Publications by authors named "Karoline Krause"

49 Publications

Cryoglobulins, Cryofibrinogens, and Cold Agglutinins in Cold Urticaria: Literature Review, Retrospective Patient Analysis, and Observational Study in 49 Patients.

Front Immunol 2021 25;12:675451. Epub 2021 May 25.

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

Introduction: Cryoproteins, such as cryoglobulins, cryofibrinogens and cold agglutinins, precipitate at low temperatures or agglutinate erythrocytes and dissolve again when warmed. Their pathogenetic and diagnostic importance in cold urticaria (ColdU) is unclear. In this study, we aimed to characterize the prevalence of cryoproteins in patients with ColdU.

Methods: We conducted 3 analyses: i) a systematic review and meta-analysis of published data using an adapted version of the Joanna Briggs Institute's critical appraisal tool for case series, ii) a retrospective analysis of 293 ColdU patients treated at our Urticaria Center of Reference and Excellence (UCARE) from 2014 to 2019, and iii) a prospective observational study, from July 2019 to July 2020, with 49 ColdU patients as defined by the EAACI/GA2LEN/EDF/UNEV consensus recommendations.

Results: Our systematic review identified 14 relevant studies with a total of 1151 ColdU patients. The meta-analyses showed that 3.0% (19/628), 1.1% (4/357) and 0.7% (2/283) of patients had elevated levels of cryoglobulins, cryofibrinogens and cold agglutinins, respectively. Our retrospective analyses showed that cryoproteins were assessed in 4.1% (12/293) of ColdU patients. None of 9 ColdU patients had cryoglobulins, and one of 5 had cold agglutinins. In our prospective study, none of our patients had detectable cryoglobulins (0/48) or cryofibrinogens (0/48), but 4.3% (2/46) of patients had cold agglutinins (without any known underlying autoimmune or hematological disorder).

Conclusion: Our investigation suggests that only very few ColdU patients exhibit cryoproteins and that the pathogenesis of ColdU is driven by other mechanisms, which remain to be identified and characterized in detail.
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http://dx.doi.org/10.3389/fimmu.2021.675451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186313PMC
May 2021

Effects of pregnancy on chronic urticaria: Results of the PREG-CU UCARE study.

Allergy 2021 May 22. Epub 2021 May 22.

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Urticaria Center of Reference and Excellence (UCARE), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Chronic urticaria (CU) predominantly affects women, and sex hormones can modulate disease activity in female CU patients. As of now, the impact of pregnancy on CU is largely unknown.

Aim: To analyze the course and features of CU during and after pregnancy.

Patients And Methods: PREG-CU is an international, multicenter study of the Urticaria Centers of Reference and Excellence (UCARE) network. Data were collected via a 47-item questionnaire completed by CU patients, who became pregnant within the last 3 years.

Results: A total of 288 pregnancies of 288 CU patients from 13 countries were analyzed (mean age at pregnancy: 32.1 ± 6.1 years, duration of CU: 84.9 ± 74.5 months; CSU 66.9%, CSU + CIndU 20.3%, CIndU 12.8%).During pregnancy, 51.1% of patients rated their CU as improved, 28.9% as worse, and 20.0% as unchanged.CU exacerbations most commonly occurred exclusively during the third trimester (in 34 of 124 patients; 27.6%) or the first (28 of 124; 22.8%). The risk factors for worsening of CU during pregnancy were having mild disease and no angioedema before pregnancy, not taking treatment before pregnancy, CIndU, CU worsening during a previous pregnancy, treatment during pregnancy, and stress as a driver of exacerbations. After giving birth, urticaria disease activity remained unchanged in 43.8% of CU patients, whereas 37.4% and 18.1% experienced worsening and improvement, respectively.

Conclusions: These results demonstrate the complex impact of pregnancy on the course of CU and help to better counsel patients who want to become pregnant and to manage CU during pregnancy.
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http://dx.doi.org/10.1111/all.14950DOI Listing
May 2021

Lower IgA Levels in Chronic Spontaneous Urticaria Are Associated With Lower IgE Levels and Autoimmunity.

Front Immunol 2021 3;12:657211. Epub 2021 May 3.

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background: The pathogenesis of chronic spontaneous urticaria (CSU) is still insufficiently understood. Recent findings suggest that immunoglobulins, in particular IgE but also IgA, play a role in the development of CSU.

Objective: Our aim was to assess differences in clinical and laboratory markers between CSU patients with and without lower levels of serum IgA and IgE.

Methods: We analyzed the data of 606 patients with CSU by dividing them into four groups based on their IgA and IgE levels. The groups were compared for their spectrum of symptoms, disease activity, concomitant autoimmunity and routine laboratory markers. Autoreactivity was assessed by basophil activation test (BAT). Moreover, IgE-anti-thyroid peroxidase (TPO) was measured.

Results: Of the patients with lower IgE levels, 66.5% also had lower IgA levels (r=0.316, p<0.001). Patients with lower IgA and lower IgE levels showed a higher prevalence of recurrent angioedema (p=0.03, p=0.04) and concomitant autoimmunity (p=0.006, p<0.001). Autoreactivity was also found more frequently in patients with lower IgA and lower IgE levels (p=0.003, p<0.001). Reduced basophil counts were linked to both, lower IgA and lower IgE levels (p<0.001), whereas low eosinophil counts were primarily present in patients with lower IgE levels (p=0.04, p<0.001). Patients with elevated IgE-anti-TPO levels had lower IgA (p=0.007) and IgE levels (p=0.001).

Conclusion: Lower IgA levels in CSU are linked to lower IgE levels and features of autoimmune urticaria. Our findings encourage to screen CSU patients for serum IgA and IgE levels and to further assess their role as disease biomarkers.
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http://dx.doi.org/10.3389/fimmu.2021.657211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128143PMC
May 2021

A novel histopathological scoring system to distinguish urticarial vasculitis from chronic spontaneous urticaria.

Clin Transl Allergy 2021 Apr;11(2):e12031

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Urticarial vasculitis (UV) is defined by long-lasting urticarial lesions combined with the histopathologic findings of leukocytoclastic vasculitis. As one of the major unmet needs in UV, diagnostic criteria are rather vague and not standardized. Moreover, there seems to be considerable overlap with chronic spontaneous urticaria (CSU), particularly for the normocomplementemic variant of UV. Therefore, this study aimed to develop a diagnostic scoring system that improves the histopathologic discrimination between UV and CSU.

Methods: Lesional skin sections of patients with clinical and histopathologic diagnosis of UV (n = 46) and CSU (n = 51) were analyzed (blinded to the diagnosis) for the following pre-defined criteria: presence of leukocytoclasia, erythrocyte extravasation, fibrin deposits, endothelial cell swelling, ectatic vessels, blurred vessel borders, dermal edema, intravascular neutrophil, and eosinophil numbers and numbers of dermal neutrophils, macrophages and mast cells.

Results: The greatest differences between UV and CSU samples were observed for leukocytoclasia (present in 76% of UV vs. 3.9% of CSU samples; p < 0.0001), erythrocyte extravasation (present in 41.3% of UV vs. 2.0% of CSU samples; p < 0.0001), and fibrin deposits (present in 27.9% of UV vessels vs. 9.7% of CSU vessels; p < 0.0001). Based on these findings, we developed a diagnostic score, the urticarial vasculitis score (UVS), which correctly assigned 37 of 46 cases of UV and 49 of 51 cases of CSU to the previously established diagnosis.

Conclusion: Our results suggest that the UVS, a combined quantitative assessment of the three criteria leukocytoclasia, fibrin deposits and extravasated erythrocytes, distinguishes UV from CSU in skin histopathology. The UVS, if validated in larger patient samples, may help to improve the diagnostic approach to UV.
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http://dx.doi.org/10.1002/clt2.12031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099228PMC
April 2021

Chronic Urticaria and Recurrent Angioedema: Clues to the Mimics.

J Allergy Clin Immunol Pract 2021 06 24;9(6):2220-2228. Epub 2021 Apr 24.

Department of Dermatology, Mayo Clinic Rochester, Rochester, Minn.

Urticaria and angioedema are experienced by up to 1 in 5 people, usually the result of common allergen or medication triggers and infections. Similarly, the majority of recurrent angioedema has an exogenous trigger, for example, angiotensin converting enzyme inhibitors, or is hereditary (type 1 and 2 hereditary angioedema); chronic spontaneous urticaria are most often autoimmune or autoallergic in routine clinical practice. There are, however, several skin and systemic conditions that can imitate the clinical appearance of either angioedema or urticaria, whereas there are several uncommon conditions that have chronic urticaria and/or recurrent angioedema as part of their disease manifestations. Correct diagnosis is paramount to ensuring subsequent tailored therapy for many of these conditions, and in many instances, diagnostic delay can be several years with morbid consequence. In this grand rounds article, we present 2 illustrative clinical cases as the backdrop to discussing a practical diagnostic approach for clinicians to recognize copycat phenotypes and "red flags" that should prompt further investigation of several uncommon mimics. We highlight key diagnostic features, epidemiology, and management for mimics where treatment is distinct from the common phenotypes of recurrent angioedema and chronic urticarias.
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http://dx.doi.org/10.1016/j.jaip.2021.03.043DOI Listing
June 2021

The Diagnostic Workup in Chronic Spontaneous Urticaria-What to Test and Why.

J Allergy Clin Immunol Pract 2021 06 20;9(6):2274-2283. Epub 2021 Apr 20.

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. Electronic address:

Background: In chronic spontaneous urticaria (CSU), the guidelines recommend very limited diagnostic procedures during the routine workup, although additional investigations might be indicated in some patients with CSU. For physicians treating patients with CSU, it is often difficult to decide which diagnostic tests are useful.

Objective: To provide recommendations on what diagnostic tests should be performed on which patients with CSU.

Methods: We performed an extensive literature search on the respective topics and identified relevant questions that should prompt diagnostic procedures based on the published evidence and expert consensus among all authors.

Results: We provide questions, diagnostic testing, where appropriate, and recommendation that should be included when assessing the history of a patient with CSU, to explore and rule out differential diagnoses, to assess patients for underlying causes and modifying conditions, to explore patients for comorbid diseases and consequences of having CSU, and to assess patients for CSU components that can help to predict their disease course and response to treatment.

Conclusions: Here, we provide physicians treating patients with CSU with information about which clues should lead to which tests and why.
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http://dx.doi.org/10.1016/j.jaip.2021.03.049DOI Listing
June 2021

Tocilizumab treatment in patients with Schnitzler syndrome: An open-label study.

J Allergy Clin Immunol Pract 2021 06 2;9(6):2486-2489.e4. Epub 2021 Feb 2.

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; Autoinflammation Reference Center Charité (ARC2), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2021.01.024DOI Listing
June 2021

Evidence of B Cell Clonality and Investigation Into Properties of the IgM in Patients With Schnitzler Syndrome.

Front Immunol 2020 3;11:569006. Epub 2020 Dec 3.

National Institute for Health Research-Leeds Musculoskeletal Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, United Kingdom.

The Schnitzler Syndrome (SchS) is an acquired, autoinflammatory condition successfully treated with IL-1 inhibition. The two main defining features of this late-onset condition are neutrophilic urticarial dermatoses (NUD) and the presence of an IgM monoclonal component. While the former aspect has been extensively studied in this disease setting, the enigmatic paraproteinaemia and its potential consequential effects within SchS, has not previously been thoroughly addressed. Previous studies analyzing clonal B cell repertoires have largely focused on autoimmune disorders such as Systemic Lupus Erythematous (SLE) and hematological malignancies such as Chronic Lymphocytic Leukaemia (CLL), where B-cell clonality is central to disease pathology. The present study uses next-generation sequencing to provide detailed insight into aspects of B cell VDJ recombination and properties of the resulting immunoglobulin chains. An overview of IgH regional dynamics in 10 SchS patients, with a particular focus on CDR3 sequences and VDJ gene usage is reported, highlighting the presence of specific B cell expansions. Protein microarray detected a substantial proportion of autoreactive IgM to nuclear target proteins, though a single universal target was not identified. Together, these genetic and functional findings impart new understanding into this rare disorder.
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http://dx.doi.org/10.3389/fimmu.2020.569006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793813PMC
May 2021

Management of urticarial vasculitis: A worldwide physician perspective.

World Allergy Organ J 2020 Mar 5;13(3):100107. Epub 2020 Mar 5.

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

Background: Urticarial vasculitis (UV) is a rare type of leukocytoclastic vasculitis characterized by long lasting urticarial skin lesions and poor response to treatment. As of yet, no clinical guidelines, diagnostic criteria, or treatment algorithms exist, and the approaches to the diagnostic workup and treatment of UV patients may differ globally. We conducted an online survey to examine how UV patients are diagnosed and treated by international specialists and to reveal the greatest challenges in managing UV patients worldwide.

Methods: Distribution of the questionnaire included an email to individuals in the World Allergy Organization (WAO) database, with no restrictions applied to the specialty, affiliation, or nationality of the participants (November 2018). The email contained a link (Internet address) to the online questionnaire. Responses were anonymous. The link to the questionnaire was further sent to the network of Urticaria Centers of Reference and Excellence (UCARE) in the Global Allergy and Asthma European Network (GALEN) as well as to the Turkish Dermatology Society and the Japanese Society of Allergology, who distributed the link to their members. In addition, the survey link was posted online in the group of the Russian Society of Allergologists and Immunologists.

Results: We received 883 completed surveys from physicians in 92 countries. UV was reported to be rare in clinical practice, with an average of 5 patients per physician per year. More than two-thirds of physicians reported wheals, burning of the skin, and residual hyperpigmentation in 60-100% of UV patients. The most frequently reported reason for receiving referrals of patients with UV was to establish the diagnosis. The most important features for establishing the diagnosis of UV were wheals of longer than 24 hours duration (72%), the results of skin biopsy (63%), and post-inflammatory hyperpigmentation (46%). The most common tests ordered in UV patients were complete blood count, erythrocyte sedimentation rate, C-reactive protein, complement components, antinuclear antibodies, and skin biopsy. Physicians considered UV to be of unknown cause in most patients, and drugs and systemic lupus erythematosus to be the most common identifiable causes. Two of 3 physicians reported that they use second-generation antihistamines in standard dose as the first-line therapy in patients with UV. The greatest perceived challenges in the management of UV were the limited efficacy of drugs and the absence of clinical guidelines and treatment algorithms.

Conclusions: UV is a challenging disease. Skin biopsy, a gold standard for UV diagnosis, is not performed by many physicians. This may lead to misdiagnosis of UV, for example, as chronic spontaneous urticaria, and to inadequate treatment. International consensus-based recommendations for the classification of UV and the diagnostic workup and treatment, as well as prospective studies evaluating potentially safe and effective drugs for the treatment of UV, are necessary.
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http://dx.doi.org/10.1016/j.waojou.2020.100107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063238PMC
March 2020

Validation of the Angioedema Control Test (AECT)-A Patient-Reported Outcome Instrument for Assessing Angioedema Control.

J Allergy Clin Immunol Pract 2020 06 12;8(6):2050-2057.e4. Epub 2020 Mar 12.

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Recurrent angioedema (RA) is an important clinical problem in routine care and emergency medicine. As of recently, the only validated tools to specifically assess disease status in patients with RA were diary-type activity assessments and angioedema-related quality-of-life questionnaires. Although these tools are particularly helpful in clinical studies, they were not designed to determine disease control or to guide treatment decisions. To close this gap, the Angioedema Control Test (AECT) was published recently.

Objective: To test the AECT for its validity and reliability, and to identify a cutoff value to aid treatment decisions.

Methods: Two AECT versions with a recall period of 4 weeks (AECT-4wk) and 3 months (AECT-3mo) were tested for their internal consistency and test-retest reliability, convergent and known-groups validity as well as screening accuracy in 81 patients with RA with bradykinin-mediated angioedema, mast cell mediator-mediated angioedema, or idiopathic angioedema.

Results: Both AECT versions showed excellent internal consistency reliability with a Cronbach alpha value of more than 0.85 and test-retest reliability with an intraclass correlation coefficient greater than 0.9. The convergent validity of both AECT versions was high. Both tools showed strong correlations with anchors of disease control, angioedema frequency, and health-related quality of life. A stratification of AECT scores into different levels of disease control together with a receiver-operating characteristic curve analysis suggested a cutoff value of 10 or more points to identify patients with well-controlled RA versus less than 10 points to identify patients with poorly controlled disease for both AECT versions.

Conclusions: The AECT is the first valid and reliable patient-reported outcome measure to assess disease control in patients with RA.
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http://dx.doi.org/10.1016/j.jaip.2020.02.038DOI Listing
June 2020

Spectrum of Genetic Autoinflammatory Diseases Presenting with Cutaneous Symptoms.

Acta Derm Venereol 2020 Mar;100(7):adv00091

Autoinflammatory diseases comprise a group of chronic disabling entities characterized by inflammation without the presence of infectious agents, auto-antibodies or antigen-specific T-cells. Many autoinflammatory diseases are caused by monogenic defects, which lead to disturbed immune signalling with release of proinflammatory mediators. In addition to interleukin-1β and interleukin-18, interferons play a key role in the pathophysiology of these disorders. Patients with autoinflammatory diseases show a broad variety of clinical symptoms, including skin involvement. Wheals, pustules and ulcerative lesions are the most common cutaneous findings observed. Knowledge of the clinical presentation of autoinflammatory diseases is crucial for establishing the diagnosis and guiding appropriate treatment. This review focuses on the dermatological findings in selected autoinflammatory disorders based on their distinct pathomechanisms.
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http://dx.doi.org/10.2340/00015555-3427DOI Listing
March 2020

Response of omalizumab in normocomplementemic urticarial vasculitis.

J Allergy Clin Immunol Pract 2020 06 5;8(6):2114-2117.e2. Epub 2020 Mar 5.

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.02.024DOI Listing
June 2020

Long-term efficacy of canakinumab in the treatment of Schnitzler syndrome.

J Allergy Clin Immunol 2020 06 12;145(6):1681-1686.e5. Epub 2020 Jan 12.

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.

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http://dx.doi.org/10.1016/j.jaci.2019.12.909DOI Listing
June 2020

Cold-induced urticarial autoinflammatory syndrome related to factor XII activation.

Nat Commun 2020 01 10;11(1):179. Epub 2020 Jan 10.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Hereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleavage of the mutated protein and spontaneous FXII activation in patient plasma and in supernatant of transfected HEK293 cells expressing recombinant W268R-mutated proteins. Furthermore, we observe reduced plasma prekallikrein, cleaved high molecular weight kininogen and elevated plasma bradykinin. Neutrophils are identified as a local source of FXII. Interleukin-1β (IL-1β) is upregulated in lesional skin and mononuclear donor cells exposed to recombinant mutant proteins. Treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduces disease activity in patients. In conclusion, our findings provide a link between contact system activation and cytokine-mediated inflammation.
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http://dx.doi.org/10.1038/s41467-019-13984-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954242PMC
January 2020

Development of the Angioedema Control Test-A patient-reported outcome measure that assesses disease control in patients with recurrent angioedema.

Allergy 2020 05 6;75(5):1165-1177. Epub 2020 Mar 6.

Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Recurrent angioedema (AE) is an important clinical problem in the context of chronic urticaria (mast cell mediator-induced), ACE-inhibitor intake and hereditary angioedema (both bradykinin-mediated). To help patients obtain control of their recurrent AE is a major treatment goal. However, a tool to assess control of recurrent AE is not yet available. This prompted us to develop such a tool, the Angioedema Control Test (AECT).

Methods: After a conceptional framework was developed for the AECT, a list of potential AECT items was generated by a combined approach of patient interviews, literature review and expert input. Subsequent item reduction was based on impact analysis, inter-item correlation, additional predefined criteria for item performance, and a review of the item selection process for content validity. Finally, an instruction section was generated, and an US-American-English version was developed by a structured translation process.

Results: A 4-item AECT with recall periods of 4 weeks and 3 months was developed based on 106 potential items tested in 97 patients with mast cell mediator-induced (n = 49) or bradykinin-mediated recurrent AE (n = 48). Eighty-four items were excluded based on impact analysis. The remaining 22 items could be further reduced by a method-mix of inter-item correlation, additional predefined criteria for item performance and review for content validity.

Conclusions: The AECT is the first tool to assess disease control in recurrent AE patients. Its retrospective approach, its brevity and its simple scoring make the AECT ideally suited for clinical practice and trials. Its validity and reliability need to be determined in future independent studies.
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http://dx.doi.org/10.1111/all.14144DOI Listing
May 2020

A mutation in the kringle domain of human factor XII that causes autoinflammation, disturbs zymogen quiescence, and accelerates activation.

J Biol Chem 2020 01 26;295(2):363-374. Epub 2019 Nov 26.

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands. Electronic address:

Coagulation factor XII (FXII) drives production of the inflammatory peptide bradykinin. Pathological mutations in the gene, which encodes FXII, provoke acute tissue swelling in hereditary angioedema (HAE). Interestingly, a recently identified mutation, causing a W268R substitution, is not associated with HAE. Instead, FXII-W268R carriers experience cold-inducible urticarial rash, arthralgia, fever, and fatigue. Here, we aimed to investigate the molecular characteristics of the FXII-W268R variant. We expressed wild type FXII (FXII-WT), FXII-W268R, and FXII-T309R (which causes HAE), as well as other FXII variants in HEK293 freestyle cells. Using chromogenic substrate assays, immunoblotting, and ELISA, we analyzed expression media, cell lysates, and purified proteins for FXII activation. Recombinant FXII-W268R forms increased amounts of intracellular cleavage products that are also present in expression medium and display enzymatic activity. The active site-incapacitated variant FXII-W268R/S544A reveals that intracellular fragmentation is largely dependent on autoactivation. Purified FXII-W268R is highly sensitive to activation by plasma kallikrein and plasmin, compared with FXII-WT or FXII-T309R. Furthermore, binding studies indicated that the FXII-W268R variant leads to the exposure of a plasminogen-binding site that is cryptic in FXII-WT. In plasma, recombinant FXII-W268R spontaneously triggers high-molecular-weight kininogen cleavage. Our findings suggest that the W268R substitution influences FXII protein conformation and exposure of the activation loop, which is concealed in FXII-WT. This results in intracellular autoactivation and constitutive low-grade secretion of activated FXII. These findings help to explain the chronically increased contact activation in carriers of the FXII-W268R variant.
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http://dx.doi.org/10.1074/jbc.RA119.009788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956518PMC
January 2020

Exploratory Study of MYD88 L265P, Rare NLRP3 Variants, and Clonal Hematopoiesis Prevalence in Patients With Schnitzler Syndrome.

Arthritis Rheumatol 2019 12 14;71(12):2121-2125. Epub 2019 Oct 14.

NIHR, Leeds, UK.

Objective: To assess the prevalence of the MYD88 L265P mutation and variants within NLRP3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS).

Methods: Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin-associated periodic syndromes (aCAPS) were included as controls. Allele-specific oligonucleotide-polymerase chain reaction was used for the detection of the MYD88 L265P variant, next-generation sequencing was applied to analyze NLRP3 and 28 genes associated with myelodysplastic syndrome, and gene scanning was performed for the detection of X chromosome inactivation.

Results: Activating NLRP3 mutations were not present in 11 SchS patients who had not been sequenced for this gene previously. The MYD88 L265P variant was present in 9 of 30 SchS patients, and somatic mutations associated with clonal hematopoiesis were identified in 1 of 30 patients with SchS and 1 of 6 patients with aCAPS. Evidence of nonrandom X chromosome inactivation was detected in 1 female patient with SchS and 1 female patient with aCAPS.

Conclusion: A shared molecular mechanism accounting for the pathogenesis of inflammation in SchS remains elusive. Clonal hematopoiesis is not associated with other somatic mutations found in individuals with SchS or aCAPS.
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http://dx.doi.org/10.1002/art.41030DOI Listing
December 2019

Diagnosis and treatment of chronic inducible urticaria.

Allergy 2019 12 2;74(12):2550-2553. Epub 2019 Jun 2.

Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1111/all.13878DOI Listing
December 2019

Skin and Systemic Inflammation in Schnitzler's Syndrome Are Associated With Neutrophil Extracellular Trap Formation.

Front Immunol 2019 22;10:546. Epub 2019 Mar 22.

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

Schnitzler's syndrome is a rare autoinflammatory disorder characterized by interleukin-1ß-mediated and neutrophil-dominated inflammation. Neutrophil extracellular traps (NETs) are web-like structures of decondensed chromatin, histones, and antimicrobial peptides released by neutrophils. NETs were initially described in the context of pathogen defense but are also involved in autoimmune-mediated skin diseases. Here, we assessed the role of neutrophil extracellular trap formation (NETosis) in Schnitzler's syndrome. Immunofluorescence co-staining of myeloperoxidase and subnucleosomal complex was performed on lesional skin samples from patients with Schnitzler's syndrome, other neutrophilic dermatoses (cryopyrin-associated periodic syndrome, Sweet syndrome, and pyoderma gangrenosum), urticarial vasculitis and chronic spontaneous urticaria as well as healthy control skin. Blood neutrophils from patients with Schnitzler's syndrome and controls were isolated, and NETosis was induced by phorbol 12-myristate 13-acetate (PMA). Also, NETosis of control neutrophils induced by symptomatic Schnitzler's syndrome sera, cytokines and sub-threshold PMA doses was studied. Immunofluorescence co-staining revealed widespread and substantial NET formation in lesional skin of Schnitzler's syndrome patients but absence of NETs in chronic spontaneous urticaria and control skin. Neutrophils undergoing NETosis were observed in the skin of other neutrophilic diseases too. Correspondingly, blood neutrophils from Schnitzler's syndrome patients showed significantly elevated NETosis rates compared to control neutrophils following stimulation with PMA. Increased NETosis correlated well with high levels of C-reactive protein (CRP). SchS patients with the lowest NETosis rates had persistent joint and bone pain despite IL-1 blockade. Stimulation of control neutrophils and sub-threshold PMA with sera of symptomatic Schnitzler's syndrome patients disclosed enhanced NETosis as compared to control sera. Our results suggest that the induction of NET formation by neutrophils contributes to skin and systemic inflammation and may support the resolution of local inflammation in Schnitzler's syndrome.
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http://dx.doi.org/10.3389/fimmu.2019.00546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438918PMC
September 2020

State of care for patients with systemic autoinflammatory diseases - Results of a tertiary care survey.

World Allergy Organ J 2019 14;12(3):100019. Epub 2019 Mar 14.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Germany.

Background: Systemic autoinflammatory diseases (SAIDs) are rare debilitating disorders of which there is limited awareness and a significant delay in diagnosis. There is no uniform approach in the diagnosis and treatment of these disorders and the real life state of SAID patient care is poorly characterized. The aim of this study was to obtain data on the epidemiology, state of care and the perception of physicians who are involved in the care of SAID patients.

Methods: We performed a questionnaire-based survey and contacted 134 university departments of dermatology, pediatrics, rheumatology and other SAID departments of tertiary care in German-speaking countries.

Results: A total of 37 departments participated in the survey. The majority of departments managed both adult and pediatric patients with a variety of monogenic and polygenic/acquired SAIDs. For monogenic SAIDs such as cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF), the diagnostic and treatment strategies were similar among the departments. The diagnostic work-up included inflammatory markers and genetic testing, the first line treatment interleukin-1 (IL-1) blockers for CAPS and colchicine for FMF. For polygenic/acquired SAIDs, we observed a significant heterogeneity in diagnostic and therapeutic approaches. As a major unmet need, diagnostic delay was identified with a median time to diagnosis of 2 (range 1-5) years. The overall state of care for SAID patients was rated to be excellent or good by only 12% of departments, and to be poor or non-sufficient by 40% of departments.

Conclusion: This study demonstrates a high need to improve the state of care and to harmonize diagnostic and treatment strategies for SAID patients.
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http://dx.doi.org/10.1016/j.waojou.2019.100019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439415PMC
March 2019

H-antihistamine inhibition of histamine- and codeine-induced wheals does not predict response in chronic cold urticaria.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):2043-2044. Epub 2019 Jan 29.

Department of Dermatology and Allergy, Allergie-Centrum Charité, Charité -Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.01.030DOI Listing
September 2020

Ein Fall von Muckle-Wells-Syndrom mit einer neuen NLRP3-Mutation.

J Dtsch Dermatol Ges 2018 Oct;16(10):1250-1252

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1111/ddg.13640_gDOI Listing
October 2018

Treatment of urticarial vasculitis: A systematic review.

J Allergy Clin Immunol 2019 02 27;143(2):458-466. Epub 2018 Sep 27.

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

Urticarial vasculitis (UV) is a difficult-to-treat condition characterized by long-lasting urticarial rashes and histopathologic findings of leukocytoclastic vasculitis. Treatment is dictated by the severity of skin and systemic involvement and the underlying systemic disease. This is a comprehensive systematic review of the efficacy of current UV treatment options. We searched for relevant studies in 7 databases, including MEDLINE, Scopus, and Web of Science. In total, 261 eligible studies and 789 unique patients with UV were included in the systematic review. Most patients with UV are adult women with chronic (≥6 weeks) and systemic disease. UV is mostly idiopathic but can be associated with drugs, malignancy, autoimmunity, and infections. It usually resolves with their withdrawal or cure. Corticosteroids are effective for the treatment of skin symptoms in more than 80% of patients with UV. However, their long-term administration can lead to potentially serious adverse effects. The addition of immunomodulatory or immunosuppressive agents often allows corticosteroid tapering and improves the efficacy of therapy. Biologicals, including omalizumab, as well as corticosteroids, cyclophosphamide, dapsone, mycophenolate mofetil, plasmapheresis, colchicine, hydroxychloroquine, intravenous immunoglobulin, nonsteroidal anti-inflammatory drugs, and cyclosporine, can be effective for both skin and systemic symptoms in patients with UV. H-antihistamines, montelukast, danazol, H-antihistamines, pentoxifylline, doxepin, and tranexamic acid are not effective in most patients with UV. As of yet, no drugs have been approved for UV, and management recommendations are based mostly on case reports and retrospective studies. Prospective studies investigating the effects of treatment on the signs and symptoms of UV are needed.
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http://dx.doi.org/10.1016/j.jaci.2018.09.007DOI Listing
February 2019

A Case of Muckle-Wells Syndrome due to novel NLRP3 mutation.

J Dtsch Dermatol Ges 2018 Oct 29;16(10):1250-1252. Epub 2018 Aug 29.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1111/ddg.13640DOI Listing
October 2018

Chronische Urtikaria - Was bringt die neue Leitlinie?

J Dtsch Dermatol Ges 2018 May;16(5):585-595

Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin Redaktion Prof. Dr. D. Nashan, Dortmund.

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http://dx.doi.org/10.1111/ddg.13531_gDOI Listing
May 2018

Chronic urticaria - What does the new guideline tell us?

J Dtsch Dermatol Ges 2018 May;16(5):584-593

Department of Dermatology, Venereology, and Allergology, Charité - University Medical Center, Berlin, Germany.

Patients with chronic urticaria experience significant impairment, and require an effective treatment. Such treatment is preceded by a thorough diagnostic workup and measurement of disease activity, disease burden and disease control using well--established tools. Treatment is subsequently adjusted according to patient needs and therapeutic response, based on the tenet "as much as necessary, as little as possible" (in that order). Once disease control has been achieved, it is recommended that intermittent attempts at medication withdrawal be made in order to identify spontaneous disease remission. Chronic urticaria should be treated until spontaneous remission occurs.
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http://dx.doi.org/10.1111/ddg.13531DOI Listing
May 2018

The role of mast cells in autoinflammation.

Immunol Rev 2018 03;282(1):265-275

Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany.

The concept of autoinflammation was proposed to define a new class of immune disorders categorized by self-directed inflammation that is driven via activation of innate immune pathways. Within innate immunity, inflammasomes serve as intracellular signaling platforms to endogenous danger molecules and pathogens. Their key function is the cleavage of pro-interleukin-1β (pro-IL-1β) into its active form to promote inflammation and programmed cell death. A growing number of inflammasome sensors were described, among which NLR family pyrin domain containing 3 (NLRP3) is the best-studied sensor. Besides macrophages, monocytes, and other innate immune cells, mast cells (MCs) were shown to express functional inflammasomes too. Also, MCs are both, a source and target of IL-1β. Here we review the functional relevance and role of MC inflammasomes and MC-derived IL-1β in contributing to the inflammation at the skin, joints, and central nervous system in rare monogenic autoinflammatory conditions and also common inflammatory and degenerative diseases.
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http://dx.doi.org/10.1111/imr.12633DOI Listing
March 2018

Ultraviolet radiation and skin mast cells: Effects, mechanisms and relevance for skin diseases.

Exp Dermatol 2018 01 14;27(1):3-8. Epub 2017 Sep 14.

Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin, Berlin, Germany.

Mast cells (MCs) are well known as versatile effector cells in allergic reactions and several other immune responses. Skin MCs and cutaneous MC responses are subject to the effects of environmental factors including ultraviolet radiation (UVR). Numerous studies have assessed the effects of UVR on MCs, in vitro and in vivo. Interestingly, UVR seems to have variable effects on non-activated and activated mast cells. In general, UV therapy is beneficial in the treatment of urticaria and mastocytosis, but the effects are variable depending on treatment regimen and type of UVR. Here, we review and summarise key reports from the older and current literature on the crosstalk of UVR and skin MCs. Specifically, we present the literature and discuss published reports on the effects of UVR on skin MCs in rodents and humans. In addition, we review the role of MCs in UVR-driven skin diseases and the influence of UV light on MC-mediated skin diseases. This summary of our current understanding of the interplay of skin MCs and UVR may help to improve the management of patients with urticaria and other MC disorders, to identify current gaps of knowledge, and to guide further research.
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http://dx.doi.org/10.1111/exd.13402DOI Listing
January 2018

Efficacy and safety of canakinumab in Schnitzler syndrome: A multicenter randomized placebo-controlled study.

J Allergy Clin Immunol 2017 Apr 19;139(4):1311-1320. Epub 2016 Sep 19.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany; Autoinflammation Reference Center Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Schnitzler syndrome is an adult-onset autoinflammatory disease characterized by urticarial exanthema and monoclonal gammopathy accompanied by systemic symptoms such as fever, bone, and muscle pain. Up to now, approved treatment options are not available.

Objective: We assessed effects of the anti-IL-1β mAb canakinumab on the clinical signs and symptoms of Schnitzler syndrome.

Methods: In this phase II, randomized placebo-controlled multicenter study, 20 patients with active disease enrolled in 4 German study centers. Patients were randomly assigned to receive single subcutaneous canakinumab 150 mg or placebo injections for 7 days, followed by a 16-week open-label phase with canakinumab injections on confirmed relapse of symptoms. The primary end point was the proportion of patients with complete clinical response evaluated by physician global assessment at day 7. Key secondary end points included changes in patient-reported disease activity (Schnitzler activity score), inflammation markers (C-reactive protein and serum amyloid A), and quality-of-life assessments (Dermatology Life Quality Index and 36-item short form health survey).

Results: The proportion of patients with complete clinical response at day 7 was significantly higher (P = .001) in the canakinumab-treated group (n = 5 of 7) than in the placebo group (n = 0 of 13). Levels of inflammation markers C-reactive protein and serum amyloid A and quality-of-life scores were significantly reduced in canakinumab-treated but not in placebo-treated individuals. Positive effects continued up to 16 weeks. Adverse events were manageable and included respiratory tract infections, gastrointestinal symptoms, and hypertension.

Conclusions: In this first placebo-controlled study, canakinumab was effective in patients with Schnitzler syndrome, and thus canakinumab may be further evaluated as a therapeutic option for this rare disease.
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http://dx.doi.org/10.1016/j.jaci.2016.07.041DOI Listing
April 2017

Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome.

Rheumatology (Oxford) 2016 Apr 14;55(4):689-96. Epub 2015 Dec 14.

Division of Pediatric Rheumatology, Department of Pediatrics, University Children's Hospital Tuebingen, and Rheumatology, Alberta Children's Hospital, University of Calgary, Alberta, Canada.

Objective: Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1β release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1β and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS.

Methods: A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted.

Results: A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%).

Conclusion: Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS.
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http://dx.doi.org/10.1093/rheumatology/kev416DOI Listing
April 2016