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Clinical Context

Immunocompromised status is generally associated with a reduced immune response to several common vaccinations. A small study by Spiera and colleagues,^[1] published May 11 in the Annals of the Rheumatic Diseases, assessed how antirheumatic treatment, particularly with anti-cluster of differentiation (CD)20 therapies, could affect the response to the COVID-19 vaccine.

The study was completed at one rheumatology practice in New York, New York. Researchers compared the rates of serologic response among patients receiving different types of antirheumatic drugs, with a special interest in patients previously treated with rituximab.

A total of 89 patients had received ≥ 1 dose of a COVID-19 vaccine and were included in the study; 93.3% of these patients had received 2 doses of the vaccine. More than a third (34%) of the patients had received rituximab, and 39% of patients were taking > 1 antirheumatic treatment at the time of assessment of serologic response.

More than a fifth (21) of the patients were found to not develop a serologic response to COVID-19 after vaccination: 20 of these patients had received rituximab, and 1 had been treated with belimumab. A longer duration since the last treatment with rituximab was associated with a better serologic response to vaccination.

An important question that this study did not address is the effect of rheumatologic disease itself on COVID-19 vaccine efficacy. Another study in the same issue of the Annals of the Rheumatic Diseases^[2] analyzed this issue.

Study Synopsis and Perspective

About 10% of patients with immune-mediated inflammatory diseases (IMIDs) fail to respond properly to COVID-19 vaccinations regardless of medication, researchers reported, and small new studies suggest those persons on methotrexate and rituximab may be especially vulnerable to vaccine failure.

Even so, it is still crucially vital for patients with IMIDs to get vaccinated and for clinicians to follow recommendations to temporarily withhold certain medications around the time of vaccination, rheumatologist Anne R. Bass, MD, of Weill Cornell Medicine and the Hospital for Special Surgery, New York, New York, said in an interview.

“We’re not making any significant adjustments,” added Bass, a coauthor of the American College of Rheumatology’s COVID-19 vaccination guidelines^[3] for patients with rheumatic and musculoskeletal diseases.

The findings appeared in a trio of studies in Annals of the Rheumatic Diseases. The most recent study,^[4] which appeared May 25, found that more than one-third of patients with IMIDs who took methotrexate did not produce adequate antibody levels after vaccination vs 10% of patients in other groups. (P < .001) A May 11 study^[1] found that 20 of 30 patients with rheumatic diseases on rituximab failed to respond to vaccination , and a May 6 study^[2] reported that immune responses against SARS-CoV-2 are “somewhat delayed and reduced” in patients with IMIDs, with 99.5% of a control group developing neutralizing antibody activity after vaccination vs 90% of patients with IMIDs (P = .0008).

Development of Neutralizing Antibodies Somewhat Delayed and Reduced

Team members were surprised by the high number of vaccine nonresponders in the May 6 IMID study, coauthor Georg Schett, MD, of Germany’s Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, said in an interview.

The researchers compared 2 groups of patients who had no history of COVID-19 and received COVID-19 vaccinations, mostly 2 shots of the Pfizer-BioNTech vaccine (96%): 84 with IMID (mean age, 53.1 ± 17 years; 65.5% female) and 182 healthy control participants (mean age, 40.8 ± 12 years; 57.1% female).

The patients with IMIDs most commonly had spondyloarthritis (32.1%), rheumatoid arthritis (RA) (29.8%), inflammatory bowel disease (9.5%), and psoriasis (9.5%). Nearly 43% of the patients were treated with biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) and 23.9% with conventional synthetic DMARDSs. Another 29% were not treated.

All of the control participants developed anti--SARS-CoV-2 immunoglobulin (Ig)G, but 6% of the patients with IMIDs did not (P = .003). The gap in development of neutralizing antibodies was even higher: 99.5% of the control participants developed neutralizing antibody activity vs 90% of the IMID group.

“Neutralizing antibodies are more relevant because the test shows how much the antibodies interfere with the binding of SARS-CoV-2 proteins to the receptor,” Schett said.

The study authors concluded that their study "provides evidence that, while vaccination against SARS-CoV-2 is well tolerated and even associated with lower incidence of side effects in patients with IMID, its efficacy is somewhat delayed and reduced. Nonetheless, the data also show that, in principle, patients with IMID respond to SARS-CoV-2 vaccination, supporting an aggressive vaccination strategy.”

In the newest study,^[4] led by Rebecca H. Haberman, MD, of New York University Langone Health, New York, New York, researchers examined COVID-19 vaccine response in cohorts in New York City and Erlangen, Germany.

The New York City cohort included 25 patients with IMIDs who were taking methotrexate by itself or with other immunomodulatory medications (mean age, 63.2 ± 11.9 years), 26 with IMIDs who were on anticytokine therapy and/or other oral immunomodulators (mean age, 49.1 ± 14.9 years) and 26 healthy control participants (mean age, 49.2 years). Most patients with IMID had psoriasis/psoriatic arthritis or RA.

The German validation cohort included 182 healthy participants (mean age, 40.8 ± 12 years), 11 patients with IMID who received tumor necrosis factor (TNF) inhibitor monotherapy (mean age, 45 ± 15.5 years), and 20 patients with IMIDs on methotrexate monotherapy (mean age, 54.5 ± 19.2 years).

In the New York City cohort, 96.1% of healthy control participants showed “adequate humoral immune response,” along with 92.3% of patients with IMIDs who were not taking methotrexate; however, those individuals on methotrexate had a lower rate of adequate response (72%), and the gap persisted even after researchers removed those persons who showed signs of previous COVID-19 (P = .045).

In the German cohort, 98.3% of healthy cohorts and 90.9% of patients with IMIDs who did not receive methotrexate reached an “adequate” humoral response vs just half (50%) of those persons who were taking methotrexate.

When both cohorts are combined, more than 90% of the healthy participants and patients with IMIDs on biologic treatments (mainly TNF blockers [n = 37]) showed “robust” antibody response; however, only 62% of patients with IMIDs who took methotrexate (n = 45) reached an “adequate” level of response. The methotrexate gap remained after researchers accounted for differences in age among the cohorts.

What is going on?

“We think that the underlying chronic immune stimulation in autoimmune patients may cause T-cell exhaustion and thus blunts the immune response,” said Schett, who is also a coauthor of this study. “In addition, specific drugs such as methotrexate could additionally impair the immune response.”

Still, the findings “reiterate that vaccinations are safe and effective, which is what the recommendations state,” he said, adding that more testing of vaccination immune response is wise.

Insights into Vaccine Response While on Rituximab

Two more reports, also published in the Annals of the Rheumatic Diseases, offer insight into vaccine response in patients with IMIDs who take rituximab.

In one report, published May 11,^[1] US researchers retrospectively tracked 89 patients with rheumatic disease (76% female; mean age, 61 years) at a single clinic who had received at least 1 dose of a COVID-19 vaccine. Of those patients, 21 showed no sign of vaccine antibody response, and 20 of them were in the group taking rituximab. (The other patient was taking belimumab.) Another 10 patients taking rituximab did show a response.

“Longer duration from most recent rituximab exposure was associated with a greater likelihood of response,” the report’s authors wrote. “The results suggest that time from last rituximab exposure is an important consideration in maximizing the likelihood of a serological response, but this likely is related to the substantial variation in the period of B-cell depletion following rituximab.”

Finally, an Austrian report published May 6^[2] examined COVID-19 vaccine immune response in 5 patients who were taking rituximab (4 with other drugs, such as methotrexate and prednisone). Researchers compared them with 8 healthy control participants, half who had been vaccinated.

The researchers found evidence that rituximab “may not have to preclude SARS-CoV-2 vaccination, since a cellular immune response will be mounted even in the absence of circulating B cells. Alternatively, in patients with stable disease, delaying [rituximab] treatment until after tihe second vaccination may be warranted and, therefore, vaccines with a short interval between first and second vaccination or those showing full protection after a single vaccination may be preferable. Importantly, in the presence of circulating B cells also a humoral immune response may be expected despite prior [rituximab] therapy.”

Bass said the findings reflect growing awareness that “patients with autoimmune disease, especially when they’re on immunosuppressant medications, don’t quite have as optimal responses to the vaccinations”; however, she said, the vaccines are so potent that they are likely to still have significant efficacy in these patients even if there’s a reduction in response.

What’s next? Schett said “testing immune response to vaccination is important for patients with autoimmune disease. Some of them may need a third vaccination.”

The American College of Rheumatology’s COVID-19 vaccination guidelines^[3] do not recommend third vaccinations or postvaccination immune testing at this time; however, Bass, one of the coauthors of the recommendations, said it is likely that postvaccination immune testing and booster shots will become routine.

Clinical Implications

• One of the current studies found that previous treatment with rituximab in particular was associated with a high rate of poor serological response to the COVID-19 vaccine.
• In the current study by Simon and colleagues, the presence of IMIDs was associated with a worse response to the COVID-19 messenger RNA vaccine; however, the type of IMID did not affect the vaccine response nor did the use of DMARD therapy.
• Implications for the healthcare team: The healthcare team should caution patients with IMID that their COVID-19 vaccines might be less effective. These patients should consider behavioral risk modification if living in areas where COVID-19 is still common.

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