Table 1w: Systematic Literature Research process step by step.
1. Clinical Question / What is the long term safety of methotrexate including cardiovascular diseases, malignancies, infections and liver toxicity?2. Translation in epidemiological terms / 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?
3. Definition of the ‘PICO”
for Population, Intervention, Control and Outcomes. / 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.
4. Definition of expected study designs / 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.
5. The choice of the Key-words / Using Mesh Term in MEDLINE with the help of a librarian and according to the PICO.
6. Search in the Literature / - 3 databases: MEDLINE, EMBASE and COCHRANE CENTRAL
- EULAR and ACR abstracts (2005-2007)
- Hand search in references of relevant studies and reviews
7. Selection of the relevant studies / Inclusion criteria: adults ≥18 years-old, diagnosis of RA according to ACR criteria 1987, receiving MTX monotherapy for more than 2 years (without other DMARD).
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 level of Evidence. / 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 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.
* ‘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), 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.
Table 2w: Key-words used in Medline, COCHRANE CENTRAL and EMBASE for the Systematic Literature research.
Population / "Arthritis, Rheumatoid"[Mesh]Intervention / "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]
Outcomes / "Safety"[Mesh]
"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]
Study designs / "Epidemiologic studies"[Mesh]*
"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.
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 / Study designs (no. of studies) [References]Toxicity in general, N=42 / 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]
1
Table 4w: Termination rates for toxicity of long term MTX in RA [41-47].
References [no.] / Study design,Level of evidence / Termination rates for toxicity (%)
Maetzel, 2000 [41] / Meta-analysis of 110 RCTs and observational studies
Level: 2a / Duration of treatment = 5 years
- MTX: 35%
- 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]
De La Mata, 1995; [43]
Morand, 1992; [44]
Galindo-Rodriguez, 1999; [45]
Grove 2001; [46]
Papadopoulos, 2002; [47] / 6 Prospective
observational studies
Level: 2b / Duration of treatment = 5-12.7 years
HCQ < MTX < SSZ < Gold ~ D-Penicillamine
(10-14%) (10-37%) (17-41%) (22-50%) (24-55%)
HCQ: hydroxychloroquine, SSZ: sulfasalazine, RCTs: Randomized controlled trials.
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].
(Level of evidence) / Results
MORTALITY
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) / - 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)
Alarcon, 1995
[67] / Prospective cohort (2b)
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 / 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)
Landewe, 2000
[68] / Retrospective cohort (4)
623 RA who started a new DMARD
Median duration of MTX: 3.5 yrs
Mean dose: NA
Follow-up: 12 yrs / 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.
CARDIOVASCULAR DISEASES (CVD)
van Halm, 2006
[69] / Case control(3b)
- Cases: 72 RA with CVD$
- Controls: 541 RA without CVD$ / 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)
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% / 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
van der Heijde,
2007 [39] / Prospective study (2b)
228 RA with MTX
Mean dose: 16.5 mg/week
Follow-up: 3 yrs / 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].
Boerbooms, 1995 [71] / Prospective cohort (4)
47 RA with MTX
Follow-up: 6 yrs / Rates of major infections μ according study period in months:
- 0-12: MTX (17%)
- 0-48: MTX (10.7%)
- 0-72: MTX (16%)
Schnabel, 1996
[72] / Prospective cohort (4)
185 RA with MTX
Follow-up: 30 mo. / 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.
Doran, 2002
[73] / Prospective cohort (2b)
609 RA (MTX: 21.8%)
Follow-up: 12.7 yrs / 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
Wolfe, 2006
[74] / Prospective cohort (2b)
10,614 RA from the NDBRD
MTX: 56.7% of patients
Follow-up: 4.5 yrs / - 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
Perhala, 1991
[75] / Retrospective cohort (4)
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).
202 total hip or knee replacements (92 in MTX group, 110 in control group)
Follow-up: 6 months post surgery / 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
MALIGNANCIES
Wolfe, 2004
[77] / Prospective cohort (2b)
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
[76] / Prospective Cohort (2b)
From NOAR:
N= 2,105 new onset inflammatory polyarthritis
582 (28%) with MTX
Follow-up : 7.4±2.3 yrs / RR and SIR** of lymphomas (95% CI), with UK local population as reference
- In RA group:
RR‡=2.32 (0.5-10.71)
SIR=2.94 (1.34-5.57)
- In inflammatory polyarthritis MTX group:
RR‡=3.31 (1.01-10.81)
SIR=4.86 (1.78-10.57)
Mariette, 2002
[78] / National prospective study (4)
25 new cases of lymphoma in RA + MTX patients (1996-1998)
Mean duration of MTX: 5.2 years (range: 1.4-13)
Mean cumulative dose: 2.2 g (range: 0.5-5.2) / - Incidence rate of lymphomas (based on an estimation
of 30,000 French RA treated with MTX ψ ) (95% CI):
NHL: 20.0 per 100,000 py (3.7-36.3)
HD: 7.8 per 100,000 py (0-18)
- SMR‡ (French registries of lymphomas):
NHL: 1.07 (0.6-1.7)
HD: 7.4 (3.0-15.3) (p<0.001)
Bologna, 1997
[79] / Retrospective cohort (4)
- RA+MTX group (n=426), duration 37.4 months
- Control group without MTX (n=420)
Follow-up: 4.6 years in MTX group, 1 year in no MTX group / - Cancers in RA+MTX group:
Prevalence: 1.88% (8 Δ /426)
- Cancers in rheumatoid controls without MTX:
Prevalence: 1.43% (6/420)
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 Diseases, NOAR: Norfolk Arthritis Register, NHL: non Hodgkin lymphoma, HD: Hodgkin disease, NS: not significant, py: patient-year.
¥ 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).
Table 6w: Results from a meta-analysis (Level 2a) of 10 prospective studies evaluating liver biopsies during MTX treatment