Maintenance of remission following successful treatment of papulopustular rosacea with ivermectin 1% cream vs. metronidazole 0.75% cream: 36-week extension of the ATTRACT randomized study.

BACKGROUND: There are a limited number of approved treatments for papulopustular rosacea (PPR) and remission is difficult to maintain after successful treatment. OBJECTIVES: To investigate remission over a 36-week extension period in patients with moderate to severe PPR successfully treated with 16 weeks' treatment with ivermectin 1% cream once daily (QD) or metronidazole 0.75% cream twice daily (BID) in a randomized, parallel-group Phase III study. METHODS: Treatment was discontinued in patients initially successfully treated [Investigator's Global Assessment (IGA) score of 0 or 1] with ivermectin 1% cream QD (n = 399) or metronidazole 0.75% cream BID (n = 365; Part A) and patients were followed every 4 weeks for up to 36 weeks (Part B). Treatment with the same study treatment as used in Part A was only re-initiated if patients relapsed (IGA ≥ 2). Efficacy assessments were: time to first relapse; relapse rate; and number of days free of treatment. Safety assessments included incidence of adverse events and local cutaneous signs and symptoms. RESULTS: The median time to first relapse was significantly longer (115 days vs. 85 days) and relapse rates at the end of the study period significantly lower (62.7% vs. 68.4%) for patients initially successfully treated with ivermectin 1% compared with metronidazole 0.75%; Kaplan-Meier plot demonstrated a statistically significant difference between the two arms (P = 0.0365). The median number of days free of treatment was higher for ivermectin compared with metronidazole (196 days vs. 169.5 days; P = 0.026). The percentage of patients who experienced a related adverse event was equally low in both groups. CONCLUSION: The results of this relapse study showed that an initial successful treatment with ivermectin 1% cream QD significantly extended remission of rosacea compared with initial treatment with metronidazole 0.75% cream BID following treatment cessation.

Non-invasive diagnosis of sweat gland dysplasia using optical coherence tomography and reflectance confocal microscopy in a family with anhidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome).

BACKGROUND: Anhidrotic ectodermal dysplasia (AED) is an inherited syndrome, which originates mainly from genetic alteration of the ectodysplasin A (EDA) gene. It regularly affects the adnexa of the skin which results in a characteristic phenotype of the patients including hypo- or anhidrosis leading to severe disturbances in the regulation of body temperature. OBJECTIVES: To prevent the development of the symptoms in early childhood promising therapeutic approaches are currently under clinical investigation. In this context, timely diagnosis of this genetic syndrome is crucial. The purpose of our study was the investigation of modern non-invasive imaging methods such as optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) in the immediate diagnosis of AED. METHODS: We examined a 3-year-old boy with the suspicion for an AED syndrome and his family members with RCM and OCT to document presence and characteristic features of sweat glands in comparison to non-affected individuals. RESULTS: The patient and the affected brother showed significantly reduced sweat glands in the imaging compared to the controls. The genetic analysis revealed a mutation of the EDA gene for hemizygosity previously associated with AED and the mother was revealed as the conductor of the genetic alteration. CONCLUSIONS: With the help of non-invasive imaging, we were able to detect sweat gland dysplasia in the affected family members without performing a biopsy which led us to the diagnosis of an AED. The application of modern dermatological imaging techniques might serve as valuable supplementary tools in the immediate, non-invasive diagnosis of genetic syndromes especially in newborns when early therapeutic approaches are planned.

Human papillomavirus status, anal cytology and histopathological outcome in HIV-positive patients.

BACKGROUND: Human papillomavirus (HPV) are responsible for a broad spectrum of mucocutaneous infections and may cause squamous cell carcinoma following long-standing infection . Oncogenic HPV, most commonly HPV 16, are detectable in over 90% of cervical intraepithelial neoplasia and anal intraepithelial neoplasia (AIN). Human immunodeficiency virus (HIV) infection is strongly associated with a higher prevalence of chronic HPV infection, a higher incidence of AIN and an increased risk for anal cancer (AC). In September 2013, guidelines concerning prevention, screening and treatment of AIN for patients affected by HIV were issued by the German AIDS society. OBJECTIVE: In order to validate the suggested screening procedure, we analysed data from 123 male and female patients with HIV infection that regularly present in our outpatient clinic. METHODS: Anal cytology, HPV typing and high-resolution anoscopy (HRA) were performed. RESULTS: Our results show that screening by anal cytology only identifies a minority of patients with high grade AIN (AIN 3) histology. Patients with normal cytology (NILM, cytology graded negative for intraepithelial lesion or malignancy; n = 5, 29.4%), atypical squamous cells of undetermined significance (ASCUS; n = 5, 71.4%) and low grade squamous intraepithelial lesion (LSIL; n = 8, 44.5%) showed highly dysplastic lesions (AIN 2 and 3) in the histological workup more frequently than expected. Additionally, high-grade squamous intraepithelial lesion (HSIL) was strongly associated with detection of high-risk oncogenic HPV. CONCLUSION: Anal cytology as the solitary screening tool for anal cancer fails to detect anal dysplasia in a considerable number of patients. Additionally, HPV typing and possibly further biomarkers might be applied to identify those patients with a higher risk of developing anal carcinoma, in order to monitor them more closely or directly transfer them to HRA.

[Massive granuloma formation after long-term use of dermal fillers]. / Ausgeprägte Granulombildung nach langjähriger dermaler Fillerinjektion.

BACKGROUND: Since dermal fillers were introduced in 1981, millions of patients have undergone wrinkle treatment with dermal fillers. Except for autologous fat, all fillers can act as potential foreign bodies, which have the potential ability to induce an immune reaction. Persisting material may induce activation of the immune system and finally granuloma formation. Frequency, histology, and clinical presentation of such foreign body reactions may vary depending on the filler used. CASE REPORT: This case describes a patient who received innumerable filler injections over the last two decades presenting with massive facial granulomas.

Intestinal neuroendocrine cells and goblet cells are mediators of IL-17A-amplified epithelial IL-17C production in human inflammatory bowel disease.

Interleukin (IL)-17C is a novel member of the IL-17 cytokine family. Its function in human inflammatory bowel disease (IBD) remains elusive as its role in colonic inflammation is entirely derived from murine models. We aimed to analyze the role of IL-17C in human IBD, focusing on T helper type 17 (Th17) cell- and intestinal epithelial cell (IEC)-dependent mechanisms. IL-17C mRNA (P=0.005), serum levels (P=0.008), and colonic staining intensity (P=0.004) is increased in active IBD. Serum IL-17C levels are modified by IL23R genotypes and IL-17C mRNA correlates (r>0.5, P<0.001) with IL-17A, tumor necrosis factor (TNF)-α, C-C motif chemokine ligand 20 (CCL20) and IL-23 mRNA in the inflamed colon of IBD patients. In the inflamed colon, IL-17C is produced by enteroendocrine and goblet cells, with contrary polar cytosolic localization of IL-17C within the cellular axis. In these two cell types, IL-17A strongly amplifies TNF-α-induced IL-17C production. On the molecular level, IL-17C production in IECs is dependent on TNF-α-activated nuclear factor-κB, extracellular signal-regulated kinase-1/2 and p38, and IL-17A-activated Akt, monocyte chemotactic protein-induced protein 1, and C/EBPδ. IL-17C upregulates the Th17 chemoattractant CCL20 in IECs. In summary, our findings support the involvement of IL-17A-amplified IL-17C production by enteroendocrine and goblet cells in the pathogenesis of active IBD, revealing an interaction between the neuroendocrine system and the Th17 pathway in human IBD.

[Skin changes as signs of gastrointestinal disorders]. / Hautmanifestationen bei gastrointestinalen Erkrankungen.

In many gastrointestinal disorders associated skin diseases and cutaneous signs can be seen as first manifestations and make a diagnosis of the internal disease possible. Gastrointestinal disorders with characteristic skin lesions include various tumors, inflammatory and vascular diseases. Knowledge of the clinical presentations and their associations is important both for dermatologists and gastroenterologists.

[Current insights into the pathophysiology of rosacea]. / Aktuelles Verständnis der Pathophysiologie der Rosazea.

Rosacea is a chronic inflammatory skin disease mainly affecting the face. Four major clinical subtypes of rosacea can be identified: erythemato-telangiectatic, papulopustular, phymatous and ocular rosacea. Still, it is currently unclear whether these subtypes develop consecutively or if any subtypes may occur individually as part of a syndrome. Rosacea is characterized by facial flushing, erythema, chronic inflammation, edema and fibrosis. Several trigger factors can worsen the disease or cause recurring episodes of inflammation. Although some aspects in the pathophysiology of rosacea have been characterized in more detail during the past years, the precise interplay of the various dysregulated systems is still poorly understood. In early disease manifestations and milder stages, dysfunction of neurovascular regulation and the innate immune system seem to be driving forces in rosacea pathophysiology. A disturbed chemokine and cytokine network further contributes to disease progression. This current review highlights some of the recent findings in rosacea pathophysiology and points out novel targets for therapeutic intervention.

HPV16 activates the AIM2 inflammasome in keratinocytes.

Human papillomaviruses (HPV) are double-stranded DNA viruses, which selectively infect keratinocytes in stratified epithelia. After an initial infection, many patients clear HPV. In some patients, however, HPV persist, and dysfunctional innate immune responses to HPV infection could be involved in the ineffective clearing of these viruses. In this study, the mechanisms of HPV-induced immune responses in keratinocytes were investigated. Binding of viral DNA leads to AIM2 inflammasome activation and IL-1ß release, while IFI16 activation results in IFN-ß release. Using immunohistochemistry, AIM2 and IFI16-two recently identified sensors for cytosolic DNA-were also detected in HPV positive skin lesions. CISH stainings further confirmed the presence of cytosolic HPV16 DNA in biopsy samples. Moreover, active IL-1ß and cleaved caspase-1 were detected in HPV infected skin, suggesting inflammasome activation by viral DNA. In subsequent functional studies, HPV16 DNA triggered IL-1ß and IL-18 release via the AIM2 inflammasome in normal human keratinocytes. Although HPV DNA did not induce IFN-ß in keratinocytes, IFN-ß secretion was observed when AIM2 was blocked. Meanwhile, blocking of IFI16 increased HPV16 DNA-induced IL-1ß, but not IL-18, secretion. These findings suggest crosstalk between IFI16 and AIM2 in the immune response to HPV DNA. In sum, novel aspects concerning HPV-induced innate immune responses were identified. Eventually, understanding the mechanisms of HPV-induced inflammasome activation could lead to the development of novel strategies for the prevention and treatment of HPV infections.

[Vitamin D and innate immunity of the skin]. / Vitamin D und die angeborene Immunabwehr der Haut.

Besides its role in bone metabolism vitamin D is involved in important regulatory mechanisms within the innate and adaptive immune system. In particular, vitamin D affects the production of antimicrobial peptides (AMPs). AMPs are endogenous 'antibiotics', produced my man himself with further immune regulatory functions in the skin and other epithelial surfaces. AMPs play a central role in the pathogenesis of several inflammatory skin diseases such as atopic eczema or psoriasis. Therefore, the vitamin D signal pathway could serve as a treatment target for those diseases. In this review we discuss the role of the vitamin D signalling pathway in the context of innate immunity in inflammatory skin diseases.

Botulinum toxin A for the treatment of keloids.

INTRODUCTION: Keloids are the result of excessive scar tissue formation. Besides their poor aesthetic appearance, keloids can be associated with severe clinical symptoms such as pain, itching, and rigidity. Unfortunately, most therapeutic approaches remain clinically unsatisfactory. Recently, injections with botulinum toxin A (BTA) were proposed for the treatment of established keloids in a clinical trial. In this study, we aimed to verify the effects of intralesional BTA for the treatment of therapy-resistant keloids using objective measurements. In addition, the underlying molecular mechanisms were investigated using cultured keloid-derived fibroblasts. MATERIALS AND METHODS: Four patients received BTA (doses varying from 70 to 140 Speywood units per session) injected directly into their keloids every 2 months for up to 6 months. Differences in height and volume were evaluated clinically and measured with a 3-D optical profiling system. Keloid-derived fibroblasts were treated with different concentrations of BTA, and expression of collagen (COL)1A1, COL1A2, COL3A1, TGF-ß1, TGF-ß2, TGF-ß3, fibronectin-1, laminin-ß2, and α-SMA was determined by real-time quantitative PCR. MTT and BrdU assays were used to analyze the effects of BTA on fibroblast proliferation and metabolism. RESULTS: Intralesional administration of BTA did not result in regression of keloid tissue. No differences in expression of ECM markers, collagen synthesis, or TGF-ß could be observed after BTA treatment of keloid fibroblasts. In addition, cell proliferation and metabolism of keloid fibroblasts was not affected by BTA treatment. CONCLUSION: The suggested clinical efficiency of intralesional BTA for the therapy of existent keloids could not be confirmed in this study. Based on our data, the potential mechanisms of action of BTA on keloid-derived fibroblasts remain unclear.

Honey bee (Apis mellifera) venom induces AIM2 inflammasome activation in human keratinocytes.

BACKGROUND: Following allergen exposure, cytokines and other pro-inflammatory signals play an important role in the immunological cascade leading to allergic sensitization. Inflammasomes sense exogenous and endogenous danger signals and trigger IL-1ß and IL-18 activation which in turn shape Th2 responses. Honey bee venom (BV) allergies are very common; however, the local inflammatory cascade leading to the initiation of allergic sensitization is poorly understood. In this study, the local inflammatory cascades in skin after exposure to BV were investigated. METHODS: The mechanisms of inflammasome activation in human skin and in cultured keratinocytes upon BV exposure were analyzed by ELISA, Western blot, flow cytometry, siRNA techniques, and immunofluorescence. RESULTS: In an ex vivo bee sting model, BV induced IL-1ß release suggesting the activation of inflammasomes. Indeed, in cultured keratinocytes, the BV component melittin triggered IL-1ß and IL-18 release via the AIM2 inflammasome. AIM2 is a cytosolic DNA receptor, and mitochondrial as well as genomic DNA was detected in the cytosol of melittin-treated keratinocytes as triggers of inflammasome activation. As a mechanism, melittin mediated destruction of mitochondrial membranes leading to the leakage of mitochondrial DNA into the cytosolic compartment. CONCLUSION: These data suggest that upon BV exposure, keratinocytes are involved in an innate immune response by the activation of the AIM2 inflammasome and subsequent IL-1ß and IL-18 release triggered by endogenous DNA. As IL-1ß and IL-18 are involved in Th2- and IgE-mediated immune reactions, these results could add to the understanding of the role of the tissue microenvironment to subsequent allergic responses.

Vitamin D and its role in allergic disease.

In Western countries, the incidence of atopy and allergic diseases is high and further rising. While genetic factors certainly play a role, epigenetic or even nutritional factors might also be important in the pathogenesis of allergies. Vitamin D - the 'sunshine hormone' - exerts profound effects on both adaptive and innate immune functions involved in the development and course of allergic diseases. As also the incidence of vitamin D insufficiency is surprisingly high in the general population, clinical and experimental studies have started to investigate if correcting vitamin D levels [measured as serum 25 hydroxy vitamin D -25(OH)D] is beneficial or even protective in patients with allergies or children at risk. This review highlights current data on the effects of vitamin D on the allergy-mediating immune system and the vitamin D status in atopic patients. Furthermore, the benefits and risks of vitamin D supplementation during pregnancy, childhood and in adults with respect to the development and course of allergic disease are discussed.

[Antimicrobial peptides, Vitamin D3 and more. How rosacea may develop]. / Antimikrobielle Peptide, Vitamin D3 und mehr. Wie Rosazea möglicherweise entsteht.

The pathogenesis of rosacea - a common, chronic inflammatory skin disease mainly affecting the central portions of the face - is only partly understood. In affected skin the expression of cathelicidin - an antimicrobial peptide and effector of innate immunity - is strongly increased. In addition, the activity of cutaneous proteases is greatly increased leading to the generation of cathelicidin peptide fragments with pro-inflammatory activity. UV irradiation and microbial factors contribute to this inflammatory cascade by increasing vitamin D(3) metabolism and the activation of toll-like receptors (TLR). Retinoids, azelaic acid and doxycycline inhibit both skin proteases and TLR expression and could mediate their anti-inflammatory effects in rosacea through these mechanisms. These data increase our understanding of the pathogenesis and therapy of rosacea. Also, these insights might uncover novel targets for innovative therapies of this common, stigmatizing skin disease.

Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) is a routine treatment for psoriasis and atopic dermatitis (AD) but its effect on vitamin D balance is not well studied. OBJECTIVES: To examine whether NB-UVB treatment in winter improves vitamin D balance in psoriasis and AD, and to study the effects of NB-UVB on antimicrobial peptide and cytokine expression in the skin. METHODS: Eighteen adult patients with psoriasis, 18 with AD and 15 healthy subjects received a total of 15 NB-UVB exposures on the whole body, given three times a week. Serum calcidiol (25-hydroxyvitamin D) was measured by radioimmunoassay. Antimicrobial peptide and cytokine expression in skin lesions was examined by real-time quantitative polymerase chain reaction. RESULTS: At onset 16 (89%) patients with psoriasis, 17 (94%) patients with AD and eight (53%) healthy subjects had vitamin D insufficiency (calcidiol < 50 nmol L(-1)). NB-UVB treatment significantly increased (P < 0.001) serum calcidiol. The increase was 59.9 nmol L(-1) (95% confidence interval, CI 53.5-66.9) in psoriasis, 68.2 nmol L(-1) (95% CI 55.4-80.1) in AD and 90.7 nmol L(-1) (95% CI 63.8-123.4) in healthy subjects. Psoriasis Area and Severity Index and SCORAD improved significantly (P < 0.001) but no correlation to the increase of serum calcidiol was found. Cathelicidin and human beta-defensin 2 (HBD2) expression was high in skin lesions of psoriasis. After six NB-UVB treatments cathelicidin increased further while HBD2 expression decreased. A similar trend was observed in AD lesions. NB-UVB caused a marked but nonsignificant decrease of interleukin (IL)-1beta and IL-17 in psoriasis lesions. CONCLUSIONS: The present study shows that in addition to a significant improvement of psoriasis and AD, NB-UVB treatment effectively corrects vitamin D insufficiency. It also increases cathelicidin and decreases HBD2 levels in healing skin lesions of psoriasis and AD. This effect might be mediated by improved vitamin D balance and the local cytokine network.