233consisting of 86 adults and pediatric patients receiving episodic infliximab retreat-
ment, Kugathasan et al. found that a drug-free interval as short as 20 weeks is asso-
ciated with high rates of severe systemic reactions in adults [ 9 ].
The level of antibody to infliximab (ATI) correlates with the risk of infusion
reactions, especially with acute infusion reactions [ 10 , 11 ]. In A Crohn’s Disease
Clinical Trial Evaluating Infliximab in a New Long-Term Treatment (ACCENT I)
trial, among 254 infusion sessions across 64 patients who had positive ATI, 17%
(42/254) of the infusion sessions were complicated by infusion reaction [ 12 ]. This
is in contrast to the infusion reaction rate of 8% (55/656) observed among 656 infu-
sions in 173 patients who had negative ATI [ 12 ]. Patients who were on a concomi-
tant immunomodulator were less likely to have ATI (4%), compared to those who
were on concurrent steroids (17%) and compared to those who were on neither
steroid nor immunomodulator (18%) [ 12 ].
Pathophysiology
The immune system is built to detect and eliminate foreign molecules [ 7 ]. Drugs,
having different structures than endogenous molecules, can also elicit an immune
response [ 7 ]. The likelihood that a drug is immunogenic depends largely on its
structure. Unlike small molecules that are often unrecognized by the immune sys-
tem as foreign, biologics are typically large proteins with complex structures, thus
having an increased risk of recognition by the immune system [ 7 ]. Antigen-
presenting cells (APCs), T cells, and B cells are involved in immunogenicity. APCs
process the biologic agents into peptides that get presented to the T cells via the major
histocompatibility complex (MHC) molecules. The peptide-MHC complex binds
to a specific T cell receptor, but a T cell immune response is only activated when
there is co-stimulation by the molecules on the surface of the APC. Without this
co-stimulatory signal, the T cells become anergic or undergo apoptosis. For this
reason, biologics that are identical or nearly identical to endogenous proteins are
expected to be relatively non-immunogenic [ 7 ].
B cell activation and antibody production can occur with or without T cell
involvement. Activated B cells produce immunoglobulin (Ig) M initially and, after
interaction with antigen-specific T helper cells, switch to productions of IgG or
IgE. A subgroup of these B cells matures into long-lived plasma cells. During sub-
sequent exposures to the antigen such as that from the biologic agent, these plasma
cells rapidly respond with secretion of large amounts of antibody, representing a
memory response [ 7 ]. Without interaction with the antigen-specific T helper cells,
B cells can still produce anti-drug-antibodies (ADA) in the form of IgM, and these
plasma cells are typically short-lived [ 7 ].
Hypersensitivity reactions, types I and III, typically occur after IgG or IgE for-
mation, which usually happen 10–14 days after initial exposure [ 7 ]. In type I hyper-
sensitivity reactions, IgE isotypes of the ADA are formed during the initial exposure
to the biologic agent and bind to mast cells and basophils via the Fc receptors. When
14 Noninfectious and Nonmalignant Complications of Anti-TNF Therapy