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).