Prevalence of hypersensitivity reactions in various forms of mastocytosis: A pilot study of 2485 adult patients with mastocytosis collected in the ECNM registry.

BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.

Modelling of patient journey in chronic spontaneous urticaria: Increasing awareness and education by shorten patients' disease journey in Germany.

BACKGROUND: Chronic spontaneous urticaria (CSU) is both physically and emotionally stressful, and guideline recommendations are often not optimally implemented in clinical practice. The objective of this study was to provide an overview on the patient journey in CSU and to develop a mathematical model based on solid data. METHODS: The journey of CSU patients in Germany was traced through literature review and expert meetings that included medical experts, pharmacists and representatives of patient organizations. The current situation's main challenges in the patient journey (education, collaboration and disease management) were discussed in depth. Then, a probabilistic model was developed in a co-creation approach to simulate the impact of three potential improvement strategies: (1) patient education campaign, (2) medical professional education programme and (3) implementation of a disease management programme (DMP). RESULTS: Chronic spontaneous urticaria patients are severely burdened by delays in diagnosis and optimal medical care. Our simulation indicates that in Germany, it takes on average of 3.8 years for patients to achieve disease control in Germany. Modelling all three optimization strategies resulted in a reduction to 2.5 years until CSU symptom control. On a population level, the proportion of CSU patients with disease control increased from 44.2% to 58.1%. CONCLUSION: In principle, effective CSU medications and a disease-specific guideline are available. However, implementation of recommendations is lagging in practice. The approach of quantitative modelling of the patient journey validates obstacles and shows a clear effect of multiple interventions on the patient journey. The data generated by our simulation can be used to identify strategies for improving patient care. Our approach might helping in understanding and improving the management of patients beyond CSU.

S1-guideline atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS).

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare cutaneous neoplasms representing histomorphological, genetic as well as epigenetic variants of a disease spectrum. Both tumors typically manifest as nonspecific, often ulcerated, skin- to flesh-colored nodules in chronically sun-damaged skin of elderly male patients. AFX is a rather well demarcated, often rapidly growing tumor. PDS tumors are poorly circumscribed and are characterized by aggressive infiltrative growth. Fast as well as slow growth behavior has been reported for both tumors. Histologically, both are composed of spindle-shaped and epithelioid tumor cells with pleomorphic nuclei as well as atypical multinucleated giant cells. Atypical mitoses are common. In contrast to AFX, PDS involves relevant parts of the subcutis and shows areas of tumor necrosis and/or perineural infiltration. Due to the poorly differentiated nature of AFX/PDS (Grade 3), histopathologically similar cutaneous sarcomas, undifferentiated carcinomas, melanomas and other diseases have to be excluded by immunohistochemical analysis. The treatment of choice is micrographically controlled surgery. In cases of AFX, a cure can be assumed after complete excision. Local recurrence rates are low as long as PDS tumors are surgically removed with a safety margin of 2 cm. Metastasis is rare and mostly associated with very thick or incompletely excised tumors; it mainly affects the skin and lymph nodes. Distant metastasis is even more rare. No approved and effective systemic therapy has been established.

Deep abscopal response to radiotherapy and anti-PD-1 in an oligometastatic melanoma patient with unfavorable pretreatment immune signature.

Radiotherapy can elicit abscopal effects in non-irradiated metastases, particularly under immune checkpoint blockade (ICB). We report on two elderly patients with oligometastatic melanoma treated with anti-PD-1 and stereotactic body radiation therapy (SBRT). Before treatment, patient 1 showed strong tumor infiltration with exhausted CD8+ T cells and high expression of T cell-attracting chemokines. This patient rapidly mounted a complete response, now ongoing for more than 4.5 years. Patient 2 exhibited low CD8+ T cell infiltration and high expression of immunosuppressive arginase. After the first SBRT, his non-irradiated metastases did not regress and new metastases occurred although neoepitope-specific and differentiation antigen-specific CD8+ T cells were detected in the blood. A second SBRT after 10 months on anti-PD-1 induced a radiologic complete response correlating with an increase in activated PD-1-expressing CD8 T cells. Apart from a new lung lesion, which was also irradiated, this deep abscopal response lasted for more than 2.5 years. However, thereafter, his disease progressed and the activated PD-1-expressing CD8 T cells dropped. Our data suggest that oligometastatic patients, where a large proportion of the tumor mass can be irradiated, are good candidates to improve ICB responses by RT, even in the case of an unfavorable pretreatment immune signature, after progression on anti-PD-1, and despite advanced age. Besides repeated irradiation, T cell epitope-based immunotherapies (e.g., vaccination) may prolong antitumor responses even in patients with unfavorable pretreatment immune signature.

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.

Resources spent on dermatological emergency patients: A twelve-month prospective data collection from Germany.

BACKGROUND AND OBJECTIVES: Rising numbers of patients consulting emergency units are associated with an increased demand for material and personnel. In order to better quantify these resources, we performed an analysis of diagnostic procedures, treatment types, and the quantity and educational level of staff involved in emergency consultations. PATIENTS AND METHODS: The study was conducted as a prospective single-center survey over twelve months in the dermatology unit of a Germany university hospital. 3155 consultations were included by consecutive sampling. RESULTS: Diagnostic tests (e.g. microbiological swab, blood testing, punch biopsy) were performed in 29 % of all consultations. Physicians prescribed treatment in 70 % of cases, with steroids and antihistamines being the most frequent topical and systemic treatment, respectively. Each patient was seen by at least one physician and a nurse, and in 25 % of cases an additional physician was involved. Less than thirty minutes was required for the consultation in the vast majority of cases. On average, emergency consultations required two hours per day of the treating physician's time, not including the time of other involved staff such as nurses and laboratory technicians. CONCLUSIONS: This study demonstrates the extent of resources involved in the treatment of dermatological emergency consultations.

Dermatological conditions presenting to the emergency dermatological unit of a university hospital in Germany.

BACKGROUND AND OBJECTIVES: Recently, there have been increasing numbers of patients consulting emergency units in all medical disciplines. Our aim was to analyze the demographics, referral mode, symptoms, localization of lesions, prior treatment, diagnoses and hospitalization rate of dermatological patients. PATIENT AND METHODS: The study was conducted as a prospective single center survey over six months in the dermatology unit of a university hospital in Germany. 1552 consultations were included with consecutive sampling. RESULTS: The study cohort had a mean age of 41 years and included 53 % females. Nearly half of the patients lived less than 10 kilometers from the study center. 72 % of patients referred themselves. The main symptoms were itching and occurrence of a rash; these symptoms had been present for more than a week on average. A general manifestation was present on the skin in most cases. 55 % of patients were seen by a dermatologist or a general practitioner before the consultation. Prior treatment had been received in 49 % of cases. Eight percent of patients were hospitalized. Eczema was the most common diagnosis, followed by urticaria and scabies. CONCLUSIONS: This study confirms that a considerable number of patients present with non-urgent diagnoses. Careful prescreening and sensitization of the population may be necessary to reverse this trend.

The Clinical Features of Hereditary Alpha-Tryptasemia.

BACKGROUND: Hereditary alpha-tryptasemia (HAT) is a genetic predisposition of autosomal dominant inheritance that leads to a high normal (≥ 8-11.4 µg/L) or pathologically elevated (>11.4 µg/L) basal serum tryptase (BST) concentration. Its prevalence in the United Kingdom and France is reportedly 5%-6%; its prevalence in Germany is unknown. Symptomatic persons with HAT suffer from a complex constellation of symptoms. As described in this review, HAT is an important differential diagnosis in interdisciplinary practice. METHODS: This review is based on publications about HAT retrieved by a selective search in PubMed, on relevant presentations at scientific meetings, and on our clinical experience. We also collected our own data on the prevalence and clinical manifestations of HAT. RESULTS: According to the literature, HAT is very common among patients in medical centers with BST values of 8 µg/L or above (64-74%). HAT is most commonly associated with neuropsychiatric symptoms such as exhaustion (85%), depressive episodes (59%), sleep disturbances (69%), and memory impairment (59%-68%), followed by gastrointestinal symptoms such as irritable bowel (30%-60%), nausea (51%), and reflux (49%-77%). Typical mast cell-mediated symptoms, such as flushing (47%), itch (69%), urticaria (37%), and anaphylaxis (14%-28%), are reported as well. Less commonly reported are cardio vascular manifestations, such as hypotonia, dizziness, and tachycardia (34%), and joint hyper - mobility (28%). HAT is more common among patients with systemic mastocytosis (SM; 12%-21%). It is often associated with severe anaphylaxis induced by insect toxins or unknown triggers. The therapeutic options include treatment with antihistamines, mastcell stabilizers, or IgE antibodies. CONCLUSION: A diagnosis of hereditary alphatryptasemia can be strongly suspected on the basis of thorough history-taking and BST measurement and then confirmed by molecular genetic testing.

Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy.

Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. Patients with dystrophic EB (DEB) and Kindler EB (KEB) have the highest propensity for developing SCCs. Another patient group that develops high-risk SCCs is immunosuppressed (IS) patients, especially after organ transplantation. Herein, we interrogate whether immune checkpoint proteins and immunosuppressive enzymes are dysregulated in EB-associated SCCs as an immune resistance mechanism and compare the expression patterns with those in SCCs from IS patients, who frequently develop high-risk tumors and sporadic SCCs, and immunocompetent (IC) individuals. The expression of indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and inflammatory infiltrates (CD4, CD8, and CD68) was assessed via immunohistochemistry and semi-quantitative analysis in 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 sporadic IC-SCCs. DEB-SCCs expressed significantly higher levels of IDO and PD-L1 in tumor cells and PD-1 in the tumor microenvironment (TME) compared with SCCs from IC and IS individuals. The number of CD4-positive T cells per mm2 was significantly lower in DEB-SCCs compared with IC-SCCs. KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs.

Identification of IDO-positive and IDO-negative human dendritic cells after activation by various proinflammatory stimuli.

Dendritic cells (DCs) can induce tolerance or immunity. We identified and characterized an IDO-expressing and an IDO-negative human DC population after stimulation by various proinflammatory stimuli. IDO expression was strongly dependent on the maturation status of the cells (CD83-positive cells only). The two DC subpopulations remained IDO positive and IDO negative, respectively, over a time period of at least 48 h. IDO enzyme activity of human DCs was highest during stimulation by strongly maturation-inducing TLR ligands such as highly purified LPS (TLR4 ligand) or polyriboinosinic-polyribocytidilic acid (TLR3 ligand); factors of the adaptive immune system such as IFN-γ, a mixture of cytokines, and IFN-α had lesser stimulatory capacity for IDO induction and activity. After stimulation with CD40L, IDO-positive DCs expressed significantly increased levels of B7 family molecules such as CD40, CD80, CD86, ICOS ligand, as well as PD-L1 (B7-H1) and PD-L2 (B7-DC) compared with the IDO-negative DC subset. At the same time, the inhibitory receptors Ig-like transcripts 3 and 4 were significantly downregulated on IDO-positive cells. Functionally, IDO-positive DCs produced significantly more IL-1ß and IL-15 and less IL-10 and IL-6 than the IDO-negative subset after CD40L stimulation. These results show that IDO expression is associated with a distinctive phenotype and functional capacity in mature DCs. It seems likely that the IDO-positive DC subset possesses a regulatory function and might skew a T cell response toward tolerance.

Indoleamine 2,3-dioxygenase expression in early keratocyte neoplasia of the lower lip correlates to the degree of cell atypia.

Actinic cheilitis (AC) is an early keratocyte neoplasia with inflammation that occurs in the lip vermillion with the potential to develop into invasive squamous cell carcinoma (SCC). The expression of the intracellular enzyme indoleamine 2,3-dioxygenase (IDO) by antigen-presenting cells and/or tumor cells has been described to arrest T cell proliferation by degrading the essential amino acid tryptophan from the environment. The expression of IDO in AC may support cancer progression by inhibiting T cell-mediated rejection responses. The aim of this study was to identify the cellular nature and extent of IDO expression in early keratocye neoplasia of the lower lip (n=25), and to correlate IDO expression to the severity of epithelial atypia (KIN I°- KIN III°) and to the extent of actinic inflammation. The expression of IDO was analyzed together with expression markers for T-cells (CD3), myeloid DCs (S100, CD11c), macrophages (CD68, CD11c), and Langerhans cells (CD1a) by immunohistochemistry and immunofluorescence analysis. Analyses showed that IDO was expressed in myeloid S100(+) CD11c(+) DCs. The expression of IDO correlated significantly with the degree of epithelial atypia (P=0.0005) but not to the extent of inflammation (P=0.4283). Expression of IDO in early atypic skin epithelial conditions might be a predictor to promote carcinogenesis.

Development and implementation of the AIDA international registry for patients with Schnitzler's syndrome.

Objective: The present paper describes the design, development, and implementation of the AutoInflammatory Disease Alliance (AIDA) International Registry specifically dedicated to patients with Schnitzler's syndrome. Methods: This is a clinical physician-driven, population- and electronic-based registry implemented for the retrospective and prospective collection of real-life data from patients with Schnitzler's syndrome; the registry is based on the Research Electronic Data Capture (REDCap) tool, which is designed to collect standardized information for clinical research, and has been realized to change over time according to future scientific acquisitions and potentially communicate with other existing or future similar registries. Results: Since its launch, 113 centers from 23 countries in 4 continents have been involved. Fifty-seven have already obtained the approval from their local Ethics Committees. The platform counts 324 users (114 Principal Investigators, 205 Site Investigators, 2 Lead Investigators, and 3 data managers) at current (April 28th, 2022). The registry collects baseline and follow-up data using 3,924 fields organized into 25 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, laboratory, instrumental exams, therapies, socioeconomic information, and healthcare access. Conclusions: This International Registry for patients with Schnitzler's syndrome facilitates standardized data collection, enabling international collaborative projects through data sharing and dissemination of knowledge; in turn, it will shed light into many blind spots characterizing this complex autoinflammatory disorder.

Indoleamine 2,3-dioxygenase-expressing myeloid dendritic cells and macrophages in infectious and noninfectious cutaneous granulomas.

BACKGROUND: The enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan, and this degradation is an immunosuppressive mechanism that is mainly used by antigen-presenting cells. IDO-expressing dendritic cells and macrophages have previously been identified as components of lymph node granulomas after Listeria monocytogenes infection. In this study we undertook an analysis of IDO expression in granulomas of infectious and noninfectious origin in the human skin. METHODS: Lesional skin biopsy specimens (n = 22) from different granulomatous skin disorders (lupus vulgaris, sarcoidosis, granuloma annulare, leprosy) were analyzed. Immunohistochemistry was performed to identify and locate the enzyme IDO within the inflammatory granulomatous infiltrate (IDO, CD11c, CD68, S100, CD3, Foxp3). Two-color immunofluorescence of IDO in combination with multiple markers was applied to characterize the IDO-expressing cells. RESULTS: Cutaneous granulomas of different origin strongly express IDO, mainly in the center and in the ring wall of the granulomas. We demonstrate that in infectious, but also in noninfectious human cutaneous granulomas the large myeloid CD11c(+)S100(+)CD68(-) dendritic cells and the CD68(+) macrophages express IDO. LIMITATIONS: This study was limited by the lack of details about the exact stage or maturity of granuloma formation in the specimens investigated. CONCLUSION: These findings reveal that IDO expression in myeloid dendritic cells and macrophages is part of an integrated response of granuloma formation, which may be a unifying feature of granulomatous reactions in the skin.