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Tuesday, February 10, 2015

Asthma phenotypes and the use of biologic medications in asthma and allergic disease

Asthma has traditionally been defined using non-specific clinical and physiologic variables which encompass multiple different phenotypes and is treated with non-specific anti-inflammatory therapies. However, it is increasingly recognized that human asthma is a heterogeneous disease. In their review, Fajt and Wenzel analyzed randomized double blind placebo controlled trials of molecularly targeted therapies in defined allergic disease and asthma phenotypes (J Allergy Clin Immunol 2015; 135: 299-310).

There is an increasing appreciation of heterogeneity within asthma and allergic diseases, based primarily on recent cluster analyses, molecular phenotyping, biomarkers and differential responses to targeted and non-targeted therapies. These pioneering studies have led to successful therapeutic trials of molecularly targeted therapies in defined phenotypes. Pathobiologic studies combined with therapeutic trials of type-2 targeted therapies either approved or in clinical trials include those targeted to IgE, IL-5, IL-13, the IL-4 receptor alpha (IL-4Rα) and thymic stromal lymphopoietin (TSLP). IgE was the first successful biological target used in allergic disease and asthma with the overall success of the drug omalizumab (humanized monoclonal anti-IgE antibody) by reducing the allergic asthmatic response. Omalizumab has been shown to be effective in treating allergic rhinitis and peanut allergy although it is not FDA approved for these indications. The authors review other therapies targeting the canonical type-2 cytokines IL-4, IL-5, and IL-13 that have shown consistent efficacy especially in asthma with evidence for a Th2/type-2 inflammation (“type-2 high asthma”).

Recent clustering, molecular studies and treatment trials have begun to suggest that type-2 asthma itself represents several different molecular phenotypes. Data are emerging that late onset, less allergic but highly eosinophilic asthma may respond better to IL-5 targeted therapies than earlier onset (allergic) asthma, while in allergic models of asthma, anti-IL-4/13 approaches appear superior. However, approximately half of all asthmatics do not have evidence for type-2 inflammation, called “type-2 low asthma” which is defined by the absence of type-2 cytokines and their downstream signatures. This group is poorly defined, clinically heterogeneous and without specific biomarkers making molecular phenotyping and targeted therapy approaches difficult.  Non-type-2 patients generally have adult onset disease, often in association with obesity, post-infectious, neutrophilic and smoking related factors and are less likely to be atopic/allergic.

As the results of these studies summarized in this manuscript are varied even for antibodies directed towards the same biologic pathway, it is appreciated that the response to a biologic medication can be confounded by multiple factors including treatment duration, dose, phenotype and differing outcome measures assessed. Moving forward, it will be critical to determine the optimal biomarkers necessary to determine which patients will derive the best therapeutic benefit from each specific targeted medication. 

Question for the authors:
Considering many who suffer from allergic asthma can have multiple allergic diseases such as atopic dermatitis, allergic rhinitis and food allergy, are there studies that resulted in improvement of multiple atopic diseases in the same patient?

There are a few studies which come to mind:

In the Corren et al. (JACI, 2011), in patients with a history of cat allergen–induced asthma, treatment with omalizumab reduced the severity of acute airway reactions and symptoms (including  allergic rhinoconjunctivitis)  caused by controlled cat room exposure to allergens.

In the SOLAR study (Vignola, Allergy, 2004), asthmatic patients with allergic rhinitis treated with omalizumab not only experienced fewer asthma exacerbations but also had clinically significant improvement in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life Questionnaire scores.

In terms of the monoclonal antibody to IL4R, dupilumab, 2 separate studies showed strong efficacy in atopic dermatitis and in asthma. In adults with moderate-to-severe atopic dermatitis despite treatment with topical corticosteroids and calcineurin inhibitors, Beck et al. (NEJM, 2014) showed that dupilumab treatment resulted in marked clinical efficacy and medication reduction.  In moderate-severe asthma on mid-high dose ICS/LABA with Type-2 High Phenotype, Wenzel et al. (NEJM, 2013) showed that dupilimab therapy resulted in a ↓ in asthma exacerbation, rescue beta agonist use, upper airway symptoms and exhaled nitric oxide.

These studies suggest that the same biologic target may be efficacious in more than 1 allergic disease, but further studies are needed to specifically address this question.

1 comment:

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