What Is New In Small Airways Research
By Ves Dimov, M.D.
Assistant Professor of Medicine and Pediatrics
University of Chicago
Monoclonal antibody (AMG 157) against a new target in asthma, thymic stromal lymphopoietin (TSLP)
Thymic stromal lymphopoietin (TSLP) is an epithelial-cell–derived cytokine that may be important in allergic inflammation. TSLP, which was discovered as a growth factor for lymphocyte progenitors, is a protein released from epithelial cells in response to irritating stimuli. It initiates signaling pathways leading to inflammation driven by type 2 helper T (Th2) cells.
TSLP could be a master switch in the signaling between airway epithelium and other inflammatory cascades or it could be a part of a concerted action by several parallel pathways (e.g., those involving interleukin-33, interleukin-25, and interleukin-17).
AMG 157 is a humanized anti-TSLP monoclonal immunoglobulin G2delta that binds human TSLP and prevents receptor interaction.
A small double-blind, placebo-controlled study included 31 patients with mild allergic asthma who received three monthly doses of AMG 157 (700 mg) or placebo IV. AMG 157 decreased measures of allergen-induced early and late asthmatic responses (FEV1, blood and sputum eosinophils before and after the allergen challenge, FeNO).
TSLP could play a key role in allergen-induced airway responses and persistent airway inflammation in allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined yet from these data. The study was funded by the AMG manufacturer, Amgen, and published in the NEJM.
Source: Gauvreau GM, O’Byrne PM, Boulet LP, Wang Y, Cockcroft D et al. Effects on an anti-TSLP antibody on allergen-induced asthmatic responses. The New England Journal of Medicine 2014; 370(22): 2102-2110 (doi:10.1056/NEJMoa1402895)
Dahlen SE. TSLP in asthma – A new kid on the block? The New England Journal of Medicine 2014; 320(2): 2144-2145 (doi:10.1056/NEJMe1404737)
New age of personalized medicine for biologic therapy in asthma
Unlike other diseases, current anti-inflammatory treatment with corticosteroids does not include any reference to biological measures which may vary among different asthma phenotypes. In half of asthmatics, chronic airway inflammation may be driven by T helper (Th)-2 cells, which release pro-inflammatory cytokines, such as interleukin (IL)-4, IL-5 and IL-13, contributing to eosinophil inflammation and IgE production.
This literature review by Sally Wenzel et al. included 32 studies (1958–2013).
Approaches to personalized medicine with expression profiling studies, genetic analysis and clinical biomarkers of Th2 inflammation have allowed identification of asthma phenotypes including a Th2 “high” phenotype.
Studies targeting IgE, IL-5, IL-13 and the IL4 receptor alpha chain have shown some efficacy in phenotyped patients. For those without evidence of Th2 inflammation, no specific therapies have been identified.
It is not yet clear whether all Type 2 high asthma will respond similarly to IL-4, 5 and 13 approaches. "Sub-phenotyping" of phenotypes may be needed to find the patients who would respond to a specific therapy.
Source: Fajt ML and Wenzel SE. Biologic therapy in asthma: entering the new age of personalized medicine. Journal of Asthma, 2014; posted online before print 13 May. (doi:10.3109/02770903.2014.910221)
Vitamin D supplementation in adults with asthma is not indicated – VIDA RCT
Vitamin D insufficiency is associated with adverse outcomes in asthma and many other diseases. What is not clear however is whether this association is causative or not. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.
This large randomized, double-blind, parallel, placebo-controlled trial evaluated if vitamin D supplementation improved the efficacy of inhaled corticosteroids in 408 adults with symptomatic asthma and lower vitamin D levels, less than 30 ng/mL (VIDA – Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma).
Oral vitamin D3 (100 000 IU once, then 4000 IU/d for 28 weeks) or placebo was added to inhaled ciclesonide (320 µg/d). In the vitamin D3 treatment group, 82% of participants achieved a serum 25-hydroxyvitamin D level of 30 ng/mL or greater (mean 42 ng/mL).
Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks.
Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.
Source: Castro M, King, TS, Kunselman SJ, Cabana MD, Denlinger L at el. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels. The VIDA Randomized Clinical Trial. JAMA 2014; 311(20): 2083-2091. (doi:10.1001/jama.2014.5052)
Related Source: Murdoch DR, Slow S, Chambers ST, Jennings LC, Stewart AW et al. Vitamin D3 supplementation did not decrease upper respiratory tract infections in healthy adults. JAMA 2012; 308(13):1333-1339. (doi:10.1001/jama.2012.12505)
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