Adalimumab in rheumatoid arthritis treatment.docx

1、Adalimumab in rheumatoid arthritis treatmentAdalimumab in rheumatoid arthritis treatment: a systematic review and meta-analysis of randomized clinical trialsMarina Amaral de vila MachadoI,*; Alessandra Almeida MacielI; Lvia Lovato Pires de LemosII; Juliana Oliveira CostaI; Adriana Maria KakehasiIII;

2、 Eli Iola Gurgel AndradeIV; Mariangela Leal CherchigliaV; Francisco de Assis AcurcioVIIPost-Graduation Program in Public Health, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilIIPost-Graduation Program in Medications and Pharmaceutical Care, School of Pharmaceuti

3、cal Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilIIIDepartment of Musculoskeletal System, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilIVPost-Graduation Program in Demographics, Universidade Federal de Minas Gerais, Belo Horizonte,

4、MG, BrazilVPost-Graduation Program in Public Health, Universidade de So Paulo, So Paulo, SP, BrazilVIPost-Graduation Program in Animal Sciences, School of Veterinary Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrazilABSTRACTSince the discovery of the role of tumor necrosis fa

5、ctor in the physiopathological process of rheumatoid arthritis, five drugs that block this cytokine have been used as therapeutic options. To evaluate the efficacy and safety of adalimumab in the treatment of rheumatoid arthritis we performed a systematic review and meta-analysis of randomized contr

6、olled trials. A search of relevant studies in Medline (through PubMed) and LILACS in June 2011 was carried out. Study selection, data collection and analysis were performed in pairs and independently by two reviewers and by a third reviewer in cases of disagreement. The meta-analysis was performed u

7、sing the software Review Manager5.1 using the random effects model. Eleven articles related to adalimumab were included and considered nine studies with 3461 patients. Ten studies showed low risk of bias regarding the blinding of participants and personnel and blinding of outcome assessment. Patient

8、s who received the combination treatment of adalimumab and methotrexate showed better efficacy results and lower radiographic progression when compared to placebo + methotrexate in 24-104 weeks. Patients who received adalimumab as monotherapy showed better efficacy outcomes when compared to placebo

9、in 24 and 26 weeks. The results of the meta-analyses of adverse events were not statistically significant, except for reactions at the injection site, which favored the control group. Adalimumab efficacy was demonstrated in monotherapy and when associated to a DMARD, but the evidence for combined us

10、e is more robust.Keywords:Rheumatoid arthritis; Adalimumab; Tumor necrosis factor; Systematic review; Meta-analysisIntroductionEvidence-based Medicine is the conscientious, explicit and sensible use of best evidence for decision-making in patient care. The practice of evidence-based Medicine integra

11、tes the individual experience of the physician with the best evidence available through systematic research.1Systematic reviews are considered Level I evidence and have stringent methods that decrease the occurrence of biases when compared to narrative reviews.2The benefits of the monoclonal antibod

12、y adalimumab in the control of rheumatoid arthritis (RA) have been widely reported in the literature and, in Brazil, this is the second most used drug of this class of biological agents for the treatment of this disease.3-5The annual cost of this treatment is high, being estimated in Brazil at R$ 71

13、,117.00 and with a ratio of incremental cost-effectiveness per quality-adjusted life year (QALY), when compared to therapy with methotrexate (MTX), of R$ 628.124,00.6This high cost emphasizes the importance of systematization of all the evidence available to aid decision-making in health care.RA is

14、a systemic inflammatory, chronic and progressive disease of unknown etiology that affects the synovial membrane of joints, leading to cartilage and bone destruction.This autoimmune disorder affects the joints, often in the hands and feet, on both sides equally and symmetrically.3,7The prevalence is

15、estimated at 0.5-1.0% of the population and is more frequent in women, according to studies performed in the United States, Europe and Brazil.8,9The care of patients with RA includes the use of diseasemodifying antirheumatic drugs (DMARDs), nonsteroidal antiinflammatory drugs (NSAIDs) and corticoste

16、roids, in addition to non-pharmacological treatment such as occupational therapy and physical therapy.10Biological DMARDs represent a breakthrough in therapy and RA and have been indicated in cases where patients do not respond to conventional treatment.The tumor necrosis factor (TNF) blockers adali

17、mumab, etanercept, infliximab, certolizumab and golimumab are included in this class.3,10,11Aiming to contribute to the practice of evidence-based Medicine, we performed a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of Adalimumab in the tre

18、atment of RA.MethodsThis study is part of a systematic review of randomized controlled trials on the efficacy and safety of the drugs adalimumab, etanercept, infliximab and rituximab in the treatment of rheumatoid arthritis.Eligibility criteriaRandomized controlled trials written in Portuguese, Engl

19、ish and Spanish were selected for the review. We considered comparisons of Adalimumab 40 mg once every 15 days as monotherapy or combined with DMARDs vs. control group in patients with rheumatoid arthritis diagnosis according to the revised criteria of the American College of Rheumatology and active

20、 disease.12Article searchThe search for studies was carried out in the Medline database (through Pubmed) and LILACS in June 2011 and supplemented by manual searching in references of systematic reviews and the studies that were found. The search strategy consisted of the following words: rheumatoid

21、arthritis, monoclonal antibodies, D2E7 antibody, Humira. The search in Pubmed was structured from Mesh (Medical Subject Headings) terms and a sensitive search was performed for randomized controlled trials.Study selection and data collectionStudy selection was carried out by analysis of the titles a

22、nd abstracts of studies selected by the search. Data were collected using a standardized form.Two reviewers independently assessed and extracted data from each study and disagreements were resolved by consensus or by a third reviewer. Data on characteristics of the study design and the population, d

23、uration of disease, previous or concomitant use of DMARDs, intervention and outcomes were collected for each trial.The primary outcome was the ACR20 response defined by the American College of Rheumatology (ACR). ACR20 response occurs when there is a decreased of 20% in the count of joints with pain

24、 and edema and improvement in 3 of the 5 variables: overall assessment by the patient and physician, pain, Health Assessment Questionnaire (HAQ) scale and acute phase inflammatory markers (C-reactive protein or erythrocyte sedimentation rate - ESR).13The secondary outcomes were ACR50 and ACR70 respo

25、nses, in which there are 50% and 70% improvement in the same parameters, in addition to functionality, measured by the HAQ scale, radiographic outcomes, loss to follow-up and safety. The authors, if necessary, were contacted to provide additional information.Methodological quality and risk of biasTh

26、e assessment of methodological quality and risk of bias was performed independently by two reviewers with access to the authors name, institution and the journal that published the study and disagreements were resolved by consensus. Quality assessment by the modified Jadad scale and risk of bias ass

27、essment proposed by the Cochrane Collaboration were employed. These tools assess methodological aspects, such as randomization, blinding and loss of participants. The modified Jadad scale scores clinical trials from 0-6 and the higher the score, the better the methodological quality.14, 15Meta-analy

28、sisThe meta-analysis was performed using the Review Manager5.1 software. We used the weighted difference in means for continuous outcomes and relative risk for dichotomous data, both considering a confidence interval of 95%.The presence of heterogeneity between studies was considered a premise and t

29、herefore the random effects model was applied. Statistical heterogeneity was considered if P 40% and in those cases, the potential factors that influenced this phenomenon were investigated.16ResultsThe search for studies of the four drugs (Adalimumab, Etanercept, Infliximab and Rituximab) resulted i

30、n 3620 articles in Pubmed and 84 in LILACS, as well as nine articles found by manual search. Eleven articles related to Adalimumab were included and considered nine studies with 3461 patients (Fig. 1).Study characteristicsSeven studies evaluated groups of patients treated with Adalimumab (ADA) 40 mg

31、 every 2 weeks combined with some DMARDs vs. DMARDs as monotherapy (plus placebo): in six studies patients used MTX and in the STAR study subjects received some DMARDs, among them MTX, chloroquine, hydroxychloroquine, leflunomide, parenteral gold, oral gold compounds, sulfasalazine, or any combinati

32、on of these.17Most patients (82.1% group ADA + DMARDs and 84.9% group placebo + DMARDs) used one or more DMARDs during the study and MTX was the most common (56.0% group ADA + DMARDs and 62.6% group placebo + DMARDs). Two trials were performed in groups using ADA 40 mg every 2 weeks as monotherapy compared to placebo. Only the PREMIER study included arms of comparison between ADA monotherapy vs. MTX monotherapy.18Patients had active RA in all studies. The study GUEPARD defined active disease by DAS28 (disease activity score) g