Etanercept, Adalimumab, Infliximab and Golimumab for the Treatment of Juvenile Idiopathic Arthritis

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; REY-ARES, L.; BARDACH, A.; CIAPPONI, A; MENGARELLI, C

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease in pediatric patients. Diagnosis is determined when arthritis in one or more joints starts before the age of 16 and remains for at least 6 weeks. Its prevalence is estimated to be 400 cases every 100,000 children.The main treatment objective is to preserve functional capacity. The use of TNF-alpha is proposed for patients whose disease remains active after corticoid intra-articular injections, non-steroidal anti-inflammatory drugs and non-biological disease-modifying drugs.TechnologyAnti-TNF-alpha is a recombinant human immunoglobulin which inhibits tumor necrosis factor-alpha functional activity, therefore decreasing inflammation and tissue damage.Etanercept and adalimumab are approved for JIA treatment by the U.S. Food and Drug Administration (FDA), the European Medicines Agency and the Argentine National Administration for Drugs, Food and Medical Technology (ANMAT). Infliximab has not been approved by the FDA or ANMAT and golimumab is under a Phase III study and has not yet been approved by any of the agencies. The Uruguay Ministry of Health has not approved any anti-TNF-alpha for JIA.PurposeTo assess the available evidence on the efficacy, safety and coverage related aspects regarding the use of etanercept, adalimumab, infliximab and golimumab in patients with Juvenile Idiopathic Arthritis.MethodsA bibliographic search was carried out on the main literature databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsTwo systematic reviews (SRs), two RCTs, one non-randomized clinical trial, seven Clinical Practice Guidelines (CPGs) and five coverage policies (England, Scotland, Australia, France and Argentina) were included. No Health Technology Assessment documents were found on the subject.One meta-analysis which included 4 randomized studies (with studies included in both SRs found) compared the use of anti-TNF-alpha (adalimumab, etanercept,) vs. placebo in patients who responded to the use of these biological agents and evaluated disease relapse after discontinuation. The follow-up time of the studies included was 4 months to 2 years and they enrolled 322 patients. In the anti-TNF-alpha treated group, a decrease in JIA flares was observed with an RR 0.46, 95% CI 0.36 ? 0.60 (anti-TNF-alpha group 50/176 vs. placebo group 108/178).One RCT evaluated the use of methotrexate plus etanercept and prednisone vs. methotrexate plus placebo and prednisone in 85 pediatric patients. Forty percent (17/42) of the patients in the methotrexate plus etanercept and prednisone group presented inactive disease at 6 months vs. 23% (10/43) in the comparator group (p=0.088).One RCR evaluated the efficacy of infliximab plus methotrexate vs. methotrexate as single agent and methotrexate plus sulfasalazine in 60 patients with a 54-week follow-up. The rate of patients who reached ACR 75 pediatric criteria (at least 75% improvement in the scale which includes joint motion, overall physical activity and quality of life) was100% (19/19) when patients received infliximab plus methotrexate, 50% (10/20, 95%CI 28%-72%) in the methotrexate alone group and 65% (13/20, 95%CI 44%- 86%) in the sulfasalazine group, (p<0.0001).In addition, the time with inactive disease was 26 weeks (95%CI 18-34), 13 weeks (95%CI 6-20) and 6 weeks (95%CI 2-10), respectively.No randomized studies comparing etanercept vs. infliximab in children were found.The CPG recommend starting etanercept (some include other anti-TNF-alpha such as adalimumab or infliximab) in pediatric patients who were treated with glucocorticoid articular injections and oral methotrexate for 3 months at the maximum dose and present moderate or high disease activity or poor prognostic signs. Furthermore, it is recommended to use them in patients with severe active disease and no poor prognostic signs who did not respond to the use of corticosteroids and methotrexate for 6 months. They are not recommended for systemic forms with no joint involvement.Most health sponsors accept to cover etarnacept and only some of them cover adalimumab.ConclusionsThe evidence found is high quality. JIA treatment with etanercept and adalimumab has demonstrated to improve disease relapse.The use of etanercept is accepted by regulatory agencies, health sponsors and CPG. The use of adalimumab is less homogeneous and depends on local costs and availability.Infliximab has not been approved by the FDA and ANMAT and golimumab is under Phase II research for JIA.They are indicated for patients 4 to 17 years old whose disease remains active with involvement in 5 or more joints after 3-6 months of treatment with methotrexate and another disease-modifying drug. They are not recommended for systemic forms with no joint involvement.