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Dermatological Allergology

Top 10 Scientific Articles in the field of dermatological allergology published in 2017.

Staphylococcus aureus: Master Manipulator of the Skin.
Williams MR, Nakatsuji T, Gallo RL.
Cell Host Microbe. 2017; 22:5. doi: 10.1016/j.chom.2017.10.015
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and

Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes.
Williams MR, Nakatsuji T, Sanford JA, Vrbanac AF, Gallo RL.
J Invest Dermatol. 2017; 137:2. doi: 10.1016/j.jid.2016.10.008
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Reasons for recommending the article:

  • These 2 papers are some of those representing the interesting work of RL Gallo on the role of Staph aureus in atopic dermatitis (AD) and how it can affect the skin and be an inducer of AD – another step forward in the understanding of this disease.

Abstracts:
Staphylococcus aureus: Master Manipulator of the Skin.
Skin colonization by Staphylococcus aureus is associated with severity of atopic dermatitis (AD). Two papers in this issue of Cell Host & Microbe by Nakagawa et al. (2017) and Liu et al. (2017) define a pathway by which epicutaneous Staphylococcus aureus promotes skin inflammation and may contribute to AD.

Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes.
Bacteria that reside on the skin can influence the behavior of the cutaneous immune system, but the mechanisms responsible for these effects are incompletely understood. Colonization of the skin by Staphylococcus aureus (S. aureus) is increased in atopic dermatitis (AD) and can result in increased severity of the disease. In this study we show that S. aureus stimulates human keratinocytes to increase their endogenous protease activity, including specific increases in trypsin activity. This increased protease activity coincided with increased expression of mRNA for kallikreins (KLKs), with KLK6, 13, and 14 showing the greatest induction after exposure to S. aureus. Suppression of mRNA for these KLKs in keratinocytes by targeted siRNA silencing prior to S. aureus exposure blocked the increase in protease activity. Keratinocytes exposed to S. aureus showed enhanced degradation of desmoglein-1 (DSG-1) and filaggrin (FLG) while siRNA for KLK6, KLK13, and KLK14 partially blocked this degradation. These data illustrate how S. aureus directly influences the skin barrier integrity by stimulating endogenous proteolytic activity and defines a previously unknown mechanism by which S. aureus may influence skin diseases.

 

When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council. 
Simpson EL, Bruin-Weller M, Flohr C, Ardern-Jones MR, Barbarot S, Deleuran M, Bieber T, Vestergaard C, Brown SJ, Cork MJ, Drucker AM, Eichenfield LF, Foelster-Holst R, Guttman-Yassky E, Nosbaum A, Reynolds NJ, Silverberg JI, Schmitt J, Seyger MMB, Spuls PI, Stalder JF, Su JC, Takaoka R, Traidl-Hoffmann C, Thyssen JP, van der Schaft J, Wollenberg A, Irvine AD, Paller AS.
J Am Acad Dermatol. 2017; 77:4. doi: 10.1016/j.jaad.2017.06.042. Epub 2017 Aug 10.
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Reasons for recommending the article:

  • Most patients with moderate-severe atopic dermatitis respond adequately to topical therapy, but in those with lack of response systemic therapy should be considered. As of yet, the guidelines for therapy advancement are missing.
  • The panel of experts suggests an algorithm for decision-making and calls for executing a holistic approach to managing the patients with severe recalcitrant atopic dermatitis 

Abstract:
Background: Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking.
Objective: To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient.
Methods: A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific literature review, referred to guidelines when available, and provided interpretation and expert opinion.
Results: We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy.
Limitations: Our work is a consensus statement, not a systematic review.
Conclusion: The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies. 

 

H1-antihistamine-refractory chronic spontaneous urticaria: it's worse than we thought - first results of the multicenter real-life AWARE study.
Maurer M, Staubach P, Raap U, Richter-Huhn G, Bauer A, Ruëff F, Jakob T, Yazdi AS, Mahler V, Wagner N, Lippert U, Hillen U, Schwinn A, Pawlak M, Behnke N, Chaouche K, Chapman-Rothe N.
Clin Exp Allergy. 2017; 47:5. doi: 10.1111/cea.12900. Epub 2017 Mar 2.
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Reasons for recommending the article:

  • A global AWARE (A Worldwide Antihistamine-Refractory chronic urticaria patient Evaluation) aims at characterizing patients with H1 antihistamine-refractory chronic spontaneous urticaria as well as the social burden of the disease in a routine clinical setting, and thus reach out to the wider patient population 
  • First data from 1,539 patients assessed in 256 sites across Germany demonstrates that CSU patients refractory to H1-antihistamines tend to have angioedema and chronic inducible urticaria, among other comorbidities, show significant impairment in quality of life, are largely undertreated and depend heavily on health care services, which brings to the fore the importance of proper assessment of the disease control, timely therapy advancement and warrants more research into the mechanisms of resistance to antihistamines. 

Abstract:
Background: Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real-life setting.
Objective: To describe the baseline characteristics of the first 1539 German AWARE patients with H1-antihistamine-refractory CSU.
Methods: This prospective non-interventional study included patients (18-75 years) with a diagnosis of H1-antihistamine-refractory CSU for > 2 months. Baseline demographic and disease characteristics, comorbidities, and pharmacological treatments were recorded. Quality of life (QoL) was assessed using the dermatology life quality index (DLQI), chronic urticaria QoL questionnaire (CU-Q2 oL), and angioedema QoL questionnaire (AE-QoL, in cases of angioedema). Previous healthcare resource utilization and sick leave data were collected retrospectively.
Results: Between March and December 2014, 1539 patients were assessed in 256 sites across Germany. The percentage of females, mean age, and mean body mass index were 70%, 46.3 years, and 27 kg/m2 , respectively. The mean urticaria control test score was 7.9, one in two patients had angioedema, and the most frequent comorbidities were chronic inducible urticaria (CIndU; 24%), allergic rhinitis (18.2%), hypertension (18.1%), asthma (12%), and depression (9.5%). Overall, 57.6% of patients were receiving at least one pharmacological treatment including second-generation H1-antihistamines (46.3%), first-generation H1-antihistamines (9.1%), and corticosteroids (15.8%). The mean DLQI, total CU-Q2 oL, and total AE-QoL scores were 8.3, 36.2, and 46.8, respectively. CSU patients reported frequent use of healthcare resources, including emergency services (29.7%), general practitioners (71.9%), and additional allergists or dermatologists (50.7%).
Conclusion and Clinical Relevance: This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.

 

Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice
Peter JG, Lehloenya R, Dlamini S, Risma K, White KD, Konvinse KC, Phillips EJ.
J Allergy Clin Immunol Pract. 2017; 5:3. doi: 10.1016/j.jaip.2017.01.025.
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Reasons for recommending the article:

  • Very nice review on types and mechanisms of severe cutaneous drug eruptions

Abstract: Most immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCARs) are an uncommon, potentially life-threatening, and challenging subgroup of IM-ADRs with diverse clinical phenotypes, mechanisms, and offending drugs. T-cell-mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis, although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short- and long-term morbidity/mortality and the potential need to treat ongoing comorbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive, diagnostic, treatment, and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying comorbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management.

 

Schnitzler syndrome: validation and applicability of diagnostic criteria in real-life patients
Gusdorf L, Asli B, Barbarot S, Néel A, Masseau A, Puéchal X, Gottenberg JE, Grateau G, Blanchard-Delaunay C, Rizzi R, Lifermann F, Kyndt X, Aubin F, Bessis D, Boye T, Gayet S, Rongioletti F, Sauleau E, Fermand JP, Lipsker D.
Allergy. 2017; 72:2. doi: 10.1111/all.13035. Epub 2016 Sep 12.
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Abstract:
Background: Schnitzler syndrome is characterized by an urticarial rash, a monoclonal gammopathy, and clinical, histological, and biological signs of neutrophil-mediated inflammation. The aim of this study was to assess the applicability and validity of the existing diagnostic criteria in real-life patients.
Methods: This multicentric study was conducted between 2009 and 2014 in 14 hospitals in which patients with Schnitzler syndrome or controls with related disorders were followed up. We compared the sensitivities and specificities and calculated the positive and negative predictive values of the Lipsker and of the Strasbourg criteria for the patients with Schnitzler syndrome and for the controls. We included 42 patients with Schnitzler syndrome, 12 with adult-onset Still's disease, 7 with cryopyrin-associated periodic disease, 9 with Waldenström disease, and 10 with chronic spontaneous urticaria.
Results: All patients with Schnitzler syndrome met the Lipsker criteria. According to the Strasbourg criteria, 34 patients had definite Schnitzler syndrome, five had probable Schnitzler syndrome, and three did not meet the criteria. One control met the Lipsker criteria and had probable Schnitzler syndrome according to the Strasbourg criteria. Sensitivity and specificity of the Lipsker criteria were 100% and 97%, respectively. For the Strasbourg criteria, sensitivity for definite and probable diagnosis was 81% and 93%, respectively, with a corresponding specificity of 100% and 97%.
Conclusion: Diagnostic criteria currently in use to diagnose Schnitzler syndrome are reliable. More investigations must be done to attest their efficiency in patients with recent-onset manifestations.

 

Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go?
Bieber T, D'Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, Schäppi G, Schmid-Grendelmeier P.
J Allergy Clin Immunol. 2017; 139:4S. doi: 10.1016/j.jaci.2017.01.008.
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Reasons for recommending the article:

  • Important review on subphenotypes of AD, as a cumulative work from this group
  • Advances in understanding the molecular basis of atopic dermatitis and modern target-specific therapies accentuate the need for a more refined patient stratification; 
  • Delineating phenotypes and endotypes of the disease and search for predictive biomarkers of therapeutic response are instrumental in developing personalised treatment strategies 

Abstract: Atopic dermatitis (AD) is a paradigmatic chronic inflammatory skin disease characterized by a complex pathophysiology and a wide spectrum of the clinical phenotype. Despite this high degree of heterogeneity, AD is still considered a single disease and usually treated according to the "one-size-fits-all" approach. Thus more tailored prevention and therapeutic strategies are still lacking. As for other disciplines, such as oncology or rheumatology, we have to approach AD in a more differentiated way (ie, to dissect and stratify the complex clinical phenotype into more homogeneous subgroups based on the endophenotype [panel of biomarkers]) with the aim to refine the management of this condition. Because we are now entering the era of personalized medicine, a systems biology approach merging the numerous clinical phenotypes with robust (ie, relevant and validated) biomarkers will be needed to best exploit their potential significance for the future molecular taxonomy of AD. This approach will not only allow an optimized prevention and treatment with the available drugs but also hopefully help assign newly developed medicinal products to those patients who will have the best benefit/risk ratio. 

 

Emerging Roles for MAS-Related G Protein-Coupled Receptor-X2 in Host Defense Peptide, Opioid, and Neuropeptide-Mediated Inflammatory Reactions.
Ali H.
Adv Immunol. 2017; 136. doi: 10.1016/bs.ai.2017.06.002. Epub 2017 Jul 24.
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Reasons for recommending the article:

  • Human mast cells express Mas related G protein coupled receptor X2 (MRGPRX2) which is a receptor for the neuropeptide substance P, major basic protein, eosinophil peroxidase, opioids, and many FDA-approved cationic drugs.
  • Increased expression of MRGPRX2 or enhanced downstream signaling likely contributes to chronic inflammatory diseases such as rosacea, atopic dermatitis, chronic urticaria, and severe asthma.
  • The author of this review discusses the expression profile and function of MRGPRX1-4 and reviews the emerging roles of MRGPRX2 on host defense, chronic inflammatory diseases, and drug-induced pseudoallergic reactions.

Abstract: Mast cells (MCs) are tissue-resident immune cells that contribute to host defense but are best known for their roles in allergic and inflammatory diseases. In humans, MCs are divided into two subtypes based on the protease content of their secretory granules. Thus, human lung MCs contain only tryptase and are known as MCT, whereas skin MCs contain both tryptase and chymase and are known as MCTC. Patients with severe asthma display elevated MCs in the lung, which undergo phenotypic change from MCT to MCTC. Although the human genome contains four Mas related G protein coupled receptor X (MRGPRX) genes, an important feature of MCTC is that they selectively express MRGPRX2. It is activated by antimicrobial host defense peptides such as human β-defensins and the cathelicidin LL-37 and likely contributes to host defense. MRGPRX2 is also a receptor for the neuropeptide substance P, major basic protein, eosinophil peroxidase, opioids, and many FDA-approved cationic drugs. Increased expression of MRGPRX2 or enhanced downstream signaling likely contributes to chronic inflammatory diseases such as rosacea, atopic dermatitis, chronic urticaria, and severe asthma. In this chapter, I will discuss the expression profile and function of MRGPRX1-4 and review the emerging roles of MRGPRX2 on host defense, chronic inflammatory diseases, and drug-induced pseudoallergic reactions. I will also examine the novel aspects of MRGPRX2 signaling in MCs as it related to degranulation and review the mechanisms of its regulation. 

 

Mast cell activation syndromes.
Akin C.
J Allergy Clin Immunol. 2017; 140:2. doi: 10.1016/j.jaci.2017.06.007.
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Reasons for recommending the article:

  • Mast cell activation syndrome refers to a group of disorders with diverse causes presenting with episodic multisystem symptoms as the result of mast cell mediator release.
  • This article reviews our current knowledge about the various types of mast cell activation disorders, their treatment, and areas of uncertainty in need of future investigation.

Abstract: Mast cell activation is common and possibly necessary for maintenance of survival. Disordered mast cell activation occurs when mast cells are pathologically overproduced or if their activation is out of proportion to the perceived threat to homeostasis. Mast cell activation syndrome refers to a group of disorders with diverse causes presenting with episodic multisystem symptoms as the result of mast cell mediator release. Despite introduction of diagnostic criteria and some advances in treatment in the last decade, many areas of mast cell activation syndrome are in need of research. This article reviews our current knowledge about the various types of mast cell activation disorders, their treatment, and areas of uncertainty in need of future investigation.

 

Autoimmune comorbidity in chronic spontaneous urticaria: A systematic review.
Kolkhir P, Borzova E, Grattan C, Asero R, Pogorelov D, Maurer M.
Autoimmun Rev. 2017;16:12. doi: 10.1016/j.autrev.2017.10.003. Epub 2017 Oct 14.
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Reasons for recommending the article:

  • Numerous autoimmune diseases (AIDs) have been linked to chronic spontaneous urticaria (CSU).
  • This review provides the first extensive and comprehensive evaluation of the prevalence of AIDs in patients with CSU and vice versa.
  • CSU patients have an increased risk of AIDs, especially adult female patients and those with a positive family history and a genetic predisposition for AIDs, who should be screened for signs and symptoms of AIDs.

Abstract:
Background and Objective: Numerous autoimmune diseases (AIDs) have been linked to chronic spontaneous urticaria (CSU). Here, we provide the first extensive and comprehensive evaluation of the prevalence of AIDs in patients with CSU and vice versa.
Methods: A Pubmed and Google Scholar search was performed to identify studies reporting the prevalence of various AIDs in CSU and vice versa published before April 2017.
Results: The prevalence of individual AIDs in CSU is increased (≥1% in most studies vs ≤1% in the general population). AIDs with relatively high prevalence in the general population are also quite common in CSU patients, whereas those with low prevalence remain a rare finding in CSU. The rates of comorbidity in most studies were ≥1% for insulin-dependent diabetes mellitus, rheumatoid arthritis (RA), psoriasis and celiac disease (CD), ≥2% for Graves' disease, ≥3% for vitiligo, and ≥5% for pernicious anemia and Hashimoto's thyroiditis. Organ-specific AIDs are more prevalent in CSU than systemic (multiorgan or non organ-specific) AIDs. >2% of CSU patients have autoimmune polyglandular syndromes encompassing autoimmune thyroid disease (ATD) and vitiligo or pernicious anemia. Antithyroid and antinuclear antibodies are the most prevalent AID-associated autoantibodies in CSU. >15% of CSU patients have a positive family history for AIDs. The prevalence of urticarial rash in AID patients is >1% in most studies. This rash is more prevalent in eosinophilic granulomatosis with polyangiitis, ATD, systemic lupus erythematosus, RA and CD.
Conclusions: CSU patients have an increased risk of AIDs, especially adult female patients and those with a positive family history and a genetic predisposition for AIDs, who should be screened for signs and symptoms of AIDs.

 

Minimum standards on prevention, diagnosis and treatment of occupational and work-related skin diseases in Europe - position paper of the COST Action StanDerm (TD 1206).
J Eur Acad Dermatol Venereol. 2017; 31:Suppl 4. doi: 10.1111/jdv.14319.
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Abstract:
Background: Skin diseases constitute up to 40% of all notified occupational diseases in most European countries, predominantly comprising contact dermatitis, contact urticaria, and skin cancer. While insufficient prevention of work‐related skin diseases (WRSD) is a top‐priority problem in Europe, common standards for prevention of these conditions are lacking.
Objective: To develop common European standards on prevention and management of WRSD and occupational skin diseases (OSD).
Method: Consensus amongst experts within occupational dermatology was achieved with regard to the definition of minimum evidence‐based standards on prevention and management of WRSD/OSD.
Results: By definition, WRSDs/OSDs are (partially or fully) caused by occupational exposure. The definition of OSD sensu stricto additionally includes diverging national legal requirements, with an impact on registration, prevention, management, and compensation. With the implementation of the classification of WRSD/OSD in the International Classification of Diseases (ICD) 11th Revision in future, a valid surveillance and comparability across countries will be possible. Currently, WRDS and OSD are still under‐reported. Depending on legislation and regulations, huge differences exist in notification procedures in Europe, although notification is crucial to prevent chronic and relapsing disease. Facilities for early diagnosis, essential for individual patient management, should be based on existing guidelines and include a multidisciplinary approach. Patch testing is essential if contact dermatitis persists or relapses. Workplace exposure assessment of WRSD/OSD requires full labelling of product ingredients on material safety data sheets helping to identify allergens, irritants and skin carcinogens. Comparable standards in primary, secondary and tertiary prevention must be established in Europe to reduce the burden of WRSD/OSD in Europe.
Conclusion: The adoption of common European standards on prevention of WRSD/OSD will contribute to reduce the incidence of OSD and their socio‐economic burden.