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Wednesday, February 11, 2015

Current biologics to treat inflammatory skin diseases

Psoriasis and atopic dermatitis (AD) are the most common inflammatory skin conditions that share similarities, including epidermal hyperplasia, marked T-cell and dendritic cell infiltration, and a relatively increased Th1 axis. However, T cell polarization differs and therapeutic targeting has confirmed that TNF-α, IL-17, and IL-23 are the main cytokine drivers of psoriasis while AD has been recently characterized as Th2/Th22 polarized, with some Th17 involvement. Noda et al detail the different therapeutic approaches that have been approved or being tested for these diseases (J Allergy Clin Immunol 2015; 135: 324-336).

Up to 3% of adults have psoriasis, which is associated with red scaly lesions, a shorter life span, and a high risk for cardiovascular diseases, obesity, and diabetes. Up to 20% of these patients have severe disease which requires systemic therapies. Conventional treatments for psoriasis such as phototherapy, methotrexate, cyclosporine, and aceitretin are associated with loss of efficacy, side effects and toxicity. This led to the introduction of biologics, selective immune antagonists, such as TNF-α and IL-12/IL-23p40, and IL-17A which have demonstrated higher efficacy and a better safety profile. Various biologics are FDA approved and have revolutionized the treatment of psoriasis and psoriatic arthritis. Despite the rapid improvements associated with biologics, high cost has driven the development of small-molecule, orally available treatments which provide alternatives to injection therapies.

AD is the most common inflammatory skin disorder affecting up to 25% of children and up to 7% of adults characterized by highly pruritic erythematous plaques that are prone to infections, which is rarely seen in patients with psoriasis.  Severe AD resistant to topical medications is treated with oral steroids, phototherapy and other immunosuppressants that are associated with inconvenience or toxicity, much like the conventional treatments for psoriasis. The inflammatory AD profile has only recently been established, characterized by overexpression of the Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17, CCL18, and CCL26), as well as the Th22 cytokine IL-22. The Th17 axis is also activated in patients with AD and might have a role in promoting Th2 differentiation.  Studies on the effects of biologics in patients with AD are lagging behind psoriasis by about a decade, and selective antagonists are only recently being examined for the treatment of AD in clinical trials.  The drug dupilumab is currently in phase III trials for AD, which binds to IL-4 receptor alpha (IL-4Rα) and blocks IL-4 and IL-13 activity. The drug significantly reduced levels of the Th2 chemokines and reversed epidermal hyperplasia in phase I and II studies. Other phase I or II trials are underway that target various antagonists such as IL-12/23p40, IL-22, IL-31, IgE and TSLP.

The authors summarize that while psoriasis develops through well-understood mechanisms and has many targeted biologics with proved efficacy, clinical trials and subsequent molecular analyses using human samples will be able to clarify the relative roles of polar cytokines in patients with AD.

Are there any known side effects of immune suppression from the long term use of biologics? For example, is there data from the long term use of biologics that have been successful in other diseases such as arthritis or Crohn’s disease?

Reactivation of tuberculosis is the concern with the use of TNF blockers. No cumulative toxicity has been reported with up to 5-year exposure to ustekinumab in psoriasis patients (Papp KA et al. Br J Dermatol 2013).

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.

Monday, February 9, 2015

Biologics and food allergy

Food allergy is an immune-mediated response to food proteins leading to symptoms affecting the skin, gastrointestinal tract or respiratory tract. Up to 8% if children and 5% if adults self-reported an allergy to at least one food. The incidence of food allergy has steadily increased over 18% between 1997-2007, suggesting that environmental influences may play a role. Despite this increase in prevalence, there are currently no approved treatments beyond allergen avoidance and treatment of reactions to accidental ingestion. Though the incidence of food allergy-related mortality is low, avoidance and fear of accidental ingestion significantly impairs the quality of life for children with food allergy and their caregivers. In their review, Bauer et al discuss the mechanisms that contribute to allergy with emphasis on future targets for biologics for the treatment of IgE mediated food allergy (J Allergy Clin Immunol 2015; 135(2): 312-323).

Recently there has been increased interest in the use of biologics which are selective immune antagonists for the treatment of allergic diseases, particularly asthma. Dupilumab, a biologic that binds to IL-4Rα and blocks the Th2 cytokines IL-4 and IL-13 activity has been successful in clinical trials for the treatment of asthma and atopic dermatitis. However, relatively few studies have investigated applications of biologics for the treatment of food allergy and no reported clinical trials have investigated the effectiveness of anti-Th2 cytokine treatments in context of food allergy. Recent basic and clinical studies have identified attractive new targets for food allergy therapeutics, including epithelial cell-derived mediators (such as IL-33 and TSLP), IgE-binding receptors (such as CD23) and IgE signaling pathways. A promising therapeutic for the treatment of food allergy is the drug omalizumab which binds IgE and reduces serum levels by 99%. If successful, omalizumab could allow for the use of rapid dose escalation protocols for allergen immunotherapy for food allergic patients. A new drug similar to omalizumab, ligelizumab is an anti-IgE antibody that binds free serum IgE, but with up to 12-times higher affinity, making it much more potent. Phase II trials are planned to assess the clinical efficacy of ligelizumab in subjects with atopic dermatitis and asthma.

Despite the increasing prevalence of food allergy and adverse impact on human health and quality of life, there is an unmet need for effective therapeutic options to treat food allergy. The authors detail a variety of potential treatment options for food allergy, although most studies have focused on asthma, allergic rhinitis, and atopic dermatitis, and future studies are needed to determine the effects on food allergic patients.