IMID patients, in particular those under immunotherapy, are at an increased risk for complications of some vaccine-preventable infections (). Hence, for this patient population the benefits of implementing a suitable vaccination protocol in daily clinical practice are potentially even greater than for the general population. When vaccination coverage in the population is high, herd immunity grants a certain extent of protection to non-vaccinated individuals by reducing the prevalence of the disease. The infection risk in non-vaccinated individuals is not negligible; however, a recent study demonstrated that non-vaccinated children in the USA have a 35 times increased risk of contracting measles in comparison with vaccinated children [33
]. These findings stress the important task that clinicians have to advocate vaccination, especially for patients with increased risk of infectious complications.
Recommendations for vaccination of IMID patients
However, vaccination coverage of IMID patients is surprisingly low. In RA patients, vaccination coverage rates rarely exceed those in the general population [34
]. A survey in IBD patients revealed that only 45% of respondents recalled tetanus immunization within the past 10 years, only 28% reported yearly influenza vaccination, 9% reported having received pneumococcal vaccine and only approximately half the patients at risk were vaccinated against hepatitis B [35
Possible explanations for under-vaccination of IMID patients are unawareness of the increased infection risk, and concerns about safety and efficacy of vaccination in this patient group. Factors to consider when evaluating the safety of a vaccine in IMID patients are the hypothetical risk for a flare of the IMID after vaccination and, for live vaccines, the risk of vaccine-induced infections. The reluctance of clinicians to vaccinate IMID patients may be due to fear of vaccine-induced disease flares, and to the concern whether the lower immune response observed in IMID patients treated with immunomodulatory drugs still provides sufficient protection against the disease.
Types of vaccines
Available vaccines can be categorized into inactivated or inert vaccines vs live vaccines (). Live vaccines have the advantage of providing good protection rates, as they reproduce the natural infection, with active virus replication and exposure of the vaccine to a large number of immunogenic epitopes, thereby inducing a fast antibody response and good immunological memory. Disadvantages of live vaccines include the risk for transmission and persistence of the virus, risk for back-mutation to a more virulent virus and more stringent transport and storage requirements.
Inactivated vaccines have indisputable advantages in terms of safety since they do not contain infectious agents and are easier to transport and store. However, they provide a less close imitation of natural infection (no replication, no intracellular penetration and limited number of epitopes in recombinant vaccines), and may therefore need adjuvants and repeated exposure (boosters) in order to induce an adequately protective immune response.
Vaccine safety: impact on disease activity in IMID patients
Part of clinicians’ concerns about the safety of vaccination in IMID originated from a number of case reports suggesting an impact of vaccination on IMID disease onset or course [36
]. These publications led to a belief among some clinicians that vaccination might trigger a flare of the underlying IMID. Despite substantial research, a direct and causal relationship between vaccination and flare of disease has not been detected [36
]. Live vaccines are generally contraindicated in immunocompromized individuals, so reports dealing with their effect on disease activity are rare. In a relatively small retrospective study, measles–mumps–rubella (MMR) booster vaccination in children with juvenile idiopathic arthritis (JIA) appeared safe, as vaccination did not induce infection, nor did it significantly increase disease activity or medication use [39
For non-live vaccines, substantial literature data (summarized in ) supports the conclusion that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Most of this evidence comes from medium-sized controlled trials in which disease activity was mostly assessed by general clinical symptoms and pain scores. Some studies additionally used standardized clinical disease activity scores such as DAS or SLEDAI. Laboratory measurements minimally included sedimentation rate or CRP in some studies supplemented with more specialized disease activity markers. This evidence indicates that inactivated vaccines for hepatitis B, influenza and pneumococcal disease can be administered safely to IMID patients (evidence Level B, except for hepatitis B vaccination in SLE: Level C, influenza vaccination in RA: Level A).
Effect of vaccination (non-live vaccines) on IMID disease activity
Vaccine safety: induction of IMID
A particular concern that certainly contributes to the reticence of clinicians to actively promote vaccination in IMID patients are the reports of a temporal association between vaccination and new onset of autoimmune disease [41
], suggesting that vaccination acts as a potential trigger of autoimmune disease.
In this context, it is important to distinguish autoimmunity, which is an abnormal immune response directed against host antigens, involving production of autoantibodies or the presence of autoreactive T cells, without clear symptoms of disease nor evolution towards an IMID, from autoimmune disease itself [41
]. Autoimmunity results from complex interactions between genetic traits and environmental factors and can be triggered by a number of stimuli, including local inflammation as well as viral, bacterial and parasitic infections [42
]. Vaccination could trigger autoimmunity through the same mechanisms as natural infection.
In 1976, a number of cases of Guillain–Barré syndrome occurred after swine flu vaccination [43
]. This phenomenon was not repeated in subsequent influenza virus campaigns [44
]. The risk for Guillain–Barré syndrome after influenza vaccination is now estimated to be lower than the risk resulting from severe influenza, and is not to be considered as an argument against influenza vaccination [45
]. In the 1990s, extensive epidemiological research in France, where 25 million people (40% of the population) received hepatitis B vaccination in this period, did not observe an association between hepatitis B vaccination and multiple sclerosis [46
] as suggested by earlier case reports [38
The incidence of idiopathic thrombocytopenia following MMR vaccination is 1/30 000 in vaccinated children. However, the risk of developing thrombocytopenia after natural measles and rubella infection amounts to 1/3000 and 1/6000, respectively [48
Incidence of joint symptoms after MMR vaccination is slightly increased, but still lower than that after natural rubella infection [49
]. A transient increase in RF levels or arthritis symptoms has been reported after immunization against a number of agents (MMR, tetanus, paratyphoid, mumps, diphtheria, polio, smallpox and hepatitis B), but the incidence of RA among the vaccinated population was similar to non-vaccinated controls [50
]. After extensive review of available studies, French pharmacovigilance [51
] and the WHO advisory committee on Vaccine Safety [52
] concluded that there is no convincing evidence of causal relationship between hepatitis B vaccination and a number of reported RA cases [37
In IBD, the observation that measles virus can persist in intestinal tissue [56
], in combination with the epidemiological association of in utero
] or perinatal [58
] measles infection with subsequent Crohn’s disease, led to the refractory ‘measles hypothesis’ of Crohn’s disease. The elevated risk for development of IBD in subjects vaccinated against measles in a controversial study by Thompson et al.
] was not confirmed in subsequent studies [60–62
]. Available evidence does not support an association between measles-containing vaccines and risk of IBD [63
]. A potential association between Bacille Calmette–Guérin (BCG) vaccination and Crohn’s disease still needs further investigation [64
Extremely rare cases of psoriasis or psoriasis-like esions have been reported following BCG vaccination [66
], and a case–control study reported rubella vaccination as a risk factor for PsA [67
]. However, these data must also be seen in relationship with the well-known Köbner phenomenon that occurs in psoriasis, i.e. the development of new plaques at sites of skin injury. In this respect, the vaccination act itself could trigger exacerbation of psoriatic skin lesions [67
Vaccine safety: infection with live vaccines
The main safety issue in vaccination of IMID patients concerns the use of live vaccines: like in other groups of immunocompromized individuals, the use of live vaccines is contraindicated in IMID patients treated with immunomodulatory drugs [68
]. Immunocompromized individuals are not capable to mount an adequate immune response towards the vaccine virus and have an increased risk of enhanced virus replication, possibly leading to persistence of the virus or even to overt vaccine-associated disease. Caution should also be exerted when vaccinating household contacts of IMID patients with live vaccines, since virus replication after vaccination is often accompanied by shedding of the virus, with possible subsequent infection of patients. Transmission of vaccine virus to household contacts increases disease protection coverage beyond vaccination coverage in the general population, but for severely immunocompromized individuals this may pose a risk of developing infectious disease with the vaccine virus. Spreading of the vaccine virus to household contacts has been described after oral poliomyelitis vaccination [69
], which is therefore contraindicated for household contacts of IMID patients [68
], and after rotavirus vaccination [70
]. MMR, varicella, zoster and BCG vaccination are not contraindicated for household contacts of IMID patients [68
Vaccine efficacy in IMID patients
Vaccine efficacy is defined as percentual risk reduction for clinically significant infection in a vaccinated group vs
a control group [71
]. Efficacy of a vaccine is preferably demonstrated through well-conducted and well-controlled field efficacy trials, evaluating different possible end points (infection, hospitalization and death) in different settings and populations. However, field efficacy data are not always available. In that case, demonstration of B-cell-generated antibodies is often used as a surrogate marker for vaccination-induced protection, because most vaccines protect against infection or disease by inducing a B-cell antibody response. In addition to seroconversion, which indicates the presence of an antibody response, the antibody titre as well as the quality of the antibody response (in terms of binding avidity and bactericidal or neutralizing activity of antibodies) are important as predictors of protection. Although antibody production accounts for the largest part of the protective response, cellular immune response is very important for immunological memory, and contributes substantially to the protection induced by some vaccines such as the influenza, varicella zoster and BCG vaccines [72
The reduced quality of the immune response in IMID patients, especially in those under immunotherapy, may thus have a negative effect on the efficacy of vaccination. Reduced seroconversion rates after vaccination in IMID patients may reduce the proportion of protected patients. Diminished quantity or quality of the antibody response may reduce the duration of protection provided by vaccination in individual patients, thus requiring shorter vaccination intervals or additional boosters.
summarizes the current evidence on antibody response after vaccination in IMID patients for different vaccines and treatment options. In a normal population, a humoral immune response to hepatitis B vaccination is expected in >90% of vaccines, whereas lower immune response rates have been described in immunocompromized patients [73
]. The percentage of RA and SLE patients producing HBsAg antibodies after hepatitis B vaccination was found to be in the normal range [74
]. Classical DMARDs do not have a negative influence on the response to hepatitis B vaccination (for RA and JIA: evidence Level B), but etanercept and the combination of etanercept and MTX significantly decrease response rates to hepatitis B vaccination (for RA, evidence Level B). The effect of the newer biologicals on the immune response after hepatitis B vaccination remains to be investigated.
Efficacy of vaccines in IMID patients
For the polysaccharide pneumococcal vaccine, vaccine response rates in RA and SLE patients were similar to those in control populations. However, a subset of patients will remain unprotected after vaccination, since a small percentage of patients responded to none or only one of the seven polysaccharide antigens [76–78
TNF-α inhibitors do not impair the response to pneumococcal vaccination, but MTX decreases the response rates to this vaccine [76
]. A recent study by Melmed et al.
] shows a normal pneumococcal vaccination response in IBD patients without immunosuppressive therapy and impaired vaccination responsiveness in patients treated with TNF blockers in combination with other immunomodulators (MTX, 6-mercaptopurine or AZA). The B-cell targeting antibody rituximab in combination with MTX significantly reduced the percentage of patients responding to pneumococcal vaccination with a 2-fold titre rise in comparison with patients treated with MTX alone [81
]. Efalizumab had no negative influence on the responsiveness towards pneumococcal vaccination in psoriasis patients [82
], whereas abatacept caused impaired responsiveness in healthy controls [83
Influenza vaccination of RA patients generates a good humoral response [84
], lower than [84
] or comparable with [85
] healthy controls. The response to influenza vaccination was not affected by the use of prednisone or DMARDs [84
]. Treatment with anti-TNF antibodies only modestly decreases the antibody response to influenza vaccination: anti-TNF treatment does not significantly decrease the proportion of IMID patients reaching a protective antibody titre after vaccination, but does lower the post-vaccination geometric mean antibody titres reached [85
]. In SLE patients without prior vaccination, the percentage of seroconversions or 4-fold titre rises after influenza vaccination was lower in comparison with controls; vaccination response was not influenced by treatment with immunosuppressive agents (AZA, HCQ, prednisone) [87
]. However, a seroconversion rate comparable with that in the control population was observed when all SLE patients, including those with prior influenza vaccination, were taken into account. This finding clearly illustrates the importance of yearly repeated influenza vaccination [87
]. Salemi et al.
] recently reported year-to-year progressive increase in immune response in RA patients treated with TNF blockers.
Mamula et al.
] observed a reduced seroconversion rate and geometric mean titre after influenza vaccination in IBD patients receiving immunotherapy (including biological therapy) compared with healthy controls, whereas vaccine response rates in patients without immunotherapy were similar to those in controls. A good seroconversion rate was observed in another study evaluating influenza vaccine in children with IBD [90
]. Some studies observed an impaired immune response after influenza vaccination in patients treated with anti-TNF agents [89
], but all studies report a significant percentage of responders in anti-TNF-treated patients [85
]. Rituximab significantly reduces seroconversion rates after influenza vaccination of RA patients [92
], and the immune responsiveness is only modestly restored after 6–10 months [93
]. The effect of abatacept and efalizumab on the responsiveness to influenza vaccination is still unknown. Although the studies described here are heterogeneous in design, evaluated parameters of vaccine responsiveness and control groups, they all conclude that a considerable proportion of IMID patients are able to respond to hepatitis B, pneumococcal and influenza vaccination, so as to warrant the administration of these vaccines to IMID patients (evidence Level B).