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Patients who take methotrexate for a variety of immune-mediated inflammatory diseases and pause taking the drug following receipt of a COVID-19 vaccine dose did not have a higher risk of disease flare and had higher antireceptor binding domain (anti-RBD) antibody titers and increased immunogenicity when compared with continuing the drug, three recent studies suggest.

In one study, British researchers examined the effects of a 2-week break in methotrexate therapy on anti-RBD titers following receipt of a third COVID-19 vaccine dose. In their paper published June 27 in The Lancet: Respiratory Medicine, naproxen good for menstrual cramps they reported results from a randomized, open-label, superiority trial that suggested pausing the drug improved immunogenicity, compared with no break.

In two trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2022 Annual Meeting, a team from India set out to determine whether holding methotrexate after receiving both doses of a COVID-19 vaccine, or holding it only after the second dose, was safe and effective. They found that pausing methotrexate only following the second dose contributed to a lower flare risk, and that patients had higher anti-RBD titers when holding methotrexate for 2 weeks following each dose.

Pausing Methotrexate After Booster

The 2-week methotrexate break and booster vaccine dose data in the Vaccine Response On Off Methotrexate (VROOM) trial showed that after a month, the geometric mean antispike 1 (S1)-RBD antibody titer was 10,798 U/mL (95% CI, 8970 – 12,997) in the group that continued methotrexate and 22,750 U/mL (95% CI, 19,314 – 26,796) in the group that suspended methotrexate; the geometric mean ratio was 2.19 (P < .0001; mixed-effects model), reported Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham in Nottingham, England, and colleagues.

Prior research showed that stopping methotrexate therapy for 2 weeks following the seasonal influenza vaccine contributed to better vaccine immunity among patients with rheumatoid arthritis, but there was no impact of stopping the drug for up to 4 weeks before vaccination on vaccine-related immunity, the researchers noted.

It is crucial in maximizing long-lasting vaccine protection in people who are possibly susceptible through immune suppression at this point in the COVID-19 vaccination regimen, the study team noted.

Dr Jeffrey Sparks

Dr Sara Tedeschi

“Evidence from this study will be useful for policymakers, national immunization advisory committees, and specialist societies formulating recommendations on the use of methotrexate around the time of COVID-19 vaccination. This evidence will help patients and clinicians make informed choices about the risks and benefits of interrupting methotrexate treatment around the time of COVID-19 vaccination, with implications for the potential to extend such approaches to other therapeutics,” they write.

In American College of Rheumatology (ACR) guidance for COVID-19 vaccination, the organization advised against using standard synthetic disease-modifying antirheumatic medicines such as methotrexate “for 1-2 weeks (as disease activity allows) after each COVID-19 vaccine dose,” given the at-risk population and public health concerns, noted Jeffrey A. Sparks, MD, MMSc, an assistant professor of medicine and associate physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, and Sara K. Tedeschi, MD, MPH, an assistant professor of medicine at Harvard Medical School, in an accompanying editorial in The Lancet: Respiratory Medicine.

However, when the ACR developed this statement, there was only one trial involving patients with rheumatoid arthritis who paused methotrexate following seasonal influenza vaccination, the editorialists say.

“Although this finding adds to the evidence base to support interruption of methotrexate after vaccination, a shared decision process is needed to weigh the possible benefit of optimizing protection from COVID-19 and the possible risk of underlying disease flare,” they add.

Abhishek and colleagues assessed 254 patients with immune-mediated inflammatory disease from dermatology and rheumatology clinics across 26 hospitals in the United Kingdom. Participants had been diagnosed with systemic lupus erythematosus, rheumatoid arthritis, atopic dermatitis, polymyalgia rheumatica, axial spondyloarthritis, and psoriasis without or with arthritis. They had also been taking ≤ 25 mg of methotrexate per week for 3 months or longer and had received two doses of either the Pfizer/BioNTech BNT162b2 vaccine or AstraZeneca/Oxford viral vector vaccine. The booster dose was most often the Pfizer BNT162b2 vaccine (82%). The patients’ mean age was about 59 years, with females comprising 61% of the cohort. Participants were randomly assigned 1:1 to either group.

Investigators performing laboratory analysis were masked to cohort assignment, and clinical research staff, data analysts, participants, and researchers were unmasked.

The elevated antibody response of patients who suspended methotrexate was the same across different kinds of immune-mediated inflammatory disease, primary vaccination platform, SARS-CoV-2 infection history, and age.

Notably, no intervention-associated adverse events were reported, the study team noted.

The conclusions that could be drawn from the booster-dose study were limited by the trial’s modest cohort size, the small number of patients in exploratory subgroup analyses, a lack of information about differences in prescription drug behavior, and early termination’s effect on the researchers’ ability to identify differences between subgroups and in secondary outcomes, the authors noted.

Other limitations included a lack of generalizability to patients with active disease who couldn’t stop therapy and were not included in the investigation, and participants were not blinded to what group they were in, the researchers said.

Expert Commentary

This current study is consistent with other studies over the last several months showing that methotrexate harms both humoral and cell-mediated COVID-19 responses, noted Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, Oregon, who was not involved in the study. And so now the new wave of studies are like this one, where they are holding methotrexate experimentally and seeing if it makes a difference,” he said.

Dr Kevin Winthrop

“The one shortcoming of this study — and so far, the studies to date — is that no one has looked at whether the experimental hold has resulted in a change in T-cell responses, which…we are [now] recognizing [the importance of] more and more in long-term protection, particularly in severe disease. Theoretically, holding [methotrexate] might help enhance T-cell responses, but that hasn’t been shown experimentally.”

Winthrop pointed out that one might get the same benefit from holding methotrexate for 1 week instead of 2 and that there likely is a reduced risk of flare-up from underlying autoimmune disease.

It is still not certain that this benefit extends to other vaccines, Winthrop noted. “It is probably true for most vaccines that if you hold methotrexate for 1 or 2 weeks, you might see some short-term benefit in responsiveness, but you don’t know that there is any clinical meaningfulness of this. That’s going to take other long-term studies. You don’t know how long this benefit lasts.”

Pausing Methotrexate During Initial COVID Vaccine Doses

Patients with either rheumatoid arthritis or psoriatic arthritis had higher anti-RBD antibody titers when methotrexate was stopped after both doses of the AstraZeneca vaccine, or simply after the second dose, than when methotrexate was continued, according to results from two single-center, randomized controlled trials called MIVAC I and II, Anu Sreekanth, MD, of the Sree Sudheendra Medical Mission in Kochi, Kerala, India, and colleagues reported at EULAR 2022.

Dr Anu Sreekanth

Results from MIVAC I indicated that there was a higher flare rate when methotrexate was stopped after both vaccine doses, but there was no difference in flare rate in MIVAC II when methotrexate was stopped only after the second dose as opposed to stopping it after both doses.

In the MIVAC I trial, 158 unvaccinated patients were randomized 1:1 to a cohort in which methotrexate was held for 2 weeks after both doses and a cohort in which methotrexate was continued despite the vaccine. In MIVAC II, 157 patients continued methotrexate while receiving the first vaccine dose. These patients were subsequently randomized to either continue or stop methotrexate for 2 weeks following the second dose.

The findings from MIVAC I demonstrated the flare rate was lower in the methotrexate-continue group than in the methotrexate-pause group (8% vs 25%; P = .005) and that the median anti-RBD titer was significantly higher for the methotrexate-pause group than the methotrexate-continue group (2484 vs 1147; P = .001).

The results from MIVAC II trial indicated that there was no difference in flare rates between the two study groups (7.9% vs 11.8%; P = .15). Yet, the median anti-RBD titer was significantly higher in the methotrexate-pause cohort than in the methotrexate-continue cohort (2553 vs 990; P = .001).

The report suggests there is a flare risk when methotrexate is stopped, Sreekanth noted. “It appears more logical to hold only after the second dose, as comparable anti-RBD titers are generated” with either approach, Sreekanth said.

Expert Commentary: MIVAC I and MIVAC II

Inés Colmegna, MD, an associate professor at McGill University in Montreal, Quebec, Canada, noted that it was intriguing that the risk of flares in MIVAC II is half of that reported after each of the doses of MIVAC I. “It is also worth emphasizing that despite the reported frequency of flares, the actual disease activity [as measured by the Disease Activity Score in 28 joints] in patients who did or did not withhold methotrexate was similar.”

Dr Inés Colmegna

“MIVAC I and II have practical implications as they help to adequately inform patients about the risk and benefit trade of withholding methotrexate post–COVID-19 vaccination,” Colmegna told Medscape Medical News.

“Additional information would help to [further] interpret the findings of these studies, including whether any of the participants were taking any other DMARDs; data on the severity of the flares and functional impact; analysis of factors that predict the risk of flares, such as higher doses of methotrexate; [and change in] disease activity scores pre- and post-vaccination,” Colmegna concluded.

Abhishek disclosed relationships with Springer, UpTodate, Oxford, Immunotec, AstraZeneca, Inflazome, NGM Biopharmaceuticals, Menarini Pharmaceuticals, and Cadilla Pharmaceuticals. Abhishek is also co-chair of the ACR/EULAR CPPD Classification Criteria Working Group and the OMERACT CPPD Working Group. Sparks disclosed relationships with Gilead, Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, and AbbVie, unrelated to this study. Tedeschi disclosed relationships with ModernaTx and NGM Biopharmaceuticals. Winthrop disclosed a r esearch grant and serving as a scientific consultant for Pfizer. Sreekanth  and Colmegna have dislosed no relevant financial relationships.

Lancet Respir Med. Published online June 27, 2022. Full Text, Editorial

EULAR 2022 Congress: Abstract LB0003. Presented June 1-4, 2022.

Ashley Lyles is an award-winning medical journalist. She is a graduate of New York University’s Science, Health, and Environmental Reporting Program. Previously, she studied professional writing at Michigan State University, where she also took premedical classes. Her work has taken her to Honduras, Cambodia, France, and Ghana and has appeared in outlets like The New York Times Daily 360, PBS NewsHour, The Huffington Post, Undark, The Root, Psychology Today, TCTMD, Insider, and Tonic (Health by Vice), among other publications.

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