The Efficacy and Toxicity of Methotrexate Monotherapy versus

THE EFFICACY AND TOXICITY OF METHOTREXATE

MONOTHERAPY VERSUS METHOTREXATE COMBINATION

THERAPY WITH NON-BIOLOGIC DISEASE-MODIFYING ANTI-

RHEUMATIC DRUGS IN RHEUMATOID ARTHRITIS

A SYSTEMATIC REVIEW AND META-ANALYSIS

by

Wanruchada Katchamart

A thesis submitted in conformity with the requirements

for the degree of Masters of Science in Clinical Epidemiology

Graduate Department of Institute of Medical Science

University of Toronto

© Copyright by Wanruchada Katchamart 2009

ii

The Efficacy and Toxicity of Methotrexate Monotherapy versus

Methotrexate Combination Therapy with Non-biologic Disease-modifying

Anti-rheumatic Drugs in Rheumatoid Arthritis

A Systematic Review and Meta-analysis

Wanruchada Katchamart

Master of Science in Clinical epidemiology

Institute of Medical Science, University of Toronto

2009

ABSTRACT Objective to systematically review randomized trials that compared methotrexate (MTX)

monotherapy to MTX in combination with other non-biologic disease-modifying anti-

rheumatic Drugs (DMARD) and to compare the performances of PubMed versus MEDLINE

(Ovid®) and EMBASE.

Methods We performed a systematic review of randomized trials comparing MTX alone

and MTX in combination with other non-biologic DMARDs. Heterogeneity was

investigated and explored. The performances of Pubmed and MEDLINE were evaluated.

The EMBASE unique trials were identified and investigated.

Results A total of 19 trials were included and grouped by the type of patients randomized.

Trials in DMARD naive patients showed no significant advantage of the MTX combination

versus monotherapy. The recall was 85% vs. 90% for Ovid and PubMed, respectively, while

the precision and number-needed-to read of Ovid and Pubmed were comparable. Only 23%

of trials were EMBASE unique trials

Conclusions In DMARD naive patients, the balance of efficacy/toxicity favours MTX

monotherapy.

iii

ACKNOWLEDGMENTS

I would like to express my deepest and sincerest gratitude to my supervisor, Dr. Claire

Bombardier for successfully convincing and supporting me to study Clinical Epidemiology.

Luckily, I believed her! I really appreciate her important support throughout this work. Her

broad knowledge, logical way of thinking, and sense of humour have been of great value to

me. Her understanding, encouragement, and personal guidance helped me to complete my

degree. I would like to express my most sincere appreciation to my thesis committee

members, Dr. George Tomlinson and Dr. Brian Feldman for their detailed and constructive

suggestions and untiring help. I would also like to thank the thesis defense examiners, Dr.

Paula Rochon and Dr. Robert Inman for their thoughtful advice on study results and

interpretation.

I would like to express my deep gratitude to Abbott International and Abbott Canada for

allowing me to participate in the 3-e Initiative project. This project ignited and introduced

me to the field of “Evidence-based guideline.” It has also broadened the horizons of my

future career.

I would like to warmly and deeply thank Dr. Vivian Bykerk for her advice, help, and support

throughout my training in Canada and Julie Amato for reviewing this thesis and for her

friendship.

My training in Canada would not have been possible without the support of my colleagues

in Rheumatology Division, Department of Medicine, Siriraj hospital at Mahidol University.

I would also like to especially thank my friends and colleagues, Dr. Praveena

Chewchanwisawakit for her help, support, and friendship and Dr. Vararak Srinonprasert for

her knowledgeable advices and support.

Finally, I would like to deeply thank my family for their understanding and unconditional

love, constant and untiring support, and ongoing encouragement.

iv

TABLE OF CONTENTS

Chapter 1 Introduction and Background……………………………………………….....1

Rheumatoid arthritis and Methotrexate..............................................................................1

Systematic review and meta-analysis…………………………………………………….2

Role and importance of systematic review in clinical practice…………………………..2

Problems and pitfalls of systematic review………………………………………………4

3-e Initiative (Evidence, Expertise, Exchange) in Rheumatology………………………..4

Chapter 2 The Efficacy and Toxicity of Methotrexate Monotherapy versus

Methotrexate Combination Therapy with Non-biologic Disease-modifying Anti-

rheumatic Drugs in Rheumatoid Arthritis: A Systematic Review and Meta-analysis…9

Introduction……………………………………………………………………………….9

Materials and methods…………………………………………………………………..15

Results…………………………………………………………………………………...18

Discussion and conclusions………………………………………………….………….24

Chapter 3 Investigating Heterogeneity in Systematic Review and Meta-analysis…….29

Introduction……………………………………………………………………………...29

Methods…………………………………………………………………………………29

Results…………………………………………………………………………………...33

Discussion and conclusions …………………………………………………………….36

Chapter 4 Search Strategy for Systematic Reviews: Comparisons between Ovid

(MEDLINE) versus Pubmed and EMBASE versus Pubmed…………………………...41

Introduction……………………………………………………………………………...41

Methods…………………………………………………………………………………46

Results…………………………………………………………………………………...52

Discussion and conclusions …………………………………………………………….53

Chapter 5 Discussion............................................................................................................58

Tables.....................................................................................................................................62

Figures…………………………………………………………………………………….100

References…………………………………………………………………………………126

Appendices………………………………………………………………………………...145

v

List of Tables

Table 1 Excluded studies and reason for exclusion................................................................62

Table 2A Characteristics of included studies.........................................................................63

Table 2B Detailed characteristics of the included studies………………………………….64

Table 3 Quality assessment of included studies.....................................................................75

Table 4 Summary the results of efficacy (dichotomous data) comparing between MTX

Combination versus Monotherapy..........................................................................................76

Table 5 Summary the results of efficacy (continuous data) comparing between MTX


Table 6 Summary the results of toxicity (dichotomous data) comparing between MTX


Table 7 Real and artifactual causes of between-study variation in effect..............................79

Table 8 Potential sources of heterogeneity............................................................................80

Table 9 Tests of heterogeneity using forest plots and eyeball test, Cochran’s Q test, and I2

test for withdrawal due to lack of efficacy and toxicity, withdrawal due to lack of efficacy,

and withdrawal due to toxicity...............................................................................................81

Table 10 Outcome measures for efficacy used in included studies.......................................82

Table 11 Toxicity reported in included studies......................................................................83

Table 12 Subgroup analysis: - Study design and Population (Pervious DMARD use).........84

Table 13 Subgroup analysis: - Trial duration.........................................................................85

Table 14 Subgroup analysis: - Study quality (high versus low)............................................86

Table 15 Subgroup analysis and Meta-regression analysis using “Withdrawal due to lack of

efficacy and toxicity”..............................................................................................................87

Table 16 Subgroup analysis and Meta-regression analysis using “Withdrawal due to lack of

efficacy”..................................................................................................................................88

Table 17 Subgroup analysis and Meta-regression analysis using “Withdrawal due to

toxicity”..................................................................................................................................89

Table 18 Summary the results of relative risk and 95% confidence interval comparing

between fixed and random effects models..............................................................................90

Table 19 Search strategies comparing between Ovid-MEDLINE and PubMed...................92

vi

Table 20 Performances of Ovid-MEDLINE and Pubmed search for randomized controlled

trials comparing the efficacy and safety of MTX combination therapy versus MTX

monotherapy in RA patients...................................................................................................94

Table 21 Results of citations retrieved from PubMed compared to EMBASE.....................95

Table 22 Reasons why studies were missed by searching in PubMed..................................96

vii

List of Figures

Figure 1 Flow diagram: - Results of the literature search and disposition of the potentially

relevant studies.....................................................................................................................100

Figure 2 Combined withdrawal due to lack of efficacy and toxicity: - Comparisons between

MTX combinations versus MTX monotherapy....................................................................101

Figure 3 Withdrawal due to lack of efficacy in DMARD naïve, MTX inadequate responder,

and non-MTX inadequate responder: - Comparisons between MTX combinations versus

MTX monotherapy...............................................................................................................102

Figure 4 ACR responses in DMARD naïve: - Comparisons between MTX combinations

versus MTX monotherapy....................................................................................................103

Figure 5 EULAR responses in DMARD naïve: - Comparisons between MTX combinations


Figure 6 Tender joint counts in DMARD naïve: - A comparison between MTX

combinations versus MTX monotherapy..............................................................................105

Figure 7 Pain in DMARD naïve: - Comparisons between MTX combinations versus MTX

monotherapy.........................................................................................................................105

Figure 8 Patient global assessment of disease activity in DMARD naïve: - A comparison

between MTX combinations versus MTX monotherapy.....................................................106

Figure 9 ESR in DMARD naïve: - Comparisons between MTX combinations versus MTX

monotherapy.........................................................................................................................106

Figure 10 CRP in DMARD naïve: - A comparison between MTX combinations versus

MTX monotherapy...............................................................................................................107

Figure 11 HAQ in DMARD naïve: - Comparisons between MTX combinations versus

MTX monotherapy...............................................................................................................107

Figure 12 Radiographic outcomes in DMARD naïve: - A comparison between MTX


Figure 13 ACR responses in MTX inadequate responders: - Comparisons between MTX


Figure 14 Tender joint counts in MTX inadequate responders: - Comparisons between


viii

Figure 15 Swollen joint counts in MTX inadequate responders: - Comparisons between


Figure 16 Pain in MTX inadequate responders: - Comparisons between MTX combinations


Figure 17 Patient global assessment of disease activity in MTX inadequate responders: -

Comparisons between MTX combinations versus MTX monotherapy...............................110

Figure 18 Physician global assessment of disease activity in MTX inadequate responders: -

Comparisons between MTX combinations versus MTX monotherapy...............................111

Figure 19 CRP in MTX inadequate responders: - A comparison between MTX


Figure 20 HAQ in MTX inadequate responders: - Comparisons between MTX


Figure 21 ESR in MTX inadequate responders: - Comparisons between MTX combinations


Figure 22 Radiographic outcomes in MTX inadequate responders: - A comparison between


Figure 23 ACR responses in non-MTX inadequate responders: - Comparisons between


Figure 24 EULAR responses in non-MTX inadequate responders: - Comparisons between


Figure 25 Tender joint counts in non-MTX inadequate responders: - A comparison between


Figure 26 Swollen joint counts in non-MTX inadequate responders: - Comparisons between


Figure 27 Patient global assessment of disease activity in non-MTX inadequate responders:

- A Comparison between MTX combinations versus MTX monotherapy...........................115

Figure 28 Physician global assessment of disease activity in non-MTX inadequate

responders: - A Comparison between MTX combinations versus MTX monotherapy.......116

Figure 29 Pain in non-MTX inadequate responders: -Comparisons between MTX


ix

Figure 30 ESR in non-MTX inadequate responders: -Comparisons between MTX


Figure 31 CRP in non-MTX inadequate responders: -A comparison between MTX


Figure 32 HAQ in non-MTX inadequate responders: -A comparison between MTX


Figure 33 Total adverse reactions: -Comparisons between MTX combinations versus MTX

monotherapy.........................................................................................................................119

Figure 34 Gastrointestinal side effects: -Comparisons between MTX combinations versus

MTX monotherapy...............................................................................................................120

Figure 35 Abnormal liver functions: -Comparisons between MTX combinations versus

MTX monotherapy...............................................................................................................121

Figure 36 Mucositis: -Comparisons between MTX combinations versus MTX

monotherapy.........................................................................................................................121

Figure 37 Hematological side effects: -Comparisons between MTX combinations versus

MTX monotherapy...............................................................................................................122

Figure 38 Infection: -Comparisons between MTX combinations versus MTX

monotherapy.........................................................................................................................122

Figure 39 Withdrawal due to adverse reaction: -Comparisons between MTX combinations


Figure 40 PubMed usage data from June, 2007 to March, 2009.........................................124

Figure 41 Diagram illustrating the use of Boolean logic operators: OR, AND, and NOT for

searching in the electronic bibliographic databases..............................................................125

x

List of Appendices

Appendix 1 Search strategy.................................................................................................145

Appendix 2 Data abstraction form.......................................................................................149

Appendix 3 Study quality assessment checklist (Cochrane Back review group)................155

1

Chapter 1 Introduction and Background

Rheumatoid arthritis and Methotrexate

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis

affecting approximately 0.5 to 1 % of the global population 1. It is characterized by the

inflammation of the synovial tissue, which if untreated, leads to permanent structural

damage and eventual long term disability and impaired quality of life 2. Early diagnosis and

aggressive treatment, therefore, is the fundamental strategy to suppress inflammation before

patients develop irreversible damage 3-6. Disease modifying anti-rheumatic drugs (DMARD)

are the mainstay of treatment in RA.

Methotrexate (MTX) is the most commonly used DMARD in RA with less toxicity

and better tolerability than others 7. It is pharmacologically classified as an anti-metabolite

due to its antagonistic effect on folic acid metabolism. Although the mechanism by which

low dose MTX modulates inflammation in RA is still unclear, the evidence for its efficacy

has been well documented in several randomized controlled trials (RCT) and meta-analyses 8-14. Unfortunately, MTX alone may not fully control disease activity. MTX rarely induces

remission 12, 15, 16 and does not halt erosive disease 17-23.

Increasingly, in the last two decades, MTX has been used in combination with other

non-biologic DMARDs based on accumulating evidence that in early RA, initial

combination therapy is associated with earlier clinical improvement, less progression of

joint damage 24-26, and improved productivity 27. MTX and non-biological DMARDS in

combinations have diverse efficacy and toxicity indices. Although many MTX and

traditional DMARD combination regimens have been studied, it is still not clear whether

MTX alone or MTX combinations should be used in RA patients when balancing the

efficacy and toxicity.

Due to its relevance to clinical practice, this clinical question was voted by

international rheumatologists from 17 countries in Europe, North and South America as one

for which a recommendation should be developed 28. To provide the most up-to-date

evidence to experts for formulating recommendations about MTX therapy, we performed a

systematic review and meta-analysis comparing the efficacy and toxicity of MTX

combination therapy versus monotherapy in RA patients.

2

Systematic review and meta-analysis

The concept of reviews in medicine is not new. Preparation of reviews has

traditionally depended on implicit, idiosyncratic methods of data collection, and

interpretation. Narrative reviews, therefore, have a number of disadvantages that may distort

their results and conclusions. They are usually broad in scope and usually provide a general

perspective on a topic. Reviewers often use informal, subjective methods to identify,

include, and interpret studies. They tend to select the studies that reinforce their

preconceived ideas or promote their own views on a topic 29. They rarely assess and

incorporate the quality of studies into their results. This method is potentially unsound and

subject to bias. The overall conclusions may be inaccurate or distorted.

Systematic review is a form of research that provides a summary of medical reports

on a specific clinical question, using explicit methods to search, critically appraise, and

synthesize the world literature systematically 30. Systematic reviews are recognized as the

highest level of research evidence 31, and their methodology is well documented 32.

Meta-analysis is a specific methodological and statistical technique for combining

quantitative data 33, which generally aims to produce a single estimate of a treatment effect 34. It is one of the tools used in preparing systematic reviews. Meta-analysis, if appropriate,

will enhance the precision of estimates of treatment effects, leading to a reduced probability

of false negative results. It is always desirable and appropriate to systematically review a

body of data, but it may be inappropriate or even misleading, to statistically pool results

from separate studies in certain situations 35.

Role and importance of systematic review in clinical practice

Although primary research is potentially useful to clinicians, researchers, and

guideline developers, many situations hinder its use. For many common disease conditions

or commonly used interventions, the volume of relevant articles is high. Healthcare

providers, researchers, and policy makers are inundated with unmanageable amounts of

information. Systematic review is a tool that can be used to refine overwhelming amounts of

information. Through critical exploration, evaluation, and synthesis, the systematic review

can separate insignificant, unsound, or redundant studies from salient and critical studies

3

that are worthy of reflection 36. Furthermore, evidence may be inconsistent or contradictory.

Systematic reviews can determine consistency among studies of the same intervention or

even among studies of different interventions (e.g., varying doses or intensities of classes of

therapeutic agents) 37, and also explain inconsistencies and conflict in the data 38.

Frequently, the generalizability of evidence can be established in systematic reviews. The

diversity of multiple included studies provides an interpretive context, not available in any

one study 39. This is because studies addressing similar questions often use different

eligibility criteria for participants, different definitions of disease, different methods of

measuring or defining exposure, different variations of a treatment, and different study

designs 40. Generalizability addressed systematically is important for developing clinical

practice guidelines (CPG) that aim to provide guidance for broad spectrums of clinical

conditions in daily practice. Sometimes many important studies assessing outcomes with a

low event rate or small effects of intervention are underpowered to demonstrate a clinically

significant benefit. In this situation, the systematic review – and especially meta-analysis –

is a useful tool to increase power and precision yielding a definitive combined effect size 38.

In other situations, data may be sparse or not available. In this case, performing a

comprehensive search, as part of a systematic review, will identify and suggest future

research relevant to clinical practice.

Although performing a systematic review is arduous and time-consuming, it is an

efficient scientific technique yielding robust evidence and is usually faster and less

expensive than embarking on a new study 38. This is also relevant to CPG development, as a

CPG should be based on the most recent evidence for current daily practice. If guideline

developers have to conduct a new study, guideline development may be delayed past the

point of being useful. Systematic reviews either previously published or created de novo by

guideline developers are, therefore, the most important evidence resource to incorporate into

guideline development. However, systematic reviews can lay the foundation for evidence-

based guideline only when they are well-developed using rigorous and explicit methodology

to reduce bias. Otherwise, they can distort the integrity of guidelines.

4

Problems and pitfalls of systematic review

Although systematic review is often recognized as the highest level of research

evidence 31, it is a form of retrospective observational study, which is potentially subject to

many biases like other retrospective studies 32. Methodological flaws can create bias that

affects the quality of reviews. Jadad, et al 41 evaluated 36 Cochrane reviews and 39

systematic reviews published in peer-review journals. They found a number of deficiencies

in the process of conducting the reviews – including lack or inadequate description of

inclusion and exclusion criteria, lack of a clearly identified primary outcome, lack of

assessment of trial quality, language restrictions, inappropriate pooling of data, and lack of

updating reviews. Even with well-conducted methods, a review based on poor quality or

poorly reported trials is unlikely to provide useful data for informing clinical decisions 42.

Making recommendations usually needs information pertaining to certain outcomes

such as quality of life, patient preferences, or rare adverse events. These outcomes are

sometimes inadequately represented in reviews 43 because most primary studies focus on

clinically objective outcomes, e.g., mortality rate, infection rate, or duration of

hospitalization, and are underpowered for rare or usual adverse events. Systematic reviews

usually narrowly focus on specific clinical questions; these sometimes limit their

generalizability for daily practice. Finally, the number of systematic reviews and meta-

analyses published has increased in recent years, leading to a rise in the number of reviews

addressing the same or very similar clinical questions, with a concomitant increase in

conflicts among reviews. Such discordance can confuse rather than clarify and causes

difficulties for decision-makers – including clinicians, patients, and policy-makers who rely

on these reviews 44.

3-e Initiative (Evidence, Expertise, Exchange) in Rheumatology

The 3-e Initiative (Evidence, Expertise, Exchange) in rheumatology is a

multinational effort, aimed at promoting evidence-based medicine by formulating evidence-

based recommendations addressing clinical problems in daily practice. It involves a broad

international panel of practising rheumatologists from Europe, North and South America.

Starting in 2006, two phases of the 3-e Initiative have been successfully accomplished. The

5

first 3-e Initiative, 2006-2007, addressed issues relevant to ankylosing spondylitis in the

areas of diagnosis, monitoring, and treatment 45. The second 3-e Initiative, 2007-2008,

developed practical recommendations for the use of MTX in rheumatic disorders 28. These

recommendations were developed with rigorous and explicit methodology by integrating

systematically generated evidence and expert opinion from a broad panel of international

rheumatologists.

In the 3-e Initiative of 2007-2008, a total of 751 rheumatologists from 17 countries

participated in three rounds of discussion and voted on the recommendations. Each country

was represented by a scientific committee, consisting of one principal investigator and 5-16

members. The bibliographic team consisted of 6 international fellows from 4 countries

(Canada, France, the Netherlands, and Spain), 3 mentors experienced in systematic review,

and a scientific organizer. During the first round of international meetings, 87 participants

formulated and selected the 10 clinical questions using a systematic approach. The first step

was a small group discussion within their countries to propose a maximum of 10 clinical

questions per country pertaining to the use of MTX in rheumatic disorders. Then all the

questions were pooled, rephrased, and grouped into similar topics by a group composed of

the bibliographic team and a principal investigator from each country. Subsequently, all

participants came together to discuss and vote for the final, most important, 10 clinical

questions via the Delphi method. The 10 questions comprised:

1) What is the best dosing strategy and optimal route of administration for MTX in

patients with RA to optimize rapid early clinical and radiographic response and

minimize toxicity? 46

2) What are indications for pausing/stopping/restarting MTX in case of elevated liver

tests and when is liver biopsy indicated? 47

3) What is the long term safety of MTX with regards to cardiovascular, malignancies,

liver and infections? 48

4) What is the difference between MTX combination therapy versus monotherapy in

terms of efficacy and toxicity in RA? 49

5) Is folic/folinic acid supplementation to MTX useful in reducing toxicity for adult

patients with RA?

6

6) What is the optimal (clinical, laboratory, imaging) safety monitoring of patients with

MTX? Which interval of time?

7) What pre-administration work-up is necessary (co-morbidities / social behavior,

physical, laboratory and radiographic data) to identify MTX exclusions and/or get a

baseline?

8) What is the optimum management of usual dose MTX in RA patients in the

perioperative period to minimize perioperative morbidity and while maintaining RA

control? 50

9) How should MTX use be managed when planning pregnancy (male and female

patients), during pregnancy and after pregnancy? 51

10) Is MTX effective as a glucocorticoid-sparing (adjuvant) treatment compared with

placebo or other DMARDS in chronic inflammatory rheumatic disorders?

The bibliographic team conducted a systematic literature review with the same

methodology following the updated guidelines of the Cochrane Collaboration under

supervision of their mentors. In the first step, the clinical questions were rephrased into

epidemiological questions and constructed using the PICO model (population-intervention-

control-outcome) for developing the comprehensive search strategy 30. The comprehensive

search was formulated and conducted by collaborating with experienced information

specialists. The relevant articles were included according to the pre-specified inclusion and

exclusion criteria. The data were abstracted using standardized forms. The quality of

evidence was assessed using the Oxford Level of Evidence 52. The evidence was

summarized and meta-analysis was performed if appropriate.

In the second round, the results of 10 systematic reviews were presented to national

scientific committees consisting of 30-60 rheumatologists, who work in academic centers or

communities in each country. Subsequently, a national meeting was held in each country

(total of 751 participants in 17 countries) to discuss the generated evidence and propose a set

of recommendations. In a third joint meeting, the scientific committees (n = 94 participants)

merged all propositions into 10 final recommendations via discussion and Delphi vote. The

grade of recommendation according to the Oxford Levels of Evidence was assessed, and the

level of agreement was measured on a 10-point visual analog scale (1 = no agreement, 10 =

7

full agreement). Finally, the potential impact among the participants was assessed using 3

statements: “this recommendation will change my practice”; “this recommendation will not

change my practice as it is already my practice”; and “this recommendation will not change

my practice as I don’t want to change my practice for this aspect”. For their dissemination,

the 10 recommendations were presented in the plenary session of the annual scientific

meeting of American College of Rheumatology (ACR) 2008 and in the poster session of the

annual scientific meeting of European League Against Rheumatism (EULAR) 2008. There

was encouragement that the recommendations and individual systematic reviews be

published in an international peer reviewed journal.

This thesis is part of evidence developed for the 3-e Initiative, 2007-2008. I worked

in this initiative as a bibliographic fellow under Professor Dr. C Bombardier’s supervision.

We conducted a systematic review to address the clinical question number 4: What is the

difference between MTX combination therapy versus monotherapy in terms of efficacy and

toxicity in RA patients? The clinical questions and concerns were uncovered during the

conduct of this systematic review. When performing this review, much variation among the

included studies was revealed. This raised questions concerning: 1) the potential sources of

heterogeneity in this review; 2) the extent and direction of the heterogeneity; and lastly, 3)

how to manage or incorporate the heterogeneity in the review to reduce bias that may

mislead audiences.

Although the process of review was standardized across the 3-e Initiative to ensure

that similar methodology was employed in all the 3-e reviews, we found a discrepancy in the

database providers used for the literature search among 6 fellows from 4 different countries.

The bibliographic team agreed to search in 3 main electronic databases: MEDLINE,

EMBASE, and the Cochrane Controlled Clinical Trial Registry. However, the database

provider differed between users of MEDLINE. All except the Canadian fellows accessed

MEDLINE via PubMed, while the 2 Canadian fellows had access to Ovid, a fee-based web

database provider. This issue was not discussed before performing the search, and this led to

the following two questions: “Is there a difference between the 2 MEDLINE database

providers, Ovid-MEDLINE and PubMed when performing a comprehensive search for

8

systematic reviews?” and “What is the impact of using the different database providers on

systematic reviews?” To answer these questions, we used the search strategy in the review

of “The efficacy and safety of MTX combination therapy versus monotherapy in rheumatoid

arthritis patients”, which was first searched through Ovid-MEDLINE. We ran the search

again using both PubMed and Ovid-MEDLINE.

Another methodological question that we planned to answer by the 10 3-e reviews

was what additional benefit searching EMBASE provided over MEDLINE when searching

for evidence in Rheumatology. All fellows were asked to record the unique citations

retrieved by EMBASE but not MEDLINE in each review. However, we had data from only

8 questions; the search for 2 clinical questions (question 6 and 7) found no evidence to

answer these 2 questions.

This thesis is organized as follows: chapter 1 lays out the background relating to

systematic reviews, meta-analysis, and the 3-e Initiative project; chapter 2 presents the

detailed systematic review and meta-analysis of “The efficacy and safety of MTX

combination therapy versus monotherapy in rheumatoid arthritis patients”; chapter 3

demonstrates the investigation of and approach to heterogeneity in this review; chapter 4

explores the consequences of using PubMed versus Ovid-MEDLINE and EMBASE in

systematic reviews in Rheumatology; and the discussion and conclusions are in chapter 5.

9

Chapter 2 The Efficacy and Toxicity of Methotrexate Monotherapy versus

Methotrexate Combination Therapy with Non-biologic Disease-modifying

Anti-rheumatic Drugs in Rheumatoid Arthritis: A Systematic Review and

Meta-analysis INTRODUCTION

RA is a chronic systemic inflammatory disease of unknown etiology. It is the most

common form of inflammatory arthritis and affects approximately 0.5 to 1 % of the global

population 1.The disease affects individuals at any age; however, it presents most commonly

in women aged 40-50 years. It is characterized by the inflammation of the synovial tissue,

which if untreated, leads to permanent structural damage and eventual long term disability

and impaired quality of life. Systemic inflammation usually occurs and leads to increased

morbidity and mortality associated with cardiovascular disease 53-57 and malignancy 58-63.

The typical manifestation is symmetrical polyarthritis involving the small joints of the hands

and feet, the large joints of the extremities, and the upper cervical spine 64. A number of

extra-articular manifestations can occur and vary with the duration and severity of the

disease 64. Approximately, 36% to 75% of patients with early RA have joint erosions and

develop the initial erosions within the first 2 years of symptom onset 2, 65. Joint damage

progresses at a consistent rate over the course of the disease and accounts for approximately

25 % of the disability. The association between radiographic damage and disability is

strongest with disease duration of more than 8 years; however, prevention of structural

damage early in the disease is likely to preserve patient function 66.

Early diagnosis and aggressive treatment, therefore, is the fundamental strategy to

suppress inflammation before patients develop irreversible damage 3-6, 67. Disease modifying

anti-rheumatic drugs (DMARDs) are the mainstay of treatment in RA. This heterogeneous

group of drugs has delayed onset of action, ranging from 3 weeks to 3 months and has no

immediate analgesic effect 68. It suppresses the inflammatory process and may retard joint

destruction.

10

Methotrexate (MTX) (4-amino-N-10-methylpteroyl glutamic acid) is among the

most effective of the DMARDs in the treatment of RA. It is an analogue of folic acid and of

aminopterin (4-amino-pteroyl glutamic acid), a folic acid antagonist 69 and was first used in

1948 to treat acute leukemia. However, over the last 20 years, it has been used in the

treatment of RA as well as many rheumatic diseases 7. Many pharmacological mechanisms

of MTX action have been suggested including:

1) Inhibition of de novo purine synthesis 70

2) Promotion of adenosine release leading to inhibition of production of

proinflammatory cytokines [TNF-α, interleukin-6 (IL-6), and IL-8] and leukocyte

accumulation 71

3) Induction of activated T cell apoptosis and clonal deletion 72

4) Inhibition of IL-1 production 73, 74

5) Reduction of IL-6, IL-8, soluble TNF receptor, and soluble IL-2 receptor level 75.

However, the mechanism by which low dose MTX modulates inflammation in RA is

still unclear. It has been shown that in RA patients low dose MTX inhibits neutrophil

chemotaxis 76, 77 by inhibiting leukotriene B4 78 and reduces in vitro prostaglandin E2 release 79 and superoxide production 80.

MTX has become the most commonly used DMARD in RA with less toxicity and

better tolerability than other DMARDs 7. In the mid 1980s, four randomized, doubled

blinded, placebo-controlled trials in RA showed a superior efficacy of MTX over placebo in

short term treatment 8-11. In a randomized, 24-week, double-blind, crossover trial comparing

oral MTX (2.5 to 5 mg every 12 hours for three doses weekly) with placebo in 28 refractory

RA patients 9, the MTX group had statistically significant reductions in the number of tender

or painful joints (26 ± 4 vs. 4 ± 4, p < 0.01), the number of swollen joints (14 ± 2 vs. 5 ± 2,

p < 0.05), disease activity according to physician and patient assessments (1.6 ± 0.2 vs. 0.1 ±

0.2, p < 0.01 and 1.5 ± 0.2 vs. 0 ± 0.2, p < 0.01, respectively), and 15-meter walking time (5

± 1 vs. 3 ± 1, P < 0.03) at the 12-week crossover visit. These variables, as well as

erythrocyte sedimentation rate, showed significant improvement at 24 weeks in the

population crossed over to MTX (no detailed data were provided, P < 0.01). Anderson, et al 11 studied 12 refractory RA patients treated with weekly pulse MTX in a double-blind,

11

placebo-controlled, crossover trial. After 13 weeks of therapy, marked clinical improvement

occurred in the patients after MTX therapy compared to after placebo therapy, judged by the

number of swollen joints (6.9 ± 1.5 vs.19.4 ± 3.5 vs., p < 0.002) and the number of tender

joints (12.6 ± 4.1 vs. 26.2 ± 4.9 , p < 0.001), the duration of morning stiffness (minute) (78 ±

34 vs. 242 ± 38, p = 0.002), and the subjective assessments of clinical condition on visual-

analogue scale (VAS) (5.8 ± 0.8 vs. 1.6 ± 0.6, p < 0.001). This improvement was associated

with a decrease in sedimentation rate (33 ± 7.5 vs. 61.1 ± 7.4, p < 0.001) and decreases in

the serum levels of immunoglobulin (Ig) G (1069 ± 83 vs.1311 ± 110, p < 0.001), IgM (170

± 30 vs. 253 ± 40, p < 0.002), and IgA (282 ± 55 vs. 361 ± 71, p < 0.005). Thompson, et al 10 compared 2 doses of injected MTX (10 and 25 mg/wk versus placebo) in 48 refractory

RA patients. At 6 weeks, the effect of the two MTX doses did not differ significantly, but

patients on MTX had fared significantly better than those given placebo [swollen joint score:

18 ± 15 vs. 35 ± 18 (p < 0.001), tender joint score : 25 ± 32 vs. 55 ± 29 (p < 0.002), pain

score on 0-100 mm VAS : 33 ± 24 vs. 65 ± 20 (p < 0.001), grip strength (mm/kg) : 126 ± 8

vs. 97 ± 7 (p < 0.005), and erythrocyte sedimentation rate (ESR) (mm/hr) : 29 ± 14 vs. 43 ±

13 (p < 0.001)]. At 12 weeks, all indices showed statistically significant improvement in two

MTX groups (no data were shown in the published article). Adverse reactions necessitated

change from 25 mg to 10 mg in some patients, but no major adverse events of MTX were

noted. William, et al 8 conducted a prospective, controlled, double-blind, multicenter trial

comparing placebo and 7.5 mg/wk of MTX in 189 RA patients. After 18 weeks, 110 patients

able to tolerate MTX therapy were significantly improved, compared with patients receiving

placebo therapy for all clinical variables measured, including the number of joint

pain/tenderness [10 (11%) vs. 30 (32%), p = 0.001], the number of the swollen joint count [4

(4%) vs. 20 (21%), p = 0.002], and patient and physician assessment of disease activity on

10 cm. VAS. [7 (7%) vs. 10 (11%), p = 0.627 and 3 (3%) vs. 9 (10%), p = 0.163]. However,

nearly one-third of the patients receiving MTX were withdrawn at the end of the trial due to

adverse drug reactions, of which elevated levels of liver enzymes was the most common.

They concluded that MTX appears to be effective in the treatment of active rheumatoid

arthritis but requires close monitoring for toxicity especially for liver toxicity. A meta-

analysis of these trials by Tugwell, et al 12 showed that MTX-treated patients received a 37%

greater improvement in swollen joint and tender joint scores, a 39% greater improvement in

12

joint pain, and a 46% greater improvement in morning stiffness. MTX was generally well-

tolerated with 0 to 32 % withdrawal due to minor toxicities, e.g., stomatitis, nausea. In 1990,

Felson, et al 13 performed a meta-analysis of placebo-controlled and comparative clinical

trials to examine the relative efficacy and toxicity of MTX, injectable gold, D penicillamine

(DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs (Hydroxychloroquine-

HCQ), the second-line drugs most commonly used to treat RA. For efficacy based on the

number of the tender joint count, grip strength, and ESR, pooled data of 66 trials showed

that MTX was superior to placebo [mean improvement ± standard error (SE): 12.6 ± 1.9 vs.

2.9 ± 0.8 for the number of the tender joint count, 42.3 ± 8.2 vs. 9.7 ± 3.4 for grip strength

(mm/kg), and 12.5 ± 4.1 vs. 0.7 ± 1.6 for ESR (mm/hr)] , oral gold [mean improvement ±

SE : 12.6 ± 1.9 vs. 8 ± 0.7 for the number of the tender joint count, 42.3 ± 8.2 vs. 19.4 ± 3.6

for grip strength (mm/kg), and 12.5 ± 4.1 vs. 9.2 ± 1.5 for ESR (mm/hr)], HCQ [mean

improvement ± SE : 12.6 ± 1.9 vs. 6.9 ± 1.7 for the number of the tender joint count, 42.3 ±

8.2 vs. 39 ± 6.9 for grip strength (mm/kg), and 12.5 ± 4.1 vs. 12.7 ± 2.6 for ESR (mm/hr)],

and comparable to SSZ [mean improvement ± SE : 12.6 ± 1.9 vs. 11.3 ± 1.5 for the number

of the tender joint count, 42.3 ± 8.2 vs. 28.8 ± 7.8 for grip strength (mm/kg), and 12.5 ± 4.1

vs. 22.7 ± 2.9 for ESR (mm/hr)], DP [mean improvement ± SE : 12.6 ± 1.9 vs. 9.4 ± 1 for

the number of the tender joint count, 42.3 ± 8.2 vs. 43.4 ± 4.5 for grip strength (mm/kg), and

12.5 ± 4.1 vs. 21.3 ± 2 for ESR (mm/hr)] and intra-muscular gold [mean improvement ± SE

: 12.6 ± 1.9 vs. 9.1 ± 0.9 for the number of the tender joint count, 42.3 ± 8.2 vs. 36.4 ± 4.6

for grip strength (mm/kg), and 12.5 ± 4.1 vs. 17.9 ± 1.8 for ESR (mm/hr)]. For toxicity, the

pooled data of 71 trials showed that injectable gold had higher toxicity rates (no data on the

toxicity rate, P < 0.05) and higher total dropout rates than any other drugs (29.9% vs. 4.7-22

%, P < 0.01), while HCQ and AUR had relatively low rates of toxicity. Unfortunately, the

toxicity rate for MTX in 195 patients was imprecise because of discrepancies between trials.

Two years later, Felson, et al 14 updated their previous review and compared the benefit-

toxicity tradeoffs of various second-line drugs in 9 efficacy/toxicity tradeoffs plots. MTX

was ranked ahead of SSZ, azathioprine (AZA), DP, AUR, antimalarial, and injectable gold.

(The results were displayed in graph of effect size between composite efficacy and toxicity

index. No actual numbers of effect size and p values were provided).

13

Despite all the favorable efficacy and acceptable toxicity results reported, MTX

alone may not fully control disease activity. MTX rarely induces remission 12, 15, 16 and does

not halt erosive disease 17-23. The evidence of slowing radiographic progression is still

controversial 17-23. Increasingly, MTX is used in combination with other non-biologic

DMARDs. In 1992, William, et al 81 compared the safety and efficacy of auranofin (AUR),

MTX, and the combination of both in the treatment of 335 active RA in a 48-week,

prospective, controlled, double-blind, multi-center trial. There were no statistically

significant differences among the treatment groups in the clinical or laboratory variables

measured (50% improvement in the swollen joint count was 34% in AUR, 43% in MTX,

and 36% in AUR+MTX). Withdrawals because of adverse drug reactions were slightly more

common for those taking combination therapy, but the differences were not statistically

significant (14% in AUR, 15% in MTX, and 21% in AUR + MTX). Withdrawals because of

lack of response were more common for single-drug therapy, with the difference between

AUR and the combination reaching statistical significance (13% in AUR, 7% in MTX, and

2% in AUR + MTX). Willkens, et al 82 compared the safety and efficacy of azathioprine

(AZA), MTX, and the combination of both in a 24-week prospective, controlled, double-

blind, multi-center trial of 212 RA patients. Intention-to-treat analysis showed that

combination therapy was not statistically superior to MTX therapy alone, but both

combination therapy and MTX alone were superior to AZA alone. A greater number of

AZA patients (38%; 28/73) than combination (26%; 18/69) or MTX patients (7%; 5 of 67)

terminated therapy prior to week 24 (P < 0.01). Trnavsky, et al 83 compared the efficacy of

HCQ alone and in combination with MTX in a randomized, placebo-controlled study lasting

6 months. The results from 40 RA patients found that combination of MTX + HCQ

significantly more efficacious than HCQ alone in pain on 0-100 mm VAS (14 vs. 30, p <

0.05), patient global assessment on Dixon’s index (77 vs. 100, p < 0.05), and ESR (mm/hr)

(24 vs.38, p < 0.05). However, statistically significant difference between the 2 groups was

not found in other clinical (Ritchie’s articular index, swollen joint count, and morning

stiffness,minute) or laboratory outcomes (Haemoglobin, IgG, IgM, and circulating immune

complex). Toxicity was comparable in both groups. Ferraz, et al 84 found that in 68 RA

patients who completed the trial, patients receiving 7.5 mg/wk of MTX plus 250 mg/d of

chloroquine (CQ) ended the study with a significantly lower joint count (4.5 vs. 7.5; P <

14

0.05), greater grip strength (mm/kg) (113.3 vs. 89.1; P < 0.05), and better functional ability

measured by Health Assessment Questionnaire (HAQ 0-3) (0.636 vs. 0.811; P < 0.05) than

the patients in the MTX alone group. Mild adverse events were more frequently observed in

the MTX + CQ combination, 17 events in 15 patients, compared to 9 events in 8 patients in

the MTX group, but it was not statistically significant. Haagsma et al 85 compared the

efficacy and safety of MTX + SSZ or MTX alone in 24 week, open-label, randomized

controlled trial (RCT) of 40 RA patients with active arthritis despite adequate SSZ therapy.

The mean decrease in the Disease Activity Score (DAS) in the group of patients receiving

the combination was significantly greater than in the MTX group (-2.6 ± 0.7 vs. -1.3 ± 0.7; p

< 0.001) with no difference in the occurrence of toxicity between the two groups. The same

combination was studied in a large, double-blind, RCT with a longer follow-up period (52

week) 86. But the population was early RA (< 1 year of disease duration) and was never

treated with DMARDs before randomization. MTX + SSZ was more efficacious than SSZ

or MTX alone based on the DAS [-1.26 for MTX + SSZ, -1.15 for SSZ, and -0.87 for MTX;

p = 0.019]. However, there were no statistically significant differences in terms of other

outcomes, either the European league against rheumatism (EULAR) good responders

(SSZ:34%; MTX:38%; SSZ + MTX:38%) or the American college of rheumatology (ACR)

criteria responders (SSZ:59%; MTX:59%; SSZ + MTX:65 %). Adverse events occurred

more frequently in the SSZ + MTX group (91%) than in SSZ (75%) and MTX group (75%)

(p = 0.025).

Although many MTX and traditional DMARD combination regimens have been

studied, several important questions remain unclear. What is the relative benefit and toxicity

of MTX monotherapy versus MTX combination with other DMARDs? When should the

combination DMARD therapy be used: initially or only after a trial of MTX monotherapy?

Finally, which is the preferred combination DMARD strategy? These questions are

particularly salient as formularies in many countries require the use of MTX monotherapy

and MTX combination therapy prior to reimbursing for the more expensive biologic drugs.

The objective of this paper is to systematically review randomized trials that compared

MTX monotherapy to MTX in combination with other non-biologic DMARDs.

15

MATERIALS AND METHODS

Literature Search

We performed a comprehensive search of electronic bibliographic databases

including MEDLINE (1950 to June Week 3 2007), EMBASE (1980 to 2007 Week 25), and

the Cochrane Central Register of Controlled Trials (CENTRAL) (2nd Quarter 2007) using a

search strategy that combined Medical subject headings (MeSH) and keywords for

“rheumatoid arthritis,” “Methotrexate,” and “randomized controlled trials” (appendix 1). We

also searched the abstracts of the Annual scientific meetings of American College of

Rheumatology (ACR) and European League Against Rheumatism (EULAR) from 2005 to

2007, as well as the references lists of all relevant studies, letters, and review articles. All

languages were included.

Study Selection

Two reviewers independently screened the titles and abstracts of the citations and

retrieved relevant articles. The following selection criteria were used:

1) Randomized controlled trials (RCTs) of MTX monotherapy versus MTX

combined with other DMARDs of at least 12 weeks of trial duration (open label extensions

were excluded as well as studies comparing DMARDs not currently used, e.g., oral gold)

2) Participants met the American College of Rheumatology (ACR; formerly, the

American Rheumatism Association) 1987 revised criteria for RA with age equal to or older

than 18 years

3) Data available on one or more of the following pre-specified outcomes:

• Outcome measures included in the Outcome Measures in Rheumatoid

Arthritis Clinical Trials (OMERACT) 1993 core set 87 including: number of

tender joints, number of swollen joints, pain (Visual Analogue Scale or VAS),

patient global assessment (VAS), physician global assessment (VAS),

functional status (Health Assessment Questionnaire or HAQ, Arthritis Impact

Measurement Scales or AIMS, and Problem Elicitation Technique or PET), and

acute phase reactant – erythrocyte sedimentation rate (ESR) and C-reactive

protein (CRP)

16

• American College of Rheumatology (ACR) core set 88: ACR 20, 50, or 70

responses 89; ACR remission 90

• Disease activity score (DAS) and Disease activity score 28 (DAS28)91 92

• European League Against Rheumatism (EULAR) response 93

• Withdrawal due to lack of efficacy (LOE)

• Withdrawal due to adverse events (AE)

• Number of patients who experienced total adverse events or individual

adverse events such as gastrointestinal (GI) adverse events (any adverse events

except liver toxicity), hepatotoxicity (transaminitis), mucositis, haematological

adverse events (anemia, leucopenia, and/or thrombocytopenia), or infection.

These are the most common adverse events related to the use of MTX and

MTX-DMARD combination. GI adverse events included all symptoms related

to GI tract except transaminitis and mucositis. Transaminitis was separately

analyzed from other GI adverse events because it is one of the most common

adverse events related to MTX, azathioprine, and leflunomide. Additionally, the

risk of liver toxicity may increase with the use of MTX combination therapy

such as the combination of MTX + leflunomide, MTX + azathioprine.

Transaminitis was defined as an increase in the level of Aspartate

aminotransferase (AST) or Alanine transaminase (ALT) above the upper limit

of normal. Mocositis also commonly occurs in MTX, intramuscular gold, and

the combination of both DMARDS. It, therefore, is analyzed separately.

Data Abstraction and Quality Assessment

Two reviewers independently extracted the data (Appendix 2) and assessed the

quality of relevant studies. If the reviewers found any discrepancy between their

information, then a consensus was reached by looking at the original article and discussing

with the senior reviewer. Study quality was assessed using the van Tulder ‘s scale (Appendix

3), which was developed by the Cochrane back review group 94. This scale comprises

questions on the following eleven criteria: addressing randomization, blinding details about

the procedure (patients, provider, and outcome assessor), concealed treatment allocation,

similarity of the important baseline characteristics, co-intervention, timing of the outcome

17

assessment, compliance and withdrawals, and intention-to-treat analysis. Each item is rated

as “yes” = 1 and “no or not clear” = 0. The total score is the sum of all items so ranges from

0 to 11. The quality of trials was assessed without masking of trial identifiers.

Data Synthesis

We used RevMan 4.2.10 for analysis. The efficacy analysis was stratified into 3

groups based on previous DMARD use. The “DMARD naïve, parallel strategy” refers to

trials where patients who never received DMARDs (including MTX) were randomized to

start MTX alone or MTX plus another DMARD. The “MTX inadequate response, step-up

strategy” refers to trials where patients with inadequate response to MTX were randomized

to continue the use of MTX alone or to add a second DMARD. The “Non-MTX DMARDs

inadequate response, step-up strategy” refers to trials where patients with inadequate

response to DMARDs (other than MTX) were randomly switched to MTX alone or MTX

plus another DMARD. The toxicity analysis was stratified by DMARD combination and

pooled across trials for each combination.

For continuous measures of efficacy, we used either end-of-trial data or change from

baseline and pooled them as weighted mean differences (WMD) or standardized mean

difference (SMD) as appropriate using a random effects model 95. For the categorical

measures of efficacy and toxicity, the end-of-trial results were pooled and estimated using

the relative risk (RR) with a random effects model. For efficacy, a RR greater than 1 favors

MTX combination therapy: MTX combination therapy increases efficacy, while for toxicity

and withdrawals, a RR greater than 1 favors MTX monotherapy: MTX combination therapy

increases toxicity or withdrawal. Our pre-specified primary analysis was based on total

withdrawal rates for efficacy or toxicity.

The heterogeneity of the trials for each pooled analysis was assessed using a visual-

graphical method (forest plot), the Cochran’s Q (or chi-square) test, and the I2 test. The

method and results of this analysis are discussed in detail in Chapter 3. Publication bias was

assessed using funnel plots – the plot of effect estimate against standard error on a reverse

18

scale. Funnel plots of relative risks and their standard errors were performed only for the

primary outcome, the withdrawal due to lack of efficacy and toxicity.

RESULTS

Our search retrieved 6,938 citations. After review of titles and abstracts and removal

of duplicates across databases, 6,846 citations were excluded. The reasons for exclusion are

presented in figure 1. Thirty-nine (39) full-text articles were retrieved for further evaluation,

and 20 articles (from 19 studies) were retained for our analysis (Figure 1). Sixteen (16) of

these 20 articles were found in all 3 databases, and 4 were identified from EMBASE only.

Two abstracts from the EULAR annual meeting were also published in full article and

included in our review. No additional citations were retrieved by the hand search of the

reference lists of relevant articles. The excluded studies and reason for exclusion after full

text review are summarized in table 1.

Characteristics of the included studies (Table 2A and 2B)

The total number of patients in the trials was 2,025. Most of the trials were 6 or 12

months in duration. The doses of MTX ranged between 5 to 20 mg/wk, but most were

between 7-15 mg/wk. MTX was administered orally in all trials. Three trial strategies were

identified according to the DMARDs used before randomization: a DMARD naïve group, a

MTX inadequate response group, and a non-MTX DMARD inadequate response group. Six

trials used a parallel strategy where DMARD naïve patients were started either on MTX

alone or on a combination of MTX + sulfasalazine (SSZ) 86, 96, 97, MTX + cyclosporine

(CSA) 98, 99, and MTX + doxycycline 100. All included early rheumatoid arthritis patients

with less than 1 year of disease duration. Five trials used a step-up strategy in MTX

inadequate responders where the patients were either continued on MTX plus placebo or a

second DMARD was added : MTX + leflunomide (LEF) 101, MTX + CSA 102,

MTX+intramuscular gold 103, MTX + levofloxacin 104, and MTX + zolendronic acid 105. The

criteria for MTX failure or inadequate response were different across the studies. The

“inadequate response” dose of MTX in these studies ranged 7.5 to 20 mg /wk. The duration

on MTX before randomization was 1 105, 3 102, 103, or 6 101, 104 months. Eight trials used a

step-up strategy in non-MTX inadequate responders (who had never received MTX before

19

randomization), they were randomized to MTX alone or to MTX + SSZ 85, 106, MTX +

azathioprine (AZA) 17, 82, MTX + chloroquine (CQ) 84, MTX + SSZ + hydroxychloroquine

(HCQ) 107, MTX + bucillamine (BUC) 108, and MTX + previous DMARDs including: gold,

D-penicillamine , BUC, and SSZ 109. The criteria for DMARD failure or inadequate

response were different across the studies. Previous DMARD use was not clear in one study 110.

Methodological quality of studies

The detailed quality of studies and total quality score are presented in table 3. Ten

studies 17, 82, 84, 96, 99-101, 103, 106, 107 demonstrated appropriate randomization, adequate blinding

of intervention in both patients and care providers as well as clearly reported number and

reason for withdrawal and drop out. Seven of these 17, 82, 84, 96, 99, 101, 107 were high quality

(comparison groups had similar baseline characteristics and co-interventions and acceptable

withdrawals and drop outs), but one study 100 had a high drop out rate (~59%). In two

studies 103, 106, there were unequal co-interventions including steroid or NSAIDS between

the treatment groups.

In five studies 86, 102, 104, 105, 108, the method of randomization was not explicitly

described. Additionally, co-intervention (NSAIDS or steroid) was either unclear 86, 102 or

higher 105, 108 in the MTX treatment group

Due to their open label nature, five studies 85, 97, 98, 109, 110 were rated lower, and the

method of randomization was also unclear in three studies 97, 109, 110.

Combined withdrawal due to lack of efficacy and toxicity (Figure 2)

Our primary analysis was based on withdrawals for both efficacy and safety; data

were available for 13 of the 19 trials. The results showed no advantage of combination

therapy over MTX monotherapy in either pooled data across all trial or subgroups [RR 0.89

(95% confidence interval (CI) 0.66 to 1.21) for all trials, RR 1.16 (95%CI 0.70 to 1.93) for

DMARD naïve, RR 0.86 (95% CI 0.49 to 1.51) for MTX inadequate response, and RR 0.75

(95% CI 0.41 to 1.35) for non-MTX DMARD inadequate response]. However, there was

statistically significant heterogeneity in non-MTX DMARD inadequate response group (I2

=57.4%, χ2 = 9.39, df = 4, p= 0.05) with one important outlier: the combination of MTX +

20

SSZ + HCQ showed better efficacy/ toxicity ratio over MTX alone with RR of 0.3 (95%CI

0.14 to 0.65).

Efficacy

Table 4 and 5 summarize an overall view of the efficacy of the DMARD treatments

according to various efficacy measures found in individual trial.

DMARD naïve, Parallel design

The number of patients who withdrew due to lack of efficacy was available in five of

the six trials (405 patients) with combination of MTX + SSZ 86, 96, 97, MTX + CSA 98, and

MTX + doxycycline 100, MTX combination therapy yielded less patient withdrawal than

monotherapy, but it was not statistically significant [RR 0.63 (95%CI 0.34 to 1.17)] (Table

4, Figure 3).

The ACR responses were available in three of the six trials that compared MTX

monotherapy to MTX combination therapy in MTX naïve patients (Figure 4). These trials

included a total of 287 patients. Combination arms were MTX + cyclosporine (CSA) 98, 99

and MTX + doxycycline 100. The only statistically significant result was for the ACR 70

response in one CSA trial with RR of 2.41 (95% CI 1.07 to 5.44) favouring the MTX

combination arm.

The EULAR response was available in an additional two trials (368 patients) with

combinations of MTX+ Sulfasalazine (SSZ) 86, 96 or MTX + CSA 99. There was no

statistically significant difference between the two groups for a “good” or “moderate”

EULAR response or remission (Table 4, Figure 5).

Individual continuous efficacy measures were available in two of the six studies

comparing MTX alone to MTX + SSZ (Table 5). There were no statistically significant

differences in responses for the number of the tender joint count 96 (Figure 6), pain 97

(Figure 7), patient global assessment 96 (Figure 8), ESR 96, 97 (Figure 9), and CRP 97 (Figure

10), [WMD -1.7 (95% CI -6.11 to 2.71), WMD -1.36 (95% CI-5.11 to 2.4), WMD 0.7

(95%CI -10.24 to 11.64), WMD -1.62 (95% CI -6.98 to 3.74), and SMD 0.66 (95% CI -2.7

to 4.1), respectively]. However, the HAQ score response was slightly higher in the

combination group of those 2 studies 96, 97 [WMD 0.1 (95% CI 0.09 to 0.11)] (Figure 11).

21

The radiographic outcome from one study of MTX+CSA 98 showed a small but statistically

significant reduced progression in the combination therapy [WMD of Modified Sharp’s

score -3.15 (95%CI -5.85 to -0.45)] (Figure 12).

MTX inadequate response, Step-up design

The number of patients who withdrew due to lack of efficacy was available in 3 of

the 5 trials (476 patients) with combination of MTX + LEF 101, MTX + CSA 102, and MTX+

intramuscular (im) gold 103 showing significantly fewer patient withdrawals than in the

MTX monotherapy group with RR of 0.42 (95%CI 0.21 to 0.84) (Table 4, Figure 3).

The ACR responses were available in four of five trials (552 patients) that compared

MTX monotherapy to MTX combination therapy in MTX inadequate response patients

(Figure 13). Combination arms included MTX + leflunomide (LEF) 101, MTX + CSA 102,

MTX + im gold 103, and MTX + levofloxacin 104. In this group of trials, combination therapy

was significantly more effective than MTX monotherapy with RR of 2.51 (95%CI 1.92 to

3.28), RR of 4.54 (95%CI 2.51 to 8.2), and RR of 5.59 (95%CI 2.08 to 15.01) for ACR 20,

50, and 70 response, respectively. There was no data on ACR remission and EULAR

response.

Individual continuous efficacy measures were also available in four of these five

trials (Table 5). There were statistically significant differences in responses for the number

of the tender joint count 101-103 (Figure 14), the number of the swollen joint count 101-103

(Figure 15), pain 101-103, 105 (Figure 16), patient global assessment 101-103, 105 (Figure 17),

physician global assessment 101-103, 105 (Figure 18), CRP 101 (Figure 19), and HAQ 101-103

(Figure 20). The MTX combination responses were significantly greater than monotherapy

[SMD -0.51 (95% CI -0.69 to -0.33), SMD -0.45 (95% C I-0.63 to -0.27), WMD -8.15 (95%

CI -14.52 to -1.79), WMD -8.15 (95% CI-14.52 to -1.79), WMD -10.91 (95%CI -18.98, -

2.84), SMD -12.1 (95% CI-19.84 to -4.36), and WMD -0.28 (95% CI -0.36 to -0.21),

respectively]. However, a statistically significant difference was not found for ESR 101-103

[WMD -0.53 (95% CI-11.47 to 10.41)] (Figure 21). The radiographic outcome from one

study 105 showed less progression in the combination of MTX+ Zolendronic acid, but it was

not statistical significance. [WMD of Modified Sharp’s score -1.4 (95%CI -2.81 to 0.01)]

(Figure 22).

22

Non-MTX DMARD inadequate response, Step-up design

The number of patients who withdrew due to lack of efficacy was available in 5 of 8

trials (329 patients) (Table 4, figure 3) with combinations of MTX + Chloroquine(CQ) 84,

MTX + SSZ+ hydroxychloroquine (HCQ) 111, MTX + SSZ 106, MTX + BUC 108, and MTX

+ previous DMARDs (BUC, D-penicillamine, and im gold) 109. MTX combination therapy

yielded significantly fewer patient withdrawals than monotherapy with RR of 0.37 (95%CI

0.16 to 0.87).

The ACR responses were available in two of eight trials (158 patients) that compared

MTX monotherpay to MTX combination therapy in non- MTX inadequate responders

(Figure 23). Only the pooled ACR 20 showed a statistically significant benefit for the

combinations of MTX+SSZ 106 and MTX+bucillamine(BUC) 108 over monotherapy with RR

of 1.85 (95%CI 1.21 to 2.83). There was no data on ACR remission.

The EULAR response criteria was available for one of these two studies 106 and

showed no statistically significant difference between two groups (Table 4, Figure 24).

Individual continuous efficacy measures were available in five of the eight trials

(Table 5). There were statistically significant differences in responses for the number of the

tender joint count 107 (Figure25), the number of the swollen joint count, 84, 85, 107 (Figure26),

patient global assessment 107 (Figure27), and physician global assessment 107 (Figure28).

The MTX combination responses were significantly greater than monotherapy [WMD -4

(95% CI -6.82 to -1.18), SMD -0.66 (95% CI -1.15 to -0.17), WMD -10 (95% CI -19.16 to -

0.40), and WMD -10 (95% CI -14.8 to -5.2), respectively]. However, statistically significant

difference were not found for pain 84, 85 (Figure29), ESR 84, 85, 107, 109 (Figure30), CRP 109

(Figure31), and HAQ 84 (Figure32) [WMD -5.99 (95% CI -24.99 to13.02), WMD -4.29

(95% CI -10.72 to 2.13), WMD -1.2 (95% CI -2.95 to 0.55), and WMD -0.17 (95% CI -0.48

to 0.14), respectively].

Toxicity

The toxicity analysis was stratified and pooled by DMARD combinations. Table 6

summarizes an overall adverse event of the DMARD treatments according to various

adverse events.

23

Total adverse reactions (Figure33) were reported in eight of the nineteen trials (797

patients: 400 in the combination vs. 397 in the monotherapy groups). Overall, the number of

adverse events was not increased in the MTX + SSZ [RR 1.13 (95%CI 0.94-1.35)] 85, 86, 96, 97

and MTX + LEF 101 combinations [RR 1 (95%CI 0.94-1.08) versus MTX monotherapy.

There was a non-significant trend for increased adverse events in the MTX + CSA

combination [RR 3.62 (95%CI 0.82-16.30)] 98. Both the MTX + AZA 17 and MTX+ im gold 103 combinations increased the risk of total adverse events with RR of 1.67 (95%CI 1.21 to

2.3) and RR of 2.61 (95%CI 1.22 to 5.55), respectively.

Gastrointestinal adverse events (Figure34) Gastrointestinal (GI) related adverse events

(excluding liver toxicity reported below) were available for seven trials (692 patients: 351

patients in combination vs. 341 in monotherapy groups). Both MTX + SSZ 85, 86, 96, 97 and

MTX + LEF 101 combination increased the risk of GI adverse events significantly (RR 1.75,

95%CI 1.14 to 2.67 for MTX + SSZ and RR 1.67, 95%CI 1.17 to 2.4 for MTX + LEF). GI

adverse events were not increased in MTX + CSA 98 [RR 4.13 (95%CI 0.49-34.89) and

MTX + intramuscular gold 103 combinations [RR 0.71 (95%CI 0.05-10.87)].

Abnormal liver function (Figure35) was analyzed in seven trials (673 patients: 336 in

combination vs. 337 in monotherapy groups). MTX + LEF 101 significantly increased the

risk of abnormal liver function with RR of 4.3 (95%CI 2.58 to 7.15). While MTX + SSZ 85,

86, 96, 97, MTX + CSA 98, and MTX + BUC 108 showed a non-statistically significant,

increased risk of abnormal liver enzymes (RR 1.77, 95%CI 0.29 to 10.78 for MTX + SSZ,

RR 3.1, 95%CI 0.13 to 73.19 for MTX + CSA, and RR 3, 95%CI 0.13 to 70.02 for MTX +

BUC).

Mucositis (Figure36) was analyzed in four trials (229 patients: 123 patients in combination

vs. 106 in monotherapy groups). MTX + intramuscular gold 103 increased the risk of

mucositis (RR 9.33, 95%CI 0.55 to 158.98), but it was not significant. There was no

increased risk in MTX + SSZ [RR 0.62 (95%CI 0.16-2.34)] 85, 86, 96, 97.

24

Hematological adverse events (Figure37) were reported in six trials (415 patients: 215 in

combination vs. 200 in monotherapy groups). No difference was demonstrated for the

combinations of MTX+SSZ 85, 86, 96, 97, MTX+ im gold 103, and MTX + BUC 108 compared

with MTX monotherapy with RR of 2.36 (95%CI 0.66-8.48), RR of 1.42 (95%CI 0.14-

14.89), and RR of 0.32 (95%CI 0.01-7.48), respectively.

Infection (Figure38) was analyzed in four trials (454 patients: 231 in combination vs. 223 in

monotherapy).The risk of infection slightly increased in MTX + SSZ [RR 1.35 (95%CI 0.6-

3.04) 96, 97 and MTX + im gold [RR 1.6 (95%CI 0.82-3.13)] 103, but it was not statistically

significant. MTX + LEF did not increase the risk of infection [RR 0.79 (95%CI 0.6-1.02) 101.

Withdrawal due to adverse reaction

Figure 39 summarizes the RR and its corresponding 95%CI of withdrawal due to

adverse reactions comparing between MTX combination and MTX monotherapy. In 17 of

the 19 trials (1,624 patients: 824 in combination group vs. 800 monotherapy group),

combination therapy resulted in more withdrawal due to adverse reactions than

monotherapy, but the differences were statistically significant only for the CSA 98, 99, 102 and

AZA 82 combinations with RR of 1.88 (95%CI 1.02 to 3.5) and RR of 5.18 (95%CI 1.58 to

16.95), respectively.

DISCUSSION

Despite the introduction of new biologic therapies, methotrexate alone or in

combination with other traditional DMARDs remains the recommended first line therapy for

most patients with RA 112. Our systematic review addressed the respective risks and benefits

of monotherapy versus combination.

Nineteen studies met our inclusion/exclusion criteria. Trials of DMARD

combinations used different designs: “DMARD naïve, parallel strategy,” “MTX inadequate

response, step-up strategy,” and “Non-MTX DMARDs inadequate response, step-up

strategy”. These 3 strategies were studied in the different populations (according to previous

treatment prior to randomization) and therefore answered different clinical questions.

25

The “DMARD naïve, parallel strategy” is the only design that addresses the

questions of whether a combination DMARD therapy should be used initially or only after a

trial of MTX monotherapy. Only ACR70 responses showed a statistically significant

improvement for the combination therapies but with increasing risk of withdrawals due to

toxicity. Additionally, none of the trials that reported other composite or single outcome

measures could demonstrate a benefit of an initial course of combination therapy over MTX

monotherapy in DMARD naïve patients over 12 to 24 months of follow-up. Although the

pooled RR of the primary outcome, withdrawal due to lack of efficacy and toxicity, showed

a trend in favour of MTX monotherapy, the benefit of MTX combination therapy over

monotherapy cannot be clearly addressed because the confidence interval was wide and

crossed 1.

The “MTX inadequate response, step-up strategy” included five trials where the

overall combination therapy was significantly more effective than MTX monotherapy.

However, when balancing between risk and benefit, the statistically significant benefit of

combination therapy was not demonstrated because the confidence interval was wide and

crossed 1. This design does not address the question of what is the preferred therapeutic

approach when patients fail MTX monotherapy because these trials continue patients who

are considered inadequate responders on the same low dose of MTX in both arms. The

response of patients in MTX monotherapy arm would be expected to be less than the

response of the patients in MTX combination arm. The results, therefore, showed the greater

benefit of combination therapy in this group than in DMARD naïve. These trials also do not

reflect current practice. The dose of MTX (7-15 mg/wk) is lower than current use, and

patients randomized to the MTX monotherapy arm were kept on the same inadequate low

dose of MTX. In actual practice, physicians would increase the dose of MTX or change to

parenteral administration before adding another DMARD. For all of these reasons, the

superiority of the combination therapies in this group of trials does not have clinical

credibility. Therefore, the current evidence for patients with inadequate response to MTX is

inconclusive pending results from new trials that compare maximum doses of MTX

monotherapy with combination therapies. On the other hands, these studies may be useful

for patients who cannot tolerate high-dose MTX because they address the question of which

26

approach is preferred, MTX combination or monotherapy, in patients who could not tolerate

high-dose MTX?

In the “Non-MTX DMARDs inadequate response, step-up strategy” 6 out of 7

studies 84, 85, 106-109 were available for efficacy analysis. This study design answers the

question of which approach is preferred, MTX combination or monotherapy, in patients who

did not respond to non-MTX DMARDs. This study design would be useful if patients failed

or had inadequate response to a DMARD and then were switched to another DMARD

combined with MTX vs. MTX alone. When balancing the risk and benefit, no conclusions

can be reached. Although, there was a trend in favour of MTX combination therapy, the

confidence interval was wide and crossed 1. In Capell’s study, patients who already failed

sulfasalazine 2 g/d were randomized to receive MTX alone or MTX+ the “same dose” of

sulfasalazine. In fact, this study compared the efficacy of MTX in both arms and did not

address this question. This study actually addressed a different clinical question that is in

patients who did not achieve sufficient benefit with SSZ, what is the preferred strategy,

adding MTX to SSZ or switching to MTX monotherapy. The Ichikawa’s and Hanyu’s study

are trials of bucillamine, which is not commonly used in North America or Europe.

For toxicity analyses, GI and liver adverse events were higher in the sulfasalazine

and leflunomide MTX combinations but did not lead to statistically significant differences in

withdrawal rates. The total number of adverse events was higher with the gold and

azathioprine MTX combinations. Withdrawal rates due to adverse reactions were higher in

all the combination therapies, but the differences were statistically significant only for the

combinations of MTX + cyclosporine and MTX + azathioprine.

The simplest criterion of benefit/risk ratio for drug evaluation is whether a drug is

stopped for inefficacy or adverse events. This data was available for 13 of the 19 trials and

therefore represents the most powerful results from our meta-analysis. Overall there was no

benefit of MTX combination therapy over monotherapy either within the three design

strategies or across all trials. However, one study of the combination MTX, SSZ, and HCQ

showed better efficacy/ toxicity ratio over MTX alone.

To answer our question of which is the preferred combination DMARD strategy, our

study suggests that one trial has a clear benefit/toxicity advantage: MTX + SSZ + HCQ, but

this result needs to be confirmed in additional trials; also the combinations of MTX+ CSA

27

and MTX + AZA should be avoided due to their serious toxicities. The combination of

MTX with SSZ or LEF should be used cautiously due to increased GI and liver adverse

events.

There are important limitations to our findings, mostly stemming from characteristics

of the primary studies they are based on. There were diverse regimens of combination

therapy. DMARDs have different efficacy and toxicity, and they also have drug interactions

when used in combination. We intended to perform subgroup analysis stratified by regimen

to demonstrate their efficacy comparing with MTX monotherapy. However, since there were

too few trials comparing the same combination regimen, the benefit of specific combinations

of therapy can not be addressed. Furthermore, outcome measures were inconsistently

reported across the trials. Some studies reported the efficacy as a composite score. The

European trials used DAS or DAS 28, while the others reported ACR response measures.

Some studies–especially those prior to 2000 – reported individual variables of clinical and

laboratory outcomes. Few studies reported radiographic outcomes and those that did used

different methods of assessment. Lastly, the duration of follow up was also different, likely

affecting the assessment and interpretation of efficacy as well as toxicity. All of this

heterogeneity complicated the pooling of results across studies. In addition, most studies

used lower doses of MTX than in current practice, and several studies were done with drugs

that are not commonly used (bucillamine, doxycycline, levofloxacin, chloroquine, im gold,

and cyclosporine). Lastly, most of the studies included in our review were short-term trials;

drawing firm risk–benefit conclusions regarding MTX combination therapy is difficult.

Nonetheless, this meta-analysis presents useful information particularly when looking at

total withdrawal rates where combination across a number of studies is possible.

Three previous systematic reviews 113-115 and 2 meta-analyses 116, 117 compared

DMARD monotherapy with combination therapy. Felson and Verhoeven studied non-

biological DMARDs with or without MTX. Hoehberg, Choy, and Douahue included both

biological and non-biological DMARDs. Felson, et al (1994) 116 and Verhoeven, et al (1998) 114 concluded that combination DMARD therapy does not substantially improve efficacy

with an increase in toxicity. This is consistent with our overall results that include more

28

recent trials. Hochberg, et al (2001) 115 included only 4 studies of MTX combined with both

biological and non-biological DMARDs (cyclosporine, leflunomide, etanercept, and

infliximab) in MTX inadequate responder studies and found that ACR responses improved

significantly when a second DMARD was added. Choy, et al (2005) 117 reached the same

conclusion in subgroup of MTX and non-MTX inadequate responders based on analysis of

withdrawals [OR 0.51 (95%CI 0.3 to 0.82)] but added that improved efficacy is associated

with an increased risk of adverse events. Donahue, et al (2008) 113 reported only on a small

subset of our included trials (mostly of SSZ combinations), and the remainder of his and

Choy’s data cannot be compared to our study because they included biologics as well as

monotherapies with non-biologic DMARDs other than MTX.

CONCLUSIONS

In summary, when the balance of efficacy and toxicity is taken into account, the

evidence from our systematic review showed no statistically significant advantage of the

MTX combination versus monotherapy; only one study with the specific combination of

MTX + SSZ + HCQ showed a better efficacy/ toxicity ratio over MTX alone. Adding

leflunomide to MTX non-responders improved efficacy but increased the risk of

gastrointestinal adverse events and liver toxicity. Withdrawals because of toxicity varied but

were most significant with the cyclosporine and azathioprine combinations. Trials are

needed that compare currently used MTX doses and combination therapies.

29

Chapter 3 Investigating Heterogeneity in Systematic Review and Meta-

analysis

INTRODUCTION

Meta-analysis aims to compare and possibly combine estimates of effect across

related studies 118. However, an uncritical use of the technique can be very misleading. In

some situations, it can be inappropriate to combine effects; for example, if the primary

studies are substantially heterogeneous or are at risk of bias 119.

Heterogeneity in a systematic review refers to any kind of variability among the

studies in a systematic review 119. It can occur by the differences in some study

characteristics (systematic variation) 120. The different types of heterogeneity have been

described. Thompson 121 described the distinction between statistical and clinical

heterogeneity. Clinical heterogeneity refers to the differences in the characteristics of the

studies; for example, differences in the study population, such as age or disease severity,

differences in the intervention, such as the dose or duration or type of intervention,

differences in outcome measures, such as timing of outcome assessment, or differences in

study design. Statistical heterogeneity is the quantitative observation that there is variability

in the review, and it may be caused by known clinical differences or unknown

characteristics. The source of heterogeneity was stratified by Glasziou and Sanders 122 into

real and artifactual variation. Real variation is the true variation in treatment effect caused

by the differences in characteristics of the population, intervention, and/or outcome, while

the differences in the study design or methodology are considered an artifact resulting in the

artifactual variation. Table 7 lists and categorizes some potential sources of variation

causing the different effect size between different studies.

In this chapter, we have investigated the potential sources of heterogeneity in our

systematic review and meta-analysis.

METHODS

1. Identifying Heterogeneity 1.1 Statistical heterogeneity

30

To identify the heterogeneity among the included studies, we used visual-graphical

methods (forest plot with the eyeball test) 120, 123 and statistical methods: Cochran’s Q test 124

and I2 test 125.

Forest plot and eyeball test

The forest plot is used to display the point estimate (which is a relative risk for

dichotomous data and a weighted mean difference or standardized mean difference for

continuous data in our review) and its corresponding confidence interval (CI) for individual

studies. Using the eyeball method, the extent to which the CIs from different studies overlap

each other represents the degree of homogeneity among the studies. Non-overlap or a small

degree of overlap of the CIs indicates likely heterogeneity among the studies.

Cochran’s Q test (chi-square test)

Statistical tests assess the observed variability between observed treatment effects is

compatible with chance alone. The usual test statistic (Cochran’s Q) is computed by

summing the squared deviations of each study’s estimate from the overall fixed-effects

estimate, weighting each study’s contribution in the same manner as in the meta-analysis. P-

values are obtained by comparing the statistic with a χ2 distribution with k−1 degrees of

freedom (where k is the number of studies). A large p value suggests that the observed

variation across studies is plausibly due to chance, and therefore, the hypothesis that studies

are estimating the same effect size cannot be safely rejected. Conversely, a small p value

indicates a small possibility that the observed variation between studies is due to chance, and

therefore, a very small p value indicates statistically significant heterogeneity across studies.

I2 test

We also quantified the inconsistency across the studies using the I2 test 125. I2 can be

calculated using the formula below.

31

I2 = x 100%

Where Q = Cochran’s heterogeneity’s statistics

df = degree of freedom = number of studies -1

The value of I2 is expressed as a percentage of the variability in the trials that may be

attributable to between study variations. No universal rule covers the definitions of ‘mild’,

‘moderate’, or ‘severe’ heterogeneity. Higgin J &Thompson S 125 suggested that a value of

less than 30 % may represent mild heterogeneity, and more than 50% may represent

substantial heterogeneity. I2 can be compared across meta-analyses for different types of

outcomes.

The major problem of statistical testing for heterogeneity is that it is underpowered.

The power of statistical tests for heterogeneity is dependent on the following two factors: the

number of studies included and the weight (inverse of the corresponding variance) allocated

to each study. The power of test for heterogeneity will be reduced when a large proportion

of the total information resides with one study 126. Therefore, the statistical tests for

heterogeneity may fail to detect the existence of true differences in the results between

studies, particularly when the number of studies included is fewer than 20 127 or the variance

of the outcome varies significantly across studies 126. A non-significant result does not

reliably identify lack of heterogeneity in the treatment effects 128. To compensate for this

problem, a P-value of less than 0.1 is usually used to indicate significant heterogeneity

among the studies as a conservative method 40. Because the statistical power of

heterogeneity tests is low, and a number of the potential sources of clinical heterogeneity

identified in this review are relevant to clinical practices and may influence the pooled effect

sizes, we investigated observed differences between studies regardless of the results of the

statistical tests of heterogeneity.

Q-df Q

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1.2 Clinical heterogeneity

From the clinical perspective in our review, there are some considerable variations

between the included studies. Table 8 summarizes the potential sources of heterogeneity in

our study. These were explored and discussed in the “results” section.

2. Investigating and approaching sources of heterogeneity 2.1. Subgroup analysis

We used subgroup analysis to separate included studies into subgroups according to

certain study-level variables that might explain the variations among the studies. Many

characteristics were considered to be sources of heterogeneity in our review (as shown in

table 8); however, we opted to explore only 3 important characteristics: treatment received

prior to randomization, timing of outcome assessment, and study quality. These study

characteristics are clinically relevant and important. The other potential sources of

heterogeneity were not explored because of too few studies in each subgroup.

Population was stratified into 3 groups: DMARD naïve, MTX inadequate responder, and

non-MTX DMARD inadequate responder.

Timing of outcome assessment was stratified into 6 months or more than 6 months.

Study quality was stratified into high vs. low quality and studies that met vs. did not meet

each criterion of the quality assessment list. For assessing the quality of an individual study,

we used the quality assessment checklist developed by the Cochrane Back Review group 129.

The details of this score were described in chapter 2 and in appendix 3. High vs. low quality

stratification was pre-defined by cut-off–points provided by the Cochrane Back review

group. High-quality trials were defined in two ways: as those that fulfilled at least 50% of

the criteria (≥ 6 of 11) and as those with scores higher than the mean of included studies (>

7.15).

The overall estimate of treatment effect was pooled within subgroups. The difference

between subgroups was assessed using meta-regression analysis. STATA 9.0 software was

used to perform the meta-regression analysis on the log RR scale, with each trial weighting

being equal to the inverse of the variance of the estimate for that study and between-study

variance estimated with the restricted maximum likelihood (REML) method, a variant of

33

maximum likelihood estimation that provides unbiased and accurate estimates of variances

by taking account of residual heterogeneity 130. In subgroup analysis, we used only primary

outcomes including withdrawal due to lack of efficacy, withdrawal due to toxicity, and

combined withdrawal due to lack of efficacy and toxicity.

2.2. Constructing a random effects estimate across all studies

Both fixed and random effects models were used for all outcomes irrespective of

statistical heterogeneity. If there is no component of variability between studies, the results

based on fixed and random effects models are essentially identical 131, 132 because using the

Dersimonian and Laird method, when there is no component of variability between studies,

the random effects analysis becomes a fixed effects analysis. When there is heterogeneity

between studies, the CI of a summary estimate of effect size will be wider with the random

effects model. For this analysis, we used all outcomes.

2.3. Meta-regression analysis

Due to sample size limitation, we did not perform multivariable regression analysis

to adjust for other potential predictors of treatment effect.

RESULTS

1.1. Statistical heterogeneity (Table 9)

For withdrawal due to lack of efficacy and withdrawal due to toxicity, the

heterogeneity was not significant based on the eyeball test, Cochran’s Q test, and I2 test.

However, when withdrawal due to lack of efficacy and toxicity were combined, the eyeball

test showed moderate overlap reflecting some degree of variability between studies. This

variability was statistically significant by Cochran’s Q test (χ2 = 20.98, df = 12, p = 0.05)

with a moderate degree of heterogeneity according to the I2 criterion (I2 = 42.8%).

1.2. Clinical heterogeneity

Population

According to DMARD treatment prior to randomization, 6 trials studied DMARD

naïve patients 86, 96-100, 5 studied MTX inadequate responders 101-105, and 7 studied non-MTX

34

inadequate responders 82, 84, 85, 106-109. In one study, the treatment received before

randomization was not clear 110.

Intervention

Ten combinations were included in our review, 6 studies of MTX+ Sulfazalazine, 3

of MTX + Cyclosporin, 1 of MTX + Leflunomide, MTX + Azathioprine, MTX +

Doxycycline, MTX + Levofloxacin, MTX + intramuscular gold, MTX + Zolendronic acid,

MTX + chloroquine, MTX + Sulfazalazine + hydroxychloroquine, MTX + Bucillamine, and

MTX + previous DMARDs. These combinations have diverse efficacy and toxicity profiles.

The dose of MTX used in these trials was also different across the trials. The mean dose of

MTX ranged between 5 and 18 mg/wk, which is somewhat lower than current practice.

These variations may influence the treatment effect. However, we did not perform subgroup

analysis based on this variation due to there being too few studies in each subgroup.

Outcome

Previously, there was no consensus on what outcome is the most appropriate tool to

measure the efficacy of interventions in the RA clinical trials, so the outcome measures used

in the included studies varied. Some used composite scores, such as the ACR response

criteria, the EULAR response criteria, the DAS, and the DAS28. Some used single

variables, such as the swollen joint count, the tender joint count, a pain score, a patient or

physician global assessment of disease activity, ESR, CRP, or withdrawal due to lack of

efficacy. Table 10 and 11 summarize the efficacy and toxicity outcomes reported in the

included studies. The different outcome measures may assess the different aspect of the

response to the treatment. This discrepancy also complicates the pooling of results across

studies.

The timing of outcome assessments was also different across the trials. Nine 82, 84, 85,

101, 102, 104, 105, 107, 110, 7 86, 96-99, 103, 106, 2 100, 108, and 1 109 studies had 6, 12 , 24, and 60-month

follow up, respectively. Most DMARDs are slow-acting 64. Therefore, it is likely that the

studies that had longer follow-up would result in a higher response rate.

35

Study characteristics

The mean of the quality score of included studies was 7.15 (range was 3 to 10 out of

11). Fourteen studies were rated as high quality studies using fulfillment of at least 50% (≥ 6

of 11) criterion, and 11 studies were above the mean of included studies. More than half had

adequate randomization (10 studies), blinded patients (13 studies), blinded care providers

(14 studies), adequate treatment allocation concealment (10 studies), acceptable drop-out

rates (10 studies), and used intention-to-treat analysis (13 studies). Only 6 studies blinded

outcome assessors. Six studies reported acceptable compliance, while others did not provide

this information. Comparable co-intervention in both arms was reported only in 7 studies.

Due to the variation in study quality and characteristics, we performed subgroup analysis to

assess their influence on the pooled effect size.

2.1 Subgroup analysis

Study design and Population (Table 12)

For withdrawal due to lack of efficacy, all study designs favoured MTX combination

therapy over MTX monotherapy, but it was statistically significant only MTX inadequate

response group [RR 0.42, 95%CI 0.21 to 0.84] and non-MTX DMARD inadequate response

group [(RR 0.47, 95%CI 0.16 to 0.87]. There was no statistically significant difference

between the pooled RR from the 3 study designs in the meta-regression analysis. For

withdrawal due to toxicity, MTX combination therapy significantly increased toxicity

compared to MTX monotherapy in DMARD naïve [RR 1.72, 95%CI 1.04 to 2.83] and MTX

inadequate response group [RR 1.89, 95% CI 1.05 to 3.41]. This finding was not statistically

significant in non-MTX DMARD inadequate response group [RR1.53, 95%CI 0.74 to 3.18].

Subgroup analysis showed no statistically significant difference between the 3 groups. When

balancing between efficacy and toxicity, there was a trend in favor of MTX monotherapy in

DMARD naïve [RR 1.16, 95% CI 0.7 to 1.93], while in MTX inadequate response and non-

MTX inadequate response group, there was a trend in favor of MTX combination therapy

[RR 0.86, 95% CI 0.49 to 1.51 and RR 0.75, 95% CI 0.41 to 1.35, respectively]. However,

the difference between groups was not statistically significant.

36

Timing of outcome assessment (Table 13)

When stratifying the trials according to trial duration, the pooled RR in the trial

duration of ≤ 6 months or > 6 months resulted in the same direction that MTX combination

therapy was significantly more efficacious than monotherapy with significantly higher

toxicity. However, the increased toxicity was statistically significant only in the trial with ≤

6 month duration. Toxicity increased in the trial duration of more than 6 months, but with

the lower end of the CI of 1. The difference between trial duration was not statistically

significant in 3 outcomes.

Study quality (Table 14)

When stratifying the studies according to quality score, there was a trend that low

quality studies (using both criteria) overestimated the pooled effect size, except for the

analysis of the withdrawal due to lack of efficacy and toxicity using the mean as a cut-off

value. However, the difference in RR according to quality was not statistically significant.

When stratifying the studies according to each criterion of study quality assessment,

there was no statistically significant difference in the primary outcomes between studies that

met and did not meet a criterion (table 15-17).

2.2. Fixed vs. random effects models (Table 18)

When comparing the results of the fixed and random effects models, the pooled

treatment effects and their 95%CI were slightly different in both analyses using all

combined 19 studies and subgroup analysis stratified by study design. The confidence

interval was wider in the random effects models as compared to the fixed effects models

reflecting some degree of heterogeneity between the included studies.

DISCUSSION

The statistical heterogeneity was not significant

In our review, the statistical heterogeneity was not significant in the three statistical

tests used, although many types of clinical heterogeneity in our review were found. One

major problem of statistical tests of heterogeneity is that they may have low power to detect

a clinically important degree of heterogeneity 126, 131, 133. In addition, our sample size is quite

37

small, perhaps leading to a lack of power to demonstrate significant heterogeneity. From a

clinical point of view, we believe that heterogeneity exists in our review. The differences in

populations and interventions are clinically relevant and should be incorporated into our

analysis. Careful investigation of heterogeneity can provide clinically important results by

examining subgroups of studies looking at patients who might benefit more or less from a

treatment.

Clinical heterogeneity and subgroup analysis

Why stratify by study design?

One clinically important characteristic of the included studies is the treatment

received before randomization. These three strategies answer different clinical questions.

The DMARD naïve subgroup is the most relevant and useful study design for clinicians in

the light of the accumulative evidence of the benefit of early diagnosis and aggressive

treatment in RA patients 6, 67, 134-139. Ideally, RA patients should be diagnosed and treated in

the early stages of the disease before they develop irreversible deformities and functional

disabilities. It, therefore, is important to use the most effective treatment possible for these

patients who would usually never receive any treatment. This study design answers the

question, “Should MTX alone or MTX combination be started in patients who never

received a DMARD?” The MTX inadequate response group answers the clinical question,

“Does the addition of a second DMARD to MTX show a greater benefit than continued

MTX alone in patients who did not fully respond to MTX?” This study design may not be of

practical use to clinicians because in actual practice physicians generally increase the dose

of MTX or change to parenteral administration before adding another DMARD. In addition,

the patients in this group were randomized to receive placebo or non-MTX DMARD in

combination with the same dose of MTX that they had already failed in both arms;

therefore, the response of patients in MTX monotherapy arm would be expected to be less

than the response of the patients in MTX combination arm. The non-MTX DMARD

inadequate response group answers the clinical question, “Should MTX combination or

monotherapy be used in patients who did not respond to non-MTX DMARDs?” This study

design would be useful if patients failed a non-MTX DMARD and then were switched to

another DMARD in combination with MTX vs. MTX alone. Due to the difference in

38

clinical implication between these 3 groups, the treatment effect should not be pooled across

the trials – even though no statistically significant differences were found between the 3

groups in any outcomes. From this subgroup analysis, we found that the response to the

treatment varied depending on the treatment status before randomization. MTX combination

is more beneficial than MTX monotherapy only in patients who failed MTX or a non-MTX

DMARD, while the benefit of MTX combination over MTX alone was not found in patients

who had never received any DMARDs. The toxicity significantly increased in all

populations. Based on this information clinicians can tailor the most appropriate regimen for

an individual patient.

The impact of trial duration

Most DMARDs are slow-acting 64. It is likely that the studies that had longer follow-

up would result in a higher response rate. However, our subgroup analysis showed similar

results in the trials of less than or equal to 6 months and more than 6 months, that in both

MTX combination therapy was more efficacious than MTX alone. For toxicity, the

increased toxicity of MTX combination was statistically significant only in the trials of less

than or equal to 6 months. This finding may be explained by the “attrition bias” rather than

the trial duration itself. The adverse events of DMARDs usually occur in the first 6 months.

The patients who continued in the trial longer than 6 months were the patients who could

tolerate to the treatment. This group of patients might be less likely to withdraw due to

toxicity afterward. The withdrawal due to toxicity in MTX combination, therefore, did not

significantly increase in those trials of more than 6 months.

The impact of study quality

The quality of the studies included in the meta-analysis influences the conclusion. It

has been shown that the results and conclusions of reviews are sensitive to methods for

appraising trial quality and incorporating quality into data synthesis 140. Differences in

quality in the reported trials may lead to increased variation in the results and also to bias 141.

Empirical studies have shown that poor quality studies influence the pooled effect size;

however, the direction is inconclusive; some overestimate 141-145 and some underestimate 146,

147 the effect size.

39

Some studies have investigated the influence of different components of

methodology on pooled effect size in randomized controlled trials. Moher, et al 142 found

that trials that used inadequate allocation concealment, compared with those that used

adequate methods, were associated with a 37% increased estimate of benefit. Linde, et al 144

investigated the influence of indicators of methodological quality on study outcomes in a set

of 89 trials of homeopathy and found that studies that were explicitly randomized and were

double-blind yielded significantly lower effect sizes. Similarly, Juni 143, Djulbegovic, et al 148, Pildal, et al 149, and Poolman, et al 150 showed that the lack of blinding overestimated the

treatment effect. Wood, et al 151 also demonstrated that the overall estimated effects were

exaggerated by 7% in non-blinded studies and by 17% in studies with unclear or inadequate

allocation concealment, but this finding was restricted to trials assessing subjective

outcomes, not mortality.

Perhaps due to sample size limitations, similar impacts – on the effect size – of study

quality and its components were not found in our review. Despite these results,

methodologically sound procedures in clinical trials are still important in the field of

Rheumatology. In Rheumatology, many outcomes used are subjective, e.g., pain score,

patient or physician global assessment, treatment allocation concealment; thus, blinding

procedures are important and necessary in maintaining the integrity of trials.

Why use random effects models?

Although the Cochran’s Q test, the I2 test, and subgroup analysis showed no

statistically significant difference between the studies, the somewhat different results from

fixed and random effects models indicated some component of variability. The confidence

interval was wider in the random effects models compared to the fixed effects models even

in the subgroup analysis. This suggested that there was residual heterogeneity, perhaps in

both known and unknown (or unrecorded) trial characteristics, and this should be taken into

account. Our conclusions, therefore, were based on subgroup analysis with random effects

models.

40

Why combine the different combinations?

One variation amongst included studies is the DMARD combination. DMARDs have

differential efficacy and toxicity profiles. Combining the treatment effect of different

DMARDs may obscure, under-, or over-estimate the results. However, we aimed to evaluate

the treatment strategy (combination vs. monotherapy), rather than to focus on the specific

regimen. The conclusions, therefore, were based on combining data of the different

combinations.

CONCLUSIONS

A meta-analysis attempts to gain greater objectivity, generalizability, and precision

by including all the available evidence from trials that pertain to the issue. For this purpose,

the trials included in the reviews usually encompass a substantial variety of study

characteristics. Investigating potential sources of heterogeneity and the influence of these

differences on the overall results needs to be explored carefully. The exploration of

heterogeneity provides opportunity to increase the relevant and valid conclusions drawn

from studies pertaining to a topic.

41

Chapter 4 Search Strategy for Systematic Reviews: Comparisons between

Ovid (MEDLINE) versus Pubmed and EMBASE versus Pubmed

This chapter will focus on the performance of 3 different databases commonly used

in systematic reviews: Ovid-MEDLINE, PubMed, and EMBASE. If there is a discrepancy

between databases, the causes will be explored. The objectives of this study are to:

1) Compare the performance of Ovid-MEDLINE and PubMed for identifying RCTs

evaluating the efficacy and safety of non-biologic DMARDs in RA.

2) Determine whether EMBASE identifies RCTs and non-experimental studies not

indexed in PubMed for use in the systematic review of RA treatments.

INTRODUCTION

Systematic review in healthcare is designed to synthesize and summarize the

available research evidence for a certain clinical question. Rigorous methods are used to

minimize bias and maximize validity of the review. These methods are based on systematic

and exhaustive search, extensive analysis, and critical appraisal methods. Unbiased and

complete identification of relevant studies is a first important step in performing

methodologically sound systematic reviews 152. Failure to include all relevant sources of

evidence could diminish the validity and reliability of the review. To completely identify all

potentially relevant articles, 2 strategies should be applied: 1) choose appropriate databases;

2) develop comprehensive and sensitive search strategies.

1. Choose appropriate databases

The Cochrane collaboration suggested that a comprehensive search should include the

following sources 153 :-

1) Bibliographic databases include:

• International healthcare databases , e.g., MEDLINE, EMBASE

• National and regional databases which concentrate on the literature produced in

those regions, and which often include journals and other literature not indexed

42

elsewhere, e.g., Chinese Biomedical Literature Database (CBM), Index Medicus

for the South-East Asia Region (IMSEAR)

• Subject-specific databases , e.g., International Pharmaceutical Abstracts, Allied

and Complementary Medicine (AMED)

• Science Citation Index / Science Citation Index Expanded is a database that lists

published articles from approximately 6,000 major scientific, technical, and

medical journals and links them to the articles in which they have been cited (a

feature known as cited reference searching)

• Dissertations and theses databases. To identify relevant studies published in

dissertations or theses, it is advisable to search specific dissertation sources, e.g.,

Index to Theses in Great Britain and Ireland

• Grey literature databases. Literature that is not formally published in sources such

as books or journal articles may be identified in the conference abstract or some

databases, e.g., Healthcare Management Information Consortium (HMIC)

2) Non-bibliographic databases include hand search of relevant journals and reference

lists of relevant articles, conference abstracts, and proceedings

3) Unpublished and ongoing studies

Searches of health-related bibliographic databases are generally the easiest and least

time-consuming way to identify an initial set of relevant reports of studies. A key advantage

of the bibliographic databases is that they can be assessed online and searched electronically

using search engine technology. The three bibliographic databases generally considered to

be the most important sources to search for reports of trials are MEDLINE, EMBASE, and

CENTRAL (Cochrane Central Register of Controlled Trials)

What is MEDLINE?

MEDLINE (Medical Literature Analysis and Retrieval System Online) is a literature

database of life sciences and biomedical information including medicine, nursing, pharmacy,

dentistry, veterinary medicine, and health care. It contains more than 18 million records

(2008) from approximately 5,000 selected publications (Feb 2007) from 1950 to the present 154. Reviewers can access MEDLINE through the fee-based database providers such as

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43

Ovid, COS (Community of Science), Datastar, and DIALOG or the free-web based version

provided by PubMed.

What is PubMed?

PubMed is a free database developed and maintained by the National Center for

Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM) located

at the National Institutes of Health (NIH). It provides access to bibliographic information

that includes MEDLINE, as well as:

• In-process citations which provide a record of an article before it is indexed with

Medical subject heading (MeSH) and added to MEDLINE or converted to out-of-

scope status.

• Some OLDMEDLINE citations that have not yet been updated with current

vocabulary and converted to MEDLINE status.

• Out-of-scope citations (e.g., articles on plate tectonics or astrophysics) from

certain MEDLINE journals, primarily general science and chemistry journals, for

which the life sciences articles are indexed for MEDLINE.

• Citations that precede the date that a journal was selected for MEDLINE

indexing.

• Some additional life science journals that submit full texts to PubMedCentral

(PMC) and receive a qualitative review by NLM

• Citations to author manuscripts of articles published by NIH-funded researchers.

Many of the scientists who receive research funding from NIH publish the results

of their research in journals that are not available in PMC. In order to improve

access to these research articles, NIH's Public Access policy asks these authors to

provide PMC both author manuscripts and final, peer-reviewed manuscripts of

such articles once they have been accepted for publication. The author

manuscripts in PMC are the author versions without revision by the independent

peer reviewers and the journal's editors.

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44

What is the difference between MEDLINE and PubMed?

In addition to the difference in the databases contained in PubMed-MEDLINE and

Ovid-MEDLINE, the methodology used for searching in these 2 database providers, e.g.,

field tag, Boolean operators, etc. is also different. Many reviewers cannot access the fee-

based versions of MEDLINE and have increasingly turned to the free web-based version,

PubMed. Data from the U.S. National Center for Biotechnology Information (NCBI) has

shown that PubMed searches have tremendously increased from 54,663,426 searches in June

2007 to 74,518,774 searches in March 2009 (Figure 40) 155. Searches in MEDLINE using

these 2 database providers may yield different citations retrieved with differential trade-offs

such as the time needed to perform searches, complexity of the search process, time to

review the citations retrieved, etc.

What is EMBASE?

As mentioned above, EMBASE is one of the major bibliographic databases used for

searches in systematic review produced by Elsevier. It covers over 4,800 active peer-

reviewed journals published in 70 countries / 30 languages, of which nearly 2,000 are

unique in that they are not found in MEDLINE.

Using PubMed versus EMBASE

It has been shown that searching only the MEDLINE database for randomized

controlled trials will inevitably miss pertinent information in many fields and topics. It has

been shown in several studies that searching in EMBASE retrieves additional articles that

may be related to reviews in many fields of Medicine 156-162. However, the database

providers used were different across studies. Two of these studies 161, 162 accessed to

MEDLINE via Ovid. Sampson, et al and Suarez-Almazor, et al 161, 162 compared the

performance of MEDLINE vs. EMBASE in the identification of articles regarding

controlled clinical trials (CCTs) using Ovid-MEDLINE. Topfer, et al 159 and Brazier, et al 160 performed searches in MEDLINE using different commercial suppliers (DIALOG and

Datastar, respectively). Database providers were not clear in the other three studies 156-158.

The PubMed database covers many extra-sources of published information in addition to

Ovid-MEDLINE. Therefore, searching in EMBASE in addition to PubMed may not retrieve

45

as many additional articles as shown in the previous studies using EMBASE in addition to

Ovid- MEDLINE.

In the field of Rheumatology, Suarez-Almazor, et al compared the performance of

MEDLINE and EMBASE for the identification of CCTs in rheumatoid arthritis,

osteoarthritis, and low back pain using hand search as the gold standard. MEDLINE and

EMBASE were searched for literature published between 1988 and 1994. They found that

the EMBASE search identified 85% of the CCT compared to 73% identified by MEDLINE,

and EMBASE retrieved 16% more CCT than MEDLINE. However, this study performed

the MEDLINE search via Ovid, and the study was not specific for the topic/clinical question

of RA. This study also did not test the ability to find non-experimental studies, e.g., cohort

or case control studies. PubMed and EMBASE have been improved and have updated the

indexing process, and new journals are added every year. The result from searching in the

most updated databases may not be significantly different between these 2 databases.

2. Developing comprehensive and sensitive search strategies

Developing the most comprehensive search strategy consists of a complete list of

search terms related to the clinical question, appropriate use of database-specific search term

syntax, and appropriate use of Boolean operators.

2.1. Complete list of search terms related to the clinical question A useful

framework for developing the comprehensive search terms related to specific clinical

questions is PICO 30. The PICO model consists of 4 domains:

P = Population or Problem

I = Intervention

C = Comparison interventions (if relevant)

O = Outcome of interest

The search term should comprise all relevant terms in each component of PICO. In

addition, some reviewers may want to focus their searches on ‘study design’. Many sensitive

search strategies related to specific study design or type of study such as randomized

46

controlled trials 152, 163-165, prognostic studies 166, 167, causation studies 168, and diagnostic

studies 169, 170 have been developed. These search terms can be added to a search strategy to

increase the precision of a search.

2.2. Appropriate use of a database-specific search term syntax The field tags

used in each search term will specify the section where the search term will be searched in

the database. The field tag system is also different across databases. Inappropriate use of

field tags may cause relevant articles to be missed. For example, in Ovid, the search term

“randomized controlled trial.ti./ab.” will be searched under titles and abstracts. If some

studies are randomized controlled trials, but this term appears only in publication type, a

search using “randomized controlled trial.ti./ab” will miss these citations.

2.3. Appropriate use of Boolean operator Since developing a search strategy using

the PICO method will result in a set of terms for each domain individually; an efficient

method is to combine all search terms in each domain together by using Boolean logic

operators. Three Boolean operators: OR, AND, and NOT are commonly used and illustrated

in figure 41. OR is used to combine synonyms or similar concepts. It allows articles

containing either term to be retrieved. AND is used to combine different concepts and will

allow only articles containing both terms to be retrieved. NOT is used to eliminate a concept

that is not wanted. It allows only articles containing one term but not the other terms to be

retrieved.

METHODS

Objective 1 To compare the performance of Ovid-MEDLINE and PubMed for identifying

RCTs evaluating the efficacy and safety of non-biologic DMARDs in RA.

Step 1: Development of search strategy for MEDLINE provided by Ovid

A comprehensive search strategy for Ovid-MEDLINE database was developed using

the PICO method as following:

47

The study design was limited to randomized controlled trials (RCT). The database

from 1950 to January 2009 was used with no language restriction. For “Rheumatoid

arthritis”, the Medical subject heading (MeSH) and textword were used without explosion.

MeSH is the controlled vocabulary term assigned by indexers at the US National Library of

Medicine to describe the contents of the articles included in the MEDLINE database.

Textword is used to search for a word that appears in the citation exactly as typed in. Ovid

automatically maps a user's search term to a database's controlled vocabulary, providing the

opportunity for a user to select subject headings that closely match the search term. If a user

searches a database that has a Tree structure, they can opt to “Explode” or “Focus” the

search term, and also choose subheadings that apply—all as part of the Mapping process 171.

For “Rheumatoid arthritis”, its mapping includes juvenile rheumatoid arthritis, Caplan’s

syndrome, Felty's syndrome, rheumatoid nodule, Sjogren’s syndrome, and Still's disease,

adult-onset. To include only terms related to our interests, we, therefore, opted not to

explode the RA subheadings and included only the following subheadings separately:

Caplan’s syndrome, Felty's syndrome, rheumatoid nodule, and Still's disease, adult-onset.

For MTX, we included the comprehensive list of generic and trade names of MTX. These

terms were used as textword with field tag “mp,” e.g., Methotrexate.mp, “mp” stands for

multi-purpose. An “mp” search looks in the title, original title, abstract, subject heading,

name of substance, and Registry Word fields. Truncation (“$” or “:”) was used in textword

searching to retrieve variant words, e.g., amethopterin$ will search for both amethopterin

and amethopterine. For RCT, we combined terms from the Cochrane Highly Sensitivity

Search Strategy (CHSSS) 152 and Glanville JM, et al’s search strategy 163.

Population = Rheumatoid arthritis

Intervention = MTX combination therapy with non-biologic DMARDs

Comparison = MTX monotherapy

Outcome = Report on efficacy and toxicity compared between both arms using any outcome

measures for RA

48

To make these terms more comprehensive, we modified some field tags. For

example, CHSSS suggests “placebo.ti” and “placebo.ab” which will retrieve articles that

have the term “placebo” in the title and abstract, respectively. We changed this to

“placebo.mp.” We also added the term “meta-analysis” and its variants to capture all related

reviews. All terms within the same subset of RA, MTX, and RCT were combined using the

Boolean operator “OR”. All citations under the subset of RA, MTX, and RCT were then

combined using the Boolean operator “AND.”

We decided not to include the list of terms related to “DMARD combination” used

with MTX and “outcome measures” because using only the term “MTX,” (which would be

included in all the desired studies) the trials related to MTX combination would be retrieved.

Step 2: Translation of Ovid-MEDLINE search strategy to PubMed format

Due to the differences in field tag functions between Ovid and PubMed, the

following strategies were applied to make the search strategy for each term as similar as

possible.

1. Explosion For the term ‘Rheumatoid arthritis’, as mentioned above we searched this

term and its related syndromes separately as this strategy was more relevant and

comprehensive than exploding “Rheumatoid arthritis” which included all

subheadings. Some subheadings were not related to our topic, e.g., juvenile arthritis,

and Sjogren’s syndrome. However, this was modified in our PubMed search because

PubMed automatically searches the MeSH headings as well as the more specific

terms beneath that heading in the MeSH hierarchy 172. We, therefore, did not explode

“Rheumatoid arthritis” by turning off automatic explosion of MeSH headings using

the field tag ‘[mesh:noexp]’ for Rheumatoid arthritis and its related terms.

2. Field tag

2.1 mp Because the field tag “mp” in Ovid is not available in PubMed, the closest

field tag/method to “mp” in PubMed is untagged term. In PubMed, untagged

terms or terms without a field tag that are entered in the search box are matched

against a MeSH translation table, a Journals translation table, the Full Author

translation table, Author index, the Full Investigator (Collaborator) translation

table, and an Investigator (Collaborator) index. If a match is found in this

http://www.nlm.nih.gov/pubs/factsheets/mesh.html�

49

translation table, the term will be searched as MeSH (that includes the MeSH

term and any specific terms indented under that term in the MeSH hierarchy),

and in all fields. If there is no match, the individual terms will be searched in “all

fields” 173. This is not exactly the same as, but close to the use of “mp” in Ovid.

2.2 adj In Ovid, we used the proximity operator “adj” (called “adjacent”) in textword

to search for words in a phrase close together rather than any occurrences spread

throughout the article title and abstract by specifying the number of words within

the required terms were to appear, for example clinical$ adj2 trial$. This feature

is not available in PubMed, so we used “AND” instead of “adj” in PubMed, for

example clinical* and trial*. This searched both terms in any distance in the

specific field.

2.3 ab In Ovid, “ab” is used to search terms in an abstract field. This feature is not

available in PubMed. The similar field tag in PubMed is [ti/ab], which will

search specific terms in titles and abstract areas.

2.4 fs In Ovid, the subheadings under each MeSH term are provided to help describe

more precisely a particular aspect of a subject, e.g., etiology, diagnosis,

laboratory, treatment, drug therapy, etc. “fs” (or floating subheading) is used to

search in a subset of MeSH terms in specific areas. In our search, we used ‘dt.fs’

to search the subheading of “drug therapy”. In PubMed, the same feature is

available with the field tag “MeSH subheading”. The ‘dt.fs’ was then translated

to ‘drug therapy[MeSH subheading]’.

2.5 pt In Ovid, field tag ‘pt’ is used to search terms in the publication type field. This

can be directly translated to PubMed into [pt] with the same function.

3. Truncation The truncation “$” or “:” used in Ovid to capture variant words was

replaced with “*” in PubMed, e.g., methotrexat$ methotrexat* with the same

function.

Step 3: Comparing the citation results from 2 searches

The citation results from Ovid and PubMed were downloaded into a bibliographic

program (Endnote®) and reviewed. The inclusion and exclusion criteria for this review were

applied to retrieve the eligible studies from these 2 searches.

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50

Step 4: Test performance characteristics of search strategy

In information retrieval, the science of searching for documents, the performance of

information retrieval systems are evaluated using the terms “recall” and “precision”. Recall

is analogous to “sensitivity”, a term used to assess the performance of diagnostic test. It is

defined as the proportion of the total number of eligible studies identified by a specific

database provider 152, 163, 174, 175 . It evaluates the completeness of the search to identify the

relevant articles; thus, recall is the most important search parameter from a scientific

perspective 176. Comprehensive searching, with a high recall, is considered standard practice

when conducting systematic reviews 177. Precision is defined as the proportion of

publications retrieved by the specific database provider that are actually eligible in the

review 152. It is equivalent to “positive predictive value” 174. Precision evaluates the burden

on the reviewers to unnecessarily review irrelevant citations. Number-needed-to-read (NNR)

was recently coined in analogy to the number-needed-to-treat (NNT) to describe the number

of irrelevant references that one has to screen to find one of relevance 170. It is the inverse of

precision. NNR helps researchers to easily interpret the performance of the search in the

context of systematic reviews.

The recall, precision, and NNR of the search strategy using 2 database providers

were calculated using the total included studies identified by the 3 electronic databases,

handsearching, and the abstracts of annual scientific meeting in our review as a gold

standard.

Recall = Number of eligible studies identified by a database provider

Total number of eligible studies in the review

Precision = Number of eligible studies identified by a database provider

Total number of citations retrieved by a database provider

Number-needed-to-read (NNR) = 1

Precision

Objective 2 To determine whether EMBASE identifies RCT and non-experimental studies

not indexed in PubMed in the systematic review of RA patients.

We used the data of 8 clinical questions from the 3-e Initiative projects 28. The

following is the list of 8 clinical questions.

x 100

x 100

51

a) What is the best dosing strategy and optimal route of administration for MTX in

patients with RA to optimize rapid early clinical and radiographic response and

minimize toxicity? (Dosing strategy) 46

b) What are indications for pausing/stopping/restarting MTX in case of elevated liver

tests and when is liver biopsy indicated? (Liver toxicity management) 47

c) What is the long term safety of MTX with regards to cardiovascular, malignancies,

liver, and infections? (Long term safety of MTX) 48

d) What is the different between MTX monotherapy versus MTX combination therapy

in terms of efficacy and toxicity in rheumatoid arthritis? (MTX mono vs. combo

therapy) 49

e) Is folic/folinic acid supplementation to MTX useful in reducing toxicity for adult

patients with RA? (Folate supplementation)

f) What is the optimum management of usual dose MTX in RA patients in the

perioperative period to minimize perioperative morbidity and while maintaining RA

control? (Management for perioperative period) 50

g) How should MTX use be managed when planning pregnancy (male and female

patients), during pregnancy, and after pregnancy? (Management in pregnancy

period) 51

h) Is MTX effective as a glucocorticoid-sparing (adjuvant) treatment compared with

placebo or other DMARDs in chronic inflammatory rheumatic disorders? (Efficacy

in other rheumatic diseases)

The search for all reviews was performed using PubMed and EMBASE. All

reviewers were asked to record the total citation hits stratified by database and the included

studies that were identified by EMBASE only. The reason for missing articles when

searching in Pubmed was investigated by reviewing the search strategy and the

PubMed/MEDLINE citations related to each article.

52

RESULTS

Objective 1 To compare the performance of Ovid-MEDLINE and PubMed for

identifying RCT evaluating the efficacy and safety of non-biologic DMARDs in RA.

The search strategies comparing Ovid-MEDLINE and PubMed are shown in table

19. The search strategy in PubMed retrieved a slightly higher number of citations than in

Ovid in all combined search terms for RA (104,892 vs. 97,213), MTX (35,593 vs.34,747),

and RCT (4,740,614 vs. 4,215,641). After combining the citations from 3 subsets with

“AND”, 2,036 were retrieved from PubMed vs. 1,930 citations from Ovid.

From a total of 20 citations included in our review, PubMed retrieved all 17 eligible

citations retrieved by Ovid with an additional 1 citation, Ichikawa et, al’s study 108.

Ichikawa, et al was the Japanese study published in the Japanese journal, Modern

Rheumatology. This journal was indexed in MEDLINE in 2007. This article was published

in 2005; therefore, it was not indexed in MEDLINE but indexed in PubMed and EMBASE.

The other 2 eligible citations not retrieved by Ovid and PubMed were retrieved by

EMBASE. The performances of Ovid-MEDLINE and PubMed were summarized in table

20. The recall was 85% for Ovid vs. 90% PubMed, while the precision was comparable,

0.881 % for Ovid vs. 0.884 % for PubMed. The NNR was 114 for Ovid vs. 113 for PubMed.

Objective 2 To determine whether EMBASE identified RCT and non-experimental

studies not indexed in PubMed in the systematic review of RA patients.

Of the 8 clinical questions related to the MTX use in rheumatic diseases, 4,218 vs.

6,651 citations were indentified in PubMed vs. EMBASE, respectively. After applying the

inclusion and exclusion criteria specific to each topic, 208 articles from 2 databases were

included in the 8 reviews (Table 21). Twenty-two (22) included articles (11 %) were

retrieved by EMBASE, but not PubMed. EMBASE did not retrieve the additional eligible

articles to PubMed in 2 out of the 8 reviews. PubMed did not retrieve any additional eligible

articles that were not indexed in EMBASE.

Reasons for missing trials in the PubMed search

Table 22 shows the reasons why 22 eligible studies were missed when searching in

PubMed. Eight articles (36%) were not indexed with the search terms used in the search

53

strategies 178-185. In another 8 articles (36%), insufficient or restricted search strategies

including an inappropriate or too limited field tag or incomprehensive search terms were

used 186-193. One study was misclassified as the trial retrieved by only EMBASE search, but

it was actually indexed and retrieved by the search in both PubMed and EMBASE 194.

Finally, in a total of 22 articles, only 5 (23%) 97, 109, 195-197 were EMBASE unique trials

(EMUT) because these trials were published in the journals that were not indexed in

PubMed. These journals include the Revue du Rhumatisme (English Edition), the Journal of

Internal Medicine of India, the Journal of Postgraduate Medical Institute, the Japanese

Journal of Rheumatology, and the Journal of Rheumatology and Medical Rehabilitation

from France, India, Pakistan, Japan, and Turkey, respectively. All were published in

English.

DISCUSSION

PubMed versus Ovid

MEDLINE is one of the most commonly used databases for the comprehensive

search in systematic review. It is provided by many database providers, but the most

commonly used database providers are PubMed and Ovid. Both of them have different

features that users may have to consider when incorporating them into their reviews. The

major differences include the citations contained in databases, the search engines, and costs.

As we mentioned in the introduction that the largest component of PubMed is MEDLINE;

however, it also contains the additional citations that may be relevant to reviews in

Medicine. Searching in PubMed will result in a higher number of citation hits rather than

searching in MEDLINE (via Ovid) only. The benefit is that reviewers can be confident that

they will not miss any relevant articles, but the drawback is that they may have to review

more citations, which may or may not be relevant to their reviews. Our study demonstrated

that searching in PubMed in a specific topic in Rheumatology yielded only a slightly higher

number of hits and identified one additional relevant article compared to searching in Ovid.

The additional study identified by PubMed is Ichikawa, et al. The impact of missing this

study may not be statistically significant. Although this study was a high-quality study, it

54

provided only 4 out of 22 outcomes used in our analysis. Additionally, it studied MTX in

combination with Bucillamine, a DMARD that is not commonly used outside Japan.

Other limitations we experienced when using PubMed is that the PubMed website is

not stable especially when we ran a high number of search terms and used many Boolean

operators to refine our search. The website crashed many times when we combined all terms

and limited the results to only ‘adult’. Unfortunately, we could not save or retrieve our

results. We finally completed our search by re-running all the search strategies several times.

This problem did not occur when we used Ovid. The save feature in PubMed is also not

suitable for the search process in systematic reviews. When users save their search

strategies, the search strategies can be saved only with the final combination of all terms.

The lists of each search term and its citation hits are not saved separately. So if users would

like to modify their search terms, they have to enter each term and re-run all search terms

manually then again combine them together. While in Ovid each search term and the final

combination are saved separately, so the users can modify their search terms, and then the

final combination will be run automatically.

Most MEDLINE search strategies for a specific topic such as randomized controlled

trial 163-165, prognostic study 166, or diagnostic study 170, 198 were developed specifically for

searching via Ovid 163-166, 198 or Datastar 170. Some groups also provided the optional format

that is compatible with the Pubmed search strategies 165, 198. However, the performances of

the suggested search strategies were based on the Ovid-MEDLINE search strategies. Using

the search strategies that were translated from Ovid format to PubMed format may not yield

the similar recall and precision as demonstrated in the literature. The translation should be

performed or suggested by an experienced information specialist.

Searching MEDLINE via Ovid for systematic reviews is comprehensive and

technically more convenient for users than searching in PubMed. However, PubMed is free

to access, while Ovid is costly; therefore, it is not available in many institutes. Our findings

were based on the results of searching in only one systematic review of one specific topic.

The generalizability of the results needs to be tested in the other reviews in other subject

55

areas. This finding can benefit from replication in other fields. Despite studying only one

review, the problems and obstacles in the use of PubMed are universal and can be useful for

other reviewers.

PubMed versus EMBASE

The benefit of searching in EMBASE in addition to MEDLINE has been shown in

several studies, in different topics and populations including RA 156-162. However, in most

studies, the MEDLINE search was performed via fee-based database providers, e.g., Ovid,

Datastar, and DIALOG. As we mentioned that PubMed has indexed citations

complementary to MEDLINE from many sources, searching via PubMed may result in less

missed citations compared to searching in MEDLINE. Our study showed that searching in

PubMed still missed relevant articles in the review of randomized controlled trials and

observational studies in RA.

Our study confirmed that a comprehensive search requires that at least 2 databases be

searched. Furthermore, we demonstrated that two other important strategies to ensure its

comprehensiveness are developing the comprehensive list of the search terms and using the

appropriate syntax and field tags related to individual database. Seeking the suggestion from

information specialists experienced in electronic searching is always necessary to design and

run search strategies for systematic reviews. The assistance of information specialists should

help to complete a list of the search terms, avoid as many errors, and ensure that the

database-specific search term syntax is appropriate, and advanced searching techniques

(e.g., exploding) can be employed where available.

The results of our study are similar to Sampson, et al’s 162 in that EMUTs were more

likely to be published outside North America. They also showed that EMUTs influenced the

pooled effect size at only 6%.

When comparing the performance of search strategies or databases, the relevance of

the article identified in the database should be the main concern as this is the ultimate goal

of the search process. Searching in EMBASE usually results in publications relating to RCT

but may not be eligible in the reviews such as synopsis, editorial, letter, or correspondence.

Suarez-Almazor, et al 161 reported that 53% of the randomized controlled trials in RA,

56

osteoporosis, and low back pain were EMUTs. However, their relevance to the specific

reviews was not explored. In the review of pre-hospital care, Brazier, et al 160 found that

33% (280 out of 849) of their search results before the reviewers assessed the eligibility of

the citations retrieved were EMUTs. However, when applying the inclusion and exclusion

criteria, only 1 out of the 41 eligible studies (or 2.4%) was EMUT. This finding was similar

to ours, although this study was done 12 years ago.

In addition, several aspects including the area or topic of reviews, the type of study

designs, the time of conducting studies, and the database providers used in the reviews have

to be taken into account when comparing the results among the studies since these factors

influence the performance of databases and search strategies.

Lastly, MEDLINE has a time lag for indexing articles in the database. In 1999,

Toper, et al 159 also found that 60% of EMUTs were finally indexed in MEDLINE in the

follow-up search. Unfortunately, the duration of time lag was not mentioned in this study.

However, PubMed has been developed to help searchers find the recent references by

indexing some of the in-process references or the online-published versions of articles

before they are officially published in journals. The time lag in PubMed is usually shorter

than in MEDLINE. This may improve the precision (or sensitivity) of searching MEDLINE

through PubMed. The additional benefit of an EMBASE search may not be as much as

demonstrated in previous studies.

CONCLUSIONS

Searching in Ovid-MEDLINE and PubMed has differential benefits and drawbacks

with diverse impact to individuals. Ovid is user-friendly especially for comprehensive

searches in systematic reviews; however, its accessibility is a major limitation. PubMed is

free web-based and contains the most recent references as well as references other than in

the MEDLINE database, but it may not be suitable for the complex search of some reviews.

We found a small additional benefit of EMBASE search on the specific topic of RA. These

findings are subject to change over time because the bibliographic databases are constantly

evolving products. The most common reasons for missing trials in the PubMed search are

57

the use of insufficient or restricted search strategies and the use of inappropriate search

terms. Consulting an experienced information specialist is an important strategy to perform a

comprehensive search for systematic reviews.

58

Chapter 5 Discussion

In this thesis, a comparison of the net benefit of MTX combination and MTX

monotherapy in RA patients is summarized. Clinical and statistical heterogeneity in this

review are investigated. In addition, the impact of a literature search using different

databases and database providers is explored and discussed.

Strengths

The efficacy of a treatment is perhaps the most important factor when making

decisions on the choice of treatments. On the other hand, toxicity is one of the factors

determining whether patients continue or discontinue treatments. The balance between

benefit and harm, therefore, is the ultimate index to determine the success of a treatment and

should be considered when summarizing the results of trials in an evidence synthesis. This

outcome also assesses patient’s preference to the medications. Some adverse events may not

be serious or life-threatening but cause withdrawal due to patient’s preference such as

alopecia especially in female patients. To summarize and compare the net benefit between

MTX combination and MTX monotherapy, combined withdrawal due to lack of efficacy

and toxicity was, therefore, used as a primary outcome in this systematic review. This

information is relevant and assists clinicians in clinical decision-makings. It is also easy to

understand from clinicians and patients’ perspectives.

Challenges

Although the benefit/risk trade off is the simplest criterion to assess the net benefit of

a treatment, the limitation in the use of this outcome is the lack of detailed information

concerning the magnitude of specific benefits and harms. By using only this outcome, we

have no data on how well the patients would be if they use MTX combination therapy

compared to MTX monotherapy. We also have no data on the severity of toxicity because

some adverse events are not serious but cause withdrawal such as alopecia from MTX or

skin hyperpigmentation from HCQ. In addition, the criteria used for withdrawal due to lack

of efficacy and toxicity usually are not clearly defined in each trial. These criteria may be

59

different across the included trials. This means that they may measure the different entities

of the same outcome.

Other limitations mostly stem from characteristics of the primary studies they are

based on. The included studies are explanatory trials, which are designed to determine the

effect of intervention in ideal circumstances. Participants in these trials were thought to have

a high chance to respond to the interventions with the lowest risk of having unfavourable

outcomes. While in actual practice, RA patients may have underlying conditions that are

prone to experience adverse events or may not be able to tolerate the interventions studied in

the trials. Consequently, the efficacy of the interventions in actual practice may not be

similar as found in the clinical trials. In addition, the conclusions of this review were based

on short-term trials, the firm conclusion for the long-term effectiveness and toxicity of the

MTX and MTX-DMARD combinations cannot be addressed. This issue is important in the

RA treatment because most RA patients have to continue DMARD treatment for at least a

year. Some have to continue DMARD treatment life long to maintain remission. This

information is more likely to be addressed in observational studies. Accordingly, the results

of our systematic reviews need to be confirmed in pragmatic trials and long-term,

observational studies.

In clinical practice where clinical decision-making depends on individual patients

and their circumstances, specific factors need to be considered and discussed, such as the

availability of the treatment, care providers’ experience, the value the patient places on the

treatment, and the context or personal circumstances of the patient, for example, medical

conditions, financial status, reimbursement system, and so on. Systematic reviews do not

usually provide such information as this information is less likely to be studied and

summarized in systematic reviews.

Future directions

Withdrawal due to lack of efficacy and toxicity are the only ‘in common’ outcomes

provided by many studies in the review in this thesis. Previously, there was no consensus on

the outcome measures that should be used to assess the efficacy of interventions in RA

trials; therefore, the outcome measures used to assess disease activity, functional status, and

radiographic damage in eligible studies are diverse. This meant that a significant number of

60

studies were excluded when each specific outcome measure was pooled across studies. This

would have led to bias in our review if the (unreported) results for excluded studies were

systematically different from the results of studies that reported an outcome. Recently, the

OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) initiative 87 and

the American College of Rheumatology (ACR) and the European League Against

Rheumatism (EULAR) 199. provided recommendations on how to report disease activity in

clinical trials of RA. These recommendations will harmonize the presentations of results

from clinical trials and facilitate the comparison of outcomes across different trials and

pooling of trial results.

Although tests of heterogeneity were not statistically significant in this review, many

types of relevant clinical heterogeneity were found, such as population, intervention (dose),

and trial duration. The variations may be obscured and difficult to statistically identify due

to the low power of heterogeneity tests and inadequate sample size. Since clinical

heterogeneity was identified and incorporate in the analysis, the conclusions drawn in this

review are more specific and clinically relevant. This also enhances the generalizability of

this review as this review provides the information related to different clinical settings seen

in clinical practice including patients who never receive any DMARD treatments, patients

who inadequately responded to MTX or non-MTX DMARDs. These patients may

differentially respond to DMARD treatment. Patients who inadequately respond to MTX or

non-MTX DMARDs are less likely to respond to the next DMARD treatment compared to

DMARD-naïve patients.

Our findings suggest that clinical heterogeneity should be explored and taken into

account when analyzing data and interpreting the results of reviews, even when tests of

heterogeneity are not statistically significant at traditional levels 121.

Comparisons between DMARDs or DMARD combinations in RA trials may be

influenced by various factors, including the dose of DMARDs, the type of DMARD

combinations, and trial duration. However, the patient’s DMARD status also influences the

61

response to treatments and should be taken into account when analyzing and interpreting the

results of RA trials and systematic reviews.

Developing a comprehensive search strategy is a very important step in conducting a

systematic review. Choices of databases and database providers are also important as

searching only one database is clearly insufficient. Pubmed is one of the most common

database providers used in systematic reviews, as it provides free access to MEDLINE and

other additional citations; however, its performance has not been assessed. This study

suggests that searching Pubmed yields additional relevant articles in the specific topic of RA

trials compared to searching Ovid (MEDLINE). Furthermore, this study demonstrated that

searching EMBASE in addition to Pubmed also yielded additional articles relevant to

specific topics in RA. This finding was demonstrated in systematic reviews of RCTs as well

as of cohort and case control studies in the RA field. However, the performance of Pubmed

should be confirmed in other fields of study as well as in systematic reviews of

observational studies.

A systematic review is a type of scientific research that provides the qualitative

and/or quantitative summary of research evidence relating to a specific clinical question.

Despite the laudable attempts to achieve objectivity in developing scientific evidences,

considerable subjective judgment is necessary in carry out systematic reviews. These

judgments relate to the relevance of studies, the quality of eligible studies, the approach to

heterogeneity, the method to incorporate heterogeneity in the analysis, as well as drawing

unbiased conclusions. Systematic reviews will be useful and valuable scientific evidence

only when they are developed using rigorous and explicit methodology, and their results

and conclusions are unbiased and relevant to current clinical practices.

62

TABLES Table 1 Excluded studies and the reasons for exclusion

Study Reason for exclusion Calguneri 1999 no MTX monotherapy arm (data combined with sulfazalazine

and Hydroxychloroquine monotherapy) Clegg 1997 no outcome of interest Haagsma 1995 summary of Haagsma et al. British Journal of Rheumatology

1994;33:1049-55(included in this review) Kremer 2004 open-label extension of randomized controlled trial Maillefert 2003 open-label extension of randomized controlled trial Matucci-Cerinic 2003 summary of Kremer et al. Annals of Internal Medicine

2002;137:726-33 9 (included in this review) Mottaghi 2005 non randomized controlled trial Mroczkowski 1999 open-label extension of randomized controlled trial Nagashima 2006 non randomized controlled trial Nisar 1994 non randomized controlled trial O'Dell 1996 open-label extension of randomized controlled trial Rou 1998 non randomized controlled trial Stein 1997 open-label extension of randomized controlled trial Trnavsky 1993 no MTX monotherapy arm Willkins 1996 published in the journal supplements and the key data has

been reported in Willkins 1995 (included in this review) Krause D et al (German) 1998

non randomized controlled trial

Geokoop-Ruiterman YPM 2005

no MTX monotherapy arm

Geokoop-Ruiterman YPM 2007

no MTX monotherapy arm

Mottonen T et al 1999 no MTX monotherapy arm Abbreviation: - MTX = methotrexate

63

Table 2A Characteristics of the included studies

MTX (mg/wk)

Study Sample size

Study duration (Month)

Strategy

Mono Combo

DMARD Quality Rating#(0-11)

Haagsma 1997 96

105 12 DMARD-N

15 7.5 SSZ 3 g/d 10

Dougados 1999 86

209 12 DMARD-N

Up to 15

Up to 15 SSZ 3 g/d 7

Marchesoni 2003 98

61 12 DMARD-N

11.2 9.5 CSA 2.5 mg/kg/d

8

Tascioglu 2003 97

70 12 DMARD-N

7.5 7.5 SSZ 2 g/d 4

Hetland 200699 160 12 DMARD-N

15 12.5 CSA 2.5 mg/kg/d

8

O’Dell 2006 100 66 24 DMARD-N

7.5-17.5 7.5-17.5 Doxycycline 20 or 100 mg

twice/d

7

Tugwell 1995 102

148 6 MTX-IR 15 15 CSA 2.5-5 mg/kg/d

7

Kremer 2002 101 263 6 MTX-IR 16.1 16.8 LEF 20 mg/d 10 Lehman 2005 103

65 12 MTX-IR 18 18 im Gold 50 mg/wk

9

Jarette 2005 105 39 6 MTX-IR 11.9 14 Zolendronic acid 5 mg iv twice

7

Ogrendik 2007 104

76 6 MTX-IR 17.5 15 Levofloxacin 500mg/d

8

Willkins 1992 82,1995 17

212 6 Non-MTX-IR

5-15 5-15 AZA 50-150 mg/d

8

Ferraz 1994 84 82 6 Non-MTX-IR

7.5 7.5 CQ 250 mg/d 9

Haagsma 1994 85

40 6 Non-MTX-IR

8.3 7.9 SSZ 2 g/d 7

O’Dell 1996 107 102 6 Non-MTX-IR

Up to 17.5

Up to 17.5

SSZ 1 g/d HCQ 400 mg/d

8

Hanyu 1999 109 37 60 Non-MTX-IR

7.5 5 Previous DMARD

(Penicillamine, Bucillamine,

im Gold)

3

Ichikawa 2005 108

71 24 Non-MTX-IR

8 8 Bucillamine 200 mg/d

6

Capell 2007 106 165 12 Non-MTX-IR

15 12.5 SSZ 2 g/d 9

Islam 2000 110 54 6 Not clear 7.5-15 SSZ 2 g/d 3

Abbreviation: - DMARD-N = DMARD naïve patients, MTX-IR = MTX inadequate response patients, Non-MTX-IR = Non-MTX DMARDs inadequate response patients, # Van Tulder’s scale, MTX = methotrexate, SSZ = sulfazalazine, HCQ =hydroxychloroquine, CQ = chloroquine, LEF= leflunomide, CSA =cyclosporin, AZA = azathioprine, im Gold = intramuscular gold

64

Table 2B Detailed characteristics of the included studies

Study Study design Participants Intervention Outcomes measured Haagsma 1997

Randomized controlled trial, double blind Design:- Parallel Sample size :- 36 (MTX+SSZ), 35 (MTX+placebo), 34(SSZ) Trial duration:- 52 weeks Analysis:- Intention-to-treat, Last observation carried forward for missing data

Active RA (DAS >3) with disease duration less than 1 year and DMARDS naive Mean age (SD) :- 57(12.2) yrs MTX+SSZ, 59.4(13.2) yrs MTX Female :- 67% MTX+SSZ, 66% MTX Disease duration (SD) :- 2.6(1.4) months- MTX+SSZ, 3(2.3) months- MTX Rheumatoid factor + :-94% MTX+SSZ, 94% MTX Mean dose of MTX:- 7.5 mg/wk MTX+SSZ, 15 mg/wk MTX Concomitant treatment - no data

SSZ 3g/d+MTX 7.5 mg/wk vs. MTX 15 mg/wk+placebo vs. SSZ 3 g/d +placebo

Ritchie articular index Swollen joint Tender joint Pain (0-100 VAS) Patient global assessment (0-100 VAS) HAQ ESR

Dougados 1999

Randomized controlled trial, double blind Design :- Paralell Sample size :- 68 (MTX+SSZ), 69 (MTX+placebo) Trial duration:- 52 weeks Analysis:- Intention-to-treat, Last observation carried forward for missing data

RA with less than 1 year of disease duration Active disease (DAS>3) DMARDS and steroid naive Mean age (SEM) :- 52(2) yrs MTX+SSZ, 50(2) yrs MTX Female :- 77% MTX+SSZ, 74% MTX Disease duration (SEM) :- 10.6(1) months- MTX+SSZ, 18.4(5.2) months- MTX Rheumatoid factor + :- 71% MTX+SSZ, 62% MTX Concomitant treatment - no data

SSZ 3 g/d+MTX 15 mg/wk vs. MTX, SSZ 3 g/d+placebo

ACR EULAR response Tender joint Swollen joint Pain (0-100 VAS) Patient global assessment (1-5 Likert scale) Physician global assessment (1-5 Likert scale) HAQ Sharp's score

Merchesoni 2003

Randomized controlled trial, single blind(the clinical investigator) Design :- Paralell Sample size :- 30 (MTX+CSA), 30 (MTX)

Active RA, DMARDS naïve Mean age (SD) :- 46.6(10.5) yrs MTX+CSA, 49.3(10.2) yrs MTX Female :- 93% MTX+CSA, 90% MTX Disease duration (SD) :- 0.9(0.7)

CSA up to 4 mg/kg/d+MTX up to 20mg/wk im vs.MTX up to 20 mg/wk

ACR HAQ Sharp/vDH

65

Trial duration:- 12 months Analysis:- Intention-to-treat, Last observation carried forward for missing data

yrs- MTX+CSA, 0.9(0.7) yrs- MTX Rheumatoid factor + 36% MTX+CSA, 74% MTX Mean dose of MTX (SD):- 9.5 (1.7) mg/wk in CSA+MTX, 11.2(3.4) mg/wk in MTX Mean dose of CSA (SD):- 2.5 (0.6) mg/kg/d Concomitant treatment :– no more than 10 mg/d of prednisolone and NSAIDS was permitted

Taschioglu 2003

Randomized controlled trial, open label Design:- Paralell Sample size :- 35 (MTX+SSZ), 35 (MTX) analysed only completers:- 27(MTX+SSZ) + 28 (MTX) Trial duration:- 12 months Analysis of missing data or withdrawals was not described

Active (DAS>3) RA with less than 1 year of disease duration, DMARDS and steroid naive Mean age (SD) :- 45.88(6.46) yrs MTX+SSZ, 45.16(5.93) yrs MTX Female :- 81% MTX+SSZ, 86% MTX Disease duration (SD) :- 6.9(6.35) months- MTX+SSZ, 7.48(4.03) months- MTX Rheumatoid factor + :- 85% MTX+SSZ, 88% MTX Mean dose of MTX:- 7.5 mg/wk both groups Concomitant treatment - NSAIDS were allowed during the study period

MTX 7.5 mg/kg + SSZ 2g/d vs. MTX 7.5 mg/wk

Swollen joint Ritchie articular index Pain (0-100 VAS) HAQ ESR,CRP

Hetland 2006

Randomized controlled trial, double blind Design :- Paralell Sample size :- 80 (MTX+CSA), 80 (MTX +placebo) Trial duration:- 52 weeks

Active RA with less than 6 months' duration and DMARDS naive Median age (IQR) :- 53.2(44.5-62.4) yrs MTX+CSA, 51(39.5-62.5) yrs MTX Female :- 64% MTX+CSA, 70%

MTX 20 mg/wk+CSA 2.5 mg/kg/d vs. MTX 20 mg/wk Intra-articular injection of betamethasone was given in all swollen joints (maximum 4 joints or 4 ml per visit) at weeks 0,2, 4, 6, 8 and every 4

ACR DAS28 HAQ Larsen's score

66

Analysis:- Intention-to-treat, Last observation carried forward for missing data

MTX Disease duration, median (IQR) :- 3.2(2.4-4.6) months MTX+CSA, 3.9(2.8-4.6) months MTX Rheumatoid factor + :- 70% MTX+CSA, 59% MTX Mean dosage of MTX :- 12.5 mg/wk MTX+CSA, 15 mg/wk MTX Concomitant treatment :- non-steroidal anti-inflammatory drugs 60% MTX+CSA, 66% MTX.

weeks thereafter up to week 52

O’Dell 2006

Randomized controlled trial, double blind Design :- Paralell Sample size :- 18 (Doxycycline 20 mg twice daily+MTX) , 24 Doxycycline 100 mg twice daily+MTX and 24 MTX+placebo Trial duration:- 2 years Analysis:-Intention-to-treat

Active RA with 6 weeks to less than 1 year of disease duration and had positive rheumatoid factor DMARD naive Mean age (range) :- 49.5(35-47) yrs doxy 100 mg+MTX, 49.9(27-74) yrs doxy 20 mg+MTX, 55.7(41-47) yrs MTX+placebo Female :- 67% doxy 100 mg+MTX, 89% doxy 20 mg+MTX and 70% MTX Disease duration (SD) :- 5(3.1) months-doxy 100 mg+MTX , 5.4(2.9) doxy 20 mg+MTX, 4.8(2.7) months- MTX Rheumatoid factor + :- 100% all three groups Mean dose of MTX:- no data Concomittant treatment - NSAIDS and prednisolone less than 7.5 mg/d were permitted. A total 2 intra-articular steroid injection were allowed but not within 6 weeks prior to the

Doxycycline 20 mg twice daily + MTX 7.5-17.5 mg/wk Doxycycline 100 mg twice daily + MTX 7.5-17.5 mg/wk Placebo + MTX 7.5-17.5 mg/wk

Tender joint Swollen joint Patient global assessment (0-10 VAS) Physician global assessment (0-10 VAS) HAQ ESR

67

evaluation period Tugwell 1995

Randomized controlled trial, double blind Design:- Step-up Sample size :- 75 (MTX+CSA), 73 (MTX+placebo) Trial duration:- 6 months Analysis:- Intention-to-treat, Last observation carried forward for missing data

RA who had partial response to MTX 15 mg/wk at stable dose for at least 3 months Mean age (SD) :- 55.4(12.9) yrs MTX+CSA, 54.3(14.5) yrs MTX Female :- 72% MTX+CSA, 73% MTX Mean dose of MTX (SD):- equal or less than 15 mg/wk Mean dose of CSA (SD):- 2.97(1.02) mg/kg/d Disease duration (SD) :- 11.2(8.3) months- MTX+CSA, 9.4(7.8) months- MTX Concomitant treatment - no more than 10 mg/d of prednisolone was permitted

CSA 2.5 mg/kg/d - 5mg/kg/d+ previous dose of MTX vs. previous dose of MTX

Tender joint Swollen joint Pain (0-100 VAS) Patient global assessment (0-10 VAS) Physician global assessment (0-10 VAS) ACR HAQ ESR

Kremer 2002

Randomized, double-blind, placebo-control trial Design :- Step-up Sample size at entry : MTX+Placebo -133, MTX+Leflunimide -133 Trial duration : 24 wk Analysis:- Intention-to-treat

Active RA despite taking stable dose of MTX 10-20 mg/wk for at least 6 months Mean age (SD) :- 55.6(11.7) LEF, 56.6(11.37) placebo Female: - 99(76.2%) LEF , 107(81%) placebo Disease duration :- 10.5(8.35) y LEF, 12.7(9.56) y placebo Positive rheumatoid factors: - 99(79%) LEF, 113(88%) placebo Mean dose of MTX(SD):- 16.8(2.7) MTX+LEF, 16.1(2.9) MTX Concomitant treatment:-systemic steroid: - 77(59.2%) LEF, 86(64.7%) placebo

LEF 20 mg/d + previous dose of MTX vs. Placebo + previous dose of MTX

Tender joint Swollen joint Pain (0-100 VAS) Patient global assessment (0-100 VAS) Physician global assessment (0-100 VAS) HAQ ESR CRP

68

Lehman 2005

Randomized controlled trial, double blind Design :- Step-up Sample size :- 38 (MTX+ intramuscular gold), 27 (MTX+placebo) Trial duration:- 48 weeks Analysis:- Intention-to-treat

RA with disease duration more than 4 months and less than 10 years suboptimal response at least 12 wk of MTX equal or more than 15 mg/wk Mean age (SD) :- 51(11) yrs MTX+gold, 54(13) yrs MTX+Placebo Female :- 84% MTX+gold, 78% MTX Disease duration (SD) :- 3.4(2.5) yrs MTX+gold, 2.8(2.7) yrs MTX Rheumatoid factor + :- 67% MTX+gold, 63% MTX Mean dosage of MTX (SD) :- 18(5.1) mg/wk MTX+ gold, 18(6.5) mg/wk MTX Concomitant treatment :- non-steroidal anti-inflammatory drugs:- 92% MTX+gold, 89% MTX systemic steroid:- 18% MTX+gold, 52% MTX

- MTX, folic acid and prednisolone (up to 10 mg/d) had to have been received at a stable dosage for 4 weeks - stable dose of previous of MTX+Gold 10-50 mg/wk or as tolerated vs. Previous dose of MTX +placebo

Tender joint Swollen joint Pain (0-100 VAS) Patient global assessment (0-100 VAS) Physician global assessment (0-100 VAS) HAQ ESR ACR

Jarette 2006

Randomized controlled trial, double blind Design :- Step-up Sample size :- 18 (MTX+Zoledronic acid), 21 (MTX+placebo) Trial duration:- 26 weeks Analysis:- Intention-to-treat

RA symptom for less than 2 years active disease and clinical synovitis in at least the wrist or hand joints were on MTX 4 weeks before randomization Mean age (range) :- 50.2(30-76) yrs MTX+Zoledronic acid, 53.5(33-72) yrs MTX+placebo Female :- 55.6% MTX+Zolindronic acid, 57.1% MTX+placebo Disease duration (range) :- 5.6 (0.4-20.6) months

Zoledronic acid 5 mg infusion at baseline and 13 week +MTX 7.5-20 mg/wk vs. MTX +placebo infusion

Tender joint Swollen joint Pain (0-100 VAS) Patient global assessment (0-100 VAS) Physician global assessment (0-100 VAS) MRI of the second to fifth proximal interphalangeal and metacarpophalageal joints and of wrist

69

MTX+Zolindronic acid, 5.5 (0.4-14.2) months MTX Rheumatoid factor + :- 83% MTX+Zolindronic acid, 71% MTX Mean dosage of MTX :- 14 mg/wk MTX+ Zolindronic acid , 11.9 mg/wk MTX Concomitant treatment:- non-steroidal anti-inflammatory drugs:- 94% MTX+Zolindronica acid, 100% MTX Intra-articular or intra-muscular steroid was not permitted

Ogrendik 2007

Randomized controlled trial, double blind Design:- Step-up Sample size :- 38 (MTX+levofloxacin), 38 (MTX+placebo) Trial duration:- 6 months Analysis :- Intention-to-treat, Last observation carried forward for missing data

Active RA Mean age (SD) :- 51(9) yrs MTX+levofloxacin, 49(10) yrs MTX+Placebo Female :- 71% MTX+ levofloxacin, 74% MTX Disease duration (SD) :- 13(9) yrs MTX+ levofloxacin, 12(8) yrs MTX Rheumatoid factor + :- 84% MTX+ levofloxacin, 74% MTX Mean dosage of MTX (SD) :- 15(8.3) mg/wk MTX+ levofloxacin, 17.5(9.1) mg/wk MTX Concomitant treatment:- systemic steroid:- 63% MTX+ levofloxacin, 68% MTX

Before receiving the study drugs, all patients had been taking MTX 15-25 mg/wk for at least 6 months and then Levofloxacin 500 mg/d + previous dose of MTX vs. Placebo + previous dose of MTX

Tender joint Swollen joint Pain (0-10 VAS) Patient global assessment (0-10 VAS) Physician global assessment (0-10 VAS) HAQ, ESR,CRP

Willkins 1992

Randomized controlled trial, double-blind Design:- Step-up Sample size :- 69(

RA with inadequate disease control or toxic response to treatment with injectable gold (at least 750 mg total dose),

Level I :- MTX 5 mg/week + AZA 50 mg/day vs MTX 5 mg/week Level II:- MTX 7.5 mg/week

Tender joint Swollen joint Patient global assessment (1-4)

70

MTX+AZA), 67(MTX+placebo) Trial duration:- 24 weeks Analysis:- Intention-to-treat

auranofin(6 months of 6 mg daily dose), penicillamine (500 mg daily dose for 3 months) Mean age (range) :- 56(29-79) yrs MTX+AZA, 54(21-85) yrs MTX Female :- 82% MTX+AZA, 74% MTX Disease duration (range) :- 8(1-54) yrs- MTX+AZA, 10(1-40) yrs- MTX Median dose of MTX and AZA:- no data Concomitant treatment - no data

+ AZA 100 mg/day vs MTX 7.5 mg/week Level III:- MTX 15 mg/week + AZA 150 mg/day vs MTX 15 mg/week All subjects entered the study at dosage level I and dosage increase were instituted at week 6, 12 and or 18 in non-responsive patients.

Physician global assessment (1-4) HAQ The primary response was a clinical response of more than 30% improvement from baseline in at least 3 of these parameter at week 24.

Willkins 1995

Continue to the Willikins 1992's study and cross over design at week 24 and were followed up in an open protocol for the ensuring 24 weeks. For those patients who continued with the initial regimen, were followed up in double-blind manner. Analysis :- Intention-to-treat analysis and patients in whom therapy was terminated at any time because of toxicity or lack of efficacy and those who crossed over at week 24 were considered non-responders at week 48

Median dose of MTX:- 7.5 mg/wk in both groups at week 48 Median dose of AZA:- 75 mg/d

Non-responders from Willkins 1992 's study were invited to cross to one of the other treatment regimens (same protocol)

Same as Willikins 1992 and radiograph of hands and wrists

Ferraz 1994

Randomized controlled trial, double blind Design :- Paralell

Active disease RA and had failed to respond to NSAIDS and at least one DMARD

MTX 7.5 mg/week + CQ 250 mg/day vs MTX 7.5 mg/week + placebo

Tender joint Swollen joint Pain (0-10 VAS)

71

Sample size :- 41 (MTX+CQ), 41 (MTX+Placebo) Trial duration:- 6 months Analysis of missing data or withdrawals was not described

had not used any DMARDS in the past 2 months , were on stable dose (up to 7.5 mg/d) of prednisolone and NSAIDS for at least 4 weeks Mean age (SD) :- 49.7(13.9) yrs MTX+CQ, 43.6(11.9) yrs MTX Female :- 82% MTX+CQ, 85% MTX Disease duration (SD) :- 9.24(7.94) yrs- MTX+CQ, 6.19(4.74) yrs- MTX Rheumatoid factor + :-24% MTX+CQ, 26% MTX Mean dose of MTX:- 7.5 mg/wk both groups Concomitant treatment - systemic steroid 24% MTX+CQ, 23% MTX

HAQ ESR

Haagsma 1994

Randomized controlled trial, open label Design :- Step-up Sample size :- 22 (MTX+SSZ), 18 (MTX) Trial duration:- 24 weeks Analysis:- Intention-to-treat, Last observation carried forward for missing data

RA patients who had an insufficient response to SSZ according to their treating physician were considered for selection. Mean age (SD) :- 59.3(12.3) yrs MTX+SSZ, 51.8(13.9) yrs MTX Female :- 82% MTX+SSZ, 78% MTX Disease duration (SD) :- 4.7(4.2) yrs- MTX+SSZ, 5.3(4.2) yrs- MTX Rheumatoid factor + :-77% MTX+SSZ, 72% MTX Mean dose of MTX:- 7.9 mg/wk MTX+SSZ, 8.3 mg/wk MTX Concomitant treatment - no data

MTX 15 mg/week + SSZ 2 g/day vs. MTX 15 mg/week

Ritchie articular index Swollen joint Pain (0-100 VAS) DAS ESR

O’Dell 1996

Randomized controlled trial, double blind

Active RA with more than 6 months of disease duration and

MTX 17.5mg/wk+SSZ 2 g/d+ HCQ 400mg/d vs. MTX

Tender joint Swollen joint

72

Design:- Paralell Sample size :- 31(MTX+SSZ+HCQ), 36 (MTX+placebo) Trial duration:- 12 months Analysis:- Intention-to-treat and patients who withdrew were considered to have had treatment failure

poor response to treatment with at least one of the following :gold, HCQ, Penicillamine, SSZ,MTX Mean age (range) :- 50(27-67) yrs MTX+SSZ+HCQ, 50(21-69) yrs MTX+placebo Female :- 66% MTX+SSZ+HCQ, 70% MTX Disease duration (SD) :- 10(10) months- MTX+SSZ+HCQ, 10(8) months- MTX Rheumatoid factor + :- 84% MTX+SSZ+HCQ, 89% MTX Mean dose of MTX:- no data Concomitant treatment - syetemic steroid of equal or less than 10 mg/d 52% in MTX+SSZ+HCQ and 53% in MTX and NSAIDS were permitted

17.5mg/wk+placebo Patient global assessment (0-10 VAS) Physician global assessment (0-10 VAS) ESR

Hanyu 1999

Randomized controlled trial, open label Design :- Step-up Sample size :- 19 (MTX+previuos DMARDS), 18 (MTX) Trial duration:- 5 years Analysis of missing data or withdrawals was not described

Active RA and insufficient response to treatment with gold, D-penicillamine, bucillamine or sulfasalazine. Mean age (SD) :- 55.6(2.2) yrs MTX+ previous DMARDS, 54(2.9) yrs MTX Female :- 79% MTX+previous DMARDS, 83% MTX Disease duration (SD) :- 13.1(2.1) yrs- MTX+previous DMARDS, 13.8(1.5) yrs- MTX Rheumatoid factor + :-89% MTX + previous DMARDS, 94% MTX Mean dose of MTX:- 5 mg/wk MTX combo, 7.5 mg/wk MTX Concomitant treatment -

MTX 5 mg/wk+ previous DMARDS(SSZ, Penicillamine, Bucillamine, Gold) vs. MTX 7.5 mg/wk

Joint score Lansbury index (calculated from duration of morning stiffness, grip strength, ESR, joint score) grip strength morning stiffness ESR CRP

73

systemic steroid 74% MTX+previous DMARDS, 78% MTX

Ichikawa 2005

Randomized controlled trial, double blind Design :- Paralell Sample size :- 24 (MTX+Bucillamine), 41 (MTX+Placebo) Trial duration:- 96 weeks Analysis:- Intention-to-treat

Active RA, MTX or Bucillamine(BUC) naive, never received prednisolone more than 7.5 mg/day Mean age (SD) :- 49.2(13.9) yrs MTX+BUC, 52.7(9.3) yrs MTX Female :- 83.3% MTX+BUC, 69.6% MTX Disease duration (SD) :- 10.6(6.6) yrs- MTX+BUC 8.2(4.8) yrs- MTX Rheumatoid factor + :-96% MTX+BUC, 83% MTX Mean dose of MTX:- 8 mg/wk both groups Concomitant treatment - systemic steroid 17% MTX+BUC, 35% MTX

MTX 8 mg/wk +Bucillamine 200 mg/d vs MTX 8 mg/wk

Tender joint Swollen joint Pain (0-100 VAS) Patient global assessment (0-100 VAS) Physician global assessment (0-100 VAS) HAQ ESR, CRP

Capell 2007

Randomised controlled trial, double-blind Design :- Step-up Sample size :- 687 in phase I and 56 (MTX+SSZ), 55(SSZ+placebo) and 54(MTX+placebo) in phase II Trial duration:- 18 months Analysis:- Intention-to-treat, Last observation carried forward for missing data

RA with less than 10 years of disease duration Active RA ( defined by DAS>2.4) Mean age (range) :- 56(30-78) yrs MTX+SSZ, 53(34-79) yrs MTX Female :- 75% MTX+SSZ, 79% MTX Disease duration (range) :- 1(1-9) yrs MTX+SSZ, 1(1-9) yrs MTX Rheumatoid factor + :- 68% MTX+SSZ, 65% MTX Median dose of MTX:- 12.5 mg/wk MTX+SSZ, 15 mg/wk MTX Concomitant non-steroidal anti-

Phase I:- All patients recieved SSZ 40 mg/kg/d or 4 g/d maximum for the initial 6 months and then patients who had DAS equal or more than 2.4 were enrolled into phase II Phase II:- Patients were randomly assigned to one of three groups including MTX 25 mg/wk+SSZ 2g/d MTX 7.5-25 mg/wk + placeboSSZ 40 mg/kg/d or 4 g/d maximum+placebo

ACR EULAR response DAS Ritchie articular index Swollen joint Pain (0-100 VAS) Patient global assessment (0-100 VAS) Physician global assessment (0-100 VAS) ESR, CRP HAQ Sharp/vDH's score,

74

inflammatory drugs and other drugs were continued. Intra-articular or intra-muscular steroid was permitted but not within 1 months of assessment period

Islam 2000

Randomized controlled trial, open label Design :- Parallel Sample size :- 27 (MTX+SSZ), 27 (MTX) Trial duration:- 6 months Analysis:- analysed only completers 19 (MTX+SSZ), 23 (MTX)

RA with less than 3 months of disease duration Mean age (SD) :- 39.74(11.08) yrs MTX+SSZ, 32.35(14.79) yrs MTX Female :- 79% MTX+SSZ, 83% MTX Mean dose of MTX:- no data Concomitant treatment - no data

SSZ 2 g/d+MTX 7.5-15 mg/wk vs. MTX 7.5-15 mg/wk

Tender joint Swollen joint Patient global assessment (0-10 VAS) Physician global assessment (0-10 VAS) Functional class (I-IV) ESR

Abbreviation: RA= Rheumatoid arthritis, DAS = Disease Activity Score, HAQ = Health Assessment Questionnaire, ESR = erythrocyte sedimentation rate, ACR = American College of Rheumatology, EULAR = European League Against Rheumatism, SD = standard deviation, VAS =visual analogue scale, SEM = standard error of mean, IQR = interquatile range, MTX = methotrexate, SSZ = sulfazalazine, HCQ =hydroxychloroquine, CQ = chloroquine, LEF= leflunomide, CSA =cyclosporin, AZA = azathioprine, im Gold = intramuscular gold

75

Table 3 Quality assessment of the included studies

* Van Tulder’s scale, ** ITT = Intention-to-treat analysis

Study Total score

(0-11)*

Adequate randomization

Blinded patients

Blinded care

provider

Blinded outcome assessor

Treatment allocation concealed

Acceptable drop-out

rate

Acceptable compliance

Similarity of baseline

characteristics between groups

Co-intervention

similar or avoid

ITT ** analysis

used

Similarity of the

timing of outcome

assessment Haagsma 1997 10 Yes Yes Yes Unclear Yes Yes Yes Yes Yes Yes Yes Dougadous 1999 7 Unclear Yes Yes Unclear Unclear Yes Yes Yes Unclear Yes Yes Marchesoni 2003 8 Yes No Yes No Yes Yes Unclear Yes Yes Yes Yes Tascioglu 2003 4 Unclear Unclear Unclear Yes No Yes Unclear Yes Unclear No Yes Hetland 2006 8 Yes Yes Yes No Yes Yes Unclear Yes No Yes Yes O' Dell 2006 7 Yes Yes Yes Unclear Yes No Unclear Yes Unclear Yes Yes Tugwell 1995 7 Unclear Yes Yes Yes Yes No Unclear Yes Unclear Yes Yes Kremer 2002 10 Yes Yes Yes Unclear Yes Yes Yes Yes Yes Yes Yes Lehman 2005 9 Yes Yes Yes Yes Yes Yes Unclear Yes No Yes Yes Jarette 2006 7 Unclear Yes Yes Unclear Unclear Yes Yes Yes No Yes Yes Ogrendik 2007 8 Unclear Yes Yes Unclear Unclear Yes Yes Yes Yes Yes Yes Willikins 1992 8 Yes Yes Yes Unclear Yes No Unclear Yes Yes Yes Yes Ferraz 1994 9 Yes Yes Yes Yes No Yes Yes Yes Yes No Yes Haagsma 1994 7 Yes No No No No Yes Yes Yes Yes Yes Yes O'Dell 1996 8 Yes Yes Yes Yes Yes No Unclear Yes No Yes Yes Hanyu 1999 3 Unclear No No No No No Unclear Yes Yes Unclear Yes Ichikawa 2005 6 Unclear Yes Yes No Unclear Yes Unclear Yes No Yes Yes Capell 2007 9 Yes Yes Yes Yes Yes No Yes Yes No Yes Yes Islam 2000 3 Unclear Unclear Unclear Unclear Unclear Yes Unclear Yes Unclear No Yes

76

Table 4 Summary of the results of efficacy (dichotomous data) comparing MTX

combination to monotherapy

DMARD naïve RR (95%CI)

MTX inadequate response

RR (95%CI)

Non-MTX inadequate response

RR (95%CI) ACR20 1.22

(0.88-1.68) 2.51*

(1.92-3.28) 1.85*

(1.21-2.83) ACR50 1.76

(0.64-4.85) 4.54*

(2.51-8.2) 1.69

(0.95-2.99) ACR70 2.41*

(1.07-5.44) 5.59*

(2.08-15.01) 1.93

(0.1-20.65) ACR remission 1.27

(0.8-2.03) No data No data

EULAR good response

0.97 (0.69,1.37)

No data 3.38 (0.73,15.53)

EULAR moderate response

1.37 (0.81,2.33)

No data No data

EULAR remission 1.26 (0.84,1.88)

No data 3.86 (0.45,33.42)

Withdrawal due to lack of efficacy

0.63 (0.34,1.17)

0.42* (0.21-0.84)

0.37* (0.16-0.87)

* Statistically significant

Abbreviation: - RR = relative risk, 95%CI = 95% confidence interval, MTX = methotrexate, DMARD = Disease modifying anti-rheumatic drug, ACR = American College of Rheumatology, EULAR = European League Against Rheumatism

77

Table 5 Summary of the results of efficacy (continuous data) comparing MTX combination

to monotherapy

DMARD naïve

WMD or SMD (95%CI)

MTX inadequate response

WMD or SMD (95%CI)

Non-MTX inadequate response

WMD or SMD (95%CI)

Swollen joint -1.05 (-2.7,0.6)

-0.45* (-0.63, -0.27)

-0.96 (-1.62, -0.3)

Tender joint -0.18 (-0.64, 0.29)

-0.51* (-0.69, -0.33)

-0.51* (-0.69, -0.33)

Pain (VAS 1-10 cm.) -1.36 (-5.12, 2.4)

-9.72* (-14.7, -4.75)

-5.99 (-24.99, 13.02)

Patient global assessment (VAS 1-10 cm.)

0.7 (-10.24, 11.64)

-8.15* (-14.52, -1.79)

-10* (-19.6, -0.4)

Physician global assessment (VAS 1-10 cm.)

- -10.91* (-18.98,-2.84)

-10* (-14.8,-5.2)

ESR -1.62 (-6.98,3.74)

-0.53 (-11.47,10.41)

-4.29 (-10.72, 2.13)

CRP 0.09 (-0.38,0.56)

-0.38* (-0.62,-0.13)

-0.44 (-1.09, 0.21)

HAQ 0.1* (0.09,0.11)

-0.28* (-0.36, -0.21)

-0.17 (-0.48, 0.14)

Modified Sharp’s score -3.15* (-5.85, -0.45)

-1.4 (-2.81, 0.01)

-

* Statistically significant Abbreviation: - WMD = weighted mean difference, SMD = standardized mean difference, 95% CI = 95% confidence interval, MTX = methotrexate, DMARD = Disease modifying anti-rheumatic drug, VAS = visual analogue scale, ESR = erythrocyte sedimentation rate, CRP = C-reactive protein, HAQ = Health Assessment Questionnaire

78

Table 6 Summary of the results of toxicity (dichotomous data) comparing MTX

combination to monotherapy

RR (95%CI) (Random effects) Total adverse event MTX+SSZ MTX+LEF MTX+CSA MTX+AZA MTX+im Gold

1.13 (0.94-1.35)

1 (0.94-1.08) 3.62 (0.82-16.30) 1.67 (1.21-2.3) * 2.61 (1.22-5.55)*

Gastrointestinal adverse events MTX+SSZ MTX+LEF MTX+CSA MTX +im Gold

1.75 (1.14-2.67)* 1.67 (1.17-2.4)* 4.13 (0.49-34.89) 0.71 (0.05-10.87)

Abnormal liver function test MTX+SSZ MTX+LEF MTX+CSA MTX+BUC

1.77 (0.29-10.78) 4.3 (2.58-7.15)* 3.1 (0.13-73.16) 3 (0.13-70.02)

Mucositis MTX+SSZ MTX +im Gold

0.62 (0.16-2.34)

9.33 (0.55-158.98)

Hematological adverse events MTX+SSZ MTX +im Gold MTX+BUC

2.36 (0.66-8.48) 1.42 (0.14-14.89) 0.32 (0.01-7.48)

Infection MTX+SSZ MTX+LEF MTX +im Gold

1.35 (0.6-3.04) 0.79 (0.6-1.02) 1.6 (0.82-3.13)

Withdrawal due to adverse events MTX+SSZ MTX+SSZ+HCQ MTX+CQ MTX+CSA MTX+AZA MTX+LEF MTX +im Gold MTX+Antibiotics MTX +BUC MTX+ miscellaneous

1.19 (0.73-1.92) 0.5 (0.14-1.76) 3 (0.33-27.42)

1.88 (1.02-3.5)* 5.18 (1.58-16.95)* 1.82 (0.83-3.97) 2.84 (0.34-24.04) 1.9 (0.48-7.49)

2.88 (0.64-12.82) 1.42 (0.48-4.22)

* Statistically significant Abbreviation: - MTX = methotrexate, SSZ = sulfazalazine, HCQ =hydroxychloroquine, CQ = chloroquine, LEF= leflunomide, CSA =cyclosporin, AZA = azathioprine, im Gold = intramuscular gold, BUC = bucillamine, RR = relative risk, 95%CI = 95% confidence interval

79

Table 7 Real and artifactual causes of between-study variation in effect Real Artifactual

Patient Disease severity

Age

Co-morbidity

Improper randomization

Differential follow-up (non-

comparable groups)

Intervention Time

Duration

Dose

Non-compliance

Cross-over

Co-intervention Drug

Therapy

Undetected co-intervention

Outcome Timing of outcome

Event type

Differential and non-differential

measurement error

80

Table 8 Potential sources of heterogeneity

Study Characteristics

Potential source of heterogeneity Subgroup

Patient • Treatment received prior to randomization

• DMARD naïve • MTX inadequate responder • Non-MTX DMARD

inadequate responder Intervention • Different DMARD combination • MTX+ SSZ (6 studies)

• MTX+ SSZ+HCQ (1 study) • MTX +Leflunomide (1 study) • MTX + CSA (3 studies) • MTX + CQ (1 study) • MTX + AZA (1 study) • MTX + Doxycycline (1 study) • MTX +Levofloxacin (1 study) • MTX + Bucillamine (1 study) • MTX + im Gold (1 study) • MTX + Zolindronic acid (1

study) • MTX+ Previous DMARDs

(Penicillamine, Bucillamine and in Gold) (1 study)

• Different dose of MTX and other DMARD

• MTX dose 5 – 17.5 mg/wk • SSZ dose 1-3 g/d • CSA dose 2.5-5 mg/kg/d

Outcome • Timing of outcome assessment • 6, 12, 24, and 60 months • Outcome measure used • Single variable outcome, e.g.,

Number of swollen joint count and tender joint count, pain score, patient or physician global assessment of disease activity, ESR, and CRP • Composite outcome, e.g., ACR

response, EULAR response, DAS, and DAS28

Study characteristics

• Quality of study (overall) • High versus low

• Criterion for assessing the quality of study

• Met versus not met each criterion

Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrextae, SSZ = sulfazalazine, HCQ =hydroxychloroquine, CQ = chloroquine, LEF= leflunomide, CSA =cyclosporin, AZA = azathioprine, im Gold = intramuscular gold, BUC = bucillamine, ESR = erythrocyte sedimentation rate, CRP = C-reactive protein, ACR = American College of Rheumatology EULAR = European League Against Rheumatism, DAS =Disease activity score

81

Table 9 Tests of heterogeneity using forest plots and eyeball test , Cochran’s Q test, and I2

test for withdrawal due to lack of efficacy and toxicity, withdrawal due to lack of efficacy,

and withdrawal due to toxicity

Outcome Withdrawal due to

lack of efficacy and

toxicity

Withdrawal due to

lack of efficacy

Withdrawal due to

toxicity

Forest plot

Eyeball Moderately

overlapped

Highly overlapped Highly overlapped

Cochran’s Q test χ2= 20.98, df = 12,

p = 0.05

χ2 = 9.52, df = 11

p = 0.57

χ2 = 15.13, df = 16,

p = 0.52

I2 42.8% 0% 0%

Abbreviation: - χ2 = chi-square, df = degree of freedom, RR = relative risk, 95%CI = 95% confidence interval

82

Table 10 Outcome measures for efficacy used in included studies

Study ACR EULAR DAS DAS 28

Withdrawal due to LOF

RAI SJC TJC Pain (VAS)

PGA (VAS)

MDGA (VAS)

ESR CRP HAQ X-ray

Haagsma 1994

X X X X X

Haagsma 1997

X X X X X X X X X X

Dougados 1999

X X X X X X X X*

Islam 2000

X X X X X

Tascioglu 2003

X X X X X X X

Capell 2007 X X X X X X X X X X X X X X O’Dell 1996 X X X X X X Lehman 2005

X X X X X X X X X X

Ferraz 1994 X X X X X X Kremer 2002

X X X X X X X X X X

Tugwell 1995

X X X X X X X X X

Marchesoni 2003

X X X X

Hetland 2006

X X X X X

Willkins 1992

Willkins 1995

O’Dell 2006 X X X X X X X X Ogrendik 2007

X X X X X X X X X

Hanyu 1999 X X X Ichikawa 2005

X X

Jarette 2005 X X X X X X

Abbreviation: - ACR =American College of Rheumatology Response criteria, EULAR = European League Against Rheumatism response criteria, DAS =disease activity score, LOF = lack of efficacy, RAI =Ritchie’s articular index, SJC =sSwollen joint count, TJC = tender joint count, VAS Visual analogue scale, PGA = patient global assessment, MDGA = physician global assessment, ESR = erythrocyte sedimentation rate, CRP = C-reactive protein, HAQ = Health Assessment Questionnaire

83

Table 11 Toxicity reported in the included studies

Study Total adverse events

Gastrointestinaladverse events

Abnormal liver function

Mucositis Hematological adverse events

Infection Withdrawal Due to adverse events

Haagsma 1994 X X X X X Haagsma 1997 X X X X X X X Dougados 1999 X X X X X Islam 2000 X Tascioglu 2003 X X X X X X X Capell 2007 X O’Dell 1996 X Lehman 2005 X X X X X X Ferraz 1994 X Kremer 2002 X X X X X Tugwell 1995 X Marchesoni 2003

X X X X

Hetland 2006 X Willkins 1992 X Willkins 1995 X O’Dell 2006 X Ogrendik 2007 X Hanyu 1999 X Ichikawa 2005 X X X Jarette 2005

84

Table 12 Subgroup analysis: - Study design and Population (Pervious DMARD use)

P-value for comparison to Outcome

Study design

RR

(95%CI) MTX-IR Non-MTX-IR

DMARD naive 0.63 (0.34 to 1.17)

0.45 0.24

MTX-IR 0.42 (0.21 to 0.84)

- 0.60


Non MTX-IR 0.47 (0.16 to 0.87)

- -

DMARD naive 1.72 (1.04 to 2.83)

0.85 0.54

MTX-IR 1.89 (1.05 to 3.41)

- 0.46

Withdrawal due to toxicity

Non MTX-IR 1.53 (0.74 to 3.18)

- -

DMARD naive 1.16 (0.7 to 1.93)

0.45 0.27

MTX-IR 0.86 (0.49 to 1.51)

- 0.76

Withdrawal due to lack of efficacy and toxicity

Non MTX-IR 0.75 (0.41 to 1.35)

- -

Abbreviation:- DMARD = disease modifying anti-rheumatic drug, MTX = methotrexate, MTX-IR = MTX inadequate responder, Non-MTX-IR = Non-MTX DMARD inadequate responder, RR = relative risk, 95%CI = 95% confidence interval

85

Table 13 Subgroup analysis: - Trial duration

RR, random effects (95%CI)

Meta-regression analysis (Univariate analysis)

Outcome Duration > 6 months

Duration ≤ 6 months

Coefficient (95%CI)

RR ratio P value


0.47 (0.29 to 0.77)

0.45 (0.21 to 0.94)

0.05 (-0.88 to 0.97)

1.05 (0.41 to 2.64)

0.92


1.43 (1 to 2.05)

1.98 (1.09 to 3.6)

-0.27 (-0.97 to 0.43)

0.76 (0.38 to 1.53)

0.43


0.9 (0.65 to 1.23)

0.88 (0.39 to 1.99)

0.1 (-0.78 to 0.98)

1.1 (0.46 to 2.67)

0.81

Abbreviation:- RR = relative risk, 95%CI = 95% confidence interval

86

Table 14 Subgroup analysis: - Study quality (high versus low)

Using 50% met criteria



Dependent variable

High quality

(score ≥ 6)

Low quality

(score < 6)

Coefficient (95%CI)

RR ratio P value


0.45 (0.3 to 0.67)

0.74 (0.17 to 3.16)

-0.52 (-2.23 to 1.2)

0.59 (0.1 to 3.32

0.52


1.61 (1.16 to 2.22)

1.75 (0.75 to 4.08)

-0.09 (-1.14 to 0.97)

0.91 (0.32 to 2.64)

0.87


0.87 (0.61 to 1.23)

1.18 (0.57 to 2.46)

-0.29 (-1.5 to 0.92)

0.75 (0.22 to 2.51)

0.61

Using “Mean”



Dependent variable High

quality (score > 7.15)

Low quality

(score ≤ 7.15)

Coefficient (95%CI)

RR ratio P value


0.46 (0.23 to 0.93)

0.49 (0.28 to 0.85)

-0.17 (-1.05 to 0.7)

0.84 (0.35 to 2)

0.67


1.81 (1.23 to 2.67)

1.91 (1.11 to 3.29)

-0.05 (-0.82 to 0.72)

0.95 (0.44 to 2.05)

0.89


0.95 (0.52 to 1.73)

0.9 (0.66 to 1.23)

0.06 (-0.77 to 0.88)

1.06 (0.46 to 2.4)

0.88

Abbreviation: - RR = relative risk, 95%CI = 95% confidence interval

87

Table 15 Subgroup analysis and Meta-regression analysis using “Withdrawal due to lack of efficacy”

RR, random effects

(95%CI)

Meta-regression analysis

(Univariate analysis)

Item Met Not met Coefficient

(95%CI) RR ratio (95%CI)

P value

Randomization, adequate

0.48 (0.29 to 0.81)

0.42 (0.2 to 0.91)

0.11 (-0.9 to 1.12)

1.12 (0.41 to 3.06)

0.81

Blinding patients, performed

0.45 (0.3 to 0.67)

0.74 (0.17 to

3.16)

-0.52 (-2.23 to 1.2)

0.59 (0.11 to 3.32)

0.52

Blinding care providers, performed

0.45 (0.3 to 0.67)

0.74 (0.17 to

3.16)

-0.52 (-2.23 to 1.2)

0.59 (0.11 to 3.32)

0.52

Blinding outcome assessors, performed

0.35 (0.18 to 0.66)

0.55 (0.34 to

0.88)

-0.48 (-1.4 to 0.43)

0.62 (0.25 to 1.54)

0.27

Treatment allocation concealment, adequate

0.46 (0.3 to 0.7)

0.49 (0.22 to

1.09)

-0.04 (-1.08 to

0.99)

0.96 (0.34 to 2.69)

0.93

Drop-out rate, acceptable

0.57 (0.32 to 1)

0.4 (0.24 to

0.67)

0.31 (-0.56 to

1.19)

1.36 (0.57 to 3.29)

0.44

Compliance, acceptable

0.73 (0.39 to 1.35)

0.36 (0.22 to

0.58)

0.66 (-0.24 to

1.56)

1.93 (0.79 to 4.76)

0.13

Co-intervention, similar

0.74 (0.36 to 1.53)

0.39 (0.25 to

0.61)

0.6 (-0.36 to

1.56)

1.82 (0.7 to 4.76)

0.21

ITT, performed 0.44 (0.3 to 0.65)

0.94 (0.25 to

3.53)

-0.71 (-2.32 to

0.91)

0.49 (0.1 to 2.48)

0.35

Abbreviation: - RR = relative risk, 95%CI = 95% confidence interval, ITT = Intention-to-treat analysis

88

Table 16 Subgroup analysis and Meta-regression analysis using “Withdrawal due to toxicity”

RR, random effects

(95%CI)





P value


1.66 (1.06 to

2.62)

1.72 (1.2 to 2.12)

-0.08 (-0.82 to 0.66)

0.92 (0.44 to

1.93)

0.82


1.54 (1.11 to

2.13)

2.09 (1 to 2.12)

-0.3 (-1.23 to 0.62)

0.74 (0.29 to

1.86)

0.49


1.61 (1.16 to

2.22)

1.75 (0.75 to 4.08)

-0.09 (-1.14 to 0.97)

0.91 (0.32 to

2.64)

0.87


1.06 (0.66 to

1.69)

2.03 (1.42 to 2.91)

-0 .65 (-1.29 to -

0.002)

0.52 (0.28 to 1)

0.05


1.63 (1.07 to

2.48)

1.78 (1.03 to 3.08)

-0.13 (-0.91 to 0.65)

0.88 (0.4 to 1.92)

0.73


1.93 (1.29 to

2.88)

1.44 (0.81 to 2.56)

0.38 (-0.29 to 1.04)

1.46 (0.75 to

2.83)

0.25


1.32 (0.87 to 2)

1.89 (1.28 to 2.8)

-0.35 (-1.02 to 0.31)

0.72 (0.36 to

1.36)

0.276


2.35 (1.45 to

3.79)

1.28 (0.9 to 1.84)

0.6 (-0.05 to 1.25)

1.82 (0.95 to

3.49)

0.07

ITT, performed 1.6 (1.14 to

2.25)

1.88 (0.85 to 4.13)

-0.17 (-1.16 to 0.82)

0.84 (0.31 to

2.27)

0.716


89

Table 17 Subgroup analysis and Meta-regression analysis using “Withdrawal due to lack of efficacy and toxicity”

RR, random effects

(95%CI)





P value


0.89 (0.54 to 1.44)

0.95 (0.66 to 1.38)

-0.11 (-0.94 to

0.71)

0.9 (0.39 to 2)

0.77


0.81 (0.58 to 1.12)

1.47 (0.76 to 2.83)

-0.64 (-1.64 to

0.37)

0.53 (0.19 to

1.45)

0.19


0.87 (0.61 to 1.23)

1.18 (0.57 to 2.46)

-0.29 (-1.5 to 0.92)

0.75 (0.22 to 2.5)

0.61


0.72 (0.42 to 1.24)

1.02 (0.74 to 1.43)

-0.41 (-1.16 to

0.33)

0.66 (0.31 to

1.39)

0.25


0.86 (0.56 to 1.33)

0.95 (0.63 to 1.43)

-0.18 (-1.03 to

0.66)

0.84 (0.36 to

1.93)

0.64


1.13 (0.75 to 1.71)

0.71 (0.47 to 1.08)

0.52 (-0.19 to

1.22)

1.68 (0.83 to

3.39)

0.13


1.07 (0.77 to 1.48)

0.78 (0.5 to 1.2)

0.41 (-0.34 to

1.17)

1.51 (0.71 to

3.22)

0.26


1.47 (0.91 to 2.39)

0.71 (0.52 to 0.96)

0.79 (0.13 to 1.45)

2.2 (1.14 to

4.26)

0.02

ITT, performed 0.83 (0.59 to 1.17)

1.34 (0.67 to 2.68)

-0.53 (-1.61 to

0.55)

0.59 (0.2 to 1.73)

0.305


90

Table 18 Summary the results of relative risk and 95% confidence interval comparing between fixed and random effects models

Outcome Fixed effects RR (95%CI)

Random effects RR (95%CI)

ACR 20 • Total 1.77 (1.53,2.04) 1.82 (1.33,2.49) • DMARD naive 1.24 (1.05,1.48) 1.22 (0.88,1.68) • MTX inadequate response 2.53(1.94,3.31) 2.51 (1.92,3.28) • Non-MTX inadequate response 1.87 (1.20,2.91) 1.85 (1.21,2.83) ACR 50 • Total 2.53 (1.83,3.5) 2.41 (1.43,4.05) • DMARD naive 1.66 (1,1.48) 1.76 (0.64,4.85) • MTX inadequate response 4.61 (2.54,8.36) 4.54 (2.51,8.2) • Non-MTX inadequate response 1.65 (0.91,2.97) 1.68 (0.94,2.99)

ACR 70 • Total 3.79 (2.05,7) 3.26 (1.78,5.99) • DMARD naive 2.41 (1.07,5.44) 2.41 (1.07,5.44) • MTX inadequate response 5.99 (2.23,16.11) 5.59 (2.08,15.01) • Non-MTX inadequate response 1.93 (0.18,20.65) 1.93 (0.18,20.65)

ACR remission • Total • DMARD naive 1.27 (0.8,2.03) 1.27 (0.8,2.03) • MTX inadequate response - - • Non-MTX inadequate response - - EULAR good response • Total 1.09 (0.78,1.52) 1.06 (0.7,1.6) • DMARD naive 0.97 (0.69,1.37) 0.97 (0.69,1.37) • MTX inadequate response - - • Non-MTX inadequate response 3.38 (0.73,15.53) 3.38 (0.73,15.53) EULAR moderate response • Total - - • DMARD naive 1.37 (0.81,2.33) 1.37 (0.81,2.33) • MTX inadequate response - - • Non-MTX inadequate response - - EULAR remission • Total 1.35 (0.91,2.01) 1.33 (0.83,2.12) • DMARD naive 1.26 (0.84,1.88) 1.26 (0.84,1.88)

91

• MTX inadequate response - - • Non-MTX inadequate response 3.86 (0.45,33.42) 3.86 (0.45,33.42) Withdrawal due to lack of efficacy • Total 0.45 (0.31, 0.65) 0.47 (0.32, 0.69) • DMARD naive 0.65 (0.35,1.22) 0.63 (0.34,1.17) • MTX inadequate response 0.43 (0.23,0.79) 0.42 (0.21,0.84) • Non-MTX inadequate response 0.34 (0.17,0.67) 0.37 (0.16,0.87) Withdrawal due to toxicity • Total 1.6 (1.26,2.2) 1.56 (1.17, 2.09) • DMARD naive 1.76 (1.07,2.87) 1.72 (1.04,2.83) • MTX inadequate response 1.91 (1.06,3.44) 1.89 (1.05,3.41) • Non-MTX inadequate response 1.47 (0.97,2.24) 1.53 (0.74,3.18) Withdrawal due to Lack of efficacy and toxicity

• Total 0.89 (0.72, 1.1) 0.89 (0.66, 1.21) • DMARD naive 1.18 (0.79,1.74) 1.16 (0.7,1.93) • MTX inadequate response 0.92 (0.63,1.34) 0.86 (0.49,1.51) • Non-MTX inadequate response 0.69 (0.49,0.98) 0.75 (0.41,1.35)

Abbreviation: - RR = relative risk, 95%CI = 95% confidence interval, DMARD = disease modifying anti-rheumatic drug, MTX = methotrexate, ACR = American College of Rheumatology, EULAR = European League Against Rheumatism

92

Table 19 Search strategies comparing between Ovid-MEDLINE and PubMed

Ovid Search term (number of citation)

PubMed Search term (number of citation)

1. arthritis, rheumatoid/ (67002) 1. Arthritis, Rheumatoid [Mesh:noexp] (67291)

2. caplan's syndrome/ (133) 2. caplan syndrome[Mesh:noexp] (133) 3. felty's syndrome/ (595) 3. Felty's Syndrome[Mesh:noexp] (595)4. rheumatoid nodule/ (762) 4. Rheumatoid Nodule[Mesh:noexp]

(757) 5. still's disease, adult-onset/ (611) 5. Still's Disease, Adult Onset

[Mesh:noexp] (599) 6. rheumatism.mp. (6945) 6. rheumatism[All Fields] (11910) 7. caplan's syndrome$.mp. (84) 7. caplan syndrome* (161) 8. felty's syndrome$.mp. (739) 8. felty's syndrome* (751) 9. rheumatoid.mp. (91164) 9. rheumatoid[All Fields] (93993) 10. Methotrexate$.mp. (33979) 10. methotrexate* (34426) 11. amethopterin$.mp. (356) 11. Amethopterin* (397) 12. mexate$.mp. (1) 12. mexate* (1) 13. Abitrexate$.mp. (0) 13. Abitrexate* (0) 14. Amethopterin$.mp. (356) 14. Amethopterin* (397) 15. A Methopterine$.mp. (1) 15. A Methopterine* (1) 16. Ametopterine$.mp. (2) 16. Ametopterine* (16) 17. Antifolan$.mp. (0) 17. Antifolan* (0) 18. Emtexate$.mp. (0) 18. Emtexate* (0) 19. Emthexate$.mp. (0) 19. Emthexate* (0) 20. Emtrexate$.mp. (1) 20. Emtrexate* (1) 21. Enthexate$.mp. (0) 21. Enthexate* (0) 22. Farmitrexate$.mp. (0) 22. Farmitrexate* (0) 23. Folex.mp. (3) 23. Folex* (3) 24. Ledertrexate.mp. (1) 24. Ledertrexate* (1) 25. Methoblastin$.mp. (0) 25. Methoblastin * (0) 26. Methohexate$.mp. (0) 26. Methohexate* (0) 27. Methotrate$.mp. (0) 27. Methotrate* (0) 28. Methotrexat$.mp. (34001) 28. Methotrexat* (34448) 29. Methylaminopterin$.mp. (9) 29. Methylaminopterin* (8) 30. Metotrexat$.mp. (134) 30. Metotrexat* (30) 31. Mtx.mp. (6274) 31. MTX (6405) 32. Novatrex$.mp. (0) 32. novatrex* (0) 33. Rheumatrex.mp. (3) 33. rheumatrex* (3) 34. randomized controlled trial.pt. 34. randomized controlled trial

http://www.ncbi.nlm.nih.gov/sites/?cmd=HistorySearch&querykey=3&tab=&�









93

(263105) [Publication Type] (258826) 35. placebo$.mp. (125474) 35. placebo* (128221) 36. random$.mp. (561059) 36. random* (582840) 37. clinical trial.pt. (446706) 37. clinical trial[Publication Type]

(548249) 38. exp clinical trial as topic/ (210045) 38. Clinical Trials as Topic[Mesh]

(206536) 39. clinical trial$.mp. (613169) 39. clinical trial* (614699) 40. controlled clinical trial.pt. (78151) 40. controlled clinical trial [Publication

Type] (77549) 41. clinical trial, phase i.pt. (9286) 41. clinical trial, phase I [Publication

Type] (9071) 42. clinical trial, phase ii.pt. (14496) 42. clinical trial, phase ii [Publication

Type]) (14182) 43. clinical trial, phase iii.pt. (4571) 43. clinical trial, phase iii [Publication

Type]) (4433) 44. clinical trial, phase iv.pt. (430) 44. clinical trial, phase iv [Publication

Type]) (412) 45. (clinical$ adj2 trial$).mp. (614943) 45. ((clinical*) AND (trial*)) (668136) 46. single-blind method/ (12487 46. Single-Blind Method [Mesh:noexp]

(12200) 47. Double-Blind Method/ (98848) 47. Double-Blind Method [Mesh:noexp]

(97431) 48. "double blind:".mp. (118209) 48. double blind* (118293) 49. ((singl$ or doubl$ or trebl$) adj2

(blind$ or mask$)).mp. (133392) 49. (((singl*) OR (doubl*) OR (trebl*))

AND ((blind*) OR (mask*))) (142681)

50. exp Research Design/ (244739) 50. Research Design[Mesh] (241338) 51. comparative study.pt. (1411129) 51. comparative study [Publication

Type] (1396104) 52. exp Evaluation Studies as topic/

(730924) 52. Evaluation Studies as Topic [Mesh]

(654983) 53. follow-up studies/ (373404) 53. Follow-Up Studies [Mesh:noexp]

(367572) 54. prospective studies/ (250873) 54. prospective studies [Mesh:noexp]

(245950) 55. (control$ or prospectiv$ or

volunteer$).mp. (2383490) 55. control* (2464096) OR prospectiv*

(361547) OR volunteer* (112176) 56. meta-analysis.pt. (19931) 56. meta analysis [Publication Type])

(19115) 57. meta-analy$.mp. (35003) 57. meta-analy* (35652) 58. meta analy$.mp. (35003) 58. meta analy* (35652)

94

59. metaanaly$.mp. (926) 59. metaanaly* (828) 60. metanaly$.mp. (112) 60. metanaly* (113) 61. or/1-9 (97213) 61. or/1-9 (104892) 62. or/10-33 (34747) 62. or/10-33 (35593) 63. or/34-60 (4215641) 63. or/34-58 (4740614) 64. 61 and 62 and 63 (2078) 64. 61 and 62 and 63 (2181) 65. limit 64 to "all child (0 to 18 years)"

(288) 65. limit 64 to "all child (0 to 18 years)"

(290) 66. limit 64 to "all adult (19 plus years)"

(1182) 66. limit 64 to "all adult (19 plus years)"

(1190) 67. or/64-66 (1330) 67. or/64-66 (1335) 68. 64 not 67 (748) 68. 64 not 67 (846) 69. 66 or 68 (1930) 69. 66 or 68 (2036)

Table 20 Performances of Ovid-MEDLINE and Pubmed search for randomized controlled

trials comparing the efficacy and safety of MTX combination therapy versus MTX

monotherapy in RA patients

Ovid-MEDLINE PubMed

Total citations retrieved 1930 2036

Eligible citations identified 17 18

Total eligible citations in this review 20 20

Recall 85 % 90 %

Precision 0.881 % 0.884 %

Number-Needed-to-read 114 113

95

Table 21 Results of the citations retrieved from PubMed compared to EMBASE

Number of study identified Number of included studies

Question Pubmed EMBASE

Total (Pubmed and

EMBASE)

EMBASE retrieved

article

A. Dosing strategy (RCT)

793 545 45 9

B. Liver toxicity management (Cohort, case control)

105 178 38 6

C. Long term safety (Cohort, case control)

1,210 499 84 1

D. MTX Combo vs. Mono therapy (RCT*)

1,662 4,591 20 2

E. Folate supplementation (RCT)

201 85 9 0

F. Management during Peri-operative period (2RCTs, 2 cohorts)

118 151 4 0

G. Management during pregnancy (case series)

52 203 4 2

H. Efficacy in other rheumatic diseases (4 RCTs, 1 cohort)

77 399 4 2

Total citations retrieved 4,218 6,651 208 22 Abbreviation: - RCT = Randomized controlled trial

96

Table 22 Reasons why studies were missed by searching in PubMed

Citation Reason

Dosing strategy Cannon GW, Reading JC, Ward JR et al. Clinical and laboratory outcomes during the treatment of rheumatoid arthritis with methotrexate. Scandinavian Journal of Rheumatology 1990;19(4):285-294

• Indexed in PubMed • Not indexed with the search term

used by researcher (a set of term for “Drug administration route/dosing”)

Williams HJ, Ward JR, Reading JC et al. Comparison of auranofin, methotrexate, and the combination of both in the treatment of rheumatoid arthritis: A controlled clinical trial. Arthritis & Rheumatism 1992; 35(3):259-69.



Westedt ML, Dijkmans BAC, Hermans J. Azathioprine compared with methotrexate for rheumatoid arthritis: An open randomized clinical trial. Revue du Rhumatisme (English Edition) 1994; 61(9)(523-529)

• Journal not indexed in MEDLINE/PubMed

Rau R, Herborn G, Menninger H et al. Progression in early erosive rheumatoid arthritis: 12 month results from a randomized controlled trial comparing methotrexate and gold sodium thiomalate. British Journal of Rheumatology 1998; 37(11):1220-1226.



Strand V, Cohen S, Schiff M et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Archives of Internal Medicine 1999; 159(21):2542-2550.

• Indexed in Pubme • Not indexed with the search term


Sharp JT, Strand V, Leung H et al. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: Results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Arthritis & Rheumatism 2000; 43(3):495-505.



97

Singh CP, Kaur BG, Singh G et al. The open, randomised trial of cyclosporine vs. methotrexate in refractory rheumatoid arthritis. Journal of Internal Medicine of India 2000; 3(1):19-25.

• Journal not indexed in MEDLINE/PubMed

Ferraccioli GF, Gremese E, Tomietto P et al. Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years. Rheumatology 2002;41(8):892-898.



Bao C, Chen S, Gu Y et al. Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase II clinical trial. Chinese Medical Journal 2003; 116(8):1228-1234.



Liver Toxicity Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. American Journal of Medicine 1983 1983;75(6 A):69-73

• Indexed in PubMed • Insufficient or restricted search

strategy • Term “Liver [majr]” was used in the

search strategy (which would search this term when it is used as MeSH as major topic). This article used liver as MeSH but liver is not the main topic

Groff GD, Shenberger KN, Wilke WS et al. Low dose oral methotrexate in rheumatoid arthritis: An uncontrolled trial and review of the literature. Seminars in Arthritis & Rheumatism 1983; 12(4):333-347.



search strategy (which would search this term when MeSH is used as major topic only). This article used liver as MeSH but liver is not the main topic

Weinstein A, Marlowe S, Korn J et al. Low-dose methotrexate treatment of rheumatoid arthritis. Long-term observations. American Journal of Medicine 1985; 79(3):331-337.



search strategy (which would search

98

this term when MeSH is used as major topic only). This article used liver as MeSH but liver is not the main topic

Boh LE, Schuna AA, Pitterle ME. Low-dose weekly oral methotrexate therapy for inflammatory arthritis. Clinical Pharmacy 1986; 5(6):503-508.


strategy • Term related to ‘liver’ not used as

MeSH in this article • Term “Liver enzyme” appeared in the

abstract but the search strategy ‘Liver enzyme[ti]’ was used which would search this term in title only

Scully CJ, Anderson CJ, Cannon GW. Long-term methotrexate therapy for rheumatoid arthritis. Seminars in Arthritis & Rheumatism 1991; 20(5):317-331.


strategy • Term related to ‘liver’ not used as

MeSH in this article • Term “Liver enzyme” appeared in the

abstract but the search strategy ‘Liver enzyme[ti]’ was used which would search this term in title only

Taqweem MA, Ali Z, Takreem A et al. Methotrexate induced hepatotoxicity in Rheumatoid Arthritis patients. Journal of Postgraduate Medical Institute 2005; 19(4):387-391.

• Journal not indexed in PubMed

Long term safety of MTX Nagashima M, Matsuoka T, Saitoh K, et al Treatment continuation rate in relation to efficacy and toxicity in long-term therapy with low-dose methotrexate, sulfasalazine, and bucillamine in 1358 Japanese patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 2006; 24(3): 260 - 267.

• Found in PubMed • Insufficient or restricted search

strategy • Publication type was ‘clinical trial’

and ‘journal article’ which was not included in the search term

MTX combination versus MTX monotherapy Hanyu T, Arai K, Ishikawa H. Long-term methotrexate (MTX) combination therapy versus MTX alone for active rheumatoid arthritis. Jpn J Rheumatol. 1999; 9:31-44.


Tascioglu F, Oner C, Armagan O. Comparison of low dose methotrexate and combination


99

therapy with methotrexate and sulphasalazine in the treatment of early rheumatoid arthritis. J Rheumatol Med Rehab. 2003; 14:142-9.

MTX as steroid-sparing in other rheumatic diseases Carneiro JR, Sato EI. Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. J Rheumatol 1999;26(6):1275-9

• Not indexed with the search term used by researcher (this article used ‘prednisone’ as MeSH. It also appeared in abstract but researcher used ‘steroid’ and ‘glucocoticoid’ search as [MeSH] and in title abstract [tiab]

Ramanan AV, Campbell-Webster N, et al. The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis & Rheum 2005; 52(11)(3570-8)

• Misclassified as not retrieved by Pubmed by the reviewer

Pregnancy outcome in MTX treated RA

Chakravarty EF, Sanchez-Yamamoto D, Bush TM.The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. J Rheumatol. 2003; 30(2):241-6.


strategy (Publication type was ‘journal article’ which was not included in the search term)

Donnenfeld AE, Pastuszak A, Noah JS, et al MTX exposure prior to and during pregnancy Teratology 1994;49(2):79-81


strategy (Publication type was ‘letter’ which was not included in the search term)

http://www.ncbi.nlm.nih.gov/pubmed/12563675?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum�




http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pastuszak%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus�

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Noah%20JS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus�

100

FIGURES Figure 1 Flow diagram: - Results of the literature search and disposition of the potentially

relevant studies

39 Full-text articles retrieved* (Not in English) • MEDLINE n = 31(1) • EMBASE n = 35(0) • CENTRAL n = 24 (0) • ACR and EULAR abstract n = 2

19 Full text articles excluded • Non-RCT (n = 9) • Not original article (n = 2) • No outcome of interest (n = 3) • No MTX ± placebo arm (n = 5)

20 Articles included (19 studies) • Duplicate in all database n = 16 • EMBASE only n = 4

Inclusion criteria - RA, age ≥ 18 y - RCT - MTX vs. MTX combo

Exclusion criteria - RCT (Open label extension)/ non-RCT - No outcome of interest - No MTX ± placebo arm - Uncommonly use DMARD

6938 Titles and abstracts identified through searches

• MEDLINE n = 1662 • EMBASE n = 4591 • CENTRAL n =374 • ACR and EULAR(2005-2007)n = 311 • Hand search n = 0

6846 Citations excluded

• Non-RA (n = 324 ) • Non-article type(n = 51 ) • Non-RCT (n =112)

Non-MTX or MTX combination (n = 647)

• Non-relevant (n = 5,627) • Relevant review (n = 39) • No outcome of interest (n = 46)

* Number is not equal to the sum of number from each database due to duplication among databases

Abbreviation: - CENTRAL= Cochrane Central Register of Controlled Trials, ACR = American College of Rheumatology Response criteria, EULAR = European League Against Rheumatism response criteria, RCT = randomized controlled trial, RA = rheumatoid arthritis, MTX = methotrexate, DMARD = disease modifying anti-rheumatic drug

101

Figure 2 Combined withdrawal due to lack of efficacy and toxicity: - Comparisons between MTX combinations versus MTX monotherapy

Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, CSA = cyclosporin, DOXY = doxycycline, LEF = leflunomide, im Gold = intramuscular gold, CQ = chloroquine, HCQ = hydroxychloroquine, BUC = bucillamine, RR = relative risk, 95%CI = 95% confidence interval

102

Figure 3 Withdrawal due to lack of efficacy in DMARD naïve, MTX inadequate responder,

and non-MTX inadequate responder: - Comparisons between MTX combinations versus

MTX monotherapy

Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = Methotrexate, SSZ = sulfazalazine, CSA = cyclosporin, DOXY = doxycycline, LEF = leflunomide, im Gold = intramuscular gold, CQ = chloroquine, HCQ = hydroxychloroquine, BUC = bucillamine, RR = relative risk, 95%CI = 95% confidence interval

103

Figure 4 ACR responses in DMARD naïve: - Comparisons between MTX combinations versus MTX monotherapy

Abbreviation: - ACR = American college of Rheumatology, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, CSA = cyclosporin, DOXY = doxycycline, RR = relative risk, 95%CI = 95% confidence interval

104

Figure 5 EULAR responses in DMARD naïve: - Comparisons between MTX combinations

versus MTX monotherapy

Abbreviation: - EULAR = European League Against Rheumatism, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, CSA = cyclosporin, RR = relative risk, 95%CI = 95% confidence interval

105

Figure 6 Tender joint counts in DMARD naïve: - A comparison between MTX combinations versus MTX monotherapy

Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

Figure 7 Pain in DMARD naïve: - Comparisons between MTX combinations versus MTX

monotherapy


106

Figure 8 Patient global assessment of disease activity in DMARD naïve: - A comparison between MTX combinations versus MTX monotherapy


Figure 9 ESR in DMARD naïve: - Comparisons between MTX combinations versus MTX

monotherapy

Abbreviation: - ESR = erythrocyte sedimentation rate, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

107

Figure 10 CRP in DMARD naïve: - A comparison between MTX combinations versus

MTX monotherapy

Abbreviation: - CRP = C-reactive protein, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

Figure 11 HAQ in DMARD naïve: - Comparisons between MTX combinations versus

MTX monotherapy

Abbreviation: - HAQ = Health Assessment Questionnaire, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

108

Figure 12 Radiographic outcomes in DMARD naïve: - A comparison between MTX

combinations versus MTX monotherapy

Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, CSA = cyclosporin, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

Figure 13 ACR responses in MTX inadequate responders: - Comparisons between MTX


Abbreviation: - ACR = American college of Rheumatology, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, CSA = Ccyclosporin, LEF = leflunomide, im Gold = intramuscular gold, LEV = levofloxacin, RR = relative risk, 95%CI = 95% confidence interval

109

Figure 14 Tender joint counts in MTX inadequate responders: - Comparisons between MTX combinations versus MTX monotherapy

Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, LEF = leflunomide, im Gold = intramuscular gold, CSA =cyclosporin, SD = standard deviation, SMD = standardized mean difference, 95%CI = 95% confidence interval

Figure 15 Swollen joint counts in MTX inadequate responders: - Comparisons between

MTX combinations versus MTX monotherapy

Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, LEF = leflunomide, im Gold = intramuscular gold, CSA = cyclosporin, SD = standard deviation, SMD = standardized mean difference, 95%CI = 95% confidence interval

110

Figure 16 Pain in MTX inadequate responders: - Comparisons between MTX combinations


Abbreviation: - MTX = methotrexate, LEF = leflunomide, im Gold = intramuscular gold, CSA = cyclosporin, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

Figure 17 Patient global assessment of disease activity in MTX inadequate responders: -

Comparisons between MTX combinations versus MTX monotherapy


111

Figure 18 Physician global assessment of disease activity in MTX inadequate responders: -

Comparisons between MTX combinations versus MTX monotherapy


Figure 19 CRP in MTX inadequate responders: - A comparison between MTX


Abbreviation: - CRP = C-reactive protein, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

112

Figure 20 HAQ in MTX inadequate responders: - Comparisons between MTX combinations versus MTX monotherapy

Abbreviation: - HAQ = Health Assessment Questionnaire, MTX = methotrexate, CSA = cyclosporin, LEF = leflunomide, im Gold = intramuscular gold, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

Figure 21 ESR in MTX inadequate responders: - Comparisons between MTX combinations


Abbreviation: - ESR = erythrocyte sedimentation rate, MTX = methotrexate, CSA = cyclosporin, LEF = leflunomide, im Gold = intramuscular gold, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

113

Figure 22 Radiographic outcomes in MTX inadequate responders: - A comparison between


Abbreviation: - MTX = methotrexate, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

Figure 23 ACR responses in non-MTX inadequate responders: - Comparisons between


Abbreviation: - ACR = American College of Rheumatology, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, BUC = bucillamine, SSZ = sulfazalazine, RR = relative risk, 95%CI = 95% confidence interval

114

Figure 24 EULAR responses in non-MTX inadequate responders: - Comparisons between MTX combinations versus MTX monotherapy

Abbreviation: - EULAR = European League Against Rheumatism, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, RR = relative risk, 95%CI = 95% confidence interval

Figure 25 Tender joint counts in non-MTX inadequate responders: - A comparison between


Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, SSZ = sulfazalazine, HCQ = hydroxychloroquine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

115

Figure 26 Swollen joint counts in non-MTX inadequate responders: - Comparisons between


Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, CQ = chloroquine, SSZ = sulfazalazine, HCQ = hydroxychloroquine, SD = standard deviation, SMD = standardized mean difference, 95%CI = 95% confidence interval

Figure 27 Patient global assessment of disease activity in non-MTX inadequate responders:

- A Comparison between MTX combinations versus MTX monotherapy


116

Figure 28 Physician global assessment of disease activity in non-MTX inadequate

responders: - A Comparison between MTX combinations versus MTX monotherapy


Figure 29 Pain in non-MTX inadequate responders: -Comparisons between MTX


Abbreviation: - DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, CQ = chloroquine, SSZ = sulfazalazine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

117

Figure 30 ESR in non-MTX inadequate responders: -Comparisons between MTX


Abbreviation: - ESR = erythrocyte sedimentation rate, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, CQ = chloroquine, SSZ = sulfazalazine, HCQ = hydroxychloroquine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

Figure 31 CRP in non-MTX inadequate responders: -A comparison between MTX


Abbreviation: - CRP = C-reactive protein, MTX = methotrexate, DMARD = Disease modifying anti-rheumatic drug, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

118

Figure 32 HAQ in non-MTX inadequate responders: -A comparison between MTX


Abbreviation: - HAQ = Health Assessment Questionnaire, DMARD = Disease modifying anti-rheumatic drug, MTX = methotrexate, CQ = chloroquine, SD = standard deviation, WMD = weighted mean difference, 95%CI = 95% confidence interval

119

Figure 33 Total adverse reactions: -Comparisons between MTX combinations versus MTX

monotherapy

Abbreviation: - MTX = methotrexate, SSZ = sulfazalazine, LEF = leflunomide, CSA = cyclosporin, AZA = azathioprine, im Gold = intramuscular gold, RR = relative risk, 95%CI = 95% confidence interval

120

Figure 34 Gastrointestinal adverse events: -Comparisons between MTX combinations


Abbreviation: - GI = gastrointestinal, MTX = Methotrexate, SSZ = sulfazalazine, LEF= leflunomide, CSA = cyclosporin, RR = relative risk, 95%CI = 95% confidence interval

121

Figure 35 Abnormal liver functions: -Comparisons between MTX combinations versus

MTX monotherapy

Abbreviation: - MTX = methotrexate, SSZ = sulfazalazine, LEF= leflunomide, CSA = cyclosporin, RR = relative risk, 95%CI = 95% confidence interval

Figure 36 Mucositis: -Comparisons between MTX combinations versus MTX monotherapy

Abbreviation: - MTX = methotrexate, SSZ = sulfazalazine, RR = relative risk, 95%CI = 95% confidence interval

122

Figure 37 Hematological adverse events: -Comparisons between MTX combinations versus

MTX monotherapy

Abbreviation: - MTX = methotrexate, SSZ = sulfazalazine, RR = relative risk, 95%CI = 95% confidence interval

Figure 38 Infection: -Comparisons between MTX combinations versus MTX monotherapy

Abbreviation: - MTX = methotrexate, SSZ = sulfazalazine, LEF= leflunomide, RR = relative risk, 95%CI = 95% confidence interval

123

Figure 39 Withdrawal due to adverse reaction: -Comparisons between MTX combinations


Abbreviation: - MTX = methotrexate, SSZ = sulfazalazine, HCQ =hydroxychloroquine, CQ = chloroquine, CSA = cyclosporin, AZA = azathioprine, LEF = leflunomide, DMARD = Disease modifying anti-rheumatic drug, RR = relative risk, 95%CI = 95% confidence interval

124

Figure 40 PubMed usage data from June, 2007 to March, 2009

125

Figure 41 Diagram illustrating the use of Boolean logic operators: OR, AND, and NOT for

searching in the electronic bibliographic databases

C. The Boolean operator “NOT” identifies only articles that contain term A but not B

Studies containing term A

Studies containing term B

Studies containing term B

B. The Boolean operator “AND” identifies only articles that contain both terms

A. The Boolean operator “OR” identifies all articles that contain either term

Studies containing term A Studies containing term B

Studies containing term A

OR

AND

NOT

A

A

A

B

B

B

126

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APPENDICES

Appendix 1 Search strategy

Database: Ovid MEDLINE(R) <1950 to May Week 5 2007> Search Strategy: 1 arthritis, rheumatoid/ 2 caplan's syndrome/ 3 felty's syndrome/ 4 rheumatoid nodule/ 5 still's disease, adult-onset/ 6 rheumatism.mp. 7 caplan's syndrome$.mp. 8 felty's syndrome$.mp. 9 rheumatoid.mp. 10 Methotrexate$.mp. 11 amethopterin$.mp. 12 mexate$.mp. 13 Abitrexate$.mp. 14 Amethopterin$.mp. 15 A Methopterine$.mp. 16 Amethopterine$.mp. 17 Ametopterine$.mp. 18 Antifolan$.mp. 19 Emtexate$.mp. 20 Emthexate$.mp. 21 Emtrexate$.mp. 22 Enthexate$.mp. 23 Farmitrexate$.mp. 24 Folex.mp. 25 Ledertrexate.mp. 26 Methoblastin$.mp. 27 Methohexate$.mp. 28 Methotrate$.mp. 29 Methotrexat$.mp. 30 Methylaminopterin$.mp. 31 Metotrexat$.mp. 32 Mexate$.mp. 33 Mtx.mp. 34 Novatrex$.mp. 35 Rheumatrex.mp. 36 randomized controlled trial.pt. 37 clinical trial.pt. 38 Double-Blind Method/

146

39 "double blind:".mp. 40 Placebos/ 41 placebo:.mp. 42 random:.mp. 43 single-blind method/ 44 exp Clinical Trials/ 45 clinical trial$.mp. 46 ((singl$ or doubl$ or trebl$) adj2 (blind$ or mask$)).mp. 47 placebo$.mp. 48 exp Research Design/ 49 comparative study.pt. 50 exp Evaluation Studies/ 51 follow-up studies/ or prospective studies/ 52 (control$ or prospectiv$ or volunteer$).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 53 controlled clinical trial.pt. 54 clinical trial, phase i.pt. 55 clinical trial, phase ii.pt. 56 clinical trial, phase iii.pt. 57 clinical trial, phase iv.pt. 58 (clinical: adj2 trial:).mp. 59 meta-analysis.pt. 60 meta-analy:.mp. 61 meta analy:.mp. 62 metaanaly:.mp. 63 metanaly:.mp. Database: EMBASE <1980 to 2007 Week 23> Search Strategy: 1 Rheumatoid Arthritis/ 2 Adult Onset Still Disease/ 3 Felty Syndrome/ 4 Rheumatoid Nodule/ 5 rheumatism.mp. 6 caplan's syndrome$.mp. 7 felty's syndrome$.mp. 8 rheumatoid.mp. 9 Methotrexate$.mp. 10 amethopterin$.mp. 11 mexate$.mp. 12 Abitrexate$.mp. 13 Amethopterin$.mp. 14 A Methopterine$.mp. 15 Amethopterine$.mp.

147

16 Ametopterine$.mp. 17 Antifolan$.mp. 18 Emtexate$.mp. 19 Emthexate$.mp. 20 Emtrexate$.mp. 21 Enthexate$.mp. 22 Farmitrexate$.mp. 23 Folex.mp. 24 Ledertrexate.mp. 25 Methoblastin$.mp. 26 Methohexate$.mp. 27 Methotrate$.mp. 28 Methotrexat$.mp. 29 Methylaminopterin$.mp. 30 Metotrexat$.mp. 31 Mexate$.mp. 32 Mtx.mp. 33 Novatrex$.mp. 34 Rheumatrex.mp. 35 random:.mp. 36 clinical trial:.mp. 37 double-blind:.mp. 38 placebo:.mp. 39 blind:.tw. 40 exp Clinical Trial/ 41 ((singl$ or doubl$ or trebl$) adj2 (blind$ or mask$)).mp. 42 exp Follow Up/ 43 exp Prospective Study/ 44 (control$ or prospectiv$ or volunteer$).mp. 45 (clinical$ adj2 trial$).mp. 46 meta-analy:.mp. 47 meta analy:.mp. 48 metaanaly:.mp. 49 metanaly:.mp. Database: EBM Reviews - Cochrane Central Register of Controlled Trials <2nd Quarter 2007> Search Strategy: 1 arthritis, rheumatoid/ 2 rheumatoid nodule/ 3 rheumatism.mp. 4 caplan's syndrome$.mp. 5 felty's syndrome$.mp. 6 rheumatoid.mp. 7 Methotrexate$.mp.

148

8 amethopterin$.mp. 9 mexate$.mp. 10 Abitrexate$.mp. 11 Amethopterin$.mp. 12 A Methopterine$.mp. 13 Amethopterine$.mp. 14 Ametopterine$.mp. 15 Antifolan$.mp. 16 Emtexate$.mp. 17 Emthexate$.mp. 18 Emtrexate$.mp. 19 Enthexate$.mp. 20 Farmitrexate$.mp. 21 Folex.mp. 22 Ledertrexate.mp. 23 Methoblastin$.mp. 24 Methohexate$.mp. 25 Methotrate$.mp. 26 Methotrexat$.mp. 27 Methylaminopterin$.mp. 28 Metotrexat$.mp. 29 Mexate$.mp. 30 Mtx.mp. 31 Novatrex$.mp. 32 Rheumatrex.mp.

149

Appendix 2 Data abstraction form

Data abstraction form

SYSTEMATIC REVIEW: MTX Monotherapy vs. Combination therapy

General information Title

Author

Country

Journal

Year

Volume

Issue

Page

Database

Funding support

Inclusion criteria. Check if present:

RCT

Adult RA (≥ 18 y)

MTX≤ 25 mg/wk

MTX+ DMARDs

follow up ≥ 12 wk

at least 1 of efficacy outcomes (TJC,SJC, pain score, PGA, EGA, HAQ, APR, ACR20/50/70, DAS, DAS28)

at least 1 of numbers of patients who had toxicity /adverse effect

Excluded?

Reason:

150

Intervention 1 Intervention 2

Intervention 3

Intervention 4

Variables

Number of Patients randomized

Mean age (±SD)

Female n,(%)

Caucasian n,(%)

Disease duration(±SD)

Duration of follow up

Rheumatoid factor positive, n (%)

Anti-CCP positive, n (%)

Mean MTX dosage (±SD), mg/wk

Concomitant NSAIDs, n, (%)

Concomitant intra-articular steroid, n (%)

Concomitant systemic steroid, n (%)

Previous DMARDs (%) , please specify

Baseline Characteristics

151

Binary outcome

Time point

Intervention

Variables n (%) Total n N (%) Total n N (%) Total n n (%) Total n

ACR 20

ACR 50

ACR 70

Remission

Radiographic erosion

Time point

Intervention


ACR 20

ACR 50

ACR 70

Remission


Time point

Intervention


ACR 20

ACR 50

ACR 70

Remission


Results

152

Binary outcome

Time point

Intervention


Toxicity

Adverse event, n (%)

GI adverse event, n (%)

Abnormal LFT, n (%)

Mucositis, n (%)

Haematological disorder, n (%)

Infection, n (%)

Withdrawal

Withdrawal due to adverse event, n(%)

Withdrawal due to lack of efficacy, n (%)

Results

153

Continuous outcome at baseline

Intervention

Duration of follow up Baseline Baseline Baseline

Outcome variables N Mean SD/SE/

95%CIp value

N Mean SD/SE/95%CIp value

N Mean SD/SE/95%CIp value

Tender joint count

Tender joint index

Specify________________

Swollen joint count

Pain score (VAS)

Patient global assessment

Physician global assessment

Functional status

Specify________________

ESR

CRP

DAS

DAS28

Larsen score

Sharp’s score

Sharp/vdH

Other radiographic

154

Continuous outcome at follow up

Intervention

Duration of follow up

Outcome variables N Mean SD/SE/

95%CIp value

N Mean SD/SE/

95%CI

p value

N Mean SD/SE/

95%CI

p value

Tender joint count

Tender joint index

Specify________________

Swollen joint count

Pain score (VAS)

Patient global assessment

Physician global assessment

Functional status

Specify________________

ESR

CRP

DAS

DAS28

Larsen score

Sharp’s score

Sharp/vdH

155

Appendix 3 Study quality assessment checklist (Cochrane Back review group)

Scoring: - Yes =1, No =0, Not clear =0

Domain Item Yes No Not clear

Randomization Was the method of randomization adequate? Was the patient blinded to the intervention? Was the care provider blinded to the intervention?

Blinding

Was the outcome assessor blinded to the intervention?

Treatment allocation concealment

Was the treatment allocation concealed?

Was the compliance acceptable in all groups?

Was the dropout rate described and acceptable?

Withdrawal & dropout

Did the study include an intention to treat analysis?

Were the groups similar at the baseline regarding the most important prognostic factors?

Were co-interventions avoided or similar?

Others

Was the timing of the outcome assessment in both groups comparable?

Score

total score 11

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