Fall 2021 Update: 7 Things We Now Know About COVID-19 Vaccines in Rheumatic Disease Patients

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Since the rollout of the COVID-19 vaccine over the past year, there has been a surge in important research on their impact on people with rheumatic diseases. Researchers and patients have been seeking answers about how taking immunosuppressive medication may affect the vaccine’s effectiveness. Other important issues include understanding side effects, the risk for disease flares, vaccine hesitancy, and more.

Though there was a disconcerting lack of data on immunocompromised conditions when the vaccine first became available last year, emerging research is now providing much more information on the COVID-19 vaccine in people with rheumatic diseases. This may help provide better protection to immunocompromised and high-risk people going forward.

Here, you’ll find a round-up of notable recent studies about the COVID-19 vaccines, many of which were just presented at the annual meeting of the American College of Rheumatology, ACR Convergence 2021.

Check out this separate round-up on the latest information on COVID-19 (infection rates, complications, and more) in rheumatic disease patients.

For more research breakthroughs from ACR 2021, check out our main guide: 100+ Arthritis & Rheumatic Disease Updates You Need to Know.

1. COVID-19 Vaccine Side Effects

We now have plenty of data that shows that people with autoimmune and inflammatory diseases do not have a higher risk of experiencing side effects from vaccination than the general population.

In a new study presented at ACR Convergence 2021, 501 patients in the Netherlands with systemic autoimmune diseases and 184 healthy controls were vaccinated against COVID-19, then surveyed about any side effects they experienced. (AstraZeneca and Pfizer vaccines were the most common vaccines in both groups.)

The majority of patients (56 percent) and controls (58 percent) experienced at least one mild adverse event — and a minority experienced at least one moderate adverse event (23 percent versus 21 percent, respectively). Severe adverse events were rare among the patients and controls (1 percent versus 0 percent). Only a small group of patients (5 percent) reported a deterioration in their autoimmune disease after vaccination. This study may provide reassurance for those who are concerned about experiencing adverse effects or disease flares after vaccination.

Meanwhile, in another study presented at the ACR Convergence 2021, researchers surveyed a total of 1,852 rheumatology outpatients in New York City who had received at least one COVID-19 vaccine dose (53.9 percent Pfizer, 44.4 percent Moderna, 1.4 percent Johnson & Johnson vaccine, and 0.3 percent AstraZeneca). Most patients had received two vaccine doses.

Adverse events (symptoms within one week of the vaccine that were not attributed to systemic rheumatic disease flares) at the first or second dose were reported by 73.3 percent of respondents. They most reported:

• Pain at the injection site (45.3 percent)
• Fatigue (38.8 percent)
• Headache (26.2 percent)
• Muscle aches (23.1 percent)
• Sore shoulder (22.2 percent)

The data demonstrate that rheumatology patients experience local or systemic adverse event post-SARS-CoV-2 vaccination at rates similar to estimates from the vaccine clinical trial data. (Less than 1 percent reported severe symptoms such as throat closing, wheezing, fainting, chest pain, difficulty breathing, bleeding, and swelling of the eyes, lips, or other parts of the body.)

Interestingly, another study showed that side effects in certain patients might correlate with vaccine effectiveness. Researchers studied the outcomes of the COVID-19 vaccines in 134 patients with chronic inflammatory disease and 44 healthy controls. They found that a higher number of reported symptoms was associated with higher antibody titers — each increase of one symptom (such as headache, fatigue, or muscle ache) was associated with a 15.9 percent increase in antibody levels. This study shows that when symptoms are present in inflammatory disease patients, they could be important indicators of vaccine response.

2. COVID-19 Vaccine and Disease Flares

The risk of disease flare after vaccination against COVID-19 appears to be small.

In a study presented at ACR Convergence 2021, Canadian researchers enrolled 220 participants — including 131 with rheumatoid arthritis, 23 with lupus, eight with other rheumatic disease, and 58 controls. Although swollen joints following both doses of an mRNA COVID-19 vaccine were more frequently reported by rheumatoid arthritis patients than controls, researchers saw no clear increase in disease activity scores post-vaccination. There were also no serious adverse events attributed to the vaccine.

Another study of lupus patients in Europe found that vaccine side effects were common but minor or moderate in more than 80 percent of lupus patients. Only 3 percent of 696 patients self-reported a medically confirmed lupus flare. These flares mainly consisted of musculoskeletal symptoms (90.5 percent) and fatigue (85.7 percent).

3. COVID-19 Vaccine Effectiveness and Immunosuppressant Medication

Several studies have shown that immunosuppressive therapies do affect vaccine effectiveness, but the specific therapies matter. For instance, rituximab has been shown repeatedly to impair immune responses to the COVID-19 vaccine, while medications like TNF inhibitors may have more modest effects.

“There’s been a lot of advancement in understanding which populations of patients are going to be more vulnerable to having poor vaccine responses,” says researcher Alfred Kim, MD, Assistant Professor of Medicine, Pathology, and Immunology at Washington University, who presented at ACR about how immunosuppressive medications impact response to the vaccine.

In a new systematic review and meta-analysis presented at the ACR Convergence 2021, researchers analyzed the results of eight different studies published from January 1, 2021 to May 30, 2021, which included data on 1,482 rheumatic disease patients. They found that the majority of rheumatic patients developed an antibody response following their second vaccine dose, but it was lower compared to healthy controls.

Here’s a look at specific medications that have been associated with a decreased response to the vaccine.

Methotrexate

A few studies indicate that methotrexate can somewhat hamper the response to the COVID-19 vaccine. Dr. Kim’s research found that methotrexate reduced antibody levels but by not nearly as much as certain other medications, such as rituximab or mycophenolate. For example, in a study presented at ACR Convergence 2021, researchers found that 80 percent of patients from a North Carolina rheumatology practice who were on methotrexate alone had an antibody response after vaccination.

Talk to your doctor about the optimal timing for your medication and the COVID-19 vaccine (including additional doses and/or boosters): Current American College of Rheumatology guidance recommends holding methotrexate for one to two weeks (as disease activity allows) after each COVID-19 vaccine dose.

Oral Steroids

Steroids such as glucocorticoids appear to decrease the immune response of the COVID-19 vaccines. Dr. Kim’s study that looked at the effects of medication on COVID-19 vaccine immune response in 197 adults with chronic inflammatory diseases and 53 immunocompetent controls before their initial vaccine dose and one to two weeks after the second dose. Researchers found that glucocorticoids had a 13-fold reduction in immune response in patients compared to immunocompetent controls.

JAK Inhibitors

In the study in which researchers measured antibody levels in patients with autoimmune inflammatory rheumatic disease in North Carolina, 91 percent of patients on JAK inhibitors tested positive for antibodies. In Dr. Kim’s research, JAK inhibitors blunted antibody levels, but not as much as glucocorticoids or B-cell depletion therapy (like rituximab).

More research is needed to determine the best timing for JAK inhibitors and COVID-19 vaccine doses. ACR guidance recommends holding JAK inhibitors for one to two weeks after each COVID-19 vaccine dose if disease activity allows. 

TNF Inhibitors

In the study from Dr. Kim’s research team, TNF inhibitor biologics had only modest impacts on antibody formation and neutralization against the earlier coronavirus variants.

But in a preliminary study of 74 patients with chronic inflammatory diseases, Dr. Kim’s research team found that there were significant reductions in neutralizing antibodies against variants of concern in those treated with TNF inhibitors, such as the Delta virus. “Neutralizing” means an antibody can prevent cells from becoming infected with a virus in a culture dish in a laboratory setting.

“With TNF inhibitors, it’s unclear how this is all going to play out,” says Dr. Kim. “While we have data that shows TNF inhibitor users have poor neutralization potential to Delta, data from the pre-Delta period showed that TNF inhibitor use was two-fold more protective against hospitalization due to COVID-19 compared to methotrexate users. We’ll need to see what the breakthrough infection rate is for TNF inhibitor users during the Delta period to see whether the neutralization data is clinically meaningful.”

Current ACR guidance is mixed on whether or not to recommend hold TNF inhibitor biologics after each vaccine dose. This is because it’s not clear how much of an impact these medications have on vaccine effectiveness. It’s a decision each patient can make with their doctor based on their disease activity, underlying health conditions, and other factors.

Rituximab

Rituximab (Rituxan) is a major drug of concern in terms of COVID-19 vaccine effectiveness. At least four separate recent studies have found that the drug dramatically impairs immune response to the COVID-19 vaccine. (Rituximab is a B-cell depleting agent, which means it gets rid of B cells in the immune system. B cells, however, are necessary for antibody production.)

For instance, a July 2021 study in the Annals of the Rheumatic Diseases analyzed data from 74 patients under rituximab treatment who were vaccinated twice with either the Pfizer or Moderna vaccine (15 healthy individuals served as controls). While all healthy controls developed antibodies, only 39 percent of the patients under rituximab treatment did.

Circulating B cells correlated with the levels of antibodies. “The data suggest that vaccination can induce SARS-CoV-2-specific antibodies in RTX-treated patients, once peripheral B cells at least partially repopulate,” note the authors.

Dr. Kim’s research has shown that in patients on B-cell depletion therapy, the lack of response to the vaccine was seen primarily in those receiving vaccination within six months of administration (with gradual recovery of antibody response to vaccination nine months after treatment with rituximab).

Current ACR guidance recommends discussing the optimal timing of dosing and vaccination with your rheumatologist. Some practitioners will measure B cells as a tool to determine booster and subsequent rituximab dosing. (See “Evaluation Before Vaccine.”) For those who elect to dose without that information or for whom measurement is not available, the guidance recommends getting the COVID-19 vaccine two to four weeks before your next anticipated rituximab dose. This is when B cell levels are likely to be highest.

4. Evaluating B Cells Before Getting the COVID-19 Vaccine

Evaluating B cell counts could help inform timing of vaccination in systemic rheumatic disease patients on rituximab and belimumab.

A new study presented at ACR Convergence 2021 showed that B cell replenishment (when your immune system has time to naturally start making B cells again) is strongly associated with COVID-19 vaccine responsiveness in rheumatic disease patients who are treated with rituximab.

In the study of 58 patients, 41 patients (71 percent) had B cell status measured at the time of an antibody test. Time from the last rituximab dose was significantly longer in patients who showed positive antibody responses than those who did not. In fact, seropositivity (the formation of antibodies) was 76 percent among those who last had rituximab exposure more than six months beforehand — but that increased to 92 percent in those with detectable B cells.

“Rituximab has been known to block complete antibody responses to COVID-19 vaccines when B cell numbers are undetected,” says Kyriakos A. Kirou, MD, DSc, FACP, rheumatologist at Hospital for Special Surgery, who did a separate study on the COVID-19 vaccine response in people on B cell therapies. “However, when B cell numbers increase to normal levels, patients can respond better to the vaccines.”

Considering B cell counts could be key for evaluating the best time to receive the COVID-19 vaccine for patients on these medications.

“Patients on rituximab should discuss with their rheumatologist the timing of COVID-19 vaccination,” says Dr. Kirou. “If their disease is stable and allows some delay, waiting until the B cell number comes up, even to a small percentage, would be helpful to allow response to the vaccine.”

Your doctor may measure your B cell levels and provide recommendations based on the results — whether that involves waiting longer after your last rituximab dose for your B cell levels to rise or moving forward with vaccination.

5. Breakthrough COVID-19 Infections

How common are breakthrough infections — getting COVID after being fully vaccinated — in rheumatic disease patients? What factors make people more likely to experience one? The research is starting to emerge, but it’s too early to draw definite conclusions.

One study from the Global Rheumatology Alliance, an international registry of rheumatic disease patients who’ve had COVID-19, identified 115 fully or partially vaccinated people who then developed COVID-19. Of the majority of fully vaccinated people (39 total), most were on B-cell depleting drugs (like rituximab) or antimetabolite medications (such as methotrexate).

In a separate study, researchers looked at a large national database of 47,303 people with various rheumatic diseases and compared them to a control group of people without rheumatic diseases (536,954). They found that generally, having an autoimmune or inflammatory rheumatic disease increased the odds for breakthrough infection. The prevalence of breakthrough COVID-19 infections per 1,000 persons after full vaccination were as follows for those without an autoimmune or inflammatory rheumatic disease versus those with an autoimmune or inflammatory rheumatic disease, respectively:

• Pfizer: 19 versus 36
• Moderna: 16 versus 33
• Johnson & Johnson: 26 versus 47

After researchers adjusted for such factors as age and comorbidities, rheumatoid arthritis, lupus, systemic sclerosis, and polymyositis were associated with increased odds of breakthrough infection. Researchers say they will “next examine the contribution of various drug exposures potentially influencing the higher risk of breakthrough infection.”

These results support the recent COVID-19 booster recommendations for people with autoimmune or inflammatory rheumatic disease.

“We don’t know what level of antibodies are sufficient to generate protection, and this gets more complicated with the immunocompromised, because many of our drugs work at multiple levels in the immune system,” says Dr. Kim. “So in an immunocompetent person, you may be able to define a threshold of protection in terms of antibody levels. Whether that same threshold is true for the immunocompromised, that’s a tricky argument to make, because there are so many impacts on the immune system that the drugs have.”

6. Extra Vaccine Doses in the Immunosuppressed

 How do third vaccine doses improve immune response in the most immunosuppressed patients — and does the type of booster matter? In a blinded randomized clinical trial, Austrian researchers assigned 60 patients under rituximab treatment who did not “seroconvert” (develop antibodies) after their primary mRNA vaccination with Pfizer or Moderna to receive a third dose, either using the same mRNA vaccine or the vector vaccine (AstraZeneca).

They found that about 27 percent of patients developed antibodies when tested a month after receiving the third vaccine dose, and the rates were comparable between the two types of vaccines.

“This study means that in some people on rituximab, which is particularly problematic for immune responses, a quarter of them can get some response to a third dose,” says Dorry Segev, MD, PhD, a transplant surgeon and researcher at Johns Hopkins Medicine, who was not involved in the study. “What they’ve shown is they didn’t see a difference between mRNA versus vector-based additional doses. One did not seem to be superior to the other, though both of them had relatively low rates of seroconversion.”

More research is needed on how extra doses affect the immune response (and breakthrough infections) in other types of immunosuppressive medication.

7. Vaccine Hesitancy

Experts are continuing to research causes of vaccine hesitancy, which may help inform how to encourage vaccination in rheumatic disease patients.

In a new study led by Medha Barbhaiya, MD, a rheumatologist at Hospital for Special Surgery, 2,384 patients completed a web-based vaccine hesitancy questionnaire on March 5, 2021; 94 percent were willing to receive or had already received the COVID-19 vaccine. However, 88 patients (3.7 percent) were undecided and 56 patients (2.3 percent) reported vaccine refusal. Undecided patients were least likely to have received other vaccines as adults, and those refusing the vaccine were most likely to have previously been infected with COVID-19. Systemic lupus erythematosus-like diseases were highest in those refusing the vaccine.

In a separate study, CreakyJoints and the Global Healthy Living Foundation (GHLF) conducted an online survey from our ArthritisPower registry between February 9 and March 24, 2021. While 54 percent (of 1,345 people) reported having been offered a COVID-19 vaccine, only 42 percent had received at least one dose of the vaccine.

Among those not vaccinated, almost 18 percent said they were unlikely to get vaccinated. The most common reasons for not getting vaccinated were use of immunosuppressive medications (52 percent), concerns of disease flare (51 percent), fear of side effects (31 percent), prior reactions to other vaccines (21 percent), and fears about the vaccine modifying DNA (16 percent).

It’s worth noting that both of these studies took place during the initial COVID-19 vaccine roll-out — and that attitudes and perceptions about the vaccine have likely shifted since then.

“Fear of flare-ups has been cited as a reason to not get the vaccine,” says Dr. Barbhaiya. “It’s an understandable concern, of course, but the literature is in general very supportive of the fact that there’s a very low risk of flares.”

Looking Ahead to Future Research

In coming months, we will learn more about the long-term efficacy of the vaccine and what that means for rheumatic disease patients.

“The six-month to one-year responses to the vaccine are going to be even more important than the short-term responses that almost everyone’s been reporting on — short-term meaning, say, the one to two weeks after the mRNA vaccine,” says Dr. Kim. “Those responses are very immature compared to the responses that eventually settle.”

Overall long-term vaccine response is important not just with regard to antibodies, but also in terms of other immune system components, such as B cells and T cells. More research will be emerging about this over the next six to 12 months, adds Dr. Kim.

Researchers will also be looking closely at the role of ongoing extra vaccines doses in immunocompromised patients.

“One big discussion right now is how do we get people to an adequate level of immunity who are immunocompromised,” says Dr. Segev. “Obviously, in some people two doses wasn’t enough. And in some people, three doses may not be enough.”

More research is needed to determine if immunocompromised people will need boosters (fourth doses) in addition to their extra third dose (and at what time intervals), and what kinds of boosters are ideal.

For people who can’t get enough protection from multiple doses of the vaccine, researchers will be examining other treatments, such as monoclonal antibodies or antiviral medications, as a potential preventive measure (even for those not yet exposed to COVID-19).

“Right now, we only allow monoclonal antibodies after somebody’s been exposed, but there are questions around if we can use pre-exposure prophylaxis to protect somebody who can’t get protected from the vaccine,” says Dr. Segev.

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