H1-antihistamine-refractory chronic spontaneous urticaria: it's worse than we thought - first results of the multicenter real-life AWARE study.

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

[Mastocytosis : Clinical aspects, diagnostics, therapy]. / Mastozytose : Klinik ­ Diagnostik ­ Therapie.

Mastocytosis is a rare, almost exclusively sporadically occurring disease involving an increase in clonal tissue mast cells. The disease spectrum is heterogenous, ranging from isolated skin lesions with a normal life expectancy to rare, aggressive forms with very poor prognosis. Children are often affected. But whereas these almost invariantly display solely a cutaneous mastocytosis with polymorphous skin lesions, in adults the lesions are small and maculopapular and in over 80% of cases accompanied by involvement of bone marrow and the D816V activating mutation of the gene for the c­Kit receptor. There are many symptoms for the disease. Patients suffer frequently from pruritus, diarrhea, abdominal cramp, palpitations and flush. Osteoporosis is often present, with osteolysis with pathological fractures frequently involved in more aggressive forms. Patients are especially at risk to severe anaphylaxis caused by hymenoptera stings. Therapy is symptomatic, with cytoreductive therapy reserved for resistant and aggressive forms.

[Update on the cutaneous neurobiology of pruritus]. / Aktuelles zur kutanen Neurobiologie von Pruritus.

The pathogenesis of chronic and acute pruritus is not yet completely understood. Interactions of neurons with resident and nonresident skin cells seem to play an important role in the regulation of pruritus. Neuronal cells which express specific receptors and are capable of releasing neuromediators play an active role in this interaction. Furthermore, released neuromediators can activate immune cells including mast cells and eosinophils, which are increased in the inflammatory infiltrate of many pruritic skin diseases. Mast cells and eosinophils express receptors for neuromediators themselves. In addition, they can release neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and cytokines including interleukin (IL)-31 which correlate with disease activity in patients with inflammatory skin diseases including atopic dermatitis and induce neuronal outgrowth. In part, a correlation of these mediators has also been described with pruritus. Although the interplay between transient and resident cells in the skin with peripheral nerves, mast cells, and eosinophils plays an important role in the mutual activation, the neurobiological mechanisms that lead to pruritus are not completely clear yet.

[Not Available]. / Kontaktallergien im Kindesalter.

Allergic contact eczema in children is frequent. If clinically suspected, a patch test should be performed. In the present study, data obtained from 116,742 patients who had undergone a patch test from 2005-2014 were analysed. The children group (range 0-12 years) included 925 patients. If at least 700 tested individuals were considered, the most frequent sensitizations in this group were nickel sulfate (8.5 %), fragrance mix I (5.5 %), and colophony (3.4 %), whereby sensitisation in adults was higher for nickel sulfate (15.5 %) and fragrance mix 1 (8.4 %), while being similar for colophony (3.7 %). In adolescents with and without a profession, nickel sulfate (11.1 and 13.6 %, respectively) and cobalt (II) chloride (3.9 and 3.4 %, respectively) were the most frequent positively tested contact allergens. Sensitisations toward fragrance mix I was low (3.9 and 3.4 %, respectively) in comparison to the adult group (8.4 %). In both children and adolescents, toluene diamine and paraphenylenediamine sensitizations were not infrequent, but it must be considered that these allergens were only tested if suspected. The data show that the sensitisation profile among children and adolescents display patterns similar to those in adults. Sensitisations in childhood and adolescence towards dyes like paraphenylendiamine may be associated with increased use of tattooing in these groups.

Guidelines on the use of extracorporeal photopheresis.

BACKGROUND: After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. RESULTS AND CONCLUSION: These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

[A rare case of a sclerodermoid chronic graft versus host disease. Successful treatment with extracorporeal photopheresis (ECP)]. / Ungewöhnliche chronische sklerodermiforme Graft-versus-Host-Erkrankung : Erfolgreiche Therapie mittels extrakorporaler Photopherese (ECP).

A 31-year-old woman presented with progressive deep linear induration on her lower abdomen, forearms and thighs. These symptoms developed three years after allogenic stem cell transplantation. Furthermore, the patient showed multiple hypopigmented lichenoid papules on the extensor surfaces of the forearms consistent with lichen sclerosus. Histological analysis of a biopsy specimen from her left thigh showed dermal sclerosis extending into the fascia, thus establishing the diagnosis of a rare combination of superficial and deep sclerodermoid chronic graft-versus-host disease. After 7 cycles of extracorporeal photopheresis, a marked resolution of the indurations and a reduction of the modified Rodnan skin score from 12 to 7 were noted.

[Disseminated microspiridiosis (Encephalitozoon intestinalis) in a patient with HIV infection]. / Disseminierte Mikrosporidieninfektion (Encephalitozoon intestinalis) bei HIV-Infektion.

HISTORY AND CLINICAL FINDINGS: A 39-year-old patient with advanced HIV infection was admitted to our hospital with a 6-month history of diarrhoea, abdominal pain and pansinusitis. INVESTIGATIONS: Ultrasound and endoscopic retrograde cholangiography revealed cholangitis of the larger bile ducts. Stool examinations and coloscopy were unremarkable. No pathogenic organisms were identified by routine investigations. Finally, microsporidia of the genus encephalitozoon were diagnosed by electron microscopy in biopsies from the bile duct and the nasal mucous membrane and in stool samples by polymerase chain reaction (PCR). TREATMENT AND COURSE: Albendazole treatment was successful. The cholestatic liver tests and the ultrasound findings normalized. Control tests of stool, bile and nasal secretions by light microscopy, electron microscopy, and PCR were negative. CONCLUSION: Microsporidia, along with human cytomegalovirus, cryptosporida and mycobacteria other than tuberculosis are increasingly recognized as causing opportunistic infections in immunodeficient patients, especially in AIDS-related cholangitis. Some species can cause systemic infection. Therefore microsporidia infection should be considered in the differential diagnosis of all patients with immunodeficiency.

[Sensitization to tea tree oil in Germany and Austria. A multicenter study of the German Contact Dermatitis Group]. / Sensibilisierung auf Teebaumöl in Deutschland und Osterreich--Eine multizentrische Studie der Deutschen Kontaktallergiegruppe.

BACKGROUND AND AIM: Tea tree oil, a distillation product of the Australian tea tree (Melalence alternitolia) is increasingly used as an alternative remedy for various dermatological diseases. Tea tree oil contains several allergenic monoterpenes and sesquiterpenes. In this multicenter study it was evaluated, whether the increasing use of tea tree oil has lead to an increased frequency of sensitization in Germany and Austria which would justify its inclusion into the standard series. PATIENTS AND METHOD: For patch testing a standardized tea tree oil was used, dissolved 5% in diethylphtalate (DEP). Consecutive patients of 11 dermatological departments in Germany and Austria were tested. Readings were taken on day 2 and 3 according to the guidelines of the German Contact Dermatitis Research Group (DKG). RESULTS: 5% tea tree oil was positive in 36/3375 patients (1.1%). Sensitization frequencies showed great regional variations and ranged from 2.3% (Dortmund), 1.7% (Buxtehude), 1.1% (Essen), 0.7% (Graz), to 0% (Berlin, Vienna). 14/36 patients (38.9%) also showed a positive patch test reaction to oil of turpentine. CONCLUSION: Our results show that tea tree oil is an important contact allergen for some centers. It should be tested, if medical history suggests its previous use. Considering the great regional differences in frequencies of sensitization its inclusion into the standard series is not recommended yet.

Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin-8/CXCR2 pathway and normalization of keratinocyte maturation.

Psoriasis is a chronic inflammatory skin disease in which epidermal hyperplasia results from the release of cytokines by infiltrating type 1 T cells. Up- regulation of endogenous interleukin-10 controls type 1 skin responses in animal models; however, interleukin-10 production is low in psoriatic lesions. Consistent with an important role of interleukin-10 in psoriasis, we and colleagues have recently demonstrated clinical efficacy of subcutaneous administration of recombinant interleukin-10 to affected patients. Here, we studied the effects of interleukin-10 on disease-related inflammatory pathways. Patients were treated with recombinant interleukin-10 over 6 wk in an open-label phase II clinical trial. Tissue was obtained before and after therapy and examined by histology/immunohistochemistry, in situ hybridization, and quantitative real-time reverse transcription-polymerase chain reaction. Ten of 14 patients showed a marked reduction of the clinical disease activity. The clinical response was associated with a significant decrease of cutaneous T cell infiltration and the lesional expression of type 1 cytokines interferon-gamma and tumor necrosis factor-alpha. Interleukin-10 inhibited the epidermal interleukin-8 pathway by downregulating the expression of interleukin-8, its receptor CXCR2, and its inducer interleukin-17, and partially reversed the aberrant keratinocyte maturation defining psoriatic epidermal pathology. Remarkably, there was evidence that genetic factors are involved in the response to interleukin-10 as individual variations in the downregulation of tumor necrosis factor-alpha were related to the presence of polymorphisms in the tumor necrosis factor-alpha promoter. These data suggest that excessive production of type 1 cytokines in human skin disease can be counter-regulated by the administration of recombinant interleukin-10. Genotypic analysis may help to identify patients that will preferentially respond to interleukin-10 therapy.

Mast cells as initiators of immunity and host defense.

Until recently, mast cells have been viewed primarily as harmful because of their key role as effector cells of allergic and potentially lethal anaphylactic reactions. Their contribution to human health appeared instead to be limited to the elimination of parasites. There is, however, growing evidence for additional beneficial functions of mast cells, particularly regarding the initiation of acquired immune reactions. Thus, mast cells can phagocytize diverse particles, take up antigens, and express a number of receptors, particularly MHC class I and II antigens, ICAM-1 and -3, CD43, CD80, CD86 and CD40L which allow them to interact with T and B lymphocytes. They can also secrete numerous cytokines that induce and enhance recruitment and functions of lymphocytes. Finally, there is good evidence that mast cells present e.g. pollen and bacterial antigens, respond to bacterial superantigens, but fail to react to endogenously produced antigens or superantigens. Mast cells can also activate B cells directly to produce IgE, but this activity and the ability to produce IL-4 or IL-13 is restricted primarily to basophil leukocytes and mucosal mast cells. Finally, recent evidence attributes a pivotal role to the cells in natural immunity to bacteria. There is also emerging evidence that mast cells can downmodulate the immune response. While these data require further clarification, the basic ability of mast cells to initiate innate and acquired immune reactions can no longer be questioned.

[Actinic prurigo]. / Aktinische Prurigo.

The non-Native American type of actinic prurigo belongs to the group of rare idiopathic photodermatoses and therefore is often diagnosed with delay. The typical clinical and epidemiological features of actinic prurigo are described in a 10 year old girl. Detailed phototesting showed urticarial early onset and prurigo-like late onset reactions towards long-wave UVA. Repetitive photoprovocation with UVB induced delayed development of papules. HLA typing showed the typical association with HLA-DR4, in particular DRB1*0407. Treatment is usually extremely difficult and unrewarding. In this patient, the course was considerably improved by more intense physical photoprotection.

Inhibition of cytokine secretion from human leukemic mast cells and basophils by H1- and H2-receptor antagonists.

H1-type antihistamines have recently been reported to inhibit cytokine secretion from human and murine mast cells and basophils. In order to confirm and expand these studies, we have compared several H1-blockers and the H2-blocker ranitidine for their effect on TNF-alpha, IL-3, 6, 8 and GM-CSF release from human leukemic mast (HMC-1) and basophilic (KU812) cells, compared to dexamethasone. Cells were stimulated for 24 h with phorbol myristate acetate (25 ng/ml) and calcium ionophore A 23187 (2.5x10(-7) M) alone or with the drugs added at 10(-4) to 10(-15) M, and production of cytokines was measured by ELISA. All antihistamines caused a dose-dependent inhibition of TNF-alpha release from HMC-1 cells, with maximal effects at 10(-12) M for azelastine, 10(-9) M for loratadine and cetirizine, and 10(-8) M for ranitidine. The inhibitory potency of H1-blockers on cytokines from HMC-1 cells was TNF-alpha >IL-8> or =IL-6> or =IL-3, with no significant effects on GM-CSF. In KU812 cells which failed to secrete TNF-alpha and GM-CSF, the sequence was IL-6 >IL-8 after preincubation. Dexamethasone inhibited all cytokines, but ranitidine only TNF-alpha and IL-3. Antihistamines had no effect on calcium flux in resting or stimulated cells. At the mRNA level, inhibition was only seen with KU812 cells and IL-8 in the presence of azelastine at 10-(10) M. These data show thus distinct inhibitory patterns for different antihistamines during cytokine production from human mast cells and basophils which may contribute to the anti-inflammatory effects of these drugs during treatment of allergic diseases.

Expression of lymphotoxin-alpha by keratinocytes: a further mediator for the lichenoid reaction.

OBJECTIVE: Lichen planus (LP) represents a disease in which autoimmune mechanisms mediated by Th1 T cells are involved. Lymphotoxin-alpha (LT-alpha) represents a Th1 cytokine with proinflammatory activities in LP, as has recently been demonstrated for interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). METHODS: Expression of LT-alpha mRNA was investigated by RT-PCR and nonradioactive in situ hybridization. Double staining methods were applied to characterize the phenotype of cells expressing LT-alpha. Cell stimulation experiments were performed on the transformed squamous cell line HaCaT. RESULTS: In contrast to normal skin, LT-alpha-specific RT-PCR products were found in all cases of LP. Cells in the inflammatory infiltrate expressing LT-alpha were identified as mainly T cells and mast cells, as shown by in situ hybridization. Furthermore, predominant LT-alpha mRNA expression could be observed in lesional keratinocytes adjacent to the band-like inflammatory infiltrate. In cell stimulation experiments, it could be shown that IFN-gamma induces LT-alpha and TNF-alpha mRNA in the human squamous cell line HaCaT, concomitant with upregulation of MHC class II and intercellular adhesion molecule-1, which could also be observed on lesional keratinocytes in LP. CONCLUSIONS: In LP, LT-alpha mRNA is predominantly expressed by lesional keratinocytes and to a lesser extent by inflammatory cells. Induction of LT-alpha in keratinocytes is closely related to the expression of TNF-alpha and MHC class II. The loci of TNF-alpha and LT-alpha map to MHC class III on chromosome 6, which is closely linked to the MHC class II gene locus. Our results suggest that stimulation of keratinocytes with IFN-gamma results in the upregulation of proinflammatory cytokines such as LT-alpha and TNF-alpha as well as MHC class II, which map to the same gene region of immunoregulatory genes on chromosome 6 and may be involved in the induction and maintenance of the disease.

Expression and functional activity of the IL-8 receptor type CXCR1 and CXCR2 on human mast cells.

To further elucidate mechanisms involved in mast cell accumulation at sites of cutaneous inflammation, we have studied the ability of human leukemic mast cells (HMC-1 cells) to express functionally active IL-8 receptors. Expression of mRNA for both types of IL-8 receptors (CXCR1 and CXCR2) was demonstrated by PCR and of both proteins by flow cytometry. Binding and competition studies with 125I-labeled IL-8 and its homologue melanoma growth stimulating activity (125I-labeled MGSA) revealed two specific binding sites for IL-8, K1 = 1.1 x 10(11) M(-1) and K2 = 5 x 10(7) M(-1); and for MGSA, K1 = 2.8 x 10(10) M(-1) and K2 = 5 x 10(7) M(-1). This finding was supported by a dose-dependent rise of cytosolic free calcium concentration ([Ca2+]i) induced by both chemokines and to a lesser extent by the homologue neutrophil-activating peptide-2 (NAP-2). A significant migratory response of human leukemic mast cells (HMC-1) was observed with all three chemokines at a range from 10(-8) M to 10(-9) M. Moreover, the formation of cellular F-actin was induced in a rapid, dose-dependent fashion, with a maximally 1.7-fold increase at 10(-7) M. Using postembedding immunoelectron microscopy, we could show the expression of CXCRI on the cytoplasmatic membrane of isolated human skin mast cells whereas CXCR2 was located in mast cell-specific granules. These findings demonstrate for the first time the functional expression of both types of IL-8 receptors on human mast cells, suggesting a role for their ligands during mast cell activation and recruitment.

Role of antigen-induced cytokine release in atopic pruritus.

In order to further evaluate the role of cytokines in the induction of atopic pruritus, leukocytes from 10 atopic eczema patients or 10 nonallergic controls were stimulated in vitro with mite or birch pollen antigen for 1 and 4 days. Subjects were prick-tested with the supernatants, and whealing and itching were evaluated 20 and 60 min later. The supernatants were also examined for the contents of GM-CSF, IL-2, IL-6 and IL-8 by ELISA and TNFalpha. Two hours prior to testing, the antihistamine cetirizine (20 mg) or a placebo tablet were given to the patients according to a randomized, double-blind study protocol. After pricking with antigen-stimulated leukocyte supernatants, 6 of 10 patients but no controls reacted mostly at 20 min with whealing and/or pruritus. In the cetirizine-treated group, no decrease in these skin reactions was seen compared to placebo. Analysis for cytokines showed increased levels of IL-8 in allergen-stimulated samples, with no correlation to the induction of itching or whealing by these supernatants. IL-6 levels were low and variable, and GM-CSF, IL-2 and TNFalpha levels were always below standard values. These data show that leukocytes selectively release IL-8 in response to in vitro antigen stimulation. They furthermore provide additional support for the concept that as yet to be identified products play a role in atopic pruritus.