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Difficulty: HardImmunologic and Inflammatory Processes

A 32-year-old man comes to the clinic due to a 4-week history of severe, crampy abdominal pain and 5 to 7 bloody bowel movements per day. He also reports tenesmus and a 3-kg (6.6-lb) weight loss during this time. His medical history is significant for severe plaque psoriasis that was refractory to high-potency topical corticosteroids and narrowband ultraviolet B phototherapy. Five months ago, his dermatologist initiated a new targeted biologic therapy, which has resulted in near-complete clearance of his skin lesions. His temperature is 37.8°C (100.0°F), pulse is 98/min, and blood pressure is 118/76 mm Hg. Physical examination shows a soft abdomen with moderate tenderness in the left lower quadrant. No cutaneous plaques are visible. Flexible sigmoidoscopy reveals continuous mucosal erythema, edema, friability, and loss of the normal vascular pattern extending from the anal verge to the splenic flexure. Which of the following describes the mechanism of action of the pharmacologic agent most likely responsible for this patient's current gastrointestinal condition?

  1. Binding and neutralization of interleukin-17AAnswer
  2. B
    Blockade of the p40 subunit of interleukin-12 and interleukin-23
  3. C
    Binding and neutralization of soluble tumor necrosis factor-alpha
  4. D
    Inhibition of phosphodiesterase-4 leading to increased intracellular cyclic AMP
  5. E
    Competitive inhibition of Janus kinase signal transducers

Answer

Binding and neutralization of interleukin-17A
The correct answer describes the mechanism of action of Interleukin-17 (IL-17) inhibitors, such as secukinumab and ixekizumab. IL-17, produced by Th17 cells, is a key driver of epidermal hyperplasia and inflammation in psoriasis. However, in the gastrointestinal tract, IL-17 plays a vital protective role by stimulating intestinal epithelial cells to produce mucins, antimicrobial peptides (e.g., defensins), and tight junction proteins. Neutralizing IL-17 disrupts this mucosal barrier, allowing luminal antigens and bacteria to penetrate the epithelium, which can trigger an unregulated inflammatory response. Consequently, IL-17 inhibitors are a known cause of new-onset inflammatory bowel disease (IBD) and are strictly contraindicated in patients with a pre-existing history of Crohn's disease or ulcerative colitis. This patient's classic presentation of ulcerative colitis shortly after initiating a highly effective psoriasis biologic points directly to an IL-17 inhibitor.

Step-by-Step Solution

1
Analyze the clinical presentation to establish the current gastrointestinal diagnosis.
The patient has symptoms of bloody diarrhea and left lower quadrant pain, with sigmoidoscopy showing continuous mucosal inflammation from the rectum to the splenic flexure, diagnostic of new-onset ulcerative colitis.
Establishing the diagnosis of ulcerative colitis is necessary to determine which medication could trigger this specific inflammatory process.
2
Review the patient's medical history to identify potential pharmacologic triggers.
The patient was started on a highly effective biologic therapy for plaque psoriasis 5 months ago, which cleared his skin but preceded the onset of his colitis.
Many biologic agents have dual effects on different organ systems, requiring knowledge of their systemic immunologic impacts.
3
Correlate the mechanism of psoriasis biologics with the adverse effect of new-onset inflammatory bowel disease.
IL-17 inhibitors (e.g., secukinumab, ixekizumab) are indicated for psoriasis but carry a specific warning for inducing or exacerbating inflammatory bowel disease due to the requirement of IL-17 for gut mucosal integrity.
Identifying the specific disrupted immunologic pathway leads directly to the correct targeted mechanism.

Key Concept

While pathogenic in the skin and joints (causing psoriasis and ankylosing spondylitis), Interleukin-17 (IL-17) plays a critical physiologic role in maintaining intestinal mucosal barrier integrity; therefore, IL-17 inhibitors are contraindicated in patients with inflammatory bowel disease and can trigger new-onset colitis.
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Topics

Immunologic and Inflammatory Processes

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