Background Various tumour necrosis factor (TNF) inhibitors in combination with methotrexate (MTX) have been shown to be significantly superior to monotherapies of each agent in inhibiting radiographic progression of small joints in patients with rheumatoid arthritis (RA). Damage to large joints, especially weight-bearing joints such as the knee, has a larger impact on functional disability than damage to small joints. Accordingly, the evaluation of large weight-bearing joints is important when assessing the efficacy of drug therapy for RA, as is the evaluation of small joints. It is also important to evaluate the long-term inhibitory effect of drug therapy on joint damage. Given that total joint arthroplasty is a common procedure for treating damaged large joints, it can serve as a surrogate for the long-term outcome of large joint destruction in patients with RA.
Objectives This study aimed to determine the effects of concomitant MTX on the incidence of total knee arthroplasty (TKA) resulting from the progression of joint destruction in patients with RA during long-term treatment with TNF inhibitors.
Methods A total of 155 RA patients (310 knee joints) received TNF inhibitors at our institute between May 1, 2005 and May 31, 2008. A total of 111 symptomatic (tender and/or swollen) knee joints in 68 patients were retrospectively studied over the course of a minimum of five years of follow-up. The median (IQR) follow-up period was 8.1 (7.0-9.3) years. All data were analysed using the knee joint as the statistical unit of analysis. TKA during treatment with TNF inhibitors was used as the outcome variable in predictive analyses. The cumulative incidence of TKA was compared by concomitant or no MTX use (MTX (+/-)).
Results Subjects were predominantly female (86%), and had a median age of 54 years, disease duration of 8 years and DAS28-CRP of 5.6 at initiation of TNF inhibitors. Based on the Larsen grade of knee joints, 5 joints were categorized as grade 0, 24 as grade I, 26 as grade II, 31 as grade III, 25 as grade IV, and 0 as grade V. Of all subjects, 79 (71%) received concomitant MTX. A total of 33 knee joints underwent TKA during treatment with TNF inhibitors. According to Kaplan-Meier estimates, the incidence of TKA for the MTX (+) group was significantly lower than that for the MTX (-) group (P=0.035) (Fig. 1). Previous studies reported that age and joint damage existing at baseline was a risk factor for the progression of large joint destruction in patients with RA treated with TNF inhibitors. Interestingly, multivariate analysis using the Cox proportional hazards model revealed that concomitant MTX predicted TKA (hazard ratio: 0.44, 95% confidence interval: 0.22 to 0.89) independently of age and joint damage at baseline (Table 1).
Conclusions Concomitant MTX effectively reduces the incidence of TKA in patients with RA during long-term treatment with TNF inhibitors, regardless of age and pre-existing joint damage. Our findings suggest that TNF inhibitors should be used preferentially in combination with MTX to inhibit the progression of large joint destruction as well as small joint destruction, and also strongly support recent EULAR recommendations to commence MTX with all bDMARDs.
Disclosure of Interest S. Asai Speakers bureau: Eisai Pharma Corporation, N. Takahashi: None declared, K. Funahashi: None declared, Y. Yoshioka: None declared, T. Takemoto: None declared, K. Terabe: None declared, N. Asai: None declared, N. Ishiguro Grant/research support from: Daiichi Sankyo, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Taisho Toyama Pharmaceutical, Kaken Pharmaceutical, Eisai, Janssen Pharmaceutical, Bristol-Myers Squibb, Abbott Japan, Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Astellas Pharma, and Pfizer Japan., Speakers bureau: Daiichi Sankyo, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Taisho Toyama Pharmaceutical, Kaken Pharmaceutical, Eisai, Janssen Pharmaceutical, Bristol-Myers Squibb, Abbott Japan, Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Astellas Pharma, and Pfizer Japan., T. Kojima Grant/research support from: Takeda Pharma Corporation, Janssen Pharmaceutical, and Astellas Pharma Corporation., Speakers bureau: Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Eisai Pharma Corporation, Abbvie, Bristol-Myers Squibb, Pfizer, Chugai Pharma Corporation, Janssen Pharmaceutical, and Astellas Pharma Corporation