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
63
64
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
65
List of abbreviations
ACR
AUR
AZA
Buc.
CQ
CRP
CSA
DAS
D-pen
DPS
Etan.
ESR
GST
HCQ
IFX
Leflu
MP
MTX
NR
Plac.
Predn.
RAI
RAM
RF
SSA
TNF
American College of Rheumatology
Auranofin
Azathioprine
Bucillamine
Chloroquine
C-reactive Protein
Cyclosporine
Disease Activity Score
D-penicillamine
Dapsone
Etanercept
Erythrocyte Sedimentation Rate
Gold Sodium Thiomulate
Hydroxychloroquine
Infliximab
Leflunomide
(Pulsed) Methylprednisolone
Methotrexate
Not reported
Placebo
Prednisone/ prednisolone
Ritchie Articular Index
RAND Appropriateness Method
Rheumatoid Factor
Sulphasalazine
Tumor Necrosis Factor
66
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 ‘firstline’ 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
67
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
68
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.
69
70
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 Creactive 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
71
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
Blinding
Was the study double blind?
Yes: 1 point
Was the method of randomisation
appropriate?
Yes: add 1 point
No: subtract 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
72
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:
9
+
Duplicates
_
Selected articles (inclusion criteria + other reviews – duplicates):
64
Accepted
28
Rejected
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,
73
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.
74
Table 2. Characteristics of Eligible Clinical Trials of Combination DMARD therapy in Rheumatoid Arthritis
Combination
First author,
Year of
publication
Time of
assessment
(weeks)
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)
RF: 68 vs
90%
25% vs
6%
5
Yes
D-pen + CQ vs.
CQ + plac. vs.
D-pen + plac.
D-pen. + MP vs.
SSA + MP vs
MP + plac.
SSA + HCQ vs.
SSA + plac. vs.
HCQ + plac.
SSA+ MP vs.
SSA + plac.
Gibson, 198734
8, 16, 24, 36,
48
72 (35/47)
Not clear
2, 4, 8, 12,
16, 20, 24
45 (16/29)
2
Not clear
71
Faarvang, 1993
4, 8, 12, 16,
20, 24
91 (35/56)
RAI: 21
Vs. 20
Vs. 22
I: 71%
II: 29%
5
Yes
Ciconelli, 1996
8, 16, 24
38 (0/38)
6.9 vs.
6.1
23% vs.
5% vs.
7.6%
26.6% vs.
46.6% vs.
86.6%
26% vs.
41% vs.
29%
25% vs.
22%
1
Neumann,
198539
3.8 vs.
5.6
months
1 vs.
3 vs.
2
4 vs.
9 vs.
8
6.3
3-5
Yes
Möttönen, 1999
12, 24, 36, 96
195
(74/121)
1
No
O’Dell, 199640
7.3 vs.
8.6
months
12, 24, 36,
48, 60, 72,
84, 96
102
(31/71)
5
Yes
ref.no
SSA + MTX + HCQ + predn.
vs.
SSA + AUR
SSA + MTX + HCQ vs.
SSA + HCQ + plac. vs.
MTX + plac.+ plac.
SSA + MTX + HCQ vs.
MTX + HCQ vs.
MTX + SSA
SSA+ MTX + predn. vs.
SSA + plac.
72
73
24% vs.
22%
22.5% vs.
60% vs.
66.6%
131
O’Dell, 2000
(abstract) 74
Boers, 199710
10 vs.
6 vs.
10
II: 95%
III: 5% vs.
II:100%
RF: 70%
vs.
66%
RF:
84% vs.
85% vs.
89%
16, 28, 40, 56
Yes
155
(64/91)
Median:
4 vs. 4
months
75
RF:
78% vs.
72%
5
9% vs.
29%
Yes
Combination
First author,
Year of
publication
Time of
assessment
(weeks)
n
patients
(m/f)
SSA + MTX vs.
MTX
Haagsma,
199441
4, 8, 12, 16,
20, 24
40 (8/32)
SSA + MTX vs.
MTX + plac. vs.
SSA + plac.
Dougados, 1999
0, 2, 4 the
every 4
weeks until
52.
2,4, then
every 4
weeks until
52
6, 12, 18, 24
205
(54/151)
ref.no
75
Haagsma,
199742
MTX + AZA vs.
AZA + plac. vs.
MTX + plac.
MTX + AUR vs.
AUR + plac. vs.
MTX + plac.
Willkens,
199236
Disease
duration
(yrs)
105
(37/68)
209
(44/165)
Disease
severity
RF:
77% vs.
72 %
RF:
71%
62%
75%
RF:
94% vs.
94% vs.
97%
II: 84% vs.
II: 80% vs.
II: 78%
4.7 vs.
5.3
10.6 vs.
18.4 vs.
10.8
months
2.6 vs.
3.0 vs.
3.1
months
Median:
8 vs.
8 vs.
10
Idem
Idem
Willkens,
199543
6, 12, 18, 24,
48
209
(44/165)
Willkens,
199644
6, 12, 18, 24,
48
209
(44/165)
Idem
Idem
Williams,
199245
6, 12, 18, 24,
36, 48
335
(106/229)
6.2 vs.
4.6 vs.
5.3
Lopez-Mendez,
199346
48
200
3 vs.
2 vs.
3
(0-3):
2.0 vs.
1.85 vs.
1.94
III: 9 %
III: 16
III: 20
76
%
withdrawals
Jadad
score
(1-5)
Concealment
of allocation
0
No
3/5
Yes
16.7% vs.
5% vs.
35%
5
Yes
26% vs.
38% vs.
75%
5
Not clear
45% vs.
64% vs.
33%
45% vs.
64% vs.
33%
37% vs.
40% vs.
34%
3-5
Not clear
3-5
Not clear
4
Not clear
N.A.
4
Yes
9% vs.
0%
25% vs.
21.7% vs.
30.9%
Combination
First author,
Year of
publication
Time of
assessment
(weeks)
n
patients
(m/f)
Disease
duration
(yrs)
Disease
severity
%
withdrawals
Jadad
score
(1-5)
Concealment
of allocation
MTX + CSA vs.
MTX + plac.
Tugwell, 199547
2, 4, 8, 12,
16, 20, 24
148
(41/107)
11.2 vs.
9.4
25% vs.
16%
5
Yes
MTX + CQ vs.
MTX + plc.
Ferraz, 199448
8, 16, 24
68 (11/57)
9.24 vs.
6.19
21% vs. 21%
5
Yes
MTX + IFX vs.
MTX + plac. vs.
IFX + plac.
Maini, 199849
4, 8, 12, 16,
26
101
(73/28)
5
Yes
MTX + cM-T412
Moreland,
199576
Trnavsky,
199350
4, 8, 12, 24,
36, 48
4, 12, 24
64 (22/42)
II: 91%
III 8% vs.
II: 82%
III: 15%
II: 88%
III:12%
Vs.
II: 79%
III:21%
RF: 72.2
vs.
76.0 vs.
90.8
II or III
3/4
Yes
4
Not clear
Haar, 199351
6, 12, 18, 24
4
Yes
ref.no
HCQ + MTX vs.
HCQ + plac.
HCQ + DPS vs.
HCQ + plac. vs.
DPS + plac
12.6 vs.
10.6 vs.
7.6
8 vs.
10.9
40 (9/31)
80 (24/56)
77
Median:
0.98 vs.
3.0 vs.
1.02
II: 45%
III: 55%
vs.
II: 50%
III: 50%
RF: 80%
vs.
93% vs.
89%
7% vs.
57% vs.
27%
NR
5%
vs.
0%
56% vs.
17% vs. 17%
Combination
First author,
Year of
publication
Time of
assessment
(weeks)
n
patients
(m/f)
Disease
duration
(yrs)
Disease
severity
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%
(1-4)
2.86 vs.
2.62
RF:
80% vs.
85%
RAI:
17 vs.
12
Seropos
73% vs.
71%
RF:
79% vs.
81%
ref.no
HCQ + D-pen vs.
HCQ + plac. vs.
D-pen + plac.
Corkill, 1990 78
2, 4, 6, 8, 10,
12, 24
59 (21/38)
5.5 vs.
6.0
Van Gestel,
199552
12, 20, 44
40 (12/28)
GST + HCQ vs.
GST + plac
Porter, 199353
26, 52
142
GST + HCQ vs.
GST + plac.
Scott, 198938
8, 16, 24, 36,
48
101
(31/70)
21.5 vs.
29.5
months
Median:
6 vs.
5
2 vs.
2
GST + CSA
Bendix, 199654
8, 16, 24
40
GST + MP vs.
GST + plac.
10.7 vs.
11.5
* ARA scale for disease activity: I-II-III
78
%
withdrawals
Jadad
score
(1-5)
Concealment
of allocation
5
Yes
37% vs.
45%
3-5
Yes
65% vs.
45%
5
Yes
14.8% vs.
18.5%
3
Yes
48% vs. 35%
4
Not clear
15.7% vs.
5%
4
Yes
59%
vs.
56%
vs.
38%
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.
79
Table 3. Characteristics and Findings of Published Reviews on Combination DMARD Therapy in Rheumatoid Arthritis
Review
Years covered
Search strategy and inclusion criteria
Boers, 1991
1956 - 1989
•
Borigini, 1995
1984 - 1994
Felson, 1994
? - December
1992
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
No description of search strategy and inclusion
criteria
•
•
•
•
•
•
•
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), Dpen (500 mg/day)
Numerical data on start and end values must
be provided
Comparison with one of the single secondline drugs listed above at full therapeutic
80
Number of
studies
7 studies (in
total: 427
patients)
Conclusions
Remarks
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
14 studies (in
total: 1547
patients)
5 studies (in
total 749
entering
patients and
516
completing
patients)
Lack of well-designed,
large, long-term, controlled clinical trials.
Combination therapy does
not offer a substantial
improvement in efficacy,
but does have higher
toxicity than single drug
therapy.
Review
Years covered
dose
Search strategy and inclusion criteria
Verhoeven,
1998
1992 - 1997
•
•
•
•
Scott, 1999
1966 - 1990
•
•
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
MEDLINE search
Randomised controlled trials, nonrandomised studies of parallel group design,
observational open studies, retrospective
reviews.
81
Number of
studies
20 studies
(10 on
parallel
treatment, 6
on step-up
strategy, and
4 on stepdown
strategy); in
total 1952
patients
11 studies (in
total: 486
patients)
Conclusions
In early RA patients, stepdown 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.
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.
Remarks
Appendix A: Weighted mean differences between DMARD and placebo (95% confidence interval) for outcomes among
patients with rheumatoid arthritis
Outcome Tender
Joint
Count
Drug
Penicillamine
-6.00
(<500 mg/d)
(-11.36, 0.64)
Penicillamine
-6.61
(500 - 1000mg/d)
(-11.37, 1.85)
Penicillamine
-8.90
(>1000 mg/d)
(-16.63, 1.16)
Sulphasalazine
-2.448
(-4.15, 0.74)
Methotrexate
-17.85
(-23.97, 11.73)
Cyclosporine
-8.20
(-12.64, 3.76)
Cyclophosphamide -9.62
(-17.72, 1.53)
Swollen Joint Pain**
Count
-2.00
(-5.96, 1.96)
-5.00
(-9.11, -0.89)
.
-2.379
(-3.73, -1.03)
-7.31
(-10.44, 4.18)
-3.19
(-4.29, -2.10)
-6.88
(-12.04, 1.71)
-11.00
(-23.19,
1.19)
-0.63
(-1.00, 0.26)
-0.61
(-0.91, 0.31)
-8.71
(-14.80, 2.62)
-3.00
(-4.07, 1.93)
-1.45
(-2.32, 0.57)
Physician
Global
Assessment
-0.42
(-0.72, 0.12)
-0.77
(-0.98, 0.56)
-1.07
(-1.36, 0.78)
-0.16
(-0.38, 0.01)
Patient
Global
Assessment
-0.36
(-0.65, 0.07)
-0.56
(-0.86, 0.26)
0.00
(0.00, 0.00)
-0.23
(-0.46,
0.00)
-0.91
-1.05
(-1.20, (-1.31, 0.63)
0.80)
0.34
0.08
(-0.02, 0.69) (-0.25,
0.41)
.
.
82
.
.
Acute Phase
reactant
(ESR)
-8.00
(-22.01, 6.01)
.
-10.65
(-20.89, -0.41)
Functional
Assessment
*
13.90
(-37.03,
9.23)
0.00
(0.00, 0.00)
-0.48
(-0.58, 0.38)
-14.39
(-23.21, -5.58)
-17.58
(-21.93, 13.23)
-8.95
(-18.17, 0.27)
.
.
.
-11.61
(-25.72, 2.51)
Azathioprine
Antimalarials
-3.08
(-5.24, 0.93)
-2.57
(-3.78, 1.36)
Injectable gold
.
-18.00
(-24.76, 11.24)
-3.71
(-4.86, -2.57)
-4.58
(-6.50, -2.65)
-25.09
(-42.11, 8.07)
-0.45
(-0.72, 0.18)
.
.
-0.39
(-0.57, 0.21)
-0.34
(-0.48, 0.20)
*Functional assessment = Steinbrocker etc.
**Pain = VAS
83
.
-0.34
(-0.53, 0.15)
-0.48
(-0.77, 0.19)
-0.24
-12.94
(-0.79, 0.31) (-33.94, 8.05)
-0.06
-6.38
(-0.29, 0.17) (-8.51, -4.24)
.
-13.16
(-18.14, -8.18)
Appendix B. Adverse affects of selected disease modifying antirheumatic drugs
(DMARDs).
Drug name
Adverse effects
%
Citation
1-5
1-5
33
18-26
60-80
<1
1-3
<1
>10
2.5
1-2
6-10
<1
<5
<1
3-5
2.5-4.5
3-10
8
0-1.5
9.6-15.2
0-2.0
0-0.5
1.5-2.0
25-80
<2
<2
11
55
Hydroxychloroquine Retinal toxicity
Sulphasalazine
Gold
(Auranofin)
Methotrexate
Azathioprine
Cyclosporine
Rash (and fever)
Myelosuppression
Gastrointestinal intolerance
Rash
Stomatitis
Myelosuppression
Thrombocytopenia
Proteinuria
Diarrhea
Gastrointestinal intolerance
Rash
Stomatitis
Alopecia
Myelosuppression
Hepatotoxicity
Pneumonitis
Leukopenia
Hepatotoxicity
Early flu-like illness with fever
Anemia
Nausea
Thrombocytopenia
Pancytopenia
Alopecia
Nephrotoxicity
Anemia
Thrombocytopenia
Hypertension
84
55
56
56
57
58-60
57
61
62
63
64
64,65
65
63
66
63
67
56
67
67
67
67
67
67
56
56
56
56
Appendix B (continued). Adverse affects of selected disease modifying
antirheumatic drugs (DMARDs).
Drug name
Leflunomide
Etanercept
D-penicillamine
Cyclophosphamide
Infliximab
Side effects
%
Transaminitis
Gastrointestinal intolerance
Teratogenicity (category x)
Rash
Alopecia
Theoretic risk of infection
Injection site reactions
Upper respiratory symptoms
Rash
Stomatitis
Dysgeusia
Proteinuria
Myelosuppression
Secondary autoimmune disease
Thrombocytopenia
Myelosuppression
Myeloproliferative disorders
Infection
Alopecia
Hepatotoxicity
Anaphylaxis
Infection
85
Citation
6
15
56
8
1-7
56
56
56
56
37
Up to 45
Up to 50
>10
>10
<1
<1
<1
5
56
40-60
56
56
56
68
68
68
68
68
69
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96
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.
97