Table 1. Overview of all included studies (n = 16), sorted by publication date in descending order.
| Reference | Number of patients | Design | Country | Participants | MTX exposure assessed | Non- MTX DMARDs assessed | T2D outcome | Other traditional CV risk factors assessed | Qi score |
|---|---|---|---|---|---|---|---|---|---|
| Agca et al., 2019 | Total RA patients 326 (Females 212; Males 114) | PCS | Amsterdam, the Netherlands | RA diagnosed according to the 1987 ACR classification criteria; mean age: 63±7 years; mean RA duration: 7±3 years; median follow-up time: 15 years; disease activity: measured by DAS-28 | Exposure to MTX was assessed as one of the DMARDs in RA patients and diabetics; there was no information about the status of using MTX, its dose or duration | cDMARDs: sulfasalazine, hydroxy-chloroquine and leflunomide. bDMARDs: no information about the drug names | T2D was one of the assessed traditional CV risk factors; it was defined by the 1999 WHO criteria of glucose ≥7.0 mmol/L (≥126 mg/dL) or treated with glucose-lowering medications | Hypertension, hypercholesterol-emia, smoking, BMI, family history of CVD, age and sex | 10.5 |
| Ruscitti et al., 2019 | Total RA patients 841 (Females 691; Males = 150) | PCS | Italy | RA diagnosed according to ACR/EULAR criteria for RA; median age: 60 years; median RA duration: 8.2 years; median follow-up time: 3 years; disease activity: measured by DAS-28 | Exposure to MTX was assessed; no information about the status, dose or duration of using MTX | cDMARDs: hydroxy-chloroquine, sulfasalazine and leflunomide. bDMARDs: TNFα inhibitors | T2D was one of the assessed traditional CV risk factors; T2D defined by the ADA criteria or the use of antidiabetic medications | Hypertension, hypercholesterol-emia, smoking, BMI, age and sex | 11 |
| Best et al., 2018 | Total RA patients 44,190 (Females 33,809; Males 10,381) | PCS | USA | RA diagnosed according to the ICD-9-CM; mean age: 58.9±13.4 years; median follow-up time: 1 year; disease activity: DAS-28 was not measured | Exposure to MTX was assessed as one of the DMARDs in RA patients; the dosage of all the medications was based on the NDC; no information about the status of using MTX, its dose or duration | cDMARDs: hydroxy-chloroquine, leflunomide and sulfasalazine. bDMARDs: etanercept, infliximab and adalimumab | Prevalence of T2D was assessed; it was defined based on the ICD-9-CM code 250.X | Age and sex | 10 |
| Gomes et al., 2018 | Total RA patients 338 (Females 307; Males = 31) | Cross-sectional study | Fortaleza, Brazil | RA diagnosed according to the ACR/EULAR 2010 criteria for RA; mean age: 53.5±12 years; mean RA duration: 2.2±8.7 years; median follow-up time: 1 year; disease activity: measured by DAS-28 | Exposure to MTX was assessed as current use of the medication; there was no information about the dose or duration of MTX use | cDMARDs: leflunomide. bDMARDs: no information about the drug names | T2D was assessed as one of the components of metabolic syndrome. T2D defined by fasting blood glucose >100mg/dL or if the patient was taking any antidiabetes medications | Hypertension, hypercholesterol-emia, smoking, BMI, family history of CVD, physical inactivity, age and sex | 7.5 |
| Chen et al., 2017 | Total RA patients 33,112 | RCS | Taiwan | RA diagnosis based on the ICD9 code 714.0 after at least 3 outpatient clinic visits and on holding a catastrophic illness certificate; mean age: 49.2±14.9 years; median follow-up time: 12 years; disease activity: DAS-28 was not measured | Exposure to oral or injectable MTX was assessed; no information on the status of using MTX, its dose or duration | cDMARDs: leflunomide, sulfasalazine, azathioprine, cyclosporine. bDMARDs: anti-TNF agents | T2D diagnosed based on the ICD-9-CM code 250.X and the concurrent prescription of any antidiabetes medications | Age and sex | 9.5 |
| Mangoni et al., 2017 | Total RA patients 86 (Females 62; Males 24) | Repeated cross-sectional study | Australia | RA diagnosed according to the 1987 ACR or the 2010 ACR/EULAR criteria for RA; mean age: 61±13 years; mean RA duration: 9±10.8 years; follow-up period: 8 months; disease activity: measured by DAS-28 | Exposure to MTX was assessed as current use of MTX; defined as using MTX for ≥8 weeks; median MTX dose: 15 mg per week; median MTX duration: 75 months | cDMARDs: hydroxy-chloroquine, leflunomide and sulfasalazine. bDMARDs: abatacept, rituximab, tocilizumab, adalimumab, etanercept, certolizumab pegol and golimumab | T2D was one of the assessed traditional CV risk factors; its definition based on physician’s diagnosis or if patient reported treatment with glucose-lowering medications at the time of assessment | Hypertension, hypercholesterol-emia, smoking, BMI, family history of CVD, physical inactivity, age and sex | 12 |
| Ozen et al., 2017 | Total RA patients 13,669 (Females = 10,953; Males = 2,716) | PCS | USA | RA was diagnosed based on rheumatologist’s diagnosis; mean age: 58.6±13.4 years; mean RA duration: 14.4±12.4 years; median follow-up time: 4.6 years; disease activity: DAS-28 was not measured | Exposure to MTX was assessed as ever use of MTX; there was no information about the MTX dose or duration | cDMARDs: hydroxy-chloroquine. bDMARDs: TNFα inhibitors, abatacept, rituximab and tocilizumab | Incident T2D based on patients’ self-report of diagnosing new T2D or initiating antidiabetic medications | Hypertension, smoking, BMI, age and sex | 11 |
| Amaya-Amaya et al., 2013 | Total RA patients 800 (Females 647; Males 153) | Cross-sectional | Colombia | RA diagnosed according to the 1987 ACR classification criteria for RA; mean age: 51.8±12.1 years; mean RA duration: 12.4±10.3 years; study period: between February 1996 and April 2012; disease activity: measured by DAS-28 | Exposure to MTX was assessed as current or past use of MTX in the RA population; there was no information about the status of using MTX, its dose or duration | cDMARDs: sulfasalazine, D-penicillamine, gold salts, leflunomide, azathioprine and cyclosporine. bDMARDs: etanercept, infliximab, adalimumab, abatacept, tocilizumab and rituximab | T2D was one of the assessed traditional CV risk factors; definition based on fasting glucose ≥7.0 mmol/L (126 mg/dL) or if treated with glucose-lowering medications at the time of assessment | Hypertension, hypercholesterol-emia, smoking, BMI, family history of CVD, abdominal obesity, physical inactivity, age and sex | 9 |
| Antohe et al., 2012 | Total RA patients 1,587 (Females 1,150; Males 437) | PCS | Central Pennsylvania, USA | RA diagnosed according to the 1987 ACR classification criteria for RA; median age: 57 years; median follow-up time: 3 years; disease activity: DAS-28 was not measured | Exposure to MTX was assessed as continuous use of the medication; continuous use was defined as a discontinuation gap of <3 months; the start and the stop dates of using MTX were recorded during the observation period; there was no information about the dose of MTX | cDMARDs: hydroxy-chloroquine bDMARDs: TNFα inhibitors including adalimumab, etanercept, golimumab and infliximab | Incident T2D was the primary outcome; it was defined based on the physician-established diagnosis or using the 2010 ADA criteria, random glucose level of ≥200 mg/dl, HbA1c ≥6.5%, or ever use of any hypoglycemic or antidiabetic medications. | BMI, age and sex | 9 |
| Bili et al., 2011 | Total RA patients 1,127 (Females 823; Males 304) | RCS | Central Pennsylvania, USA | RA diagnosed according to the 1987 ACR classification criteria for RA; mean age: 60.7±15.1 years; median follow-up time: 2 years; disease activity: DAS-28 was not measured | Exposure to MTX was assessed as continuous use of the medication; continuous use was defined as a discontinuation gap of <3 months; the start and stop dates of using MTX were recorded during the observation period; there was no information about the dose of MTX | cDMARDs: hydroxy-chloroquine. bDMARDs: TNFα inhibitors | Incident T2D based on the 2010 ADA criteria: random glucose ≥200 mg/dL or HbA1c ≥6.5% or ever use of hypoglycemic/ antidiabetic medications | BMI, age and sex | 10 |
| Innala et al., 2011 | Total patients at entry 700 (Females 481; Males 219;); Total patients at end 442 (Females 301; Males 141;) | PCS | Sweden | Early RA diagnosed by ARA criteria; patient records and self-reported questionnaire on comorbidity and local rheumatologist follow-up assessments were used; mean age: 55.2±14.3 years; mean disease duration: 3.3 months; median follow-up time: 5 years; disease activity: measured by DAS-28 | Exposure to ever use of MTX was assessed; accumulated number of months of treatment was considered, there was no information about the MTX duration or its dose | cDMARDs: sulfasalazine, chloroquine, azathioprine, mycopheno, atmophetil, myocrisine, auranofin, cyclosporine and leflunomid. bDMARDs: etanercept, adalimumab, infliximab, anakinra and rituximab | T2D was one of the assessed traditional CV risk factors; there was no standardized definition for T2D, it was assessed based on patients’ self-reported questionnaire on comorbidity | Hypertension, hypercholesterol-emia, smoking, BMI, age and sex | 11 |
| Solomon et al., 2011 | Total RA patients 11,327 (Females 8,900; Males = 2,427) | PCS | USA | RA diagnosed based on at least 2 visits to the rheumatologist using the ICD-9-CM 714.x criteria; mean age: 53.7±13.2 years; median follow-up time: 5.8 months; disease activity: DAS-28 was not measured | Exposure to oral or injectable MTX was assessed; there was no information about the MTX status, dose or duration of use | cDMARDs: hydroxy-chloroquine, sulfasalazine, leflunomide, cyclosporine, azathioprine, cyclo-phosphamide, mycophenolate mofetil, 6-thioguanine, acitretin, D-penicillamine, gold, auranofin, myochrysine, and solganol; bDMARDs: TNFα inhibitors including dalimumab, etanercept an infliximab | Incident T2D defined by presence of at least 1 diagnosis of T2D based on ICD-9-CM250.x, and a new user of T2D-specific medications including all insulin preparations and oral antidiabetic agents | Age and sex | 10 |
| Radovits et al., 2009 | Total RA patients 222 (Females 145; Males 77) | Nested case-control study | Nijmegen, the Netherlands | RA diagnosed according to the 1987 revised ACR criteria; random selection of controls from the PCS; mean age: 67.5±10 years; mean RA duration: 4.3±8.5 years;; disease activity: measured by DAS-28 | Exposure to MTX was assessed among RA cases and controls; cumulative MTX dose among RA cases and controls: 1791.6 vs. 1943.9 mg; total MTX treatment duration among RA cases and controls: 152.9 vs. 161.9 weeks | bDMARDs: TNFα inhibitors | T2D was one of the assessed traditional CV risk factors; there was no standardized definition for T2D | Hypertension, hypercholesterol-emia, smoking, BMI, family history of CVD, age and sex | 11 |
| Assous et al., 2007 | Total RA patients 239 (Females 196; Males 43) | RCS | France | RA diagnosed according to the 1987 revised ACR criteria; mean age: 56.3±15.7 years; mean RA duration: 11.6±8.8 years; mean follow-up time: 5.4±1.8 years; disease activity: DAS-28 was not measured | Exposure to MTX was assessed as one of the DMARDs in RA patients; duration of use ≥1 month; there was no information about the status of using MTX or its dose | bDMARDs: infliximab, etanercept, and adalimumab | T2D was one of the assessed traditional CV risk factors; there was no standardized definition for T2D | Hypertension, hypercholesterol-emia, smoking, BMI, age and sex | 7 |
| Wasko et al., 2007 | Total RA patients 4,905 | PCS | USA | RA diagnosed according to the 1987 ACR revised classification criteria for RA; mean age: 58.2±13.9 years; mean RA duration: 13±11.7 years; median follow-up time: 21.5 years; disease activity: DAS-28 was not measured | Exposure to MTX was assessed as ever or never use of MTX; there was no information about the MTX dose, duration of MTX use (percentage of observation time): 39% | cDMARDs: hydroxy-chloroquine | Incident T2D based on patients’ self-report of the diagnosis or the new use of hypoglycemic medications | Age and sex | 10 |
| del Rincon et al., 2001 | Total RA patients 236 (Females 146; Males 90) | RCS | Mexico | RA diagnosed according to 1987 ACR criteria; O´RALE cohort used; matched non-RA: SAHS cohort; median age: 56 years (range 22–80); median follow-up: time 7 years; disease activity: DAS-28 was not measured | Exposure to MTX was current use of the medication. It was one of the DMARDs assessed in RA patients; there was no information about the duration of using MTX or its dose | No information about DMARDs (MTX exposure, dose, or duration) | T2D was one of the assessed traditional CV risk factors; it was defined based on the 1997 criteria of the ADA: glucose ≥7.0 mmol/L (≥126 mg/dL) or if treated with glucose-lowering medications at the time of assessment | Systolic blood pressure, hypercholesterol-emia, cigarette smoking, BMI, age and sex | 11 |
ACR = American College of Rheumatology; ADA = American Diabetes Association; ARA = American Rheumatism Association; bDMARDs = biological disease-modifying antirheumatic drugs; BMI = body mass index; CV = cardiovascular; CVD = cardiovascular diseases; DAS-28 = Disease Activity Score 28; EULAR = American College of Rheumatology/European League Against Rheumatism; HbA1c = glycosylated hemoglobin; ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification; MTX = methotrexate; NDC = national drug codes; O´RALE = Outcome of Rheumatoid Arthritis Longitudinal Evaluation (del Rincon et al 2001); PCS = prospective cohort study; Qi = quality score; RA = rheumatoid arthritis; RCS = retrospective cohort study; SAHS = San Antonio Heart Study cohort; T2D = type 2 diabetes; cDMARDs = conventional disease-modifying antirheumatic drugs; TNFα = tumor necrosis factor alpha; USA = United States of America; WHO = World Health Organization.