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Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy

http://www.sciencedirect.com/science/article/pii/S235239641730066X

Ebiomedicine – Available online 12 February 2017

Christian Lupinek, Kurt Derfler, Silvia Lee, Thomas Prikoszovich, Oliver Movadat, Eva Wollmann, Carolin Cornelius, Milena Weber, Renate Fröschl, Regina Selb, Katharina Blatt, Dubravka Smiljkovic, Volker Schoder, René Cervenka, Thomas Plaichner, Gottfried Stegfellner, Hans Huber, Rainer Henning, Justyna Kozik-Jaromin, Thomas Perkmann, Verena Niederberger, Ventzislav Petkov, Peter Valent, Adelheid Gauly, Hans Peter Leinenbach, Ingrid Uhlenbusch-Koerwer, Rudolf Valenta

Highlights

• An IgE-specific immunoadsorber, IgEnio, was developed.

• IgEnio selectively depleted IgE from subjects with allergic asthma.

• IgEnio treatment was safe and well tolerated.

• IgE-depletion prevented increase of pollen-induced symptoms.

• In treated subjects, decreased skin- and basophil-reactivities were recorded.

IgE-associated allergy affects more than 25% of the population. Symptoms of allergy are caused by activation of inflammatory cells by IgE-allergen immune complexes. We developed an immunoadsorber, IgEnio, for the selective, effective and safe depletion of IgE from patients suffering from allergic asthma by immunoadsorption. IgE immunoadsorption with IgEnio may be useful for the treatment of allergen-induced asthma and perhaps other manifestations of IgE-associated allergies.

Abstract

Background

Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody-fragment and can be used for the specific extracorporeal desorption of IgE.

Objective

To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes.

Methods

Fifteen subjects were enrolled and randomly assigned to the treatment group (n = 10) or to the control group (n = 5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro.

The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014.

Results

IgE immunoadsorption with IgEnio selectively depleted 86.2% (± 5.1% SD) of IgE until the end of the last cycle (p < 0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro.

The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids.

Conclusions

This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes.

This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

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Mitogen-activated protein kinases as therapeutic targets for asthma

http://www.sciencedirect.com/science/article/pii/S0163725817300384

Pharmacology & Therapeutics – Available online 14 February 2017

MirHojjat Khorasanizadeh, Mahsa Eskian, Erwin W. Gelfand, Nima Rezaei (Molecular Immunology Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Boston, MA, USA)

Abstract

Corticosteroid-resistant asthmatics, although comprising only a portion of the asthma population, account for most of the morbidity, mortality and economic burden associated with asthma. Moreover, corticosteroids are not effective inhibitors of airway remodeling changes, and their long-term use is associated with debilitating systemic side effects. Therefore, potent and safe novel therapeutic alternatives, targeting basic pathophysiological mechanisms responsible for the severe asthmatic phenotype are urgently needed. Mitogen-activated protein kinases (MAPKs) are ubiquitously expressed signaling enzymes that are involved in almost all aspects of the asthmatic inflammatory network; as such, they represent an emerging target for the treatment of asthma. This paper provides a rationale for targeting MAPKs in the treatment of asthma by reviewing the in vitro evidence of its relevance to asthma pathogenesis. This is followed by discussing the results of MAPK inhibition in pre-clinical models of asthma. Finally, the potential safety concerns regarding MAPK inhibition in human disease, as well as the future prospects for its clinical development are explored. In conclusion, this review underlines the promising results of MAPK inhibition in animal asthma models especially in restoring corticosteroid sensitivity, as well as recent clinical safety and efficacy evidence obtained from trials in similar disease areas such as COPD, and of course, the paucity of clinical evidence for targeting MAPKs in asthma. Based on this review, a more rigorous effort for clinical development of MAPK inhibitors in asthma is justified.

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IBD immunopathogenesis: A comprehensive review of inflammatory molecules

http://www.sciencedirect.com/science/article/pii/S1568997217300538

Autoimmunity Reviews – Available online 14 February 2017

Jae Hyon Park, Laurent Peyrin-Biroulet, Michael Eisenhut, Jae Il Shin (Yonsei University College of Medicine, Seoul, Korea; Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, France; Department of Paediatrics, Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton, LU40DZ, United Kingdom; Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea)

Abstract

Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn’s disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro-and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn’s disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn’s disease in relation to their effects on the overall intestinal inflammatory process.

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Utilities of Various Mast Cell Mediators in Diagnosing Mast Cell Activation Syndrome

http://www.bloodjournal.org/content/126/23/5174?sso-checked=true

Nicolas Zenker and Lawrence B Afrin

Blood 2015 126:5174

Abstract

Distinct from mastocytosis and simple allergy and characterized by constitutive mast cell (MC) activation and aberrant MC reactivity with little to no excessive MC accumulation, MC activation syndrome (MCAS) presents as acute-on-chronic multisystem polymorbidity of generally inflammatory ± allergic theme; severity may be disabling. Given suspicion of epidemic prevalence of MCAS (Molderings GJ et al., PLoS One 2013;8(9):e76241), diagnostic testing efficiency is important. Diagnosis (Molderings GJ et al., J Hematol Oncol 2011;4:10) presently rests on identifying clinical presentation consistent with chronic/recurrent aberrant MC mediator release, identifying elevated MC mediator levels, and eliminating other relevant diagnostic considerations. MCs produce >200 mediators, but few can be tested in clinical laboratories; even fewer are relatively specific to the MC. Mediators often tested in MCAS work-ups include serum tryptase (sTryp) and chromogranin A (sCgA), plasma prostaglandin D2 (pPGD2) and histamine (pHist) and heparin (pHep), random (r) and 24-hour (24h) urinary PGD2 (uPGD2) and N-methylhistamine (uNMH) and leukotriene E4 (LTE4), and 24h urinary 11-β-PGF2α (u11βPGF2α). Testing the entire suite may be prohibitively expensive, but few data on frequency of elevation of MC mediators are available to guide cost-effective testing (pHep may be the most sensitive per Vysniauskaite M et al., PLoS ONE 2015;10(4):e0124912). Test accuracy for many MC mediators (especially heparin and the eicosanoids) is also challenged by thermolability and half-lives as short as ~1 minute. Loss of specimen chill during handling (e.g., unrefrigerated centrifugation (UCF)) or transport may yield false negatives.

Methods: We reviewed the charts of 198 adult pts (97% Caucasian, 84% female) evaluated at our center and diagnosed with MC activation disease (MCAD: MCAS (184), CM (4), indolent SM (9), aggressive SM (1)) from July 2014 through July 2015.

Results: Table 1 shows performance in MCAS pts of MC mediators in tests accessioned at our center (testing accessioned elsewhere censored to reduce bias from variability in specimen handling by pts and lab staff not known to have been educated regarding proper specimen handling). Our sTryp results agree closely with Vysniauskaite et al. but are lower than found in smaller cohorts in Zblewski D et al., Blood 2014;124(21):3204 (>33%) and Ravi A et al., J Allergy Clin Immunol Pract 2014;2(6):775.

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A Clinico Etiological Study of Chronic Urticaria and the Assessment of Quality of Life in Chronic Urticaria

http://www.indianjournals.com/ijor.aspx?target=ijor:ijcs2&volume=5&issue=1&article=011

International Journal of Contemporary Surgery – Year : 2017, Volume : 5, Issue : 1

Thiriveedhi Praveena, Saheb D Masthan, Latha M Madhavi (Department of Skin and VD, Santhiram Medical College and General Hospital, National Highway 18, Nandyal, Kurnool, Andhra Pradesh)

Abstract

Background

Urticaria is defined as a skin lesion consisting of a wheal and flare reaction in which localized intracutaneous oedema is surrounded by an area of redness that is typically pruritic. Chronic urticaria(CU) is prevalent and has devastating effects on quality of life (QoL).

Objectives

To evaluate etiological factors and assess quality of life in patients of chronic urticaria in relation to different types of urticaria.

Method

This descriptive study is conducted in a total of 150 patients of chronic urticaria attending DVL OPD, Santhiram Medical College and General Hospital. Complete history, physical examination is done and ASST, other specific investigations are done when required. The severity of urticaria is assessed using enhanced urticaria severity score while quality of life is assessed using modified Chronic Urticaria Quality of life questionnaire.

Results

On statistical analysis, the study sample consisted of 67 males and 83 females with mean age of 34 yrs. 28.7% patients had Chronic Idiopathic urticaria, 46.7% had chronic idiopathic urticaria along with physical urticaria, 5.3% had chronic auto immune urticaria, and 14.7% had chronic autoimmune urticaria with physical urticaria while 4.7% had physical urticaria without spontaneous hives. 20.7% showed positive result for ASST. Statistically significant increase in affect in females was noted in aspects like pruritus, wheals, angioedema, and interference in regular and recreational activity, mood disturbances, irritability, embarrassment while increased affect of side effects was noted in males.

Conclusion

Chronic Urticaria is common in females. Physical urticaria is common followed by idiopathic, autoimmune, and overlaps with other types. Mood disturbance is the commonly affected aspect of QOL. Quality of life is affected more in autoimmune urticaria when compared to other urticarial types.

Keywords

Chronic urticaria, angioedema, quality of life, chronic urticaria quality of life score, urticaria severity score.

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Allogeneic NK cells eradicate myeloblasts but not neoplastic mast cells in systemic mastocytosis associated with acute myeloid leukemia

http://onlinelibrary.wiley.com/doi/10.1002/ajh.24673/full

American Journal of Hematology – Accepted manuscript online: 10 February 2017

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Ampicillin/sulbactam-induced Kounis syndrome with cardiogenic shock

https://www.ncbi.nlm.nih.gov/pubmed/28209929

Anatol J Cardiol. 2017 Feb;17(2):154-155. doi: 10.14744/AnatolJCardiol.2016.7612.

Kounis NG, Koniari I (Department of Cardiology, University of Patras Medical Schhol; Patras-Greece)

Anaphylactic cardiogenic shock is a complex and extremely dangerous complication of anaphylaxis; it involves complex patho-physiological mechanisms, and its treatment remains unclear to date.

During anaphylactic shock, the main contributors to coronary hypoperfusion, leading to myocardial damage, are systemic vasodilatation, reduced venous return, leakage of plasma and volume loss due to increased vascular permeability, and diminished cardiac output (1). However, experimental and clinical evidence has shown that the heart, particularly the coronary arteries, is the main target of anaphylaxis. The experimental evidence of a rapid increase in left ventricular end-diastolic pressure during the initial phase of anaphylactic shock is attributed to coronary vasoconstriction than to leakage of plasma and volume loss (2). This is supported by clinical evidence that anaphylactic cardiogenic shock does not always respond to fluid

replacement but needs anti-allergic and myocardial infarction protocol treatment (3).

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