Biologics And Biomarkers For Asthma, Atopic Dermatitis, Urticaria, And Nasal Polyposis
Posted: April 2018
Thomas B. Casale, MD
Professor of Medicine And Pediatrics
University of South Florida
Many patients have uncontrolled symptom despite the wide array of therapeutic options for allergic and respiratory disorders. Knowledge about critical pathophysiologic mechanisms involved in allergic and respiratory disorders has led to the possibility of more targeted therapy or ‘‘precision medicine” aimed at underlying pathophysiologic mechanisms important to individual patients. Indeed, responses to a specific therapeutic agent in patients with the same disease can vary dramatically. The successful use of biologic agents that target specific and critical pathways important in the pathogenesis of allergic and respiratory disorders in an individual is a challenge in treating allergic and respiratory diseases. Broad-spectrum biologic agents that affect multiple immune pathways are problematic because of potential adverse consequences. Biologics that are very specific in their mechanisms of action might not be effective in a large segment of a population with the same disease. Due to the potential for significant adverse events and the high costs of biologics, attempts at identifying biomarkers to help predict clinical responsiveness and adverse event profiles in individual patients have been critical in elucidating the utility of specific biologics for individual patients. Ideally, a biomarker should not only be capable of identifying who will respond in a beneficial way to a specific biologic, but be something that can be assessed without difficulty and high expense at the point of care. In this review I will focus on the utility of biologics for asthma, urticaria, atopic dermatitis and nasal polyps.
There are 2 major inflammatory phenotypes defined for asthma: type 2–high and type 2–low asthma. The former is typically characterized by eosinophilic inflammation and the latter by either a neutrophilic or paucigranulocytic inflammatory pattern. Biologic agents developed for asthma therapy have thus far focused on the type 2–high pattern of inflammation, probably because there are more readily available biomarkers that one can measure to identify these patients (e.g., blood eosinophils). Patients with type 2–low asthma are more difficult to characterize and identify, and type 2–low asthma is often described as asthma with the absence of type 2–high characteristics.
For type 2–high allergic asthma, the monoclonal anti-IgE antibody, omalizumab, is likely the therapy of choice. For type 2–high nonallergic eosinophilic asthma, IL-5 blockers (mepolizumab, reslizumab and benralizumab) or dupilumab (an IL-4/13 blocker) would be good choices. As to which of these would be best for an individual patient is unclear, but should be tailored to each patient based on method of administration, frequency of treatment, and symptomatic improvement. Despite the documented benefit of these biologic agents, a key factor in their efficacy outside a controlled research setting is adherence to the therapy, which depends largely on convenience for the patient and cost.
Major characteristics of biologic agents aimed at type 2–high asthma patients are summarized in the table below. Not covered are agents that have not yet reached phase 3 clinical development.
Patients with eosinophilic or neutrophilic nasal mucosal inflammation have predominant T2 cytokine or T1 cytokine profiles, respectively. Therefore, as with asthma, attempts at treating nasal polyposis have focused primarily on biologics with capabilities of blocking critical T2-high pathways since the availability of anti-T1 profile pathway blockers is limited. There is rationale behind using anti-IgE, since increased IgE concentrations have been found in nasal polyp tissue and elevated IgE in nasal secretions resulting from local polyclonal IgE production has been associated with increased disease severity. Prominent nasal polyp and mucosal eosinophilia with increased tissue expression of IL-5 have prompted investigators to explore the clinical utility of IL-5–blocking strategies. Because of the putative importance of IL-4 and IL-13 in the pathogenesis of eosinophilic polyposis, dupilumab has also been studied as a potential treatment.
No biologic therapies are currently FDA approved for nasal polyposis, but omalizumab, mepolizumab, benralizumab and dupilumab are being examined in phase 3 clinical trials based on positive outcomes in anecdotal reports, small case series and phase 2 studies. Given that none of the biologic therapies are currently approved for nasal polyposis, no official recommendations or comparisons among the different agents can be made. Determination of which of these agents would be best for specific individuals awaits the results of phase 3 studies. Key outcome variables of interest include symptom improvement and reduced polyp size and need for surgical intervention.
Atopic dermatitis is an immunologically complex disease that may be disfiguring, intensely pruritic, and associated with increased infection risk, thereby significantly reducing quality of life. Patients with atopic dermatitis often have elevated levels of IgE. Thus, omalizumab has been studied in small case series for the treatment of atopic dermatitis. Overall, the data are mixed and no specific recommendation can be made at this time as to the potential clinical benefit of blocking IgE in this disease.
IL-4 and IL-13 are putatively important in the pathogenesis of atopic dermatitis. As a result, dupilumab has been investigated for the therapy of this disorder. Clinical trials in adults have shown improvements in the Eczema Area and Severity Index scores, Investigator Global Assessment scores, body surface area scores and the pruritus numerical-rating scale scores, the latter of which is very important since pruritus is one of the more debilitating symptoms of atopic dermatitis. These positive results lead to the approval of dupilumab for the therapy of moderate to severe atopic dermatitis in patients 18 years of age and older. The approved dose of dupilumab is 300 mg subcutaneously every two weeks, and this can be self-administered at home. Clinical trials with dupilumab are ongoing in patients six months to 18 years of age. Currently, dupilumab is the only FDA approved biologic therapy for atopic dermatitis.
Patients with chronic urticaria experience recurrent episodes of pruritic hives, often associated with angioedema, for greater than 6 weeks. The intense itching and potentially adverse effects on appearance can significantly decrease quality of life. First-line therapies consist of high-dose second-generation (nonsedating) antihistamines, but approximately 50% of patients do not achieve adequate control of their symptoms on these agents. As a result, there is great interest in biologics as alternative therapeutic options for chronic urticaria.
Omalizumab is the only FDA approved biologic for chronic idiopathic/spontaneous urticaria in adults and adolescents 12 years and older who remain symptomatic despite antihistamines. Omalizumab is administered at either 150 mg or 300 mg subcutaneously every 4 weeks. Most experts agree that the 300 mg dose is more efficacious and should be the initial starting dose. One of the potential pathologic mechanisms involved in chronic urticaria is autoantibodies directed against IgE or more relevant, against the α-chain of FcεR1. Omalizumab can simultaneously inhibit both of these pathologic mechanisms by inducing a significant reduction in serum free IgE levels, which subsequently triggers internalization of FcεR1 on mast cells, thereby preventing IgE autoantibody binding to FcεR1. Patients with autoantibodies appear to have a more delayed onset of clinical effectiveness, with some patients without autoantibodies responding within 1 day. Omalizumab also improves angioedema-related symptoms in those who have hives and angioedema. Omalizumab’s effectiveness appears to be independent of underlying treatment and patient characteristics with reports of >70% of subjects having clinical improvement by 24 weeks. It should be noted that 24 weeks or even 48 weeks of treatment may not be enough to induce long standing remission. Omalizumab treatment does result in significant and clinically important improvements in quality of life, sleep and anxiety levels associated with urticaria. Newly approved global guidelines for the management of urticaria suggest that omalizumab should be used if failure of high-dose second-generation antihistamines.
Omalizumab has also been used to treat urticarial vasculitis and a variety of physical urticarias, including cholinergic, cold, heat, delayed pressure, aquagenic, solar, and dermatographic, with anecdotal positive results.
Quilizumab, a second-generation anti-IgE molecule, is also in clinical trials for chronic spontaneous urticaria.
D-dimer, C-reactive protein, Prothrombin fragment 1+2, IL- 6 and mean platelet volume are biomarkers associated with increased disease activity. Higher levels of D-dimer are associated with poor response to antihistamines and lower levels are associated with better responses to cyclosporine. Better responses to omalizumab are associated with lower IL-31 levels whereas worse responses are associated with lower IgE levels at baseline and decreased basophil FceRI receptor expression.
Several familial autoinflammatory syndromes in the cryopyrin associated periodic syndromes (CAPSs) spectrum, such as Muckle- Wells syndrome, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease, are associated with recurrent urticaria. CAPSs are attributable to autosomal dominant mutations of the NLRP3 gene, which leads to defective synthesis of cryopyrin. This altered cryopyrin induces constitutive production of IL-1β. The FDA has approved three IL-1 antagonists for CAPSs: anakinra, a recombinant human IL-1Rα antagonist; canakinumab, a humanized anti–IL-1β monoclonal antibody; and rilonacept, which acts as a soluble decoy receptor and subsequently blocks IL-1β signaling. These biologics also appear to work in patients with Schnitzler syndrome, characterized by fever, myalgias, lymphadenopathy, and urticaria.
Below is a table of biologics used in the therapy of various urticarial disorders.
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