Trials with leukotriene inhibitors have demonstrated an important role for leukotrienes in aspirin-exacerbated respiratory disease (AERD), a disease that combines the features of asthma, chronic rhinosinusitis with nasal polyposis, and reactions to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase-1 (COX-1). Aspirin-exacerbated respiratory disease occurs in approximately 5–10% of patients with asthma. In these patients, ingestion of even a very small dose of aspirin causes profound bronchoconstriction, nasal congestion, and symptoms of systemic release of histamine, such as flushing and abdominal cramping. Because this reaction to aspirin is not associated with any evidence of allergic sensitization to aspirin or its metabolites and because it is produced by any of the NSAIDs that target COX-1, AERD is thought to result from inhibition of prostaglandin synthetase (cyclooxygenase), shifting arachidonic acid metabolism from the prostaglandin to the leukotriene pathway, especially in platelets adherent to circulating neutrophils. Support for this idea was provided by the demonstration that leukotriene pathway inhibitors impressively reduce the response to aspirin challenge and improve overall control of asthma on a day-to-day basis.
Of these agents, montelukast is by far the most prescribed, because it may be taken without regard to meals, is taken once daily, and does not require periodic monitoring of liver function, as zileuton does. Although not considered first-line therapy, the leukotriene-modifying agents are sometimes given in lieu of inhaled corticosteroids for mild asthma when prescription of an ICS meets patient resistance. The receptor antagonists have little toxicity. Early reports of Churg-Strauss syndrome (a systemic vasculitis accompanied by worsening asthma, pulmonary infiltrates, and eosinophilia) appear to have been coincidental, with the syndrome unmasked by the reduction in prednisone dosage made possible by the addition of zafirlukast or montelukast.
As the pathophysiologic mechanisms responsible for asthma have become better understood, anti-inflammatory therapy targeting specific inflammatory pathways has been developed. Specifically, monoclonal antibodies targeting IgE and IL-5 have been brought to market, and an antibody targeting the receptor for IL-4 and IL-13 is under development (Table 20–1).
The monoclonal antibody omalizumab was raised in mice and then humanized, making it less likely to cause sensitization when given to human subjects (see Chapter 55). Because its specific target is the portion of IgE that binds to its receptors (Fcε-R1 and
TABLE 20–1 Monoclonal antibodies for use in asthma.1 1Approved or in phase 2 or 3 clinical trials.
Fcε-R2 receptors) on dendritic cells, basophils, mast cells, and other inflammatory cells, omalizumab inhibits the binding of IgE but does not activate IgE already bound to its receptor and thus does not provoke mast cell degranulation.