In-stent Restenosis after Drug-eluting Stent Implantation in Rheumatoid Arthritis: Possible Protective Effect of Methotrexate

To the Editor:

Patients with rheumatoid arthritis (RA) are at higher risk of cardiovascular events compared with the general population¹. Therefore, these patients with RA have a greater chance of undergoing percutaneous coronary intervention (PCI). In-stent restenosis (ISR) after PCI results from damage to arteries with subsequent neointimal tissue proliferation² and is considered the most significant problem in coronary interventional treatment. Compared with bare-metal stents (BMS), drug-eluting stents (DES) have dramatically reduced the rate of ISR³. Nevertheless, ISR after DES still exists, with an occurrence of 3–20%.

Methotrexate (MTX), the most important drug used in RA, is a folate antagonist that blocks the S phase of cell division and consequently blocks mitosis⁴. An intravenous injection of MTX resulted in the reduction of in-stent neoatherosclerosis in an animal model⁵. Further, a clinical study suggested the positive effect of oral MTX on ISR after BMS implantation⁶. However, little is known about the effect of oral MTX on ISR after DES implantation. Therefore, we aimed to assess whether the oral administration of MTX in patients with RA has a beneficial effect in preventing ISR after DES implantation.

We retrospectively reviewed patients with RA who underwent DES implantation at a tertiary referral hospital in Seoul, South Korea, between January 2005 and March 2017. All patients fulfilled the 1987 American College of Rheumatology criteria for the classification of RA. The established risk factors [young age, diabetes mellitus, multivessel disease, ostial lesion, treatment of multiple lesions, type of DES, longer physical length of stent, small reference diameter, and non-left anterior descending artery (LAD) lesions]^7,8,9 for ISR after DES and ISR incidence were compared between the MTX group and non-MTX group. MTX group was defined as patients who had ever used MTX after DES implantation. To exclude the possible confounding effect of hydroxychloroquine (HCQ), which is known to have a cardioprotective effect, we also compared the MTX group and non-MTX group among the HCQ users (subgroup analysis). This study was approved by the Institutional Review Board (Asan Medical Center, IRB No. 2017-0919).

Mann–Whitney U test and Fisher’s exact test were performed to compare continuous and categorical variables, respectively. Cox proportional hazard model was performed to evaluate whether MTX is associated with risk of developing ISR. Because MTX is a time-varying variable, cumulative dose of MTX was used for this analysis. Survival rates were analyzed using the Kaplan–Meier method and compared using the log-rank test.

A total of 29 patients with RA underwent PCI. Forty-one vessel lesions were treated by DES implantation. The median age was 67 years, and 44.8% were female. The most commonly used disease-modifying antirheumatic drug was MTX [21 (72.4%)], followed by HCQ and sulfasalazine. Biologic agent was used in 1 patient (etanercept, 3.4%).

Among the 21 patients receiving MTX, there were 29 treated vessels. Further, there were 12 treated vessels in the 8 patients not receiving MTX. A comparison between the 2 groups is shown in Table 1. Established predictors of ISR did not differ between the 2 groups, except for the longer stented length in the MTX group [median 29.0 (IQR 22.5–47.5) vs 21.0 (15.0–30.3), p = 0.025]. Nevertheless, the incidence of ISR was significantly lower in the MTX group than in the non-MTX group [0 (0%) vs 4 (33.3%), p = 0.005]. In the subgroup analysis of HCQ users, risk factors of ISR did not differ between the MTX group and non-MTX group. Incidence of ISR remained lower in the MTX group [0 (0%) vs 1 (25.0%), p = 0.017; Supplementary Table 1, available with the online version of this letter]. On Cox proportional hazard model, cumulative dose of MTX was associated with decreased risk of developing ISR (HR 0.174, 95% CI 0.032–0.940, p = 0.042). Kaplan–Meier curves showed a significantly higher rate of ISR in the treated vessels in the non-MTX group than in the MTX group (p = 0.001; Figure 1). The median time from DES implantation to ISR in the non-MTX group was 106.8 (81.1–109.0) months, which is “late” restenosis. Considering that there was no occurrence of ISR during the longterm followup in the MTX group, MTX might be beneficial in the late restenosis after DES implantation.

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Figure 1.

Kaplan–Meier survival curves for in-stent restenosis between MTX-treated (MTX group) and non-MTX groups. MTX: methotrexate; DES: drug-eluting stents.

Neointimal hyperplasia is the primary component of restenosis after stent deployment. When vascular injury occurs, inflammatory cells and proinflammatory cytokines lead to the proliferation and migration of vascular smooth muscle cells within the media and intima, resulting in restenosis¹⁰. MTX has both antiproliferative and antiinflammatory properties⁴. Considering the pathogenesis of ISR, antiproliferative and antiinflammatory effects of MTX might have contributed in suppressing neointimal formation.

Based on our real-world results, we have shown that administration of oral MTX in patients with RA was associated with lower incidence of ISR after DES implantation. Because the study population was too small and multiple vessels from the same patients were counted, which might be a potential source of bias, further studies are needed to confirm the present finding in larger sample sizes.