (MFM) é uma droga imunossupressora utilizada no tratamento de doenças auto-imunes, incluindo o lúpus eritematoso sistêmico juvenil, particularmente nos casos de nefrite lúpica refratária à terapia com corticosteróides, ciclofosfamida, azatioprina, metotrexato e/ou ciclosporina. Relatamos a eficácia e os eventos adversos do MFM em quatro pacientes com nefrite lúpica refratária. Os pacientes foram acompanhados por um período de 2,1 a 11,1 anos (média de 6,8 anos) e tratados com MFM na dose de 1 a 3g/dia por um período de 3 a 36 meses (média de 13,75 meses). Dois pacientes (um classe histológica renal IV e outro classe V) responderam ao tratamento com MFM e apresentaram melhora da proteinúria de 24h. A melhor resposta ocorreu na paciente com classe V, como é descrito na literatura. Dois pacientes não obtiveram resposta (um classe III e um classe IV) e evoluíram para insuficiência renal aguda, um deles com manutenção da proteinúria nefrótica. Não foram observados eventos adversos. O MFM pode ser uma alternativa terapêutica em pacientes juvenis com nefrite lúpica refratária, particularmente nas classes histológicas renais V e IV.