Immunizations in autoimmune inflammatory rheumatic disease in adults

INTRODUCTION — Patients with autoimmune inflammatory rheumatic disease (AIIRD), such as rheumatoid arthritis (RA) and systemic lupus erythematosus, are at higher risk for serious infections, which is likely due to both disease-related immune dysfunction and immunosuppressive medication use. Because of this risk, vaccination is an important part of care.

Vaccination schedules, vaccine efficacy and safety, and contraindications to vaccination for patients with AIIRD will be reviewed here. The effects of biologic and nonbiologic immunomodulatory therapies on the immune system, the risk of specific infections, and coronavirus disease 2019 (COVID-19) immunization for patients with AIIRD are discussed separately. (See "Glucocorticoid effects on the immune system" and "Secondary immunodeficiency induced by biologic therapies" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

IMPORTANCE OF VACCINATION — Morbidity and mortality due to vaccine-preventable illnesses, such as influenza, COVID-19, and Streptococcus pneumoniae pneumonia, is higher among patients with autoimmune AIIRD compared with the general population [1-5]. Vaccinations against these illnesses are recommended for patients with AIIRD by most major national and international medical societies, including the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) [6,7].

Despite these recommendations, vaccine rates among patients with AIIRD is low [8-11]. As an example, in a large multinational cohort study evaluating 3920 patients with rheumatoid arthritis (RA), over half of patients had never received a pneumococcal or influenza vaccination, and less than one-third were appropriately vaccinated [8]. Among patients, the primary reason cited for lack of vaccination was the absence of a recommendation from their health care provider [9]. The reasons why providers do not routinely vaccinate patients with AIIRD are less clear but may include concerns about vaccine efficacy, safety, and appropriate timing. There may also be confusion over which clinicians should be administering vaccines (eg, primary care physicians versus rheumatologists).

Although randomized trials directly evaluating the efficacy of vaccination in patients with AIIRD are limited, available evidence suggests that routine vaccination for patients with AIIRD is warranted.

APPROACH TO VACCINATION

Recommended vaccines — As part of our initial evaluation of patients with AIIRD, we review each patient's vaccination, exposure, and planned travel in detail. Ideally, this review should be performed before the start of immunosuppressive therapy, when the likelihood of developing a protective immune response to any needed vaccine is highest and when live vaccines can be given safely. COVID-19 vaccination for patients with AIIRD is discussed separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

Patients who are not up to date on other routinely recommended vaccines (based on age or other risk factors) should receive any needed nonlive vaccines regardless of immunosuppression (table 1). (See "Standard immunizations for nonpregnant adults".)

In addition to routine vaccines recommended for the general population, adult patients with AIIRD who are planning to start immunosuppression or who are currently immunosuppressed require the following nonlive vaccines, regardless of age or other risk factors [6,7,12,13] :

●Pneumococcal vaccine(s) (See 'Pneumococcal vaccines' below.)

●Recombinant zoster vaccine (RZV) (See 'Zoster vaccines' below.)

In selected patients between the ages of 26 to 45 years that have not received the human papillomavirus vaccine (HPV) previously, HPV vaccine can be administered to those who may benefit from it (eg, patients with no prior sexual experience or a limited number of prior sexual partners who are deemed to have a future risk for HPV exposure) based on shared decision making with the patient [7]. (See "Human papillomavirus vaccination", section on 'Indications and age range'.)

Any needed live vaccines (eg, measles, rubella, varicella) should ideally be administered ≥4 weeks prior to the start of immunosuppression. However, exceptions can be made for patients on low-dose immunosuppression who require certain live vaccinations (eg, varicella, live zoster vaccine) and in other selected circumstances when the benefits of vaccination outweigh the risk of discontinuing or lowering immunosuppressive medications. Specific instruction on the administration of these vaccines in patients with AIIRD is provided below. (See 'Vaccine administration' below.)

Our approach to vaccination is generally consistent with the Advisory Committee on Immunization Practices in the United States and most major medical societies, including the American College of Rheumatology and the European Alliance of Associations for Rheumatology (EULAR; formerly known as the European League Against Rheumatism) [6,7,12,13].

Timing of vaccination — For maximal protection, vaccinations should be given several weeks prior to the start of immunosuppressive therapy. This increases the likelihood of developing a protective immune response, particularly for rituximab, which substantially impairs humoral immunity (table 2) [14]. Vaccinating prior to immunosuppressive therapy also allows for administration of any needed live vaccines, which are generally contraindicated once immunosuppressive therapy has started.

●Nonlive vaccines − When administering nonlive vaccines prior the start of immunosuppression, we aim to complete any needed series ≥2 weeks before immunosuppressive medications are given, if possible.

When administering vaccines prior to immunosuppression is not feasible, we give any necessary nonlive vaccines as soon as possible and ideally during periods when immunosuppression is low. Some studies suggest that holding immunosuppression temporarily around the time of vaccination may augment immune response; thus for patients taking methotrexate, we generally hold the methotrexate dose for one to two weeks starting at the time of the administration of a nonlive vaccine [15]. Any potential benefit likely varies with the underlying disease state and other individual patient characteristics.

For patients receiving rituximab, we delay any vaccinations until at least three months (and ideally six months) after their last administration of rituximab, as patients do not mount a humoral response until three to six months after receiving rituximab. If a patient needs to receive a vaccine, we vaccinate five to six months after their last dose and then wait two to four weeks before administering the next rituximab dose. Although some experts assess B cell repopulation using CD19 cell assays, we generally do not check CD19 cell levels to guide timing of vaccination because it adds a significant amount of testing burden and does not necessarily correlate with T cell responses, which can be an important aspect of the immunogenic response depending on the vaccine. At least with COVID-19 mRNA vaccines where it has been studied, some patients develop good T cell responses with either initial or repeated boosting doses of a vaccine [16].

●Live vaccines − Live attenuated vaccines (eg, measles, varicella, yellow fever) should generally be avoided in immunosuppressed patients. Live vaccines should be given at least ≥2 weeks prior to the start of immunosuppression. However, we often extend this window to ≥4 weeks for patients who will be receiving more potent immunosuppressive medications to avoid the risk of disseminated disease with live vaccines [17].

In rare circumstances (eg, travel or residence in an area where yellow fever is endemic) when the benefits of vaccination outweigh the risk of temporarily stopping immunosuppressive medications, live vaccines can be given. While the optimal approach has not been determined, we generally stop any immunosuppressive medication ≥4 weeks (or more depending on medication half-lives) prior to administering a live vaccine and continue to hold any immunosuppressive medications for ≥4 weeks thereafter. (See 'Live vaccines' below.)

Schedules and appropriate timing for specific vaccines are discussed below.

VACCINE ADMINISTRATION

Nonlive vaccines

Pneumococcal vaccines — We recommend pneumococcal vaccination to all patients with AIIRD who are receiving or planning to receive immunosuppressive therapy [18].

●Vaccine selection − We agree with the Advisory Committee on Immunization Practices (ACIP) recommendations that patients should receive either the 20-valent pneumococcal vaccine (PCV20) alone or the 15-valent pneumococcal vaccine (PCV15) followed by the 23-valent polysaccharide vaccine (PPSV23) at least eight weeks later. Choice of vaccine is generally based on availability and ease of dosing.

For patients who have already received a previously recommended pneumococcal conjugate vaccine (eg, PCV13, PCV10) or PPSV23, the dosing schedule varies (table 3 and table 4). Some UpToDate contributors have a different approach to vaccine selection; this is discussed elsewhere. (See "Pneumococcal vaccination in adults", section on 'Approach to vaccination'.)

●Timing of vaccination − Ideally, all pneumococcal vaccines should be given ≥2 weeks before the start of any immunosuppressive therapies. This is particularly true for anti-CD20 agents (eg, rituximab), abatacept, tofacitinib, and methotrexate, each of which has been shown to diminish the immune response to pneumococcal vaccination (table 2); this may be less necessary for tocilizumab [19-22].

When vaccination cannot be given prior to immunosuppression, we give these vaccines as soon as possible and ideally during a period when immunosuppression is low. Although the immune response may be diminished, vaccination is still expected to provide protective benefit for most patients. (See 'Vaccine efficacy and immunogenicity' below.)

Recommendations for revaccination (eg, booster dosing) with PPSV23 vary among experts and clinical practice guideline [18,23]. This is discussed in detail separately. (See "Pneumococcal vaccination in adults", section on 'Revaccination'.)

Seasonal influenza vaccine — All patients should receive a seasonal influenza vaccine annually, unless contraindications are present (eg, hypersensitivity to vaccine components) [24].

●Vaccine selection – For patients with AIIRD who are on immunosuppressants, we prefer to administer either the adjuvanted or high-dose formulations of the influenza vaccine, when possible [7]. One randomized trial of 287 patients with rheumatoid arthritis suggests that the high-dose vaccine augments humoral immune response without an increase in disease activity or adverse effects [25].

●Timing of vaccination – When possible, we give seasonal influenza vaccines prior to the start of immunosuppression. However, because the vaccine is given annually just before the influenza season, this is often not feasible. For patients who are receiving immunosuppressive medications, we try to vaccinate during periods when immunosuppression and inflammatory disease activity is low [26]. For patients receiving methotrexate, we hold methotrexate for one to two weeks after administration of the influenza vaccine [7]. Multiple randomized studies demonstrate that seroprotection rates are higher in patients whose methotrexate was held for one or two weeks after vaccine receipt when compared with those in whom methotrexate was continued [15,26-28]. Whether the incremental increase in seroprotection results in improved efficacy remains to be determined. (See 'Vaccine efficacy and immunogenicity' below.)

Additional detail on influenza vaccinations is provided separately. (See "Seasonal influenza vaccination in adults".)

Hepatitis A virus (HAV) vaccine — Hepatitis A virus vaccine should be given to at-risk adult patients who have not been previously vaccinated, as recommended for the normal adult population. High-risk adults include those with chronic liver disease, human immunodeficiency virus, or occupational and lifestyle risk factors [29]. We administer a two-dose series with a single-antigen HAV vaccine (HAVRIX or VAQTA) per the same schedule used for otherwise healthy adults. For patients who are receiving immunosuppressive medications, completing the two-dose series is particularly important as it is associated with a marked increase in seroprotection rates when compared with receipt of a single dose [30]. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Protection prior to exposure'.)

For those with imminent travel or who need a reliable and early level of protection, two vaccine doses given at the same time or a month apart followed by another dose at six months has been shown to provide higher levels of seroconversion in patients with rheumatoid arthritis on immunosuppression [31].

Additional detail on HAV vaccination is provided elsewhere. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Vaccination'.)

Hepatitis B virus (HBV) vaccine — All patients <60 years old regardless of risk and those ≥60 years old with risk factors (eg, chronic liver disease, injection drug use, household contacts with hepatitis B, occupational risk) should be vaccinated against hepatitis B [32].

Whether standard- or higher dose HBV vaccine should be used in those with rheumatic diseases or other inflammatory conditions remains to be determined. To maximize the likelihood of response, we generally give the higher dose vaccine series (either one dose of 40 mcg/mL [Recombivax HB] administered on a three-dose schedule at 0, 1, and 6 months or two doses of 20 mcg/mL [Engerix-B] administered simultaneously on a four-dose schedule at 0, 1, 2, and 6 months). This dosing schedule is concordant with the United States Advisory Committee on Immunization Practices for immunocompromised patients [33]. The risk-benefit ratio of using vaccines with novel adjuvants (eg, Heplisav-B) in patients with AIIRD is unclear. Because such vaccines pose the theoretical risk of augmenting autoimmune disease activity, some clinicians avoid their use in patients with AIIRD. (See 'Autoimmune disease exacerbations' below.)

Following completion of the vaccine series, we check an antibody titer to ensure that hepatitis B surface antibody seroconversion has been achieved. This is particularly important for patients receiving tumor necrosis factor (TNF)-alpha inhibitors, which have been shown to blunt the immune response to HBV vaccination [34]. For patients who fail to seroconvert, repeating the vaccine series (or using a different vaccine; eg, Heplisav) may be needed. (See "Hepatitis B virus immunization in adults", section on 'Postvaccination testing'.)

Additional detail on HBV vaccinations is provided separately. (See "Hepatitis B virus immunization in adults".)

Human papillomavirus (HPV) vaccine — The ACR suggests shared decision making with the patient regarding the benefits of HPV vaccination in patients above the age of 26 years [7]. We typically reserve vaccination for patients who have had minimal previous sexual activity and are deemed likely to have future exposure to HPV based on a shared decision-making discussion with the patient. Many patients with AIIRD are at higher risk for developing persistent HPV infections leading to higher risk of squamous intraepithelial lesions and cervical cancer. Although data are scarce, extending the age of HPV vaccine administration to age 45 years has not been demonstrated to be detrimental and can possibly reduce the risk of cervical dysplasia and cancer in some patients [6].

COVID-19 vaccines — We recommend COVID-19 vaccination in all patients with AIIRD who are receiving or planning to receive immunosuppressive therapy. Although the immunogenicity and efficacy of COVID-19 vaccines can be decreased in some patients with AIIRD receiving these medications, the potential for benefit from vaccination outweighs these uncertainties. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

Other nonlive vaccines — Other nonlive vaccines (eg, tetanus, diphtheria, pertussis [Tdap]; tetanus, diphtheria [Td]; and meningococcal vaccines) should be given per the same indications and schedules as the general adult population. (See "Standard immunizations for nonpregnant adults" and "Tetanus-diphtheria toxoid vaccination in adults" and "Human papillomavirus vaccination" and "Meningococcal vaccination in children and adults".)

Zoster vaccines — We agree with the revised recommendations from the United States ACIP that have expanded the age range for vaccination against herpes zoster with recombinant (nonlive) herpes zoster vaccine (RZV) to include all immunocompromised adults ≥19 years of age [35]. This includes patients with AIIRD who are presently receiving or planning to start immunosuppressive therapy; direct data in this specific population are very limited but the benefits likely exceed the risk.

Globally, there are two available vaccine formulations against herpes zoster: RZV (Shingrix) and the live attenuated zoster vaccine (ZVL; Zostavax); ZVL is no longer available in the United States. For all patients who warrant vaccination, we prefer the two-dose RZV series over a single dose of the ZVL vaccine due to RZV’s efficacy and safety profile [35-37]. Detailed information and a description of the differences between the two vaccines is discussed elsewhere. (See "Vaccination for the prevention of shingles (herpes zoster)".)

●RZV as preferred option – RZV is administered in two doses spaced at least four weeks apart (ideally two to six months apart). Vaccination should ideally be completed ≥2 weeks prior to the start of immunosuppression to help ensure maximal immune response. When vaccination cannot be given prior to immunosuppression, we give the vaccine as soon as feasible and ideally during a period when immunosuppression is low. Although the immune response may be diminished, vaccination is still expected to provide protective benefit for most patients. (See 'Vaccine efficacy and immunogenicity' below.)

Individuals who have received ZVL in the past should be revaccinated with RZV, regardless of when ZVL was administered, due to the suboptimal efficacy and the waning immunity of ZVL.

There are no clinical efficacy data of RZV in patients with active AIIRD. RZV has been shown to be safe in the general population [36]. The vaccine’s novel adjuvant has been associated with high reactogenicity rates in healthy adults, leading to the concern that it potentially could cause a flare of some underlying autoimmune diseases. However, most observational evidence suggests that there is not a meaningfully increased risk of flare with RZV [38,39]. As an example, in an analysis of approximately 80,000 individuals with AIIRD who received at least one dose of RZV, the risk of flare (hospitalization, ED visit, or glucocorticoid therapy) was similar in the period following vaccination compared with a six-week control period [39]. Another study suggested that the risk of flare after RZV was associated with glucocorticoid use at the time of vaccination (a likely surrogate for unstable disease/high disease activity) [40]. These studies did not evaluate immunogenicity or effectiveness of RZV.

●ZVL as less preferred alternative – In settings where RZV is not available, ZVL can be an alternative option for the vaccination of patients with AIIRD who are planning to start immunosuppression soon. ZVL is given as a one-time dose and should ideally be administered at least one month prior to the initiation of immunosuppressive agents to avoid the theoretical risk of disseminated zoster due to vaccine strain [41]. ZVL is contraindicated in patients receiving some immunosuppressive agents due to this theoretical risk, although is likely safe in those on low-dose immunosuppression who have primary immunity (ie, prior exposure) [42]. Low dose immunosuppressive regimens include prednisone at doses <20 mg/day (or equivalents), methotrexate doses ≤0.4 mg/kg/week, azathioprine doses ≤3 mg/kg/day, or 6-mercaptopurine doses ≤1.5 mg/kg/day [43], hydroxychloroquine, leflunomide, minocycline, and sulfasalazine, used alone or in combination with low-dose methotrexate [7]. ZVL has been shown to be safe to give to those using TNF inhibitors alone or in combination with methotrexate and/or prednisone (<10mg/day) [42].

There is no clear consensus on when the live zoster vaccine can be given following receipt of moderately to highly immunosuppressive agents. In general, it is reasonable to wait for at least one month (depending on the half-life of the immunosuppressive medication) or one dosing interval following the last receipt of the agent before giving the vaccine and then defer any additional immunosuppressive therapy for at least one month thereafter [44,45]. (See 'Live vaccines' below.)

Immunity induced by ZVL has been shown to decrease within five to ten years of vaccination. Thus, those who receive ZVL should be revaccinated with RZV once it becomes available.

Additional detail on the vaccination of the prevention of herpes zoster is provided separately. (See "Vaccination for the prevention of shingles (herpes zoster)".)

Live vaccines — Most live attenuated vaccines can be given safely up to ≥2 weeks prior to the start of immunosuppression. However, we often extend this window to ≥4 weeks for patients who will be receiving more potent immunosuppressive medications to avoid the risk of disseminated disease with live vaccines. After starting immunosuppressive medications, live vaccines should generally be avoided or deferred until the immune system is more robust.

Live attenuated vaccines that are commonly used in the United States include the measles, mumps, and rubella (MMR) and varicella vaccine.

●Measles, mumps, and rubella vaccination – For patients with AIIRD who may have MMR exposure due to work, travel, or community exposure and who were born between 1957 and 1980 (those born before 1957 are likely to have been exposed to wild-type viruses) and not known to have received two doses of vaccine, it is reasonable to check a measles virus IgG level prior to immunosuppression. Those who are nonimmune should be vaccinated if the start of immunosuppression can be reasonably deferred for four weeks following MMR vaccine receipt [41].

●Varicella vaccination – For patients with AIIRD without previous history of varicella and who are not yet immunosuppressed, we administer the two-dose single-antigen live varicella vaccine series four to eight weeks apart. Vaccine series should be completed ≥4 weeks prior to the onset of immunosuppression. Live varicella vaccine is contraindicated in patients who are already immunosuppressed. In patients with AIIRD who are already immunosuppressed and have no documented history of varicella, administration of recombinant nonlive zoster vaccine (RZV) is a reasonable option. Post exposure prophylaxis may be indicated if the patient is exposed to varicella. This is discussed in detail elsewhere. (See "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'Approach to post-exposure prophylaxis'.)

●Yellow fever vaccine – Patients who live in regions of the world where yellow fever is endemic (figure 1 and figure 2) should ideally be vaccinated several weeks prior to the start of immunosuppression. Following the start of immunosuppression, receipt of the vaccine is generally contraindicated due to the potential for developing yellow fever vaccine-associated viscerotropic disease [44,46-50]. However, in selected circumstances (eg, active yellow fever outbreaks), the benefits of vaccination may outweigh the risks if immunosuppressive therapy can be temporarily discontinued or substantially lessened (ideally for ≥1 month before and after vaccination) [51-54]. These decisions are typically made on a case-by-case basis. Recommendations for immunocompromised patients planning to travel to regions where yellow fever is endemic are discussed separately. (See "Travel advice for immunocompromised hosts", section on 'Yellow fever'.)

Other live attenuated vaccines include the influenza nasal spray, rotavirus, oral typhoid, and some formulations of the Japanese encephalitis vaccine. For most adults living in developed regions, these are not indicated apart from in selected circumstances (eg, travel). For some, alternative nonlive formulations are available (eg, influenza vaccines and typhoid vaccines).

Special circumstances

Concurrent asplenia or hyposplenism — Splenic function can be impaired in a subset of patients with autoimmune disorders, such as systemic lupus erythematosus or rheumatoid arthritis. Patients with AIIRD who have concurrent impaired splenic function may require vaccinations (eg, Haemophilus influenzae, pneumococcal and meningococcal vaccines) in addition to what is mentioned above. Detailed discussion on identifying patients with impaired splenic function and their vaccination needs is provided separately. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations' and "Clinical features, evaluation, and management of fever in patients with impaired splenic function", section on 'Identifying patients at risk'.)

Travel — Patients with AIIRD who are planning to travel overseas should be evaluated by a travel medicine specialist familiar with the patient's condition and immunosuppressive or immunomodulatory medications. Specific vaccination needs and other advice will vary with the intended destinations. However, live vaccines (eg, oral polio vaccine, yellow fever vaccine, certain formulations of the Japanese encephalitis vaccine) are contraindicated for most patients with AIIRD receiving immunosuppressive medications. Some may wish to modify their travel plans as to avoid endemic regions, especially for yellow fever [55,56]. (See "Travel advice for immunocompromised hosts".)

VACCINE EFFICACY AND IMMUNOGENICITY — For most patients with AIIRD using conventional synthetic disease-modifying antirheumatic drugs (DMARDs), most biologics, and glucocorticoids, vaccinations are expected to confer adequate protection, although the immune response to some vaccines may be blunted [57-69]. The degree to which the immune response may be altered by these medications varies based on the specific immunomodulatory regimen and vaccines used (table 1 and table 2). In general, rituximab is associated with the greatest decline in immune response to vaccinations, followed by methotrexate and abatacept. Immune responses to vaccination among patients treated with tumor necrosis factor inhibitors (TNFis) tend to be well preserved, with the exception of the response to hepatitis B virus (HBV) vaccination.

●Anti-CD20 antibodies – Anti-CD20 antibodies such as rituximab impair the humoral immune response to pneumococcal vaccines (particularly the polysaccharide vaccine), influenza, and messenger nucleic acid (mRNA) COVID-19 vaccines [67,70-73]. Despite the decreases in immune responses seen with anti-CD20 antibody use, vaccination still likely confers some protective benefit and continues to be recommended.

Two studies have directly evaluated the effect of rituximab on the immune response to the seasonal influenza vaccine in patients with AIIRD [71,72]. In one study, antibody responses to vaccination were detected in 26 percent of rituximab-treated patients versus 68 percent of DMARD-treated patients and 47 percent of healthy controls; cell-mediated immune responses were similar across groups [72]. Similar decreases in immune responses to pneumococcal vaccination were detected in rituximab-treated patients based on subgroup analyses from two cohort studies included in a systematic review [67]. Similarly, in a prospective study of 404 patients with AIIRD who received two doses of an mRNA COVID-19 vaccine, those on rituximab therapy were less likely to develop an antibody response compared with patients on other immunosuppressants (eg, glucocorticoid monotherapy, TNFi) [73].

●Methotrexate – Methotrexate appears to attenuate the immune response to vaccination in patients with AIIRD. In a systematic review of nine cohort studies, methotrexate was associated with lower seroprotection rates against pneumococcus (RR 0.42, 95% CI 0.28-0.63) and seasonal influenza (H1N1; risk ratio [RR] 0.88, 95% CI 0.69-1.11) compared with controls [60]. Despite lower seroprotection rates for pneumococcus with methotrexate use, observational data suggest that pneumococcal vaccination is effective for these patients [74]. In a retrospective cohort study evaluating 152 patients with rheumatoid arthritis (RA) treated with methotrexate, the relative risk of pneumonia among patients who had not received pneumococcal vaccinations was 9.7 (3.1 to 38.7, z statistic 3.825) when compared with vaccinated patients [74]. In a larger cohort study evaluating 497 patients with RA or spondyloarthritis treated with varied immunomodulatory regimens, receipt of the 7-valent pneumococcal conjugative vaccine was associated with 45 percent reduction in serious pneumococcal infections when compared with lack of vaccination [75]. Methotrexate also appears to attenuate humoral immunity to COVID-19. This is discussed in detail elsewhere. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

●Abatacept – Limited data suggest that there is a modest decline in immune response to seasonal influenza and pneumococcal vaccinations in rheumatoid arthritis patients treated with abatacept [59,70,76,77].

●Anti-IL-6 receptor antibodies – In those receiving tocilizumab, immune responses to influenza or polysaccharide vaccines do not appear to be affected [19,20]. In a randomized trial evaluating the effect of tocilizumab on the pneumococcal polysaccharide vaccine in 91 patients with RA, the immune response to vaccination was not significantly different among patients treated with tocilizumab plus methotrexate versus methotrexate alone [19]. Similarly, no decline in immune response to seasonal influenza vaccination has been observed among patients being treated with tocilizumab [20].

●Glucocorticoids – Glucocorticoid use alone has not been associated with a decline in immune response to influenza vaccination, but the immune response to the polysaccharide pneumococcal vaccine may be reduced among patients receiving ≥20 mg of prednisone per day [57].

●Janus kinase inhibitors – Responses to 13-valent pneumococcal vaccine (PCV13) have been specifically evaluated in those using Janus kinase inhibitors; while no control groups were included in these studies, most patients had satisfactory responses to vaccination. In one of these studies, however, tetanus vaccine was also studied among baricitinib users (primarily on background methotrexate), and its immunogenicity appeared less than expected [68]. In patients with RA treated with tofacitinib, diminished responses to the pneumococcal polysaccharide vaccine have been observed [78].

●Tumor-necrosis-factor inhibitors (TNFi) – TNFi appear to attenuate immune responses to some vaccines, in particular the hepatitis B vaccine. In a systematic review of nine cohort studies analyzing the effects of TNFi use on influenza and pneumococcal vaccination in adults with rheumatoid arthritis, quantitative rises in vaccine-induced humoral responses were often mildly diminished. The seroprotection rates against pneumococcus and seasonal influenza (H1N1) viruses were similar with TNFi use compared with controls [60]. The effect of TNFi on HBV vaccine response has been better studied in patients with inflammatory bowel disease [34] but this diminished effect is likely operative in patients with AIIRD as well.

Immune responses to vaccines other than the COVID-19 mRNA, influenza, and pneumococcal vaccines have not been well studied in patients with AIIRD but are generally thought to provide adequate immune responses [14,19,73,79-81].

SAFETY CONCERNS

Live vaccines

Use in immunocompromised patients — Live attenuated vaccines are generally contraindicated for immunocompromised patients but can be given prior to the start of immunosuppression and in other selected circumstances. (See 'Timing of vaccination' above and 'Live vaccines' above.)

Vaccination of close contacts — The attenuated virus strains used in some live vaccines can be transmitted to the close contacts of vaccinated individuals. However, the risk of transmission is very low and the benefits of vaccinating close contacts of patients with AIIRD greatly outweigh the risks of avoiding vaccination.

When possible, we advise that close contacts of patients with AIIRD receive any needed live-virus vaccines prior to the start of immunosuppression. Following the start of immunosuppression, we continue to advise that close contacts of patients with AIIRD receive all needed vaccines but to select nonlive formulations when possible. When live-virus vaccines are needed for (or have been given to) the close contacts of immunocompromised patients, we advise additional precautions for those vaccines that have been associated with transmission of virus to others [41].

●Varicella and herpes zoster vaccination – Vaccinations against varicella-zoster virus (VZV) are available for the prevention of varicella (chickenpox) and herpes zoster. For the prevention of herpes zoster, the recombinant VZV vaccine is preferred over the live formulation for the close contacts of immunocompromised patients, although the live zoster vaccine (ZVL) is not contraindicated.

For the prevention of varicella (ie, "chicken pox"), the only available vaccine is a live-virus vaccine. Transmission of VZV following receipt of this vaccine (or the live formulation of the zoster vaccine) is believed to occur almost exclusively from individuals who develop skin lesions following vaccination. Thus, immunocompromised patients whose close contacts have received a live VZV vaccine should contact their health care providers and avoid close contact with the vaccinated individual if that individual develops skin lesions. In the absence of skin lesions, no particular precautions are recommended. (See "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Contacts of immunocompromised hosts'.)

●Influenza vaccination – Vaccination with the live attenuated influenza vaccine (LAIV) is generally contraindicated for close contacts of severely immunocompromised patients because alternate vaccine formulations are available [24]. While severely immunocompromised patients are advised to avoid close contact with individuals who received the LAIV for seven days following LAIV receipt, transmission of influenza from the LAIV has not been reported among patients with AIIRD. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines", section on 'United States'.)

●Rotavirus vaccination – Because rotavirus can be shed in the stool for several weeks following vaccination, we advise immunocompromised patients to practice careful hand hygiene and avoid changing diapers of vaccinated infants for at least four weeks following vaccination. (See "Rotavirus vaccines for infants", section on 'Shedding and transmission of vaccine virus'.)

●Poliovirus vaccination – The nonlive poliovirus is the preferred form for all persons in developed countries, including the close contacts of immunocompromised patients. The oral formulation is live, typically used in developing regions of the world, and contraindicated for the close contacts of immunocompromised patients. (See "Poliovirus vaccination".)

The vaccine-strain pathogens used in most other live vaccines (eg, oral typhoid vaccine; yellow fever; measles, mumps, and rubella) are generally not considered transmissible (apart from rare transmission via breast milk for the last two viruses) [41]. No particular precautions for immunocompromised persons whose close contacts have been vaccinated with these vaccines have been recommended [41].

Autoimmune disease exacerbations — There is a theoretical concern that the immune response to vaccination may induce autoimmune disease exacerbations. However, limited available evidence suggests that administering vaccines does not augment disease activity among patients with AIIRD [38,39,42,82-87]. As an example, in a cohort study of 48 patients with dermatomyositis/polymyositis, no change in disease activity was detected following influenza vaccination either by patients or their treating physicians [84]. Serious adverse events and seroconversion rates were similar when comparing dermatomyositis/polymyositis patients with healthy controls.

In another study evaluating the effects of influenza vaccination on 36 patients with Sjögren's syndrome, there was no significant change in disease course in the year following vaccination when compared with the prior year; however, vaccination was associated with an increase in mean anti-Ro/SSA and anti-La/SSB antibodies during that year. No other changes in autoantibodies were detected [83].

Among patients with systemic lupus erythematosus, no vaccine-related exacerbations were observed in a study evaluating the quadrivalent human papillomavirus vaccine and the hepatitis B virus vaccine [82,85].

Because the theoretical concern for inducing an autoimmune disease exacerbation may be higher when using high-dose vaccines or vaccines with novel adjuvants (eg, high-dose influenza vaccine, the recombinant zoster vaccine, certain formulations of the hepatitis B vaccine [Heplisav-B]), some experts prefer to avoid such vaccines when alternate formulations are available. Whether this approach is beneficial or comes at the cost of diminished immune response is not clear.

POSTEXPOSURE PROPHYLAXIS — Postexposure prophylaxis (PEP) may be warranted for selected immunocompromised patients who have been exposed to certain pathogens, including varicella-zoster virus (VZV), influenza virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, hepatitis B virus, measles virus, meningococcus, rabies virus, and tetanus. Although the decision to use PEP is usually individualized based on the type of exposure, timing of the exposure, and degree of immunosuppression, it is often prudent to provide PEP for patients who have not been vaccinated against the pathogen to which they were exposed and/or for those who are severely immunocompromised.

Specific PEP regimens vary based on the pathogen and may include antimicrobial prophylaxis, vaccination, and/or passive immunization (ie, generic or pathogen-specific immune globulin). For immunocompromised patients with AIIRD, live vaccines recommended in some PEP regimens may need to be replaced or supplemented with immunoglobulin administration. As an example, the standard PEP regimen for varicella exposure includes vaccination with the live varicella vaccine. Because use of the live varicella vaccine is contraindicated for most immunosuppressed patients, VZV immune globulin (VariZIG) and/or acyclovir prophylaxis should be given in its place.

Specific PEP indications and recommendations are discussed separately for each pathogen:

●(See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

●(See "Post-exposure prophylaxis against varicella-zoster virus infection".)

●(See "Management of nonoccupational exposures to HIV and hepatitis B and C in adults", section on 'Exposure to hepatitis B virus'.)

●(See "Measles, mumps, and rubella immunization in adults", section on 'Post-exposure prophylaxis'.)

●(See "Treatment and prevention of meningococcal infection", section on 'Antimicrobial chemoprophylaxis'.)

●(See "Rabies immune globulin and vaccine", section on 'Post-exposure prophylaxis'.)

●(See "Infectious complications of puncture wounds".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunizations in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Vaccines for adults (The Basics)" and "Patient education: What you should know about vaccines (The Basics)")

●Beyond the Basics topic (see "Patient education: Vaccines for adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Importance of vaccination − Patients with autoimmune inflammatory rheumatic disease (AIIRD) are at higher risk for serious infections, which is likely due to both disease-related immune dysfunction and immunosuppressive medication use. Because of this risk, vaccination is an important part of care. (See 'Introduction' above and 'Importance of vaccination' above.)

●Approach to vaccination − As part of our initial evaluation of patients with AIIRD, we review each patient's vaccination history and ensure that patients are up to date on all routinely recommended age-/risk-appropriate vaccinations (table 1). (See 'Approach to vaccination' above.)

●Recommended vaccines − In addition to the vaccinations that are routinely recommended for the general adult population (eg, seasonal influenza vaccine, hepatitis B vaccine, COVID-19 vaccine), we ensure that any patient with AIIRD who is starting or receiving immunosuppressive therapy are vaccinated against Streptococcus pneumoniae and herpes zoster, because of the increased prevalence and associated morbidity of these infections in patients with AIIRD. (See 'Recommended vaccines' above.)

●COVID-19 − COVID-19 vaccination for patients with AIIRD is discussed separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

●Vaccine administration and timing

•For maximal protection, any needed nonlive vaccines should be given ≥2 weeks prior to the start of immunosuppressive therapy. This increases the likelihood of developing a protective immune response, particularly if the patient is to be given rituximab, which substantially impairs the humoral immune response (table 2). Vaccinating prior to immunosuppressive therapy also allows for administration of any needed live vaccines, which are generally contraindicated once immunosuppressive therapy has started. (See 'Timing of vaccination' above.)

•For patients who have not been adequately vaccinated before the start of immunosuppressive treatment, we give any necessary nonlive vaccines as soon as is feasible and ideally during periods when immunosuppression is low. For patients taking methotrexate, we hold the methotrexate for two weeks after administering the adjuvanted or high-dose influenza vaccine. For patients taking rituximab, vaccinations should be given at least three but preferably six months or longer after the last dose of rituximab.

•Live vaccines should generally be avoided for immunosuppressed patients. (See 'Timing of vaccination' above.)

●Vaccine safety − Because of the theoretical concern that vaccination may exacerbate autoimmune diseases, we typically try to vaccinate patients when disease activity is low or quiescent. (See 'Autoimmune disease exacerbations' above.)

●Vaccination of close contacts − When possible, we advise that close contacts of patients with AIIRD receive any needed live-virus vaccines prior to the start of immunosuppression. When live-virus vaccines are needed for (or have been given to) the close contacts of immunocompromised patients, we advise additional precautions for those vaccines that have been associated with transmission of virus to others. (See 'Vaccination of close contacts' above.)

●Postexposure prophylaxis − Following exposure to certain pathogens (eg, varicella-zoster virus, measles virus, SARS-CoV-2 virus, or hepatitis B virus), passive immunization (eg, administration of immunoglobulin) and/or postexposure antimicrobial prophylaxis may be warranted for profoundly immunocompromised patients and/or for those who have not been vaccinated against these pathogens. (See 'Postexposure prophylaxis' above.)