Immunosuppression, Rheumatism Don't Up Breakthrough COVID Risk

Becky McCall

June 07, 2022

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

COPENHAGEN – Most patients with immune-mediated inflammatory diseases (IMID) should not be considered at high risk for severe COVID-19 breakthrough infections, but those on anti-CD20 therapy are the exception, data from a large prospective, cohort study show.

"Overall, the data are reassuring, with conventional risk factors, such as age, and comorbidities seeming to be more important regarding risk of severe COVID-19 breakthrough infections than rheumatic disease or immunosuppressant medication," said Laura Boekel, MD, from Amsterdam UMC, who presented the study at the annual European Congress of Rheumatology.

But, she added, there was an exception for anti-CD20 therapy. "This is especially relevant for patients with conventional risk factors that might accumulate, and rheumatologists might want to consider alternative treatment options if possible. It is important to inform patients about the risks of anti-CD20."

Another study, presented during the same session at the congress by Rebecca Hasseli, MD, from the University of Giessen (Germany) saw no deaths and no COVID-19 related complications in a cohort of triple-vaccinated patients with inflammatory rheumatic diseases, despite a higher median age and a higher rate of comorbidities compared to double-vaccinated and unvaccinated cohorts.

Ingrid Jyssum, MD, from Diakonhjemmet Hospital, Oslo, who presented results of the Nor-vaC study investigating the impact of different DMARDs on the immunogenicity of a third COVID-19 vaccine dose, welcomed the research by Boekel and Hasseli.

"The findings of Hasseli are interesting in the light of our data on serological response after the third dose, with a lack of breakthrough infections after three doses corresponding well to the robust antibody response that we found in our cohort," she remarked. "This is very reassuring for our patients. Our own work together with the findings of Hasseli and Boekel demonstrate that additional vaccine doses are important to keep this population well protected against severe COVID-19 infections."

The Nor-vaC study was conducted with a cohort of 1,100 patients with inflammatory joint and bowel diseases. "These patients had attenuated antibody responses after two vaccine doses; however, we found that a third vaccine dose brought the humoral response in patients up to the antibody levels that healthy controls had after two doses," said Jyssum. "In addition, we found that the decline in antibodies after the third dose was less than the decline seen after the second dose. Importantly, the third dose was safe in our patients, with no new safety issues."

Breakthrough Infections and Immunosuppressants

"Like the rest of the world, we were wondering if our patients were at increased risk of COVID-19, and if the immunosuppressants used by these patients influenced their risk," said Boekel.

The researchers compared both the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 Delta variant in a population of fully vaccinated IMID patients taking immunosuppressants and controls (IMID patients not taking immunosuppressants and healthy controls).

Two large ongoing, prospective, multicenter cohort studies provided pooled data collected between February and December 2021 using digital questionnaires, standardized electronic case record forms, and medical files.

Finger-prick tests were used to collect blood samples that were analyzed after vaccination against SARS-CoV-2 for anti–receptor-binding domain (RBD) antibodies, and antinucleocapsid antibodies to identify asymptomatic breakthrough infections. Any associations between antibodies and the incidence of breakthrough infections were generated, and results were adjusted for sex, cardiovascular disease, chronic pulmonary disease, obesity, and vaccine type.

The analysis included 3,207 IMID patients taking immunosuppressants, and 1,810 controls (985 IMID patients not on immunosuppressants and 825 healthy controls).

Initially, Boekel and her colleagues looked at incidence of infections and hospitalizations prior to vaccination, and then after vaccination, which was the main aim of the study.

Prior to vaccination, hospitalization risk for COVID-19 was somewhat higher for IMID patients overall compared with controls, reported Boekel. "But those treated with anti-CD20 therapy, demonstrated much greater risk for severe disease."

After the SARS-CoV-2 vaccination campaign began, the researchers then looked at how immunosuppressants influenced humoral response to SARS-CoV-2 vaccination.

"Anti-CD20 therapy showed the greatest impact on humoral immune response after SARS-CoV-2 vaccination," said Boekel. Other immunosuppressant drugs had variable effects on humoral and cellular immunity.

Once they had established that immunosuppressant drugs impaired immune responses to SARS-CoV-2 vaccination, the researchers wanted to determine if this affected clinical outcomes. Blood samples taken 28 days after the second vaccination enabled Boekel and her colleagues to see if antibody production was associated with breakthrough infections.

Breakthrough infections were seen in 5% of patients on immunosuppressants, 5% of patients not on immunosuppressants, and 4% of healthy controls. Also, asymptomatic COVID-19 breakthrough cases were comparable between IMID patients taking immunosuppressants and controls, at 10% in each group.

"We saw that the incidence [of getting COVID-19] was comparable between groups, independent of whether they were receiving immunosuppressants or not, or healthy controls. However, if they developed antibodies against the two vaccinations the chance of getting infected was lower," reported Boekel.

Hospitalization (severe disease) rates were also comparable between groups. "Patients with rheumatic diseases, even when treated with immunosuppressants were not at increased risk of severe disease from Delta breakthrough infections," added the researcher. "Cases that were hospitalized were mainly elderly and those with comorbidities, for example cardiovascular disease and cardiopulmonary disease."

Hospital admissions were 5.4% in patients on immunosuppressants, 5.7% in those not on immunosuppressants, and 6% in health controls.

However, once again, there was one exception, Boekel stressed. "Patients treated with anti-CD20 therapy were at increased risk of severe disease and hospitalization."

Omicron variant has a different transmissibility than Delta, so the researchers continued the study looking at the Omicron variant. The data "were mostly reassuring," said Boekel. "As expected, hospitalization rates decreased overall, with the exception of patients on anti-CD20 therapy where, despite overall reduced pathogenicity, patients remain at increased risk."

She said that they were awaiting long-term data so the data reflect only short-term immunity against Omicron. "However, we included many elderly and patients with comorbidities, so this made the analysis very sensitive to detect severe cases," she added.

Breakthrough infection among double- and triple-vaccinated patients

A lower rate of COVID-19 related complications and deaths were seen in patients who were triple-vaccinated against SARS-CoV-2, than in double-vaccinated or unvaccinated patients, despite the former having more comorbidities and use of rituximab (Rituxan), said Hasseli.

"These data support the recommendation of booster vaccination to reduce COVID-19-related mortality in patients with inflammatory rheumatic diseases [IRDs]," she said.

"A small number of COVID-19 cases were seen in patients with IRD after vaccinations, and in a few cases, hospitalizations were required. Breakthrough infections were mostly seen in patients on B-cell depletion therapy," she added.

Hasseli and her colleagues looked at the characteristics and outcomes of SARS-CoV-2 breakthrough infections among double- and triple-vaccinated patients with IRD.

"We wanted to understand if patients with IRD are protected in the same way as the general population following vaccination, given that these patients receive drugs that might impair the immune response," she explained.

Data for analysis were drawn from the German COVID-19-IRD registry covering February 2021 and January 2022, and patients who were double- or triple- vaccinated against COVID-19 either 14 days or more prior to a SARS-CoV-2 infection were included. Type of IRD, vaccine, immunomodulation, comorbidities, and outcome of the infection were compared with 737 unvaccinated IRD patients with COVID-19. Those with prior COVID-19 were excluded.

Cases were stratified by vaccinations status: unvaccinated (1,388 patients, median age 57 years); double vaccinated (462, 56 years) and triple vaccinated (301, 53 years). Body mass index was similar across groups (25-26 kg/m2), and time between SARS-CoV-2 infection and last vaccination was 156 days in double-vaccinated patients, and 62 days in triple-vaccinated patients.

Patients had rheumatoid arthritis in 44.7% and 44.4% of unvaccinated and double-vaccinated patients respectively, but fewer triple-vaccinated patients had RA (37.2%). Triple vaccination was seen in 32.2% of patients with spondyloarthritis, 16.6% connective tissue diseases, 5.3% other vasculitis, and 3.3% ANCA-associated vasculitis. Of triple-vaccinated patients, 26.2% were treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors, and 6.3% with rituximab, while 5.3% were not on immunomodulation. At least 25% were treated with glucocorticoids, reported Hasseli.

"Arterial hypertension and diabetes, that might be risk factors for COVID-19, were less frequently reported in triple-vaccinated patients. More patients in the double-vaccinated group [42.9%] than the triple-vaccinated [23.8%] reported absence of relevant comorbidities," she said.

COVID-19 related complications were less often reported in double- and triple-vaccinated groups with hospitalizations at 9.5% and 4.3% in double and triple-vaccinated people respectively.

Boekel and Hasseli report no relevant conflicts of interest.

This article originally appeared on, part of the Medscape Professional Network.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.