Break From Methotrexate Boosts Flu Shot Efficacy in RA


With a drug holiday, patients with rheumatoid arthritis could improve their response to influenza vaccinations without increasing disease activity.

For patients who live with rheumatoid arthritis, taking a 2-week break from regular methotrexate treatment can improve the efficacy of the seasonal flu shot, according to a new study presented at the 2017 ACR/ARHP Annual Meeting in San Diego.

In addition to its use for controlling rheumatoid arthritis disease activity, methotrexate is an immunosuppressant that can lower vaccine efficacy in persons who have rheumatoid arthritis.

Researchers led by Jin Kyun Park, Assistant Professor of Medicine at Seoul National University Hospital in the Republic of Korea, set out to investigate whether patients with rheumatoid arthritis could improve their response to influenza vaccinations without increasing rheumatoid arthritis disease activity by temporarily pausing methotrexate use for 2 weeks after receiving their flu shot.

The study
They conducted a prospective, multicenter, randomized, parallel-group trial from October 2016 to January 2017. The 316 patients with rheumatoid arthritis, all taking a stable methotrexate dose, were randomly assigned to 2 groups: 156 continued their regular methotrexate and 160 discontinued their dose for 2 weeks after receiving their flu shot. All patients were given a seasonal, quadrivalent influenza vaccine that contained H1N1, H3N2, B-Yamagata, and B-Victoria.

The study’s primary outcome measurement was the frequency of a satisfactory response to the vaccine, defined as the patients having a 4-fold or greater increase in hemaglutination inhibition (HI) antibody titer at 4 weeks after vaccination against 2 or more vaccine strains. The researchers also measured seroprotection rate and fold-change in antibody titers relative to baseline in geometric mean titer.

The findings
Of the patients who continued their regular methotrexate dosing, 54.5% achieved satisfactory vaccine response. In comparison, 75.5% of the patients who temporarily discontinued their methotrexate achieved a satisfactory vaccine response.

The seroprotection rate was also higher for all 4 antigens measured in the group who took a 2-week break from methotrexate than in patients who continued with their regular dose. Patients who paused their methotrexate also achieved a higher increase of H1 antibody titer in geometric mean titer for each antigen.
The 2-week methotrexate break did not lead to a change in rheumatoid arthritis disease activity.

Implications for physicians
Patients with rheumatoid arthritis are more susceptible to infections, including seasonal flu, because of their abnormal immune function as well as the immune suppression associated with taking medications like methotrexate. For this reason, vaccination of patients against preventable infectious diseases despite immune suppression decreasing vaccine response is particularly important.

The results present a novel immunization protocol for patients with rheumatoid arthritis to optimize vaccine response, including increasing immunogenicity of flu vaccines without increasing rheumatoid arthritis disease activity.

“Patients should be advised to hold methotrexate for two weeks after vaccination,” Dr Park said in a press release. “This approach can be applied to other vaccines, such as pneumonia or zoster.”

The findings also indicate that methotrexate has an immediate effect on immune response. Thus, short-term methotrexate discontinuation could be considered in cases of infections or surgery.

Potential limitations of the study include only assessing the effect of a temporary methotrexate discontinuation on the vaccine’s antibody production after a flu shot. Because antibody production does not always guarantee immune protection, more studies are needed to address whether holding methotrexate for 2 weeks can prevent flu infection.


American College of Rheumatology Press Release. “Methotrexate Drug Holiday Improves Flu Vaccine Efficacy in Rheumatoid Arthritis Patients.” November 4, 2017.

Park JK, Shin K, Ha YJ, et al. “Temporary Methotrexate Discontinuation for 2 Weeks Improves Immunogenicity of Seasonal Influenza Vaccination in Patients with Rheumatoid Arthritis: A Randomized Clinical Trial.” Abstract Number 827. 2017 ACR/ARHP Annual Meeting; San Diego, California.

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