Reviewed by Dr. Lauren Smith
Park J, et al. Ann Rheum Dis. 2017 May 3; 76:1559–1565

Each fall and winter, rheumatologists across the country encourage patients to get their annual influenza vaccination, however, current research has shown that patients on immunosuppressive agents like methotrexate (MTX) have an unsatisfactory response to influenza vaccination. This article describes a single center, randomized, single-blinded, parallel-group study evaluating influenza vaccination response with temporary discontinuation of methotrexate in patients with rheumatoid arthritis (RA). Inclusion criteria were 18 years of age, diagnosis of RA and methotrexate use for at least 6 weeks prior to start of the study. Most patients were female and had similar disease activity and treatment regimens at baseline including MTX and steroid use. Notable exclusion criteria included acute infection, previous anaphylactic reaction to eggs or vaccine components, pregnant or lactating women, other recent vaccine administration or concurrent rheumatic disease except Sjogren’s. The study included 277 patients randomized to four groups: 1) continue MTX at current dose, 2) hold MTX for 4 weeks prior to vaccination, 3) hold MTX for 2 weeks prior to vaccination and 2 weeks afterwards and 4) hold MTX for 4 weeks after vaccination. Patients had a pre-vaccination antibody titer drawn prior to vaccination and serum was re-evaluated 4 weeks after vaccine administration to assess for satisfactory response. Patients were also seen in clinic 16 weeks after vaccination to assess RA disease activity. The primary endpoint (in the per-protocol population) was a satisfactory vaccine response which was defined as ³4-fold increase in antibody titer (tested H1N1, H3N3, or B-Yamagata) 4 weeks after vaccine administration. At each visit, a patient’s disease activity was measured with the 28-joint disease activity score (DAS-28) – an increase by >1.2 was considered an RA flare.

Patients in group 3 (holding MTX 2 weeks prior and 2 weeks post vaccination) had the best response to all components of the vaccination compared to group 1 (p=0.044). When looking at individual components of the vaccine, groups 3 and 4 had higher H3N2 antibody response (p=<0.001 and p=0.043, respectively) and B-Yamagata antibody response (p=0.48 and p=<0.01, respectively) compared to group 1. The response to antibody titer for H1N1 was greater in groups 3 and 4 but not statistically significant compared to groups 1 and 2. Of note, group 2 was similar to group 1 with every vaccine variable evaluated. Furthermore, in patients who lacked seroprotection at baseline, each group achieved a satisfactory response to the H3N3 antibody; however, groups 3 and 4 became seroprotected against H1N1 and B-Yamagata antibodies more frequently than groups 1 and 2. With regards to RA disease activity, flares were seen more commonly in groups 2 and 3 (34.1% and 38.8%, respectively) compared to groups 1 and 4 (24.1% and 21.2%, respectively) but these results were not statistically significant.

This study highlights a potential benefit to temporarily discontinuing methotrexate in patients with RA prior to influenza vaccine administration. However, there are several study limitations – (1) this was a single-center study in Korea where all patients were of Korean ancestry, (2) low recruitment led the study to be underpowered and (3) only patients with stable RA and low disease activity were included. Moreover, the study did not address if a higher antibody titer is associated with decreased incidence of contracting influenza among patients with RA. However, a previous study has shown a correlation between titers and vaccine-induced protection. Given the higher incidence of RA flares in the groups with best vaccination response, future studies with larger and more generalizable populations are needed to assess the risk/benefit ratio of stopping MTX at time of vaccination. Overall, this study is suggestive that there may be some benefit to temporary discontinuation of MTX for improved humoral vaccine response to influenza vaccination in patients with RA on a stable dose of MTX.