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01-03-2021 | COVID-19 | Feature | Article

COVID-19 vaccination in patients with rheumatic diseases

Claire Barnard

medwireNews: With COVID-19 vaccination programs underway in many countries, we answer some of the key questions rheumatologists may have, drawing on recommendations from professional organizations.

Amendment June 8, 2021Article updated to include data on COVID-19 vaccination presented at the EULAR 2021 Virtual Congress.

Amendment May 26, 2021Article updated to include the results of a study on methotrexate and the immune response to vaccination, a case series describing the characteristics of vaccine nonresponders, and a link to guidance from the Canadian Rheumatology Association.

Amendment May 19, 2021: Article updated to include information on COVID-19 vaccination in children and adolescents with rheumatic diseases.

Amendment May 11, 2021Article updated to include research demonstrating impaired antibody responses to COVID-19 vaccination in people with inflammatory diseases, and the results of a small study evaluating humoral and cell-mediated responses in people undergoing rituximab treatment.

Amendment March 31, 2021: Article updated to include study results that demonstrate immunogenicity of messenger (m)RNA vaccines against SARS-CoV-2 in people with chronic inflammatory diseases, and provide information on local and systemic adverse events following vaccination.

Should people with rheumatic and musculoskeletal diseases have a COVID-19 vaccine?

Yes. A number of rheumatology societies have now released guidance on COVID-19 vaccination in people with rheumatic and musculoskeletal diseases (RMDs), and all broadly recommend vaccination.

The American College of Rheumatology (ACR) guidance recommends that RMD patients “should be prioritized for vaccination before the nonprioritized general population of similar age and sex.” The recommendations also state that with the exception of existing allergies to components of the vaccine, there are no known contraindications in RMD patients.

“[T]he benefit of COVID-19 vaccination outweighs any small, possible risks for new autoimmune reactions or disease flare after vaccination”

Jeffrey Curtis, chair of the ACR COVID-19 Vaccine Clinical Guidance Task Force

Similarly, EULAR recommends that the current COVID-19 vaccines, all of which are non-live, “can be used safely in patients with RMDs as well as in patients receiving drugs that influence the immune system,” while the British Society for Rheumatology (BSR) says that “[a]ll patients should be encouraged to receive a COVID-19 vaccine, regardless of treatment regimen or underlying diagnosis.”

May 26, 2021: The Canadian Rheumatology Association issued a recommendation for COVID-19 vaccination in patients with RMDs, which was graded as conditional due to "uncertainty about the effects in the population of interest.”

Is there a risk for disease flare with COVID-19 vaccination?

While the ACR guidance acknowledges that there is a “theoretical risk” for RMD flare or disease worsening following COVID-19 vaccination, it stresses that the benefits of vaccination are much greater.

“Although there is limited data from large population-based studies, it appears that patients with autoimmune and inflammatory conditions are at a higher risk for developing hospitalized COVID-19 compared to the general population and have worse outcomes associated with infection,” said Jeffrey Curtis, chair of the ACR COVID-19 Vaccine Clinical Guidance Task Force, in a press release.

Therefore, “the benefit of COVID-19 vaccination outweighs any small, possible risks for new autoimmune reactions or disease flare after vaccination,” he added.

March 31, 2021: A small study by Bimba Hoyer (University Medical Center Schleswig-Holstein Campus Kiel, Germany) and colleagues, published in the Annals of the Rheumatic Diseases, reported no disease flares among 26 patients with chronic inflammatory diseases who had received both doses of either the Pfizer–BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccine. Disease activity was measured before and 1 week after each vaccination, and there were no changes to DMARD or glucocorticoid therapy during the study period.

June 8, 2021Study findings from the COVAX Registry presented at the EULAR 2021 Virtual Congress suggested that RMD flares following COVID-19 vaccination are "rare." Among 1519 patients, 5% experienced a disease flare following vaccination, but presenting author Pedro Machado (University College London, UK) said that it was difficult to determine whether or not the flares were related to vaccination.

Will COVID-19 vaccines work in people with RMDs and how can effectiveness be measured?

Although limited data are available, the ACR guidance notes that the immune response to COVID-19 vaccination is “likely to be blunted” among people with RMDs compared with the general population. The recommendations say that vaccination would ideally be carried out when RMDs are well-controlled, but stress that the COVID-19 vaccine should be given “as soon as possible for those for whom it is being recommended, irrespective of disease activity and severity.”

March 31, 2021: The study by Hoyer and colleagues found that the Pfizer–BioNTech (BNT162b2) and Moderna (mRNA-1273) vaccines elicited an appropriate immune response in patients with RMDs, albeit with significantly lower antibody levels among the 26 patients with chronic inflammatory diseases relative to 42 healthy controls 1 week after the second vaccine dose. The researchers conclude that further studies are needed to establish antibody titer persistence in immunosuppressed individuals, and suggest that booster doses may be needed. Additional study results by Dorry Segev and colleagues from Johns Hopkins University in Baltimore, Maryland, USA, demonstrated that almost three-quarters of 123 RMD patients developed detectable antibody response following the first dose of an mRNA vaccine against COVID-19, but certain treatment regimens, including rituximab and mycophenolate, may compromise the vaccine response.

May 11, 2021: Research by Georg Schett (Friedrich-Alexander University Erlangen-Nuremberg, Germany) and team showed that humoral immune responses to the Pfizer–BioNTech (BNT162b2) vaccine may be "delayed and reduced" among RMD patients relative to healthy controls. However, the study authors found that vaccination "essentially works" in this patient population, supporting current recommendations.

May 26, 2021A case series published in the Annals of Internal Medicine described the clinical characteristics of 20 patients with RMDs who did not have detectable antibodies against the SARS-CoV-2 spike protein 1 month after receiving their second dose of the Pfizer–BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccine. The most common RMD diagnosis in this group of nonresponders was systemic lupus erythematosus (50%), rituximab was the most frequently prescribed biologic (55%), and mycophenolate mofetil was the most commonly used conventional DMARD (50%).

June 8, 2021: Study findings presented at the EULAR 2021 Virtual Congress indicated that the Pfizer–BioNTech (BNT162b2) vaccine is immunogenic in most RMD patients. Victoria Furer (Tel Aviv Sourasky Medical Center, Israel) reported an 86% seropositivity rate among 686 patients with RMDs, compared with 100% among 121 healthy controls.

Writing in a review article published in Clinical and Experimental Rheumatology in February 2021, Piercarlo Sarzi-Puttini (Milan University School of Medicine, Italy) and co-authors recommend that protective immunity “should be assessed by evaluating humoural and cell immune responses to COVID-19 antigens” following vaccination in RMD patients, noting that “[n]eutralising antibody titres are good biomarkers of protective efficacy.”

The ACR guidance, however, provides a recommendation with a strong level of consensus that healthcare providers should not routinely order laboratory tests to assess COVID-19 immunity following vaccination.

Anne Bass, panel member of the ACR COVID-19 Vaccine Clinical Guidance Task Force, elaborated on this point at a virtual town hall event. She explained that many commercially available sensitive serologic tests for COVID-19 infection measure antibodies to the nucleocapsid protein, whereas vaccines elicit the production of antibodies against the spike protein, so nucleocapsid tests would produce a negative result “and that doesn’t tell you anything.”

Bass noted that even with assays measuring antibodies against the spike protein, the issue is that “we don’t yet have any [data on] correlation between levels of antibodies by those assays and seroprotection.” She said that studies addressing this question are “clearly needed,” particularly for RMD patients, and hopes that using antibody titers to assess immunity following COVID-19 vaccination is a possibility in the near future.

Is one type of vaccine better than another?

Based on currently available data, there are no recommendations supporting use of one vaccine over another.

The UK’s Arthritis and Musculoskeletal Alliance (ARMA) has issued Principles for COVID-19 Vaccination in Musculoskeletal and Rheumatology for Clinicians, which compare the vaccines available in the UK, including dosing schedules and approval dates. This guidance specifies that none of the approved vaccines are live. This includes the Oxford–AstraZeneca (ChAdOx1 nCoV-2019) vaccine, which contains a live, but non-replicating, adenovirus vector and therefore cannot cause infection and is recommended for use in people who are immunosuppressed.

Do patients need to stop or alter RMD drug treatments when having a COVID-19 vaccine?

The ACR guidance provides a table of different drug treatments and considerations in regard to the timing of both immunomodulatory therapy and COVID-19 vaccination. For many of the drugs – including tumor necrosis factor inhibitors, interleukin inhibitors, low-dose glucocorticoids (prednisone-equivalent dose <20 mg/day), sulfasalazine, hydroxychloroquine, and leflunomide – no modifications to either immunomodulatory therapy or vaccination timing are recommended. However, there are some exceptions, namely rituximab, methotrexate, Janus kinase inhibitors, abatacept, and cyclophosphamide, for which guidance is given.

Jeffrey Curtis said in a press release that there was “vigorous debate” on the expected magnitude of benefit for people receiving immunomodulatory therapies.

“Ultimately, the task force agreed that in almost all cases, proceeding with vaccination and obtaining at least a partial response would be better than deferring vaccination, since deferring provides no protection at all,” he added.

May 26, 2021: Study findings from Jose Scher (New York University Langone Health, USA) and colleagues suggested that methotrexate treatment may be associated with a blunted humoral and cell-mediated immune response in patients with inflammatory diseases. The researchers suggest that strategies such as additional vaccine doses or temporary methotrexate discontinuation may be required to improve vaccine effectiveness in methotrexate-treated patients.

What are the considerations with rituximab?

In their review article, Sarzi-Puttini and colleagues explain that the generation of protective antibodies against SARS-CoV-2 will likely be attenuated as a result of rituximab-induced B cell depletion, suggesting that interrupting rituximab treatment may permit effective vaccination against COVID-19.

Indeed, guidance from the AARA and the ACR advises special considerations regarding the scheduling of COVID-19 vaccination in rituximab-treated patients in order to ensure an adequate gap between vaccine administration and the next rituximab dose.

May 11, 2021: A small study from Daniel Aletaha (Medical University of Vienna, Austria) and team found that although rituximab-treated patients with depleted B cells have an impaired antibody response to the Pfizer–BioNTech (BNT162b2) vaccine, these people may still be able to mount a T cell-mediated response. They conclude that rituximab "may not have to preclude SARS-CoV-2 vaccination," but stress the need for more research into whether T cell-mediated immunity is sufficient to protect against COVID-19.

What are the considerations with steroids?

There are limited data available at present. The UK AARA guidance provides a number of general principles – including not to delay vaccination for people taking steroids – but emphasizes that the benefits and risks of delaying steroid doses should be discussed with individual patients. The ACR panel did not reach consensus for a recommendation on vaccination timing in patients taking prednisone-equivalent doses of 20 mg/day or higher.

I would really emphasize that we should be looking to vaccinate where we can

Reuben Arasaratnam, panel member of the ACR COVID-19 Vaccine Clinical Guidance Task Force

Speaking at the ACR town hall event, Reuben Arasaratnam, transplant and infection specialist and panel member of the ACR COVID-19 Vaccine Clinical Guidance Task Force, said that patients on these higher doses were excluded from the phase 3 trial of the Moderna (mRNA-1273) vaccine, but previous studies of influenza and pneumococcal vaccines have shown that doses at this range and below are “unlikely to have a significant [impact] on antibody titers.”

He said that COVID-19 vaccination is unlikely to generate a sufficient immune response during high-dose pulsing of steroids, and “we would be encouraged to vaccinate” patients on chronic stable low-doses, but “there is a gray area in between.” Arasaratnam recommended considering kinetics of steroids, other concomitant medications that may impair immune responses, and patients’ individual risk for getting COVID-19.

“I would really emphasize that we should be looking to vaccinate where we can,” he added.

Should children and adolescents with RMDs receive a COVID-19 vaccine?

May 19, 2021: In May 2021, the US FDA expanded the emergency use authorization for the Pfizer–BioNTech (BNT162b2) vaccine to include adolescents aged 12–15 years. The vaccine was previously approved for those ages 16 years and older. Following this approval, the Centers for Disease Control and Prevention recommended that everyone aged 12 years and above in the USA should receive a COVID-19 vaccination.

In Europe, the Paediatric Rheumatology European Association (PReS) recommends that pediatric rheumatology patients aged 16 years and older should be vaccinated against COVID-19 with vaccines approved for use in this age group. 

The PReS says that patients with low disease activity or remission who are treated with methotrexate or biologic agents should be vaccinated, and recommends a gap of at least 2 weeks between receipt of an influenza and a COVID-19 vaccine.

Are there any issues with vaccine uptake in RMD patients and how can we improve uptake?

A European survey study found that 87% of 1505 adults with rheumatic, autoimmune, and autoinflammatory conditions said they would have the COVID-19 vaccine, while 11% were unsure and 2% said they did not intend to have the vaccine when offered.

As outlined in a letter to Rheumatology, 51% of respondents who answered a question about reasons for not having the COVID-19 vaccine said that a lack of information was a factor, including concerns about potential medication contraindications, adverse events, and suitability of the vaccine for people with autoimmune conditions. The authors note that only “a very small minority” of respondents were against vaccination due to conspiracy theories.

Richard Beesley (Juvenile Arthritis Research, Tonbridge, UK) and co-authors therefore recommend that “[c]lear, concise and accessible information is likely to increase vaccination uptake and reduce direct calls to rheumatology centres.”

In accordance with these findings, two studies published in The Lancet Rheumatology found that RMD patients’ willingness to receive a COVID-19 vaccine improved if their physician recommended vaccination. The first found that 69% of 515 patients from the Netherlands who were initially uncertain about whether they would accept a vaccine and 31% of 118 who were unwilling said they would change their minds following advice from their physician.

Similarly, the second study of 1266 patients found that willingness to be vaccinated increased from 54.2% to 62.8% when recommended by a physician, with specialists (eg, rheumatologists and internists) the most trusted healthcare provider regarding vaccination recommendations. These findings led the researchers to conclude that rheumatologists have a “crucial and timely role” in improving vaccination uptake.

March 31, 2021: Caoilfhionn Connolly (Johns Hopkins University, Baltimore, Maryland, USA) and team reported the findings of a study evaluating COVID-19 vaccine safety in RMD patients. As outlined in a letter to the Annals of the Rheumatic Diseases, they found that local and systemic adverse events in RMD patients following receipt of an mRNA COVID-19 vaccine were consistent with those seen in the clinical trial populations. The team says that their “reassuring” findings may help to address concerns regarding vaccine hesitancy.

June 8, 2021The authors of a study presented at the EULAR 2021 Virtual Congress aimed to address vaccine hesitancy in RMD patients using an educational video focused on vaccine safety that was delivered on mobile phones. Lavanya Rajagopala (The Royal Wolverhampton NHS Trust, UK) reported that 52% of 664 individuals said they were unsure about vaccine safety prior to watching the video, but 77% said they would be more likely to have a COVID-19 vaccine after watching the video.

What resources are available on COVID-19 vaccination in RMD patients?

Some resources and guidance are summarized in the table.


ACR guidance (USA)

EULAR viewpoints (Europe)

ARMA guidance (UK)

BSR guidance (UK)

COVID-19 vaccination in patients with psoriatic disease: Joint guidance statement from IFPA and GRAPPA (international)

German Society for Rheumatology viewpoint on COVID-19 vaccination
Canadian Rheumatology Association recommendation on COVID-19 vaccination

Are there any registries for reporting COVID-19 vaccination in RMD patients?

Rheumatologists in Europe are being asked to complete the EULAR COVAX survey for all vaccinated patients with RMDs at any time following the first or second vaccine dose. EULAR advises that the survey takes 1–2 minutes to complete for patients without adverse events, and less than 5 minutes for those with adverse events.

“This data will be an important contribution to the arguments brought forward to encourage patients to be vaccinated,” said EULAR in an announcement about the survey.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

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