Patients Receiving Methotrexate Monotherapy Research Articles

Impact of Upadacitinib on Laboratory Parameters and Related Adverse Events in Patients with RA: Integrated Data Up to 6.5 Years.

Upadacitinib (UPA) is a Janus kinase inhibitor that has demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA) with an acceptable safety profile. We investigated laboratory parameter changes in UPA RA clinical trials. Pooled data from six randomized trials in the SELECT phase 3 program were included. Key laboratory parameters and safety data were measured for UPA 15 and 30mg once daily (QD), adalimumab (ADA) 40mg every other week + methotrexate (MTX), and MTX monotherapy. Exposure-adjusted event rates (EAERs) of adverse events were calculated. A total of 3209 patients receiving UPA 15 mg QD (10 782.7 patient-years [PY]), 1204 patients receiving UPA 30mg QD (3162.5 PY), 579 patients receiving ADA + MTX (1573.2 PY), and 314 patients receiving MTX monotherapy (865.1 PY) were included, representing up to 6.5years of total exposure. Decreases in mean levels of hemoglobin, neutrophils, and lymphocytes, and increases in mean levels of liver enzymes and creatinine phosphokinase were observed with UPA, with grade 3 or 4 changes observed in some patients. Mean low- and high-density lipoprotein cholesterol ratios remained stable for patients receiving UPA 15 mg QD. EAERs of anemia and neutropenia occurred at generally consistent rates between UPA and active comparators (3.1-4.3 and 1.7-5.0 events [E]/100 PY across treatment groups, respectively). Rates of hepatic disorder were higher with MTX monotherapy, UPA 15mg and UPA 30mg (10.8, 9.7, and 11.0 E/100 PY, respectively) versus ADA + MTX (6.4 E/100 PY). Rates of lymphopenia were highest with MTX monotherapy (3.2 E/100 PY). Treatment discontinuations due to laboratory-related events were rare, occurring in 1.1% and 2.2% of patients treated with UPA 15 and 30mg QD, respectively. The results of this integrated long-term analysis of laboratory parameters continue to support an acceptable safety profile of UPA 15 mg QD for moderate-to-severe RA.

Joint-level responses to tofacitinib and methotrexate: a post hoc analysis of data from ORAL Start

BackgroundRheumatoid arthritis (RA) has a variable impact on different synovial joints, with inflammation being more commonly observed in some joints than others. Emerging evidence suggests that the anatomical variation in pathophysiology could result in differential responses to treatments across the joints, both within and between modes of action. This analysis aimed to characterize joint-specific responses to tofacitinib and methotrexate monotherapy in patients with RA.MethodsThis was a post hoc analysis of data from the phase III trial ORAL Start (NCT01039688), in methotrexate-naïve patients with RA. A paired joint pathology score (PJPS), derived from bilateral tender/swollen joint counts, was calculated. The percentage change from baseline in PJPS (%∆PJPS) and treatment-specific responses (tofacitinib 5 and 10 mg twice daily [BID] vs methotrexate; tofacitinib 5 vs 10 mg BID) for each patient joint pair, except for those with baseline/post-baseline PJPS = 0, were calculated at month 3, month 6, and month 12. Radiographic progression was similarly assessed using the Modified Total Sharp Score at month 6 and month 12.ResultsIn methotrexate-naïve patients, differences in %∆PJPS demonstrated greater responses with tofacitinib vs methotrexate in most joint locations. Lesser responses with tofacitinib vs methotrexate were observed in most joints of the feet, particularly at month 12. Despite this, radiographic progression at month 12 was significantly worse in the foot (and metacarpophalangeal) joints of patients receiving methotrexate vs tofacitinib.ConclusionWe observed variation in joint-specific responses with tofacitinib and methotrexate monotherapy. Despite a proximal–distal efficacy gradient, with better clinical responses in the feet, patients receiving methotrexate monotherapy demonstrated more radiographic progression in the foot joints compared with those receiving tofacitinib. These findings suggest that body site- and therapy-specific characteristics may interact to produce differential treatment responses.Trial registrationClinicalTrials.gov, NCT01039688.

Effect of prednisolone and saireito co-administration on T-cells of rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is an autoimmune disease. Methotrexate (MTX) and prednisolone (PSL) are used in combination for severe RA therapy. However, it can increase the risk of osteoporosis and osteonecrosis. Saireito (114) can be used to reduce PSL dose owing to its immunosuppressive effects. However, the effect of combination therapy of PSL+114 on the immune system of RA patients remains unknown. This study compared the effect of PSL alone and PSL+114 on peripheral blood mononuclear cell (PBMC) proliferation, T-cell subsets, and cytokine production in adult RA patients receiving MTX monotherapy. We isolated PBMCs from 14 consenting RA patients, and cultured them with PSL (0.0001-1.0 μM) in combination with or without 114 (300 μg/mL) for 96 h in the presence of concanavalin A. We measured the proliferation rates of PBMC, proportions of CD4+, CD8+, and CD4+CD25+Foxp3+T-cells (induced T-regulatory cells), and concentrations of interferon-γ, interleukin (IL)-6, IL-10, IL-17A, and tumour necrosis factor in the culture supernatant. Compared to the blank, the PBMC proliferation rate significantly decreased at a reduced PSL concentration after 114 administration. The 50% inhibition concentration was 0.43 μM PSL for the PSL-only group as compared to 0.29 μM PSL for the PSL+114 co-administration group. The PSL+114 co-administration group had a significantly higher concentration of IL-6 compared to the PSL-only group. The use of 114 in combination with low-concentration PSL intensified its immunosuppressive effect. However, the concentration of IL-6 was elevated in the co-administration group, suggesting exacerbation of RA activity.

Soluble Markers of Antibody Secreting Cell Function as Predictors of Infection Risk in Rheumatoid Arthritis.

Background Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with immune dysregulation and increased risk of infections. The presence of autoantibodies and immunoglobulin abnormalities indicates B-cell and antibody-secreting cell (ASC) dysfunction. We hypothesize that soluble factors associated with B-cell and ASC activity are decreased in RA patients and that this is linked to higher susceptibility to infections. Methods Using the Johns Hopkins Arthritis Cohort and Biorepository, we contrasted serum protein levels of soluble factors involved in B-cell activation (CD40, CD40L) and B-cell/ASC homing (CXCL10, CXCL11, and CXCL13) or survival (BAFF, APRIL, TACI, and BCMA) in 10 healthy subjects and 23 adult RA patients (aged 24-65 years). We subdivided RA patients into those with (n = 17) and those without infections (n = 6) within a 2-year period. In order to reduce the effect of RA treatment, we only included patients receiving methotrexate monotherapy or no RA treatments at baseline. Soluble serum protein levels of B-cell/ASC factors were quantified by multiplex immunoassays. Results We identified that (1) serum levels of soluble BCMA, APRIL, CD40, and CD40L were significantly decreased in RA patients relative to healthy individuals; (2) serum soluble BCMA, predominantly released by ASC, correlated with serum concentrations of class-switched immunoglobulins, IgG and IgA; and (3) RA patients with a history of infections had significantly lower soluble BCMA levels compared with healthy donors and with RA patients without infections. Conclusions Our study using soluble factors linked to B-cell/ASC activation and survival suggests that there is a paucity of ASC in a subset of RA patients and that this may be linked to altered antibody production and increased risk of infections. Further delineating the link between ASC and infection susceptibility in RA may optimize disease management and provide novel insights into disease pathogenesis that are susceptible to intervention.

Predictors of Remission Maintenance after Etanercept Tapering or Withdrawal in Early Rheumatoid Arthritis: Results from the PRIZE Study

Objective: To explore the influence of early treatment response to etanercept-methotrexate therapy on sustained remission after tapering/withdrawal of etanercept in methotrexate/biologic-naïve patients with early rheumatoid arthritis in the PRIZE study (ClinicalTrials.gov: NCT00913458). Method: In the initial 52-week open-label phase, enrolled patients received once-weekly etanercept 50 mg plus methotrexate. Patients who achieved DAS28 ≤3.2 at week 39 and <2.6 at week 52 were randomized to etanercept 25 mg plus methotrexate, methotrexate monotherapy, or placebo once weekly for 39 weeks in the double-blind phase. The relationships between responses in the open-label phase and sustained remission (DAS28 <2.6 at weeks 76 and 91, without glucocorticoid rescue therapy from weeks 52 to 64) in the double-blind phase were analyzed. Results: In the open-label phase, 70% of patients achieved DAS28 remission at week 52. In the double-blind phase, 63%, 40%, and 23% of patients had sustained DAS28 remission in the reduced-dose combination-therapy, methotrexate-monotherapy, and placebo groups, respectively. In patients receiving reduced-dose combination therapy, sustained remission was more likely in those who achieved DAS28 remission (p = 0.005) or low disease activity (p=0.044) in a shorter time, and who had a lower DAS28 (p = 0.016) or achieved ACR/EULAR Boolean remission (p < 0.05) at the end of the open-label phase. In patients receiving methotrexate monotherapy, sustained remission was associated with a lower acute-phase response (C-reactive protein, p = 0.007; erythrocyte sedimentation rate, p = 0.016) at the end of the open-label phase. Conclusion: Fast response and suppression of inflammation with etanercept-methotrexate therapy may predict successful etanercept tapering/withdrawal in patients with early rheumatoid arthritis.

Effect of Treat-to-target Strategies Aiming at Remission of Arterial Stiffness in Early Rheumatoid Arthritis: A Randomized Controlled Study.

To determine the efficacy of 2 tight control treatment strategies aiming at Simplified Disease Activity Score (SDAI) remission (SDAI ≤ 3.3) compared to 28-joint count Disease Activity Score (DAS28) remission (DAS28 < 2.6) in the prevention of arterial stiffness in patients with early rheumatoid arthritis (RA). This was an open-label study in which 120 patients with early RA were randomized to receive 1 year of tight control treatment. Group 1 (n = 60) aimed to achieve SDAI ≤ 3.3 and Group 2 (n = 60), DAS28 < 2.6. Pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months. A posthoc analysis was also performed to ascertain whether achieving sustained remission could prevent progression in arterial stiffness. The proportions of patients receiving methotrexate monotherapy were significantly lower in Group 1 throughout the study period. At 12 months, the proportions of patients achieving DAS28 and SDAI remission, and the change in PWV and AIx, were comparable between the 2 groups. In view of the lack of differences between the 2 groups, a posthoc analysis was performed at Month 12, including all 110 patients with PWV, to elucidate the independent predictors associated with the change in PWV. Multivariate analysis revealed that achieving sustained DAS28 remission at months 6, 9, and 12 and a shorter disease duration were independent explanatory variables associated with less progression of PWV. With limited access to biologic disease-modifying antirheumatic drugs, treatment efforts toward DAS28 and SDAI remission had similar effects in preventing the progression of arterial stiffness at 1 year. However, achieving sustained DAS28 remission was associated with a significantly greater improvement in PWV. [Clinical Trial registration: Clinicaltrial.gov NCT01768923.].

TREAT-TO-TARGET STRATEGY FOR EARLY PSORIATIC ARTHRITIS (PRELIMINARY RESULTS OF THE REMARCА STUDY)

The aim of a treat-to-target (T2T) strategy is to achieve a remission or minimal disease activity (MDA). Objective : to investigate the efficiency of the T2T strategy for early psoriatic arthritis (ePsA). Subjects and methods. Twenty-three patients (8 men and 15 women) with ePsA, who met the CASPAR criteria (mean age was 39.1±10.6 years; the median duration of ePsA was 7 [4; 24] months and that of psoriasis was 36 [12; 84] months), were examined. At the patient inclusion and then every 3 months, the investigators assessed the activity of ePsA by DAS and DAS28 and that of psoriasis by BSA (%) and PASI and determined erythrocyte sedimentation rate (ESR) (mm/h), C-reactive protein (CRP) level (mg/l), HAQ. All the patients received monotherapy (MoT) with subcutaneous methotrexate (MTX) (methoject) in a dose of 10 mg/week that was increased by 5 mg every 2 weeks until 20–25 mg/week was reached. The number of patients who had achieved remission (DAS <1.6 or DAS28 ≤ 2.4), low disease activity (LDA) (1.6 ≤ DAS <2.4 or 2.4 < DAS28 ≤ 3.6), MDA, and 20%, 50%, and 70% improvements according to the American College of Rheumatology (ACR) criteria. When LDA/MDA or remission was absent at 3 months of treatment, combined therapy (CoT) with MTX and adalimumab 40 mg once two weeks was used. Results . The baseline median DAS was 3.97 [3.07; 4.67]; DAS28 – 4.33 [3.68; 4.73], PASI, 6 [3.1; 9.7]; BSA, 1 [0.5; 3.65]; CRP, 15 [8.6; 25.1] mg/l; ESR, 15 [8.6; 25.1] mm/h; and HAQ, 0.75 [0.63; 1.25]. After 3 months of MoT, remission defined by DAS and DAS28 was in 13/22.7% of the patients; LDA in 21.7/27.3%, and MDA in 26.1%, respectively. ACR 20, 50, and 70 responses were obtained in 65.2, 26.15, and 8.7% of the patients, respectively. There were significant decreases in the level of CRP (to 5.7 [2.3; 10.7] mg/l), HAQ (0.38 [0; 0.87]), BSA (1 [0.3; 2]), and PASI (7.1 [0; 32.5]). ESR remained substantially unchanged (18 [10; 26] ml/h). Four patients with persistent high disease activity were given CoT; 19 patients continued MTX MoT. After 6 months, DAS/DAS28 remission was in 34.8/39.1% of the patients; DAS/DAS28 LDA in 26.1/39.1%; and MDA in 47.8%, respectively. ACR 20, 50, and 70% improvements were seen in 73.9, 60.9, and 47.8% of the patients, respectively. There were significant reductions in the level of CRP (4.9 [0.9; 8.3]), HAQ (0.13 [0; 0.63]), and BSA (0.35 [0; 1.6]). After MTX MoT, DAS/DAS28 remission was observed in 36.8/36.8% of the 19 patients; LDA in 15.8/36.8%; and MDA in 47.4%. ACR 20, 50, and 70 responses were seen in 68.4, 52.6, and 42.1% of the patients receiving MTX MoT and in 100, 100, 75% of the patients (n = 4) having CoT, respectively; MDA was noted in 50% of the cases. Conclusion. The use of the T2T strategy during a 6-month period could provide ACR 70 response and MDA in half of the patients and remission in one third of the patients with ePsA.

Methotrexate pharmacokinetic genetic variants are associated with outcome in rheumatoid arthritis patients.

Methotrexate (MTX) is the most used drug for the treatment of rheumatoid arthritis (RA) although outcome differs among patients. To evaluate whether polymorphisms in pharmacokinetic genes are associated with outcome in RA patients receiving MTX. We analyzed 28 SNPs in SLC19A1/RFC1, ABCB1, FPGS and GGH genes. We studied 194 RA patients receiving MTX monotherapy. Two FPGS SNPs, rs10987742 and rs10106, were associated with response (p = 0.033 and p = 0.041, respectively). The FPGS rs10106 variant was also associated with MTX survival (p = 0.005) and toxicity (p = 0.021). Three ABCB1 SNPs, rs868755, rs10280623 and rs1858923, were associated with toxicity (p = 0.025, p = 0.048 and p = 0.031, respectively). FPGS and ABCB1 genetic variants can influence the outcome in RA patients receiving MTX monotherapy.

Clinical Pharmacogenetic Model to Predict Response of MTX Monotherapy in Patients with Established Rheumatoid Arthritis After DMARD Failure

The performance of a clinical pharmacogenetic model to predict nonresponse of methotrexate (MTX) monotherapy in patients with established rheumatoid arthritis (RA) and failure of disease-modifying antirheumatic drugs (DMARDs) was studied. For 75 RA patients receiving MTX monotherapy for 6 months, DNA and clinical data were available. Risk scores for nonresponse at 6 months (disease activity score >2.4), were calculated using the pharmacogenetic prediction model utilizing four clinical factors and four polymorphisms in the genes MTHFD1, AMPD1, ITPA and ATIC. At 6 months, there were 25 responders and 50 nonresponders. Using the clinical pharmacogenetic prediction model, 75% (56 out of 75) were categorized into predicted responders (risk score ≤ 3.5) and predicted nonresponders (risk score ≥ 6). At 6 months, the negative predictive value was 81% (21 out of 26) and the positive predictive value was 47% (14 out of 30). The pharmacogenetic model predicts nonresponse to MTX monotherapy, but performs better in DMARD naive recent-onset RA patients than in patients with preceding DMARD failure.

Prescribing practices in a US cohort of rheumatoid arthritis patients before and after publication of the American College of Rheumatology treatment recommendations.

To examine prescribing practices in the use of biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) to treat patients with rheumatoid arthritis (RA), before and after publication of the American College of Rheumatology (ACR) treatment recommendations. Biologics-naive RA patients under the care of a rheumatologist in the US were identified from the Consortium of Rheumatology Researchers of North America registry. Patients were included if their visits occurred prior to and/or at least 6 months after publication of the ACR treatment recommendations (time periods of February 2002-June 2008 versus December 2008-December 2009). The population was divided into 2 mutually exclusive cohorts: 1) methotrexate (MTX) monotherapy users, and 2) multiple nonbiologic DMARD users. Initiation or dose escalation of biologic and nonbiologic DMARDs in response to active disease was assessed cross-sectionally and longitudinally in comparison to the ACR recommendations. The impact of the publication of the ACR recommendations on treatment practices was assessed using logistic regression, stratified by disease activity and adjusted for clustering of physicians and geographic region. After 1 visit, 24-37% of patients receiving MTX monotherapy who had moderate disease activity and a poor prognosis or high disease activity received care consistent with the ACR recommendations; after 2 visits, 34-56% of the MTX monotherapy group received care consistent with the recommendations. In the patients receiving multiple nonbiologic DMARDs, 31-47% of those with moderate or high disease activity received care consistent with the recommendations after 1 visit, and 43-51% received such care after 2 visits. Publication of the recommendations did not significantly change treatment patterns for those with active disease. Substantial numbers of RA patients with active disease did not receive care consistent with the current ACR treatment recommendations. Innovative approaches to improve care are necessary.

Rheumatoid Arthritis Disease-modifying Antirheumatic Drug Intervention and Utilization Study: Safety and Etanercept Utilization Analyses from the RADIUS 1 and RADIUS 2 Registries

to report the rates of serious adverse events (SAE), serious infectious events (SIE), and events of medical interest (EMI) in patients receiving etanercept; to identify the risk factors for SAE, SIE, and EMI; and to report time to switching from etanercept therapy, reasons for switching, and time to restarting treatment with etanercept in patients with rheumatoid arthritis (RA) in US clinical practice. adults ≥ 18 years of age who fulfilled the 1987 American Rheumatism Association criteria for RA were eligible for enrollment in 2 prospective, 5-year, multicenter, observational registries. RADIUS 1 (Rheumatoid Arthritis DMARD Intervention and Utilization Study) enrolled patients with RA who required a change in treatment [either an addition or a switch of a biologic or nonbiologic disease-modifying antirheumatic drug (DMARD)]. In RADIUS 2, patients with RA were required to start etanercept therapy at entry. Patients were seen at a frequency determined by their rheumatologist. RADIUS 1 and RADIUS 2 were registered under the US National Institutes of Health ClinicalTrials.gov identifiers NCT00116714 and NCT00116727, respectively. in these patients, SAE, SIE, and EMI occurred at rates comparable to those seen in clinical trials. No unexpected safety signals were observed. Rates for SAE, SIE, and EMI in etanercept-treated patients were comparable to rates observed in patients receiving methotrexate monotherapy and did not increase with greater exposure to etanercept therapy. the RADIUS registries provide a better understanding of the safety of etanercept in patients with RA in the US practice setting.

Repair of erosions occurs almost exclusively in damaged joints without swelling

BackgroundNegative radiographic change scores obtained under blinded time-sequence conditions suggest that repair of joints may indeed occur. It is likely that, if repair truly exists, it would be preferentially seen...

Use of methotrexate therapy is not associated with decreased prevalence of metabolic syndrome - authors' response

We thank Raterman and colleagues for their interest in our article 'Methotrexate therapy associates with a reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60: more than just an anti-inflammatory effect? A cross-sectional study' [1]. Raterman and colleagues replicated our analyses in their cohort of 353 rheumatoid arthritis (RA) patients from Holland but were unable to demonstrate or confirm an association between methotrexate (MTX) use and the metabolic syndrome (MetS) defined by the National Cholesterol Education Program (NCEP) 2004 and NCEP 2001 criteria. In an attempt to address this discrepancy, they have raised several interesting questions. The first is whether this association was present only in RA patients treated with MTX monotherapy or also in the subgroup treated with MTX as part of combination therapy. The results presented in our original paper were based on analysing all patients receiving MTX (n = 214), irrespectively of whether this was monotherapy or combination therapy; however, adjustment was made in our multivariate model for other antirheumatic medications. In addition to this, in the subgroup of patients taking MTX monotherapy (n = 116) (Table ​(Table1),1), we have now replicated our original findings, thus again supporting the possibility of a drug-specific effect. Second, Raterman and colleagues request further clarification of factors found to be independent predictors of the MetS in our regression analyses. As stated in this [1] and previous [2] papers on this cohort, factors found to be independent predictors of the MetS in our population were older age (β = 0.034, P < 0.001), higher health assessment questionnaire score (β = 0.335, P = 0.024), and less MTX use β = 0.663, P = 0.001). Diabetes and body mass index were also independent predictors of the MetS but since they are included in the MetS criteria, they were not included in the multivariate model (for reasons of co-linearity). Although hypothyroidism is clearly an important cardiometabolic risk factor, only 3/387 of our patients were hypothyroid and this was not an independent predictor of the MetS. Table 1 Odds ratios for having the metabolic syndrome in patients receiving methotrexate monotherapy compared with those not on methotrexate In summary, despite further investigation, we continue to demonstrate a strong association between MTX and reduced prevalence of the MetS. We remain unable to account for the conflicting findings reported by Raterman and colleagues, particularly as the descriptive characteristics of their population are similar to ours. Clearly, both studies are limited by their cross-sectional designs: the only way of establishing the 'true' effect of MTX on the MetS would be in a large prospective longitudinal study.

Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis

The risk of cardiovascular disease (CVD) is increased in patients with rheumatoid arthritis (RA), most likely because of increased systemic inflammation. Prior research suggests that immunosuppressive medications may reduce the risk of CVD among RA patients. This study was undertaken to investigate the effects of various immunosuppressive medications on the risk of cardiovascular events among a group of older patients with RA. In this nested case-control study, the source cohort was derived from Medicare beneficiaries receiving a drug benefit from the state of Pennsylvania. These individuals were required to have been diagnosed as having RA on at least 2 visits and to have filled a prescription for an immunosuppressive agent. Cases were defined as those patients who were hospitalized for a cardiovascular event such as myocardial infarction or stroke, and 10 control subjects were matched to each case by age, sex, and calendar year of the index date (the time of the first cardiovascular event in each case). Current use of an immunosuppressive medication was defined as having filled a prescription for these agents within the 90 days prior to the index date. Multivariate logistic regression models that included important covariates were assessed to determine the risk of cardiovascular events associated with immunosuppressive agents and their combinations. Among the study cohort, we identified 3,501 RA patients who fulfilled our eligibility criteria. During followup of this cohort, 946 patients were hospitalized for a cardiovascular event. Although the 95% confidence intervals (95% CIs) were wide in adjusted risk regression models with methotrexate (MTX) monotherapy as the reference group, biologic immunosuppressive agents showed neither protective nor deleterious effects (with biologics monotherapy, odds ratio [OR] 1.0, 95% CI 0.5-1.9; with biologics plus MTX combination therapy, OR 0.8, 95% CI 0.3-2.0; and with biologics plus other immunosuppressive agents, OR 1.2, 95% CI 0.7-2.2). Monotherapy with oral glucocorticoids was associated with an increased risk of cardiovascular events (OR 1.5, 95% CI 1.1-2.1), and a similar trend in the direction of risk was seen with glucocorticoid combination therapy (OR 1.3, 95% CI 0.8-2.0). Cytotoxic immunosuppressive agents other than MTX (azathioprine, cyclosporine, and leflunomide) were also associated with an increased risk of cardiovascular events (with both monotherapy and combination treatment, OR 1.8, 95% CI 1.1-3.0). When compared with RA patients receiving MTX monotherapy, those receiving biologic immunosuppressive agents had neither an increased nor decreased risk of experiencing a cardiovascular event, whereas use of oral glucocorticoids and cytotoxic immunosuppressive agents was associated with significant increases in the risk of cardiovascular events.