1. What is the clinical efficacy of using biologics as first-line therapy in the treatment of patients with rheumatoid arthritis?

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1 TITLE: Biologic Response Modifier Agents as First-line Treatment for Patients with Rheumatoid Arthritis: A Review of the Clinical Efficacy, Cost-effectiveness and Guidelines DATE: 06 March 2013 CONTEXT AND POLICY ISSUES Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 300,000 Canadians. 1 It is characterized by pain, swelling and progressive joint damage, an increase in morbidity and mortality, and a reduction in quality of life and daily activities. 1 Traditional disease modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX), leflunomide, sulfasalazine and hydroxychloroquine, have been shown to modify the clinical course of RA and to slow or stop radiographic progression. The newer biologic disease modifying agents target specific mechanisms of inflammation and have increased the therapeutic options for patients with RA. In Canada, these agents include the tumor necrosis factor (TNF) inhibitors (adalimumab, etanercept, infliximab, golimumab, and certolizumab), T cell costimulatory inhibitor (abatacept), B lymphocyte-depleting agent (rituximab), interleukin 6 antagonist (tocilizumab) and interleukin 1 inhibitor (anakinra). 1 Based on a CADTH therapeutic review completed in 2010, biologic agents were recommended for use in adults with RA who had an inadequate response to optimal doses of DMARDs. Since that review, a number of studies have been published including trials in patients who are DMARD naïve. 2,3 There are outstanding questions regarding the optimal use of biologic agents, as earlier and more aggressive treatment strategies are being used in clinical practice. This report will review the evidence on the clinical efficacy, cost-effectiveness and guidelines for use of biologic agents as first line therapy in adults with RA. RESEARCH QUESTIONS 1. What is the clinical efficacy of using biologics as first-line therapy in the treatment of patients with rheumatoid arthritis? Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the 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 liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 2. What is the cost-effectiveness of using biologics as first-line therapy in the treatment of patients with rheumatoid arthritis? 3. Are evidence-based clinical practice guidelines recommending biologic response modifier agents as first-line therapy? KEY FINDINGS Randomized controlled trials of biologic agents used as first line treatment of patients with rheumatoid arthritis, who have not previously received methotrexate or other disease modifying antirheumatic therapies, have shown benefit in terms of clinical response and radiographic progression in the short-term (up to one year), compared to methotrexate monotherapy. The cost-effectiveness of first line biologic therapy exceeded commonly reported willingness to pay thresholds in six of eight economic evaluations conducted in countries other than Canada. Evidence based guidelines were inconsistent, with one recommending against first line biologic therapy, and three advocating for biologic use in a subset of patients with poor prognostic factors or high disease activity. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, Ovid MEDLINE, Ovid EMBASE, The Cochrane Library (2013, Issue 1), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies containing safety data, economic studies, and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2008 and February 5, A search for relevant conference abstracts published between January 1, 2011 and February 5, 2013 was also conducted. Selection Criteria and Methods One reviewer screened citations to identify publications that met the inclusion criteria. Potentially relevant articles were retrieved based on the review of titles and abstracts. Full-text articles were considered for inclusion based on the selection criteria listed in Table 1. Table 1: Selection Criteria Population MTX-naïve or traditional DMARD naïve patients with: -early RA or established RA -any severity of disease (mild-severe) Intervention Biologic response modifier agents as first-line therapy (with or without combination MTX or DMARD): abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, Early Biologic Treatment for Rheumatoid Arthritis 2

3 Comparator MTX or traditional DMARD, combination DMARD therapy, placebo Biologic vs. biologic Outcomes Clinical efficacy, safety, harms, cost-effectiveness, clinical practice guideline recommendations Study Designs Q1. Health technology assessment, meta-analysis, systematic review, RCT Q2. Cost-effectiveness or cost-utility study Q3. Evidence based clinical practice guidelines DMARD=disease modifying anti-rheumatic drug; MTX=methotrexate; RA=rheumatoid arthritis; RCT=randomized controlled trial; Exclusion Criteria Articles were excluded if they did not satisfy the selection criteria, or were full text articles published prior to January 2008 or conference abstracts published prior to Health technology assessments, meta-analyses, systematic reviews and guidelines were excluded if there was incomplete reporting of methods or if they were superseded by a more recent or more rigorous review or guideline. Randomized controlled trials (RCTs) were excluded if were described in a systematic review included in this report. Critical Appraisal of Individual Studies Key methodologic aspects relevant to each study design were appraised and summarized narratively. The methods used when conducting the literature search, study selection, quality assessment, data extraction, and summarizing the data were appraised for systematic reviews. For RCTs, this included assessment of allocation concealment, blinding, intention to treat analysis and losses to follow up. The domains evaluated for evidence based guidelines included the scope and purpose, stakeholder involvement, rigor of development, clarity and presentation, applicability, and editorial independence, according to the AGREE instrument. 4 Economic studies were assessed for completeness of reporting of the model, model inputs, data sources, and disaggregated results, and the sensitivity analyses conducted, based on the British Medical Journal Checklist for economic studies. 5 SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 1336 citations. Upon screening titles and abstracts, 1261 citations were excluded and 75 potentially relevant articles were retrieved for full-text review. An additional four potentially relevant reports were retrieved from grey literature or other sources. Of the 79 potentially relevant reports 55 were excluded. Five clinical 6-10 systematic reviews and one economic 11 systematic review, nine RCTs, five economic evaluations, and four evidence based guidelines 1,26-28 met the inclusion criteria. The process of study selection is outlined in the PRISMA flowchart (Appendix 1). A total of 283 conference abstracts were screened and three met the inclusion criteria. These reports included an open label extension study of the PREMIER RCT, a mixed treatment comparison study of the safety and efficacy of biologic agents in MTX naïve RA patients, and a Early Biologic Treatment for Rheumatoid Arthritis 3

4 Spanish cost-effectiveness study of TNF inhibitors. The abstracts have been listed in Appendix 2 but have not been appraised or summarized. A. Clinical studies Summary of Study Characteristics From the five clinical systematic reviews and nine individual clinical trial reports included in this review, a total of 17 RCTs were found that enrolled patients with RA who were MTX or DMARD naïve. Table 2 lists these RCTs and the data sources for these studies. Data from eight RCTs were reported in more than one publication and in some cases the same descriptive and outcome data were reported in the different sources. For these RCTs, data were taken from multiple reports, while minimizing duplication. One systematic review focused specifically on RA patients who were MTX naïve and provided data on work related outcomes. 7 In all other systematic reviews, data from patients who were treatment naïve were extracted from subgroup analyses or from summary data on individual RCTs. Since there were no systematic reviews that included the population and all interventions and outcomes relevant to this report, we focused on summarizing individual RCTs, rather than findings from systematic reviews. For reference, the characteristics of the systematic reviews are available in Appendix 3 Table 1 but these reviews have not been summarized in this section. Table 2. List of RCTs in MTX or DMARD naïve RA patients Biologic agent Study name Author, Year TNF inhibitor Adalimumab HIT HARD Detert PREMIER Strand Source RCT van Vollenhoven Breedveld ,8,9,29 HOPEFUL1 Takeuchi GUEPARD Soubrier PROWD Bejarano ,29 Certolizumab No data No data Etanercept TEAR Moreland Golimumab COMET Anis ,29 Emery 2008 ERA Bathon ,9,29 GO- BEFORE Genovese ,29 Kosinski 2002 Emery Emery ,29 Infliximab NEO RACo Leirisalo-Repo BeSt Klarenbeek Durez SR Early Biologic Treatment for Rheumatoid Arthritis 4

5 Biologic agent Study Author, Year Source name RCT SR ASPIRE Smolen ,29 St. Clair Quinn ,8 Bejarano Other biologic agents Abatacept AGREE Westhovens ,9,29 Westhovens 2008 Anakinra No data No data Rituximab IMAGE Tak 2009 (abstract) 10 Tocilizumab AMBITION Jones DMARD=disease modifying antirheumatic drugs; MTX=methotrexate; RA=rheumatoid arthritis; RCT=randomized controlled trial; SR=systematic review; TNF=tumor necrosis factor Of the 17 included RCTs, 15 were double blind, one was single blind and one was an open label study (Appendix 3, Table 2) Sixteen studies exclusively enrolled patients who were MTX or DMARD naïve, and in one other study 20 67% of those enrolled were treatment naïve. The sample size ranged from 20 to 1004 patients (median 508) and the studies were six months to five years in duration. The biologic agents evaluated included adalimumab (5 RCTs), etanercept (3), golimumab (1), infliximab (5), abatacept (1), rituximab (1) and tocilizumab (1). 6-10,12-20 Data from one RCT on rituximab (Tak 2009) was obtained from an abstract. 10 No RCTs were identified that evaluated the efficacy of certolizumab or anakinra in RA patients who were MTX or DMARD naïve. Summary of Critical Appraisal The critical appraisal of clinical studies is summarized in Appendix 3, Table 2 and in Appendix 4. Overall, the systematic reviews were conducted using acceptable methods to identify, extract, appraise and summarize studies. Limitations included minimal or no grey (unpublished) literature search, 6-10 search of a single electronic database, 10 inclusion of English language publications only, 8-10 article selection by a single researcher, 7 and limited reporting of methods or study characteristics. 6,8,9 The critical appraisal of seven 13-18,20 of the 17 RCTs in treatment naïve patients was done by CADTH, and all other studies were based on the assessment supplied in the systematic reviews. All but two of the RCTs were double blinded. 15,18 The treatment allocation was concealed from all study participants until after randomization in eight studies, and there was insufficient information available to assess allocation concealment in nine RCTs. One study (St. Clair 2004), did not use an intention to treat (ITT) analysis, three studies (Bathon 2000, Emery 2009, Tak 2009) provided insufficient information to evaluate how data were handled, and all others used ITT procedures. In three studies 13,14,18 the proportion of patients who withdrew differed across treatment groups, and in one other RCT, one third of patients left the study early. 16 Four RCTs had a sample size of less than 100 patients (Leirisalo-Repo 2012, Quinn 2005, Durez 2007, Soubrier 2009). Early Biologic Treatment for Rheumatoid Arthritis 5

6 Summary of Findings Clinical response The proportion of patients who achieved the American College of Rheumatology (ACR) 20, 50 or 70 clinical response criteria was reported for patients receiving first line therapy with adalimumab, etanercept, golimumab, infliximab, abatacept, rituximab, and tocilizumab (Appendix 5, Table 1). 6,9,10,13-17,20 The ACR response criteria represents a 20%, 50% or 70% improvement in tender and swollen joint counts, and improvement in three of five other measures (patient and physical global assessment of disease activity, pain, functional status and an acute phase reactant). 10 Pooled data reported in the review by Nam et al. 9 found that patients treated with first line therapy with a biologic agent combined with MTX for 12 months were statistically significantly more likely to achieve an ACR20, 50 or 70 response, compared to those given MTX [ACR 20 relative risk (RR) 1.24, 95% confidence interval (CI) 1.15 to 1.34; ACR (1.30 to 1.56); ACR (1.45 to 1.83)]. Among the other seven RCTs not included in this meta-analysis, three found that patients treated with adalimumab, 14 golimumab, 6 or rituximab 10 plus MTX were more likely to achieve ACR20, 50 or 70 criteria than those who received MTX alone. Three other studies found no statistically significant difference in the proportion achieving an ACR response between adalimumab, 13,15 or etanercept 16 plus MTX versus MTX monotherapy. One other RCT that compared first line infliximab plus three DMARDs versus triple DMARDs therapy, found no statistically significant difference between groups on the proportion achieving ACR50 or 70 criteria. 17 The pooled 12 month RR of ACR20 response from two studies comparing first line biologic monotherapy to MTX monotherapy was 0.98 (95% CI 0.76 to 1.26). 9,29 Similar results were found for ACR50 and ACR70 (Appendix 5, Table 1). Six month ACR20 or 50 criteria was not statistically significantly different for golimumab versus MTX based on one RCT. 6,29 Tocilizumab was associated with a higher proportion of patients achieving ACR20, 50 and 70 criteria compared to MTX (P < 0.01 for all outcomes) in a subgroup of patients who were MTX naive. 20 Remission The proportion of patients achieving clinical remission was reported for studies with adalimumab, etanercept, infliximab, golimumab, abatacept and tocilizumab (Appendix 5, Table 2). 8,9,13,15-20 In these studies, remission was defined as those who had a 28 Joint Disease Activity Score <2.6, or met the ACR criteria for remission. Among those who received first line biologic therapy, 34% to 66% were in remission at 6 months to 8 years, compared with 0% to 59% of those who received a DMARD. 9,13,15-20,29 The 12 month pooled RR of remission was 1.74 (95% CI 1.54 to 1.98) based on seven RCTs for abatacept, adalimumab, etanercept or infliximab plus MTX versus MTX. 8 Among the studies not included in the meta-analysis, the proportion of patients achieving remission was not statistically significantly different for five studies comparing adalimumab, 13,15 etanercept, 16 or infliximab 17,18 plus DMARD versus DMARD after one to five years. Patients who received golimumab plus MTX, but not golimumab monotherapy, were more likely to achieve remission at six months than those who received MTX. 9,29 Similar results were observed for the PREMIER trial that compared adalimumab plus MTX and adalimumab monotherapy to MTX. 9,29 In one RCT where Early Biologic Treatment for Rheumatoid Arthritis 6

7 67% of those enrolled were MTX naïve, the odds ratio (OR) of remission at six months was 5.8 (95% CI 3.3 to10.4) for tocilizumab versus MTX. 20 Radiographic progression Patients who received first line biologic therapy were less likely to show signs of radiographic progression compared to DMARD, based on pooled data from four studies (RR 1.30, 95% CI 1.01 to 1.68), and four other RCTs with abatacept, adalimumab, etanercept, and infliximab. 8,13,14,17,18 Non-statistically significant differences were found on radiographic progression outcomes in three other RCTs (adalimumab or etanercept). 9,15,16 Health-related quality of life Health related quality of life was reported in eight studies with adalimumab, etanercept, infliximab and abatacept. 9,12,13,15,18,19,29 Pooled data from three RCTs on the physical component of the Short Form Health Survey (SF-36) showed statistically significant differences for biologics plus MTX versus MTX, favoring biologics. 29 Pooled data on the SF-36 mental component showed no overall difference between groups. 29 One other RCT found a clinically important improvement in the SF-36 physical component for adalimumab plus MTX, and the mental component for adalimumab monotherapy, compared to MTX. 12 Work related outcomes One systematic review focused on work related outcomes such as employment status, absenteeism and presenteeism (reduced work input while at work)(appendix 5, Table 3). 7 Of the four RCTs that enrolled MTX naïve patients, two studies reported statistically significantly fewer patients treated with an TNF inhibitor plus MTX lost employment over 1 year compared to those who received MTX. 7 Two other RCTs found no statistically significant difference between groups in the change in employment status. Patients on TNF inhibitors lost fewer days of work (range 17.6 to 19.5 days: 2 RCTs), and were statistically significantly more likely to have no work days lost, than those receiving MTX (79% versus 67%, P < 0.01; 1 RCT). 7 Both studies reporting on presenteeism, found statistically significant improvement in presenteeism for those receiving TNF inhibitors plus MTX versus MTX monotherapy. 7 Safety Data on adverse events was available in 13 RCTs with adalimumab, etanercept, golimumab, infliximab and tocilizumab (Appendix 5, Table 4). 6,13-18,20 The incidence of adverse events ranged from 72% to 96% and was similar between the biologic and control groups. 14,16-18,20 The rate of withdrawals due to adverse events ranged from 3% to 11% and from 0% to 13% among those treated with a biologic versus control, respectively. 6,13,14,16,20 Serious adverse events were reported by 4% to 31% of those who received a biologic agent for first line treatment, compared to 2% to 33% of those receiving a control therapy over a six month to five year period ,20 Early Biologic Treatment for Rheumatoid Arthritis 7

8 B. Economic evaluations Summary of Study Characteristics One systematic review of economic studies met the inclusion criteria (Appendix 6, Table 1). 11 The authors, van der Velde et al., 11 evaluated the cost-effectiveness of biologic agents compared to DMARDs in adults with RA. They summarized 18 cost-effectiveness or cost-utility analyses of which three studies evaluated first line therapy with biologic agents in patients with no previous DMARD exposure (Choi 2002, Chen 2006, Spalding 2006). 11 Five other economic studies were found that were relevant to this report and included patients with RA who were DMARD naïve Among these eight economic studies there was one cost-effectiveness analysis (CEA) and seven cost-utility analyses (CUA) (Appendix 6, Table 2). These studies were conducted in the US (5 studies), Netherlands (2), and Sweden (1), and took a payer (6 studies) or societal perspective (6). The time horizon ranged from 6 months to lifetime. The studies evaluated the cost-effectiveness of sequential therapy for RA, allowing for treatments to be switched based on non-response or intolerance. The initial treatment in each sequential treatment regimen was listed in Appendix 6, Table 2. All studies included a biologic agent, alone or in combination with a DMARD, as first line therapy in one of the treatments modeled. The biologic agents evaluated were adalimumab (3 studies), etanercept (5), infliximab (4) or TNF inhibitor drug class (2). No studies were found for abatacept, anakinra, certolizumab, golimumab, rituximab, or tocilizumab. The comparators were methotrexate or other DMARDs, alone, or in combination. Biologic agents may have been included in the treatment regimens for patients who stop the initial DMARD treatment. One study included a treatment regimen consisting of NSAIDs, steroids and other non-pharmacologic therapies as initial treatment, with DMARDs added at one year. 24 It was beyond the scope of this project to provide detailed descriptions of the treatments modeled or to assess if they were consistent with current clinical practice. Summary of Critical Appraisal Van der Velde et al. 11 used robust methods to conduct their systematic review of economic evaluations (Appendix 7). The three studies from the review that were relevant to this report appear to have met most of the British Medical Journal (BMJ) criteria for appraising economic studies. One of these reports (Spalding 2006), was limited by failure to report details regarding valuation of benefits, ranges for sensitivity analyses, and disaggregated results. 11 All the economic studies provided a description of the model, time horizon, perspective, dollar, and discounting. There was incomplete reporting of the treatments included in the model in one study, 24 and model parameters in two studies. 21,22 Some of these data may be available in supplementary tables, however, due to the volume of included studies, we did not review this additional material. One study did not report disaggregated results (i.e. separate reporting of total costs and benefits for each treatment). 21 One study included the costs of managing adverse events in the model. 23 Early Biologic Treatment for Rheumatoid Arthritis 8

9 Summary of Findings The seven CUA reported incremental costs per quality adjusted life year (QALY) for first line biologic agents compared to DMARDs ranging from US$ 42,700 to C$ 1,775,600, from the payer perspective, and from 13,500 to US$ 540,000, from a societal perspective (Appendix 8, Table 1). 11,21-25 For first line treatment with adalimumab, with or without MTX, the incremental cost effectiveness ratio (ICER) ranged from US$ 42,700 to C$ 451,400 from the payer perspective, and from US$ 19,700 to US$ 23,400 from a societal perspective. 11,23 Etanercept and infliximab plus MTX first line treatment were extendedly dominated by adalimumab plus MTX in one study (i.e. etanercept and infliximab were less cost-effective). 23 In other studies, etanercept mono- or combination therapy had ICER values that ranged from C$ 130,400 to C$206,800 from the payer perspective, and was 13,500 from a societal perspective. 11,21 The ICER values for infliximab ranged from 190,000 to C$ 1,775,600 and from 22,000 to 130,000, from the payer and societal perspective, respectively. 11,25 One study evaluated the cost-effectiveness of the TNF inhibitors as a class and reported ICER values exceeding 136,000 relative to MTX from both the payer and societal perspective. 22 In another study, biologic agents (drug not specified) were dominated by DMARDs (i.e. biologic was less cost effective) and had ICER values exceeding US$ 540,000 relative to initial therapy with NSAIDS, steroids, and non-pharmacologic management of RA. 24 One CEA examined the incremental cost per patient achieving an ACR20 or ACR70 response for etanercept versus DMARD monotherapy in patients with no prior MTX exposure (Choi 2002). 11 The ICER values ranged from US$ 62,000 to US$ 90,000 across all the analyses and from the payer and societal perspective. 11 C. Evidence-based Guidelines Summary of Study Characteristics The guidelines included in this report were published in 2010, , 28 and ,26 One guideline was Canadian, 1 one was American, 26 one was Scottish, 28 and one was European, 27 The recommendations are from the Canadian Rheumatology Association (CRA), 1 the American College of Rheumatology (ACR), 26 the Scottish Intercollegiate Guidelines Network (SIGN), 28 and the European League Against Rheumatism (EULAR). 27 The guidelines 1,26-28 focused on adult populations with all stages of RA, with the exception of the ACR 26 who also provided recommendations on those with high risk factors (including those with hepatitis, congestive heart failure, and malignancy) 26 and the CRA who also provided recommendations on those patients with early inflammatory arthritis suspected of having RA. 1 The interventions of interest for all guidelines included the use of traditional and biologic DMARDs for the treatment of RA. 1,26-28 Grading of recommendations and levels of evidence Detailed characteristics on the grading of evidence can be found in Appendix 9. Early Biologic Treatment for Rheumatoid Arthritis 9

10 All of the guidelines developed their recommendations by reviewing the literature 1,26-28 and three graded the strength of their recommendations based on the quality of the evidence. 1,27,28 Recommendations were graded according to the types of studies from which the evidence was acquired. In general, Grade A recommendations were based on evidence from single/multiple randomized controlled trials or systematic reviews; 26,27 Grade B recommendations were based on direct evidence from a single randomized controlled trial/non-randomized study 26 or metaanalyses/systematic reviews of observational studies, individual observational studies and RCT subgroup/post-hoc analyses; 1 and Grade C recommendations were based on evidence from case series or extrapolations from higher levels of studies. 27 In one instance, the recommendations were not graded but simply supported by meta-analyses, systematic reviews of RCTs, and RCTs with low risk of bias. 28 Summary of Critical Appraisal All of the guidelines were clear in their overall objectives, the populations for whom the guidance was intended, and their clinical questions were either explicitly stated 1,28 or implied. 26,27 Guideline development groups were appropriately represented in all the guidelines. In addition, views and preferences from patient groups were sought in the CRA, 1 ACR, 26 and EULAR 27 guidelines. All guidelines were evidence-based with described methods for guideline formulation. Three guidelines included all forms of original evidence (systematic reviews, randomized controlled trials, non-randomized studies) while the CRA 1 used a modified ADAPTE framework to systematically identify and appraise international RA guidelines. The criteria for evidence selection were clearly stated in the SIGN, 28 CRA, 1 and ACR 26 guidelines and, aside from the CRA guideline, 1 it was clear that the recommendations were peer reviewed. Recommendations in all guidelines were specific, unambiguous, and easily identifiable while only the CRA 1 guidelines addressed barriers to implementation and were supported by implementation tools. It was clear that the ACR, 26 EULAR, 27 CRA, 1 and SIGN 28 all had plans to review their guidance. Summary of Findings All guidelines provided recommendations on the use of biologics as first line therapy in patients with early RA. 1,26-28 An overview of the recommendations is provided in Table 3. Guidelines from the CRA, 1 ACR, 26 and EULAR 27 recommend that anti-tnf biologics may be used in early RA patients (defined as disease duration 6 months) who have poor prognostic features, high disease activity, 1,26,27 are DMARD naïve 1,27 or have structural damage. 27 This therapy may be used as monotherapy 1,26 or in combination with methotrexate. 26,27 In addition, the CRA stated that methotrexate should be the anchor drug in combination therapy unless there is a contraindication, then another DMARD may be considered on a case-by-case basis. 1 When considering the use of infliximab, the ACR recommends only using it in combination therapy with methotrexate in early RA patients with poor prognostic features. 26 The CRA 1 clearly outlined a recommendation to assess the following prognostic features when considering treatment decisions at baseline: rheumatoid factor (RF) positivity, anticyclic citrullinated peptide antibodies (anti-ccp) positivity, functional limitation, high number of swollen and tender joints, early erosions, extra-articular features, high erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Early Biologic Treatment for Rheumatoid Arthritis 10

11 The SIGN guideline recommended against the use of TNF-α inhibitors for the treatment of patients with severe, progressive, and active RA who had not been previously treated with MTX or another DMARD. 28 Table 3: Summary of Recommendations for Early Biologics for RA Summary of Recommendations for Early Biologics for RA Poor Prognostic Features 1. When considering and making treatment decisions at baseline the following prognostic features should be assessed 1 : Rheumatoid factor (RF) positivity Anticyclic citrullinated peptide antibodies (anti-ccp) positivity Functional limitation High number of swollen and tender joints Early erosions Extraarticular features High erythrocyte sedimentation rate (ESR) C-reactive protein (CRP) Recommendations For the Use of Early Biologics in RA as First Line Therapy 2. Anti-TNF biologics as monotherapy 1,26 or in combination with MTX 26,27 can be used as first line therapy in patients with early RA (defined as disease duration 6 months) who have poor prognostic features with high disease activity 1,26,27 and in those who are DMARD naïve 1,27 and have structural damage In combination therapy, MTX should be the anchor drug unless contraindicated at which time other DMARDs are to be considered on a case-by-case basis Infliximab must be used in combination with MTX in patients with early RA (defined as disease duration 6 months) who have poor prognostic features with high disease activity. 26 Recommendations Against the Use of Early Biologics in RA as First Line Therapy 5. TNF-α inhibitors are not recommended for the treatment of patients with severe, active, and progressive RA not previously treated with MTX or other DMARDs (1++ for level of evidence but no grading). 28 DMARD=disease modifying antirheumatic drugs; MTX=methotrexate; RA=rheumatoid arthritis; TNF= tumor necrosis factor Limitations A total of 17 RCTs of moderate to good methodologic quality met the inclusion criteria. The key limitations were unclear allocation concealment (9 RCTs), lack of double blinding (2), and withdrawal rates exceeding 20% or that differed between treatments (4). Four RCTs had a sample size less than 100 and the duration of 12 studies was one year or less. No RCTs were Early Biologic Treatment for Rheumatoid Arthritis 11

12 found for certolizumab or anakinra, and a single study was available for each of golimumab, abatacept, rituximab or tocilizumab in RA patients who were MTX or DMARD naive. The definition of clinical remission and radiographic progression differed across studies, thus it is difficult to compare results. The external validity of RCTs for work related outcomes may be limited and the follow up time may be insufficient to be relevant for work outcomes. In addition, there is no defined minimum relevant difference in work outcomes. 7 Limited safety data were reported in RCTs and systematic reviews and the study duration and sample size of RCTs may have been insufficient to detect difference in the incidence of less common adverse events. Of the eight included economic evaluations, none were Canadian, and thus have limited generalizability. Two of the studies had a time horizon of 2 years or less, which may be insufficient to capture all relevant costs and outcomes for a chronic disease such as RA. However, there may be more uncertainty in long-term studies, as data from shorter term RCTs or observational studies is extrapolated over a lifetime. The treatment of RA continues to evolve and older studies may use treatment regimens that are no longer considered appropriate. It was beyond the scope of this project to evaluate the treatment regimens used in the clinical and economic studies to determine if they were consistent with current clinical practice. Of the four guidelines included in this review, one was published by a Canadian professional society. 1 These guidelines were not based on original evidence rather on systematically identified and appraised international RA guidelines (using the modified ADAPTE framework). 1 Consequently, there is a distinct chance that important information was not included in the development of their guidelines. Even though three of the guidelines produced similar recommendations 1,26,27 the EULAR guideline stated that the recommendation to start biologics plus methotrexate as first line therapy in early RA patients with poor prognostic factors and high disease activity was met with the lowest agreement of all of their recommendations. 27 In direct contrast to the CRA, ACR, and EULAR guidelines, SIGN did not recommend the use of TNF-α inhibitors for the treatment of patients with severe, progressive, and active RA not previously treated with MTX or other DMARDs. 28 However, it should be noted that grading of the SIGN recommendation was not included, only the level of evidence upon which the recommendation was based. This guidance is also based on a 2007 NICE technology appraisal and may not reflect the most current evidence. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING First line treatment with biologic antirheumatic drugs in adults with rheumatoid arthritis (RA) was evaluated in 17 randomized controlled trials (RCTs) of moderate to good quality, published between 2000 and Methotrexate (MTX) or disease modifying antirheumatic drug (DMARD) naïve patients who received a biologic agent plus MTX were more likely to show a clinical improvement that met the American College of Rheumatology (ACR) 20, 50 or 70 criteria at six to 12 months, compared to those who received MTX alone. Patients on biologic agents plus MTX were more likely to achieve clinical remission versus MTX alone, based on pooled data from seven RCTs, however studies published more recently have not shown a consistent advantage to early biologic therapy. Most studies found that radiographic progression was less likely to occur for patients treated with biologic agents compared to DMARDs, although interpretation of these findings was difficult due to differences in how progression was defined. The impact of first line biologic therapy on health related quality of life and work related Early Biologic Treatment for Rheumatoid Arthritis 12

13 outcomes were not consistent, and no conclusions can be drawn on the safety of biologic agents based on the data available. A total of eight economic evaluations met the inclusion criteria, none of which were conducted in Canada. If the willingness to pay threshold is $50,000 per quality adjusted life year, then first line biologic agents would be considered cost-effective in two studies, relative to DMARDs. The generalizability of these findings to Canada, however, may be limited. The recommendations from evidence-based guidelines were inconsistent on the use of biologics in RA patients who were DMARD naïve. Three guidelines from Canada, US and Europe recommended that TNF inhibitors may be used as first line mono- or combination therapy in early RA patients (defined as disease duration 6 months) who are DMARD naïve and have poor prognostic factors, high disease activity, or have structural damage. One guideline from Scotland recommended against the use of TNF inhibitors in adults not previously treated with DMARDs. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Early Biologic Treatment for Rheumatoid Arthritis 13

14 REFERENCES 1. 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 [Internet] Aug [cited 2013 Feb 11];39(8): Available from: 2. Canadian Agency for Drugs and Technologies in Health. CADTH therapeutic review. Clinical and economic overview: biological response modifier agents for adults with rheumatoid arthritis. Ottawa: CADTH; 2010 Nov. [cited 2013 Mar 4]. Available from: 3. Canadian Agency for Drugs and Technologies in Health. CADTH therapeutic review: panel final recommendations. Biological response modifier agents for adults with rheumatoid arthritis. Ottawa: CADTH; 2010 Jul. [cited 2013 Mar 4]. Available from: 4. The AGREE Collaboration. Appraisal of guidelines for research and evaluation (AGREE) instrument [Internet]. London: The AGREE Research Trust; 2001 Sep. [cited 2013 Feb 26]. Available from: 5. Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ [Internet] Aug 3 [cited 2013 Mar 4];313(7052): Available from: 6. Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordstrom DC, Blom M. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS ONE [Internet] [cited 2013 Feb 11];7(1):e30275, Available from: 7. ter Wee MM, Lems WF, Usan H, Gulpen A, Boonen A. The effect of biological agents on work participation in rheumatoid arthritis patients: a systematic review. Ann Rheum Dis Feb;71(2): Kuriya B, Arkema EV, Bykerk VP, Keystone EC. Efficacy of initial methotrexate monotherapy versus combination therapy with a biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission. Ann Rheum Dis Jul;69(7): Nam JL, Winthrop KL, van Vollenhoven RF, Pavelka K, Valesini G, Hensor EM, et al. Current evidence for the management of rheumatoid arthritis with biological diseasemodifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis Jun;69(6): Volkmann ER, Agrawal H, Maranian P, Furst DE. Rituximab for rheumatoid arthritis: a meta-analysis and systematic review. Clin Med Insights Ther. 2010;2: Early Biologic Treatment for Rheumatoid Arthritis 14

15 11. van der Velde G, Pham B, Machado M, Ieraci L, Witteman W, Bombardier C, et al. Costeffectiveness of biologic response modifiers compared to disease-modifying antirheumatic drugs for rheumatoid arthritis: a systematic review. Arthritis Care Res (Hoboken) Jan;63(1): Strand V, Rentz AM, Cifaldi MA, Chen N, Roy S, Revicki D. Health-related quality of life outcomes of adalimumab for patients with early rheumatoid arthritis: results from a randomized multicenter study. J Rheumatol [Internet] Jan [cited 2013 Feb 11];39(1): Available from: Detert J, Bastian H, Listing J, Weiss A, Wassenberg S, Liebhaber A, et al. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis Jul Takeuchi T, Yamanaka H, Ishiguro N, Miyasaka N, Mukai M, Matsubara T, et al. Adalimumab, a human anti-tnf monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study. Ann Rheum Dis [Internet] Jan 11 [cited 2013 Feb 11]. Available from: Soubrier M, Puechal X, Sibilia J, Mariette X, Meyer O, Combe B, et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford) [Internet] Nov [cited 2013 Feb 11];48(11): Available from: Moreland LW, O'Dell JR, Paulus HE, Curtis JR, Bathon JM, St Clair EW, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum Sep;64(9): Leirisalo-Repo M, Kautiainen H, Laasonen L, Korpela M, Kauppi MJ, Kaipiainen- Seppanen O, et al. Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, doubleblind, placebo-controlled study (the NEO-RACo Study). Ann Rheum Dis Jun Klarenbeek NB, Guler-Yuksel M, van der Kooij SM, Han KH, Ronday HK, Kerstens PJ, et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann Rheum Dis Jun;70(6): Bejarano V, Conaghan PG, Quinn MA, Saleem B, Emery P. Benefits 8 years after a remission induction regime with an infliximab and methotrexate combination in early rheumatoid arthritis. Rheumatology (Oxford) [Internet] Oct [cited 2013 Feb 11];49(10): Available from: Early Biologic Treatment for Rheumatoid Arthritis 15

16 20. Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis Jan;69(1): Kobelt G, Lekander I, Lang A, Raffeiner B, Botsios C, Geborek P. Cost-effectiveness of etanercept treatment in early active rheumatoid arthritis followed by dose adjustment. Int J Technol Assess Health Care Jul;27(3): Schipper LG, Kievit W, Den Broeder AA, van der Laar MA, Adang EMM, Fransen J, et al. Treatment strategies aiming at remission in early rheumatoid arthritis patients: starting with methotrexate monotherapy is cost-effective. Rheumatology (Oxford) [Internet] [cited 2013 Feb 12];50(7): Available from: Davies A, Cifaldi MA, Segurado OG, Weisman MH. Cost-effectiveness of sequential therapy with tumor necrosis factor antagonists in early rheumatoid arthritis. J Rheumatol Jan;36(1): Finckh A, Bansback N, Marra CA, Anis AH, Michaud K, Lubin S, et al. Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis. Ann Intern Med Nov 3;151(9): van den Hout WB, Goekoop-Ruiterman YP, Allaart CF, De Vries-Bouwstra JK, Hazes JM, Kerstens PJ, et al. Cost-utility analysis of treatment strategies in patients with recent-onset rheumatoid arthritis. Arthritis Rheum [Internet] Mar 15 [cited 2013 Feb 11];61(3): Available from: Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) May;64(5): Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis [Internet] Jun [cited 2013 Feb 11];69(6): Available from: Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis [Internet]. Edinburgh: SIGN; (SIGN publication no. 123). [cited 2013 Feb 25]. Available from: Nam JL, Winthrop KL, van Vollenhoven RF, Pavelka K, Valesini G, Hensor EM, et al. Current evidence for the management of rheumatoid arthritis with biological diseasemodifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis Jun;69(6): Supplementary material. Available online only. Early Biologic Treatment for Rheumatoid Arthritis 16

17 APPENDIX 1: Selection of Included Studies 1336 citations identified from electronic literature search and screened 1261 citations excluded 75 potentially relevant articles retrieved for scrutiny (full text, if available) 4 potentially relevant reports retrieved from other sources (grey literature, hand search) 79 potentially relevant reports 55 reports excluded: -irrelevant population (27) -irrelevant intervention/comparator (3) -irrelevant outcomes (1) -already included in at least one of the selected systematic reviews or a more recent or rigorous report (9) -study design not of interest (13) -duplicate (2) 24 reports included in review Early Biologic Treatment for Rheumatoid Arthritis 17

18 APPENDIX 2: Conference Abstracts 1. Breedveld F, Keystone E, van der Heijde D, Landewe R, Smolen JS, Guerette B, et al. Initial combination therapy with adalimumab plus methotrexate leads to better long-term outcomes than with either monotherapy in patients with early rheumatoid arthritis: 8-year results of an open-label extension of a phase 3 trial [abstract]. Rheumatology (United Kingdom) May;51:iii118-iii119. (Presented at British Society for Rheumatology and British Health Professionals in Rheumatology Annual Meeting 2012; Glasgow; 2012 May 1-3). Background: PREMIER was a phase 3, randomized, controlled trial (RCT) in MTX-naive, early RA patients who received blinded methotrexate (MTX), adalimumab (ADA), or ADA+MTX for 2 years. PREMIER demonstrated radiographic, clinical, and functional superiority of initial combination therapy over monotherapies; results were extended through 5 years, including 3 years open-label (OL) treatment. This analysis evaluated longterm outcomes in patients treated with ADA+/-MTX for up to 8 years (6 years beyond the 2- year RCT). Methods: Patients completing the RCT were eligible to receive OL ADA for a total of 10 years (trial ongoing); MTX could be added at investigator's discretion during OL. This post hoc analysis evaluated the 8-year-completers cohort with radiographic data available at baseline (BL) and year 8; results are summarized overall and by initial treatment arms. Radiographic damage [mtss, sum of joint-erosion (JE) and joint-spacenarrowing (JSN)] was assessed at BL and years 2, 6, and 8; progressors were defined as change () in mtss from BL>0.5. Differences in mtss were assessed using longitudinal ANCOVA following adjustment for BL mtss. Clinical outcomes assessed were DAS28, SJC66, and TJC68. Function was assessed using HAQ-DI. Results: 299 of 799 randomized patients (37.4%; 103/96/100 from initial ADA+MTX/MTX/ADA arms, respectively) received OL ADA+/-MTX through year 8. Through 8 years of ADA+/-MTX, patients continued to demonstrate inhibition of radiographic progression and effective disease control (mean: mtss=8.6, DAS28=2.6, HAQDI =0.6). Approximately half of patients experienced absence of swollen (52.5%) and tender (47.9%) joints. Initial randomization to ADA+MTX resulted in lower mean mtss, JE, and JSN at year 8 (3.8, 1.4, 2.4, respectively) compared with either MTX (11.4, 6.1, 5.2) or ADA (10.8, 5.6, 5.3) monotherapy (P<.001 for both mtss comparisons); ADA+MTX patients had fewer radiographic progressors (56.3% versus 72.9% and 73.0% for MTX/ADA monotherapy, respectively). OL ADA+/-MTX treatment inhibited radiographic progression in patients initially randomized to MTX or ADA monotherapy to levels comparable with those during OL treatment of initial ADA+MTX patients. Initial randomization to combination therapy was also associated with greater proportions of patients achieving high-level disease control and normal physical function at year 8 (DAS28<2.6: 71.3%/58.4%/49.5%, and HAQ-DI<0.5: 60.2%/ 55.9%/47.4%, for ADA+MTX/MTX/ADA, respectively). Conclusions: Through 8 years of ADA+/-MTX treatment, patients with early, aggressive RA maintained effective disease control. Patients who initially received ADA+MTX demonstrated better long-term outcomes than those initially receiving either monotherapy. Early Biologic Treatment for Rheumatoid Arthritis 18