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Drugs for the management of rheumatoid arthritis: clinical evaluation – Project Protocol

June 2016



DMARD disease modifying antirheumatic drug
FDA Food and Drug Administration
F/P/T Federal, Provincial, Territorial governments
IL interleukin
JAK Janus-associated kinase
NMA network meta-analysis
RA rheumatoid arthritis
SEB subsequent entry biologic


Moderate rheumatoid arthritis Patients with moderate disease activity as defined by the American College of Rheumatology guidelines 20151.
Severe rheumatoid arthritis Patients with high disease activity as defined by the American College of Rheumatology guidelines 20151.
Treatment-experienced Patients previously treated for rheumatoid arthritis. Example of previous treatments include: traditional DMARD; combination DMARDs (double or triple DMARDs); biologic drug alone; biologic drug in combination with methotrexate, tofacitinib, or any of the emerging drugs for rheumatoid arthritis.
Treatment intolerance Intolerance to treatment due to an adverse event or contraindication to treatment.
Treatment failure Less than optimal response to treatment due to a lack of efficacy (i.e., patient does not attain low disease activity).
Inadequate treatment Patients with treatment intolerance or treatment failure.
DMARD monotherapy methotrexate, sulfasalazine, hydroxychloroquine, or leflunomide.
Double DMARD therapy any two of methotrexate, sulfasalazine, hydroxychloroquine, or leflunomide.
Triple DMARD therapy methotrexate with sulfasalazine and hydroxychloroquine.
DMARD combination therapy double or triple DMARD therapy.



Rheumatoid arthritis (RA) is a chronic, autoimmune condition that affects bone joints.2 It causes pain, inflammation, stiffness and joint erosion, and consequently joint destruction.2 RA is associated with premature death, disability, and a decrease in quality of life.2 Patients with RA are more likely to have comorbid conditions such as cardiovascular disease, infections, and cancer.2

The prevalence of RA in Canada has been estimated at 300,000 people living with RA.3 A recent study of residents of Ontario revealed that the prevalence of RA in that province was approximately 1%.4 Internationally, the prevalence of RA ranges between 0.4% and 1.3%.2

Goals of treatment include symptom relief, reduction in disease activity, reduction in joint damage, and increase in quality of life.5 Recently, a “treat-to-target” approach has been recommended, in which disease remission is the ultimate target and treatment strategies are maximized until the target is achieved. Low disease activity is an appropriate alternative goal.6 Early and aggressive treatment has been shown to alter the course of disease and slow or stop radiographic progression.7,8

The 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis recommends monotherapy with a disease modifying antirheumatic drug (DMARD) as initial therapy in patients with early or established RA; methotrexate is recommended as the DMARD of choice.1 In patients with moderate or high disease activity despite a DMARD, various treatment strategies are recommended, which include combination therapy using DMARDs and biologics. No recommendations are made prioritizing one treatment strategy over another.1 One study showed that DMARDs are non-inferior to biologics drugs in established RA. 9 One network meta-analysis showed that combination treatment of a biologic and a DMARD is not superior to dual or triple combination DMARDs.10

The most often used DMARDs are methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine. According to the clinical expert consulted for the development of this protocol, intramuscular gold, azathioprine, and cyclosporine are available but rarely used. Biologic drugs include:

  • tumour necrosis factor inhibitors (adalimumab, etanercept, infliximab, golimumab, and certolizumab pegol)
  • T cell costimulatory inhibitor (abatacept)
  • B lymphocyte-depleting drug (rituximab)
  • interleukin (IL)-6 antagonist (tocilizumab)
  • IL-1 inhibitor (anakinra; almost never used to treat adult RA according to the clinical expert consulted for this protocol).

In 2010, CADTH published a therapeutic review of drugs used in RA, which focused on biologics. Specifically, the CADTH therapeutic review evaluated the comparative effectiveness, harms, and cost-effectiveness of eight biologics indicated for the treatment of RA in Canada at the time of the therapeutic review. The comparative efficacy and harms were explored through a systematic review and indirect mixed treatment comparison meta-analyses. The clinical and economic evaluations were used to generate recommendations about the optimal use of biologics in the treatment of RA.

Since then, the therapeutic area of RA has continued to evolve. Tofacitinib, a Janus-associated kinase (JAK) inhibitor, received Health Canada approval in April 201411, and another drug of the same class, baricitinib, has been submitted to the US Food and Drug Administration for review and market approval.12These are small molecules, which have the advantage of being administered orally. Two biologics, sarilumab and sirukumab, both IL-6 receptor inhibitors, are in late-stage development.13,14

The introduction of subsequent entry biologics (SEBs) to the Canadian market offers the potential to decrease health care expenditures and provide patients with access to additional treatment options. Infliximab SEB has been approved in Canada. The etanercept SEB has been approved in the European Union15, and the adalimumab SEB has phase 3 clinical trial data in RA.16

The topic of RA is of importance to the federal, provincial, and territorial (F/P/T) drug plans and they have requested that CADTH undertake a review of all treatments used in RA. With the recent introduction of oral small molecules and SEBs, it would be important to determine the relative effectiveness of all drugs used in RA in treatment-experienced patients. Specifically, there is a need to determine which are the more effective second line and third-line drugs and the relative safety of all drugs. Questions of interest gathered from the F/P/T drug plans, which informed the policy questions, included:

  • For patients whose response to methotrexate is less than optimal, should a biologic be added to methotrexate, should a biologic be prescribed alone, or should other DMARDs be added or substituted for methotrexate?
  • For patients who cannot tolerate methotrexate due to an adverse event or a contraindication, should DMARDs, alone or in combination, be tried ahead of a biologic?
  • What is the relative efficacy of dual DMARD therapy compared with triple DMARD therapy?
  • For patients who are inadequately treated with a biologic (alone or with methotrexate), what should be tried next?
  • What is the place in therapy of tofacitinib and other JAK inhibitors?
  • What are the benefits and harms of innovator biologics and subsequent entry biologics?

To make this project manageable, the scope was limited to treatment-experienced patients. A decision was made to exclude certain groups. For example an in-depth analysis of patients with early or mild disease, DMARD-naive patients, patients with comorbidities, or patients with a poor prognosis was not part of the research plan.



To inform the final scope of the protocol development, a proposed scope was developed with the assistance of clinical experts and CADTH’s F/P/T customers. In addition, targeted stakeholder feedback from patient groups and industry was solicited.

This protocol was written a priori and will be followed throughout the review process.



This project aims at completing a clinical review that will include a systematic review and network meta-analysis of drugs used in treatment-experienced adult patients with moderate to severe RA. The focus of this review will be on the clinical evidence of benefits and harms.



The policy questions for this project, which were developed by CADTH’s jurisdictional clients, are:

  • For patients with moderate to severe rheumatoid arthritis who are inadequately treated due to treatment failure or intolerance with methotrexate, what is the most effective treatment?
  • For patients with moderate to severe rheumatoid arthritis who are intolerant to methotrexate due to an adverse event or a contraindication, what is the most effective DMARD combination?
  • For patients with moderate to severe rheumatoid arthritis who are inadequately treated due to treatment failure or intolerance with a biologic (alone or with methotrexate), what is the most effective treatment?
  • For treatment-experienced patients with moderate to severe rheumatoid arthritis, what is the comparative evidence between dual and triple DMARD therapy?
  • For treatment-experienced patients with moderate to severe rheumatoid arthritis, what is the comparative evidence for dual and triple DMARD therapy versus a biologic alone or with methotrexate?
  • What is the comparative evidence between using dual DMARDs or triple DMARDs as first-line therapy, followed by a biologic alone or with methotrexate as second-line therapy, compared with using methotrexate as first-line therapy, followed by one or two additional DMARDs as second-line therapy?



There is one research question for this project. This was developed to address the aforementioned policy issues:

  • What is the comparative clinical efficacy and safety of drugs used in the management of moderate to severe rheumatoid arthritis in treatment-experienced adult patients?



The CADTH clinical evaluation will bring together, and build upon, existing systematic reviews and network meta-analyses conducted by Cochrane.17-19 The search criteria for these reviews will be updated and supplemented as needed to address the selection criteria outlined in this protocol.

METHODS - Literature Search Strategy

The literature search will be performed by a research information specialist using a peer-reviewed search strategy.

Published literature will be identified by searching the following bibliographic databases: MEDLINE with in-process records & daily updates through Ovid; Embase through Ovid; EBM Reviews — Cochrane Central Register of Controlled Trials through Ovid; Cochrane Library through Wiley; and PubMed. The search strategy will be comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings) and keywords. The main search concepts will be: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, anakinra, tocilizumab, abatacept, rituximab, methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, infliximab SEB, adalimumab SEB, etanercept SEB, tofacitinib, baricitinib, sarilumab, sirukumab, and RA.

Methodological filters will be applied to limit retrieval to randomized controlled trials and controlled clinical trials. Where possible, retrieval will be limited to the human population and English language. Due to the use of previous publications,17-19 searches and retrieval will be limited by various publication years (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, anakinra, tocilizumab, abatacept, rituximab published between January 1, 2015 to present; methotrexate published between January 1, 2014 to present; hydroxychloroquine, sulfasalazine, leflunomide, infliximab SEB, adalimumab SEB, etanercept SEB, tofacitinib, baricitinib, sarilumab, sirukumab no publication date limit). Conference abstracts will be excluded from the search results. See Appendix 1 for draft literature search strategies.

Regular alerts will be established to update the search until the publication of the final report. Regular search updates will be performed on databases that do not provide alert services.

Grey literature (literature that is not commercially published) will be identified by searching the Grey Matters checklist (, which includes the websites of regulatory agencies, health technology assessment agencies, clinical guideline repositories, and professional associations. Google and other Internet search engines will be used to search for additional web-based materials. These searches will be supplemented by reviewing the bibliographies of key papers and through contact with appropriate experts and industry.

METHODS - Selection Criteria

Two reviewers will independently screen titles and abstracts for relevance to the clinical research questions. Full texts of potentially relevant articles will be retrieved and independently assessed for possible inclusion based on the predetermined selection criteria (Table 1). The two reviewers will then compare their chosen included and excluded studies; disagreements will be discussed until consensus is reached. The study selection process will be presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart.

Table 1: Study Selection Criteria

Inclusion Criteria

Treatment-experienced adults with moderate to severe, active RA

  • moderate and severe RA
  • oral and subcutaneous methotrexate
  • patients with methotrexate intolerance and methotrexate failure
  • patients with a biologic intolerance and patients a biologic failure
  • patients using a biologic as second-line and third-line therapy
  • patients using a biologic alone after DMARD failure or using a biologic in combination with a DMARD
  • TNF inhibitors and non-TNF inhibitors

Drugs used in the treatment of RA

DMARDs alone or in combination (dual or triple therapy)

  • methotrexate, hydroxychloroquine, sulfasalazine, leflunomide

Biologics (alone or in combination with methotrexate)

  • any of the nine biologics: tumour necrosis factor blockers (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), IL-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab)

Small Molecules (alone or in combination with methotrexate)

  • tofacitinib


  • infliximab SEB (alone or in combination with methotrexate)

Products under development (alone or in combination with methotrexate)

  • adalimumab SEB, etanercept SEB, baricitinib, sarilumab, sirukumab
  • Head-to-head comparisons of any of the interventions, including combinations of DMARDs
  • Placebo


  • disease severity [e.g., ACR 20, ACR 50, ACR 70, Disease Activity Score (DAS/DAS 28)]
  • disability [e.g., Health Assessment Questionnaire Disability Index (HAQ-DI)]
  • remission (e.g., ACR / EULAR definitiona, DAS 28 remission)
  • health-related quality of life [e.g., SF-36, Arthritis Impact Measurement Scale (AIMS), Rheumatoid Arthritis Quality of Life (RAQoL)]
  • symptoms (e.g., fatigue, pain)
  • radiographic progression
  • withdrawal due to lack of efficacy, time to withdrawal due to lack of efficacy


  • serious adverse events, withdrawal due to adverse events, , hospitalization, mortality

Notable harms

  • serious infections, tuberculosis, cancer, leukemia, lymphoma, congestive heart failure, MACEs, herpes zoster
Study Design


  • Randomized controlled trials


  • Randomized controlled trials, controlled clinical trials, clinical trial registries, and US Food and Drug Administration (FDA), Health Canada, European Medicines Agency reports, labels and warnings.
Exclusion Criteria
  • non-English publications
  • conference abstracts
  • trials < 12 weeks duration
  • combination biologics (i.e., two biologics given concurrently)

ACR = American College of Rheumatology; DMARD = disease modifying antirheumatic drug; EULAR = European League Against Rheumatism; MACE = major adverse cardiovascular event; RA = rheumatoid arthritis; SEB = subsequent entry biologic; TNF = tumour necrosis factor.
aACR / EULAR definition of remission: simple disease activity index (SDAI) ≤ 3.3; or clinical disease activity index (CDAI) ≤ 2.8; or tender joint count, swollen joint count, patient global assessment of all ≤ 120.

METHODS - Data Extraction

All information will be extracted using a standardized data abstraction form, which will be developed, piloted and modified as necessary. Abstraction will include: characteristics of trial participants including, inclusion and exclusion criteria; type of interventions, including dose, duration and co-medication; and results of the clinical safety and efficacy/effectiveness outcomes of the intervention. All extracted data will be checked for accuracy by two independent review authors. The original, primary publication for each unique study included will be used for data extraction, except where multiple publications for a single primary study are found. Multiple publications for a unique study (e.g., supplemental online appendices, companion publications of specific outcomes or populations from the original study) will be handled by extracting the most recently adjudicated data for each outcome specified a priori.

METHODS - Critical Appraisal of Clinical Studies

Quality assessment will be considered using the Cochrane Collaboration’s tool for assessing risk of bias.

Reporting bias will be assessed by constructing funnel plots for each outcome. An asymmetric plot would imply publication bias; and in the absence of bias, the plot should resemble an inverted funnel. Also bias indicators will be considered (e.g., Egger, Harbold-Egger).

METHODS - Data Analysis and Synthesis

Network Meta-Analysis

Bayesian network meta-analyses (NMAs) will be conducted for outcomes pre-specified in the protocol, following careful assessment of heterogeneity across trials in terms of patient characteristics, trial methodologies, and treatment protocols. The effect estimate will depend on the outcome of interest and availability of data. For reference case NMAs, appropriate comparators will be considered and some comparators may be stratified by dose. Both fixed and random-effects models will be conducted; model selection will be based on the Deviance Information Criterion (DIC) and residual deviance. R (R Foundation for Statistical Computing, Vienna, Austria) and WinBUGS (MRC Biostatistics Unit, Cambridge, UK) will be used for Bayesian NMA according to the routing that accommodates evidence structures, which may consist of multi-arm trials as developed at the Universities of Bristol and Leicester (

Specific therapies will be identified as the reference group for all Bayesian NMAs. Posterior densities for unknown parameters will be estimated using Markov Chain Monte Carlo (MCMC) methods. Basic parameters will be assigned non-informative or vague prior distributions; more informative priors will be considered; for example, an informative prior for the between-study variance will be considered following Turner et al.21 Point estimates and 95% credible intervals will be used to summarize findings. The probability of a comparator being optimal will be estimated for each outcome based on the proportion of MCMC simulations in which its relative measure of effect was best. The mean rank for each comparator will also be calculated. Consistency between direct and indirect evidence will be formally assessed using back-calculation and node splitting techniques. Graphical methods and numerical summaries will be developed for presenting results from NMAs. Model diagnostics will also include trace plots and the Gelman-Rubin-Brooks statistic to assess and ensure model convergence. Two chains will be fit in WinBUGS for each analysis, each usually employing approximately 20,000 iterations, with a burn in of approximately 20,000 iterations. Provided sufficient data are available to inform the evidence network, a meta-regression and/or subgroup analysis will be conducted for key demographic, medical, and study design characteristics to test the robustness of the reference case analyses. In other sensitivity analyses, studies will be removed from the network that are of poor methodological quality or removed based on study design.


The data will first be summarized descriptively. A meta-analysis will be undertaken using fixed or random-effects models when data are available, sufficiently similar and of sufficient quality. The effect sizes for the identified dichotomous outcomes will be expressed in terms of the risk ratio or odds ratio (OR). In cases when events are rare, the Peto OR will be used. It is essential to know both estimated relative and absolute differences in the important benefits and harms, absolute mean difference, and relative per cent change from baseline will be included in the summary of findings table.

Results will be assessed for both clinical diversity and methodological diversity. Clinical diversity will be assessed by checking that the populations, interventions, and comparators are not too different from each other, such that combining them would be inappropriate. Methodological diversity will be assessed by checking that the studies are similar in terms of study design and risk of bias. Once satisfied that the studies are minimally diverse and that it makes sense to pool them together in a meta-analysis, an assessment of the statistical heterogeneity will be undertaken by examining the forest plot and result of the I2 statistic; the forest plots providing a visual sense of heterogeneity and the I2 statistic indicating the presence of statistical heterogeneity. If the effects observed across trials are inconsistent, and vary to a large extent (e.g., I2 > 50%), the results will again be explored to assess whether the differences can be explained by some clinical or methodological feature. Inconsistency that cannot be reduced by pre-specified subgroup or meta-regression analyses will lead to an overall estimate with less confidence when interpreting the inference from the meta-analysis. In this case, a more conservative random-effects model approach would be used so that the uncertainty of the single effect estimate is reflected in wider confidence intervals.

Sensitivity analyses will be conducted based on aspects of the PICO statement and study methodology to examine the robustness of the results to the risk of bias and the influence of other variables. In particular, the results of the low-risk-of-bias-studies will be compared to studies with a higher-risk-of-bias and if they differ, the conclusions of the review will be based on analyses of low-risk studies only.

Major outcomes will be assessed in the identified subgroups in specific populations if noted in the protocol. Subgroups are selected to confirm clinically sound hypotheses and as few subgroups as possible were pre-specified and justified against the criteria proposed by Sun et al.;22 wherein the greater the number of criteria that are satisfied for each subgroup and outcome, the more plausible is the hypothesized subgroup effect.

METHODS - Data Availability

The primary source of data is in the public domain. All stakeholders will be given the option of identifying and providing unpublished data on the condition that, if used, it would be included in publicly available reports and documents, related to the clinical review.

METHODS - Drafting of Protocol

Stakeholder Feedback

The policy and research questions and the PICOS were distributed to patient groups and the industry for feedback. Comments were incorporated into the protocol as required.

Protocol Registration and Peer Review

The protocol is registered in the PROSPERO database: Requested.

The health technology assessment report will be peer-reviewed by two external clinical experts and one external methodologist.

Areas for Potential Amendments

Protocol amendments will be tracked throughout the review, along with reasons for the changes, by the project lead. For amendments that relate to additional outcomes or subgroup analyses that are not identified in the original protocol, consideration will be given to whether the literature search or screening will need to be updated.

Conflict of Interest

In the preparation of this protocol, the following conflicts of interest were reported:

  • Jacob Karsh was a paid consultant on advisory boards of AbbVie, Amgen, Astra Zeneca, Bristol- Myers Squibb, Celgene, Janssen, Novartis, Roche, and Sanofi. He received a travel grant from AbbVie, and funding from AbbVie, Amgen, Bristol Myers Squibb, Celgene, and Health Canada for educational lectures.
  • Jasvinder Singh was a paid consultant for Allergan Inc., Bioibérica, Iroko Pharmaceuticals, Merz Pharma, Regeneron Pharmaceuticals Inc., Savient Pharmaceuticals Inc., and Takeda Pharmaceutical USA Inc.; he was an investigator for Horizon Pharma Inc.; and received an honorarium for a speaking engagement with WebMD.
  • Peter Tugwell received funding for travel from Omeract and Elsevier Publishing Ltd.; received an honorarium for a speaking engagement from Astra Zeneca; was a paid consultant for the Canadian Reformulary Group Inc., Eli Lilly and Company, Hoffmann-La Roche Limited, Hospira Healthcare Corporation, Pfizer Inc. Canada, UCB Biosciences; was an unpaid advisory board member to the Ontario Rheumatology Association, Ontario Biologics Registry Initiative Council; and received royalty payments from Elsevier, Little Brown, Wolters Kluwer Ltd., and John Wiley & Sons Ltd. as a contributing author/ editor for journals, textbooks, and articles.
  • George Wells received honoria for speaking engagements with Abbott, Amgen, Eli Lilly, Novartis, and Cornerstone Research Group.

Sarah Berglas, Judith Fisher, Sarah Jennings, Sarah Jones, Christine Perras, Danielle Rabb, Shannon Sullivan, and Hongbo Yuan report no conflict of interest.



  1. Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol [Internet]. 2016 Jan [cited 2016 May 19];68(1):1-26. Available from:
  2. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): Centers for Disease Control and Prevention. Rheumatoid Arthritis (RA); 2015 Oct [cited 2016 Mar 22]. Available from:
  3. Bykerk VP, Baron M, Boire C, Haraoui B, Khraishi M, Leclercq S. Canadian consensus statement on early optimal therapy in early rheumatoid arthritis. J Can Rheumatol Assoc [Internet]. 2004 [cited 2016 Mar 22];14(3):11-3. Available from:
  4. Widdifield J, Paterson JM, Bernatsky S, Tu K, Thorne JC, Ahluwalia V, et al. The rising burden of rheumatoid arthritis surpasses rheumatology supply in Ontario. Can J Public Health. 2013 Nov;104(7):e450-e455.
  5. Jansen JP, Buckley F, Dejonckheere F, Ogale S. Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis. Health Qual Life Outcomes [Internet]. 2014 [cited 2016 Mar 22];12:102. Available from:
  6. Solomon DH, Bitton A, Katz JN, Radner H, Brown EM, Fraenkel L. Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis? Arthritis Rheumatol [Internet]. 2014 Apr [cited 2016 Mar 22];66(4):775-82. Available from:
  7. Bykerk VP, Akhavan P, Hazlewood GS, Schieir O, Dooley A, Haraoui B, et al. Canadian Rheumatology Association recommendations for pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. J Rheumatol. 2012 Aug;39(8):1559-82.
  8. Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis [Internet]. 2014 Mar [cited 2016 Mar 22];73(3):492-509. Available from:
  9. Scott DL, Ibrahim F, Farewell V, O'Keeffe AG, Walker D, Kelly C, et al. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial. BMJ [Internet]. 2015 [cited 2016 Jan 27];350:h1046. Available from:
  10. Graudal N, Hubeck-Graudal T, Tarp S, Christensen R, Jurgens G. Effect of combination therapy on joint destruction in rheumatoid arthritis: a network meta-analysis of randomized controlled trials. PLoS One [Internet]. 2014 [cited 2016 Mar 22];9(9):e106408. Available from:
  11. Summary basis of decision: Xeljanz [Internet]. Ottawa: Health Canada; 2015 Dec 9. [cited 2016 Mar 23]. Available from:
  12. Lilly and Incyte announce submission of new drug application to FDA for oral once-daily baricitinib for treatment of moderate-to-severe rheumatoid arthritis [Internet]. New York: PR Newswire; 2016 Jan 19. [cited 2016 Mar 23]. Available from:
  13. Goodman A. Promising results with sarilumab in rheumatoid arthritis. 2014 Jun 13. In: Medscape [Internet]. New York: WebMD LLC; ©1994 - ©2016. Available from: Available via free subscription.
  14. GSK receives positive top-line results from sirukumab phase III programme supporting regulatory filings for rheumatoid arthritis in 2016 [Internet]. London: GlaxoSmithKline; 2015 Dec 16. [cited 2016 Mar 23]. Available from:
  15. Kaufman MB. Etanercept biosimilar approved in EU, plus FDA reviews brodalumab for plaque psoriasis. The Rheumatologist [Internet]. 2016 Feb 3 [cited 2016 Apr 18]. Available from:
  16. Amgen biosimilars: first submission for Humira biosimilar in the United States [Internet]. [place unknown]: Biosimilar News; 2015 Nov 26. [cited 2016 Mar 23]. Available from:
  17. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. BMJ [Internet]. 2016 [cited 2016 May 5];353:i1777. Available from:
  18. Singh JA, Wells GA, Christensen R, Tanjong GE, Maxwell L, Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;(2):CD008794.
  19. Singh JA, Hossain A, Tanjong GE, Kotb A, Christensen R, Mudano AS, et al. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2016 May 13;5:CD012183.
  20. Zhang B, Combe B, Rincheval N, Felson DT. Validation of ACR/EULAR definition of remission in rheumatoid arthritis from RA practice: the ESPOIR cohort. Arthritis Res Ther [Internet]. 2012 [cited 2016 May 5];14(3):R156. Available from:
  21. Turner RM, Jackson D, Wei Y, Thompson SG, Higgins JP. Predictive distributions for between-study heterogeneity and simple methods for their application in Bayesian meta-analysis. Stat Med [Internet]. 2015 Mar 15 [cited 2016 May 19];34(6):984-98. Available from:
  22. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ. 2010;340:c117.



Embase, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R)

# Searches
1 exp Arthritis, Rheumatoid/ use pmez
2 exp rheumatoid arthritis/ use oemezd
3 (rheumatic* or rheumatoid* or rheumatis*).ti,ab,kf,kw.
4 ((Caplan* or Felty* or Sjogren* or Sicca*) adj3 syndrome*).ti,ab,kf,kw.
5 Still* Disease*.ti,ab,kf,kw.
6 or/1-5
7 Adalimumab/
8 Certolizumab Pegol/
9 Etanercept/
10 golimumab/ use oemezd
11 Infliximab/
12 tocilizumab/ use oemezd
13 Abatacept/
14 Rituximab/
15 (adalimumab or Humira or Trudexa or certolizumab pegol or Cimzia or Perstymab or etanercept or Enbrel or golimumab or Simponi or infliximab or Inflectra or Remicade or Remsima or Reemsima or Remmicade or Remykeyd or Revellex or anakinra or Kineret or Antril or tocilizumab or Actemra or Aktemra or RoActemra or atlizumab or abatacept or Orencia or Belatacept or Nulojix or rituximab or Rituxan or Mabtera or Mabthera or Reditux or Relito or Rituxim).ti,ab,kw,kf.
16 Methotrexate/
17 (abitrexate or amethopterin* or amethpterin* or ametopterin* or antifolan or Artrait or Atrexal or Bertanel or Biotrexate or brimexate or canceren or cytotrex or ebetrex or ebetrexat* or emtexate or emthexat* or Emthrxate or emtrexate or enthexate or farmitrexat* or farmotrex or Hytas or Imutrex or ifamet or imeth or fermitrexat* or fauldexato or folex or hdmtx or lantarel or ledertrexate or lumexon or maxtrex or medsatrexate or Meisusheng or merox or metatrexan or metex or Metrex or Methoblastin or methohexate or methotrate or Methox or meticil or Metodik or methotrexat* or Methylaminopterin* or methrotrexate or methopterin* or methpterin* or metopterin* or Metotressato or Metotrexato or Metotreksat or metoject or Metrotex or mexate or MTX or Novatrex or Otrexup or Rasuvo or Rheumatrex or texate or tremetex or trexeron or Trexall or trixilem or Midu or Mtrex or Neotrexat* or Onkomet or Otaxem or Pterin or Quinux or Reumatrex or Sanotrexat* or Texorate or Trexan or Trexate or Trexol or Trexonate or Trexxol or Unitrexates or Viztreksat or Xantromid or Zexate).ti,ab,kw,kf.
18 Hydroxychloroquine/
19 (Hydroxychloroquin* or Oxychlorochin* or Oxychloroquin* or Hydroxychlorochin* or Plaquenil or Idrossiclorochina or Oxichlorochinum or Hydroxyquine or Advaquenil or Arthroquin or Axokine or Chloguin or Diclor or Dimard or Dolquine or Duloc or Duroc or Ercoquin or Evoquin or Fen Le or Geniquin or Haloxin or HCQS or Hydroquin or Hydroquine or Hyquin or Ilinol or Immard or Metirel or Oxcq or Oxiklorin or Plakvenil or Plaquinol or Quensyl or Quinoric or Reconil or Reuquinol or Roquin or Supretic or Winflam or Yuma or Zyq or chloroquinol).ti,ab,kf,kw.
20 Sulfasalazine/ use pmez
21 salazosulfapyridine/ use oemezd
22 (Salicylazosulfapyridin* or salazosulfpyridin* or salazopyrin* or salazopyridin* or Sulphasalazin* or Salazosulfapyridin* or Pleon or azopyrin* or azosulfidin* or benzosulfa or colopleon or Ulcol or Ucine or Azulfidin* or azlufidin* or Azulfadin* or pyralin or Asulfidine or Azulfin or azulfid* or Bomecon or Disalazin or Falazine or Gastropyrin or Lazafin or Lazo or rorasul or Rosulfant or SAAZ or Salazex or Salazine or Salazo or Salazodin or Salivon or salisulf or Salopyr or Salopyrine or Saridin* or Sazo or Sulcolon or Sulfasalazin or Sulfasalizin* or sulfosalazin* or Sulfitis or Sulzin or Zopyrin).ti,ab,kw,kf.
23 leflunomide/
24 (leflunomid* or arava or Airuohua or Arabloc or Arastad or Aravida or Arheuma or Arolef or Arresto* or Artrilab or Cartina or Imaxetil or Inflaxen or Kinetos or Lara or Leflu or Lefluar or Lefluartil or Leflyutab or Lefno or Lefora or Lefra-20 or Motoral or Movelef or Nodia or Repso or Rheufact or Rheumide or Rualba or Synomid or Youtong).ti,ab,kw,kf.
25 tofacitinib/
26 (Tofacitinib* or tasocitinib* or Xeljanz* or Kselyanz*).ti,ab,kw,kf.
27 baricitinib/
28 (Baricitinib* or ISP4442I3Y or LY3009104 or INCB028050 or ISP 4442I3Y or LY 3009104 or INCB 28050 or "INCB 028050").ti,ab,kf,kw.
29 sarilumab/
30 (Sarilumab* or NU90V55F8I or SAR153191 or REGN88 or SAR 153191 or REGN 88).ti,ab,kw,kf.
31 sirukumab/
32 (sirukumab* or 640443FU93 or CNTO136 or CNTO 136).ti,ab,kw,kf.
33 or/7-32
34 Infliximab/ or Adalimumab/ or Etanercept/
35 (adalimumab or Humira or Trudexa or infliximab or Inflectra or Remicade or Remsima or Reemsima or Remmicade or Remykeyd or Revellex or etanercept or Enbrel).ti,ab,kw,kf.
36 (reference or innovator or originator or generic or generics or biosimilar or bio-similar or biosimilars or bio-similars or follow-on or subsequent-entry or SEB or SEBs or biobetter or biobetters or bio-better or bio-betters or biosuperior or biosuperiors or bio-superior or bio-superiors or next generation or second-generation or third-generation or next-gen).ti,ab.
37 (biologic* or biological*).ti,kw,kf.
38 exp *Biological Products/ use pmez
39 exp *biological product/ use oemezd
40 (34 or 35) and (36 or 37 or 38 or 39)
41 6 and (33 or 40)
42 (Randomized Controlled Trial or Controlled Clinical Trial or Pragmatic Clinical Trial).pt.
43 Randomized Controlled Trial/
44 exp Randomized Controlled Trials as Topic/
45 "Randomized Controlled Trial (topic)"/
46 Controlled Clinical Trial/
47 exp Controlled Clinical Trials as Topic/
48 "Controlled Clinical Trial (topic)"/
49 Randomization/
50 Random Allocation/
51 Double-Blind Method/
52 Double Blind Procedure/
53 Double-Blind Studies/
54 Single-Blind Method/
55 Single Blind Procedure/
56 Single-Blind Studies/
57 Placebos/
58 Placebo/
59 Control Groups/
60 Control Group/
61 (random* or sham or placebo*).ti,ab,hw,kf,kw.
62 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw.
63 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw.
64 (control* adj3 (study or studies or trial*)).ti,ab,kf,kw.
65 (Nonrandom* or non random* or non-random* or quasi-random* or quasirandom*).ti,ab,hw,kf,kw.
66 allocated.ti,ab,hw.
67 ((open label or open-label) adj5 (study or studies or trial*)).ti,ab,hw,kf,kw.
68 or/42-67
69 41 and 68
70 exp animals/
71 exp animal experimentation/ or exp animal experiment/
72 exp models animal/
73 nonhuman/
74 exp vertebrate/ or exp vertebrates/
75 or/70-74
76 exp humans/
77 exp human experimentation/ or exp human experiment/
78 or/76-77
79 75 not 78
80 69 not 79
81 80 not conference
82 limit 81 to English language


Search Query
#13 Search #11 AND publisher[sb] Sort by: PublicationDate Filters: English
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#10 Search randomized controlled trial[pt] OR randomized controlled trials as topic[mh] OR random allocation [mh] OR double-blind method[mh] OR single-blind method[mh] OR random*[tw] OR "Placebos"[Mesh] OR placebo[tiab] OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw]) AND (mask*[tw] OR blind*[tw] OR dumm*[tw])) NOT "Review"[Publication Type]
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#3 Search (Hydroxychloroquin*[tiab] OR Oxychlorochin*[tiab] OR Oxychloroquin*[tiab] OR Hydroxychlorochin*[tiab] OR Plaquenil[tiab] OR Idrossiclorochina[tiab] OR Oxichlorochinum[tiab] OR Hydroxyquine[tiab] OR Advaquenil[tiab] OR Arthroquin[tiab] OR Axokine[tiab] OR Chloguin[tiab] OR Diclor[tiab] OR Dimard[tiab] OR Dolquine[tiab] OR Duloc[tiab] OR Duroc[tiab] OR Ercoquin[tiab] OR Evoquin[tiab] OR Fen Le[tiab] OR Geniquin[tiab] OR Haloxin[tiab] OR HCQS[tiab] OR Hydroquin[tiab] OR Hydroquine[tiab] OR Hyquin[tiab] OR Ilinol[tiab] OR Immard[tiab] OR Metirel[tiab] OR Oxcq[tiab] OR Oxiklorin[tiab] OR Plakvenil[tiab] OR Plaquinol[tiab] OR Quensyl[tiab] OR Quinoric[tiab] OR Reconil[tiab] OR Reuquinol[tiab] OR Roquin[tiab] OR Supretic[tiab] OR Winflam[tiab] OR Yuma[tiab] OR Zyq[tiab] OR chloroquinol[tiab] OR Salicylazosulfapyridin*[tiab] OR salazosulfpyridin*[tiab] OR salazopyrin*[tiab] OR salazopyridin*[tiab] OR Sulphasalazin*[tiab] OR Salazosulfapyridin*[tiab] OR Pleon[tiab] OR azopyrin* [tiab] OR azosulfidin*[tiab] OR benzosulfa [tiab] OR colopleon[tiab] OR Ulcol[tiab] OR Ucine[tiab] OR Azulfidin*[tiab] OR azlufidin*[tiab] OR Azulfadin*[tiab] OR pyralin[tiab] OR Asulfidine[tiab] OR Azulfin[tiab] OR azulfid*[tiab] OR Bomecon[tiab] OR Disalazin[tiab] OR Falazine[tiab] OR Gastropyrin[tiab] OR Lazafin[tiab] OR Lazo[tiab] OR rorasul[tiab] OR Rosulfant[tiab] OR SAAZ[tiab] OR Salazex[tiab] OR Salazine[tiab] OR Salazo[tiab] OR Salazodin[tiab] OR Salivon[tiab] OR salisulf[tiab] OR Salopyr[tiab] OR Salopyrine[tiab] OR Saridin*[tiab] OR Sazo[tiab] OR Sulcolon[tiab] OR Sulfasalazin[tiab] OR Sulfasalizin*[tiab] OR sulfosalazin*[tiab] OR Sulfitis[tiab] OR Sulzin[tiab] OR Zopyrin[tiab] OR leflunomid*[tiab] OR arava[tiab] OR Airuohua[tiab] OR Arabloc[tiab] OR Arastad[tiab] OR Aravida[tiab] OR Arheuma[tiab] OR Arolef[tiab] OR Arresto*[tiab] OR Artrilab[tiab] OR Cartina[tiab] OR Imaxetil[tiab] OR Inflaxen[tiab] OR Kinetos[tiab] OR Lara[tiab] OR Leflu[tiab] OR Lefluar[tiab] OR Lefluartil[tiab] OR Leflyutab[tiab] OR Lefno[tiab] OR Lefora[tiab] OR Lefra-20[tiab] OR Motoral[tiab] OR Movelef[tiab] OR Nodia[tiab] OR Repso[tiab] OR Rheufact[tiab] OR Rheumide[tiab] OR Rualba[tiab] OR Synomid[tiab] OR Youtong[tiab] OR Tofacitinib*[tiab] OR tasocitinib*[tiab] OR Xeljanz*[tiab] OR Kselyanz*[tiab] OR Baricitinib*[tiab] OR ISP4442I3Y[tiab] OR LY3009104[tiab] OR INCB028050[tiab] OR ISP 4442I3Y[tiab] OR LY 3009104[tiab] OR INCB 28050[tiab] OR INCB 028050[tiab] OR Sarilumab*[tiab] OR NU90V55F8I[tiab] OR SAR153191[tiab] OR REGN88[tiab] OR SAR 153191[tiab] OR REGN 88[tiab] OR sirukumab*[tiab] OR 640443FU93[tiab] OR CNTO136[tiab] OR CNTO 136[tiab])
#2 Search (abitrexate[tiab] or amethopterin*[tiab] or amethpterin*[tiab] or ametopterin*[tiab] or antifolan[tiab] or Artrait[tiab] or Atrexal[tiab] or Bertanel[tiab] or Biotrexate[tiab] or brimexate[tiab] or canceren[tiab] or cytotrex[tiab] or ebetrex[tiab] or ebetrexat*[tiab] or emtexate[tiab] or emthexat*[tiab] or Emthrxate[tiab] or emtrexate[tiab] or enthexate[tiab] or farmitrexat*[tiab] or farmotrex[tiab] or Hytas[tiab] or Imutrex[tiab] or ifamet[tiab] or imeth[tiab] or fermitrexat*[tiab] or fauldexato[tiab] or folex[tiab] or hdmtx[tiab] or lantarel[tiab] or ledertrexate[tiab] or lumexon[tiab] or maxtrex[tiab] or medsatrexate[tiab] or Meisusheng[tiab] or merox[tiab] or metatrexan[tiab] or metex[tiab] or Metrex[tiab] or Methoblastin[tiab] or methohexate[tiab] or methotrate[tiab] or Methox[tiab] or meticil[tiab] or Metodik [tiab] or methotrexat*[tiab] or Methylaminopterin*[tiab] or methrotrexate [tiab] or methopterin*[tiab] or methpterin*[tiab] or metopterin* [tiab] or Metotressato[tiab] or Metotrexato[tiab] or Metotreksat [tiab] or metoject[tiab] or Metrotex[tiab] or mexate[tiab] or MTX[tiab] or Novatrex[tiab] or Otrexup[tiab] or Rasuvo[tiab] or Rheumatrex[tiab] or texate[tiab] or tremetex[tiab] or trexeron[tiab] or Trexall[tiab] or trixilem[tiab] or Midu[tiab] or Mtrex[tiab] or Neotrexat*[tiab] or Onkomet[tiab] or Otaxem[tiab] or Pterin[tiab] or Quinux[tiab] or Reumatrex[tiab] or Sanotrexat*[tiab] or Texorate[tiab] or Trexan[tiab] or Trexate[tiab] or Trexol[tiab] or Trexonate[tiab] or Trexxol[tiab] or Unitrexates[tiab] or Viztreksat[tiab] or Xantromid[tiab] or Zexate[tiab])
#1 Search (adalimumab[tiab] or Humira[tiab] or Trudexa[tiab] or certolizumab pegol[tiab] or Cimzia[tiab] or Perstymab[tiab] or etanercept[tiab] or Enbrel[tiab] or golimumab[tiab] or Simponi[tiab] or infliximab[tiab] or Inflectra[tiab] or Remicade[tiab] or Remsima[tiab] or Reemsima[tiab] or Remmicade[tiab] or Remykeyd[tiab] or Revellex[tiab] or anakinra[tiab] or Kineret[tiab] or Antril[tiab] or tocilizumab[tiab] or Actemra[tiab] or Aktemra[tiab] or RoActemra[tiab] or atlizumab[tiab] or abatacept[tiab] or Orencia[tiab] or Belatacept[tiab] or Nulojix[tiab] or rituximab[tiab] or Rituxan[tiab] or Mabtera[tiab] or Mabthera[tiab] or Reditux[tiab] or Relito[tiab] or Rituxim[tiab])



PROSPERO Registration Number: Requested.

This protocol was prepared by:

  • George Wells, Primary Investigator, Drug Safety and Effectiveness Network (DSEN), University of Ottawa
  • Shannon Sullivan, Lead Researcher, DSEN, University of Ottawa
  • Christine Perras, Program Development Officer and Project Owner, Canadian Agency for Drugs and Technologies in Health (CADTH)
  • Danielle Rabb, Research Information Specialist, CADTH
  • Judith Fisher, Manager, Drug Technology Assessment, Department of Health and Wellness, Nova Scotia

With the support of:

  • Jacob Karsh, University of Ottawa, Clinical Expert
  • Peter Tugwell, University of Ottawa, Clinical Expert
  • Jasvinder Singh, University of Alabama, Clinical Expert

CADTH staff:

  • Sarah Berglas, Patient Engagement Officer
  • Sarah Jennings, Knowledge Mobilization Officer
  • Sarah Jones, Research Information Specialist
  • Hongbo Yuan, Advancing the Science

Cite as: Drugs for the management of rheumatoid arthritis: clinical evaluation – project protocol. Ottawa: CADTH; 2016 Jun.

This report is prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH) in collaboration with the Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network (DSEN). This report contains a comprehensive review of existing public literature, studies, materials, and other information and documentation (collectively the “source documentation”) available to CADTH at the time it was prepared, and its creation was guided by expert input and advice throughout its preparation.

The information in this report is intended to help health care decision-makers, patients, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. The information in this report should not be used as a substitute for the application of clinical judgment in respect to the care of a particular patient or other professional judgment in any decision-making process, nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of this report to ensure that its contents are accurate, complete, and up-to-date, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or as a result of the use (or misuse) of any information contained in or implied by the information in this report. CADTH takes sole responsibility for the final form and content of this report. The statements, conclusions, and views expressed herein do not necessarily represent the view of Health Canada or any provincial or territorial government.

Production of this report is made possible through a financial contribution from Health Canada and CIHR-DSEN.

Copyright © 2016 CADTH. This report may be reproduced for non-commercial purposes only and provided that appropriate credit is given to CADTH.