Regulation of melanocortin 1 receptor in allergic rhinitis in vitro and in vivo.

BACKGROUND: α-melanocyte-stimulating hormone (α-MSH) was shown to inhibit allergic airway inflammation and exert suppressive effects on human basophils. OBJECTIVE: This study aims to extend our current knowledge on the melanocortin 1 receptor (MC1R) expression in nasal tissue of patients with allergic rhinitis (AR) and functional effects of α-MSH in human basophils especially from patients with allergic rhinitis. METHODS: MC1R expression before and after nasal allergen provocation was studied in nasal mucosal tissue of AR patients and in a mouse model of allergic airway inflammation using immunofluorescence. In vitro regulation of the MC1R and CD203c surface expression on whole-blood basophils of patients with AR and controls was assessed with flow cytometry. Functional effects of α-MSH on isolated basophils were analysed regarding apoptosis with flow cytometry and chemotaxis using a Boyden chamber assay. RESULTS: We detected an accumulation of MC1R-positive basophils in nasal mucosa tissue of patients with AR 24 h after nasal allergen provocation. Such accumulation was not present in mucosa sections from healthy controls. In mice with allergic airway inflammation, we found a clear accumulation of MC1R-positive basophils in the nasal tissue compared to control mice. MC1R expression was inducible in AR patients and controls by stimulation with anti-IgE. α-MSH inhibited anti-IgE and grass pollen induced upregulation of CD203c, but had no effect on chemotaxis or apoptosis of basophils in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: MC1R-positive basophils accumulate in the nasal mucosa of patients with AR after nasal allergen provocation. Since α-MSH suppresses proinflammatory effector functions in human basophils via the MC1R, it constitutes an interesting novel target for modulating the allergic inflammatory response.

The anti-IL-4 receptor alpha antibody dupilumab: facing a new era in treating atopic dermatitis.

INTRODUCTION: Atopic dermatitis is the most common chronic inflammatory skin disease with high prevalence rates in adults and even higher among children. For the numerous patients suffering from moderate to severe disease, standard systemic treatment regimens such as cyclosporine A, methotrexate or azathioprine are not suited for long-term treatment due to their unfavorable safety profile. A promising alternative would be the newly developed IL-4 receptor alpha antibody dupilumab which has been investigated in several clinical trials during the last years. AREAS COVERED: Recently, four phase I and II studies have been published providing a favorable efficacy and safety profile. Clinical scores such as EASI were reduced by 74% after 12 weeks of treatment with early onset of first improvement after already one week. Safety data showed no evidence of drug-related serious adverse events and no organ toxicity. EXPERT OPINION: First clinical data of treating AD with dupilumab provided strong evidence for a highly significant efficacy and safety. In the case, future phase III studies will confirm these findings, dupilumab has the potential to become a new first line standard treatment for patients with severe AD.

Comparison of pegylated interferon α-2b plus psoralen PUVA versus standard interferon α-2a plus PUVA in patients with cutaneous T-cell lymphoma.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy profile of pegylated interferon α-2b (PEG-IFN α-2b) in combination with photochemotherapy (PUVA) in the treatment of cutaneous T-cell lymphoma (CTCL) in comparison with standard IFN α plus PUVA. DESIGN: Retrospective cohort study over a period of 7 years. PATIENTS AND INTERVENTIONS: A total of 17 consecutive CTCL patients (stage IA-IV) were retrospectively analysed for toxicity and response rates associated with PEG-IFN α-2b (1.5 µg/kg weekly) plus PUVA (n = 9) or standard IFN α-2a (9 MIU 3×/week) plus PUVA (n = 8). MAIN OUTCOME MEASURES: Differences of response rates (complete/partial remission), progression-free survival, discontinuation of therapy, safety and toxicity profiles according to World Health Organization - Common Terminology Criteria of Adverse Events (WHO-CTCAE). RESULTS: Myelosuppression and liver toxicity occured more frequently during PEG-IFN α-2b plus PUVA treatment than during standard IFN α-2a plus PUVA therapy [77.8 vs. 50% (odds ratio 1.477) and 77.8 vs. 50% (odds ratio 1.692), respectively]. By contrast, the occurence of constitutional side-effects (mainly fatigue) [100 vs.77.8% (odds ratio 0.889)] and more adverse events leading to study discontinuation was considerably higher in the standard IFN α-2a plus PUVA group. The overall response rate in the PEG-IFN α-2b plus PUVA group (89%) was significantly superior. CONCLUSIONS: In patients with cutaneous T-cell lymphoma PEG-IFN α-2b plus PUVA might become a promising treatment alternative as its higher rate of myelosuppression and liver toxicity is outweighed by its lower percentage of constitutional side-effects, and its significantly higher overall response. Due to the small number of participants at this retrospective study, a larger prospective study is essential to verify our results.

Case mix measures and diagnosis-related groups: opportunities and threats for inpatient dermatology.

OBJECTIVE: The changing healthcare environment world-wide is leading to extensive use of per case payment systems based on diagnosis-related groups (DRG). The aim of this study was to examine the impact of application of different DRG systems used in the German healthcare system. METHODS: We retrospectively analysed 2334 clinical data sets of inpatients discharged from an academic dermatological inpatient unit in 2003. Data were regarded as providing high coding quality in compliance with the diagnosis and procedure classifications as well as coding standards. The application of the Australian AR-DRG version 4.1, the German G-DRG version 1.0, and the German G-DRG version 2004 was considered in detail. To evaluate more specific aspects, data were broken down into 11 groups based on the principle diagnosis. MAIN OUTCOME MEASURE: DRG cost weights and case mix index were used to compare coverage of inpatient dermatological services. Economic impacts were illustrated by case mix volumes and calculation of DRG payments. RESULTS: Case mix index results and the pending prospective revenues vary tremendously from the application of one or another of the DRG systems. The G-DRG version 2004 provides increased levels of case mix index that encourages, in particular, medical dermatology. CONCLUSIONS: The AR-DRG version 4.1 and the first German DRG version 1.0 appear to be less suitable to adequately cover inpatient dermatology. The G-DRG version 2004 has been greatly improved, probably due to proceeding calculation standards and DRG adjustments. The future of inpatient dermatology is subject to appropriate depiction of well-established treatment standards.

[Pruritus in pregnancy. A frequent diagnostic and therapeutic challenge]. / Pruritus in der Schwangerschaft. Eine häufige diagnostische und therapeutische Herausforderung.

Pruritus is the leading dermatological symptom during pregnancy. Besides preexisting or acquired dermatoses, there are a number of pregnancy-specific dermatological diseases such as PEP (polymorphic eruption of pregnancy, previously named PUPPP), pemphigoid (herpes) gestationis, and pruritus gravidarum that are accompanied by severe itching and scratching. Because of potential effects on the fetus, the treatment of pruritus in pregnancy requires prudent consideration. The use of topical and systemic treatments depends on the underlying aetiology of pruritus and the stage and status of the skin. In general, emollients, topical anti-pruritics and topical corticosteroids appear to be the safest options for localised forms of pruritus in pregnancy whereas systemic treatments and/or UV phototherapy are adequate for generalized pruritus. Systemic corticosteroids and a restricted number of antihistamines may be administered in severe cases. This paper highlights the major aetiologies of pruritus during pregnancy and points out the cornerstones of antipruritic therapy in recognition of our own clinical experiences and the current literature.

[Pruritus in childhood. A diagnostic and therapeutic challenge]. / Pruritus im Kindesalter. Eine diagnostische und therapeutische Herausforderung.

From the clinician's point of view, pruritus in children is quite frequent. It mainly occurs along with dermatoses but rarely with systemic diseases such as renal and liver failure or with genetic disorders. Mostly, it appears in the setting of atopic dermatitis (AD). Other frequent differential diagnoses comprise e.g. scabies, impetigo, varicella, tinea, urticaria, mastocytosis and psoriasis. In children, pruritus is most often associated with severe scratching leading to artefacts. This group of patients requires a therapeutical regimen of its own. The use of topical and systemic treatments depends on the underlying aetiology of pruritus and the stage and status of the skin. The physician has to consider that topically applied drugs may cause intoxication due to the different body volume/body surface proportion, especially in newborns and infants. The dosages of systemic drugs need to be adapted in children and UV phototherapy should be performed with caution due to possible longterm photo damage of the skin. Physicians feel more insecurity treating pruritus in children, especially when systemic treatments are taken into consideration. We want to highlight the major aetiologies of pruritus in children and point out the cornerstones of antipruritic therapy in this challenging group of patients in recognition of our own clinical experiences and the current literature.

[Cytokines: current status and prospects in the treatment of skin tumors]. / Zytokine. Stand und Perspektiven in der Behandlung von Hauttumoren.

Various therapeutic options using cytokines have been described in the treatment of melanoma, T cell lymphoma, B cell lymphoma, squamous cell carcinoma, basal cell carcinoma and Merkel cell carcinoma. The treatment regimens include cytokine substitution, cytokine induction, cytokine transfection and therapeutic cytokine constructs. In the adjuvant treatment of melanomas, IFN-alpha has become well established. Statistical evaluations of different adjuvant trials show that a significant prolongation of recurrence-free intervals can be achieved. IL-2 has a role in the therapy of advanced melanomas as well as in vaccination strategies. Further possible therapeutic immune modulations, which have been evaluated in experimental approaches and pilot studies, include treatment with IL-4, IL-7 and GM-CSF. Treatment with IL-12 promises to open new perspectives. A well established regimen in the treatment of T cell lymphoma stages Ia-IIb is the combination of PUVA and IFN-alpha. In vitro data also indicate an important (patho)physiological role for IL-12, so that this agent has been tested in phase I studies. IL-2, IFN-gamma, and the fused cytokine-toxin molecules DAB389IL-2 offer further therapeutic alternatives. B cell lymphomas are treated with antibody-IL-2 fusion proteins. Advanced or inoperable squamous cell carcinoma and basal cell carcinoma may be treated with local IFN-alpha injections. IFN-alpha or TNF-alpha may be considered for the treatment of recurrent or advanced Merkel cell carcinoma. In dermatological oncology cytokine treatment focuses on melanome an T cell lymphome. Cytokine application is mainly an integral part of multimodal regimens.

Neutral endopeptidase terminates substance P-induced inflammation in allergic contact dermatitis.

Sensory nerve-derived neuropeptides such as substance P demonstrate a number of proinflammatory bioactivities, but less is known about their role in inflammatory skin disease. The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP(-/-) knockout and NEP(+/+) wild-type mice and compared with the irritant contact dermatitis response in these animals. NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels. The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augmented ACD response in NEP(-/-) animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin. Similar to NEP(-/-) mice, the acute inhibition of NEP in NEP(+/+) animals resulted in an augmented ACD response. In contrast to the ACD responses, little differences were observed in the irritant contact dermatitis response of NEP(-/-) compared with NEP(+/+) animals after epicutaneous application of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathogenesis of ACD.

High-dose UVA1 therapy for atopic dermatitis: results of a multicenter trial.

BACKGROUND: The results of an open, single-center study suggested that phototherapy with high doses of UVA1 radiation (UVA1R; 340-400 nm) is effective for acute, severe exacerbations of atopic dermatitis (AD). OBJECTIVE: The purpose of this study was to assess the effectiveness of high-dose UVA1 phototherapy for acute, severe AD in a randomized multicenter trial in direct comparison with topical glucocorticoid therapy. METHODS: Patients were treated with high-dose UVA1R (10 days, 130 J/cm2/day; n = 20), topically with fluocortolone (10 days, 1 x daily; n = 17), or with UVA-UVB therapy (10 days, 1 x daily, minimal erythema dose-dependent; n = 16). RESULTS: With a clinical scoring system, significant differences in favor of high-dose UVA1R and fluocortolone therapy were observed (p < 0.0001), as compared with UVA-UVB therapy. At day 10, high-dose UVA1R was superior to fluocortolone (p < 0.002) therapy. Serum levels of eosinophil cationic protein and the blood eosinophil count were significantly reduced after high-dose UVA1 or fluocortolone, but not UVA-UVB therapy. CONCLUSION: This study confirms the therapeutic effectiveness of high-dose UVA1 monotherapy for treatment of severe exacerbations of AD.

Recent developments in the treatment of atopic eczema.

Atopic eczema remains a therapeutic challenge. However, new developments in the understanding of the pathogenesis of this complex disease have prompted new therapeutic strategies. This review focuses on recently described treatment modalities for atopic eczema that are currently available or under investigation. The effectiveness of phototherapy, cytokines, and immunosuppressive drugs is evaluated. In addition, some new and promising but still experimental approaches are discussed.

In vivo effects of interleukin-10 on contact hypersensitivity and delayed-type hypersensitivity reactions.

Interleukin (IL) 10 is a recently discovered cytokine, originally isolated from T-helper 2 (Th2) cells, which inhibits cytokine production of T-helper 1 (Th1) cells. Because Th1 cells appear to be of importance during the contact hypersensitivity reaction (CHS) we hypothesized that IL-10 might modulate the outcome of CHS in vivo. Intraperitoneal injection of murine recombinant IL-10 (1000 ng) into naive mice 24, 72, or 120 h before sensitization by epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) did not affect ear swelling when ears were challenged 5 d later. However, intraperitoneal injection of IL-10 into already sensitized mice 24 h before challenge resulted in a significant suppression of the ear swelling response, suggesting that under the conditions employed IL-10 is able to block the effector phase, but not the induction phase of CHS in vivo. The suppression could be reversed by the concurrent injection of an IL-10 antibody. Moreover, heat inactivation of native IL-10 resulted in loss of the inhibitory capacity. When mice were sensitized by subcutaneous injection of trinitrophenyl-coupled spleen cells (DTH) instead of epicutaneous application of the hapten (CHS), intraperitoneally-injected IL-10 suppressed the effector phase, but also the induction phase of DTH. IL-10 did not inhibit the toxic ear-swelling response induced by topical application of two irritants tested (croton oil or benzalkonium chloride). The capacity of IL-10 to suppress the effector phase of CHS and DTH supports an important role for this cytokine in the downregulation of type IV immune reactions in vivo. The finding that IL-10 suppresses the induction of DTH, but not of CHS, further suggests that CHS and DTH are related but distinct immune reactions.

Cytokine release by peripheral blood mononuclear cells is affected by 8-methoxypsoralen plus UV-A.

Psoralen plus UV-A (PUVA) is an effective therapy for psoriasis but also for other inflammatory dermatoses. The precise mechanisms of action, however, are not absolutely clear. Therefore, the effect of PUVA on the release of the proinflammatory cytokines interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor alpha (TNF alpha) was studied. Peripheral blood mononuclear cells (PBMC) obtained from humans were incubated with 8-methoxypsoralen (8-MOP) and exposed to UV-A (20 kJ/m2). This treatment resulted in a significant reduction of IL-6 and IL-8 amounts in the supernatants. In addition, an inhibition of IL-1 beta and TNF alpha production by lipopolysaccharide (LPS)-stimulated PBMC was observed upon PUVA treatment. Accordingly, northern blot analysis showed decreased levels of mRNA encoding for IL-1 beta, IL-6, IL-8 and TNF alpha in PUVA-treated PBMC. Finally PBMC were obtained from psoriatics undergoing oral photochemotherapy before the beginning and after completion of treatment. The PBMC collected after PUVA spontaneously produced significantly less IL-6 and IL-8 in comparison to the respective samples obtained before therapy. A similar suppression of IL-1 beta and TNF alpha by in vivo PUVA was found in LPS-stimulated PBMC. The present data demonstrate that PUVA both in vitro and in vivo suppresses the production of the proinflammatory cytokines IL-1 beta, IL-6, IL-8 and TNF alpha by PBMC. Because these cytokines are important in the mediation of inflammatory reactions, one may speculate that the inhibitory effects could contribute to the antiinflammatory activity of PUVA.

Pentoxifylline suppresses irritant and contact hypersensitivity reactions.

Pharmacologic suppression of the effector phase of contact hypersensitivity appears to have major relevance with regard to treatment of type IV reactions like contact dermatitis. Recently, tumor necrosis factor alpha has been shown to be a critical mediator in hapten-induced irritant and contact hypersensitivity reactions, thus offering new possibilities, for therapeutic intervention. Pentoxifylline, a methylxanthine derivative used in the treatment of vascular disorders, currently has been found to suppress the production of tumor necrosis factor alpha by human and murine leukocytes. Therefore, the effect of pentoxifylline on the elicitation phase of contact hypersensitivity was studied. Intraperitoneal injection of pentoxifylline into sensitized Balb/c and C3H/HeN mice before application of the challenging hapten dose resulted in a significant reduction of the outcome of the contact hypersensitivity reaction. The suppressive effect of pentoxifylline was dose dependent and maximally pronounced upon injection 3 h before hapten application. In contrast to the effector phase of contact hypersensitivity, induction of contact hypersensitivity was not affected by pentoxifylline when injected into naive mice before performance of sensitization. In addition, irritant dermatitis induced by 1% croton oil or 5% benzalkonium chloride was suppressed by pentoxifylline as well. These data suggest a potential pharmacologic intervention, with pentoxifylline as a means to treat contact dermatitis.