A 38-year-old woman comes to the office due to abdominal pain. For the last 2-3 weeks, she has had increasingly severe abdominal pain associated with watery diarrhea. The patient has a history of Crohn disease treated for the last year with adalimumab, which has controlled the symptoms until now. Vital signs are normal except for a temperature of 37.8 C (100 F). Examination shows moderate tenderness in the right lower quadrant with no peritoneal signs. Laboratory results show an undetectable trough adalimumab level. Which of the following is the most likely explanation for this patient's worsening symptoms?
This patient with Crohn disease initially responded to treatment with adalimumab but subsequently experienced treatment failure with a relapse of symptoms after nearly a year of therapy. Adalimumab is a recombinant human IgG that binds tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine involved in promoting leukocyte migration, neutrophil and macrophage function, and granuloma integrity. Adalimumab prevents TNF-alpha from associating with its cell-surface receptors, blocking its pro-inflammatory effects. TNF-alpha inhibitors are used for a variety of inflammatory disorders such as Crohn disease, psoriasis, and rheumatoid arthritis.
However, use of adalimumab can induce the formation of antidrug antibodies (ADAs), which reduce the activity of the agent and lead to more rapid drug clearance and lower trough levels between doses. Patients with ADAs against adalimumab typically experience declining effectiveness of treatment and can develop hypersensitivity reactions after administration. The formation of ADAs can also be seen with other immunoglobulin-based anti-TNF agents (eg, infliximab) but is uncommon with etanercept, a recombinant TNF-receptor fusion protein.
(Choice B) Glargine is a long-acting insulin analogue that forms insoluble complexes. This leads to the formation of microprecipitates at the injection site that then slowly dissolve and are released into the circulation throughout the day. Adalimumab is given as a subcutaneous injection but does not form insoluble complexes at the injection site.
(Choice C) Enterohepatic recirculation of certain cancer chemotherapeutic agents (eg, irinotecan) can lead to increased exposure of the intestinal mucosa to the agent and significant gastrointestinal toxicity. However, monoclonal antibodies do not undergo enterohepatic recirculation.
(Choice D) Adalimumab and other therapeutic monoclonal antibodies are eliminated primarily by degradation via receptor-mediated endocytosis in the reticuloendothelial system. Renal elimination of adalimumab can lead to increased drug clearance in patients with protein-losing glomerular disorders but otherwise does not significantly affect pharmacokinetics.
(Choice E) Cytochrome P-450 enzyme inducers (eg, rifampin, carbamazepine, phenobarbital) can cause accelerated clearance of drugs that are metabolized primarily in the liver. Adalimumab does not undergo metabolism by the P-450 system.
Educational objective:
Adalimumab is a recombinant human IgG that binds tumor necrosis factor-alpha (TNF-alpha). Antidrug antibodies can develop against adalimumab (or other immunoglobulin-based anti-TNF agents) that can block its interaction with TNF-alpha, preventing the drug from functioning and leading to more rapid drug clearance.