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The American College of Rheumatology (ACR) has issued a guidance document about COVID-19 vaccinations for patients with rheumatic and musculoskeletal diseases (RMDs). Included is information on general concerns and foundational principles, timing of vaccination, and adaptations to therapy.

ACR cautioned, however, that the recommendations are still conditional and are based on indirect evidence derived from experience with other vaccines.

The document differs from ACR's formal guidelines, which typically take a year or more to develop, explained Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and colleagues.

"The ACR develops 'guidance' documents when the components needed to develop a formal guideline are not present, e.g., if the need to provide guidance is more urgent than a longer guidelines timeline would allow, there is not enough peer-reviewed evidence available to conduct a formal literature review, or when there is very limited expertise and experience ... to help inform the development of recommendations," the authors wrote online in .

To create the document, a task force consisting of nine rheumatologists, two infectious disease specialists, and two public health physicians was established to provide accelerated guidance to both clinicians and patients. The information will be updated as the pandemic situation evolves, and should be considered a "living document," Curtis and co-authors said.

General Considerations

This first guidance statement asserted that rheumatologists are responsible for discussing COVID-19 vaccination with their patients in a shared decision-making process.

In addition, decisions should be individualized, reflecting the variability among patients with regard to disease severity, comorbidities, and treatments. Given the limited vaccine availability and competing concerns for individual and societal needs, "simplicity should be the touchstone: to avoid confusion, improve implementation, and maintain scientific credibility," the authors advised.

Additional general considerations were that patients with autoimmune and inflammatory rheumatic diseases are at increased risk for viral infections in general, have a greater likelihood to require hospitalization with COVID-19, and generally have worse outcomes than the general population. Therefore, patients with these underlying diseases should be prioritized for vaccination, the authors advised.

However, the panel emphasized the wide range of disease severity, noting that a patient with rheumatoid arthritis whose disease is controlled with hydroxychloroquine is likely to be at far less risk than someone with severe vasculitis being treated with intravenous cyclophosphamide or rituximab (Rituxan).

Accordingly, vaccination should take place when the underlying disease is well controlled, if possible, but there is a theoretical risk for disease flare or worsening after vaccination.

Another concern was the uncertain future landscape of COVID-19 regarding long-term vaccine safety and efficacy and emerging viral strains.

Finally, the task force acknowledged that much of the evidence for the safety and efficacy of the COVID vaccine was extrapolated from studies of other vaccines, and that the response for patients receiving immunomodulatory drugs "was likely to be blunted, albeit with uncertain diminution in either the magnitude or duration of response compared to the general population."

Medication Concerns

Although recognizing that there was little evidence to guide the timing of vaccination, the panel recommended that vaccination not be deferred because of disease severity or activity, with the exception of patients experiencing life-threatening illness requiring treatment in the intensive care unit.

The panel stated that there was no preference for one vaccine over another, and that patients should receive whatever was most easily available.

Strong consensus (i.e., agreement by all panel members) was seen for the statement that there was no need to delay vaccination for patients receiving hydroxychloroquine, sulfasalazine, leflunomide, apremilast (Otezla), or intravenous immune globulin.

A similar, though moderate consensus, existed for the majority of other immunomodulators, with the exception of rituximab. Patients receiving rituximab should schedule their vaccination to be initiated 4 weeks before their next scheduled rituximab dose. This recommendation derived from a study showing differences in response to influenza vaccination depending on timing of the rituximab dose, the authors explained.

As to the timing of immunomodulatory treatment in relation to vaccination, the panel recommended that methotrexate be withheld for a week after each dose of the vaccine -- a recommendation that was based on studies of pneumococcal and influenza vaccines. A similar recommendation was made for JAK inhibitors, "based on concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response," the authors explained.

They also recommended that abatacept (Orencia) be withheld for a week before and after the first dose of the vaccine only. This recommendation was based on data suggesting a possible negative effect of this drug on the immunogenicity of the vaccine, and also because "the first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA4, and abatacept is a CTLA4-Ig construct," the panelists explained.

For intravenous cyclophosphamide, which is generally given at intervals of 2 or 4 weeks, the recommendation was to arrange for the cyclophosphamide dosing to be given a week after the vaccine doses, if possible.

Rituximab administration was recommended to take place 2 to 4 weeks after the second vaccine dose if feasible, but only if the disease is sufficiently controlled to permit such a delay. However, this recommendation was based on immune responses to other vaccines, which may not be fully generalizable to the COVID vaccine "especially since the degree to which efficacy is attributable to induction of host T cell vs B cell (antibody-based) immunity is uncertain at this time," Curtis and co-authors cautioned.

Research Agenda

They also set forth a series of goals to be addressed as additional experience and data accrue -- for example, calling for more information about the risks of flare and vaccine reactogenicity among RMD patients, and for data on long-term safety and durability, particularly in the context of immunomodulatory therapy and the emergence of new viral strains.

The team also recommended that a biorepository be established to coordinate vaccine-related research, "considering the future potential to identify lab-based correlates of protection relevant for individual patients."

The document also suggested that serologic tests be developed that could detect inadequate responses to the vaccine among patients who might benefit from additional booster doses, and that vaccine hesitancy be addressed for at-risk RMD patients, particularly those belonging to vulnerable and underserved populations.

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