Evidence for Association

Biologic Plausibility

A causal relation between immunization with tetanus or diphtheria toxoid and arthritis is biologically plausible on the basis of the toxoid's potential to induce a systemic form of immune complex disease (serum sickness). However, generalized serum sickness-like reactions require excess circulating antigen, an unlikely occurrence in view of the small amount of protein contained in currently used vaccines. No studies in animals or human subjects suggest an association between tetanus or diphtheria toxoid and arthritis on the basis of any other mechanism.

The immune response to tetanus toxoid is commonly used as a model system to investigate patients suspected of having immunologic abnormalities, either deficiencies of their immune responsiveness or exaggerated, uncontrolled immune responsiveness. Thus, in many studies of diseases thought to be caused by abnormally high inflammatory responses, such as rheumatoid arthritis or systemic lupus erythematosus, the immune responses to tetanus toxoid have been studied in detail. The response to tetanus toxoid also is measured as a control in assessing the response to antigens from infectious agents known to cause disease associated with arthritis in humans (Borrelia species, group A streptococci, and Yersinia species) or in animals (mycobacteria). In patients with these infections, antigens from the infectious agents are suspected of triggering abnormally high responses to self-antigens, such as the components of joint tissue (collagen). Tetanus toxoid is used as a control because most subjects have immunity to this antigen induced by prior immunization. In the extensive literature reporting the results of those studies (Desai et al., 1989; Devey et al., 1987; Herman et al., 1971; Höyeraal and Mellbye, 1974; Yu et al., 1980), no examples of enhanced reactivity specific for tetanus toxoid have been found. Under some experimental conditions, subjects with rheumatoid arthritis had increased reactivities to all antigens to which they had been exposed (Burmester et al., 1991), but when compared with other antigens, tetanus toxoid was also a poor stimulator of synovial cell inflammation (Pope et al., 1989; Söderströn et al., 1990). One study showed that immune complexes containing tetanus toxoid were only weak activators of neutrophils (Langholz and Nielsen, 1990).

Case Reports, Case Series, and Uncontrolled Observational Studies

Jawad and Scott (1989) described a previously healthy 34-year-old woman who developed rheumatoid arthritis following immunization with tetanus toxoid. She received two doses of tetanus toxoid 1 month apart, and 1 week



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