Rheumatologists Navigate Treatment Plans in the Era of COVID-19 Vaccines

In approaching the end of another full year within the COVID-19 pandemic, there's still much being learned about the dangerous respiratory virus that has seized the world. Developments in the last 12 months include greater confirmation that wearing masks do help to stop the spread, the virus can affect even the healthiest individuals long-term, and the first available vaccines offer extensive, but not complete, protection.

For certain populations, the protection offered by receiving a vaccine is even more limited. This year, rheumatologists found this to be the case for their patients who are on immunosuppressants or immunomodulatory treatments—a realized concern 1 year after learning the severity by which immunosuppressed patients can be affected by COVID-19.

An array of studies have been performed in hopes of gaining a better understanding on this topic. The research revealed some great insight, but an important takeaway was that patients who are on immunosuppressants or immunomodulatory treatments still benefit from receiving the vaccine, even if it's not as effective as it is in the general population.

Earlier this year, Ruth Fernandez-Ruiz, MD, MS, Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, conducted a study that evaluated the immune response and disease status in patients with systemic lupus erythematosus (SLE) which was presented at the American College of Rheumatology 2021 Convergence.

Starting From Scratch

In an interview with HCPLive®, Fernandez-Ruiz explained that all the phase 3 trials that were performed for the COVID-19 vaccines excluded patients who were taking immunosuppressants or immune-modifying drugs within 6 months from the time of enrollment.

“At the time we initiated the study,” Fernandez-Ruiz said, “the data on rheumatic disease patients was virtually absent.”

Previous research looked at this phenomenon with other vaccines, like the flu vaccine, and found that taking immunosuppressants did impact vaccine efficacy.

Prior to this study, Fernandez-Ruiz also collaborated on research that examined antibody responses in patients with lupus who had natural infection of SARS-COV-2.

“We found that most patients were able to generate and maintain an antibody response after COVID-19 disease,” Fernandez-Ruiz said. “So overall, it wasn’t really clear how our patients were going to respond to the COVID-19 vaccine, and there was a real need to study rheumatic disease patients.”

Vaccination Status Matters

Charalampos Papagoras, MD, PhD, Assistant Professor of Rheumatology at Department of Medicine, Democritus University of Thrace, led research on the outcomes of COVID-19 in vaccinated patients compared with unvaccinated patients who have systemic rheumatic diseases.

His study concluded that the severity of breakthrough COVID-19 cases depended on the vaccination status of the patient.

Aside from vaccination status, there were no differences in demographics, systemic rheumatic disease type, treatment or comorbidities between the 3 groups. However, hospitalization and mortality rates were higher in the unvaccinated group (29.3% and 4.1%, respectively), even when compared with the partially vaccinated group (21% and 0%).

Of course, patients who were fully vaccinated had the best outcome when faced with a COVID-19 breakthrough infection (10.3% and 0%).

Learning What This Means for Lupus Patients

The CDC was unclear if there were any disease-specific factors that could play a role in vaccine responses, Fernandez-Ruiz mentioned. Therefore, the team of investigators were compelled to focus particularly on the lupus population.

Their results showed approximately 30% of patients with lupus had a decrease in COVID-19 antibody responses and microneutralization titers compared to controls. Additionally, a correlation was found between circulating antibody levels against the spike protein and interfering gamma production by immune cells.

A low vaccine response was defined as less than or equal to 100 units per ml, which is the lowest value seen in controls.

After a patient’s vaccine response level was defined, the investigators further compared the 26 lupus patients who had a low response to the 64 lupus patients who had adequate response.

“We found that a normal anti-double stranded DNA antibody, and taking any immunosuppressant medication, other than antimalarials like hydroxychloroquine, were associated with a decreased vaccine response,” Fernandez-Ruiz said,

This particular study she led didn’t have a large enough sample size to look at the effect of each individual medication, but Fernandez-Ruiz emphasized that research in this area has grown.

“We do know now,” she said, “that other studies have shown that medications like methotrexate, mycophenolate mofetil, B-cell depleting agents like rituximab, and systemic steroids are likely playing a major role in blunting antibody response to the vaccine.”

An Analysis of Treatment Outcomes

A study led by Jean Liew, MD, MS, Assistant Professor, Rheumatology, Boston University School of Medicine, found that most of the patients with rheumatic disease who had to be hospitalized for COVID-19, despite being vaccinated, were the patients taking B-cell depletion therapy medication.

The results of the trial, “SARS-COV-2 Infections Among Vaccinated Individuals with Rheumatic Disease: Results from the COVID-19 Global Rheumatology Alliance Provider Registry,” noted that of the 87 fully-vaccinated patients with rheumatic disease, 22 of them had breakthrough cases so severe they needed to be hospitalized.

Liew said in an interview with HCPLive that these results weren’t exactly surprising because they were in line with other laboratory-based studies she read.

While the findings are meaningful, the other side to these data are equally enlightening. B-cell depleting medications like rituximab, and antimetabolites like mycophenolate appeared as treatments in the hospitalized group, but what about the treatment options that were absent from this group?

“Overall, the results should be reassuring,” Liew explained, “that other medication classes that are immunomodulatory that we use for rheumatic disease patients, like TNF inhibitors and other biologics that target specific cytokines, they’re not really represented in the people who were hospitalized after they were fully vaccinated.”

For the highest risk patients, it’s imperative to continue to look at other prophylactic strategies pre or post exposure, like monoclonal antibodies or the potential antiviral oral medication, according to Liew.

Walking the Thin Line

Patients in this particular high-risk population, and the providers that treat them, have to walk a thin line.

For them, the only option for treatment is ultimately limited to the immunomodulatory or immunosuppressive medication that leaves them vulnerable to a breakthrough COVID-19 infection.

Adjusting or switching to another treatment simply wouldn’t be effective at maintaining control of the disease and would then leave the patient vulnerable to a disease flare, which in turn could lead to poor outcomes if they were to be infected with COVID-19.

“There’s not really an alternative therapy for these people,” Liew said, “which makes the implication here that we need to think about what other things we can do in addition to vaccinating them.”

Fernandez-Ruiz’s study monitored for disease flare and found that 11% of vaccinated patients had a lupus flare.

“Only 1 of these patients had a severe flare,” she explained, “which means that this was overall rare, and these findings really support the safety of the COVID-19 vaccine in patients with lupus.”

The line may be thin, but it can be walked.

Individualizing the Treatment Journey

The American College of Rheumatology continuously updates their guidelines surrounding the COVID-19 vaccines with new data that arise. They recommend withholding most immunosuppressant medications after vaccination for a period of time.

Fernandez-Ruiz emphasized that these are guidelines, and rheumatologists have to make individualized decisions with each patient. The patient’s disease, the medication they’re on, the disease activity at the time, are all factors that need to be considered when discussing this with a patient.

“I’ve encountered situations where the disease activity, or the specific manifestations we’re treating, they’re life-threatening or they’re organ-threatening, so we can’t have the luxury of just simply holding the medication,” she said.

It’s a process to be taken step-by-step. And Fernandez-Ruiz is already working on the next one.

Along with a team of investigators, Fernandez-Ruiz said she is currently studying the frequency and severity of breakthrough infections.

“We also need to better understand whether holding immunosuppressants post-vaccination, and administering an additional dose of the vaccines, actually leads to improved humoral and cellular immunity to these vaccines,” she said.

Even though approximately 30% of patients showed a relatively low response, we don’t know if that response is enough to protect them from very poor outcomes of COVID-19. We think about infection prevention in general as an ideal outcome but also preventing hospitalization, oxygen requirement, ICU admission, intubation, these are all great things that we should aim for.

This year, we have certainly expanded our knowledge and understanding on the various ways COVID-19 has affected our lives and we’re on the path to continue doing so.

“You can see it either way,” Fernandez-Ruiz said. “We saw 30% of patients had a low-vaccine response, but 70% of patients had a pretty good response, and this is without the booster or third dose shot, the additional dose that we’re recommending now, so that’s actually pretty good.”