Epidemiology of Autoimmune Reactions Induced by Vaccination

doi:10.1006/jaut.2000.0491, available online at http://www.idealibrary.com on

Journal of Autoimmunity (2001) 16, 309–318

Epidemiology of Autoimmune Reactions Induced by Vaccination Robert T. Chen, Robert Pless and Frank DeStefano Vaccine Safety and Development Activity, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA

Key words: epidemiology, autoimmune, vaccine safety, immunizations, surveillance

In order for vaccinations to ‘work’, the immune system must be stimulated. The concern that immunizations may lead to the development of autoimmune disease (AID) has been questioned. Since AID occur in the absence of immunizations, it is unlikely that immunizations are a major cause of AID. Epidemiological studies are needed, however, to assess whether immunizations may increase the risk in some susceptible individuals. This paper discusses the evidence for and against vaccination as a risk factor for AID. Evidence for immunizations leading to AID come from several sources including animal studies, single and multiple case reports, and ecologic association. However more rigorous investigation has failed to confirm most of the allegations. Unfortunately the question remains difficult to address because for most AIDs, there is limited knowledge of the etiology, background incidence and other risk factors for their development. This information is necessary, in the absence of experimental evidence derived from controlled studies, for any sort of adequate causality assessment using the limited data that are available. Several illustrative examples are discussed to highlight what is known and what remains to be explored, and the type of epidemiological evidence that would be required to better address the issues. Examples include the possible association of immunization and multiple sclerosis (and other demyelinating diseases), type 1 diabetes mellitus, Guillain-Barre Syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis. © 2001 Academic Press

Introduction

temporally associated with vaccinations [6, 7] (Table 1). Ideally, progress in our scientific understanding to immunology and autoimmunity would permit us to arrive at reasonable conclusions about whether such observations are causal or just coincidental; and if causal, what was the pathogenesis or risk factors, thereby opening the door to future prevention. This occurred for example when the etiologic basis for idiopathic thrombocytopenic purpura (ITP) after measles-mumps-rubella (MMR) vaccine was found to be associated with egg protein from the cell culture [8]. Unfortunately, the pathogenic mechanism (or mechanisms) of most AIDs [9], let alone autoimmune reactions following immunization [2], have yet to be elucidated. To further complicate things, the mechanisms are likely to vary by specific exposure and specific AID. For example, molecular mimicry (i.e., similarity between exposure antigen and self-antigen leads to crossreactive antibodies) appears to play a role in group A streptococcal-induced rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis [10]. Therefore, it is likely that each vaccine exposure and each AID outcome would need to be studied

Active immunization stimulates the immune system to produce antigen-specific humoral and cellular immunity [1]. Since autoimmune diseases (AIDs) also involves the stimulation of the immune system against certain antigens in the individual, it is not surprising that some concerns have arisen as to whether immunizations may lead to the development of AID [2]. One well known incident occurred in 1976 in the United States when recent recipients of the ‘swine influenza’ vaccine were found to have an eight-fold increased risk of developing Guillain-Barre syndrome compared to non-vaccinees [3]. More recent examples of such concerns range from whether hepatitis B immunization causes multiple sclerosis (MS) [4] to whether early infant immunization may cause type 1 diabetes mellitus [5]. The medical literature is also filled with many case reports of a wide range of autoimmune illnesses Correspondence to: Robert T. Chen, MD MA, Chief, MS-E61, Vaccine Safety and Development Activity, National Immunization Program, CDC, Atlanta, GA 30333. Fax: 404-639-8834. E-mail: [email protected] 309 0896–8411/01/030309+10 $35.00/0

© 2001 Academic Press

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Table 1. Evidence for or against a determination of causal relation (depends on the particular vaccine) [6, 7] Adverse event

Biologic plausibility

Diphtheria/tetanus toxoid CNS Demyelinating diseases Guillain-Barre Syndrome

Demonstrated Demonstrated

Brachial neuritis

Theoretical only

Case reports, case series, uncontrolled studies

Controlled studies and controlled clinical trials

For For (T) Indeterminate (DT, Td) For (T) Indeterminate (Td) No data (DT) Indeterminate

No data No data

No data Indeterminate (measles) No data (MMR) No data Indeterminate No data No data

No data

Arthritis Measles vaccine Thrombocytopenia

Theoretical

Guillain Barre Syndrome Type 1 diabetes Optic neuritis Transverse myelitis Mumps vaccine Type 1 diabetes Thrombocytopenia Polio vaccines (OPV/IPV) Guillain Barre

Demonstrated Theoretical only Demonstrated Demonstrated

Indeterminate (measles) For (MMR) Indeterminate Indeterminate Indeterminate Indeterminate

Demonstrated Demonstrated

Indeterminate Indeterminate

Indeterminate No data

Demonstrated (OPV) Theoretical (IPV) Demonstrated (OPV) Theoretical (IPV) Theoretical only

For (OPV) Indeterminate (IPV) Indeterminte (OPV) No data (IPV) No data

For (OPV) No data (IPV) No data

Demonstrated Demonstrated Demonstrated

Indeterminate Indeterminate Indeterminate

No data No data No data

Theoretical only Theoretical only Theoretical only

Indeterminate Indeterminate Indeterminate

No data Indeterminate No data

No data* No data* No data*

Indeterminate Indeterminate Indeterminate

No data Indeterminate No data

Demonstrated Demonstrated Indeterminate

For Indeterminate No data

Indeterminate No data

Transverse myelitis Thrombocytopenia (IPV) Hepatitis B vaccine Guillain Barre syndrome CNS Demyelinating diseases Arthritis Haemophilus type b Guillain Barre syndrome Thrombocytopenia Transverse myelitis DPT vaccine Guillain Barre syndrome Type 1 diabetes Thrombocytopenia Rubella vaccine Arthritis (chronic) Neuropathies Thrombocytopenic purpura

Demonstrated

No data

*For DPT and Rubella vaccines [6], the table included ‘no data’. For other vaccines [7], the committee considered all adverse events theoretically plausible, therefore all events were categorized that plausible or demonstrated.

separately. Since most AIDs occur in the absence of immunizations, it is unlikely that immunizations are a major cause of AID per se. Nevertheless, there are at least three separate reasonable hypotheses to explore between immunizations and AID: (1) Is vaccine ‘X’ associated with a new unique AID ‘Y’? (2) Can immunizations with vaccine ‘X’ increase the risk of nonunique AID ‘Y’ in some susceptible individuals? (Figure 1). If so, is there a true persistent increased risk over time? Alternatively, is the increase simply a short term ‘trigger’ effect with subsequent compensatory decrease in risk resulting in no overall elevation in risk. (3) Can vaccine ‘X’ be safely administered to patients with existing diagnosis of AID ‘Y’? In each of the above hypotheses, it is important to define exposure with vaccine ‘X’ broadly to include

any the ingredients contained in the final administered vaccine. In addition to the antigens of the vaccine-preventable disease, this may include adjuvants (e.g., aluminum), stabilizers (e.g., gelatin), bacteriostatic agents (e.g., thimerosal), as well as various residues from cell culture or other manufacturing processes. Hogenesch et al. have shown, for example, that dogs immunized with routine veterinary vaccines develop antibodies against fibronectin and other cell culture residues that are also found in the vaccines [11]. Beeler et al.’s work with MMR and ITP demonstrates that this is more than a theoretical concern in human vaccines [8]. As the silicone breast implant and AID episode taught us, however, case reports alone are inadequate in answering questions of causation with AID,

Odds ratio

Epidemiology of autoimmune vaccine reactions

2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0

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Association Temporal shift No-effect

1

2 3 4 Weeks after immunization

>4

Figure 1. Graphic representation of three possible relationships between immunization and an adverse event: (1) there is an association, the relative risk (RR) exceeds 1.0 at all time intervals after immunizations and there is a net excess of risk compared to if immunization was not admninistered; (2) immunization results in a temporal shift in earlier onset of the adverse event that would have occurred otherwise; RR>1.0 immediately after immunization but then falls to <1.0; the area under the curve above and below 1.0 are approximately equal; immunization does not result in net excess risk in the population, it only acts as one of the mutliple ‘triggers’ of the adverse event; (3) there is no effect, RR remains stable around 1.0 at all time intervals after immunization (adapted from Goodman et al. [77]).

population-based epidemiologic studies are needed [12]. Furthermore, for AID that do not have laboratory or clinical markers unique to the putative exposure in question, epidemiologic studies should come first (rather than second) relative to studies of pathogenesis. This desired sequence was followed for example with MMR and ITP, where multiple epidemiologic studies confirmed an attributable risk on the order of 1:40,000 doses [13] before subsequent research on pathogenesis was initiated. This paper discusses how epidemiological studies might be designed to gather evidence for and against each of the three main hypotheses on immunizations and AID. Several current examples are further discussed for illustration.

Sources of Epidemiologic Data on Immunizations and Autoimmune Disease Pre-licensure Vaccines are tested for safety and efficacy in the laboratory, in animals, and in phased human clinical trials before licensure. Due to their experimental design (i.e., randomization, placebo-control, blinding), inferences on the causal relationship of an adverse event with the vaccine in such trials are relatively straightforward. Unfortunately, while helpful in providing data on common acute vaccine reactions (e.g., fever, swelling), pre-licensure trials usually cannot provide data on rare reactions (e.g., occurring

<1/1,000 doses), reactions with delayed onset (e.g., ≥30 days after vaccinations), or reactions in subpopulations (e.g., premature infants normally excluded from trials) [14]. Since any association between immunizations and AID are likely to be quite rare (e.g., <1/10,000 doses), it is unlikely that data on Hypotheses 1 or 2 can be gathered during pre-licensure with any degree of certainty. Furthermore, since the prevalence of AID is relatively low in the general population, it is unlikely that many with AID would be immunized to provide data on Hypothesis 3. In fact, most pre-licensure vaccine trials purposefully include only healthy subjects.

Post-licensure Post-licensure (also called post-marketing) evaluation of safety once vaccines are administered to millions of persons is therefore critical. Historically, such monitoring has relied on passive surveillance systems like the Vaccine Adverse Event Reporting System (VAERS) [15]. The reporting of all clinically significant adverse events following immunizations to VAERS, irrespective of degree of certainty regarding actual vaccine causality, are encouraged in order for it to fulfill its goal as a ‘sentinel’ for detecting an increase in known reactions or potential new adverse events, as exemplified in the recent detection of intussusception after rotavirus vaccine [16]. Unfortunately, well-characterized diagnoses like intussusception are the exception rather than the rule in VAERS reports. Not uncommonly, the described adverse event is a mix of symptoms and signs without a definitive diagnosis (occasinally from a nonmedically trained person). Furthermore, because rare events or syndromes occur rarely, most clinicians reporting to VAERS will be describing the illness for the first time without the benefit of any standard case definition or protocol. This creates challenges in the analysis of VAERS data. To overcome these difficulties, CDC is in the process of establishing new regional Clinical Immunization Safety Assessment (CISA) centers. Selected VAERS patients that may represent a specific illness or syndrome (e.g., an AID) can then be referred to the CISA centers for standardized evaluation, including appropriate specimens for laboratory testing. These CISA centers can also assist in the new international Brighton Collaboration for developing standardized case definition for vaccine adverse events in both pre- and post-licensure settings . We forsee these CISA centers to be invaluable in helping to answer Hypothesis 1. Once a case series of specific AID after immunization has been well characterized, it is then possible to do appropriate follow-up epidemiologic or laboratory studies to assess etiologic relationship with specific immunizations. To answer Hypothesis 2, it is necessary to conduct an epidemiologic study to complete all four cells of a ‘2×2’ table of Exposure vs. AID in an unbiased manner (Table 2) [14]. This in turn permits one to calculate

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Table 2. Four cells of a data table that need to be collected in an unbiased manner to calculate if there is an epidemiologic relationship between receipt of vaccine and an adverse event (incidence rate of adverse event in vaccinated [a/(a+b)] >unvaccinated [c/(c+d)]

Vaccinated—yes Vaccinated—no

Adverse event —yes

Adverse event —no

a c

b d

whether a difference in incidence rate of AID among immunized compared to unimmunized persons exists or not. When a high proportion of the population are immunized so that the unimmunized is no longer comparable to the immunized population (e.g., most routine childhood vaccinations), two alternative analytical strategies are possible. The first is to determine, a priori, a time risk window that the AID is most biologically plausible to occur following immunizations. One then examines the data for potential increases in incidence of AID during these risk windows compared to time-periods outside the risk window. A second approach is the case series approach [17], where cases of AID are examined for the time interval between immunizations and onset of the AID. Should there be non-random clustering of these onset intervals, especially when they are consistent with biologic plausibility, this would favor a causal relationship. With either approach, plotting the relative risk over time after immunizations permits resolution of the question whether the increase risk is simply a short-term ‘trigger’ or a true long-term increase (Figure 1). A substantial sample size in the study would be needed, however, to permit answering this question with any certainty. Neither epidemiologic approach is useful however, if the onset of AID is insidious or variable in timing; in which case, causality would have to be drawn based on nonepidemiologic approaches (e.g., laboratory). Historically, ad hoc epidemiologic studies had to be organized to gather data for Table 2. Pre-established large-linked databases are now available that improve the timeliness and efficiency of such studies [17, 18]. Since 1991, CDC has organized the Vaccine Safety Datalink (VSD) project to study rare associations by combining large-linked databases prospectively under protocol from several health maintenance organizations [19]. Despite their promise, some caveats should be noted about epidemiologic studies in general. In contrast to the randomization design of pre-licensure trials, post-licensure epidemiologic studies are ‘observational’. This means that the allocation to the immunized and unimmunized populations are no longer random; substantial analytic rigor is necessary therefore, to ensure adequate control for bias and confounding [14], which may not always be possible [20]. The ‘case series’ approach developed by Farrington is uniquely suited to control for confounding as each

individual serves as their own control [17]. As noted earlier, if the timing of the onset of the AID of interest is insidious, variable, or substantially delayed after immunization, epidemiologic studies may not be sensitive enough to detect an association. Finally, because childhood immunizations are usually much better documented than adult immunizations, either in paper or electronic format, it is generally much easier to conduct studies of the safety of childhood immunizations. Yet most AID have their onset during adulthood and are mostly linked with adult immunizations. Hypothesis 3 is best answered via a randomized clinical trial or a case series analysis [17]. Both approaches have been taken in examining immunization of patients with the diagnosis of multiple sclerosis (MS) following influenza [21] and hepatitis B vaccinations [29].

Lines of evidence for causality In the hierarchy of weight of scientific evidence, data from well-designed randomized clinical trials clearly outweigh that from well-controlled observational studies, which in turn, is hierarchically better than uncontrolled observational studies, case series, and then finally, case reports [6]. An adverse event can be causally attributed to a vaccine if: (a) it conforms to a specific clinical syndrome (such as anaphylaxis immediately following vaccination); (b) a laboratory result confirms the association (for example, isolation of vaccine-strain mumps vaccine virus from a patient with aseptic meningitis); or (c) a controlled clinical trial or carefully designed epidemiologic study shows greater risk of adverse events among vaccinated than control groups. Few of the adverse events reported to VAERS meet the first two criteria, however, and clinical trials are almost always too small to provide useful information on serious rare events. Therefore, epidemiologic evidence, considered in conjunction with (a) strength of association, (b) analytic bias, (c) biologic gradient/dose-response, (d) statistical significance, (e) consistency, and (f) biologic plausibility/coherence [22, 6], form the basis for assessing causality for most rare vaccine adverse events [13]. A number of AIDs have been associated with immunization over the years based almost exclusively on case reports, the weakest of scientific evidence. In 1991 and 1993, the Institute of Medicine (IOM) found either none or inadequate evidence to accept or reject a causal association in the majority of them (e.g., between arthritis and the use of pertussis, tetanus, diphtheria, measles, mumps, polio, hepatitis B, and haemophilus influenza type B vaccines). The IOM favored a causal association between chronic arthritis and rubella vaccination, based on case reports and biological plausibility. However, a recent rigorous epidemiologic study in the VSD failed to confirm a causal relationship [23]. This reaffirms the import of replication and consistency in advancing scientific knowledge.

Epidemiology of autoimmune vaccine reactions

Specific Case Studies: Immunizations and Autoimmune Diseases Immunization and multiple sclerosis (MS) Several case reports of onset or recurrence of symptoms of demyelination within a few days to a few months of vaccination have raised concerns that vaccines, particularly hepatitis B vaccine, may cause or exacerbate MS or other central nervous systerm (CNS) demyelinating disorders [24, 25, 4, 26, 27]. The reported cases, however, may simply represent coincidental temporal associations with vaccination. Current evidence does not support a causal association between hepatitis B vaccine (or any other vaccine) and onset or exacerbation of MS. MS is a disease of the central nervous system characterized by the destruction of the myelin sheath surrounding neurons. It is generally believed to be an autoimmune disease that occurs in genetically susceptible people. Unknown environmental factors are also suspected to be involved in its pathogenesis. Environmental factors, such as vaccines, could be involved in actually causing the disease, resulting in an overall excess of MS in the population, or as possible triggers for the clinical expression of MS in genetically susceptible individuals, without causing an excess in disease incidence. For patients who already have MS, there may be theoretical reasons to be concerned that the immunologic stimulation from vaccination could trigger an exacerbation [28]. This possibility has been evaluated in a recent European study involving 643 patients with relapses of MS [29]. The study used a casecrossover design in which patients served as their own controls by comparing the risk of relapse during the 2 months following vaccination with the risk during other time periods. No increased risk of relapse was found following tetanus, hepatitis B, or influenza vaccination. The relative risk of relapse was 0.71 following any vaccination and 0.67 after hepatitis B vaccination; neither relative risk was statistically significant. Additional evidence of the safety of vaccination of patients with MS comes from a randomized controlled trial of influenza vaccination [21]. That study did not find any statistically significant differences in attack rates or disease progression over 6 months between vaccine and placebo recipients, although the number of participants was limited (n=104) for detecting small differences. A few studies have been conducted to evaluate hepatitis B vaccine as a risk factor for onset of MS in previously healthy people. The first to be published, a case-control study conducted within the U.S. Nurses’ Health Study, did not find an association between hepatitis B vaccine and risk of MS [30]. The study included 192 women with MS and 645 matched controls. The relative risk associated with hepatitis B vaccination at anytime prior to onset of disease was 0.9 and the corresponding relative risk associated with vaccination within 2 years before disease onset was 0.7; neither result was statistically significant. Two other case-control studies have been conducted in

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Europe and another was perormed in the CDC VSD project, but final results from these studies have no yet been published. Two recently published studies provide evidence against an association with hepatitis B vaccine. An analysis of a U.S. pharmacy benefits management database did not find a statistically significant association between claims for hepatitis B vaccination and subsequent claims for treatment of CNS demyelinating disorders [31]. A study of the occurrence of adolescent onset cases of MS in British Columbia found no differences between time periods before (1986– 1992) and after (1992–1998) the initiation of an annual hepatitis B vaccination program of students in sixth grade (11–12 years of age) [32]. The World Health Organization [33] and the Viral Hepatitis Prevention Board [34] have reviewed the available evidence and concluded that a causal association between hepatitis B immunization and CNS demyelinating diseases has not been demonstrated and there is no need to change current immunization policies. Immunization and type 1 diabetes mellitus Type 1 diabetes results from autoimmune destruction of pancreatic
-cells. its cause is not known, although genetic and environmental factors are believed to be involved. Vaccinations are among the environmental factors that have been studied, but most studies have not found an increased risk of type 1 diabetes associated with vaccination [35, 36, 37]. Classen has proposed that diabetes risk may be related to timing of vaccination; that is, certain vaccines if given at birth may decrease the occurrence of diabetes, whereas if initial vaccination is administered after 2 months of age the occurrence of diabetes increases. The theory is based on results from experiments in laboratory animals [38], as well as comparisons of the rates of diabetes between countries with different immunization schedules [5]. The possibility that vaccination shortly after birth may protect against the development of diabetes is supported by experiments in animal models conducted by other investigators [39, 40, 37]. Data in humans, however, are lacking. The possibility that vaccination may increase the risk of type 1 diabetes has been evaluated in a few epidemiologic studies. Classen has provided the only evidence of a possible increased risk, but the nature of the evidence is strictly ecologic, involving comparisons between countries or between different time periods in the same country. Such comparisons, however, may be influenced by many factors unrelated to vaccination, such as genetic predisposition and other environmental exposures. Moreover, similar ecologic analyses conducted by other investigators have not found significant correlations between diabetes and several vaccines, including BCG, pertussis, and mumps [41, 35, 42]. None of the epidemiological studies that included control or comparison groups found an increased risk of type 1 diabetes associated with vaccination. One

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of the largest and most comprehensive was a casecontrol study conducted in Sweden in the mid-1980’s [43]. Overall, the 339 cases and 528 controls had similar vaccination histories for BCG, smallpox, pertussis, tetanus, rubella, and mumps vaccines. The only significant difference was a decreased risk of type 1 diabetes associated with measles vaccination. In a retrospective cohort study conducted in Canada, no association was found between BCG vaccine and risk of diabetes, although there was a suggestion that vaccination may have delayed the onset of diabetes [44]. A 10-year follow-up study of over 100,000 Finnish children who participated in a clinical trial of Haemophilus influenzae type b (Hib) vaccine also did not find an increased risk of diabetes associated with vaccination or with number of vaccinations received [45]. Data from the Diabetes Autoimmunity Study also provide evidence against the notion that vaccination or timing of vaccination is associated with the development of type 1 diabetes [46]. This was a prospective study of 317 children who had a first degree family member with type 1 diabetes. The children were monitored for the development of autoimmunity to pancreatic
-cells, an early precursor in the development of type 1 diabetes. No association was found between development of
-cell autoimmunity and receipt of any of a number of vaccines, including hepatitis B, Hib, polio, or diphtheria tetanus pertussis (DTP); nor was there an association with age at first vaccination with any of these vaccines. In conclusion, the weight of the epidemiologic evidence does not support an association between any vaccine and increased risk of type 1 diabetes. A similar conclusion was reached by participants at a recent workshop, who concluded that no changes in childhood immunization schedules are indicated [37].

seasons for GBS was 1.7 (95% confidence interval=1.0–2.8; P=0.04) during the 6 weeks following vaccination, indicating an excess of slightly more than one additional case of GBS per millions persons vaccinated [51]. Therefore, other than the 1976 swine influenza vaccine, no large increase in influenza vaccine-associated GBS has been observed. The estimated risk for GBS of slightly more than one additional case per million persons vaccinated is substantially less than the risk for severe influenza and influenza-related complications [52]. Although the estimated risk of GBS is extremely small, whether influenza vaccine increases the risk for recurrence of GBS among persons with a history of GBS, or if the risk of GBS varies according to the composition (viral strains) of the vaccine remains unclear.

Influenza vaccine and Guillain-Barre´ syndrome

Hepatitis B vaccine and rheumatoid arthritis (RA)

Concerns about the risk of developing Guillain-Barre´ syndrome (GBS) after influenza vaccination have been present since the association was first noticed during the 1976–1977 (swine influenza) vaccination campaign [3]. Among persons who received the A/New Jersey swine influenza vaccine, the rate of GBS exceeded the background rate by slightly less than 10 cases per million persons vaccinated. Relative risks ranged from 4.0 to 7.6 for six- or eight-week periods after vaccination [3]. Subsequent studies of GBS and influenza vaccines found low relative risks that were not statistically significant (1.4 in 1978–1979, 0.6 to 1.4 in 1979–1980 and 1980–1981, and 1.1 in 1987–1988 [47, 48, 49]. During the 1990–1991 influenza season, an elevated risk was found only among vaccinated persons 18–64 years of age (relative risk, 3.0; 95% confidence interval, 1.5 to 6.3) [50]. During the 1993–1994 season, an increased number of GBS reports after influenza vaccine were submitted to the national VAERS. The results of the epidemiologic study initiated to investigate this signal showed the overall risk for the 1992–1993 and 1993–1994

The evidence for this association has been limited to case reports or case series [58]. The largest described a cluster of firefighters and a further six patients who developed RA following vaccination [59]. Most patients shared HLA types associated with RA. The authors concluded that vaccination may trigger the development of RA in susceptible individuals. On the other hand, influenza vaccination of patients with RA has not been shown to exacerbate disease, neither in adults [60] nor children [61]. Further, recently presented data from the General Practice Research Database in the UK failed to detect an elevated risk of RA following hepatitis B vaccination [62]. The overall incidence of RA in that database was more than one per thousand, two-fold higher in females.

MMR and Thrombocytopenia MMR vaccine can, in rare instances, cause thrombocytopenia. The reported frequency of clinically apparent thrombocytopenia after MMR vaccination has ranged from 1 in 22,300 to 1 in 40,000 vaccinated children [13, 17, 53, 53a]. The clinical course of these cases was usually transient and benign [8]. The risk for thrombocytopenia during rubella or measles infection is much greater than the risk after vaccination [54]. The risk for MMR-associated thrombocytopenia may be increased for persons who have previously had immune thrombocytopenic purpura, particularly for those who had thrombocytopenic purpura after an earlier dose of MMR vaccine [7, 55, 56]. This MMRassociated risk should be weighed against that from that of the wild disease in such patients still not immune [57].

Lyme disease vaccination and arthritis After infection with B. burgdorferi, some vaccinees are more likely to develop chronic, poorly responsive Lyme arthritis associated with high levels of antibody

Epidemiology of autoimmune vaccine reactions

to the vaccine antigen OspA, in serum and synovial fluid [63]. Researchers have proposed that an autoimmune reaction might develop within the joints as a result of molecular mimicry between OspA and human leukocyte function associated antigen 1 (hLFA-1) [64]. Thus there is concern that immunization with Lyme vaccine may also lead to the development of chronic arthritis. To date, this evidence is lacking despite media attention to a number of case reports being alleged following vaccine licensure. In a pre-licensure trial of Lyme vaccine, a total of 10,936 subjects received three doses of vaccine or placebo [65]. Although myalgia, influenza-like illness, fever, arthralgia and chills were more common among vaccine recipients than placebo recipients, reports of arthritis were not significantly different between vaccine and placebo recipients. No statistically significant differences existed between vaccine and placebo groups in the incidence of adverse events more than 30 days after receiving a dose, including those with a self-reported previous history of Lyme disease [66]. Nevertheless, post licensure surveillance of Lyme vaccine is underway to more thoroughly investigate the concerns.

Hepatitis B vaccine and systemic lupus erythematosus (SLE) Concerns over exacerbation or induction of SLE by vaccination have been reported over the years. Nevertheless, the importance of disease prevention in these patients has led to a number of small studies examining both the efficacy and safety of immunization. Several papers examined the response to, and safety of influenza vaccination in patients with SLE [67]. A more recent study of three vaccines (tetanus toxoid, pneumococcal polysaccharide and haemophilus influenza type B) given concurrently to patients with SLE found that the vaccines did not alter disease activity, while eliciting protective antibodies in the majority of patients [68]. Letters in response to this paper described similarly favorable experience with pneumococcal vaccination, however at the same time describing exacerbation of SLE following hepatitis B vaccination in one patient [69]. The authors of the original paper also went on to describe a series of patients who developed SLE following vaccination [70]. Although they could not exclude coincidental association, additional studies were suggested. Consequent to several spontaneous reports in France, a case-control study of SLE and hepatitis B vaccination was conducted using the General Practice Research Database in the UK. Preliminary as yet unpublished data show nonstatistically significant 1.9-fold risk of vaccination within 12 months [71].

Hepatitis B vaccine and Graves’ disease Though not previously discussed in the literature as far as we could find, French investigators recently

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presented data, again consequent to several spontaneous case reports in France, showing a slightly elevated risk of Graves’ disease following hepatitis B vaccination [72]. Using the General Practice Research Database in the UK, they found an increased risk of 1.6 (95%CI:1.0–2.7) following past exposure to hepatitis B vaccination. Recent exposure to vaccine was not associated with an elevated risk. The overall incidence of Graves’ disease was almsot 2 per 10,000 personsyears, with a four-fold higher incidence in females.

Macrophagic Myofasciitis (MMF) and aluminum-containing vaccines During the last 5 years, French researchers have identified a new histopathologic entity detected on muscle biopsy they have name macrophagic myofasciitis (MMF) [73, 74]. In a series of patients presenting with diffuse myalgias, arthralgias and/or muscle weakness. The majority of patients had a documented history of vaccination with an aluminum-containing product, usually hepatitis B vaccine. The biopsies of patients with this disorder are found to have a sea of macrophages with ingested aluminum crystals. While the source of these crystals are most likely from the aluminum adjuvant used in vaccines, it is unclear to date to what extent they are responsible for the range of non-specific illnesses like myalgia, arthralgia, and muscle weakness that constitute MMF. All the case patients were derived from a population presenting to a neuromuscular disorders clinic and undergoing evaluation with muscle biopsy. There are, however, supporting data showing a comparable lesion after intramuscular injection of aluminum-containing vaccines in experimental animal models [75], and the cases were more likely to complain of myalgias. The hypothesis is that some recipients of hepatitis B vaccine may have difficulty clearing the aluminum adjuvant in the vaccine, possibly creating the conditions for this hypothesized autoimmune disorder. A World Health Organization expert advisory committee reviewed the evidence and suggested, as indicated earlier, that although the local lesion which characterizes MMF may be caused by im injection of aluminum-containing vaccines, important issues such as the clinical correlations between the lesion and illness, still remain to be addressed [76].

Conclusions While current understanding of the potential association between immunizations and AID is fairly limited, several developments underway offer great promise to improve our understanding. The linkage of standardization of case definitions for adverse events (Brighton Collaboration) with Clinical Immunization Safety Assessment (CISA) centers will permit identification and clarification of AID syndromes for further epidemiologic and laboratory studies. Several studies

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underway will clarify the association between hepatitis B vaccine and several AIDs. New insights on the potential role of additives (e.g., aluminium) and cell culture residues (e.g., fibronectin) in immunizations nd AID, if proven, may permit eventual continued use of immunizations while preventing any rare associated AID.

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Acknowledgements

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The authors thank Ms Annie Huang for her assistance with the references.

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