RESUMEN
PURPOSE OF REVIEW: To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD. RECENT FINDINGS: Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi's abrocitinib (ABRO), baricitinib (BARI), and upadacitinib (UPA), are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10 years with moderate-to-severe AD. Fortunately, major safety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred. There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD.
Asunto(s)
Dermatitis Atópica , Inhibidores de las Cinasas Janus , Humanos , Dermatitis Atópica/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Inhibidores de las Cinasas Janus/administración & dosificación , Niño , Adolescente , Purinas/uso terapéutico , Administración Oral , Azetidinas/uso terapéutico , Azetidinas/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Resultado del TratamientoRESUMEN
AIM: This study assessed the efficacy and safety of upadacitinib (UPA), in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), in Chinese, Brazilian, and South Korean patients with active rheumatoid arthritis (RA) and an inadequate response (IR) to csDMARDs. METHODS: Patients on stable csDMARDs were randomized (1:1) to once-daily UPA 15 mg or matching placebo (PBO) for a 12-week, double-blind period. The primary endpoint was the proportion of patients achieving ≥20% improvement in American College of Rheumatology criteria (ACR20) at week 12. RESULTS: In total, 338 patients were randomized and treated, of whom 310 (91.7%) completed the double-blind phase. The study met the primary endpoint of ACR20 at week 12 for UPA 15 mg vs PBO (71.6% vs 31.4%, P < .001), with a treatment difference observed as early as week 1. All ranked and other key secondary endpoints, including more stringent responses such as ACR50, ACR70 (≥50%/70% improvement in ACR criteria), and Disease Activity Score in 28 joints using C-reactive protein <2.6, were met for UPA 15 mg vs PBO. The incidence of serious infections (2.4% vs 0.6%) and herpes zoster (HZ: 1.8% vs 0.6%) was higher with UPA 15 mg vs PBO. There was one case of venous thromboembolism reported in the UPA group. CONCLUSION: UPA 15 mg in combination with csDMARDs demonstrated clinical and functional improvement and an acceptable safety profile over 12 weeks among patients from China, Brazil, and South Korea who had moderately to severely active RA and an IR to csDMARDs.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Inhibidores de las Cinasas Janus/administración & dosificación , Adulto , Antirreumáticos/uso terapéutico , Brasil , China , Método Doble Ciego , Quimioterapia Combinada , Femenino , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Masculino , Persona de Mediana Edad , República de Corea , Resultado del TratamientoRESUMEN
OBJECTIVE: One-third of patients with severe rheumatoid arthritis (RA) do not achieve remission or low disease activity, or they have side effects from cDMARD and bDMARD. They will need a new treatment option such as the small molecule JAK inhibitors. In this systematic review, we evaluate the efficacy and safety data of the current jakinibs: tofacitinib, peficitinib, decernotinib, upadacitinib, baricitinib and filgotinib in patients in whom treatment with conventional or biological disease-modifying antirheumatic drugs (cDMARD and/or bDMARD) failed. METHODS: We searched for randomized controlled trials comparing efficacy and safety of jakinibs for RA treatment using the Web of Science, Scopus, PubMed, and clinicaltrials.gov databases with the terms: "rheumatoid arthritis" OR "arthritis rheumatoid" OR "RA" AND "inhibitor" OR "jak inhibitor" AND "clinical trial" OR "treatment" OR "therapy". RESULTS: All jakinibs achieved good results in ACR 20, 50, 70 and with CRP-DAS28 for LDA and remission, upadacitinib showed better results compared to the others. In ESR-DAS28 for remission, tofacitinib achieved the best result. Regarding the safety of all jakinibs, peficitinib, baricitinib and filgotinib did not register deaths in their studies unlike tofacitinib that presented 11 deaths. Despite all benefits of jakinibs, the use in patients with severe liver and kidney disease should be avoided. CONCLUSIONS: Jakinibs in monotherapy or in combination with methotrexate can be considered a viable alternative in the treatment of moderate-to-severe RA. Even after failures with combination of cDMARDS and bDMARDS, jakinibs demonstrated efficacy.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de las Cinasas Janus/administración & dosificación , Antirreumáticos/efectos adversos , Artritis Reumatoide/enzimología , Azetidinas/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Quimioterapia Combinada , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/diagnóstico , Metotrexato/administración & dosificación , Piperidinas/administración & dosificación , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Sulfonamidas/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Herpes Zóster/epidemiología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inhibidores de las Cinasas Janus/efectos adversos , Psoriasis/tratamiento farmacológico , Espondilitis Anquilosante/tratamiento farmacológico , Artritis Reumatoide/inmunología , Artritis Reumatoide/mortalidad , Azetidinas/efectos adversos , Herpes Zóster/inducido químicamente , Herpes Zóster/inmunología , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/mortalidad , Inhibidores de las Cinasas Janus/administración & dosificación , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/inmunología , Quinasas Janus/metabolismo , Piperidinas/efectos adversos , Placebos/administración & dosificación , Placebos/efectos adversos , Psoriasis/inmunología , Psoriasis/mortalidad , Purinas , Pirazoles , Piridinas/efectos adversos , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/mortalidad , Sulfonamidas/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Triazoles/efectos adversosRESUMEN
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Efficacy and safety of tofacitinib in Brazilian patients from Phase 2 (P2) and Phase 3 (P3) global studies of up to 24 months' duration were evaluated. METHODS: Data were pooled from Brazilian patients with RA and an inadequate response to conventional synthetic or biologic disease-modifying antirheumatic drugs enrolled in P2/P3 tofacitinib studies who received tofacitinib 5 or 10âmg twice daily (BID), or placebo, as monotherapy or in combination with methotrexate. Efficacy, safety, and patient-reported outcomes were assessed over 24 months. RESULTS: Patients (226) from Brazil were treated in tofacitinib global P2/P3 studies. At Month 3, there were improvements in American College of Rheumatology 20/50/70 response rates, Disease Activity Score in 28 joints, erythrocyte sedimentation rate, and Health Assessment Questionnaire-Disability Index scores with both tofacitinib doses. Improvements from baseline in pain, fatigue, and health-related quality of life with tofacitinib 5 and 10âmg BID were reported. Efficacy improvements were sustained up to Month 24. The most frequent class of adverse events was infections and infestations. No cases of tuberculosis or other opportunistic infections were reported. CONCLUSION: In a Brazilian subpopulation of patients with RA, tofacitinib reduced disease signs and symptoms and improved physical function up to Month 24, with a safety profile consistent with findings from global studies.