COVID-19 vaccination in patients with rheumatic diseases
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.
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.”
August 17, 2021: Following the US FDA's authorization of a third COVID-19 vaccine dose for certain immunosuppressed individuals, the Centers for Disease Control and Prevention confirmed that people with RMDs undergoing active treatment with high-dose corticosteroids, tumor necrosis factor inhibitors, other immunosuppressive or immunomodulatory biologics, alkylating agents, or antimetabolites would be eligible for the booster.
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.
A small number of studies have been carried out to address this question, finding that RMD flare following COVID-19 vaccination is uncommon.
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.”
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, “we don’t yet have any [data on the] 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.
Research has shown that people with RMDs tend to mount an antibody response, but that it is blunted compared with that in healthy controls. Studies have also shown that certain therapies – including rituximab and abatacept – may be associated with a reduced antibody response, and have emphasized the importance of having both doses for vaccines with a two-dose schedule.
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.
September 13, 2021: Early study results published in a letter to the Annals of the Rheumatic Diseases suggest that RMD patients given Johnson & Johnson’s Janssen (JNJ-78436735) vaccine may have more limited humoral responses than those given mRNA vaccines.
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 TNF 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.
July 14, 2021: UK research by Catherine Smith (King’s College London) and colleagues found that treatment with methotrexate may dull the humoral, but not cellular, immune response to the first dose of the Pfizer–BioNTech (BNT162b2) vaccine. On the other hand, targeted biologics were not associated with an impaired immune response in the study. Similarly, Serena Bugatti (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy) report in a letter to the Annals of the Rheumatic Diseases that methotrexate, but not anticytokine therapy, was associated with impaired immunogenicity to a single dose of the same vaccine in a study of 140 people with inflammatory arthritis.
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.
Subsequent research demonstrated that rituximab treatment is associated with a blunted immune response to vaccination, but people may be able to mount an effective response. Predictors of vaccine response have also been identified in rituximab-treated patients.
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.
September 13, 2021: Findings from a study of 21 TNF inhibitor-treated adolescents with juvenile idiopathic arthritis suggest that mRNA SARS-CoV-2 vaccines are well tolerated and do not provoke disease flares. Dimitra Dimopoulou (University of Athens, Greece) and colleagues conclude in a letter to Arthritis & Rheumatology that "further studies are needed to evaluate the immune response" to COVID-19 vaccination in this patient population.
Are there any issues with vaccine uptake in RMD patients and how can we improve uptake?
A number of studies have evaluated RMD patients' willingness to receive a COVID-19 vaccine, factors influencing uptake, and interventions to address vaccine hesitancy.
What resources are available on COVID-19 vaccination in RMD patients?
Some resources and guidance are summarized in the table.
|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.
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