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Stopping methotrexate for 2 weeks after COVID-19 vaccination boosts immune response

30th June 2022

Halting methotrexate for two weeks after a COVID-19 vaccination boosted the level of antibodies generated compared with continued drug use

Stopping methotrexate (MTX) for two weeks after a third COVID-19 vaccination significantly enhanced the level of antibodies produced compared to continuing with the drug, according to the results of a randomised trial by a team of UK researchers.

The use of the immunomodulatory drug methotrexate, is known to adversely affect the humoral and cellular immune response to COVID-19 mRNA vaccines. In fact, studies have shown that seroconversion rates after COVID-19 vaccination are significantly lower in immunocompromised patients, especially organ transplant recipients.

As a result, it is important to implement strategies that can enable those who are immunocompromised to mount a satisfactory immune response.

It has been shown that discontinuation of immunosuppressant drugs such as methotrexate in patients with rheumatoid arthritis, for either 4 weeks before, 2 weeks before and for 2 weeks after vaccination, improves the immunogenicity of seasonal influenza vaccination.

In fact, the highest immune response occurred when MTX was discontinued two weeks after vaccination and this effect was confirmed in another study that specifically focused on stopping the drug two weeks after seasonal influenza vaccination.

Since the effectiveness of this approach has not been formally evaluated for the COVID-19 vaccine, for the present study, the UK undertook a randomised trial among immunocompromised patients prescribed methotrexate.

The Vaccine Response On/Off Methotrexate (VROOM) trial, randomised participants 1:1 to either suspension of MTX (suspend methotrexate) for two weeks immediately after their COVID-19 booster dose, or to continue with the drug as usual (continue methotrexate). Individuals were recruited from both rheumatology and dermatology clinics and who had been taking low dose MTX (< 25 mg/week) for at least 3 months. In addition, the researchers only enrolled participants who had previously received two COVID-19 vaccine doses.

The primary outcome of the study was the antibody response against the receptor-binding domain of the COVID-19 spike protein (S1-RBD) 4 weeks after receipt of the third COVID-19 vaccine dose. Secondary outcomes included S1-RBD antibody titres at 12 weeks post-vaccination and self-reported levels of disease activity.

Methotrexate suspension and S1-RBD antibody response

A total of 254 individuals with a mean age of 59.1 years (61% female) were included in the trial and randomised equally to either strategy. Overall, 51% of participants had rheumatoid arthritis, 34% psoriasis and 20% a skin condition alone. The median dose of methotrexate taken as 20 mg/week.

After 4 weeks, the geometric mean SI-RBD antibody titre was 22,750 U/ml in the suspend methotrexate group and 10,798 U/ml in the continue methotrexate group (p < 0.0001). This increase was independent of the dose and administration route of methotrexate, as well as type of immune-mediated inflammatory disease and age. Moreover, this difference in response remained significant at week 12 (16,520 vs 8094).

One downside of the study was that significantly more patients in the suspend methotrexate group self-reported at least one disease flare over the 12 week period compared to those who continued with the drug (71% vs 45%, odds ratio, OR = 2.83, 95% CI 1.64 – 4.88). However, these flares were generally self-managed and without any major impacts on quality of life.

The authors concluded that their strategy of stopping MTX was both safe and boosted the level of COVID-19 antibodies and called for further studies to examine the effect of stopping other immunosuppressant drugs on the level of antibody response.

Abhishek A et al. Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial. Lancet Resp Med 2022

COVID-19 antibodies detected in 11% of those unaware of being infected

17th February 2022

COVID-19 antibodies have been detected in 11% of individuals who had no prior knowledge or suspicion of being infected with the virus

COVID-19 antibodies have been detected in 11% of individuals tested for the virus despite being unaware that they they had ever been infected. This was the conclusion of a study by researchers from the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, US.

It has become apparent that not everyone who becomes infected with COVID-19 develops antibodies. In fact, one study of 72 individuals with an acute infection, noted that 36% of recovered patients did not produce an antibody response. The authors concluded that patients who have a low COVID-19 viral load in their respiratory tract, are not always likely to mount a systemic antibody response.

Consequently, there is some uncertainty over the wider prevalence of serological non-responders and equally, the extent to which the immune response persists after a natural infection.

For the present study, the US team set out to characterise the extent and durability of the immune response among individuals who had not received one of the COVID-19 vaccines but who had potentially been naturally infected with the virus.

They turned to social media to recruit unvaccinated individuals and who completed an online questionnaire which enquired about demographics, COVID-19 status and mask use. Based on these findings, the researchers categorised individuals into three distinct groups.

Those who had a test-confirmed COVID-19 infection (COVID-19 confirmed group), those who felt they had been infected but were not tested (COVID-unconfirmed) and finally, those who did not believe that they had ever been infected and were never tested (NO-COVID). All individuals then agreed to undergo antibody testing.

COVID-19 antibodies and serological testing

A total of 816 individuals with a median age of 48 years (52% women) of whom the majority (82%) were of white ethnicity were included in the analysis. Surprisingly, nearly half (44%) reported that they ‘rarely’ wore a mask with only 14% reporting that they ‘routinely’ wore a mask.

Among the 295 individuals who were deemed COVID-confirmed cases, not surprising, 99% tested positive for COVID-19 antibodies. In contrast, this figure was much lower (55%) in the 275 COVID-unconfirmed group. Detectable antibody levels were observed up to 20 months after a COVID-19 positive test result which was considerably better than the response reported 6 months after receipt of a COVID-19 vaccination.

What was most surprising was that among the 246 no-COVID group, 11% tested positive for COVID-19 antibodies, despite no evidence or even a perception that they had been infected in the past.

The authors recognised that their study had several potential limitations including the use of a convenience sample and which was potentially subject to selection bias and that COVID-19 status and testing was self-reported.

Nevertheless, they were encouraged to observe that after a natural infection, the immune response was still detectable some 20 months later but recognised the uncertainty of the extent to which the natural protection would help guard against infection with any emerging variants in the future.

Alejo JL et al. Prevalence and Durability of SARS-CoV-2 Antibodies Among Unvaccinated US Adults by History of COVID-19 JAMA 2022