Publications by authors named "Karin Hartmann"

109 Publications

COVID-19 vaccination in mastocytosis: recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM).

J Allergy Clin Immunol Pract 2021 Apr 5. Epub 2021 Apr 5.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.

Mastocytosis is a neoplasm characterized by an accumulation of mast cells in various organs and increased risk for severe anaphylaxis in patients with concomitant allergies. Covid-19 is a pandemic that is associated with a relatively high rate of severe lung disease and mortality. The mortality is particularly high in those with certain comorbidities and increases with age. Recently, several companies have developed an effective vaccination against Covid-19. Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of Covid-19 vaccination in patients with severe allergies and mastocytosis. However, even in these patients, severe adverse reactions are rare. We therefore recommend the broad use of Covid-19 vaccination in patients with mastocytosis on a global basis. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication and post-vaccination observation should be considered in all patients with mastocytosis, depending on the individual personal risk and overall situation in each case. The current article provides a summary of published data, observations and expert opinion that form the basis of these recommendations.
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http://dx.doi.org/10.1016/j.jaip.2021.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019658PMC
April 2021

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.
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http://dx.doi.org/10.3390/ijms22052586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961542PMC
March 2021

Structured diagnostic assessment of hand eczema in cleaning workers.

J Dtsch Dermatol Ges 2021 Mar 25. Epub 2021 Mar 25.

Dermatology, Basel University Hospital and Basel University, Basel, Switzerland.

Hand dermatitis is a widespread problem among cleaners. In most cases, it is caused by a combination of wet work and contact with irritants, which can result in irritant (toxic) contact dermatitis. In some cases, the irritant contact eczema then evolves into allergic contact dermatitis, although not all cases of allergic contact dermatitis are preceded by irritant contact dermatitis. This mini-review proposes a two-step diagnostic algorithm based on patch testing, which can be used if allergic contact dermatitis is suspected in cleaning workers. As a first step, we recommend performing the DKG standard series (German Contact allergy research group, DKG), the DKG rubber series, both DKG "further fragrances" series as well as the DKG preservative and disinfectant series. If there are clear hints of an occupational contact dermatitis, the first step can also involve testing patients' own products alongside the standardized tests. In a second step (at the latest), if standardized tests do not suffice to identify the culprit allergen and there is well-founded suspicion, we recommend testing the patients' own products. If necessary, the second step can also include testing the individual contact allergens contained in the screening mixes that are part of the standard series.
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http://dx.doi.org/10.1111/ddg.14452DOI Listing
March 2021

Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and USA: Position statement of the German Allergy Societies: Medical Association of German Allergologists (AeDA), German Society for Allergology and Clinical Immunology (DGAKI) and Society for Pediatric Allergology and Environmental Medicine (GPA).

Allergo J Int 2021 24;30(2):51-55. Epub 2021 Feb 24.

Allergologie und Immunologie, Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.

Two employees of the National Health Service (NHS) in England developed severe allergic reactions following administration of BNT162b2 vaccine against COVID-19 (coronavirus disease 2019). The British SmPC for the BNT162b2 vaccine already includes reference to a contraindication for use in individuals who have had an allergic reaction to the vaccine or any of its components. As a precautionary measure, the Medicines and Healthcare products Regulatory Agency (MHRA) has issued interim guidance to the NHS not to vaccinate in principle in "patients with severe allergies". Allergic reactions to vaccines are very rare, but vaccine components are known to cause allergic reactions. BNT162b2 is a vaccine based on an mRNA embedded in lipid nanoparticles and blended with other substances to enable its transport into the cells. In the pivotal phase III clinical trial, the BNT162b2 vaccine was generally well tolerated, but this large clinical trial, used to support vaccine approval by the MHRA and US Food and Drug Administration, excluded individuals with a "history of a severe adverse reaction related to the vaccine and/or a severe allergic reaction (e.g., anaphylaxis) to a component of the study medication". Vaccines are recognized as one of the most effective public health interventions. This repeated administration of a foreign protein (antigen) necessitates a careful allergological history before each application and diagnostic clarification and a risk-benefit assessment before each injection. Severe allergic reactions to vaccines are rare but can be life-threatening, and it is prudent to raise awareness of this hazard among vaccination teams and to take adequate precautions while more experience is gained with this new vaccine.
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http://dx.doi.org/10.1007/s40629-020-00160-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903024PMC
February 2021

Clinical Impact of Skin Lesions in Mastocytosis: A Multicenter Study of the European Competence Network on Mastocytosis.

J Invest Dermatol 2021 Feb 11. Epub 2021 Feb 11.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria. Electronic address:

Mastocytosis is a rare neoplasm characterized by the expansion and accumulation of mast cells in various organ systems. Systemic mastocytosis (SM) may or may not present with cutaneous lesions. To examine the frequency and clinical impact of cutaneous involvement, data on 1,510 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis were analyzed. Cutaneous involvement was found in 1,195 of 1,510 patients (79.1%). Of these, 286 had cutaneous mastocytosis, and 721 had SM with skin involvement. Adult patients with skin involvement who did not have a bone marrow examination (n = 188) were defined as having mastocytosis in the skin. In 315 patients, SM without skin involvement was found. The percentage of cases with cutaneous involvement was higher in indolent SM (100%) and smoldering SM (87.9%) compared to aggressive SM (46.8%) or mast cell leukemia (38.5%). After a median follow-up of 5.6 years, no patient with cutaneous mastocytosis had died, but 2.6% of the patients with mastocytosis in the skin, 5.7% of the patients with SM with skin involvement, and 28.95% of the patients with SM without skin involvement had died. Overall survival was longer in patients with skin involvement (cutaneous mastocytosis and/or mastocytosis in the skin and/or SM with skin involvement) than in patients with SM without skin involvement (P < 0.0001). These data argue for a thorough examination of both the skin and bone marrow in adult patients with mastocytosis.
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http://dx.doi.org/10.1016/j.jid.2020.12.030DOI Listing
February 2021

Management of Hypersensitivity Reactions to Nondextran Iron Products: New Insights Into Predisposing Risk Factors.

J Allergy Clin Immunol Pract 2021 Jan 21. Epub 2021 Jan 21.

Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: Hypersensitivity reactions (HSRs) to nondextran iron products (NDIPs) are rare, but can manifest with severe signs and symptoms. Predisposing risk factors are not well understood.

Objective: To characterize patients with HSRs to NDIPs, with a special focus on possible risk factors.

Methods: We analyzed clinical characteristics of patients with HSRs to NDIPs referred to our allergy division between 2007 and 2019 compared with tolerant controls, including the type of the eliciting NDIP, severity and characteristics of the HSR, atopy status, history of allergies and urticaria, laboratory and skin test results, and outcome of reexposure with NDIPs.

Results: We evaluated the data of 59 patients and 21 controls. Sixteen patients and 4 controls received the NDIP iron sucrose and 41 patients and 15 controls received ferric carboxymaltose. In 2 patients and in 2 controls, the culprit NDIP was not known. Twenty-seven patients (46%) experienced an anaphylactic reaction grade I, 15 (25%) a grade II reaction, and 17 (29%) a grade III reaction according to Ring and Messmer. On analyzing the history, we found that 22 patients (37%) and 3 controls (14%) reported previous HSRs to other medications. Interestingly, more than half the patients (n = 35 [59%]) compared with only 7 controls (33%) reported an episode of any type of urticaria in their previous history. Most patients (n = 15 [79%]) tolerated reexposure of an NDIP using a low-reactogenic administration protocol.

Conclusions: A history of drug hypersensitivity and urticaria represent potential risk factors for HSRs to NDIPs. On the basis of our findings, we propose an algorithm for practical management of patients receiving NDIPs aiming to prevent HSRs.
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http://dx.doi.org/10.1016/j.jaip.2021.01.009DOI Listing
January 2021

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis.

Theranostics 2021 1;11(1):292-303. Epub 2021 Jan 1.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; 0.001). Correspondingly, organomegaly (male: 23% female: 13%, 0.007) was more, whereas skin involvement (male: 71% female: 86%, 0.001) was less frequent in males. In all patients together, OS ( 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly ( 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% 5%, 0.006) or molecular aberrations (// profile; 63% 40%, 0.003) were more frequently present in males. Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.
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http://dx.doi.org/10.7150/thno.51872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681091PMC
January 2021

Scoring the Risk of Having Systemic Mastocytosis in Adult Patients with Mastocytosis in the Skin.

J Allergy Clin Immunol Pract 2021 Apr 23;9(4):1705-1712.e4. Epub 2020 Dec 23.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.

Background: Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients.

Objective: To develop a risk score to predict SM in adults with MIS.

Methods: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 ± 13.3 years. The median serum tryptase level amounted to 29.3 ± 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves.

Results: In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated.

Conclusions: Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis.
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http://dx.doi.org/10.1016/j.jaip.2020.12.022DOI Listing
April 2021

Healthcare provision for insect venom allergy patients during the COVID-19 pandemic.

Allergo J Int 2020 8;29(8):257-261. Epub 2020 Dec 8.

Department and Outpatient Clinic for Dermatology and Allergology, University Hospital Munich, Munich, Germany.

The population prevalence of insect venom allergy ranges between 3-5%, and it can lead to potentially life-threatening allergic reactions. Patients who have experienced a systemic allergic reaction following an insect sting should be referred to an allergy specialist for diagnosis and treatment. Due to the widespread reduction in outpatient and inpatient care capacities in recent months as a result of the COVID-19 pandemic, the various allergy specialized centers in Germany, Austria, and Switzerland have taken different measures to ensure that patients with insect venom allergy will continue to receive optimal allergy care. A recent data analysis from the various centers revealed that there has been a major reduction in newly initiated insect venom immunotherapy (a 48.5% decline from March-June 2019 compared to March-June 2020: data from various centers in Germany, Austria, and Switzerland). The present article proposes defined organizational measures (e.g., telephone and video appointments, rearranging waiting areas and implementing hygiene measures and social distancing rules at stable patient numbers) and medical measures (collaboration with practice-based physicians with regard to primary diagnostics, rapid COVID-19 testing, continuing already-initiated insect venom immunotherapy in the outpatient setting by making use of the maximal permitted injection intervals, prompt initiation of insect venom immunotherapy during the summer season, and, where necessary, using outpatient regimens particularly out of season) for the care of insect venom allergy patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1007/s40629-020-00157-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722411PMC
December 2020

Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine.

Int J Mol Sci 2020 Nov 27;21(23). Epub 2020 Nov 27.

Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20852, USA.

Mast cell activation (MCA) is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell (MC) disorders, and hereditary alpha tryptasemia (HAT). MCA-related symptoms range from mild to severe to life-threatening. The severity of MCA-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of MCs, organs affected, and the type and consequences of comorbid conditions. In severe systemic reactions, MCA is demonstrable by a substantial increase of basal serum tryptase levels above the individual's baseline. When, in addition, the symptoms are recurrent, involve more than one organ system, and are responsive to therapy with MC-stabilizing or mediator-targeting drugs, the consensus criteria for the diagnosis of MCA syndrome (MCAS) are met. Based on the etiology of MCA, patients can further be classified as having i) primary MCAS where -mutated, clonal, MCs are detected; ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or iii) idiopathic MCAS, where neither a triggering reactive state nor -mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where -mutated MCs, IgE-dependent allergies and sometimes HAT are detected. These patients may suffer from life-threatening anaphylaxis and are candidates for combined treatment with various types of drugs, including IgE-blocking antibodies, anti-mediator-type drugs and MC-targeting therapy. In conclusion, detailed knowledge about the etiology, underlying pathologies and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine.
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http://dx.doi.org/10.3390/ijms21239030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731385PMC
November 2020

Practical management of adverse events in patients with advanced systemic mastocytosis receiving midostaurin.

Expert Opin Biol Ther 2021 Apr 15;21(4):487-498. Epub 2021 Jan 15.

University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

Introduction: Systemic mastocytosis (SM) is characterized by the overproduction and accumulation of neoplastic mast cells (MCs) in the bone marrow, skin, and visceral organs. The D816V mutation is found in approximately 90% of cases. In advanced SM (advSM), inferior survival often relates to MC-induced organ damage that may impact multiple organ systems. In addition, mediator symptoms related to MC activation can severely impact the quality of life. The oral multikinase/KIT inhibitor midostaurin was approved by the US Food and Drug Administration and the European Medicines Agency as monotherapy for advSM based on data from phase 2 clinical studies.

Areas Covered: This review discusses the management of common adverse events (AEs) in patients with advSM who participated in phase 2 clinical studies that led to the approval of midostaurin.

Expert Opinion: In the advSM population undergoing treatment with midostaurin, treatment-related AEs are often difficult to distinguish from disease-related symptoms, which can lead to premature discontinuation and improper dose reduction of midostaurin therapy in patients who might have benefitted from continued therapy. Here we present strategies to help optimize AE management and maximize the potential benefits of midostaurin in advSM.
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http://dx.doi.org/10.1080/14712598.2021.1837109DOI Listing
April 2021

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts.

Theranostics 2020 29;10(23):10743-10768. Epub 2020 Aug 29.

Departments of Pathology and of Microbiology and Immunology, and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, USA.

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.
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http://dx.doi.org/10.7150/thno.46719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482799PMC
August 2020

Emerging treatments in COVID-19: Adverse drug reactions including drug hypersensitivities.

J Allergy Clin Immunol 2020 10 22;146(4):786-789. Epub 2020 Jul 22.

Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833501PMC
October 2020

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions.

J Allergy Clin Immunol 2020 08 17;146(2):300-306. Epub 2020 Jun 17.

Division of Allergy, Department of Dermatology, and Department of Biomedicine, University of Basel, Basel, Switzerland.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
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http://dx.doi.org/10.1016/j.jaci.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297685PMC
August 2020

Utility and risk of dermatologic medications during the COVID-19 pandemic.

Dermatol Ther 2020 11 5;33(6):e13833. Epub 2020 Aug 5.

Department of Dermatology and Allergy, University Hospital Basel, Basel, Switzerland.

In the era of staggering speed in development of the novel coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we have reviewed the dermatologists' tools at hand for their utility (and potential risks) in patients affected by COVID-19. This review aims to shed light on the antiviral and proviral potential of drugs routinely used in dermatology to modulate COVID-19. The literature search included peer-reviewed articles published in the English language (clinical trials or scientific reviews). Studies were identified by searching electronic databases (MEDLINE and PubMed) from January 1990 to March 2020 and by reference lists of respective articles. Somewhat to our surprise, we have found that several of our drugs widely used in dermatology have antiviral potential. On the other hand, we also frequently use immunosuppressive drugs in our dermatologic patients that potentially pose them at increased risk for COVID-19.
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http://dx.doi.org/10.1111/dth.13833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323423PMC
November 2020

Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.

J Allergy Clin Immunol 2020 08 11;146(2):356-366.e4. Epub 2020 May 11.

University Medical Center Groningen, Department of Hematology, University of Groningen, Groningen, The Netherlands.

Background: Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level.

Objective: We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM.

Methods: In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated by using a specific physician-reported questionnaire.

Results: Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms.

Conclusion: QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
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http://dx.doi.org/10.1016/j.jaci.2020.03.044DOI Listing
August 2020

Getrübter Badespaß: Hautveränderungen nach Kontakt mit Quallen.

J Dtsch Dermatol Ges 2020 May;18(5):473-476

Klinik für Dermatologie, Allergologie und Venerologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck.

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http://dx.doi.org/10.1111/ddg.14088_gDOI Listing
May 2020

Multilocular bullous fixed drug eruption elicited by paracetamol and migraine attacks, but not by paracetamol alone.

Contact Dermatitis 2020 Sep 13;83(3):233-234. Epub 2020 May 13.

Division of Allergy, Department of Dermatology, University Hospital Basel, Basel, Switzerland.

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http://dx.doi.org/10.1111/cod.13567DOI Listing
September 2020

Natatorial mishap: Skin lesions caused by jellyfish stings.

J Dtsch Dermatol Ges 2020 May 20;18(5):473-475. Epub 2020 Apr 20.

Department of Dermatology, Allergology and Venereology, Schleswig-Holstein University Medical Center, Lübeck, Germany.

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http://dx.doi.org/10.1111/ddg.14088DOI Listing
May 2020

Urticaria: Collegium Internationale Allergologicum (CIA) Update 2020.

Int Arch Allergy Immunol 2020 30;181(5):321-333. Epub 2020 Mar 30.

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU.
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http://dx.doi.org/10.1159/000507218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265766PMC
November 2020

Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.

Allergy 2020 08 16;75(8):1927-1938. Epub 2020 Mar 16.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.

Background: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM.

Methods: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM.

Results: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly.

Conclusion: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.
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http://dx.doi.org/10.1111/all.14248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115854PMC
August 2020

Activation of Siglec-7 results in inhibition of in vitro and in vivo growth of human mast cell leukemia cells.

Pharmacol Res 2020 08 5;158:104682. Epub 2020 Feb 5.

Pharmacology & Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel. Electronic address:

Advanced systemic mastocytosis is a rare and still untreatable disease. Blocking antibodies against inhibitory receptors, also known as "immune checkpoints", have revolutionized anti-cancer treatment. Inhibitory receptors are expressed not only on normal immune cells, including mast cells but also on neoplastic cells. Whether activation of inhibitory receptors through monoclonal antibodies can lead to tumor growth inhibition remains mostly unknown. Here we show that the inhibitory receptor Siglec-7 is expressed by primary neoplastic mast cells in patients with systemic mastocytosis and by mast cell leukemia cell lines. Activation of Siglec-7 by anti-Siglec-7 monoclonal antibody caused phosphorylation of Src homology region 2 domain-containing phosphatase-1 (SHP-1), reduced phosphorylation of KIT and induced growth inhibition in mast cell lines. In SCID-beige mice injected with either the human mast cell line HMC-1.1 and HMC-1.2 or with Siglec-7 transduced B cell lymphoma cells, anti-Siglec-7 monoclonal antibody reduced tumor growth by a mechanism involving Siglec-7 cytoplasmic domains in "preventive" and "treatment" settings. These data demonstrate that activation of Siglec-7 on mast cell lines can inhibit their growth in vitro and in vivo. This might pave the way to additional treatment strategies for mastocytosis.
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http://dx.doi.org/10.1016/j.phrs.2020.104682DOI Listing
August 2020

New developments in the field of mastocytosis and mast cell activation syndromes: a summary of the Annual Meeting of the European Competence Network on Mastocytosis (ECNM) 2019.

Leuk Lymphoma 2020 05 26;61(5):1075-1083. Epub 2019 Dec 26.

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.

Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical mast cells in one or several organs/tissues, often accompanied by mast cell activation. Whereas in children the disease manifestations are mostly limited to the skin, in adults the disease is usually systemic (systemic mastocytosis; SM) and involves the bone marrow and/or other internal organs. Several variants of SM have been defined. Whereas most patients have indolent SM, some patients have advanced SM, which underlines the complexity of SM. In 2002, a European consortium of clinicians and scientists initiated a multidisciplinary, multi-national cooperative network, termed the 'European Competence Network on Mastocytosis' (ECNM), with the aim to improve diagnosis and therapy of patients with mastocytosis and other mast cell activation disorders. Since then, members of the ECNM have organized Annual Meetings in several European countries. The present article provides a summary of advances in the field presented during the 17th Annual ECNM meeting held in Salzburg in October 2019.
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http://dx.doi.org/10.1080/10428194.2019.1703974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115828PMC
May 2020

Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry.

Leukemia 2020 04 18;34(4):1090-1101. Epub 2019 Nov 18.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Vienna, Austria.

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5 × 10/l), and 3.1% hypereosinophilia (HE; >1.5 × 10/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p < 0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n = 1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.
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http://dx.doi.org/10.1038/s41375-019-0632-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115841PMC
April 2020