Narrowband-ultraviolet B vs Broadband-ultraviolet B in Treatment of Chronic Pruritus: A Randomized, Single-blinded, Non-inferiority Study.

Narrowband-ultraviolet B has shown increased efficacy over broadband-ultraviolet B in pruritic skin diseases, such as psoriasis and atopic dermatitis. In patients with chronic pruritus, e.g. in end-stage renal disease, broadband-ultraviolet B is recommended, but narrowband-ultraviolet B has also shown efficacy in reducing pruritus. This randomized, single blinded, non-inferiority study investigated the effects of narrowband-ultraviolet B compared with broadband-ultraviolet B. Patients with chronic pruritus were treated with either broadband- or narrowband-UVB 3 times a week for 6 weeks and clinical response was monitored. Pruritus, sleep disturbance, and the patients' subjective overall response to treatment were evaluated by the patients on a visual analogue scale (0-10). Skin excoriations were evaluated by investigators on a 4-point scale (0-3). Both phototherapeutic modalities showed significant antipruritic activity (itch reduction 48% and 66.4%, respectively) by broadband-ultraviolet B and narrowband-ultraviolet B. Narrowband-ultraviolet B proved to be not inferior to broadband-ultraviolet B in treating pruritus in patients with chronic pruritus, assuming a 20% non-inferiority margin.

Quality of Life, Anxiety, and Depression in Patients With Early-Stage Mycosis Fungoides and the Effect of Oral Psoralen Plus UV-A (PUVA) Photochemotherapy on it.

Background: Little is known about psychological discomfort and quality of life (QoL) in early stage mycosis fungoides (MF) and the effect of psoralen plus UV-A (PUVA) on it. Objective: To evaluate QoL, anxiety, and depression with validated instruments in early stage MF patients and whether PUVA treatment improves it. Methods: Patients with stage IA to IIA MF were treated with PUVA twice weekly for 12-24 weeks, followed by maintenance treatment or not, in a prospective randomized clinical trial. Patients completed a questionnaire on DLQI as well as the Hospital Anxiety and Depression Scale (HADS) prior to therapy, after their last PUVA exposure, and after the PUVA maintenance or observance phase. Results: For 24 patients with early stage MF, completed questionnaires were available and analyzed. Prior to treatment, 17% reported strong (DLQI > 10) and 29% moderate impairment (DLQI 6-10) in QoL; 33% of patients reported HADS scores indicating anxiety, and 21% reported scores indicating depression. PUVA significantly improved overall QoL by reducing mean DLQI scores by 58.6% (p = 0.003), HADS-A by 30% (p = 0.045), and HADS-D by 44% (p = 0.002). Improvements in QoL and psychological well-being seemed to be sustained, irrespective of maintenance treatment or not. Limitations: Small sample size. Conclusions: PUVA sustainably improves QoL and psychological well-being in patients with early stage MF. Clinical trial registration: ClinicalTrials.gov identifier: NCT01686594.

Evaluation of Low-Dose, Low-Frequency Oral Psoralen-UV-A Treatment With or Without Maintenance on Early-Stage Mycosis Fungoides: A Randomized Clinical Trial.

Importance: Psoralen-UV-A (PUVA) photochemotherapy is standard first-line treatment for skin-limited, early-stage mycosis fungoides capable of producing high initial complete response (CR) rates. However, much remains unknown about PUVA's therapeutic mechanisms, optimal duration and frequency of treatment, dose escalation, or use as maintenance therapy. Objectives: To evaluate low-dose, low-frequency PUVA, and whether maintenance treatment extends disease-free remission in patients with mycosis fungoides. Design, Setting, and Participants: This prospective randomized clinical trial with defined PUVA dosing regimen was carried out in 5 centers (Graz, Vienna, Hietzing, Innsbruck, and Salzburg) across Austria. Patients with stage IA to IIA mycosis fungoides (n = 27) were enrolled in the study beginning March 13, 2013, with the last patient enrolled March 21, 2016. These patients were treated with oral 8-methoxypsoralen followed by UV-A exposure 2 times per week for 12 to 24 weeks until CR. Patients with CR were randomized to PUVA maintenance for 9 months (14 total exposures) or no maintenance. The study was conducted from April 27, 2012, to July 27, 2018. Data analysis of the primary end point was of the intention-to-treat population, and the secondary end point analysis was of the evaluable population. Main Outcomes and Measures: Efficacy of the PUVA regimen was determined by the rate of CR as defined by a modified severity-weighted assessment tool (mSWAT) score reduction to 0. Levels of proinflammatory molecules in serum and histologic features and percentage of clonal T cells in skin were assessed to search for biomarkers of clinical response. Results: In 27 patients with mycosis fungoides, 19 (70%) were male with mean (range) age 61 (30-80) years. At baseline, patients with CR had a mean (range) mSWAT score of 18.6 (1-66) compared with 16.8 (3-46) in patients with partial response. The 12- to 24-week PUVA induction regimen reduced the mSWAT score in all patients and led to CR in 19 (70%) of 27 patients and a low mean cumulative UV-A dose of 78.5 J/cm2. The subsequent standardized 9-month PUVA maintenance phase prolonged median (range) disease-free remission from 4 (1-20) months to 15 (1-54) months (P = .02). High density of histologic infiltrate and high percentage of clonal TCR sequences in skin biopsy specimens at baseline were inversely associated with therapeutic response. No severe adverse effects were seen during the PUVA induction or maintenance phase. Conclusions and Relevance: This proof-of-concept study identifies potential biomarkers for therapeutic response to PUVA in mycosis fungoides; it also demonstrates that low-dose, low-frequency PUVA appears to be highly effective, and maintenance treatment may extend disease-free remission. Trial Registration: ClinicalTrials.gov identifier: NCT01686594.

Frequency of occurrence of polymorphic light eruption in patients treated with photohardening and patients treated with phototherapy for other diseases.

BACKGROUND: Medical phototherapy can lead to the manifestation of polymorphic light eruption (PLE), though little is known about the frequency of such events. AIMS: The aim of this Austrian single center study was to retrospectively investigate over a 4-year time period the frequency of PLE in patients prone to the condition and patients with other diseases under phototherapy (mainly narrow-band and broad-band UVB). MATERIALS AND METHODS: The data for analysis were obtained from the electronic health and patient record database and patient files of the Photodermatology Unit, Department of Dermatology, Medical University of Graz, Austria. RESULTS: PLE occurred in 24.3% (18/74) of PLE patients but only 0.7% (3/421) of psoriasis patients under phototherapy (chi-square; P < 0.0001). PLE also occurred in 1.2% (3/257) of patients with atopic eczema, 0.8% (1/118) with prurigo, 3.5% (4/115, P = 0.0206) with parapsoriasis en plaques/mycosis fungoides, 7.4% (2/27, P = 0.0013) with granuloma anulare, 14.3% (1/7, P = 0.0002) with scleroderma, and 16.7% (1/6, P < 0.0001 vs. psoriasis) with pityriasis lichenoides chronica or pityriasis lichenoides eruptiva et varioliformis acuta. DISCUSSION AND CONCLUSION: These results are helpful for treatment allocation and risk estimation of PLE occurrence with regard to obtaining informed consent not only from PLE-prone patients but also from patients with other skin disorders commonly treated by phototherapy.

Nodular Sclerodermatous Chronic Cutaneous Graft-Versus-Host Disease (GvHD): A New Clinicopathological Variant of Cutaneous Sclerodermatous GvHD Resembling Nodular/Keloidal Scleroderma.

Cutaneous chronic graft-versus-host disease (GvHD) has a broad spectrum of clinicopathological presentations, the most common ones being poikiloderma, lichen planus-like eruptions, lichen sclerosus-like lesions, morphea-like plaques, and deep sclerosis. New forms of chronic cutaneous GvHD with different clinicopathological characteristics have been described, most of them mimicking cutaneous manifestations of autoimmune diseases. We report the case of a 35-year-old man who underwent allogenic stem cell transplantation for a therapy-associated acute myeloid leukemia and developed an acute GvHD with involvement of skin and gastrointestinal tract. He subsequently presented with chronic sclerodermatous cutaneous GvHD, followed by the appearance of indurated erythematous papules and plaques located on his back, resembling the nodular/keloidal form of cutaneous scleroderma on both clinical and histopathological grounds. This peculiar clinicopathologic presentation of chronic cutaneous GvHD was never described previously.

Desired response to phototherapy vs photoaggravation in psoriasis: what makes the difference?

Psoriasis commonly responds beneficially to UV radiation from natural sunlight or artificial sources. Therapeutic mechanisms include the proapoptotic and immunomodulating effects of UV, affecting many cells and involving a variety of pro- and anti-inflammatory cytokines, downregulating the Th17/IL-23 response with simultaneous induction of regulatory immune cells. However, exposure to UV radiation in a subset of psoriasis patients leads to exacerbation of the disease. We herein shed light on the predisposing factors of photosensitive psoriasis, including genetics (such as HLA-Cw*0602 or CARD14), gender and coexisting photodermatoses such as polymorphic light eruption (PLE) in the context of potential molecular mechanisms behind therapeutic photoresponsiveness or photoaggravation. UV-induced damage/pathogen-associated molecular patterns, damage to self-coding RNA (signalling through Toll-like receptors), certain antimicrobial peptides and/or inflammasome activation may induce innate immunity, leading to psoriasis at the site of UV exposure when there is concomitant, predisposing resistance against UV-induced suppression of the adaptive immune response (like in PLE) that otherwise would act to reduce psoriasis.

Survival and Effectiveness of Tumour Necrosis Factor-alpha Inhibitors in the Treatment of Plaque Psoriasis under Daily Life Conditions: Report from the Psoriasis Registry Austria.

This retrospective multicentre analysis from the Psoriasis Registry Austria (PsoRA) was conducted to determine drug effectiveness and survival of anti-tumour necrosis factor alpha (anti-TNF-α) agents in patients with moderate-to-severe chronic plaque psoriasis over a 9-year period. Data on 1,019 treatment cycles with adalimumab (n = 460), etanercept (n = 501), and/or infliximab (n = 58) administered to 827 patients (272 women, 555 men) were available for analysis. Compared with etanercept, adalimumab and infliximab showed superior short-term effectiveness. Intention-to-treat-calculated median drug survivals for adalimumab (1,264 days) and etanercept (1,438 days) were similar to each other (p = 0.74), but significantly superior to that of infliximab (477 days) (p = 7.0e-07 vs. adalimumab and p=2.2e-07 vs. etanercept, respectively). Their drug survival rates at 36 months were 51.6%, 56.0%, and 22.6%, respectively. Survival rates correlated significantly with effectiveness for adalimumab and etanercept, but not for infliximab.

Comedonal graft-vs-host disease: a distinct clinical expression of a lichenoid follicular GVHD.

We report two cases of chronic follicular graft-vs-host disease (GVHD) that resemble closed and open acne-like comedones. We propose the term 'comedonal GVHD' for this variant. A 47-year-old man presented with multiple 2-4-mm acne-like follicular papules in facial areas on day 82 status post bone marrow transplantation. A biopsy showed follicular infundibular dilation with keratotic plugs, hypergranulosis and vacuolar alteration (hydropic degeneration) of the basal layer, with dyskeratotic (apoptotic) keratinocytes, scattered lymphocytes and vascular ectasia of the superficial dermal plexus. We diagnosed chronic follicular lichenoid GVHD. The second patient was a 53-year-old female. On day 420 after transplantation, she presented with generalized dark to grayish, confluent, indurated lesions with confluent papules and unevenly distributed comedo-like lesions. Skin biopsy showed sclerotic dermis and also dilated follicular infundibula with keratotic plugging, hypergranulosis and vacuolar alteration (hydropic degeneration) of the basal layer of the epidermis. We established the diagnosis of chronic sclerodermoid GVHD with follicular lichenoid involvement. The presence of open and closed comedones on the trunk and facial region of an adult raises several differential diagnosis but in our patients, histopathologic study demonstrated typical features of GVHD, which led to this diagnoses despite the peculiar clinical findings.

Polymorphous light eruption: clinic aspects and pathogenesis.

Polymorphous light eruption is an immunologically mediated photodermatosis with high prevalence, particularly among young women in temperate climates, characterized by pruritic skin lesions of variable morphology, occurring in spring or early summer on sun-exposed body sites. A resistance to ultraviolet radiation (UVR)-induced immunosuppression and a subsequent delayed-type hypersensitivity response to a photoantigen have been suggested as key factors in the disease. Molecular and immunologic disturbances associated with disease pathogenesis include a failure of skin infiltration by neutrophils and other regulatory immune cells on UVR exposure linked to a disturbed cytokine microenvironment. Standard management is based on prevention.

Photohardening of polymorphic light eruption patients decreases baseline epidermal Langerhans cell density while increasing mast cell numbers in the papillary dermis.

The pathogenesis of polymorphic light eruption (PLE) has been linked to a lack of UV-induced immune suppression. To determine the role of Langerhans cells (LC), mast cells and regulatory T cells, biopsies from PLE patients were taken from exposed sites in spring before and after photohardening with 311 nm or PUVA as well as again in summer. Skin sections were assessed for the presence of Langerin/CD1a+ LC and CD3+, CD4+, CD25+ or FoxP3+ T cells and mast cells. Photohardening transiently decreased the density of epidermal LC and significantly increased a low baseline mast cell density in the papillary dermis of PLE patients. Baseline T cell numbers in the skin were low, and there was no difference in PLE patients among any time point. This suggests that LC suppression together with recruitment of mast cells into photohardened skin may be a key cellular event underlying the mechanism by which phototherapy protects from PLE.

Involvement of IL-9 in Th17-associated inflammation and angiogenesis of psoriasis.

It is thought that a Th1/Th17-weighted immune response plays a predominant role in the pathogenesis of psoriasis. Our findings now indicate a link between IL-9, a Th2 and Th9 cytokine, and Th17 pathway in psoriasis. In K5.hTGF-ß1 transgenic mice, exhibiting a psoriasis-like phenotype, we found increased IL-9R and IL-9 expression in the skin and intradermal IL-9 injection induced Th17-related inflammation. IL-9 also promoted angiogenesis and VEGF and CD31 overexpression in mice in vivo and increased tube formation of human endothelial cells in vitro. Injecting anti-IL-9 antibody into K5.hTGF-ß1 transgenic mice not only diminished inflammation (including skin infiltration by T cells, monocytes/macrophages, and mast cells) and angiogenesis but also delayed the psoriasis-like skin phenotype. Notably, injection of anti-psoriatic acting anti-IL-17 antibody reduced skin IL-9 mRNA and serum IL-9 protein levels in K5.hTGF-ß1 transgenic mice and prevented IL-9-induced epidermal hyperplasia and inflammation of the skin of wild type mice. In addition, we observed that IL-9R expression in lesional skin from psoriasis patients was markedly higher than in healthy skin from control subjects. Moreover, IL-9 significantly enhanced IL-17A production by cultured human peripheral blood mononuclear cells or CD4+ T cells, especially in psoriasis patients. Thus, IL-9 may play a role in the development of psoriatic lesions through Th17-associated inflammation and angiogenesis.

Phototherapeutic hardening modulates systemic cytokine levels in patients with polymorphic light eruption.

The etiopathogenesis of polymorphic light eruption (PLE) has been linked to impaired UV-immunosuppression, Langerhans cell (LC) retention, and an absence of neutrophil infiltration into UV-exposed PLE skin. We have previously shown that photohardening restores the impaired neutrophil responsiveness to the chemoattractants leucotriene B4 and formyl-methionyl-leucyl-phenylalanin in PLE patients. The aim of this study was to investigate whether photohardening modulates baseline chemokine and cytokine levels which would alter chemoresponsiveness and hence immune function in PLE patients. Sixteen PLE patients received photohardening therapy for 4-9 weeks by 311 nm UVB. Plasma samples were taken both before and within 48 h of the penultimate phototherapeutic exposure. Plasma from these 16 patients, 8 non-irradiated PLE patients, and 14 control subjects was analyzed for IL-1ß, CXCL8 (IL-8), IL-10, IL-17, TNF, CCL2 (MCP-1), CCL5 (RANTES), CCL11 (eotaxin), and CCL22 (MDC). These cytokines and chemokines were measured in early spring (March to April) and again in late spring (April to June). PLE patients had a significantly elevated level of CCL11 (p = 0.003) and IL-1ß (p = 0.002) in early spring (before phototherapy). In late spring, after phototherapy, PLE patients had significantly elevated CCL2 (p = 0.002) and TNF (p = 0.002) but a trend for lowered plasma levels of CXCL8 (p = 0.021). When comparing the cytokine shifts from early to late spring, while healthy controls and non-UV-irradiated PLE patients showed an increase, PLE patients undergoing photohardening exhibited a trend for decrease in IL-1ß (p = 0.012). Taken together, our results indicate that photohardening may alter the complex cytokine milieu in PLE, in particular via IL-1ß, helping to normalise the pathophysiologic response to subsequent UV exposure.

Patients with polymorphic light eruption have decreased serum levels of 25-hydroxyvitamin-D3 that increase upon 311 nm UVB photohardening.

BACKGROUND: Polymorphic light eruption (PLE) is a very common condition whose pathogenesis may involve immunological abnormalities. Vitamin D sufficiency is thought to be important for normal immune function. OBJECTIVE: To determine whether PLE patients are vitamin D deficient and to study how photohardening with 311 nm UVB affects the vitamin D status of PLE patients. METHODS: The vitamin D status of 23 PLE patients (21 females and 2 males; age range, 18-55 years) was analysed at four different time points (early spring, late spring, summer, and winter) by measuring 25-hydroxyvitamin-D(3) (25(OH)D) serum levels through a standardised immunoassay. Fifteen of those patients received 311 nm UVB in early spring for prevention of PLE symptoms. 25(OH)D levels of the PLE patients were compared to that of 23 sex-, age-, and body-mass-index post hoc-matched control subjects. RESULTS: PLE patients had low levels of 25(OH)D throughout the year compared to that of the control subjects. At baseline in early spring, the mean ± SD 25(OH)D level was 14.9 ± 3.0 ng ml(-1) in the PLE patients that would later receive 311 nm UVB and 14.4 ± 2.4 ng ml(-1) in the patients not receiving 311 nm UVB. Successful prophylactic treatment with 311 nm UVB significantly increased 25(OH)D levels to a mean of 21.0 ± 3.4 ng ml(-1) (p < 0.001; ANOVA, Tukey's test). Heading into summer, the 25(OH)D levels in treated patients decreased again, reaching their lowest levels in winter. In contrast, the 25(OH)D levels of untreated PLE patients stayed in the low range in early and late spring but increased by trend towards summer, reaching similar levels to that of the PLE patients who had received 311 nm UVB (17.1 ± 2.3 vs. 17.3 ± 6.0 ng ml(-1)). Like the treated PLE patients, 25(OH)D levels of untreated patients significantly decreased in winter to comparable levels (12.2 ± 1.9 vs. 13.8 ± 1.8 ng ml(-1)). Taken together, the 25(OH)D levels of PLE patients were significantly lower at all time points than that observed in the matched control population (34.4 ± 12.5 ng ml(-1)) (p < 0.000003). CONCLUSIONS: PLE patients have low 25(OH)D serum levels. 311 nm UVB phototherapy that prevented PLE symptoms increased those levels. Thus, we speculate that boosting levels of vitamin D may be important in ameliorating PLE.

311 nm ultraviolet B-accelerated response of psoriatic lesions in adalimumab-treated patients.

BACKGROUND: Treatment with the tumor necrosis factor-alpha antibody adalimumab for 12-16 weeks produces a satisfactory response [i.e., 75% reduction in psoriasis area and severity index (PASI)] in a majority (70-80%) of patients with psoriasis. We asked whether 311 nm ultraviolet B (UVB) can improve therapeutic response of psoriatic lesions to adalimumab. METHODS: Four patients (age range, 49-67 years) with moderate to severe plaque-type psoriasis were treated with standard dosage of adalimumab. During adalimumab therapy, a randomly selected body half (left or right, excluding the head) was irradiated with 311 nm UVB three times weekly for 6 weeks. Treatment response was monitored weekly in terms of half-body PASI. RESULTS: 311 nm UVB significantly accelerated the therapeutic response during adalimumab treatment. At the start of 311 nm UVB therapy, the mean PASI was 14.8. After 6 weeks of 311 nm UVB therapy, the mean PASI was 2.0 on UV-irradiated body halves and 6.9 on non-irradiated body halves (difference, 4.9; 95% confidence interval, 0.4-9.4; P=0.041; 2-tailed paired t-test). This corresponded to an overall mean PASI reduction from baseline (i.e., adalimumab start) of 86% on UV-irradiated body halves vs. 53% on non-irradiated body halves. CONCLUSION: 311 nm UVB may accelerate and improve the clearance of psoriatic lesions in adalimumab-treated patients.

Topical liposomal DNA-repair enzymes in polymorphic light eruption.

Polymorphic light eruption (PLE) is a very frequent photodermatosis in Europe whose pathogenesis may involve resistance to UV-induced immune suppression and simultaneous immune reactions against skin photoneoantigens. We performed a randomized, double-blind, placebo-controlled intra-individual half-body trial to investigate the protective effect of an after-sun (AS) lotion containing DNA-repair enzymes (photolyase from Anacystis nidulans and Micrococcus luteus extract with endonuclease activity). Fourteen PLE patients were exposed to suberythemal doses of solar-simulated UV radiation on 4 consecutive days at 4 symmetrically located PLE-prone test fields per patient. The test fields were treated with (i) active AS lotion or (ii) a placebo lotion immediately after each UV exposure, or (iii) an SPF30 sunscreen before UV exposure or left untreated. All test fields were exposed to photoactivating blue light 1 h after each UV exposure. As shown by a newly established specific PLE test score (AA + SI + 0.4P [range, 0-12], where AA is affected area score [range, 0-4], SI is skin infiltration score [range, 0-4], and P is pruritus score on a visual analogue scale [range, 0-10]), PLE symptoms were significantly fewer on test sites treated with active AS lotion than on untreated (P = 0.00049) or placebo-treated test sites (P = 0.024). At 144 h after first UV exposure (the time point of maximal PLE symptoms), the mean test scores for untreated, active AS lotion-treated, and placebo-treated test fields were 4.39, 1.73 (61% reduction; 95% confidence interval (CI), 36% to 85%), and 3.20 (27% reduction; 95% CI, 3% to 51%), respectively. Pretreatment with SPF30 sunscreen completely prevented PLE symptoms in all patients. The present results indicate that DNA damage may trigger PLE and that the application of topical liposomes containing DNA repair enzymes to increase DNA repair may effectively prevent PLE.

Photohardening restores the impaired neutrophil responsiveness to chemoattractants leukotriene B4 and formyl-methionyl-leucyl-phenylalanin in patients with polymorphic light eruption.

A failure to induce immune suppression after UV exposure has been implicated in the pathogenesis of polymorphic light eruption (PLE). This immunological resistance has been linked to an impaired neutrophil infiltration into the skin following UV exposure. Therapeutic photohardening can restore this abnormal neutrophil infiltration in PLE skin and is thought to be responsible for the prophylactic efficacy. The aim of this study was to elucidate the pathogenic mechanism of the described neutrophil deficiency in PLE. Peripheral blood neutrophil responses to the chemoattractants leukotriene B4 (LTB(4)) and formyl-methionyl-leucyl-phenylalanin (fMLP) were investigated in vitro. Samples from 10 patients with PLE before and after 6 weeks of photohardening therapy were assessed. Flow cytometry was used to measure the changes associated with neutrophil activation. We found a significantly reduced neutrophil responsiveness to LTB(4) and fMLP in PLE patients, which was restored to normal levels after phototherapy. Indeed, PLE neutrophil responsiveness to these two chemoattractants after (but not before) phototherapy was similar to that of age- and sex-matched healthy control subjects. This indicates that an abnormal chemotactic potential to neutrophils is a crucial factor in the pathogenesis of PLE. Normalization following photohardening may therefore account for the therapeutic efficacy by restoring UV-induced neutrophil skin infiltration. Our results reveal a completely novel pathogenic mechanism involved in PLE and offer unique targets for therapy.

New insights into the mechanisms of polymorphic light eruption: resistance to ultraviolet radiation-induced immune suppression as an aetiological factor.

An abnormal immune response has long been thought responsible for the patho-aetiology of polymorphic light eruption, the most common photodermatosis. Recent evidence indicates that polymorphic light eruption patients are resistant to the immune suppressive effects of sunlight, a phenomenon that leads to the formation of skin lesions upon seasonal sun exposure. This immunological abnormality in polymorphic light eruption supports the concept of the biological significance and evolutionary logic of sunlight-induced immune suppression, i.e. the prevention of immune responses to photo-induced neo-antigens in the skin, thereby preventing autoimmunity and skin rashes. This article focuses on the immunological alterations in polymorphic light eruption and the pathogenic significance to the disease state and skin carcinogenesis.