Temporary Methotrexate Discontinuation in RA: Ensuring Vaccination Immunogenicity

syringe, vials
syringe, vials
Rheumatologists should coordinate with the patient's primary care provider to facilitate an effective and comprehensive vaccination schedule.

Although disease-modifying antirheumatic drugs (DMARDs) significantly reduce the burden of disease in individuals with rheumatoid arthritis (RA), the resulting immunosuppression further increases their vulnerability to infection. Compared with the general population, the rate of infection leading to hospital admission and death is 1.5 to 2.0 times higher among patients with RA.1,2

Professional guidelines have emphasized the need for vaccination against preventable disease in this patient group.3 However, antirheumatic drugs have been shown to interfere with vaccine response. “Many of the DMARDs and biologic agents used to manage RA reduce the immune response to some vaccines, and this impairment of the immune response may increase the likelihood of a viral illness [developing] in an individual already at increased risk for infection,” Allan Gibofsky, MD, JD, MACR, FACP, FCLM, professor of medicine at Weill Medical College of Cornell University, and attending rheumatologist at Hospital for Special Surgery, told Rheumatology Advisor.

For example, multiple studies have noted a significant reduction in the response to pneumococcal and influenza vaccines in patients with RA treated with methotrexate (MTX).4,5 In light of these observations, the authors of a recent pilot study examined the effects of temporary discontinuation of MTX on vaccine immunogenicity and disease activity in patients with RA.6

They found that both a 4-week discontinuation following influenza vaccination and discontinuation for 2 weeks before and 2 weeks after vaccination led to a significant increase in immunogenicity. However, the risk for disease flare was increased by up to 1.4-fold during the subsequent 16 weeks. In a prospective randomized controlled trial reported in the Annals of the Rheumatic Diseases, the same researchers investigated whether a 2-week discontinuation of MTX would have a similar effect on immunogenicity while minimizing the risk for RA flare.7

Patients with RA on a stable dose of MTX were assigned to either continue (MTX-continue group; n=156, mean age, 52.2 years) or discontinue (MTX-hold group; n=160, mean age, 53.7 years) MTX for 2 weeks after receiving the 2016-2017 quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata, and B-Victoria strains.

The 2 groups were comparable in terms of baseline demographic and disease characteristics, as well as baseline treatment regimens, including MTX dose and use of systemic corticosteroids.

The results showed that the MTX-hold group had higher rates of satisfactory vaccine response, defined as ≥4-fold increase of hemagglutination inhibition antibody titer against ≥2 of the 4 strains at 4 weeks postvaccination, compared with the MTX-continue group (75.5% vs 54.5%; P <.001).

Secondary end point results were as follows:

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  • The MTX-hold group had higher seroprotection rates for all 4 influenza antigens compared with the MTX-continue group. The percentage difference between the MTX-hold group and the MTX-continue group was 10.7% for the H1N1 strain (95% CI, 2.0%-19.3%; P =.016), 15.9% for the H3N2 strain (95% CI, 5.9%-26.0%; P =.002), 13.7% for the B-Yamagata strain (95% CI, 5.2%-22.4%; P =.002), and 14.7% for the B-Victoria strain (95% CI, 4.5%-25.0%; P =.005).
  • The MTX-hold group had greater increases in antibody titers against all 4 influenza antigens (all P <.05) vs the MTX-continue group.
  • During the 1-year follow-up period, there were no reports of serious adverse events related to vaccination. An influenza-like illness developed in 1 patient in the MTX-hold group and 3 patients in the MTX-continue group during follow-up.
  • Compared with baseline, the mean Disease Activity Score in 28 joints increased by only 0.1 in both groups (0.0±0.7 for MTX-continue vs 0.1±0.8 for MTX-hold; P =.365).
  • In the 4 weeks postvaccination, 5.1% of patients in the MTX-continue group and 10.6% of those in the MTX-hold group experienced RA flare (P =.07).
  • During follow-up, 4.5% of patients in the MTX-continue group required rescue medications for increased joint pain vs 6.3% in the MTX-hold group. However, of the patients who experienced a flare, 0% of those in the MTX-continue group and 17.6% of those in the MTX-hold group used a rescue medication.

Overall, the current findings indicate that a 2-week hold on MTX after vaccination improves the response to influenza vaccine in patients with RA without a significant effect on disease activity. According to the authors, the observation of a more satisfactory vaccine response for the less exposed type B viral strains “suggest that this MTX discontinuation strategy might be more crucial for response to influenza viruses relatively new to humans.”

Dr Gibofsky offered the following suggestions for clinicians:

  • One of the most important practical tips for rheumatologists is to have close communication and coordination with the patient’s primary care provider to facilitate an effective and comprehensive vaccination schedule. Studies have shown that influenza and pneumococcal vaccination rates are lower than they could be.
  • Systems need to be developed to make sure vaccinations are being administered, either by rheumatologists or by another provider. The use of prompts or flags in electronic health records helps, and  midlevel practitioners are particularly excellent at reviewing health maintenance issues as part of the visit.
  • Once the diagnosis of an autoimmune disease is made by the clinician, the patient should receive all relevant vaccinations before treatment is started.

Future research should explore whether this approach could be applied to other vaccines with low immunogenicity. “The effects of temporary discontinuation of a conventional synthetic DMARD or a biologic DMARD needs to be formally investigated for other agents,” added Dr Gibofsky. “It also needs to be established whether development of a greater immune response following vaccination will result in lower rates of clinical infection.”


  1. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002;46(9):2287-2293.
  2. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis.Arthritis Rheum. 1994;37(4):481-494.
  3. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762-784.
  4. Kapetanovic MC, Kristensen L-E, Saxne T, Aktas T, Mörner A, Geborek P. Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis.Arthritis Res Ther. 2014;16(1):R2.
  5. Hua C, Barnetche T, Combe B, Morel J. Effect of methotrexate, anti-tumor necrosis factor α, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2014;66(7):1016-1026.
  6. Park JK, Lee MA, Lee EY, et al. Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis. 2017;76(9):1559-1565.
  7. Park JK, Lee YJ, Shin K, et al. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial [published online March 23, 2018].Ann Rheum Dis. doi:10.1136/annrheumdis-2018-213222