systematic review of combination dmard therapy in ... review of combination dmard therapy in...

Systematic review of combination DMARD therapy

in rheumatoid arthritis

Beusekom I. van1, C. MacLean2, C.F. Allaart3, and F.C. Breedveld3.

October 2000

RE-2000.14

1) RAND Europe, Leiden, The Netherlands 2) RAND, UCLA school of medicine 3) Leiden University Medical Centre

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CONTENTS List of abbreviations 66 Introduction 67 Systematic review of combination therapy in rheumatoid arthritis 71 Results 73 Summary of reviews on combination DMARD therapy 79 Appendix A: Weighted mean differences between DMARD and placebo 82 Appendix B: Adverse effects of selected disease modifying antirheumatic drugs (DMARDs) 84 References 86 Data abstraction tables 97 TABLES AND FIGURES: Table 1. Search terms used for electronic databases 71 Figure 1. Assessing the Jadad score 72 Figure 2. Literature retrieval flow chart 73 Table 2. Characteristics of eligible clinical trials of combination DMARD therapy in rheumatoid arthritis 75 Table 3. Characteristics and findings of published reviews on combination DMARD therapy in rheumatoid arthritis 80

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List of abbreviations ACR American College of Rheumatology AUR Auranofin AZA Azathioprine Buc. Bucillamine CQ Chloroquine CRP C-reactive Protein CSA Cyclosporine DAS Disease Activity Score D-pen D-penicillamine DPS Dapsone Etan. Etanercept ESR Erythrocyte Sedimentation Rate GST Gold Sodium Thiomulate HCQ Hydroxychloroquine IFX Infliximab Leflu Leflunomide MP (Pulsed) Methylprednisolone MTX Methotrexate NR Not reported Plac. Placebo Predn. Prednisone/ prednisolone RAI Ritchie Articular Index RAM RAND Appropriateness Method RF Rheumatoid Factor SSA TNF

Sulphasalazine Tumor Necrosis Factor

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INTRODUCTION

Rheumatoid arthritis is a systemic autoimmune disease of unknown aetiology. The most striking symptom is a chronic, symmetric synovitis of peripheral joints. Up to 70% of patients may ultimately develop bone erosions.1 Pain and swelling due to the inflammation, and later due to joint destruction, cause the patient limitation of movement and loss of functional abilities.

The therapeutic approach of rheumatoid arthritis (RA) aims to suppress the inflammatory process in order to reduce pain and disability, and prevent future joint destruction. Non-steroid anti-inflammatory drugs (NSAIDs) can be of value in reducing pain and stiffness, but are ineffective in suppressing the disease itself. Antirheumatic drugs, known as ‘second-line’ (being introduced in the past only after failure of ‘first-line’ NSAIDs), ‘slow-acting’ (because of the period of 6 to 8 weeks or sometimes more before the effects of the drug become noticeable), or ‘disease modifying’ (hence abbreviated as DMARDs) attenuate the disease itself through a variety of mechanisms. Reductions in pain,2-7 swelling,2-9 acute phase reactants,3,7,9 and the progression of bony erosions10-15 have been demonstrated with these agents. Additionally, these agents are associated with improvements in functional status.4 However, the efficacy of these agents has been neither large in magnitude nor sustained in duration. Furthermore, side effects among these agents are common and may be severe or life threatening.16-20 Few patients continue individual second line agents for longer than 2 or 3 years perhaps as a result of the limited efficacy and toxic side effects of these agents.21-24

Based in large part on the recognition that joint destruction may occur within the first years of disease onset,1,25 the approach to therapy for rheumatoid arthritis has become more aggressive over recent years. Patients are being treated earlier and with more potent (and toxic) agents now than previously. It is thought that early intervention may prevent joint erosions and may prevent the disease from becoming self-sustaining.10

The few studies that have evaluated the efficacy of early intervention support this hypothesis.26-28 In one study, early introduction of DMARDs was more effective in suppressing disease activity than treatment with NSAIDs alone.28 In another study, early relative to later initiation of DMARDs resulted in improved functional status and attenuated radiographic progression that persisted for 5 years.27,28

The rationale behind using therapies including combinations of DMARDs with potentially greater toxicities in RA, centres around the premise that these agents will retard structural damage and prevent disability more effectively than less toxic agents. Although the efficacy of most single agents compared to placebo in the treatment of RA has been demonstrated,2-9 the relative efficacy of various DMARDs compared to other DMARDs and the relative efficacy of different combinations of DMARDs is less well understood. This no doubt stems in large part from the large number of different agents available to treat RA. Given that treatment regimens may include DMARDs (antimalarials, azathioprine, cyclosporine, cyclophosphamide, gold, leflunomide, methotrexate, sulfasalazine), corticosteroids in higher or lower dosages and different

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ways of administration, and biological agents (etanercept, infliximab), the number of possible combinations with two or more of these agents is quite large. The majority of these possible combinations have not been tested for effectiveness and safety. Some combinations that were tested in earlier years now appear to be farfetched or obsolete.

This review is part of a study for the Dutch Health Care Insurance Council [College voor zorgverzekeringen (CVZ)], which has called for a study to develop a generic method for examining combinations of medications. The goal of this study is to develop a method that can be used to determine where clinical research on pharmaceutical combinations is needed by evaluating the existing published evidence and clinical expertise about the use of these combinations. This generic method is to be pilot-tested by addressing the problem of prioritising clinical research on combination medications for rheumatoid arthritis (RA).

Regarding rheumatoid arthritis specifically, the CVZ realises that there is much uncertainty regarding the relative efficacy of different combinations of DMARD therapy and would like to help resolve this uncertainty by financing clinical trials to assess the efficacy of combination therapy. In order to determine which DMARD combinations should be studied in these clinical trials, the CVZ would like to understand what has been published as well as the opinions of experts about the efficacy of combination DMARD therapy. This project will synthesise the existing published literature and expert opinion on this topic by using the RAND Appropriateness Methods (RAM).

The RAM was originally developed over 15 years ago by a team of researchers at RAND and UCLA29,30 to assist in determining the extent of overuse of medical and surgical procedures (“inappropriate care”). The RAND Appropriateness Method (RAM) to determine "appropriate" care involves the following steps. When a topic has been selected, the first step of a study using the RAM is to perform a detailed literature review to synthesise the latest available scientific evidence on the procedure to be rated. The present document is the literature review for the appropriateness study on combination therapy with DMARDs. At the same time, a list of indications is produced in the form of a matrix that categorises patients who might present for the procedure in question in terms of their symptoms, past medical history and the results of relevant diagnostic tests.

The literature review and the list of indications are sent to the members of an expert panel. These panel members individually rate the appropriateness of using the procedures for each indication on a nine-point scale, ranging from extremely inappropriate (=1) to extremely appropriate (=9) for the patient described in the indication. The panel members assess the benefit-risk ratio for the "typical patient with specific characteristics receiving care delivered by the typical surgeon in the typical hospital."

After this first round of ratings, the panel members meet for one day under the leadership of a moderator. During this meeting, the panellists discuss their previous

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ratings, focusing on areas of disagreement, and are given the opportunity to modify the original list of indications and/or definitions. After discussing each chapter of the list of indications, they re-rate each indication individually. The two-round process is focused on detecting consensus among the panel members. No attempt is made to force the panel to consensus.

Previous uses of the RAM have concentrated on determining the appropriateness or inappropriateness of treatment.30,31 Here, we instead are using the method to reveal uncertain, but promising combinations.

The following systematic review and summary of reviews on combination DMARD therapy in RA were performed as the first step of the RAM.

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SYSTEMATIC REVIEW OF COMBINATION DMARD THERAPY IN RHEUMATOID ARTHRITIS Identification of Clinical Trials

We searched for clinical trials of combination therapy with DMARDs for the treatment of rheumatoid arthritis by using electronic searches of MEDLINE (1966- June 2000), EMBASE (1966 – June 2000) and the Cochrane Clinical Trials Registry (1965 –June 2000). The search terms used for each of these searches are described in table 1. Also, the bibliographies of major articles and reviews were screened for additional studies. Table 1. Search terms used for electronic databases. Database Search strategy Cochrane Clinical Trial Register “Arthritis, Rheumatoid” Embase “Combination therapy” and “Rheumatoid

Arthritis” and names of single DMARDs Medline “Combination therapy” and “Rheumatoid

Arthritis” and names of single DMARDs Inclusion Criteria

We included only randomised clinical trials that reported the efficacy of combinations of two or more DMARDs for the treatment of rheumatoid arthritis among patients 18 years of age or older. For this review, corticosteroids administered on a daily basis were considered DMARDs. Only studies that included at least one of the following outcome measures were included in this review: tender and/or swollen joint count, pain, physician or patient global assessment, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), radiographic outcome measures. Titles and abstracts for English and non-English language reports were reviewed to identify published studies. Articles in English, Dutch, German, French, Spanish and Danish were reviewed.

Data Extraction Two trained reviewers collected qualitative data including the methodological

attributes of the studies and characteristics of the study populations for each study using a standardised form. Disagreements were resolved by consensus. The data abstraction forms for each study have been included in this review.

Assessment of Methodological Attributes of Studies We assessed the methodological attributes of the studies by determining whether

or not descriptions of the following were present in each study: randomisation, appropriateness of randomisation, blinding, appropriateness of blinding, withdrawals and dropouts, and concealment of allocation. Each of these items has been validated as an indicator of methodological quality either individually32-34 or as part of a scale.32,35,36 We assigned an overall quality score to each study using the method developed by Jadad.35 This method assigns points based upon the description of specific methodological parameters (see figure 1). Studies are assigned one point each for describing

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randomisation, blinding, and withdrawals and dropouts. An additional point each is added for describing an appropriate method of randomisation and an appropriate method of blinding; one point each is deducted if studies describe inappropriate methods of randomisation and inappropriate methods of blinding. The maximum score possible is 5. Studies with scores of three or more on this scale are considered high quality32,37,38 and report systematically different treatment effects in some clinical settings than studies with lower scores.32,37,38

Figure 1. Assessing the Jadad-score

Randomisation Was method of randomisation described? Yes: 1 point

Was the method of blinding appropriate? Yes: add 1 point No: subtract 1 point

Withdrawals and dropouts Was there a description of withdrawals and dropouts? Yes: 1 point

Jadad score

Was the method of randomisation appropriate? Yes: add 1 point No: subtract 1 point

Blinding Was the study double blind? Yes: 1 point

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Assessment of characteristics of study population Because baseline characteristics of study subjects may affect response to therapy,

we abstracted data on the age, functional class, disease duration and prior use of DMARDs for all study arms in each study. Reviewers also qualitatively assessed whether meaningful differences in baseline characteristics of the study groups that could affect comparisons between arms were present in each study. RESULTS Trials Results from our literature search are detailed in figure 2. Figure 2. Literature retrieval flow chart.

Citations from electronic search: CCTR: 1905 Medline: 259 Embase: 105 Total: 2269 Abstracts: CCTR: 66 Medline: 71 Embase: 61 Total: 198 Met inclusion criteria

Check other reviews: Duplicates 9 _ +

Selected articles (inclusion criteria + other reviews – duplicates): 64

Accepted Rejected 28 35 (19 – no study 2 – language 5 – no RCT 9 – no combination therapy) Number of included studies: Total: 28

Our electronic search identified 2269 titles. Among these, 198 pertained to

combination therapy with DMARDs for RA. The abstract for each selected title was reviewed and from these 64 articles were selected for review. Among these, 62 (97%) were retrieved and 24 met our inclusion criteria. The search of bibliographies of major articles and reviews resulted in eight more articles to be retrieved. Four of these eight met our inclusion criteria. Among the articles rejected, 17 did not describe a clinical trial,

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but rather were letters, comments or reviews; 2 did not meet our language requirement (one article in Russian and one in Japanese); 5 were not randomised; and 8 articles were not about combination therapy as we defined it.

The characteristics of the 28 studies included in this review are presented in table 2. Together, these studies assess the effects of 22 different combinations of DMARD therapies among 2819 patients. The majority (15) of the articles described studies on combinations with methotrexate, mostly combined with sulphasalazine, azathioprine, hydroxychloroquine or cyclosporine. The number of patients varied from 24 to 211 and the number of treatment groups from 2 to 7. Quality scores

The quality of the general methods of the studies assessed was generally good. The Jadad score was 3 or higher in 21 (79%) studies; concealment of allocation was described in 16 (57%) studies.

Characteristics of study populations

The average age of study participants ranged from 43.2 to 64. In most studies, the participants were aged 18-80. Disease duration ranged from 2.6 months to 11.5 years. Disease severity was described either in terms of functional class or the presence of rheumatoid factor in 8 and 12 studies respectively. Among studies that reported functional class, patients with Class I comprised 10% of the total subjects, Class II 73%, Class III 19% and Class IV 0.5%. Among studies reporting presence of rheumatoid factor, all reported that between 62 and 97% of the patients were rheumatoid factor positive. Whether or not DMARDs were used prior to study enrolment was described in 13 (46%) of the studies. In 11 studies, patients had been treated with DMARDs prior to study enrolment. In 18 studies, patients were randomly distributed over the different treatment arms, in 10 the procedure of allocation to treatment arms was less clear. In some cases there were some uncertainties about the comparability of the patients in the different arms (especially sex distribution and disease duration). In general, trials that compare newly started single drugs with newly started drug combinations offer a better insight than add-on studies, that compare the effect of adding another drug (or a placebo) to a drug that already failed.

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Table 2. Characteristics of Eligible Clinical Trials of Combination DMARD therapy in Rheumatoid Arthritis Combination First author, Time of

assessment (weeks)

Year of publication ref.no

n patients (m/f)

Disease duration (yrs)

Disease severity

% withdrawals

Jadad score (1-5)

Concealment of allocation

CSA + CQ vs. CQ + plac.

Borne van den, 199870

0, 12, 24 88 (25/63) 3.8 vs. 5.6 months

RF: 68 vs 90%

25% vs 6%

5 Yes

D-pen + CQ vs. CQ + plac. vs. D-pen + plac.

Gibson, 198734 8, 16, 24, 36, 48

72 (35/47) 1 vs. 3 vs. 2

23% vs.5% vs. 7.6%

1 Not clear

D-pen. + MP vs. SSA + MP vs MP + plac.

Neumann, 198539

2, 4, 8, 12, 16, 20, 24

45 (16/29) 4 vs. 9 vs. 8

RAI: 21 Vs. 20 Vs. 22

26.6% vs. 46.6% vs. 86.6%

2 Not clear

SSA + HCQ vs. SSA + plac. vs. HCQ + plac.

Faarvang, 1993 71

4, 8, 12, 16, 20, 24

91 (35/56) 6.3 I: 71% II: 29%

26% vs. 41% vs. 29%

5 Yes

SSA+ MP vs. SSA + plac.

Ciconelli, 1996 72

8, 16, 24 38 (0/38) 6.9 vs. 6.1

II: 95% III: 5% vs. II:100%

25% vs. 22%

3-5 Yes

SSA + MTX + HCQ + predn. vs. SSA + AUR

Möttönen, 1999 73

12, 24, 36, 96 195 (74/121)

7.3 vs. 8.6 months

RF: 70% vs. 66%

24% vs. 22%

1 No

SSA + MTX + HCQ vs. SSA + HCQ + plac. vs. MTX + plac.+ plac.

O’Dell, 199640 12, 24, 36, 48, 60, 72, 84, 96

102 (31/71)

10 vs. 6 vs. 10

RF: 84% vs. 85% vs. 89%

22.5% vs. 60% vs. 66.6%

5 Yes

SSA + MTX + HCQ vs. MTX + HCQ vs. MTX + SSA

O’Dell, 2000 (abstract) 74

131 Yes

SSA+ MTX + predn. vs. SSA + plac.

Boers, 199710 16, 28, 40, 56 155 (64/91)

Median: 4 vs. 4 months

RF: 78% vs. 72%

9% vs. 29%

5 Yes

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Combination First author, Time of

assessment (weeks)


n patients (m/f)


Disease severity

% withdrawals

Jadad score (1-5)


SSA + MTX vs. MTX

Haagsma, 199441

4, 8, 12, 16, 20, 24

40 (8/32) 4.7 vs. 5.3

RF: 77% vs. 72 %

9% vs. 0%

0 No

Dougados, 1999 75

0, 2, 4 the every 4 weeks until 52.

205 (54/151)

10.6 vs. 18.4 vs. 10.8 months

RF: 71% 62% 75%

25% vs. 21.7% vs. 30.9%

3/5 YesSSA + MTX vs. MTX + plac. vs. SSA + plac.

Haagsma, 199742

2,4, then every 4 weeks until 52

105 (37/68)

2.6 vs. 3.0 vs. 3.1 months

RF: 94% vs. 94% vs. 97%

16.7% vs. 5% vs. 35%

5 Yes

Willkens, 199236

6, 12, 18, 24 209 (44/165)

Median: 8 vs. 8 vs. 10

II: 84% vs. II: 80% vs. II: 78%

26% vs. 38% vs. 75%

5 Not clear

Willkens, 199543

6, 12, 18, 24, 48

209 (44/165)

Idem Idem 45% vs.64% vs. 33%

3-5 Not clear

MTX + AZA vs. AZA + plac. vs. MTX + plac.

Willkens, 199644

6, 12, 18, 24, 48

209 (44/165)

Idem Idem 45% vs.64% vs. 33%

3-5 Not clear

Williams, 199245

6, 12, 18, 24, 36, 48

335 (106/229)

6.2 vs. 4.6 vs. 5.3

(0-3): 2.0 vs. 1.85 vs. 1.94

37% vs. 40% vs. 34%

4 Not clearMTX + AUR vs. AUR + plac. vs. MTX + plac.

Lopez-Mendez, 199346

48 200 3 vs.2 vs. 3

III: 9 % III: 16 III: 20

N.A. 4 Yes

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assessment (weeks)


n patients (m/f)


Disease severity

% withdrawals

Jadad score (1-5)


MTX + CSA vs. MTX + plac.

Tugwell, 199547 2, 4, 8, 12, 16, 20, 24

148 (41/107)

11.2 vs. 9.4

II: 91% III 8% vs. II: 82% III: 15%

25% vs. 16%

5 Yes

MTX + CQ vs. MTX + plc.

Ferraz, 199448 8, 16, 24 68 (11/57) 9.24 vs. 6.19

II: 88% III:12% Vs. II: 79% III:21%

21% vs. 21% 5 Yes

MTX + IFX vs. MTX + plac. vs. IFX + plac.

Maini, 199849 4, 8, 12, 16, 26

101 (73/28)

12.6 vs. 10.6 vs. 7.6

RF: 72.2 vs. 76.0 vs. 90.8

7% vs. 57% vs. 27%

5 Yes

MTX + cM-T412 Moreland, 199576

4, 8, 12, 24, 36, 48

64 (22/42) 8 vs. 10.9

II or III NR 3/4 Yes

HCQ + MTX vs. HCQ + plac.

Trnavsky, 199350

4, 12, 24 40 (9/31) II: 45% III: 55% vs. II: 50% III: 50%

5% vs. 0%

4 Not clear

HCQ + DPS vs. HCQ + plac. vs. DPS + plac

Haar, 199351 6, 12, 18, 24 80 (24/56) Median: 0.98 vs. 3.0 vs. 1.02

RF: 80% vs. 93% vs. 89%

56% vs. 17% vs. 17%

4 Yes

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assessment (weeks)


n patients (m/f)


Disease severity

% withdrawals

Jadad score (1-5)


HCQ + D-pen vs. HCQ + plac. vs. D-pen + plac.

Bunch, 1984 77 24, 48, 72, 96 56 (17/39) 6.3 vs. 5.5 vs. 6.4

ARA*: II: 41% III: 59% Vs. II: 44% III: 44% Vs. II: 57% III: 38%

59% vs. 56% vs. 38%

5 Yes

Corkill, 1990 78 2, 4, 6, 8, 10, 12, 24

59 (21/38) 5.5 vs. 6.0

(1-4) 2.86 vs. 2.62

37% vs. 45%

3-5 YesGST + MP vs. GST + plac.

Van Gestel, 199552

12, 20, 44 40 (12/28) 21.5 vs. 29.5 months

RF: 80% vs. 85%

65% vs. 45%

5 Yes

GST + HCQ vs. GST + plac

Porter, 199353 26, 52 142 Median: 6 vs. 5

RAI: 17 vs. 12

14.8% vs. 18.5%

3 Yes

GST + HCQ vs. GST + plac.

Scott, 198938 8, 16, 24, 36, 48

101 (31/70)

2 vs. 2

Seropos 73% vs. 71%

48% vs. 35% 4 Not clear

GST + CSA Bendix, 199654 8, 16, 24 40 10.7 vs. 11.5

RF: 79% vs. 81%

15.7% vs. 5%

4 Yes

* ARA scale for disease activity: I-II-III

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SUMMARY OF REVIEWS ON COMBINATION DMARD THERAPY

During the literature search, reviews about combination therapy were retrieved as well, in order to get an oversight of existing systematic overviews. The most important reviews are summarised in table 3.

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Table 3. Characteristics and Findings of Published Reviews on Combination DMARD Therapy in Rheumatoid Arthritis Review Years covered Search strategy and inclusion criteria Number of

studies Conclusions Remarks

Boers, 1991 1956 - 1989 • Search in MEDLINE, Index Medicus, Excerpta Medica, and Science Citation Index, and search of bibliographies of retrieved articles

• Randomised trials and cohort studies - studies with evidence rated strong, moderate and weak are included

• Concurrent therapy with at least 2 antirheumatic drugs, compared with one single drug

• Outcome measure: severity of disease • Toxicity related to treatment is reported

7 studies (in total: 427 patients)

The available trials provide insufficient data to decide with confidence that any combination of antirheumatic drugs is to be preferred over a single drug.

Strict definition of active RA: 6 swollen joints plus 2 of 3 of the following criteria: - 9 or more tender

joints - morning stiffness 45

minutes - ESR 28 mm/h

Borigini, 1995 1984 - 1994 No description of search strategy and inclusion criteria


Lack of well-designed, large, long-term, control-led clinical trials.

Felson, 1994 ? - December 1992

• MEDLINE, bibliographic searches, hand searches of 5 international rheumatology journals, and abstracts of ACR-meetings

• Randomized clinical trials • Patients > 18 years of age • Two full-dose second-line drugs started

concurrently • Drugs and minimal dose: AUR (6 mg/day),

HCQ (200 mg/day), CQ (250 mg/day), i.m. gold (50 mg/week), MTX (7.5 mg/week), AZA (1 mg/kg/day), SZA (2 mg/day), D-pen (500 mg/day)

• Numerical data on start and end values must be provided

• Comparison with one of the single second-line drugs listed above at full therapeutic

5 studies (in total 749 entering patients and 516 completing patients)

Combination therapy does not offer a substantial improvement in efficacy, but does have higher toxicity than single drug therapy.

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dose Review Years covered Search strategy and inclusion criteria Number of

studies Conclusions Remarks

Verhoeven, 1998

1992 - 1997 • MEDLINE search and search of bibliographies of the retrieved articles.

• English, French, German, Dutch • Randomized studies - studies with evidence

rated as strong or moderate are included • Comparison with a one-type single

DMARD control group

20 studies (10 on parallel treatment, 6 on step-up strategy, and 4 on step-down strategy); in total 1952 patients

In early RA patients, step-down bridge therapy that includes corticosteroids leads to much enhanced efficacy at acceptable or low toxicity. The effects on joint damage may be persistent, but the symptomatic effects are probably dependent on continued corticosteroid dosing. In late patients, cyclosporine improves a suboptimal clinical response to methotrexate, and the triple combination of methotrexate, sulphasalazine, and hydroxychloroquine appears clinically better than the components. Other combinations are either untested, tested at low sample, or show negative interaction.

Scott, 1999 1966 - 1990 • MEDLINE search • Randomised controlled trials, non-

randomised studies of parallel group design, observational open studies, retrospective reviews.


The balance of evidence in 1990 suggested that combination therapy had a modest advantage. However, the trials were too small to detect its true value, and the combinations used were not ideal.

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Appendix A: Weighted mean differences between DMARD and placebo (95% confidence interval) for outcomes among patients with rheumatoid arthritis

Outcome Drug

Tender Joint Count

Swollen Joint Count

Pain** PhysicianGlobal Assessment

Patient Global Assessment

Functional Assessment*

Acute Phase reactant (ESR)

Penicillamine (<500 mg/d)

-6.00 (-11.36, -0.64)

-2.00 (-5.96, 1.96)

-11.00 (-23.19, 1.19)

-0.42 (-0.72, -0.12)

-0.36 (-0.65, -0.07)

. -8.00 (-22.01, 6.01)

Penicillamine (500 - 1000mg/d)

-6.61 (-11.37, -1.85)

-5.00 (-9.11, -0.89)

-0.63 (-1.00, -0.26)

-0.77 (-0.98, -0.56)

-0.56 (-0.86, -0.26)

. -10.65 (-20.89, -0.41)

Penicillamine (>1000 mg/d)

-8.90 (-16.63, -1.16)

. -0.61 (-0.91, -0.31)

-1.07 (-1.36, -0.78)

0.00 (0.00, 0.00)

13.90 (-37.03, 9.23)

-14.39 (-23.21, -5.58)

Sulphasalazine -2.448(-4.15, -0.74)

-2.379 (-3.73, -1.03)

-8.71 (-14.80, -2.62)

-0.16 (-0.38, 0.01)

-0.23 (-0.46, 0.00)

0.00 (0.00, 0.00)

-17.58 (-21.93, -13.23)

Methotrexate -17.85(-23.97, -11.73)

-7.31 (-10.44, -4.18)

-3.00 (-4.07, -1.93)

-1.05 (-1.31, -0.80)

-0.91 (-1.20, -0.63)

-0.48 (-0.58, -0.38)

-8.95 (-18.17, 0.27)

Cyclosporine

-8.20(-12.64, -3.76)

-3.19 (-4.29, -2.10)

-1.45 (-2.32, -0.57)

0.34 (-0.02, 0.69)

0.08 (-0.25, 0.41)

. .

Cyclophosphamide

-9.62(-17.72, -1.53)

-6.88 (-12.04, -1.71)

. . . .-11.61 (-25.72, 2.51)

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Azathioprine

-3.08(-5.24, -0.93)

-18.00 (-24.76, -11.24)

-25.09 (-42.11, -8.07)

. .-0.24 (-0.79, 0.31)

-12.94 (-33.94, 8.05)

Antimalarials -2.57(-3.78, -1.36)

-3.71 (-4.86, -2.57)

-0.45 (-0.72, -0.18)

-0.39 (-0.57, -0.21)

-0.34 (-0.53, -0.15)

-0.06 (-0.29, 0.17)

-6.38 (-8.51, -4.24)

Injectable gold .

-4.58 (-6.50, -2.65) .

-0.34 (-0.48, -0.20)

-0.48 (-0.77, -0.19)

. -13.16 (-18.14, -8.18)

*Functional assessment = Steinbrocker etc. **Pain = VAS

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Appendix B. Adverse affects of selected disease modifying antirheumatic drugs (DMARDs).

Drug name Adverse effects % Citation

Hydroxychloroquine Retinal toxicity Sulphasalazine Rash (and fever)

Myelosuppression Gastrointestinal intolerance

1-5 1-5 33

55 55 56

Gold (Auranofin)

Rash Stomatitis Myelosuppression Thrombocytopenia Proteinuria Diarrhea

18-26 60-80

<1 1-3 <1 >10

56 57

58-60 57 61 62

Methotrexate Gastrointestinal intolerance Rash Stomatitis Alopecia Myelosuppression Hepatotoxicity Pneumonitis

2.5 1-2 6-10 <1 <5 <1 3-5

63 64

64,65 65 63 66 63

Azathioprine Leukopenia Hepatotoxicity Early flu-like illness with fever Anemia Nausea Thrombocytopenia Pancytopenia Alopecia

2.5-4.5 3-10

8 0-1.5

9.6-15.2 0-2.0 0-0.5

1.5-2.0

67 56 67 67 67 67 67 67

Cyclosporine Nephrotoxicity Anemia Thrombocytopenia Hypertension

25-80 <2 <2 11

56 56 56 56

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Appendix B (continued). Adverse affects of selected disease modifying antirheumatic drugs (DMARDs).

Drug name Side effects % Citation

Leflunomide Transaminitis Gastrointestinal intolerance Teratogenicity (category x) Rash Alopecia

6 15 8

1-7

56 56 56 56 56

Etanercept Theoretic risk of infection Injection site reactions Upper respiratory symptoms

37

Up to 45

56 56

D-penicillamine Rash Stomatitis Dysgeusia Proteinuria Myelosuppression Secondary autoimmune disease Thrombocytopenia

Up to 50 >10 >10 <1 <1 <1 5

56 68 68 68 68 68 69

Cyclophosphamide Myelosuppression Myeloproliferative disorders Infection Alopecia Hepatotoxicity

40-60

56

Infliximab Anaphylaxis Infection

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Data abstraction tables

In the following part of the literature review, you will find that some pages have been left blank. This has been done on purpose, as some tables are read more easily if the pages face eachother.

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systematic review of combination dmard therapy in ... review of combination dmard therapy in...

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