History of Suspected Association

An association between hepatitis B vaccine and acute arthralgia, arthritis, or both has been suggested since the initial use of plasma-derived hepatitis B vaccines. Joint symptoms have also been reported following receipt of recombinant hepatitis B vaccines (Cockwell et al., 1990; McMahon et al., 1992). The reported instances of arthropathy have occurred more frequently in adults than in infants and children. These data may, however, be misleading, because hepatitis B vaccines have primarily been used in high-risk adult populations in the United States (Committee on Infectious Diseases, 1985).

Evidence for Association

Biologic Plausibility

Biologic plausibility for a relation between hepatitis B vaccine and arthritis derives from the knowledge that experimental acute serum sickness is accompanied by arthritis and that hepatitis B infection is associated with arthropathies and a serum sickness-like syndrome. Experimental acute serum sickness with arthritis can be produced by one or several closely spaced injections of heterologous serum protein. With the initial exposure, the disease usually develops 1 to 2 weeks after antigen injection. On repeated exposure, the disease develops more rapidly after antigen injection. In either case the disease appears as antibody formation begins; the essence of serum sickness is the interaction between antigen and antibody in the circulation with the formation of antigen-antibody complexes in an environment of antigen excess.

Chronic serum sickness with persistent arthritis can be produced in animals if antigen is injected daily in small amounts—just sufficient to be in balance with the amount of antibody produced. This model of chronic serum sickness resembles chronic polyarteritis nodosa in humans.

During the 4-week to 6-month incubation period of hepatitis B infection, but prior to the overt clinical manifestations of hepatitis, a serum sickness-like syndrome consisting of fever, rash, urticaria, arthralgias, or acute arthritis occurs in 10-20 percent of adolescents and adults. This syndrome is accompanied by HBsAg-antibody complexes and low levels of serum complement in the synovial fluid of affected joints (Schumacher and Gall, 1974; Wands et al., 1975). In the serum sickness-like illness associated with acute hepatitis B virus infection, the arthritis, fever, and rash are generally of short duration (3-7 days). These manifestations occur during the period of antigen excess, when the quantitative relation between HBsAg and specific antibody allows the formation of immune complexes that are



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