Biologic Response Modifier Agents as First-line Treatment ... · MTX or traditional DMARD,...

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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?

Early Biologic Treatment for Rheumatoid Arthritis 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, 2013. 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,


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 2011. 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 clinical6-10 systematic reviews and one economic11 systematic review, nine RCTs,12-20 five economic evaluations,21-25 and four evidence based guidelines1,26-28 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


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 Source

RCT SR TNF inhibitor

Adalimumab HIT HARD Detert 2012 13

PREMIER Strand 2012 12

van Vollenhoven 2010 7

Breedveld 2006 6,8,9,29

HOPEFUL1 Takeuchi 2012 14

GUEPARD Soubrier 2009 15

PROWD Bejarano 2008 7-9,29

Certolizumab No data No data

Etanercept TEAR Moreland 2012 16

COMET Anis 2009 6-9,29

Emery 2008

ERA Bathon 2000 6,9,29

Genovese 2002 9,29

Kosinski 2002

Golimumab GO-BEFORE

Emery 2009 6

Emery 2008 9,29

Infliximab NEO RACo Leirisalo-Repo 2012 17

BeSt Klarenbeek 2011 18

--- Durez 2007 8


Biologic agent

Study name

Author, Year Source

RCT SR ASPIRE Smolen 2006

6-9,29

St. Clair 2004

-- Quinn 2005 6,8

Bejarano 2010 19

Other biologic agents

Abatacept AGREE Westhovens 2009 Westhovens 2008

8,9,29

Anakinra No data No data

Rituximab IMAGE Tak 2009 (abstract) 10

Tocilizumab AMBITION Jones 2010 20

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 study20 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 seven13-18,20 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 studies13,14,18 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).


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; ACR50 1.43 (1.30 to 1.56); ACR70 1.63 (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 rituximab10 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 etanercept16 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 infliximab17,18 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


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.13-18,20


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.21-25 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


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 2010,27 2011,28 and 2012.1,26 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 guidelines1,26-28 focused on adult populations with all stages of RA, with the exception of the ACR26 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.


All of the guidelines developed their recommendations by reviewing the literature1,26-28 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 study26 or meta-analyses/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 stated1,28 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 EULAR27 guidelines. All guidelines were evidence-based with described methods for guideline formulation. Three guidelines26-28 included all forms of original evidence (systematic reviews, randomized controlled trials, non-randomized studies) while the CRA1 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 ACR26 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 CRA1 guidelines addressed barriers to implementation and were supported by implementation tools. It was clear that the ACR,26 EULAR,27 CRA,1 and SIGN28 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 EULAR27 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 naïve1,27 or have structural damage.27 This therapy may be used as monotherapy1,26 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 CRA1 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).


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 assessed1:

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 monotherapy1,26 or in combination with MTX26,27 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

activity1,26,27 and in those who are DMARD naïve1,27 and have structural

damage.27

3. 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.1

4. 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


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 recommendations1,26,27 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 2012. 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


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: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


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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: http://www.cadth.ca/media/pdf/TR_RA_Clinical_and_Economic_Overview_e.pdf

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: http://www.cadth.ca/media/pdf/Biologics_for_RA_TRP_Final_Recommendations_e.pdf

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: http://www.agreetrust.org/?o=1085

5. Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ [Internet]. 1996 Aug 3 [cited 2013 Mar 4];313(7052):275-83. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2351717/pdf/bmj00553-0039.pdf

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]. 2012 [cited 2013 Feb 11];7(1):e30275, 2012. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260264/pdf/pone.0030275.pdf

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. 2012 Feb;71(2):161-71.

8. 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. 2010 Jul;69(7):1298-304.

9. 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 disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010 Jun;69(6):976-86.

10. Volkmann ER, Agrawal H, Maranian P, Furst DE. Rituximab for rheumatoid arthritis: a meta-analysis and systematic review. Clin Med Insights Ther. 2010;2:749-60.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260264/pdf/pone.0030275.pdf


11. van der Velde G, Pham B, Machado M, Ieraci L, Witteman W, Bombardier C, et al. Cost-effectiveness of biologic response modifiers compared to disease-modifying antirheumatic drugs for rheumatoid arthritis: a systematic review. Arthritis Care Res (Hoboken). 2011 Jan;63(1):65-78.

12. 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]. 2012 Jan [cited 2013 Feb 11];39(1):63-72. Available from: http://www.jrheum.org/content/39/1/63.full.pdf+html

13. 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. 2012 Jul 10.

14. 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]. 2013 Jan 11 [cited 2013 Feb 11]. Available from: http://ard.bmj.com/content/early/2013/01/10/annrheumdis-2012-202433.full.pdf+html

15. 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]. 2009 Nov [cited 2013 Feb 11];48(11):1429-34. Available from: http://rheumatology.oxfordjournals.org/content/48/11/1429.full.pdf+html

16. 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. 2012 Sep;64(9):2824-35.

17. 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, double-blind, placebo-controlled study (the NEO-RACo Study). Ann Rheum Dis. 2012 Jun 30.

18. 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. 2011 Jun;70(6):1039-46.

19. 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]. 2010 Oct [cited 2013 Feb 11];49(10):1971-4. Available from: http://rheumatology.oxfordjournals.org/content/49/10/1971.full.pdf+html

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http://rheumatology.oxfordjournals.org/content/48/11/1429.full.pdf+html



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. 2010 Jan;69(1):88-96.

21. 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. 2011 Jul;27(3):193-200.

22. 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]. 2011 [cited 2013 Feb 12];50(7):1320-30. Available from: http://rheumatology.oxfordjournals.org/content/50/7/1320.full.pdf+html

23. Davies A, Cifaldi MA, Segurado OG, Weisman MH. Cost-effectiveness of sequential therapy with tumor necrosis factor antagonists in early rheumatoid arthritis. J Rheumatol. 2009 Jan;36(1):16-26.

24. 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. 2009 Nov 3;151(9):612-21.

25. 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]. 2009 Mar 15 [cited 2013 Feb 11];61(3):291-9. Available from: http://onlinelibrary.wiley.com/doi/10.1002/art.24169/pdf

26. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 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). 2012 May;64(5):625-39.

27. 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]. 2010 Jun [cited 2013 Feb 11];69(6):964-75. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935329/pdf/ard-69-06-0964.pdf

28. Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis [Internet]. Edinburgh: SIGN; 2011. (SIGN publication no. 123). [cited 2013 Feb 25]. Available from: http://www.sign.ac.uk/pdf/SIGN123.pdf

29. 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 disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010 Jun;69(6):976-86. Supplementary material. Available online only.


http://onlinelibrary.wiley.com/doi/10.1002/art.24169/pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935329/pdf/ard-69-06-0964.pdf

http://www.sign.ac.uk/pdf/SIGN123.pdf


APPENDIX 1: Selection of Included Studies

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

1336 citations identified from electronic literature search and

screened


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). 2012 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 long-term 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-space-narrowing (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.


2. Yazici Y, Swearingen C, Nadkarni A, Rosenblatt L. Comparative efficacy and tolerability of biologic therapies in early rheumatoid arthritis utilizing a bayesian approach [abstract]. Arthritis Rheum. 2011 Oct;60(10 Suppl 1). (Presented at Annual Scientific Meeting of the American College of Rheumatology and Association of Rheumatology Health Professionals 2011; Chicago (IL); 2011 Nov 4-9). Background/Purpose: Currently, five biologic disease-modifying antirheumatic drug (DMARD) therapies are used in MTX-naive, early rheumatoid arthritis (RA). In the absence of head to head studies, indirect approaches are required in order to gain insight into the comparative efficacy and tolerability of these agents. Objectives: To determine the relative efficacy and tolerability of biologic agents approved for the treatment of MTX-naive early RA patients using mixed treatment comparison (MTC) methodology. Methods: A systematic literature review was performed to identify RCTs published between January 1, 1990 and June 16, 2010 that measured efficacy and safety endpoints in an MTX-naive, early RA population. Those RCTs that included any one of the approved biologics abatacept (ABA), adalimumab (ADA), etanercept (ETN), golimumab (GOL), and infliximab (INF), were included in the MTC that compared the following outcomes at 1 year: American College of Rheumatology (ACR) 20/50/70, Disease Activity Score 28 (DAS 28) remission, severe adverse events (AEs), serious infections and withdrawals due to an AE or due to any reason. Results: No difference in the odds of achieving ACR 50 or ACR 70 scores was seen between the biologics, although both INF (odds ratio [OR]=0.48, 95% CI=0.27-0.82) and ADA (OR=0.53, 95% CI=0.29-0.94) had significantly lower odds of achieving ACR20 compared with ETN. The odds of achieving DAS28 remission was also found to be similar between all biologic therapies with the exception of INF which had significantly lower odds (OR=0.54, 95% CI=0.30-0.97) compared with ADA. Tolerability to the biologic agents was not significantly different with the exception of INF and GOL, as the former had significantly higher odds of experiencing serious infections compared with ETN (OR=5.12, 95% CI=1.20-24.80) and significantly higher odds of discontinuing treatment due to AEs compared with ABA (OR=4.80, 95% CI=1.45-17.08) and ETN (OR=4.28, 95% CI=1.75-11.35), while GOL had higher odds of discontinuing treatment due to AEs compared with those receiving ETN (OR=3.43, 95% CI=1.07-12.67). Conclusion: In general, all biologic agents used in MTX-naive early RA demonstrated similar efficacy and tolerability, except for INF which appeared to have less favorable efficacy and tolerability. For specific outcomes studied, ETN and ABA were not significantly different from each other and were the only biologics that did not demonstrate a significantly decreased likelihood of efficacy or tolerability compared with any of the other agents.


3. Villoro R, Hidalgo A, Ferro B, Talavera P. Cost-utility analysis of certolizumab pegol versus alternative tumor necrosis factor-inhibitors, for the treatment of moderateto-severe rheumatoid arthritis in Spain [abstract]. Value Health. 2011 Nov;14(7):A310-A311. (Presented at ISPOR 14th Annual European Congress; Madrid, Spain; 2011 Nov 5-8). OBJECTIVES: To evaluate the cost-utility of CZP compared with standard-of-care first-line administered TNF-inhibitors + MTX in the treatment of moderate-tosevere RA in Spain. METHODS: A Markov (cohort health state transition) model was developed to evaluate the cost-utility of CZP versus the other TNF-inhibitors licensed and recommended in Spain (etanercept [ETA], adalimumab [ADA], and infliximab [IFX]). Treatment efficacy was measured using ACR-responses (ACR20, ACR50 or ACR70) at 6 months. ACR estimated response rates were based on adjusted indirect comparison (MTX as the common comparator) of published clinical trials. Utilities were derived from EQ-5D data collected in CZP RA clinical trials. Clinical history and resource use data came from published literature. Unit costs (drug, administration, monitoring, and resources) were taken from Spanish routine sources or published references (cost year 2009). Base case analysis was conducted from the payer perspective, with a lifetime horizon, annual discounting rates of costs and outcomes of 3.5% and inflation rate for 2009 onwards of 3%. One-way sensitivity analyses were conducted. RESULTS: The average lifetime costs for CZP+MTX, ETA+MTX, ADA+MTX and IFX+MTX were 140,971, 141,197, 139,148 and 136,961, respectively. The quality-adjusted life-years (QALYs) gained were 6.578, 6.462, 6.430 and 6.318, respectively. The deterministic cost-effectiveness analysis found that CZP+MTX dominated ETA+MTX (lower cost, greater QALYs), and that CZP+MTX was cost-effective vs ADA+MTX and IFX+MTX at the 30,000/ QALY willingness-to-pay threshold (ICERs of 12,346/QALY and 15,414/QALY, respectively). One-way sensitivity analyses showed that ICERs were most sensitive to the change in annual discount rates, the model cycle (evaluation of ACR response at 3 instead of 6 months), the analysis perspective and the estimation of utilities (HAQ-DI mapping instead of direct evaluation from EQ-5D). CONCLUSIONS: This analysis shows that CZP-MTX is cost-effective versus the other considered TNFinhibitors recommended in Spain for the treatment of RA.


APPENDIX 3: Characteristics of Included Studies

Table 1. Summary of Systematic Reviews

Author, year, study design,

Key inclusion criteria, N studies

Interventions Outcomes

Aaltonen 20126 SR/MA

RCTs of patients ≥16 years of age with RA N=26 RCTs (MTX naïve: 5 RCTs)

TNF inhibitor

Placebo or placebo+MTX

Clinical response, adverse events

ter Wee 20127 SR

RCTs and observational studies in patients with RA N=19 studies (MTX naïve: 4 RCTs)

TNF inhibitor

Any comparator or no control group

Employment status, sick leave or presenteeism (reduced work input while at work)

Kuriya 20108 SR/MA

RCTs of adults with early RA (<3 years since diagnosis) with no or minimal (≤4 weeks) MTX treatment. Prior SSZ, HCQ or CHL allowed N=7 RCTs

Biologic agent + MTX

MTX

Clinical remission; radiographic non-progression at 1 year

Nam 20109 SR/MA

SR, MA, RCT, and observational studies of patients with RA N=87 articles, 40 abstracts (MTX naïve: 7 RCTs)

Biologic agent

Any comparator

Clinical response, remission, radiographic progression

Volkmann 201010 SR/MA

RCTs and CCTs of patients ≥16 years of age with RA N=5 RCTs, 1 CCT (MTX naïve: 1 RCT)

RTX ± DMARD

Placebo, DMARD or other biologic agent

Clinical response, adverse events

CCT=controlled clinical trial; CHL=chloroquine; DMARD=disease modifying antirheumatic drug; HCQ=hydroxychloroquine; HRQL=health related quality of life; MA=meta-analysis; MTX=methotrexate; N=number; RA=rheumatoid arthritis; RCT=randomized controlled trial; RTX=rituximab; SSZ=sulfasalazine; SR=systematic review; TNF=tumor necrosis factor alpha;


Table 2. Summary of Randomized Controlled Trials

Study name, Author, Year

Population, N, Country

Intervention, Duration

Key Outcome Quality assessment

AC DB ITT

TNF inhibitor

Adalimumab

HIT HARD Detert 201213

Adults (≥18 years) with early RA (≤1 year duration) with no previous exposure to DMARDs or biologics N=172 Germany

ADA+MTX

MTX+Plac 6 mo treatment, then MTX monotherapy for all pts for another 6 mo

Clinical response, remission, radiographic progression, HRQL, adverse events

NR DB ITT

PREMIER Strand 2012 12 van Vollenhoven 20107 Breedveld 20066,8,9

Adults (≥18 years) with RA (<3 years duration) and MTX naïve N=799 N America, Europe, Australia

ADA+MTX

ADA+Plac

MTX+Plac 2 years

Clinical response, remission, radiographic progression, HRQL, work-related, adverse events

NR DB ITT

HOPEFUL1 Takeuchi 201214

Adults (≥20 years) with early RA (≤2 years) with no previous exposure to MTX, LEF or >2 other DMARD drugs N=334 Japan

ADA+ MTX

MTX+ Plac 6 mo

Clinical response, radiographic progression, adverse events

NR DB ITT

GUEPARD Soubrier 200915

Adults (≥18 years) with early RA (<6 mo duration), who have not received MTX or biologics N=65 France

ADA+MTX

MTX Therapy titrated up or down every 3 mo based on DAS28 1 year

Clinical response, radiographic progression, remission, HRQL, adverse events

NR open label

ITT

PROWD Bejarano 20087-9

MTX naïve RA patients N=148 NR

ADA+MTX

MTX+Plac 1 year

Clinical response, remission, radiographic progression, work-related

AC DB ITT

Etanercept

TEAR Moreland

Adults (≥18 years) with early RA (<3

MTX+ETAN

MTX+SSZ+

Clinical response, radiographic

NR DB ITT






AC DB ITT

201216 years since diagnosis) Prior use of LEF, HCQ, SSZ <2 months; MTX ≤40 mg) N=755 US

HCQ

MTX with step up to MTX+ETAN

MTX with step up to MTX+SSZ+HCQ at 6 mo

2 years

progression, remission, adverse events

COMET Anis 20097 Emery 20086,8,9


ETAN+MTX

MTX+Plac 1 year

Clinical response, remission, radiographic progression, work-related, adverse events

AC DB ITT

ERA Bathon 20006,9 Genovese 20029


ETAN+Plac

MTX+Plac 1 year

Clinical response, radiographic progression, adverse events

NR DB NR

Golimumab

GO-BEFORE Emery 20096,9


GOL+Plac

GOL+MTX

MTX+Plac 1 year

Clinical response, remission, adverse events

AC DB NR

Infliximab

NEO RACo Leirisalo-Repo 201217

MTX naïve adults (18-60years) with early RA (≤1 year duration) N=99 Finland

INF

Plac For 6 mo Both groups received MTX+SSZ+HCQ+PRED 2 years

Clinical response, remission, radiographic progression, adverse events

AC DB ITT

BeSt Klarenbeek 201118

DMARD naïve adults (≥18 years) with recent onset RA (≤2 years) N=508 Netherlands

Sequential monotherapy (MTX initial therapy)

Step up combination therapy (MTX initial

Remission, radiological progression, HRQL; adverse events

AC SB ITT






AC DB ITT

therapy)

Initial combination therapy with PRED (MTX+ SSZ+ PRED)

Initial combination therapy with INF (MTX+ INF)

5 years

ASPIRE St. Clair 20046,8,9 Smolen 20067


INF+MTX

MTX+Plac 1 year

Clinical response, remission, radiographic progression, work-related, adverse events

AC DB Not ITT

Quinn 20056,8 Bejarano 201019

MTX naïve RA patients N=20 UK

INF+MTX

MTX+Plac 1 year

Clinical response, remission, HRQL

NR DB ITT

Durez 20078 MTX naïve RA patients N=29 NR

INF+MTX

MTX 1 year

Remission AC DB ITT

Other biologics

Abatacept

AGREE Westhovens 20098,9


ABT+MTX

MTX+Plac 1 year

Clinical response, remission, radiographic progression,

AC DB ITT

Rituximab

IMAGE Tak 200910

Pts with RA who are MTX naïve (mean RA duration <1 year) N=755 NR

RTX+MTX

MTX+Plac 13 mo

Clinical response NR DB NR

Tocilizumab

AMBITION Adults (≥18 years) TOC+Plac Clinical response, NR DB ITT






AC DB ITT

Jones 201020 with moderate to severe RA, who have not received MTX in past 6 mo. Excluded those who have failed anti-TNF or MTX N=673 MTX naïve: 67% US, Canada, Israel

MTX+Plac

Placebo (substudy in some sites)

6 mo

remission, adverse events

ABT=abatacept; AC=allocation concealment; ADA=adalimumab; CHL=chloroquine; DAS=disease activity score; DB=double blind; DMARD=disease modifying anti-rheumatic drug; ETAN=etanercept; GOL=golimumab; HCQ=hydroxychloroquine; HRQL=health related quality of life; INF=infliximab; ITT=intention to treat; LEF=leflunomide; mo=months; MA=meta-analysis; mo=months; MTX=methotrexate; N=number; NR=not reported; PRED=prednisone; pts=patients; Plac=placebo; RCT=randomized controlled trial; RTX=rixtuximab; SB=single blind; SR=systematic review; SSZ=sulfasalazine; TNF=tumor necrosis factor alpha; TOC=tocilizumab


APPENDIX 4: Critical Appraisal of Clinical Studies

Author, year, study design

Strengths Limitations

Systematic reviews Aaltonen 20126 SR/MA

literature search of multiple databases to Jun 2010; no language restrictions

robust methods used to select studies, and for quality assessment, data extraction, and data synthesis

no grey literature search

reporting of study characteristics was limited

ter Wee 20127 SR

literature search of multiple databases to Jan 2011

robust methods for quality assessment, data extraction, and summary of findings


article selection by one reviewer

Kuriya 20108 SR

literature search of multiple databases to Apr 2009

robust methods used to synthesize data


English language only

Not clear if article selection, quality assessment and data extraction done in duplicate by two researcher

Nam 20109 SR/MA

literature search of multiple databases to Feb 2009

robust methods for data extraction and data synthesis; clear inclusion criteria

limited grey literature search


nNot clear if article selection, quality assessment and data extraction done in duplicate by two researcher

Volkmann 201010 SR/MA

Robust methods for study selections, data extraction, quality assessment and data synthesis

Pubmed only database searched (up to Mar 2010)



RCTs Adalimumab HIT HARD Detert 2012

13

Randomized, double blind

ITT analysis

Methods to randomize, conceal allocation not reported

Differential withdrawal rate (ADA+MTX: 13%, MTX: 33%). Drop outs had significantly higher disease activity than completers.


14


ITT analysis

Methods to randomize, conceal allocation not reported

Differential withdrawal rate (ADA+MTX: 13%, MTX: 21%).





15

Randomized

ITT analysis; withdrawals 12%

Open label

Sample size limited (N=65, under powered)

Methods to randomize, or conceal allocation not reported

Etanercept TEAR Moreland 2012

16


ITT analysis

Methods to randomize, or conceal allocation not reported

Withdrawal rate 32% over 2 years; no difference across groups

Infliximab NEO RACo Leirisalo-Repo 2012

17

Centrally randomized with adequate allocation concealment

Double blind

ITT analysis; withdrawal 9%

Sample size <100


18

Randomized, allocation concealed

ITT analysis

Single blind (outcome assessor)

Over 5 years, 15% of patients withdrew from the study; rates were difference across groups (range 9% to 22%)

Tocilizumab AMBITION Jones 2010

20

Randomized, double blind (double dummy design)

ITT analysis; 8% withdrawals

Methods of randomization not reported

Unclear allocation concealment

MTX naïve population not a pre-defined subgroup

ADA=adalimumab; ITT=intention to treat; MA=meta-analysis; MTX=methotrexate; N=number; RCT=randomized controlled trial; SR=systematic review;


APPENDIX 5: Summary of Results of Clinical Studies

Note: statistically significant results are presented in italics. Table 1. Summary of clinical response outcomes Study name, Author, Year

Interventions

Time Clinical response

ACR20 ACR50 ACR70

Biologic Control Biologic Control Biologic Control

TNF inhibitors

Adalimumab HIT HARD Detert 2012

13

ADA+MTX vs MTX

12 mo 66% 75%, p=0.21

53% 51%, p=0.88 41% 34%, p=0.40

PREMIER Breedveld 20069,29

ADA+MTX vs MTX

12 mo RR 1.16 (95% CI 1.03, 1.31)

RR 1.29 (95% CI 0.92, 1.82)

RR 1.64 (95% CI 1.29, 2.07)

ADA vs MTX 12 mo RR 0.86 (95% CI 0.74, 0.99)

RR 0.89 (95% CI 0.73, 1.08)

RR 0.92 (95% CI 0.70, 1.22)


14

ADA+MTX vs MTX

6 mo 75% 56%, p<0.001

64% 39%, p<0.001 47% 23%, p<0.001


ADA+MTX vs MTX

12 mo 85% 81%, p=NS

67% 68%, p=NS 42% 58%, p=NS

PROWD Bejarano 20089,29

ADA+MTX vs MTX

12 mo RR 1.31 (95% CI 1.02, 1.69)

RR 1.24 (95% CI 0.90, 1.71)

RR 1.37 (95% CI 0.94, 1.99)


16

1. ETAN+MTX

2. Step up ETAN+MTX

24 mo 1. 50% 2. 48%

3. 45% 4. 47%, p=NS

1. 38% 2. 33%

3. 31% 4. 38%, p=NS

1. 21% 2. 15%

3. 11% 4. 12%, P=0.01 for pooled ETAN vs DMARD



Interventions


ACR20 ACR50 ACR70


3. MTX+SSZ+HCQ

4. Step up MTX+SSZ+HCQ

groups

COMET Emery 20089,29

ETAN+MTX vs MTX

12 mo RR 1.34 (95% CI 1.20, 1.49)

RR 1.51 (95% CI 1.29, 1.76)

RR 1.78 (95% CI 1.40, 2.27)

ERA Bathon 20009,29

ETAN vs MTX

12 mo RR 1.11 (95% CI 0.97, 1.26)

NR NR

Golimumab

GO-BEFORE Emery 20099,29

GOL+MTX vs MTX

6 mo RR 1.25 (95% CI 1.04, 1.49)

RR 1.31 (95% CI 0.99, 1.72)

NR

GOL vs MTX RR 1.04 (95% CI 0.84, 1.30)

RR 1.11 (95% CI 0.80, 1.55)

Infliximab

NEO RACo Leirisalo-Repo 201217

INF+DMARD vs DMARD

24 mo NR 96% 92%, p=0.44 86% 71%, p=0.09

Aaltonen 20126 Pooled data

INF+MTX vs MTX

12 mo RR 1.20 (95% CI 1.07, 1.36), I2=NR N=2 RCTs (Quinn 2005, St. Clair 2004)

RR 1.52 (95% CI 1.26, 1.82), I2=NR N=2 RCTs (Quinn 2005, St. Clair 2004)

RR 1.68 (95% CI 1.32, 2.14), I2=NR N=2 RCTs (Quinn 2005, St. Clair 2004)

Other biologic agents

Abatacept

AGREE Westhovens

ABT+MTX vs MTX

12 mo NR RR 1.36 (95% CI 1.14, 1.63)

RR 1.57 (95% CI 1.22, 2.10)



Interventions


ACR20 ACR50 ACR70


20089,29

Rituximab

Tak 200910 RTX+MTX vs MTX

13 mo NR OR 2.04 (95% CI 1.42, 2.93)

NR

Tocilizumab

AMBITION Jones 201020 Subgroup: MTX naive

TOC vs MTX 6 mo 69% 54%, p<0.004

45% 33%, p=0.01 27% 14%, p=0.005

Any biologic agent (pooled data)

Nam 20109,29

biologic+MTX vs MTX

12 mo RR 1.24 (95% CI 1.15, 1.34), I2=18% N=4 RCTs* (ADA, ENAN, INF)

RR 1.43 (95% CI 1.30, 1.56) I2=0% N=5 RCTs* (ABT, ADA, ETAN, INF)

RR 1.63 (95% CI 1.45, 1.83) I2=0% N=5 RCTs* (ABT, ADA, ETAN, INF)

biologic vs MTX

12 mo RR 0.98 (95% CI 0.76, 1.26), I2=85%, N=2 RCTs† (ADA, ETAN)

RR 0.89 (95% CI 0.73, 1.08), N=1 RCT† (ADA)

RR 0.92 (95% CI 0.70, 1.22) N=1 RCT† (ADA)

ABT=abatacept; ACR=American College of Rheumatology; ADA=adalimumab; CI=confidence interval; DMARD=disease modifying anti-rheumatic drug;

ETAN=etanercept; GOL=golimumab; HCQ=hydroxychloroquine; INF=infliximab; NR=not reported; mo=months; MTX=methotrexate; NS=non statistically

significant; RCT=randomized controlled trial; RR=relative risk; SSZ=sulfasalazine; TNF=tumor necrosis factor; TOC=tocilizumab

*Pooled data from Bejarano 2008 (PROWD), Breedveld 2006 (PREMIER), Emery 2008 (COMET), St. Clair 2004 (AGREE) for ACR20/50/70, and including

Westhovens 2008 (AGREE) for ACR50 and ACR70.

†Pooled data from Breedveld 2006 (PREMIER) for ACR20/50/70 and Bathon 2000 (ERA) for ACR20.


Table 2. Summary of remission, radiographic progression and HRQL outcomes Study name, Author, Year

Interventions

Time Remission (DAS28<2.6 or ACR definition)

Radiographic non-progression

Health related quality of life (HRQL)

Biologic Control Biologic Control


13

ADA+MTX vs MTX

12 mo 42% 37%, p=0.47

ADA+MTX had less progression than MTX group based on erosion, joint space narrowing, Sharp, and Ratingen scores (p≤0.01)

NS difference in SF-36 mental component score (adj difference -1.4) or physical component score (adj difference -0.5)

PREMIER Breedveld 20069,29 Strand 201212

ADA+MTX vs MTX

24 mo/ 12 mo

RR 1.96 (95% CI 1.54, 2.51)

RR 1.74 (95% CI 1.45, 2.08)

SF-36 at 24 mo: Physical component score SS better for ADA+MTX vs MTX (48.8 vs 45.9, p<0.0001) Mental component score NS different (51.8 vs 52.4, p=0.76)

ADA vs MTX RR 1.01 (95% CI 0.75, 1.36)

RR 1.38 (95% CI 1.13, 1.68)

Physical component score NS different for ADA vs MTX (44.7 vs 45.9, p=0.39) Mental component score SS lower (49.8 vs 52.4, p=0.015


14

ADA+MTX vs MTX

6 mo NR 62% 35%, p<0.001

NR


ADA+MTX vs MTX

12 mo 39% 59%, p=0.15

42% 50%, p=0.41

NS difference between groups on SF-36 physical and mental components (data not shown)



Interventions





Etanercept

TEAR Moreland 2012

16

1. ETAN+MTX

2. Step up ETAN+MTX

3. MTX+SSZ+HCQ

4. Step up MTX+SSZ+HCQ

24 mo 1. 57% 2. 53%

3. 59% 4. 57%, p=0.93

1. 79% 2. 71%

3. 65% 4. 68%, p=0.33

NR

ERA Genovese 20029

ETAN vs MTX

12 mo NR RR 1.04 (95% CI 0.85, 1.28)

NS differences between groups on the SF-36 mental and physical component scores

Golimumab

GO-BEFORE Emery 20099

GOL+MTX vs MTX

6 mo RR 1.35 (95% CI 1.02, 1.80)

NR NR

GOL vs MTX RR 0.89 (95% CI 0.62, 1.29)

Infliximab NEO RACo Leirisalo-Repo 2012

17

INF+DMARD vs DMARD

24 mo 66% 53%, p=0.19

80% 53%, p=0.006

NR


18

1. Mono-therapy (MTX)

2. Step up combo therapy

5 years

NS difference between groups, p=0.94 (range 42% to 50%)

SS more progression in groups 1 & 2 versus initial INF+MTX group (p<0.01). NS difference between group 3 & initial INF+MTX.

SF-36 Physical component score increased from baseline in all groups [overall mean score:33 (baseline), 45 (5 year), NS difference between



Interventions





(MTX) 3. Initial

MTX+ SSZ+ PRED

4. Initial INF+MTX

groups] Mental component score also improved [overall mean score: 47 (baseline), 52 (5 year), NS different between groups)

Bejarano 2010

19 (see

Quinn 2005)

INF+MTX vs MTX

8 years

44% 0%, p=NR NR RAQoL score NS different between groups, p=0.18 INF: 3 MTX: 8

Tocilizumab

AMBITION Jones 201020 67% MTX naive

TOC vs MTX 6 mo 34% 12% NR NR

OR 5.8 (95% CI 3.3, 10.4)

Any biologic (pooled data)

Kuriya 20108

Biologic+MTX vs MTX

12 mo RR 1.74 (95% CI 1.54, 1.98), I2=0% N=7 RCTs† (ABT, ADA, ETAN, INF)

RR 1.30 (95% CI 1.01, 1.68), I2=95% N=4 RCTs‡ (ABT, ADA, ETAN, INF)

NR

Nam 20109,29 Biologic+MTX vs MTX

12 mo Similar pooled results as in Kuriya 2010

Similar pooled results as in Kuriya 2010

SF-36 physical component: SMD 0.19 (95% CI 0.10, 0.28) p<0.0001 favoring biologic, I2=0% N=3 RCTs** (ABT, ETAN, INF)



Interventions





SF-36 mental component: SMD 0.07 (-0.14, 0.29), p=0.52, I2=64% N=2 RCTs** (ABT, ETAN)

ABT=abatacept; ACR=American College of Rheumatology; ADA=adalimumab; adj=adjusted; CI=confidence interval; DAS28=28 joint Disease Activity Score;

DMARD=disease modifying anti-rheumatic drug; ETAN=etanercept; GOL=golimumab; HCQ=hydroxychloroquine; HRQL=health related quality of life;

INF=infliximab; NR=not reported; mo=months; MTX=methotrexate; NS=non statistically significant; OR=odds ratio; RAQoL=Rheumatoid Arthritis Quality of Life

Questionnaire; RCT=randomized controlled trial; RR=relative risk; SF-36= Short Form Health Survey 36 questions (generic HRQL instrument); SMD=standardized

mean difference; SSZ=sulfasalazine; TOC=tocilizumab

†Pooled data from Westhovens 2009 (AGREE), Bejarano 2008 (PROWD), Breedveld 2006 (PREMIER), Emery 2008 (COMET), Durez 2007, St. Clair 2004

(AGREE), and Quinn 2005.

‡Pooled data from Westhovens 2009 (AGREE), Breedveld 2006 (PREMIER), Emery 2008 (COMET), St. Clair 2004 (ASPIRE)

**Pooled data from Westhovens 2009 (AGREE) and Kosinski 2002(ERA) for mental component, and also including St. Clair 2004 (ASPIRE) for physical

component.


Table 3. Summary of work related outcomes Study name, Author, Year

Interventions Time Loss of employment Absenteeism (days missed)

PROWD Bejarano 20087

ADA+MTX vs MTX

12 mo NS difference NR

PREMIER Van Vollenhoven 20107

ADA+MTX vs MTX

12 mo OR 0.64 (95% CI 0.42, 1.00), p=0.048

MD -19.5 days over 2 years, p=NR

ADA vs MTX 12 mo OR 0.78 (95% CI 0.51, 1.19)

MD -18.2 days, p=NR

COMET Anis 20097

ETAN+MTX vs MTX

12 mo ETAN+MTX: 9% MTX: 24%, p=0.004

MD -17.6 days (95% CI -34.4, -2.2) over 1 year

ASPIRE Smolen 20067

INF+MTX vs MTX

12 mo NS difference Patients with 0 days absent over 1 year: INF: 79% MTX: 67%, p<0.01

ADA=adalimumab; CI=confidence interval; ETAN=etanercept; INF=infliximab; MD=mean difference: mo=months; MTX=methotrexate; NR=not reported; NS=non

statistically significant; OR=odds ratio


Table 4. Summary of adverse events Study name, Author, year

Interventions Time Withdrawals due to adverse events

Serious adverse events

Adverse events



13

ADA+MTX vs MTX 12 mo 5% 8% 14% 20% NR NR


ADA+MTX vs MTX 6 mo 4% 4% 4% 2% 81% 72%

PREMIER Breedveld 20066

ADA+MTX vs MTX 12 mo 11% 7%, p=NS NR NR NR NR


ADA+MTX vs MTX 12 mo NR NR 15% 16% NR NR


16

1. ETAN+MTX 2. Step up

ETAN+MTX 3. MTX+SSZ+HCQ 4. Step up

MTX+SSZ+HCQ

24 mo 1. 5% 2. 4%

3. 5% 4. 2%, p=NS

1. 14% 2. 13%

5. 14% 6. 13%, p=NS

1. 79% 2. 73%

3. 77% 4. 74%, p=NS

COMET Emery 20086

ETAN+MTX vs MTX 12 mo 11% 13%, p=NS NR NR NR NR

ERA Bathon 20006

ETAN vs MTX 12 mo 5% 11%, p<0.05

NR NR NR NR

Golimumab

GO-BEFORE Emery 20096

GOL+MTX vs MTX 6 mo 3% 1%, p=NS NR NR NR NR

Infliximab

NEO RACo Leirisalo-

INF+DMARD vs DMARD

24 mo NR NR 6% 8% 90% 96%


ADA=adalimumab; AD=adverse events; DMARD=disease modifying anti-rheumatic drug; ETAN=etanercept; GOL=golimumab; HCQ=hydroxychloroquine; INF=infliximab; mo=months; MTX=methotrexate; NR=not reported; NS=non statistically significant; SAE=serious adverse events; SSZ=sulfasalazine; TOC=toclizumab; WDAE=withdrawals due to adverse events

Repo 201217 BeSt Klarenbeek 2011

18

1. Mono-therapy (MTX)

2. Step up combo therapy (MTX)

3. Initial MTX+ SSZ+ PRED

4. Initial INF+MTX

5 years NR NR 4. 31% 1. 33% 2. 28% 3. 28%, p=0.76

4. 88% 1. 87% 2. 85% 3. 84%, p=0.84

Quinn 20056 INF+MTX vs MTX 12 mo 10% 0%, p=NS NR NR NR NR

ASPIRE St. Clair 20046

INF+MTX vs MTX 12 mo 10% 3%, p<0.05 NR NR NR NR

Tocilizumab

AMBITION Jones 201020 67% MTX naive

TOC vs MTX 6 mo 4% 5%, p=0.40 4% 3%, p=0.50

80% 78%, p=0.48


APPENDIX 6: Characteristics of Economic Studies

Table 1. Summary of systematic reviews

Author, year Key inclusion criteria, N studies

Interventions Outcomes

van der Velde 201111

CEA or CUA in adults with RA N=18 studies (3 in DMARD naïve patients, with biologic as first line therapy)

Biologic agent

DMARD

Cost-effectiveness (cost/QALY) converted to 2009 Canadian dollars

CEA=cost-effectiveness analysis; CUA=cost-utility analysis; DMARD=disease-modifying antirheumatic drug; QALY=quality adjusted life year; RA=rheumatoid

arthritis


Table 2. Summary of economic studies Study, Location, Funding

Study design, model

Perspective, Time Horizon, Dollar

Population Intervention† Comparators†

Studies included in van der Velde 201111

Choi 2002 US NR

CEA Decision tree

Societal 6 month 1999 US$*

Adults with RA and no prior DMARD exposure

ETAN 1. SSZ 2. MTX 3. LEF

Chen 2006 US Non-industry

CUA Discrete event simulation

Payer Lifetime 2004 UK£*


1. ADA 2. ADA+MTX 3. ETAN 4. ETAN+ MTX 5. INF+MTX

MTX (sequential DMARD therapy)

Spalding 2006 US Non-industry

CUA Markov model

Payer Lifetime 2005 US$*


1. ADA 2. ADA+MTX 3. ETAN 4. INF+MTX

MTX (sequential therapy)

Other economic studies

Kobelt 201121 Sweden Industry

CUA Markov model

Societal 10 years 2008 Euro

Adults with early RA (based on COMET trial)

ETAN+MTX (lower dose if achieve remission)

MTX (sequential therapy)

Schipper 201122 Netherlands Industry

CUA Markov model

Payer, Societal 5 years NR, Euro

Adults with early RA (<1 year) and no prior DMARD use

TNF inhibitor+MTX (sequential therapy)

1. MTX (sequential therapy)

2. MTX+LEF (sequential therapy)

Davies 200923 US Industry

CUA Individual patient simulation model

Payer Societal Lifetime 2007 US$

Early RA (<3 year duration) and MTX naive

1. ADA+MTX 2. ETAN 3. INF+MTX 4. ADA+MTX/ ETAN

(2nd line) (sequential therapies)

MTX (sequential DMARD)


Finchk 200924 US Non-industry

CUA Decision analytic model

Payer, Societal Lifetime 2007 US$

US adults with early RA (<3 mo duration)

TNF inhibitor+MTX (sequential therapy)

1. NSAIDS+steroids (step-up to DMARD at 1 year)

2. DMARDs (sequential therapy)

Van den Hout 200925 Netherlands Industry

CUA Costs and benefits collected as part of BeSt RCT

Payer, Societal 2 years 2008 Euro

Adults with RA (≤2 year duration); DMARD naïve

MTX+INF (sequential therapy)

1. MTX (sequential mono-therapy)

2. MTX+SSZ+PRED (sequential therapy)

3. MTX (step up combination therapy)

ADA=adalimumab; CEA=cost-effectiveness analysis; CUA=cost-utility analysis; DMARD=disease-modifying antirheumatic drug; ETAN=etanercept; INF=infliximab;

LEF=leflunomide; mo=months; MTX=methotrexate; NR=not reported; NSAIDs=non-steroidal anti-inflammatory drugs; PRED=prednisone; QALY=quality adjusted

life year; RA=rheumatoid arthritis; RCT=randomized controlled trial; SSZ=sulfasalazine; TNF=tumor necrosis factor alpha;

† Initial treatment listed for sequential treatment regimens

*All results in van der Velde11

were converted to 2009 Canadian dollars.


APPENDIX 7: Critical Appraisal of Economic Studies



van der Velde 201111 SR of economic studies

literature search of multiple databases to Nov 2008

robust methods for article selection, quality assessment, and data extraction

and summary of findings



Davies 200923 CUA

Model design data sources, model inputs, and disaggregated results clearly reported

Deterministic and probabilistic sensitivity analysis

Included costs of AE

Discounted costs and benefits

Productivity costs were limited to absenteeism

Kobelt 201121 CUA

Model design and data sources clearly reported



Incomplete reporting of resources, unit costs, and disaggregated results

Extrapolated treatment response from a 2 year RCT

AE not included in model

Finckh 200924 CUA

Model design and data sources, model inputs, and disaggregated results clearly reported



Productivity costs were limited to absenteeism

Did not specify which biologics were used in model

Schipper 201122 CUA

Model design and disaggregated results clearly reported



Efficacy data based on cohort studies

Incomplete reporting of some model inputs or parameters.

Van den Hout 200925 CUA

Study methods and data collected reported clearly


Costs and resources collected as part of RCT may not reflect clinical practice

Limited sensitivity analyses

Time horizon restricted to duration of clinical trial (2 years)

CEA=cost-effectiveness analysis; CUA=cost-utility analysis; RCT=randomized controlled trial; SR=systematic review


APPENDIX 8: Summary of Results of Economic Studies

Table 1. Results of Cost-Utility Studies Author, Year

Country Intervention Comparator ICER (costs/QALY)

Payer perspective Societal perspective

Chen 200611 †

US

ADA DMARD C$ 138,445 NR

ADA+MTX DMARD C$ 451,420

ETAN DMARD C$ 130,358

ETAN+MTX DMARD C$ 206,842

INF+MTX DMARD C$ 1,775,640

Spalding 200611 †

US

ADA MTX C$ 84,267 NR

ADA+MTX MTX C$ 257,139

ETAN MTX C$ 118,629

INF+MTX MTX C$ 541,163

Kobelt 201121

Sweden

ETAN+MTX MTX NR € 13,518

Schipper 201122

Netherlands TNF inhibitor +MTX MTX € 138,056 € 136,207

Davies 200923

US ADA+MTX DMARD US$ 47,157 US$ 23,377

ADA+MTX/ ETAN (2nd line)

DMARD US$ 42,727 US$ 19,663

ETAN DMARD Extendedly dominated* Extendedly dominated*

INF+MTX DMARD Extendedly dominated* Extendedly dominated*

Finckh 200924

US Biologic DMARD Dominated* Dominated*

Biologic NSAIDS+steroids (step-up to DMARD)

US$ 727,894 US$ 540,054

van den Hout 200925

Netherlands MTX+INF (initial biologic therapy)

MTX+SSZ+PRED (initial combination therapy)

€ 190,000 € 130,000** € 22,000‡

ACR=American College of Rheumatology; ADA=adalimumab; CEA=cost-effectiveness analysis; CUA=cost-utility analysis; DMARD=disease-modifying

antirheumatic drug; ETAN=etanercept; INF=infliximab; LEF=leflunomide; mo=months; MTX=methotrexate; NR=not reported; NSAIDs=non-steroidal anti-

inflammatory drugs; PRED=prednisone; QALY=quality adjusted life year; RA=rheumatoid arthritis; RCT=randomized controlled trial; SSZ=sulfasalazine;

TNF=tumor necrosis factor alpha;


†All results reported by van der Velde11

were converted to 2009 Canadian dollars.

*A dominated strategy gives less benefit and has higher costs than the comparators. An extendedly dominated treatment has a higher incremental cost-effectiveness than a comparator that yields a higher number of QALYs. ** productivity costs calculated using friction method (from the employer’s perspective, lost productivity hours for a 6 month period are included, as only a limited

time is required to find and train a replacement worker)

‡ productivity costs estimated using the human capital method (from the patient’s perspective, any hour not worked is considered a loss).

Table 2. Results of Cost-Effectiveness Studies Author, Year

Country Intervention Comparator ICER (costs/ACR response)

Payer perspective Societal perspective

Choi 200211†

US ETAN SSZ, MTX, or LEF

ACR20: C$ 70,000 to 90,000 ACR70: C$ 70,000 to 77,000

ACR20: C$ 66,000 to 78,000 ACR70: C$ 62,000 to 74,000

ACR=American College of Rheumatology; ETAN=etanercept; ICER=incremental cost-effectiveness ratio; LEF=leflunomide; MTX=methotrexate; SSZ=sulfasalazine †All results reported by van der Velde

11 were converted to 2009 Canadian dollars.


APPENDIX 9: Grading of Recommendations and Levels of Evidence

Guideline Level of evidence Grading of Recommendation

ACR26 Not available A: data were derived from multiple

RCTs

B: data were derived from a single

randomized trial or nonrandomized

studies

C: data were derived from consensus

opinion of experts, case studies, or

standards of care

EULAR27 1a: SR (with homogeneity) of RCTs

1b: Individual RCT (with narrow

Confidence Interval)

1c: All or none

2a: SR (with homogeneity) of cohort

studies

2b: Individual cohort study (including

low quality RCT; e.g., <80% follow-up)

2c: "Outcomes" Research; Ecological

studies

3a: SR (with homogeneity*) of case-

control studies

3b: Individual Case-Control Study

4: Case-series (and poor quality cohort

and case-control studies)

5: Expert opinion without explicit critical

appraisal, or based on physiology,

bench research or "first principles"

A: consistent level 1 studies

B: consistent level 2 or 3

studies or extrapolations from level 1

studies

C: level 4 studies or extrapolations

from level 2 or 3 studies

D: level 5 evidence or troublingly

inconsistent or inconclusive studies of

any level

CRA1 I: Meta-analyses, systematic reviews of

RCT, or individual RCT

II: Meta-analysis, systematic reviews of

observational studies (cohort/case

control studies), or individual

observational studies OR RCT

subgroup/post-hoc analyses

III: Nonanalytic studies, e.g., case

A: Strong recommendation:

• Direct level I evidence

• Direct level II evidence or

extrapolated level I evidence

C: Weak recommendation

• Direct level III evidence or


Guideline Level of evidence Grading of Recommendation

reports, case series

IV: Expert opinion

NR: Recommendations are not linked

to evidence

extrapolated level II evidence

D: Consensus recommendation:

• Expert opinion based on very limited

evidence

SIGN28 1++: High quality meta-analyses,

systematic reviews of RCTs, or RCTs

with a very low risk of bias

1+: Well conducted meta-analyses,

systematic reviews, or RCTs with a low

risk of bias

1 -: Meta-analyses, systematic reviews,

or RCTs with a high risk of bias

2++: High quality systematic reviews of

case control or cohort studies

High quality case control or cohort

studies with a very low risk of

confounding or bias and a high

probability that the relationship is

causal

2+: Well conducted case control or

cohort studies with a low risk of

confounding or bias and a moderate

probability that the relationship is

causal

2 -: Case control or cohort studies with

a high risk of confounding or bias and a

significant risk that the relationship is

not causal

3: Non-analytic studies, eg case

reports, case series

4: Expert opinion

A: At least one meta-analysis,

systematic review, or RCT rated as

1++, and directly applicable to the

target population; or

A body of evidence consisting

principally of studies rated as 1+,

directly applicable to the target

population, and demonstrating overall

consistency of results

B: A body of evidence including

studies rated as 2++, directly

applicable to the target population, and

demonstrating overall consistency of

results; or

Extrapolated evidence from studies

rated as 1++ or 1+

C: A body of evidence including

studies rated as 2+, directly applicable

to the target population and

demonstrating overall consistency of

results; or


rated as 2++

D: Evidence level 3 or 4; or


rated as 2+

ACR= American College of Rheumatology; CRA=Canadian Rheumatology Association; DMARD=disease modifying

antirheumatic drugs; EULAR= European League Against Rheumatism; NR=not reported; RA=rheumatoid arthritis;

SIGN=Scottish Intercollegiate Guidelines Network; SR=systematic review; US=United States


APPENDIX 10: Summary of Critical Appraisal Using AGREE Instrument4

Guideline,

Country,

Indication


ACR26

US

Use of DMARDs

and Biologic

Agents in RA

Clearly defined objectives

Comprehensive literature

search

Recommendations overlap

previously published ACR

(2008) guidelines on DMARDs

and Biologic Agents in RA and

are evidence-based

Clinical questions covered by the

guidelines are not specifically

described

Barriers to implementation NR

No tools for dissemination were

reported

Unsure of grading used to make

recommendation on infliximab

EULAR27

Europe

Management of

RA with synthetic

and biological

DMARDs

Recommendations are

evidence based

Clinical questions covered by the

guidelines are not specifically

described

Literature search and selection

criteria were NR in this article

Barriers to implementation NR

No tools for dissemination were

reported

Grading of evidence was level B

or C

CRA1

Canada

Pharmacological

management of

RA with

Traditional and

Biologic DMARDs

Recommendations are

evidence based

Appraisal using AGREE

Recommendations are directly

linked to the evidence

Implementation tools have

been developed

Selected recommendations

are based on Grade 1A or 2B

evidence

SR of original literature not

performed (modified approach

based on the ADAPTE framework

was used to systematically

identify, appraise, synthesize, and

adapt international RA guidelines)

One selected recommendation

based on Grade 4D evidence

Unclear whether guideline was

externally reviewed or tested

SIGN28

Scotland

Management of

early RA

Recommendations based

mostly on Level 1++ or 1+

evidence

Peer review by independent

experts

Patients perspectives may not

have been accounted for

Tools for implementation NR

ACR= American College of Rheumatology; CRA=Canadian Rheumatology Association; DMARD=disease modifying

antirheumatic drugs; EULAR= European League Against Rheumatism; NR=not reported; RA=rheumatoid arthritis;

SIGN=Scottish Intercollegiate Guidelines Network; SR=systematic review; US=United States


APPENDIX 11: Guidelines and Recommendations on Early Biologics for RA

Guideline, Country,

Indication

Recommendations

ACR26

US

Use of DMARDs and

Biologic Agents in

RA

“Indications for starting, resuming, adding, or switching

DMARDs or biologic agents.”

“Early RA (disease duration ≤6 months). In patients with

early RA, the panel recommends:

…use of an anti-TNF biologic with or without

methotrexate in patients who have high disease

activity with poor prognostic features (level of

evidence A and B). Infliximab is the only exception

and the recommendation is to use it in combination

with methotrexate, but not as monotherapy.” (Unsure

of grading) pg. 631

EULAR27, Europe

Management of RA

with synthetic and

biological DMARDs

“DMARD naïve patients with poor prognostic markers might be

considered for combination therapy of MTX plus a biological agent.”

pg. 966

o “…the committee strongly felt that there are some patients

for whom first-line biological treatment combined with MTX

has to be considered. Such patients will usually have

unfavorable prognostic signs, including very active disease

or early structural damage. Currently, only TNF inhibitors

are licensed for such patients,…(Level of evidence 2b;

grading C)” pg. 969

CRA1, Canada

Pharmacological

management of RA

with Traditional and

Biologic DMARDs

“The presence of the following poor prognostic features should be

assessed at baseline and considered when making treatment

decisions: 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) or C-reactive

protein (CRP). (Level II; Strength B).” pg. 1565, 1566

“When treating with combination therapy, methotrexate (MTX)

should be used as the anchor drug unless contraindicated.

Combinations not including MTX can be considered on a case-by-

case basis. (Level I; Strength A).” pg. 1571

“Anti-TNF therapy is recommended for the treatment of patients

with RA after an inadequate response to DMARD. In exceptional


Guideline, Country,

Indication

Recommendations

circumstances involving patients with DMARD contraindications or

high disease activity and poor prognostic factors (particularly early

disease), anti-TNF therapy may be an option after failure of

DMARD monotherapy or in DMARD naïve patients. (Level I;

Strength A).” pg. 1573

SIGN28, Scotland

Management of

early RA

“Use of the TNF-α inhibitors for the treatment of severe, active and

progressive rheumatoid arthritis in adults not previously treated with

methotrexate or other DMARDs is not recommended.” (based on

evidence rated 1++ - See Appendix 9 ) pg. 3

ACR= American College of Rheumatology; CHF= chronic heart failure; CRA=Canadian Rheumatology Association;

DMARD=disease modifying antirheumatic drugs; EULAR= European League Against Rheumatism; IGRA=

interferon-ɣ–release assays; LTBI=latent TB infection; MTX=methotrexate; RA=rheumatoid arthritis; SIGN=Scottish

Intercollegiate Guidelines Network; TNF= tumor necrosis factor; TB=tuberculosis; US=United States

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