array(41) {
  ["project_title"]=>
  string(141) "Influence of demographic and environmental factors on anti-TNF efficacy in rheumatoid arthritis: a systematic review and meta-analysis of RCT"
  ["project_narrative_summary"]=>
  string(613) "The treat-to-target strategy in RA has been proposed to increase the therapeutic efficacy while minimizing the risk of adverse events. Therefore, it is important to assess if demographics and environmental factors (age, gender, disease duration, disease activity, CRP/ESR levels, RF and ACPA status, smoking status, BMI, physical activity) could influence anti-TNF treatment effect and the direction of this influence. These factors could therefore be considered when initiating anti-TNF in RA in order to increase response rate and anticipate and avoid failure.
Prospero registration number: CRD42018071079" ["project_learn_source"]=> string(11) "data_holder" ["project_learn_source_exp"]=> string(0) "" ["project_key_personnel"]=> array(4) { [0]=> array(6) { ["p_pers_f_name"]=> string(6) "Sophie" ["p_pers_l_name"]=> string(7) "Derolez" ["p_pers_degree"]=> string(38) "Resident (10th year of Medical School)" ["p_pers_pr_affil"]=> string(37) "University Hospital of Tours (France)" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } [1]=> array(6) { ["p_pers_f_name"]=> string(8) "Theodora" ["p_pers_l_name"]=> string(16) "Bejan-Angoulvant" ["p_pers_degree"]=> string(6) "PhD MD" ["p_pers_pr_affil"]=> string(37) "University Hospital of Tours (France)" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } [2]=> array(6) { ["p_pers_f_name"]=> string(5) "Denis" ["p_pers_l_name"]=> string(8) "Mulleman" ["p_pers_degree"]=> string(6) "PhD MD" ["p_pers_pr_affil"]=> string(37) "University Hospital of Tours (France)" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } [3]=> array(6) { ["p_pers_f_name"]=> string(12) "Marc Antoine" ["p_pers_l_name"]=> string(7) "Sparfel" ["p_pers_degree"]=> string(22) "Intern of Rheumatology" ["p_pers_pr_affil"]=> string(37) "University Hospital of Tours (France)" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } } ["project_ext_grants"]=> array(2) { ["value"]=> string(68) "No external grants or funds are being used to support this research." ["label"]=> string(68) "No external grants or funds are being used to support this research." } ["project_funding_source"]=> string(0) "" ["project_assoc_trials"]=> array(10) { [0]=> object(WP_Post)#4717 (24) { ["ID"]=> int(1132) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2014-09-22 10:56:00" ["post_date_gmt"]=> string(19) "2014-09-22 10:56:00" ["post_content"]=> string(0) "" ["post_title"]=> string(241) "NCT00264550 - A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFa Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(192) "nct00264550-a-multicenter-randomized-double-blind-placebo-controlled-trial-of-golimumab-a-fully-human-anti-tnfa-monoclonal-antibody-administered-subcutaneously-in-subjects-with-active-rheumato" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-11-30 13:49:01" ["post_modified_gmt"]=> string(19) "2023-11-30 18:49:01" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(241) "https://dev-yoda.pantheonsite.io/clinical-trial/nct00264550-a-multicenter-randomized-double-blind-placebo-controlled-trial-of-golimumab-a-fully-human-anti-tnfa-monoclonal-antibody-administered-subcutaneously-in-subjects-with-active-rheumato/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [1]=> object(WP_Post)#4716 (24) { ["ID"]=> int(1138) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2014-09-22 10:59:00" ["post_date_gmt"]=> string(19) "2014-09-22 10:59:00" ["post_content"]=> string(0) "" ["post_title"]=> string(267) "NCT00299546 - A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFa Monoclonal Antibody, Administered Subcutaneously in Subjects with Active Rheumatoid Arthritis and Previously Treated with Biologic Anti TNFa Agent(s)" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(193) "nct00299546-a-multicenter-randomized-double-blind-placebo-controlled-trial-of-golimumab-a-fully-human-anti-tnfa-monoclonal-antibody-administered-subcutaneously-in-subjects-with-active-rheumatoi" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-02-06 13:12:39" ["post_modified_gmt"]=> string(19) "2023-02-06 13:12:39" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(242) "https://dev-yoda.pantheonsite.io/clinical-trial/nct00299546-a-multicenter-randomized-double-blind-placebo-controlled-trial-of-golimumab-a-fully-human-anti-tnfa-monoclonal-antibody-administered-subcutaneously-in-subjects-with-active-rheumatoi/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [2]=> object(WP_Post)#4715 (24) { ["ID"]=> int(1141) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2014-09-22 11:01:00" ["post_date_gmt"]=> string(19) "2014-09-22 11:01:00" ["post_content"]=> string(0) "" ["post_title"]=> string(240) "NCT00361335 - 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A Randomized, Double-blind, Trial of Anti-TNFa Chimeric Monoclonal Antibody (Infliximab) in Combination With Methotrexate Compared With Methotrexate Alone for the Treatment of Patients With Early Rheumatoid Arthritis" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(194) "nct00236028-a-randomized-double-blind-trial-of-anti-tnfa-chimeric-monoclonal-antibody-infliximab-in-combination-with-methotrexate-compared-with-methotrexate-alone-for-the-treatment-of-patients-w" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-08-05 04:46:12" ["post_modified_gmt"]=> string(19) "2023-08-05 04:46:12" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(243) "https://dev-yoda.pantheonsite.io/clinical-trial/nct00236028-a-randomized-double-blind-trial-of-anti-tnfa-chimeric-monoclonal-antibody-infliximab-in-combination-with-methotrexate-compared-with-methotrexate-alone-for-the-treatment-of-patients-w/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [6]=> object(WP_Post)#4712 (24) { ["ID"]=> int(1540) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2016-06-23 12:12:00" ["post_date_gmt"]=> string(19) "2016-06-23 12:12:00" ["post_content"]=> string(0) "" ["post_title"]=> string(233) "NCT00973479 - 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RA alters quality of life and increases cardiovascular, infectious and other morbidity risks. Anti-TNF drugs are efficient, yet primary or secondary failure is still a problem for one patient out of 3, even if exposition to anti-TNF drugs is correct. Therefore, searching for determinants of treatment response is essential. ?
Objective : To study the influence of demographics and disease-related factors on anti-TNF drugs? efficacy in randomized controlled trials (RCT) in rheumatoid arthritis.
Study design : Systematic review and meta-analysis of published RCT following the PRISMA recommendations.
Participants : Adults (?18 years of age) with RA according to ACR 1987 or ACR/EULAR 2010 criteria.
Outcomes: primary: ACR20, secondary: ACR50, ACR70, DAS28-CRP, DAS28-ESR, CDAI, SDAI.
Statistical analysis: A meta-analysis of aggregate data will be performed. A fixed effect model will be performed first, with addition of a random effect model in case of significant heterogeneity.
Prospero registration number: CRD42018071079." ["project_brief_bg"]=> string(3117) "Rheumatoid arthritis (RA) is a relatively frequent immune mediated disease with a prevalence of 3 to 8/1,000 patients. RA alters quality of life and increases cardiovascular, infectious and other morbidity risks. Anti-TNF drugs are efficient, yet primary or secondary failure is still a problem for one patient out of 3, even if exposition to anti-TNF drugs is correct. Therefore, searching for determinants of treatment response is essential. ?Description of the treatment effect modifiers considered in this review and how these factors could influence the response to anti-TNF drugs
We considered the following demographic and environmental factors that could modify the response to anti-TNF drugs:
- Age and gender. Elderly patients with RA have an increased risk of serious infection. Female gender was shown to be independently associated with a lower rate of remission and a lower response rate to anti-TNF drugs.
- Disease duration. A long disease duration was associated with a poor response rate to anti-TNF.
- Disease activity and/or severity markers such as disease activity score on 28 joints status (DAS28), CRP level, rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA). In a prospective register, ACPA positivity was negatively related to clinical response and ACPA and RF-positivity was predictive of poor response. High disease activity at baseline was directly associated with favorable response as measured by ACR50 and ACR70 but GISEA study confirmed that high disease activity at baseline was associated with lower response.
- Smoking status. Current cigarette smoking was shown to be associated with a lower response rate to infliximab, and cigarette smoking is a well-recognized risk factor for the development of RA and has also been associated with a more severe disease, disability and extra-articular manifestations, particularly nodules
- Weight or body mass index (BMI). Baseline BMI was shown to be positively correlated with DAS28, indicating a more-active disease in overweight patients. Further, a higher BMI was shown to be associated with a decreased clinical response to infliximab.
- Physical activity. Findings indicate that RA patients who participate in appropriate exercises programs may lessen fatigue levels and experience other positive effects without worsening their condition but we did not found studies that showed that physical activity could influence the response to anti-TNF drugs.
Why it is important to do this review
The treat-to-target strategy in RA has been proposed to increase the therapeutic efficacy while minimizing the risk of adverse events. Therefore, it is important to assess if demographics and environmental factors listed above could influence anti-TNF treatment effect and the direction of this influence. These factors could therefore be considered when initiating anti-TNF in RA in order to increase response rate and anticipate and avoid failure. That is why we are studying the treatment effect in subgroups of interest (eg treatment effect measured by age or gender." ["project_specific_aims"]=> string(157) "To study the influence of demographics and disease-related factors on anti-TNF drugs? efficacy in randomized controlled trials (RCT) in rheumatoid arthritis." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(4) { [0]=> array(2) { ["value"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" ["label"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" } [1]=> array(2) { ["value"]=> string(32) "Summary-level data meta-analysis" ["label"]=> string(32) "Summary-level data meta-analysis" } [2]=> array(2) { ["value"]=> string(69) "Meta-analysis using data from the YODA Project and other data sources" ["label"]=> string(69) "Meta-analysis using data from the YODA Project and other data sources" } [3]=> array(2) { ["value"]=> string(69) "Meta-analysis using data from the YODA Project and other data sources" ["label"]=> string(69) "Meta-analysis using data from the YODA Project and other data sources" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(722) "In a first step, we searched CENTRAL, PubMed and EMBASE and selected eligible studies.
- Inclusion criteria: randomized controlled trials comparing an anti-TNF drug (infliximab, adalimumab, golimumab, certolizumab pegol or etanercept) versus placebo or conventional DMARDs, in rheumatoid arthritis (RA) patients and reported efficacy data by subgroups of demographic and disease related factors of interest.
The following factors of interest will be considered: age, sex, BMI, smoking status, disease duration, DAS28, CRP, ACPA, RF, and physical activity.
- Exclusion criteria: non-randomized controlled trials, observational studies, randomized trials comparing 2 anti-TNF drugs without a control group." ["project_main_outcome_measure"]=> string(141) "Primary outcome : ACR20
The ACR20 is reported as ?20% improvement, comparing disease activity at baseline and post-baseline comparison." ["project_main_predictor_indep"]=> string(148) "- Age : 25
- physical activity < 30 min/week or ? 30 min/week
We created an excel extraction sheet if you need for collecting the data." ["project_other_variables_interest"]=> string(4) "none" ["project_stat_analysis_plan"]=> string(394) "A meta-analysis of aggregate data will be performed, following appropriate methods (relative risks or standardized mean difference) depending of the nature of the outcome considered. A fixed effect model will be performed first, with addition of a random effect model in case of significant heterogeneity. Heterogeneity will be considered significant if the m-value of the heterogeneity test is" ["project_timeline"]=> string(270) "Estimation dates :
project start date : november 2017
analysis completion date : july 2018
date manuscript drafted : october 2018
first submitted : october-november 2018
date results reported back to the YODA Project : october-november 2018" ["project_dissemination_plan"]=> string(97) "EULAR congress 2019
JBS, Rheumatology, Arthritis & care, BMJ, Journal of Rheumatology, ARD." ["project_bibliography"]=> string(5294) "

– Krintel SB, Dehlendorff C, Hetland ML, Hrslev-Petersen K, Andersen KK, Junker P, et al. Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J. 2016 Apr;16(2):141?6.
– Hetland ML, Christensen IJ, Tarp U, Dreyer L, Hansen A, Hansen IT, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum. 2010 Jan;62(1):22?32.
– Sugihara T, Harigai M. Targeting Low Disease Activity in Elderly-Onset Rheumatoid Arthritis: Current and Future Roles of Biological Disease-Modifying Antirheumatic Drugs. Drugs Aging. 2016 Feb;33(2):97?107.
– Hyrich KL, Watson KD, Silman AJ, Symmons DPM, British Society for Rheumatology Biologics Register. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatol Oxf Engl. 2006 Dec;45(12):1558?65.
– Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000 Jan;43(1):22?9.
– Jawaheer D, Olsen J, Hetland ML. Sex differences in response to anti-tumor necrosis factor therapy in early and established rheumatoid arthritis — results from the DANBIO registry. J Rheumatol. 2012 Jan;39(1):46?53.
– Stoffer MA, Schoels MM, Smolen JS, Aletaha D, Breedveld FC, Burmester G, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update. Ann Rheum Dis. 2016 Jan;75(1):16?22.
– Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000 Jan;43(1):22?9.
– Canho H, Rodrigues AM, Mouro AF, Martins F, Santos MJ, Canas-Silva J, et al. Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis. Rheumatol Oxf Engl. 2012 Nov;51(11):2020?6.
– Gibbons LJ, Hyrich KL. Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response. BioDrugs Clin Immunother Biopharm Gene Ther. 2009;23(2):111?24.
– Kristensen LE, Kapetanovic MC, Glfe A, Sderlin M, Saxne T, Geborek P. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatol Oxf Engl. 2008 Apr;47(4):495?9.
– Lannone F, Gremese E, Gallo G, Sarzi-Puttini P, Botsios C, Trotta F, et al. High rate of disease remission in moderate rheumatoid arthritis on etanercept therapy: data from GISEA, the Italian biologics register. Clin Rheumatol. 2014 Jan;33(1):31?7.
– Mattey DL, Brownfield A, Dawes PT. Relationship between pack-year history of smoking and response to tumor necrosis factor antagonists in patients with rheumatoid arthritis. J Rheumatol. 2009 Jun;36(6):1180?7.
– Sderlin MK, Petersson IF, Geborek P. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug. Scand J Rheumatol. 2012 Feb;41(1):1?9.
– Klaasen R, Wijbrandts CA, Gerlag DM, Tak PP. Body mass index and clinical response to infliximab in rheumatoid arthritis. Arthritis Rheum. 2011 Feb;63(2):359?64.
– Ottaviani S, Gardette A, Tubach F, Roy C, Palazzo E, Gill G, et al. Body mass index and response to infliximab in rheumatoid arthritis. Clin Exp Rheumatol. 2015 Aug;33(4):478?83.
– Eurenius E, Stenstrm CH. Physical activity, physical fitness, and general health perception among individuals with rheumatoid arthritis. Arthritis Rheum. 2005 Feb 15;53(1):48?55.
– Stenstrm CH, Minor MA. Evidence for the benefit of aerobic and strengthening exercise in rheumatoid arthritis. Arthritis Rheum. 2003 Jun 15;49(3):428?34.
– Smolen JS, Landew R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017 Jun;76(6):960?77.
– Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006?12.
– Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315?24.
– Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010 Sep;69(9):1580?8.

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2018-2931

General Information

How did you learn about the YODA Project?: Data Holder (Company)

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT00264550 - A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFa Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy
  2. NCT00299546 - A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFa Monoclonal Antibody, Administered Subcutaneously in Subjects with Active Rheumatoid Arthritis and Previously Treated with Biologic Anti TNFa Agent(s)
  3. NCT00361335 - A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFa Monoclonal Antibody, Administered Intravenously, in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy
  4. NCT01248780 - A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Golimumab in the Treatment of Chinese Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy
  5. NCT00269867 - A Placebo-Controlled, Double-Blinded, Randomized Clinical Trial of Anti-TNF Chimeric Monoclonal Antibody (cA2) in Patients With Active Rheumatoid Arthritis Despite Methotrexate Treatment
  6. NCT00236028 - A Randomized, Double-blind, Trial of Anti-TNFa Chimeric Monoclonal Antibody (Infliximab) in Combination With Methotrexate Compared With Methotrexate Alone for the Treatment of Patients With Early Rheumatoid Arthritis
  7. NCT00973479 - A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, an Anti-TNFalpha Monoclonal Antibody, Administered Intravenously, in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy
  8. NCT00207714 - A Randomized, Double-blind, Dose-ranging Trial of CNTO 148 Subcutaneous Injection Compared With Placebo in Subjects With Active Rheumatoid Arthritis Despite Treatment With Methotrexate
  9. NCT00202852 - A Placebo-Controlled, Double-Blinded, Randomized Clinical Trial of Anti-TNF Chimeric Monoclonal Antibody (cA2) in Korean Patients With Active Rheumatoid Arthritis Despite Methotrexate
  10. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis
What type of data are you looking for?:

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Data Request Status

Status: Ongoing

Research Proposal

Project Title: Influence of demographic and environmental factors on anti-TNF efficacy in rheumatoid arthritis: a systematic review and meta-analysis of RCT

Scientific Abstract: Background : Rheumatoid arthritis is a relatively frequent immune mediated disease with a prevalence of 3 to 8/1,000 patients. RA alters quality of life and increases cardiovascular, infectious and other morbidity risks. Anti-TNF drugs are efficient, yet primary or secondary failure is still a problem for one patient out of 3, even if exposition to anti-TNF drugs is correct. Therefore, searching for determinants of treatment response is essential. ?
Objective : To study the influence of demographics and disease-related factors on anti-TNF drugs? efficacy in randomized controlled trials (RCT) in rheumatoid arthritis.
Study design : Systematic review and meta-analysis of published RCT following the PRISMA recommendations.
Participants : Adults (?18 years of age) with RA according to ACR 1987 or ACR/EULAR 2010 criteria.
Outcomes: primary: ACR20, secondary: ACR50, ACR70, DAS28-CRP, DAS28-ESR, CDAI, SDAI.
Statistical analysis: A meta-analysis of aggregate data will be performed. A fixed effect model will be performed first, with addition of a random effect model in case of significant heterogeneity.
Prospero registration number: CRD42018071079.

Brief Project Background and Statement of Project Significance: Rheumatoid arthritis (RA) is a relatively frequent immune mediated disease with a prevalence of 3 to 8/1,000 patients. RA alters quality of life and increases cardiovascular, infectious and other morbidity risks. Anti-TNF drugs are efficient, yet primary or secondary failure is still a problem for one patient out of 3, even if exposition to anti-TNF drugs is correct. Therefore, searching for determinants of treatment response is essential. ?Description of the treatment effect modifiers considered in this review and how these factors could influence the response to anti-TNF drugs
We considered the following demographic and environmental factors that could modify the response to anti-TNF drugs:
- Age and gender. Elderly patients with RA have an increased risk of serious infection. Female gender was shown to be independently associated with a lower rate of remission and a lower response rate to anti-TNF drugs.
- Disease duration. A long disease duration was associated with a poor response rate to anti-TNF.
- Disease activity and/or severity markers such as disease activity score on 28 joints status (DAS28), CRP level, rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA). In a prospective register, ACPA positivity was negatively related to clinical response and ACPA and RF-positivity was predictive of poor response. High disease activity at baseline was directly associated with favorable response as measured by ACR50 and ACR70 but GISEA study confirmed that high disease activity at baseline was associated with lower response.
- Smoking status. Current cigarette smoking was shown to be associated with a lower response rate to infliximab, and cigarette smoking is a well-recognized risk factor for the development of RA and has also been associated with a more severe disease, disability and extra-articular manifestations, particularly nodules
- Weight or body mass index (BMI). Baseline BMI was shown to be positively correlated with DAS28, indicating a more-active disease in overweight patients. Further, a higher BMI was shown to be associated with a decreased clinical response to infliximab.
- Physical activity. Findings indicate that RA patients who participate in appropriate exercises programs may lessen fatigue levels and experience other positive effects without worsening their condition but we did not found studies that showed that physical activity could influence the response to anti-TNF drugs.
Why it is important to do this review
The treat-to-target strategy in RA has been proposed to increase the therapeutic efficacy while minimizing the risk of adverse events. Therefore, it is important to assess if demographics and environmental factors listed above could influence anti-TNF treatment effect and the direction of this influence. These factors could therefore be considered when initiating anti-TNF in RA in order to increase response rate and anticipate and avoid failure. That is why we are studying the treatment effect in subgroups of interest (eg treatment effect measured by age or gender.

Specific Aims of the Project: To study the influence of demographics and disease-related factors on anti-TNF drugs? efficacy in randomized controlled trials (RCT) in rheumatoid arthritis.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: Confirm or validate previously conducted research on treatment effectiveness Summary-level data meta-analysis Meta-analysis using data from the YODA Project and other data sources Meta-analysis using data from the YODA Project and other data sources

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: In a first step, we searched CENTRAL, PubMed and EMBASE and selected eligible studies.
- Inclusion criteria: randomized controlled trials comparing an anti-TNF drug (infliximab, adalimumab, golimumab, certolizumab pegol or etanercept) versus placebo or conventional DMARDs, in rheumatoid arthritis (RA) patients and reported efficacy data by subgroups of demographic and disease related factors of interest.
The following factors of interest will be considered: age, sex, BMI, smoking status, disease duration, DAS28, CRP, ACPA, RF, and physical activity.
- Exclusion criteria: non-randomized controlled trials, observational studies, randomized trials comparing 2 anti-TNF drugs without a control group.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Primary outcome : ACR20
The ACR20 is reported as ?20% improvement, comparing disease activity at baseline and post-baseline comparison.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: - Age : 25
- physical activity < 30 min/week or ? 30 min/week
We created an excel extraction sheet if you need for collecting the data.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: none

Statistical Analysis Plan: A meta-analysis of aggregate data will be performed, following appropriate methods (relative risks or standardized mean difference) depending of the nature of the outcome considered. A fixed effect model will be performed first, with addition of a random effect model in case of significant heterogeneity. Heterogeneity will be considered significant if the m-value of the heterogeneity test is

Narrative Summary: The treat-to-target strategy in RA has been proposed to increase the therapeutic efficacy while minimizing the risk of adverse events. Therefore, it is important to assess if demographics and environmental factors (age, gender, disease duration, disease activity, CRP/ESR levels, RF and ACPA status, smoking status, BMI, physical activity) could influence anti-TNF treatment effect and the direction of this influence. These factors could therefore be considered when initiating anti-TNF in RA in order to increase response rate and anticipate and avoid failure.
Prospero registration number: CRD42018071079

Project Timeline: Estimation dates :
project start date : november 2017
analysis completion date : july 2018
date manuscript drafted : october 2018
first submitted : october-november 2018
date results reported back to the YODA Project : october-november 2018

Dissemination Plan: EULAR congress 2019
JBS, Rheumatology, Arthritis & care, BMJ, Journal of Rheumatology, ARD.

Bibliography:

– Krintel SB, Dehlendorff C, Hetland ML, Hrslev-Petersen K, Andersen KK, Junker P, et al. Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J. 2016 Apr;16(2):141?6.
– Hetland ML, Christensen IJ, Tarp U, Dreyer L, Hansen A, Hansen IT, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum. 2010 Jan;62(1):22?32.
– Sugihara T, Harigai M. Targeting Low Disease Activity in Elderly-Onset Rheumatoid Arthritis: Current and Future Roles of Biological Disease-Modifying Antirheumatic Drugs. Drugs Aging. 2016 Feb;33(2):97?107.
– Hyrich KL, Watson KD, Silman AJ, Symmons DPM, British Society for Rheumatology Biologics Register. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatol Oxf Engl. 2006 Dec;45(12):1558?65.
– Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000 Jan;43(1):22?9.
– Jawaheer D, Olsen J, Hetland ML. Sex differences in response to anti-tumor necrosis factor therapy in early and established rheumatoid arthritis — results from the DANBIO registry. J Rheumatol. 2012 Jan;39(1):46?53.
– Stoffer MA, Schoels MM, Smolen JS, Aletaha D, Breedveld FC, Burmester G, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update. Ann Rheum Dis. 2016 Jan;75(1):16?22.
– Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000 Jan;43(1):22?9.
– Canho H, Rodrigues AM, Mouro AF, Martins F, Santos MJ, Canas-Silva J, et al. Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis. Rheumatol Oxf Engl. 2012 Nov;51(11):2020?6.
– Gibbons LJ, Hyrich KL. Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response. BioDrugs Clin Immunother Biopharm Gene Ther. 2009;23(2):111?24.
– Kristensen LE, Kapetanovic MC, Glfe A, Sderlin M, Saxne T, Geborek P. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatol Oxf Engl. 2008 Apr;47(4):495?9.
– Lannone F, Gremese E, Gallo G, Sarzi-Puttini P, Botsios C, Trotta F, et al. High rate of disease remission in moderate rheumatoid arthritis on etanercept therapy: data from GISEA, the Italian biologics register. Clin Rheumatol. 2014 Jan;33(1):31?7.
– Mattey DL, Brownfield A, Dawes PT. Relationship between pack-year history of smoking and response to tumor necrosis factor antagonists in patients with rheumatoid arthritis. J Rheumatol. 2009 Jun;36(6):1180?7.
– Sderlin MK, Petersson IF, Geborek P. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug. Scand J Rheumatol. 2012 Feb;41(1):1?9.
– Klaasen R, Wijbrandts CA, Gerlag DM, Tak PP. Body mass index and clinical response to infliximab in rheumatoid arthritis. Arthritis Rheum. 2011 Feb;63(2):359?64.
– Ottaviani S, Gardette A, Tubach F, Roy C, Palazzo E, Gill G, et al. Body mass index and response to infliximab in rheumatoid arthritis. Clin Exp Rheumatol. 2015 Aug;33(4):478?83.
– Eurenius E, Stenstrm CH. Physical activity, physical fitness, and general health perception among individuals with rheumatoid arthritis. Arthritis Rheum. 2005 Feb 15;53(1):48?55.
– Stenstrm CH, Minor MA. Evidence for the benefit of aerobic and strengthening exercise in rheumatoid arthritis. Arthritis Rheum. 2003 Jun 15;49(3):428?34.
– Smolen JS, Landew R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017 Jun;76(6):960?77.
– Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006?12.
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