Dupilumab: A review of its use in the treatment of atopic dermatitis

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Melinda J. Gooderham, H. Chih-ho Hong, Panteha Eshtiaghi, Kim A. Papp
Atopic dermatitis (AD) is a chronic, pruritic immune-mediated inflammatory dermatosis characterized by a T helper 2 (Th2) immune response phenotype and may be associated with systemic inflammation. Dupilumab is an interleukin 4 (IL-4) receptor α-antagonist that inhibits IL-4 and IL-13 signaling through blockade of the shared IL-4α subunit. Blockade of IL-4/13 is effective in reducing Th2 response. Dupilumab has recently been approved in the United States and Europe for the treatment of adult patients with moderate-to-severe AD. Clinical trials have shown that adults with moderate-to-severe AD who receive weekly or biweekly dupilumab injections have significantly improved clinical and patient-reported outcomes, including Eczema Area Severity Index, SCORing Atopic Dermatitis, Dermatology Life Quality Index, and itch Numeric Rating Scale scores. Concomitant use of topical corticosteroids along with dupilumab results in a greater improvement in signs and symptoms of AD than with use of dupilumab alone. Biomarker analyses show that dupilumab modulates the AD molecular signature and other Th2-associated biomarkers. Common adverse events reported in the clinical trials were nasopharyngitis, upper respiratory tract infection, injection site reactions, skin infections, and conjunctivitis. These were mild-to-moderate in nature, and overall rates of adverse events occurred with similar frequency between the treatment and placebo groups. There were no significant serious safety concerns identified in phase III clinical trials. Dupilumab, as monotherapy or with concomitant use of topical corticosteroids, can significantly improve clinical outcomes and quality of life in patients suffering from moderate-to-severe AD. Ongoing studies of dupilumab will help determine the clinical efficacy and safety profile of its long-term use.



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New therapies for atopic dermatitis: Additional treatment classes

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Paras P. Vakharia, Jonathan I. Silverberg
BackgroundA wide array of miscellaneous agents is being studied for the treatment of atopic dermatitis (AD), including targeted topical, oral systemic, and biologic agents.ObjectiveTo review the known efficacy and safety to date for such agents being studied for the treatment of AD.MethodsA nonsystematic review of the literature was performed. PubMed and ClinicalTrials.gov were searched for studies assessing agents not described previously for the treatment of AD. Randomized controlled trials were primarily sought, but other study types were also included if they contained pertinent data. Agents are presented by mechanism of action, with analysis of mechanism of action and data regarding efficacy and safety in patients with AD.ResultsData regarding the following agents are presented: omiganan (an antimicrobial peptide), tapinarof (a nonsteroidal anti-inflammatory agent), PR022 (hypochlorous acid), asimadoline (a κ-opioid agonist), DS107 (dihomo-γ-linolenic acid), ZPL-389 (a histamine H4 receptor antagonist), secukinumab (an interleukin 17A inhibitor), and fezakinumab (interleukin 22 inhibitor).LimitationsLimited clinical data exist for many of the described agents.ConclusionsAs recent research has improved our understanding of AD pathogenesis, various agents with unique mechanisms of action have been studied for the treatment of AD. Many of these hold great therapeutic promise for AD, and continued research and development is warranted.



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Monoclonal antibodies against interleukin 13 and interleukin 31RA in development for atopic dermatitis

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Carsten R. Hamann, Jacob P. Thyssen
The interleukin 13 (IL-13) and IL-31 cytokines and inflammatory pathways have been identified as important for the pathophysiology of atopic dermatitis (AD). Monoclonal antibodies against IL-13 have been studied for the treatment of asthma since 2011. More recently, 2 phase 2 trials have been completed with these antibodies in AD treatment. In both trials, significant reductions of Eczema Area and Severity Index scores were seen. IL-31 is thought to play a role transmitting itch sensation to the central nervous system, and blocking IL-31 activity reduces itch in patients with AD. One phase 2 trial has been completed for a humanized antibody against IL-31 receptor alpha, which is 1 subunit of the IL-31 receptor complex. This study showed significant dose-dependent reductions in pruritus, Eczema Area and Severity Index scores, and markers of sleep quality. Initial clinical trials for monoclonal antibodies against IL-13 and IL-31 receptor A all show promise, although long-term safety and efficacy data are lacking. Nevertheless, these medications will likely play a role in the treatment of moderate-to-severe AD.



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Phosphodiesterase 4 inhibitors

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Rema Zebda, Amy S. Paller
Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration–approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety.



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Emerging therapies for atopic dermatitis: JAK inhibitors

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): David G. Cotter, David Schairer, Lawrence Eichenfield
The Janus kinase–signal transducer and activator of transcription pathway is a conserved master regulator of immunity and myeloproliferation. Advanced understanding of this pathway has led to development of targeted inhibitors of Janus kinases (Jakinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Given such success, use of JAK inhibitors for mitigation of atopic dermatitis is under active investigation. Herein, we review the evolving data on the safety and efficacy of JAK inhibitors in treatment of atopic dermatitis. Although it is still early in the study of JAK inhibitors for atopic dermatitis, evidence identifies JAK inhibitors as effective alternatives to conventional therapies. Nonetheless, multiple large safety and efficacy trials are needed before widespread use of JAK inhibitors can be advocated for atopic dermatitis.



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Emerging therapies for atopic dermatitis: TRPV1 antagonists

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Jonathan G. Bonchak, Robert A. Swerlick
Transient receptor potential (TRP) ion channels are important mediators of somatosensory signaling throughout the body. Our understanding of the contribution of TRPs to a multitude of cutaneous physiologic processes has grown substantially in the past decade. TRP cation channel subfamily V member 1 (TRPV1), one of the better-understood members of this large family of ion channels, affects multiple pathways involved in pruritus. Further, TRPV1 appears to play a role in maintaining skin barrier function. Together, these properties make TRPV1 a ripe target for new therapies in atopic dermatitis. Neurokinin antagonists may affect similar pathways and have been studied to this effect. Early trials data suggest that these therapies are safe, but assessment of their efficacy in atopic dermatitis is pending as we await publication of phase II and III clinical trials data.



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T-cell inhibitors for atopic dermatitis

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): W. James Tidwell, Joseph F. Fowler
The management of atopic dermatitis is changing with the development of novel biologic agents to target specific molecules in the inflammatory cascade. Following the ability of dupilumab has proved its ability to act on the interleukin 4 receptor in treating atopic dermatitis. Thymic stromal lymphopoietin monoclonal antibody (AMG157/MEDI9929) and OX40 blocking antibody (GBR 830) were developed by targeting the same pathway as dupilumab further upstream. The clinical data on the efficacy for these drugs are not yet known. There is some early evidence that AMG157/MEDI9929 attenuates most measures of allergen-induced asthmatic responses. However, there are no public data on its ability to treat atopic dermatitis. In a phase 2a study, GBR 830 showed at least a 50% reduction in the Eczema Area and Severity Index scores of 17 of 23 patients, but it was not sufficiently powered for identification of statistical differences between GBR 830 versus placebo. Although there is potential for these 2 drugs to greatly improve the management of severe atopic dermatitis, significant clinical trials have not yet been completed to prove efficacy, and there are not yet any available phase 3 clinical trials, which are needed to truly evaluate their efficacy in affecting T-cells.



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Emerging therapies for atopic dermatitis: The prostaglandin/leukotriene pathway

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Daniel A. Yanes, Joy L. Mosser-Goldfarb
The role of leukotrienes and prostaglandins in development of atopy has been prototypically established in studies of asthma pathogenesis. Likewise, both in vitro and in vivo studies of atopic dermatitis have demonstrated that these molecules maintain important pathophysiologic roles. Thus, it follows that targeted therapies against these molecules may be promising in management of atopic dermatitis. Montelukast has had questionable efficacy in patients with atopic dermatitis, whereas small pilots using zileuton did have some clinically significant improvement. There are several agents in development that target leukotrienes and/or prostaglandins as well, including OC000459, Q301, and ZPL-521. In atopic dermatitis, OC000459 did not demonstrate efficacy in clinical trials, and the efficacy of the other 2 agents remains to be seen. Should these medications prove promising, these topical agents may play a future role in chronic maintenance therapy and flare prophylaxis in atopic dermatitis, as antileukotriene therapy does in asthma.



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Editorial Board and Contents

Publication date: March 2018
Source:Trends in Endocrinology & Metabolism, Volume 29, Issue 3





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Taking Aim at Glycolysis with CDK8 Inhibitors

Publication date: Available online 20 February 2018
Source:Trends in Endocrinology & Metabolism
Author(s): Robert P. Fisher
Dependence on glycolysis under aerobic conditions, a frequent metabolic derangement in cancer cells, suggests a therapeutic opportunity. Now, through chemical genetics, CDK8, a kinase associated with the Mediator transcriptional coactivator complex, has emerged as an upstream inducer of glycolysis and a possible target for anticancer drug discovery.



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Brain Feeding Circuits after Roux-en-Y Gastric Bypass

Publication date: Available online 20 February 2018
Source:Trends in Endocrinology & Metabolism
Author(s): Mohammed K. Hankir, Florian Seyfried, Alexander D. Miras, Michael A. Cowley
Metabolic surgical procedures, such as Roux-en-Y gastric bypass (RYGB), uniquely reprogram feeding behavior and body weight in obese subjects. Clinical neuroimaging and animal studies are only now beginning to shed light on some of the underlying central mechanisms. We present here the roles of key brain neurotransmitter/neuromodulator systems in food choice, value, and intake at various stages after RYGB. In doing so, we elaborate on how known signals emanating from the reorganized gut, including peptide hormones and microbiota products, impinge on newly mapped homeostatic and hedonic brain feeding circuits. Continued progress in the rapidly evolving field of metabolic surgery will inform the design of more effective weight-loss compounds.



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Generalization and maintenance of functional communication training for individuals with developmental disabilities: A systematic and quality review

Publication date: Available online 19 February 2018
Source:Research in Developmental Disabilities
Author(s): Leslie Neely, Elaina Garcia, Brooke Bankston, Andrew Green
BackgroundFunctional communication training (FCT) is considered an evidence-based practice for treating problem behavior in individuals with developmental disabilities (e.g. autism, intellectual disabilities, down syndrome, etc.). However, there is little known on how to sustain behavioral change following FCT interventions. This systematic and quality review synthesizes the current literature base evaluating the maintenance and generalization of behavioral effects following FCT.MethodA systematic review identified 37 studies that met the pre-set inclusion criteria. Those studies were summarized in terms of: (a) generalization dimension, (b) generalization assessment design, (c) maintenance assessment design, (d) maintenance and generalization teaching strategy, and (e) latency to maintenance probes. All studies employed single-case research designs and were evaluated using the What Works Clearinghouse pilot single-case research standards (Kratochwill et al., 2013) as adapted by Maggin, Briesch, and Chafouleas (2013). Maintenance and generalization data were evaluated using a researcher-developed rubric based on the WWC standards.Results and discussionResults indicate that 30 studies met standards or met standards with reservations while only six studies also met all of the maintenance and generalization standards. Of the six studies, five did not implement any additional strategies beyond the contacting natural contingencies that is inherent in the FCT intervention. Implications for future research and practice are discussed.



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Functional richness: Overview of indices and underlying concepts

Publication date: February 2018
Source:Acta Oecologica, Volume 87
Author(s): G. Legras, N. Loiseau, J.-C. Gaertner
Functional richness, currently defined as the amount of niche space occupied by the species within a community, is one of the three major components of functional diversity. Different indices have been developed in order to quantify this component. However, the range of indices available for assessing functional richness, often mathematically complex and based on different rationales, can cause confusion for field ecologists and lead to misinterpretation of the results obtained. In this context, we have provided the first study exclusively focused on the comparison of the definitions, advantages and drawbacks of a large set of functional richness indices. The first part of this work is focused on four indices (FDP&G, FRic, TOP and N-hypervolumes indices) that are currently the most commonly used for assessing functional richness. We have completed our study by including recently developed indices that enable us to take into account the intraspecific trait variability (i.e. FRim index and TDP framework), because there is currently a growing scientific consensus regarding the necessity of including this aspect in the assessment of the functional diversity of communities.We demonstrate that although authors have argued that their index describes the functional richness, each of them describes only part of it, and this part may strongly differ from one index to another. Rather than advocating the general use of a single index and/or systematically avoiding others, our study highlights the need for selecting indices in close relation with the context, the available data and the aims of each study. Such a strategy is an essential preliminary step for preventing misunderstanding and artefactual controversies. Along these lines, we propose some guidelines to help users in selecting the most appropriate indices according both to the facet of functional richness on which they wish to focus and to the characteristics of the available data.



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Below and above-ground carbon distribution along a rainfall gradient. A case of the Zambezi teak forests, Zambia

Publication date: February 2018
Source:Acta Oecologica, Volume 87
Author(s): Justine Ngoma, Eddy Moors, Bart Kruijt, James H. Speer, Royd Vinya, Emmanuel N. Chidumayo, Rik Leemans
Understanding carbon (C) stocks or biomass in forests is important to examine how forests mitigate climate change. To estimate biomass in stems, branches and roots takes intensive fieldwork to uproot, cut and weigh the mass of each component. Different models or equations are also required. Our research focussed on the dry tropical Zambezi teak forests and we studied their structure at three sites following a rainfall gradient in Zambia. We sampled 3558 trees at 42 plots covering a combined area of 15ha. Using data from destructive tree samples, we developed mixed-species biomass models to estimate above ground biomass for small (<5 cm diameter at breast height (DBH, 1.3 m above-ground)) and large (≥5 cm DBH) trees involving 90 and 104 trees respectively, that belonged to 12 species. A below-ground biomass model was developed from seven trees of three species (16–44 cm DBH) whose complete root systems were excavated. Three stump models were also derived from these uprooted trees. Finally, we determined the C fractions from 194 trees that belonged to 12 species. The analysis revealed that DBH was the only predictor that significantly correlated to both above-ground and below-ground biomass. We found a mean root-to-shoot ratio of 0.38:0.62. The C fraction in leaves ranged from 39% to 42%, while it varied between 41% and 46% in wood. The C fraction was highest at the Kabompo site that received the highest rainfall, and lowest at the intermediate Namwala site. The C stocks varied between 15 and 36 ton C ha⁻¹ and these stocks where highest at the wetter Kabompo site and lowest at the drier Sesheke site. Our results indicate that the projected future rainfall decrease for southern Africa, will likely reduce the C storage potential of the Zambezi teak forests, thereby adversely affecting their mitigating role in climate change.



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Qualitative aspects of the effectiveness of Culpeo foxes (Lycalopex culpaeus) as dispersers of Prosopis alba (Fabaceae) in a Bolivian dry valley

Publication date: February 2018
Source:Acta Oecologica, Volume 87
Author(s): D.E. Maldonado, A.P. Loayza, E. Garcia, L.F. Pacheco
Foxes disperse several plant species in arid and semi-arid environments, but their effectiveness as dispersal agents still remains unclear. In this study, we examined qualitative components of the effectiveness of L. culpaeus as a disperser of P. alba seeds in an inter-Andean dry valley of La Paz, Bolivia. Specifically, we determined seed deposition microhabitats, and the probabilities of germination, seed removal and seedling recruitment in these microhabitats. Additionally, we assessed the effect of gut-passage on P. alba germination. We collected 159 scats, which contained a total of 3402 endocarps fragments. Foxes dispersed seeds into two microhabitats: open areas and under woody vegetation, but more frequently in the former. The probability of germination did not differ between gut-passed and control seeds, but control seeds germinated faster than gut-passed ones. The likelihood of removal was greater for endocarps fragments in open microhabitats than under woody vegetation. Only a small percentage of the seeds in each microhabitat germinated, but none survived more than a week. We conclude that although the Culpeo fox can defecate intact P. alba seeds, it does not provide effective dispersal services.



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Meetings Calendar

Rejuvenation Research Feb 2018, Vol. 21, No. 1: 77-84.


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Longevity Escape Velocity Medicine: A New Medical Specialty for Longevity?

Rejuvenation Research Feb 2018, Vol. 21, No. 1: 1-2.


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ATP Synthase, a Target for Dementia and Aging?

Rejuvenation Research Feb 2018, Vol. 21, No. 1: 61-66.


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Commentary on Some Recent Theses Relevant to Combating Aging: February 2018

Rejuvenation Research Feb 2018, Vol. 21, No. 1: 70-76.


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Validated Living Worldwide Supercentenarians, Living and Recently Deceased: February 2018

Rejuvenation Research Feb 2018, Vol. 21, No. 1: 67-69.


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