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the biologic agent is administered again, it binds to these antibodies, causing rapid
release of histamine and other mediators, resulting in anaphylaxis that can be mild
to fatal [ 7 , 13 ]. Another mechanism through which a type I hypersensitivity reaction
can occur involves the binding of the IgG isotype of ADA to neutrophils via their Fc
receptors. Upon reexposure, the biologic cross-links the surface IgG molecules
causing neutrophil activation which results in release of platelet-activating factor.
Platelet-activating factor can initiate an atypical anaphylactic response that is 10,000
times more potent than histamine [ 14 , 15 ].
Immediate type I hypersensitivity reactions are thought to play a role in injection
site reaction with release of preformed chemokines, granule-associated mediators,
membrane-derived lipids, and cytokines [ 5 ]. When an allergen interacts with an IgE
that is bound to mast cells or basophils, the allergen-IgE-mast cell complex triggers
the release of histamine, leukotrienes, prostaglandins, and platelet-activating factor
[ 16 ]. As noted previously, platelet-activating factor can initiate an atypical anaphy-
lactic response [ 14 , 15 ]. Most infusion reactions are not true IgE-mediated type I
hypersensitivity events, however [ 17 ]. The serum sickness syndrome seen in delayed
infusion reaction is due to type III hypersensitivity reactions [ 18 ]. In type III hyper-
sensitivity reactions, the biologic-ADA immune complexes are deposited in blood
vessels, skin, and joint tissue, eliciting complement activation and inflammation
leading to tissue damage [ 18 ].
Diagnosis and Management
Mild infusion reactions are often self-limiting and can be managed with supportive
care, without the need to permanently discontinue therapy [ 2 ]. Management of mild
infusion reactions includes temporary interruption of the infusion or decreasing the
infusion rate [ 2 ]. Additional doses of acetaminophen and diphenhydramine and/or
methylprednisolone can be given as well (see Table 14.1). Mild injection site reac-
tions can be managed with cooling, topical corticosteroids, rotation of injection
sites, and pain control if necessary [ 2 ]. However, it is important to keep in mind that
mild infusion or injection reactions may be the first manifestations of immunoge-
nicity against the biologic agent, with potentially worsening of hypersensitivity
symptoms with each infusion [ 2 ]. Severe infusion or injection reactions with ana-
phylaxis generally warrant immediate discontinuation of the drug [ 2 ]. Delayed infu-
sion or injection site reactions can be managed with supportive care with
antihistamine and acetaminophen (see Table 14.1). A short course of oral corticoste-
roids may be considered in more severe cases [ 18 ].
Skin allergy testing can help risk-stratify patients for recurrence of severe hyper-
sensitivity reactions. If a patient who had immediate type I hypersensitivity reaction
to a biologic agent had a negative skin test, standard infusion can be continued with
premedication [ 19 ]. If the patient tested positive on the skin test, then desensitiza-
tion or change in therapy should be considered [ 19 , 20 ]. If the patient developed
desquamation, skin blistering, or serum sickness with skin testing, avoidance of the
medication is recommended [ 19 ].
U. Wong and R.K. Cross