Introduction

Infections are a major cause of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs). Factors contributing to the increased risk for infection include immune system dysfunction induced by the underlying disease, organ or mucosal injury (e.g., spleen infarcts, and skin ulcers), comorbidities, frequent hospitalizations, surgical procedures, and the use of immunosuppressive medications. Under-immunized patients with ARDs are vulnerable to serious infections, whereas inappropriate administration of vaccines in such patients can lead to serious adverse events [1–3]. Scientific societies in many countries have developed practice guidelines and/or recommendations aiming to provide guidance on the optimal use of vaccines and improve vaccination rates among patients with ARDs. The purpose of this review is to compare the existing recommendations in Europe, North America, and Australia.

Materials and methods

A Medline search was undertaken to identify immunization guidelines, recommendations, or consensus statements of National Societies for Rheumatology. Search terms included “society for rheumatology” OR “rheumatology association” OR “college of rheumatology” AND “guidelines” OR “recommendations” OR “consensus.” Of all articles retrieved, only those that included guidelines on immunization of adult patients with ARDs from Europe, North America, and Australia were included. An additional search in the references of retrieved systematic reviews was also performed.

Further search for guidelines/recommendations was conducted in the Web sites of national scientific societies, national health authorities, national committees on immunization practices (NCIP), professional organizations of rheumatologists, and organizations of rheumatologic patients. More specifically, we assessed the Web sites of the European National Societies for Rheumatology, the American College of Rheumatology, the Canadian Rheumatology Association, the Australian Rheumatology Association, the European League Against Rheumatism, and the International League Against Rheumatism. An additional search for Adult National Immunization Programs (NIPs) was performed in the Web sites of the European Center for Disease Control, the National Health Agencies of European countries, the Center for Disease Control and Prevention, the Public Health Agency of Canada, the Australian Department of Health and Ageing, and the World Health Organization. Links to Web pages of relevant scientific societies were followed.

There were no language or publication date restrictions. For articles written in languages other than English and French, electronic translators were used (http://translate.google.com/, http://www.bing.com/translator), either for primary translation or translation support.

Results

Countries with guidelines for the vaccination of patients with ARDs

We identified national recommendations on vaccination of adult patients with ARDs in 21 of the 55 countries included in our search (52 European countries, Canada, United States (US), and Australia). We also identified immunization guidelines developed by 17 National Societies for Rheumatology (Italy, Switzerland, Germany, Austria, Finland, United Kingdom, the Netherlands, Belgium, Spain, Portugal, Estonia, Czech Republic, France, Sweden, United States, Canada, and Australia) and 17 adult NCIPs (Italy, Greece, Denmark, Ireland, Slovenia, Czech Republic, Switzerland, Germany, Austria, Finland, United Kingdom, Spain, Belgium, France, United States, Canada, and Australia). The recommendations were made by working groups or panels and were based mainly on expert opinions, since clinical data are lacking.

Keeping immunization records

In eight countries (Switzerland [4], Germany [5–7], Finland [8], United Kingdom [9], Sweden [10], France [11–18], United States [19], and Canada [20, 21]), it is recommended to keep immunization record in all patients with the diagnosis of an ARD. More specifically, vaccination status should be checked during the initial workup of patients with ARDs, and catch-up vaccination for missed vaccine doses according to the general population program should be scheduled as soon as possible. Physicians should ensure that all vaccines indicated for patients with ARDs are kept up to date throughout the course of the disease.

Inactivated vaccines

A summary of recommendations for inactivated vaccines is provided in Table 1 [4–61].

Table 1 Recommendations on the administration of inactivated vaccines in Europe, North America, and Australia
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Ideal timing for administering inactivated vaccines

Inactivated vaccines should ideally be administered prior to starting immunosuppressive treatment (12 countries) [4–8, 11–34]. Waiting at least 2 weeks before the initiation of immunomodulators is advised in six countries [8, 9, 14, 15, 20–23, 25–29, 33]. Alternatively, vaccinating during treatment breaks is suggested in three recommendations [22, 29, 31], with two [21, 29] recommending vaccination not earlier than 3 months after discontinuation of immunosuppressive drugs.

With regard to inactivated vaccines, if not previously administered or if booster vaccination is required, they can be given during treatment with DMARDs and biologics (16 countries) [5–7, 10–19, 21–27, 30–33, 35–41]. However, guidelines in eight countries [4, 5, 8, 10, 12, 13, 27, 30, 42, 43] include specific recommendations for rituximab (RTX), and all strongly recommend that inactivated vaccines should be administered before initiating RTX. In six countries, a specific interval of at least 4 weeks between vaccine administration and initiation of rituximab therapy is suggested. For patients already on rituximab, vaccination should be postponed for at least 2–6 months after the last infusion (Table 2) [4, 5, 8, 13, 27, 42, 43]. Additionally, three countries’ guidelines recommend waiting 2 weeks before initiation of treatment with abatacept [5, 14, 30, 44]. Waiting 2 weeks before treatment with tocilizumab is recommended in the French guidelines [18]. Finally, vaccinating patients at a time when the disease is stable or when the dose of immunosuppressives is low is recommended in five guidelines [5, 10, 21, 22, 29].

Table 2 Existing guidelines on the ideal timing for administering inactivated vaccines to patients on rituximab
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Specific inactivated vaccines

Annual influenza vaccination is recommended in 19 countries [4–19, 21–28, 30–33, 35, 38, 40, 41, 47, 48, 50, 56–58]. In Australia, immunocompromised patients who receive influenza vaccine for the first time are recommended to receive 2 vaccine doses, at least 4 weeks apart and 1 dose annually thereafter. Additionally, in the setting of an influenza pandemic, it is advised to vaccinate immunocompromised persons with 2 doses of inactivated influenza vaccine, at least 4 weeks apart [41].

Pneumococcal vaccination is recommended in 19 countries [4–19, 21–28, 30–33, 35, 38, 40, 41, 43, 46–50, 59–62]. With regard to the type of pneumococcal vaccine, pneumococcal conjugate vaccine (PCV13) or pneumococcal polysaccharide vaccine (PPSV23), recommendations vary among different countries (Table 3) [4–11, 19, 20, 22–24, 27, 30, 36, 41, 50, 59–66]. More specifically, PCV13 is recommended in three countries, PPSV23 is recommended in seven countries, and various combinations of the two vaccines are recommended in nine countries.

Table 3 Guidelines on pneumococcal vaccination in patients with autoimmune rheumatic diseases and/or iatrogenic immunosuppression
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Patients should be vaccinated with the tetanus–diphtheria–pertussis vaccine as recommended for the general population. This is mentioned specifically in the recommendations of 13 countries [4–18, 21–24, 29–37, 41, 49, 51]; however, in other countries, the general recommendation that “no precaution is needed as regards administering inactivated vaccines to immunocompromised patients,” includes the Td(p) vaccine.

In the Netherlands, vaccinating patients with RA against typhoid fever vaccine is recommended [47].

Human papillomavirus (HPV) vaccination is generally recommended for patients with increased risk of persistent HPV infection and HPV-related disease, such as patients with systemic lupus erythematosus, but it may also be offered to all patients when adult catch-up vaccination is implemented in the NIP [5, 10, 11, 19, 20, 32, 36, 49]. The Australian Technical Advisory Group on Immunization (ATAGI) recommends HPV vaccine for immunocompromised adult patients regardless of age, even for men aged >26 and women aged >45 [41].

Meningococcal and Hemophilus influenza type b (Hib) vaccines are recommended for all patients with altered immune status only in Italy [53], Germany [5–7], and Austria [24], while in all other countries they are reserved for patients with asplenia or hypocomplementemia.

In twelve countries, hepatitis B virus (HBV) vaccination is not routinely recommended for patients with ARDs, but it is indicated if additional risk factors exist, especially before treatment with biologics [5, 6, 10, 12–19, 22–24, 27, 30, 33, 35, 36, 46, 51, 52, 54]. Routine vaccination of patients undergoing treatment with biologics if HBV serology markers are negative is recommended in Spain [28]. Vaccinating patients with chronic psoriatic lesions of the skin of the hands is recommended in Italy [53]. HBV vaccine is recommended in all eligible immunocompromised patients in Australia, due to the high possibility of severe disease [41].

Australian recommendations advise that the Q fever vaccine should be avoided in patients with altered immune status, as there are no data on the accuracy of skin testing or the efficacy and safety of Q fever vaccine in this population [41].

Booster doses

A special notice that the magnitude and duration of vaccine-induced immunity are often reduced in immunocompromised individuals is found in the recommendations of nine countries [5, 8, 21–24, 26, 31, 37, 40, 41, 46, 55]. In order to determine the need for booster doses, it might be useful to measure post-vaccination antibody titers. In the United States [31] and the United Kingdom [26, 46], all vaccine doses received while the patient is receiving immunosuppressive therapy or during the 2 weeks preceding therapy are not considered valid, and patients should be revaccinated with all vaccines that are still indicated at least 3 months after discontinuation of therapy.

Live vaccines

Vaccination with live vaccines is generally contraindicated during treatment with immunosuppressive agents, including high-dose steroids, DMARDs, and/or biologics.

Live vaccines and steroids

The steroid dose that is considered to be sufficiently immunosuppressive to cause concerns for the safety of live vaccines is different among national guidelines (Table 4) [4, 5, 8, 9, 15, 20–23, 26, 29, 31, 37, 39, 40, 47, 61]. In most countries, live vaccines are contraindicated when a dose of >20 mg of prednisone or equivalent per day is administered systematically for >2 weeks [4, 5, 8, 20–23, 29, 31, 37]. In other national guidelines, the steroid dose that should restrain the use of live vaccines is >10 mg prednisone or equivalent per day administered systematically for >2 weeks [9, 15, 26, 39, 47]. An equivalent prednisone dose of >40 mg per day for >1 week is a contraindication for live vaccines in the United Kingdom [9]. In Australia, live-attenuated vaccines are contraindicated for adults receiving daily doses of oral corticosteroids in excess of 60 mg of prednisone (or equivalent) for more than 1 week [40]. If vaccination with a live vaccine is necessary, it should be postponed until at least two to twelve weeks after steroid treatment has been discontinued.

Table 4 Recommendations on the administration of live vaccines in patients receiving corticosteroids
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Live vaccines and DMARDs or/and biologics

The vaccination with live vaccines should be deferred for at least 3–6 months after discontinuation of DMARDs and 3–12 months after discontinuation of biologics. Treatment can be (re)-started 2–6 weeks after vaccination with a live vaccine. All information regarding specific drugs and variations among countries is included in Table 5 [4, 5, 8–10, 12–18, 20, 21, 24, 26, 29–31, 33, 35, 36, 39–41, 45, 47, 50, 51, 69, 70]. In Switzerland [4], Germany [5], the Netherlands [47], Czech Republic [71], France [11], and Australia [50], treatment with antimalarials and/or sulfasalazine is not a limitation for the administration of live vaccines. In Finland, a drug washout before vaccination with live vaccines is recommended for biologics but not for DMARDs. Moreover, the second dose of measles, mumps, and rubella vaccine, as well as varicella vaccine can be administered without previous biologic washout period [8].

Table 5 Recommendations for the administration of live vaccines in patients with ARDs receiving DMARDs and/or biologics
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Specific live vaccines

Varicella zoster virus (VZV) vaccine, indicated for use in adults over 60 years to prevent shingles, is recommended for selected patients with ARDs. The Advisory Committee on Immunization Practices (ACIP) [72], the ACR [19], the Canadian Immunization Guide [20, 21], and the Canadian Rheumatology Association [33] suggests that it may be administered to patients treated with short-term (<14 days) or low-to-moderate dose (<20 mg/day) corticosteroid therapy, leflunomide, sulfasalazine, low-dose methotrexate (≤0.4 mg/kg/week), or azathioprine (≤3.0 mg/kg/day) but it is not recommended for patients on biologics. According to the ATAGI [41], it may be appropriate to vaccinate with the zoster vaccine all patients anticipating immunosuppressive therapy, at least 1 month prior to the onset of immunosuppression; vaccination while receiving immunosuppressive therapy is not recommended.

Passive immunization

Intramuscular immune serum globulin can prevent or reduce the severity of disease if administered to susceptible individuals, such as patients with ARDs, within 6 days after exposure [73]. Passive immunization with the appropriate preparation of immunoglobulin (varicella zoster immunoglobulin or human normal immunoglobulin) after significant exposure to chickenpox, shingles, or measles should be considered in non-immune patients receiving immunosuppressive agents (Germany [6, 7], Austria [24, 51], United Kingdom [9, 74], Sweden [10], United States [75], Canada [76], Australia [41, 77]). Rituximab-treated patients with large and/or contaminated wounds should be given passive immunization with tetanus immunoglobulin (Sweden [10]). Human rabies immune globulin should be administered in previously unvaccinated immunocompromised patients with bites, scratches, or licks on broken skin/mucous membrane in a rabies-endemic area (Australia [41]). No specific recommendations regarding passive immunization of immunocompromized patients were identified in other countries.

Travelers with ARDs

Basic principles for administering travel-related vaccines to patients on immunosuppressive drugs are given in nine countries (Table 6) [5–8, 10, 12–18, 26, 27, 40, 41, 47, 78–80]. Patients should be vaccinated according to general recommendations, with the exception of live-attenuated vaccines that should be avoided. Travelers with severe immunosuppression should be strongly discouraged from traveling in yellow fever endemic areas. For patients who still wish travel to countries where yellow fever vaccination is mandatory, the general recommendations regarding treatment discontinuation before live vaccines and/or the time interval before treatment (re)initiation apply.

Table 6 Recommendations for vaccination of patients with ARDs traveling to endemic areas
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Household contacts of patients with ARDs

Recommendations regarding vaccination of household contacts are given in ten countries (Table 7) [5–7, 9, 18, 20–22, 24, 26, 31, 40, 41, 53, 55].

Table 7 Gudelines for the vaccination of household contacts of patients with ARDs receiving immunosuppressive agents
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Discussion

We have identified agreements and differences regarding vaccination of adult patients with ARDs among national recommendations in Europe, North America, and Australia.

Points of agreement

Existing guidelines universally recommend vaccination for influenza and pneumococcal disease in patients with ARDs, based on the increased risk of pulmonary infections and evidence supporting efficacy and safety of these vaccines in ARD populations [81, 82]. Patients with asplenia or hypocomplementemia should additionally receive vaccination against H. influenza and N. meningitidis to provide optimal protection against encapsulated bacteria to which these individuals are highly susceptible [82, 83].Td boosters should be administered as scheduled for the general population regardless of immune status, since Td is not infectious and in patients with ARDs, it has demonstrated efficacy comparable to healthy controls [84]. HBV vaccination is efficacious in most patients with ARDs but the risk of hepatitis B in these patients is unknown [81]. Existing recommendations include HBV screening of patients with ARDs, in whom immunosuppression is being considered, and vaccination of non-immune patients at high risk for HBV infection [85, 86].

Regarding the ideal vaccination timing, there is consensus that administering inactivated vaccines prior to immunosuppressive therapy maximizes the immune response. Evidence linked to this recommendation is studies that showed an attenuated response to vaccination in recipients treated with immunosuppressive agents [87]. If, however, waiting to start treatment is not feasible, a general rule is that inactivated vaccines can be given safely to patients treated with immunomodulators. An important exception is treatment with rituximab. Several studies on the efficacy and safety of immunization in patients treated with B cell-depleting agents (i.e., rituximab) showed reduced response to influenza [88] and pneumococcal [89] vaccines; therefore, vaccines should be administered at least 4 weeks before RTX is started, or at least 6 months after therapy.

The administration of live vaccines in immunocompromised patients has been linked to substantial risk for infection due to the possibility of fatal reactivation of the infectious agent contained in the vaccine [81]. Recommendations emphasize that live vaccines should not be used during immunosuppressive treatment, including high-dose steroids, DMARDS, and biologics.

Regarding travel guidelines, it is unknown whether the risk of travel-related infections is increased in ARD patients [81]. Before traveling to an endemic area, consultation with an infectious disease specialist should be sought. No limitations for inactivated travel-related vaccines were found. On the contrary, all travel-related live vaccines should be avoided in ARD patients treated with immunosuppressive drugs. These include BCG, oral poliomyelitis, oral typhoid fever, oral cholera, and yellow fever vaccines.

Differences among guidelines

Most differences concern the safe use of live vaccines in patients with ARDs, as there are no data regarding the required free of immunosuppressive therapy time for safe administration of these vaccines. A noteworthy exception is the Finish Society for Rheumatology recommendation that DMARD discontinuation is not necessary before vaccination with live vaccines. Moreover, the steroid dose that interferes with immune response and causes concerns for vaccine safety is different among guidelines as definitive studies are lacking.

Another notable discrepancy concerns the vaccine for varicella zoster virus (VZV). ARDs and their therapies may put patients at increased risk for shingles, but since this is a live-attenuated vaccine, caution is advised. NCIPs and rheumatology associations in Europe and Australia recommend avoiding VZV vaccination in patients receiving any immunosuppressive treatment since no studies have been performed in patients with ARDs. The European League Against Rheumatism (EULAR) task force on vaccination also recommends avoiding the use of any live-attenuated vaccine in immunosuppressed patients with ARDs; nevertheless, EULAR recommendations, recognizing the high burden of VZV in these patients, suggest that VZV vaccination may be an exception in selected, mildly immunosuppressed patients [41, 81]. On the contrary, the ACR, ACIP, and the Canadian Rheumatology Association suggest that VZV vaccination in patients with ARDs should only be restricted during treatment with biologics and high-dose steroids. However, it should be emphasized that these recommendations are based on expert opinion [19–21, 33, 72]. Differences regarding the type of pneumococcal vaccine that patients with ARDs should receive were also found. These may be attributed to the delayed inclusion (2011) of the conjugate vaccine in the NIPs after receiving approval for the adult indication in the Europe [90] and the United States [91]. Moreover, data on PCV13 vaccination in patients with ARDs are still lacking [92].

Other differences include expanding vaccination coverage against Haemophilus influenza and N. meningitidis to all patients with ARDs (Germany, Austria, and Italy), and against HBV to all immunocompromised patients (Australia), all patients undergoing treatment with biologics (Spain) or patients with chronic psoriasis involving the skin of the hands (Italy). These differences are due to the lack of evidence on the safety and effectiveness of the relevant vaccines in patients with ARDs.

Our study has some limitations. Possible omission of recommendations cited elsewhere than Medline and National Health and Vaccination/National Rheumatology Societies official Web sites, or cited in Web pages, which require membership, or not retrieved due to deficient electronic translation of a Web page, must be acknowledged. Many NIPs and National Committees on Immunization make general recommendations for immunocompromised patients and do not give specific advice on patients with ARDs. Every effort was made to include solely recommendations for patients with ARDs and/or patients receiving steroids, DMARDs, and biologics.

In conclusion, vaccination national guidelines and/or recommendations in patients with ARDs have points of agreement but also several discrepancies. As evidence-based data are still limited, most recommendations are based on experts’ opinion. Studies examining the effectiveness and safety of specific vaccines in patients with ARDs need to be conducted, as proper immunization is fundamental in this specific patient population. Future challenges include the harmonization of the existing guidelines and their implementation by integration into local care processes.