Guideline Update: ACR Advises on Vaccinations for Patients with Rheumatic Diseases

The COVID-19 pandemic has brought increased global attention to the importance of vaccine-preventable infections and intensified efforts to best utilize vaccines in patients with rheumatic and other immune diseases. Patients with rheumatic and immune disease have a greater risk of infections as well as serious complications from infections. People with rheumatic disease also may have different immune reactivity to vaccines than the general population. Further, immunosuppressive medications may blunt vaccine immunogenicity, and such medications may need to be held or rescheduled around the timing of vaccinations.

Two guidelines for vaccinations in patients with rheumatic diseases were published by the American College of Rheumatology (ACR) in the past few months. They include general guidelines for all vaccines other than for COVID-19¹ and targeted guidelines for COVID-19 vaccination.² This article will review these guidelines for adults with rheumatic diseases, focusing on topics of interest to primary care and pain specialists.

The new guidelines follow the ACR format, utilizing an expert panel of rheumatologists, other healthcare professionals, and patients with rheumatic disease. The panel was sub-divided into a core leadership team, a literature review team, a voting panel, and a patient panel. Recommendations required a 70% agreement from the voting panel, with each recommendation categorized as strong or conditional.

The general vaccine guidelines for non-COVID infections focused on two important non-live attenuated vaccines, influenza and pneumococcal vaccines, as well as the zoster live attenuated vaccine (see Table I). The guidelines for other vaccines were grouped together, as those for the non-live attenuated haemophilus, hepatitis, tetanus, and meningococcal vaccines, and those for the live attenuated MMR, rotavirus, varicella, and intranasal influenza and oral typhoid vaccines.

Below is a summary of the guideline recommendations for the most common vaccines.

Influenza Vaccination

Adult patients with rheumatic disease receiving immunosuppressive medications and any patient 65 years or older with rheumatic disease should receive high-dose or adjuvanted influenza vaccine at an optimal time related to the seasonal nature of influenza. The high dose influenza vaccine is a quadrivalent vaccine, which contains 4 times the antigen as the standard dose.³ The adjuvanted vaccine contains the MF59 adjuvant, which elicits a strong antigen response not requiring a higher antigen dose. Although these should be used whenever possible in patients with rheumatic disease, it is preferable to give any influenza vaccine at the optimal time, rather than delay vaccination, while waiting for the best vaccine option.

Pneumococcal Vaccination

Patients with rheumatic disease who are taking immunosuppressive medications are at increased risk for pneumococcal infection. Any patients less than 65 yearstaking immunosuppressive medications should be given pneumococcal vaccination, either with the conjugate vaccine (PCV13 or PCV15) followed 2 months later by the pneumococcal polysaccharide vaccine, or the single dose PCV20 vaccine. The single-dose PCV20 vaccine may supplant the 2-dose regimen in the near future.

Recombinant Varicella-Zoster Virus (VZV) Vaccination

Any adult with rheumatic disease taking immunosuppressive medication should receive the recombinant VZV vaccine. The VZV is conditionally recommended in younger patients on immunosuppressives.

Human Papillomavirus (HPV) Vaccination

Patients taking immunosuppressive medications may be at increased risk of cervical dysplasia and cancer. It is conditionally recommended that patients with rheumatic disease between 26 and 45 years taking immunosuppressive medication and not previously vaccinated for HPV be given the HPV vaccine.

Higher doses of glucocorticoids may blunt vaccine immunogenicity. Because of the importance of timely influenza vaccine administration, it is recommended that the influenza vaccine be timed seasonally rather than trying to lower the dose of glucocorticoids, such as prednisone equivalent of <20 mg daily. However, for other vaccinations, it is reasonable to defer the vaccine until the dose of prednisone can be lowered to <20 mg/day, if disease activity allows. See Table II.

Methotrexate significantly blunts the immunogenicity of influenza vaccination. Therefore, it is recommended to hold methotrexate for 2 weeks after the influenza vaccine. Methotrexate does not need to be held with other vaccines. Other immunosuppressive medications, including rituximab, should be continued on schedule after influenza vaccine.

Rituximab blunts the response to pneumococcal vaccine. Whenever possible, give any vaccination prior to beginning therapy with rituximab. For patients on rituximab, when receiving pneumococcal and other non-live attenuated vaccines, it is recommended to defer vaccination until the next rituximab injection is due, vaccinate, and then wait 2 weeks before restarting rituximab.

For live-attenuated vaccines, it is recommended that if patients with rheumatic disease are taking immunosuppressive medications, these medications should be held for an appropriate time period before vaccination and 4 weeks after administration of live attenuated vaccination. The recommended time period to hold the immunosuppressive before the live virus vaccine is usually 4 weeks or one dosing interval, but longer for rituximab and intravenous immunoglobulin (IVIG). For some live attenuated virus vaccines, inactivated alternatives can be used, such as for oral polio, oral typhoid, and influenza vaccines.

Although there have been rare instances of vaccinations precipitating a rheumatic disease flare, there is a general consensus that the potential benefit of vaccination outweighs such concern. Non-live attenuated vaccines should be given regardless of disease activity. However, it is recommended that the administration of live-attenuated vaccines be deferred, following the schedule in the previous paragraph and Table II.

The COVID-19 vaccine recommendations have been evolving over the past three years and the latest ACR recommendations are the fifth version during that brief time frame. When the COVID-19 vaccines became available in the US in late 2020, there was no population-level immunity to SARS-CoV-2, and the public health goal was to maximize vaccine uptake and efficacy. As population immunity to COVID-19 has skyrocketed, there is now greater consideration being given to optimize the timing of COVID-19 vaccination to avoid any rheumatic disease exacerbation or blunt vaccine immunogenicity. See Table III.

Patients with rheumatic disease are at greater risk of hospitalization and poor outcome from SARS-CoV-2 infection than the general population. This varies with disease activity, and it is important to optimally control the underlying rheumatic disease. This should take precedence over concern that immunosuppressive medications may result in a blunted vaccine response. There is little evidence of greater COVID-19 vaccine reactions in patients with rheumatic disease compared to the general population, although rarely the COVID-19 vaccine may trigger a flare in the underlying rheumatic disease.

The consensus is that the benefits from the COVID-19 vaccine outweigh the risks in patients with rheumatic disease, including concern regarding new-onset autoimmune reactions.

There is some limited evidence that acetaminophen and/or nonsteroidal anti-inflammatory drugs may impair vaccine reactivity, and it was recommended that these medications be held for 24 hours prior to vaccination, assuming that the rheumatic disease is stable. There was no recommendation to limit their use in patients who experience local or systematic symptoms postvaccination. There was no strong recommendation for adjusting the glucocorticoid dosage during COVID vaccination. Hydroxychloroquine therapy does not have to be interrupted at the time of COVID vaccination.

It was conditionally recommended to hold methotrexate for 2 weeks after COVID-19 vaccination if disease activity permits. For most other immunosuppressive drugs, including tumor necrosis factor (TNF) and JAK inhibitors, abatacept, and azathioprine, it was recommended to hold these medications for 1 to 2 weeks after each COVID-19 vaccine. For rituximab, it was recommended to vaccinate about 4 weeks prior to the next scheduled dose.

The new ACR guidelines for vaccination in patients with rheumatic diseases should serve to remind healthcare providers and patients of the importance of maintaining a timely vaccination schedule. Missed vaccination opportunities should be minimized. This is vital in rheumatic diseases that are associated with altered immunity, either because of disease activity or from immunosuppressive medications. Patients with immune-mediated rheumatic disease are at greater risk of infection and adverse consequences of any infection. Therefore, they should be prioritized for vaccination. Patients with rheumatic disease who have conditions not associated with significant systemic inflammation or autoimmunity, including osteoarthritis, gout, and fibromyalgia, do not usually require special considerations for vaccination compared to the general population.

Many of the vaccination recommendations are likely to change as more experience accumulates, particularly regarding COVID-19 vaccines. For example, the new guidelines debated whether it is preferable to vaccinate in a timely fashion or wait until the patient is in optimal immune status, for example, when the rheumatic disease is under control, or the patient is not taking significant amounts of glucocorticoids or immunosuppressive medications. During 2020-21, ACR guidelines favored giving the COVID-19 vaccine in a timely fashion rather than waiting for optimal disease control or adjustment of immunosuppressive medication.

As we have gained more familiarity with COVID-19 vaccines, the recommendations for their administration now are similar to those of other routine vaccinations:

1. Indicated vaccinations should be administered in a timely fashion.

2. Pneumococcal and recombinant zoster should be given to all patients with rheumatic disease who take immunosuppressive medications.

3. Methotrexate should be held for 2 weeks following immunization.

4. Adjustment for immune medications, such as rituximab or cytokine inhibitors, at the time of vaccination should be discussed with the patient’s rheumatologist.

An open and frank discussion about the important role of vaccination is essential and should include specialty and primary care physicians. Despite the phenomenal success of the COVID-19 vaccines, general vaccine hesitancy has become increasingly strong. Healthcare providers need to anticipate our patients’ concerns about vaccinations.

See also, the author’s series on COVID and pain syndromes including fibromyalgia as well as long COVID.

Rare adverse, immune reactions to vaccines do occur and should be discussed. The most common following COVID-19 vaccine is myocarditis, but this is almost always self-limited and very rare.⁴ The odds of getting myocarditis following COVID-19 infection are much greater than myocarditis as a result of the vaccine.

We also should make patients with immune diseases aware of the importance of discussing with their healthcare providers that their illness or medications may make them less likely to attain adequate protection from routine vaccinations. This may require higher vaccine doses or more boosters.⁵ The overarching message should be that the safety and efficacy of vaccinations far outweigh concerns about their toxicity in patients with rheumatic diseases.