Table 1w: Systematic Literature Research process step by step.
1. Clinical Question
2. Translation in
epidemiological
terms
3. Definition of the
‘PICO”
for Population,
Intervention, Control
and Outcomes.
4. Definition of
expected study
designs
5. The choice of the
Key-words
What is the long term safety of methotrexate including cardiovascular diseases,
malignancies, infections and liver toxicity?
In RA patients receiving MTX monotherapy for more than 2 years:
- What is the mortality rate?
- What are the incidence rates of cardiovascular diseases, liver toxicity,
malignancies, infections and other adverse events?
- What is the termination rate for toxicity of MTX monotherapy compared to
other DMARDs applied as monotherapy?
Population = adult patients with RA
Intervention = MTX monotherapy (i.e. without other DMARD) for more than 2 years.
Control = RA patients who do not receive MTX but other DMARDs or placebo.
Outcomes = prevalence, incidence rate, risk ratio, odds ratio, standardized mortality
rate or standardized incidence rate regarding mortality, cardiovascular diseases,
malignancies, liver toxicity, infections, other adverse events and the proportion of
patients discontinuing MTX for toxicity.
Best option = randomized controlled trial (RCT) that compares RA patients who
receive MTX with placebo or other DMARDs.
Less optimal = observational studies in decreasing order of preference: prospective
cohorts, retrospective cohorts and case-control studies.
Least preferred = case-series of patients with RA who experienced adverse events after
more than 2 years of MTX therapy. We included case-series only if more than 3 cases
were described.
Using Mesh Term in MEDLINE with the help of a librarian and according to the
PICO.
- 3 databases: MEDLINE, EMBASE and COCHRANE CENTRAL
- EULAR and ACR abstracts (2005-2007)
- Hand search in references of relevant studies and reviews
Inclusion criteria: adults ≥18 years-old, diagnosis of RA according to ACR criteria
7. Selection of the
1987, receiving MTX monotherapy for more than 2 years (without other DMARD).
relevant studies
Exclusion criteria: no data on safety, duration of MTX unknown, reviews, guidelines,
comments, replies, case reports and studies written in languages that could not be
translated by one of the members of the 3E initiative.
8. Assessment of the Using the Levels of Evidence 1-5 scale (Oxford, May 2001, http://www.cebm.net).
- Level 1=evidence based on systematic review of RCTs (a), on individual RCTs (b),
level of Evidence.
- Level 2=evidence based on systematic review of cohort studies (a), on individual
cohort study (b).
- Level 3=evidence based on systematic review of case-control studies (a), on
individual case-control study (b).
- Level 4 =evidence based on case-series and poor quality cohort and case control
studies*.
- Level 5 = expert opinion without explicit critical appraisal is available.
6. Search in the
Literature
* ‘poor quality’ was defined as follows: a cohort study that failed to clearly define comparison
groups and/or failed to measure exposures and outcomes in the same (preferably blinded),
1
objective way in both exposed and non-exposed individuals and/or failed to identify or
appropriately control known confounders and/or failed to carry out a sufficiently long and
complete follow-up of patients; a case-control study that failed to clearly define comparison
groups and/or failed to measure exposures and outcomes in the same (preferably blinded),
objective way in both cases and controls and/or failed to identify or appropriately control known
confounders.
2
Table 2w: Key-words used in Medline, COCHRANE CENTRAL and EMBASE for the
Systematic Literature research.
Population
"Arthritis, Rheumatoid"[Mesh]
"Methotrexate"[Mesh]
– Amethopterin
– Methotrexate Hydrate
– Hydrate, Methotrexate
– Methotrexate, (D)-Isomer
– Methotrexate, (DL)-Isomer
– Methotrexate, Dicesium Salt
– Dicesium Salt Methotrexate
– Methotrexate, Disodium Salt
– Disodium Salt Methotrexate
– Methotrexate, Sodium Salt
– Sodium Salt Methotrexate
– Mexate
"Methotrexate/adverse effects"[Mesh] OR"Methotrexate/toxicity"[Mesh]
"Safety"[Mesh]
Outcomes
"Risk Management"[Mesh]
"Product Surveillance, Postmarketing"[Mesh]
"Treatment outcome" [Mesh]
"Risk assessment" [Mesh]
“Risk factors” [Mesh]
“Time factors” [Mesh]
“Population surveillance” [Mesh]
"Mortality" [Mesh]
"Morbidity" [Mesh]
"Drug toxicity" [Mesh]
“Cardiovascular diseases” [Mesh]
“Liver diseases OR Liver function tests” [Mesh]
“Infection” [Mesh]
“Neoplasms” [Mesh]
“Lung disease, interstitial” [Mesh]
“Blood cell count” [Mesh] OR “pancytopenia” [Mesh]
"Epidemiologic studies"[Mesh]*
Study designs
"Multicenter Study "[Publication Type]
"Comparative Study "[Publication Type]
"Evaluation Studies"[Mesh].
*The term «Epidemiologic Studies » includes: case-control studies, retrospective studies, cohort
studies, longitudinal studies (follow-up and prospective studies) and cross-sectional studies.
Intervention
3
Table 3w: 88 published studies [4-29, 31-39, 41-94] and 3 abstracts from EULAR and ACR
annual meetings [95-97] classified according to the topic and study design.
Topics, total no. of studies
Toxicity in general, N=42
Study designs (no. of studies) [References]
Meta-analysis (1), [41]
Prospective Studies (34), [4-27, 42-47, 95]
Restrospective Studies (6), [52-57]
Case-serie (1), [58]
Lung disease, N=4
Prospective studies (4) [59-62]
Cytopenia, N=6
Retrospective study (4), [28, 29, 63, 96]
Case-series (2), [64, 65]
Mortality, N=3
Prospective Cohort (2), [66, 67]
Retrospective Cohort (1), [68]
Cardiovascular diseases, N=2
Case-controls (2), [69, 70]
Infections, N=6
Prospective Studies (5), [39, 71-74]
Restrospective Study (1), [75]
Malignancies, N=10
Prospective Studies (4), [76-78, 97]
Retrospective Study (1), [79]
Case-series (5), [31, 80-83]
Liver toxicity, N= 18
Meta-analysis (1), [84]
Prospective Studies (9), [32-38, 85, 86]
Restrospective Studies (4), [87-90]
Case-series (4), [91-94]
4
Table 4w: Termination rates for toxicity of long term MTX in RA [41-47].
References [no.]
Study design,
Termination rates for toxicity (%)
Level of evidence
Maetzel, 2000 [41]
Meta-analysis of 110 RCTs
Duration of treatment = 5 years
and observational studies
- MTX: 35%
Level: 2a
- SSZ: 52%
- Gold: 64%
The median survival times (including all types of withdrawals)
were 41 months (range: 6-72) for MTX, 24 months (range: 6-60)
for Gold and 18 months (6-60) for SSZ.
Aletaha, 2003; [42]
6 Prospective
Duration of treatment = 5-12.7 years
De La Mata, 1995; [43]
observational studies
HCQ <
Morand, 1992; [44]
Level: 2b
(10-14%) (10-37%) (17-41%) (22-50%)
MTX <
SSZ <
Gold ~ D-Penicillamine
(24-55%)
Galindo-Rodriguez, 1999; [45]
Grove 2001; [46]
Papadopoulos, 2002; [47]
HCQ: hydroxychloroquine, SSZ: sulfasalazine, RCTs: Randomized controlled trials.
5
Table 5w: Results from 16 studies regarding the mortality, the risk for cardiovascular diseases, infections and malignancies in RA
patients receiving long term of MTX [39, 66-79].
References
[no.]
Study’s characteristics
(Level of evidence)
Choi, 2002
[66]
Prospective cohort (2b)
1,240 patients with RA
Follow-up: 6 yrs (SD: 5)
- RA+MTX and 1 other DMARD
(n=588)
Mean dose: 13 mg/w
- RA without MTX (n=652)
Alarcon, 1995
Prospective cohort (2b)
[67]
RA with MTX (n=152)
Mean dose: 13.6 (SD: 7.1) mg/w
Mean duration: 80.4 (SD: 20.2) mo.
Follow-up: 10 yrs
Reference: US general population
Landewe, 2000
Retrospective cohort (4)
[68]
623 RA who started a new DMARD
Median duration of MTX: 3.5 yrs
Mean dose: NA
Follow-up: 12 yrs
Results
MORTALITY
- Mortality incidence rate (per 1000 patient-years):
RA+MTX : 23.0
RA no MTX : 26.7
- Adjusted Hazard Ratio¥ MTX versus no MTX use (95%CI):
All-cause mortality: 0.4 (0.2-0.8)
Cardiovascular mortality: 0.3 (0.2-0.7)
Non-cardiovascular mortality: 0.6 (0.2-1.2)
27 deaths/152 (17.7%)
- Mortality incidence rate: 31.3 per 1000 patient-years
- SMR (95% CI):
All causes: 1.9 (1.3-2.8)
Infectious diseases: 11.3 (1.4-40.8)
Musculoskeletal diseases: 56.9 (11.7-166.4)
Cancers: 1.0 (0.3-2.6)
Cardiovascular diseases: 1.4 (0.6-2.6)
Cerebrovascular diseases : 2.9 (0.6-8.6)
Adjusted relative risk (RR) of mortality in RA patients with CVD and
who started MTX versus “no CVD/no MTX”, “no CVD/MTX” and
“CVD/no MTX” groups:
RR=3.4, p value = 0.005.
CVD was defined as peripheral or central atherosclerotic vascular disease
and/or high blood pressure.
6
CARDIOVASCULAR DISEASES (CVD)
van Halm, 2006
[69]
Case control (3b)
- Cases: 72 RA with CVD$
- Controls: 541 RA without CVD$
Assous, 2006
[70]
Case control within a prospective
cohort (3b)
Follow-up: 5.4 (SD: 1.8) yrs
239 RA without history of CVD*
Mean age: 56.3± 15.7 years
Women: 82%
RA duration: 11.6 ±8.8 years
194 RA with MTX (81.2%)
Steroids use: 88%
Treated hypertension: 34%
Diabetes: 8%
Smoking: 15%
Treated hypercholesterolemia: 10%
van der Heijde,
Prospective study (2b)
2007 [39] 228 RA with MTX
Mean dose: 16.5 mg/week
Follow-up: 3 yrs
Boerbooms,
Prospective cohort (4)
1995 [71] 47 RA with MTX
Follow-up: 6 yrs
Adjusted OR** for CVD$ (95% CI), with “never MTX, SSZ or HCQ” as
reference:
- “only MTX ever”: OR = 0.11 (0.02- 0.56) (p<0.05)
- “only SSZ ever”: OR= 0.37 (0.14-0.99) (p<0.05)
- “only HCQ ever”: OR= 0.47 (0.15-1.46)
17 CVD§ events (cases)
222 no CVD events (controls)
RR of CVD§ associated with MTX (univariate analysis):
2.4 (CI 95%: 0.3-18.3),
p value = 0.4.
INFECTIONS
Rate of serious infectious (no. of patients reporting ≥1event) during the
3-year duration of treatment:
- Any infections: 8.3% of patients, pneumonia: 1.8% of patients,
skin infections: 1.3% of patients.
79% occurred during the first 2 years of treatment [68].
Rates of major infections μ according study period in months:
- 0-12: MTX (17%)
- 0-48: MTX (10.7%)
- 0-72: MTX (16%)
7
Schnabel, 1996
Prospective cohort (4)
[72]
185 RA with MTX
Follow-up: 30 mo.
Doran, 2002
Prospective cohort (2b)
[73]
609 RA (MTX: 21.8%)
Follow-up: 12.7 yrs
Wolfe, 2006
Prospective cohort (2b)
[74]
10,614 RA from the NDBRD
MTX: 56.7% of patients
Follow-up: 4.5 yrs
Perhala, 1991
Retrospective cohort (4)
[75]
121 RA:
- 60 with MTX (mean dose: 8.2
mg/week, mean duration: 63.6 months),
- 61 who have never taken MTX.
No difference on the daily dose of
prednisone between the 2 groups
(around 4 mg/day).
65 major infectionsφ occurred in 56 patients (30.2%)
Rates according study period in months:
- 0-12 mo.: 30.7% (20/65)
- 13-30 mo.: 69.2% (45/65)
48% of respiratory tracts infections
45% occurred during steroid treatment
4 deaths with infections being implicative as causative.
Hazard ratios for MTX (95%CI, univariate analysis):
- Infections : 0.96 (0.64-1.45), p=0.85
- Infections requiring hospitalization: 0.91 (0.57-1.45), p=0.69
- Incidence rate of HZ: 13.2 per 1000 person-years (11.9-14.5)
- Hazard ratios£ according treatments (95%CI):
MTX: 1.0 (0.8-1.3), p=0.720
Prednisone: 1.5 (1.2-1.8), p<0.001
Cox-2 NSAID: 1.3 (1.1-1.6), p=0.023
Leflunomide: 1.4 (1.1-1.8), p=0.008
Azathioprine: 2.0 (1.2-3.3), p=0.005
All infectious complications:
RA+MTX: 8 γ /92 (8.7%)
RA without MTX: 6 ε /110 (5.5%), p=0.37
Deep sepsis with infection of the prosthesis:
RA+MTX: 3/92 (3.3%)
RA without MTX: 2/110 (1.8%), p=0.66
202 total hip or knee replacements (92 in
MTX group, 110 in control group)
Follow-up: 6 months post surgery
8
MALIGNANCIES
Wolfe, 2004
Prospective cohort (2b)
[77]
From NDBRD:
- RA+MTX: n=5,501
- RA, no MTX, no biologic: n=4,399
Follow-up: 1.5 yrs
- Incidence rates of lymphomas:
MTX group: 96.8 per 100,000 py
No MTX group: 55.9 per 100,000 py
- SIR‡ (95% CI) (National Cancer Institute):
MTX group: 1.7 (0.9-3.2)
No MTX group: 1.0 (0.4-2.5).
Franklin, 2006
RR and SIR** of lymphomas (95% CI), with UK local population as
Prospective Cohort (2b)
[76]
From NOAR:
reference
N= 2,105 new onset inflammatory
- In RA group:
polyarthritis
RR‡=2.32 (0.5-10.71)
582 (28%) with MTX
SIR=2.94 (1.34-5.57)
Follow-up : 7.4±2.3 yrs
- In inflammatory polyarthritis MTX group:
RR‡=3.31 (1.01-10.81)
SIR=4.86 (1.78-10.57)
Mariette, 2002
- Incidence rate of lymphomas (based on an estimation
National prospective study (4)
[78]
25 new cases of lymphoma in RA +
of 30,000 French RA treated with MTX ψ ) (95% CI):
MTX patients (1996-1998)
NHL: 20.0 per 100,000 py (3.7-36.3)
Mean duration of MTX: 5.2 years
HD: 7.8 per 100,000 py (0-18)
(range: 1.4-13)
- SMR‡ (French registries of lymphomas):
Mean cumulative dose: 2.2 g (range: 0.5NHL: 1.07 (0.6-1.7)
5.2)
HD: 7.4 (3.0-15.3) (p<0.001)
Bologna, 1997
- Cancers in RA+MTX group:
Retrospective cohort (4)
[79]
- RA+MTX group (n=426), duration
Prevalence: 1.88% (8 Δ /426)
37.4 months
- Cancers in rheumatoid controls without MTX:
- Control group without MTX (n=420)
Prevalence: 1.43% (6/420)
Follow-up: 4.6 years in MTX group, 1
year in no MTX group
SMR: Standardized Mortality Ratio, SD: Standard deviation, yrs: years, NA: not available, SSZ: sulfasalazine, HCQ:
hydroxychloroquine. RR: Relative Risk, OR: Odds Ratio, RF: Rheumatoid Factor, NDBRD: National Data Bank for Rheumatic
9
Diseases, NOAR: Norfolk Arthritis Register, NHL: non Hodgkin lymphoma, HD: Hodgkin disease, NS: not significant, py: patientyear.
¥
Estimated from weighted Cox models adjusted for age, sex, rheumatoid factor, calendar year, duration of disease, smoking,
education, health assessment questionnaire score, patient global assessment, joint counts, erythrocyte sedimentation rate, prednisone
status and number of other disease-modifying anti rheumatic drugs used.
* At baseline: Myocardial ischemia, ventricular or supraventricular rhythm disorders, congestive heart failure, transient ischemic
attack, stroke, or symptomatic occlusive arterial disease of the lower limbs.
§
Cardiovascular diseases: acute myocardial ischemia, stroke or cardiovascular death (due to myocardial infarction, stroke, congestive
heart failure or sudden death).
$
Cardiovascular diseases: coronary artery, cerebral arterial and peripheral arterial diseases.
**Adjusted on age, gender, smoking, RA duration, positive rheumatoid factor test and erosions.
μ
Infections requiring antibiotics use φ Episodes of bacterial infections severe enough to require antibiotic treatment and herpes zoster
£
Adjusted on age, sex, education level, smoking status, diabetes, ever acute myocardial infarction, RA duration, HAQ.
γ
3 sepsis with infection of the prostheses, 2 infected haematoma, 2 necrotic eschars and 1 non-communicating serous drainage.
ε
2 infected joints, 1 joint dehiscence, 1 infected hematoma, 1deep abscess and 1 long term drainage.
Ψ
Estimated from 2 independent surveys among rheumatologists, between 1996 and 1998. ** compared with the local population, UK
‡Age and sex adjusted.
Δ
8 incident cases of cancers: 1 melanoma, 1 lung, 1 gastric, 1 cervix, 1 breast, 1 womb malignancies, 1 NHL and 1HD.
- Mean cumulative dose of MTX: 1213.1 mg,
- Outcomes: 2 deaths, 6 remissions (follow-up 48.3±18.1 months).
10
Table 6w: Results from a meta-analysis (Level 2a) of 10 prospective studies evaluating liver biopsies during MTX treatment
(Roenigk classification*) [84]
All RA patients (n=334)
Women: 66.5%
Mean dose of MTX: 9.3 mg/week
Mean cumulative dose: 2061.8 mg
Mean duration of MTX: 55 months
“Light” alcohol consumption
(<100 g/week), n=169
Incidence of progression of at
least one grade**
(95%CI)
81/334
24.3%
(19.8-29.2)
p value
Incidence of patients with
advanced changes
(Grades IIIb or IV) (95%CI)
9/334
2.7%
(1.2-5.1)
p value
33/120
5/169
27.5%
3.0%
(17.9-37.1)
(0.8-7.2)
p=0.02
p=0.01
3/3
4/22
“Heavy” alcohol consumption
(≥ 100 g/week), n=22
100%
18.2%
(29.4-100)
(5.2-40.3)
In 6 of these 10 studies, only post-treatment biopsies were available and in 5 studies, biopsies were performed at baseline and posttreatment. (1 study, contained data on patients with baseline and post treatment biopsies and other patients with only post treatment
biopsies).
* Roenigk classification included the following:
- Grade I is normal, although mild fatty infiltration, nuclear variability, and portal inflammation are allowed;
- Grade II requires moderate to severe fatty infiltration, nuclear variability, portal tract inflammation and necrosis;
- Grade IIIA requires mild fibrosis, slight enlargement of portal tracts, and some formation of fibrotic septae;
- Grade IIIB requires moderate to severe fibrosis with all other changes of grade IIIA;
- Grade IV describes cirrhosis.
** The definition of progression was:
- At least one grade worse in post treatment biopsy in comparison with baseline biopsy
- If no baseline biopsy was done, then progression was defined as a post treatment biopsy showed grade II or more.
11
Duplicates between
Cochrane and Medline or
Embase: n=80
Duplicates n=42
N=2,574
Medline
n = 1210
Embase
n = 499
Cochrane Central
n = 201
ACR (05-07) n = 179
EULAR (05-07) n= 485
1046 excluded by titles/abstracts:
N=180
 Reviews (n=171)
No MTX (n=27)
Cases-reports, replies (n=142)
Duplicates (n=207)
No data on safety (n=205)
Combination therapies (n=158)
Not adult RA (n=100)
Duration of MTX ≤2 years (n= 14)
Language (n=22)
For detailed review
n = 164
488 excluded by titles/abstracts:
196 excluded by titles/abstracts:
 Reviews (n= 144)
No MTX (n=80)
Duplicates (n=54)
No data on safety (n=60)
Combination therapies (n=92)
Not adult RA (n=50)
Duration of MTX ≤2 years (n=6)
Not in Humans (n=2)
 Duplicates (n= 46)
No MTX (n=33)
No data on safety (n=34 )
Combination therapies (n=53)
Not adult RA (n=10)
Duration of MTX ≤2 years (n=18)
Language (n=2)
For detailed review
n = 11
For detailed review
n=5
Excluded, n=96
 Reviews or letters (n=4)
No MTX (n=2)
No data on safety (n=3)
Combination therapies (n=30)
Not only adult RA (n=6)
Duration of MTX ≤2 years or unknown (n= 51)
91 included studies:
- From databases: 84 studies,
- From hand search: 4 studies
- 3 abstracts from ACR and EULAR.
12
Figure 1: Flow-chart: articles retrieved by the different search strategies and result of selection and appraisal process.
13
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