The association between atopic dermatitis and inflammatory bowel disease in adults: A cross-sectional study in a specialized atopic dermatitis clinic.

BACKGROUND: Atopic dermatitis (AD) and inflammatory bowel disease (IBD) share genetic susceptibility loci with immune regulation functions. Atopic dermatitis was associated with IBD mostly in database studies. OBJECTIVE: To assess whether AD is associated with an increased prevalence of IBD in a tertiary dermatology clinic. METHODS: A retrospective cross-sectional analysis using medical records of adults with verified AD followed up at an AD clinic, compared with age- and sex-matched (1:2) controls from the general dermatology clinic in the same hospital. RESULTS: Overall, 9/364 (2.47%) of patients with AD had verified IBD, compared with 7/725 (0.97%) of controls (p = 0.0512). In multivariable logistic regression adjusting for age, gender and smoking, the association became significant (adjusted OR = 3.89, 95% CI: 1.28-11.85). Stratified for AD severity, only moderate-to-severe AD was associated with IBD (p = 0.035), with an adjusted OR of 4.45 (95% CI: 1.43-13.90). Mild AD was not associated with IBD, but the study was not powered for this sub-analysis. In the AD group, older age was associated with IBD (p = 0.0172). CONCLUSION: This study, in a robustly verified cohort of patients, supports an association between AD, especially the moderate-to-severe forms, and IBD. A multidisciplinary approach for patients with moderate-to-severe AD should extend to consider IBD.

Paediatric mycosis fungoides - characteristics, management and outcomes with particular focus on the folliculotropic variant.

BACKGROUND: The literature on paediatric mycosis fungoides (MF) and especially its folliculotropic variant (FMF) is sparse. OBJECTIVES: To describe the clinical manifestations, treatments, outcomes and long-term course of paediatric MF, including FMF. METHODS: A retrospective analysis was conducted of all consecutive MF patients diagnosed at ≤18 years attending two medical centres in 1995-2015. RESULTS: The cohort included 71 patients, all but two of whom had early-stage disease: hypopigmented (55%), folliculotropic (42%) and classical MF (39%), alone or in combination. The head and neck area were involved in 43% of patients with early-stage FMF compared to 12% of the non-FMF group (P = 0.004). There was no difference in the involvement of other body areas between the groups. Pruritus, although mild, was more often recorded among patients with early-stage FMF compared to non-FMF (58% vs. 29%, respectively, P = 0.02). Complete response (CR) was achieved in 60 of the 69 patients with early-stage MF (87%) after an average of 1.8 treatment modalities. NBUVB was the most administered treatment to non-FMF patients with CR rates of 63% vs. 29% of FMF patients (P = 0.04). Systemic/bath PUVA and UVA+NBUVB were the most administered treatments to FMF patients with CR rates of 60% vs. 81% for non-FMF patients (P = 0.17). During a mean follow-up of 9.2 years (range 1-24), stage progression was observed in four (6%) of the patients with early-stage disease, two of whom (all FMF) to advanced stage. CONCLUSIONS: Paediatric MF presents as an early-stage disease with over-representation of hypopigmented and FMF variants. NBUVB and UVA-based therapies yield good response rates in non-FMF and FMF patients, respectively. Disease course is indolent, and even on relatively long follow-up, it has a very low progression rate from early to advanced-stage disease, occurring in patients with FMF. We propose a treatment algorithm for paediatric MF.

Percutaneous ethanol sclerotherapy is a promising treatment for recalcitrant angiolymphoid hyperplasia with eosinophilia.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare benign vascular proliferation, which manifests as characteristic red nodules and papules, mostly located on the scalp and periauricular regions. Patients seek treatment for both aesthetic and functional reasons, as lesions may ulcerate, bleed and itch. Many therapeutic approaches have been reported, with variable success, and relapse remains a troublesome issue. The aim of this study was to report our experience treating ALHE using percutaneous ethanol sclerotherapy (PES). We present a retrospective case series of three patients treated with PES (1-2 treatment sessions each). All patients had tried and failed other treatments prior to this intervention, but following PES treatment, all patients demonstrated significant improvement, which was sustained at follow-up (range 8-17 months after first treatment). Adverse effects were tolerable and transient. This case series demonstrates PES as a promising treatment for recalcitrant ALHE.

Multicentric EORTC retrospective study shows efficacy of brentuximab vedotin in patients who have mycosis fungoides and Sézary syndrome with variable CD30 positivity.

BACKGROUND: Brentuximab vedotin (BV) was approved as a therapy for mycosis fungoides (MF) based on the ALCANZA trial. Little real-world data, however, are available. OBJECTIVES: To evaluate the efficacy and safety of BV in patients with MF/Sézary Syndrome (SS) with variable CD30 positivity in a real-world cohort and to explore potential predictors of response. METHODS: Data from 72 patients with MF/SS across nine EORTC (European Organization for Research and Treatment of Cancer) centres were included. The primary endpoint was to evaluate the proportion of patients with: overall response (ORR), ORR lasting over 4 months (ORR4), time to response (TTR), response duration (RD), progression-free survival (PFS) and time to next treatment (TTNT). Secondary aims included a safety evaluation and the association of clinicopathological features with ORR, RD and TTNT. RESULTS: All 72 patients had received at least one systemic treatment. ORR was achieved in 45 of 67; ORR4 in 28 of 67 with a median TTR of 8 weeks [interquartile range (IQR) 5·5-14] and with a median RD of 9 months (IQR 3·4-14). Median PFS was 7 months (IQR 2-12) and median TTNT was 30 days (6-157·5). Patient response, RD, PFS and TTNT were not associated with any clinicopathological characteristics. In the MF group, patients with stage IIB/III vs. IV achieved longer PFS and had a higher percentage of ORR4. There was a statistically significant association between large-cell transformation and skin ORR (P = 0·03). ORR4 was more frequently achieved in patients without lymph node involvement (P = 0·04). CONCLUSIONS: BV is an effective option for patients with MF/SS, including those with variable CD30 positivity, large-cell transformation, SS, longer disease duration and who have been treated previously with several therapies.

Mycosis fungoides-derived exosomes promote cell motility and are enriched with microRNA-155 and microRNA-1246, and their plasma-cell-free expression may serve as a potential biomarker for disease burden.

BACKGROUND: Literature regarding exosomes as mediators in intercellular communication to promote progression in mycosis fungoides (MF) is lacking. OBJECTIVES: To characterize MF-derived exosomes and their involvement in the disease. METHODS: Exosomes were isolated by ultracentrifugation from cutaneous T-cell lymphoma (CTCL) cell lines, and from plasma of patients with MF and controls (healthy individuals). Exosomes were confirmed by electron microscopy, NanoSight and CD81 staining. Cell-line exosomes were profiled for microRNA array. Exosomal microRNA (exomiRNA) expression and uptake, and plasma-cell-free microRNA (cfmiRNA) were analysed by reverse-transcriptase quantitative polymerase chain reaction. Exosome uptake was monitored by fluorescent labelling and CD81 immunostaining. Migration was analysed by transwell migration assay. RESULTS: MyLa- and MJ-derived exosomes had a distinctive microRNA signature with abundant microRNA (miR)-155 and miR-1246. Both microRNAs were delivered into target cells, but only exomiR-155 was tested, demonstrating a migratory effect on target cells. Plasma levels of cfmiR-1246 were significantly highest in combined plaque/tumour MF, followed by patch MF, and were lowest in controls (plaque/tumour > patch > healthy), while cfmiR-155 was upregulated only in plaque/tumour MF vs. controls. Specifically, exomiR-1246 (and not exomiR-155) was higher in plasma of plaque/tumour MF than in healthy controls. Plasma exosomes from MF but not from controls increased cell migration. CONCLUSIONS: Our findings show that MF-derived exosomes promote cell motility and are enriched with miR-155, a well-known microRNA in MF, and miR-1246, not previously reported in MF. Based on their plasma expression we suggest that they may serve as potential biomarkers for tumour burden.

Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.

Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.

BACKGROUND: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. OBJECTIVES: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. METHODS: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. RESULTS: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. CONCLUSIONS: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.

Epidemiology of cutaneous porphyria in Israel: a nationwide cohort study.

BACKGROUND: From a dermatologist's perspective, there are four major types of cutaneous porphyrias (CPs): porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Scarce data are available regarding the epidemiology of CPs. OBJECTIVES: To describe the epidemiology of CPs in Israel, including distribution, incidence and prevalence rates of major types. METHODS: This retrospective study includes all patients who were diagnosed with CPs between the years 1988-2018. It is based on data from Israel's National Service for the Biochemical Diagnoses of Porphyrias, and Israeli patients' nationwide electronic medical charts. Incidence and prevalence rates were calculated. RESULTS: Of 173 patients with CPs diagnosed during a 30-year period, 65 (38%) had VP, 62 (36%) had PCT, 31 (18%) had HCP and 15 (9%) had EPP; with incidence rates of 0.29, 0.30, 0.17, 0.07, and prevalence rates of 6.3, 4.8, 2.9, 1.6, respectively, per million population. Characteristics of patients with PCT differed from those with other CPs with regard to lack of family history, older mean age at diagnosis [51 vs. 36 (VP), 35 (HCP) and 25 (EPP) years] and male predominance (81% vs. similar distribution). All patients with PCT were diagnosed at adulthood, while 20%, 19% and 15% of patients with VP, HCP and EPP, respectively, were diagnosed during childhood or adolescence. CONCLUSIONS: Variegate porphyria and PCT were found to be the most prevalent in Israel; however, CPs might be underdiagnosed, thus dermatologists' awareness of these rare disorders is highly important.

Real-life experience in the treatment of solar urticaria: retrospective cohort study.

BACKGROUND: Solar urticaria (SU) is a rare photodermatosis causing a significant impact on patients' quality of life (QoL), and treatment is often challenging. AIM: To analyse clinical experience with a tailored stepwise therapeutic approach. METHODS: A retrospective cohort design was used. Patients with suspected SU underwent laboratory investigations and photoprovocation. Those with a high minimal urticaria dose (MUD) were treated with a single antihistamine (protocol 1), and those with a lower MUD received three types of antihistamines (protocol 2); both protocols included a leucotriene receptor antagonist (LRA). In cases of failure, treatment was switched to omalizumab at doses of < 300 mg/month with incremental dosage increases as necessary (monthly dose range, 150-600 mg/month). Symptom relief and photoprovocation under treatment were evaluated. RESULTS: In total, 30 patients (10 men, 20 women) were enrolled. Most (87%) were sensitive to visible light (1-70 J/cm2 ) with or without extension to ultraviolet A. Of the 30 patients, 23 opted for our stepwise approach: 22 achieved complete remission on protocols 1 or 2 (n = 17) or after switching to omalizumab (n = 5), and another patient achieved partial remission under omalizumab. There were no treatment-related severe adverse effects. CONCLUSIONS: Symptoms of SU can be well controlled by treatment with antihistamines and an LRA tailored to the degree of photosensitivity, followed by omalizumab in refractory cases. This has important implications for patient QoL.

Unilesional mycosis fungoides is associated with increased expression of microRNA-17~92 and T helper 1 skewing.

BACKGROUND: The molecular basis of unilesional mycosis fungoides (MF), characterized by a solitary lesion that is clinicopathologically indistinguishable from multifocal patch or plaque MF (early MF), is unknown. OBJECTIVES: To investigate the microRNA profile in unilesional MF distinguishing it from early MF. METHODS: Biopsy samples of unilesional MF and early MF were evaluated with the Affymetrix microRNA array, with further comparison with inflammatory dermatosis, using quantitative polymerase chain reaction. NanoString technology was applied to analyse the gene expression of T helper (Th)1 immune markers, and immunohistochemistry was used to evaluate CXCR3 and GATA-binding protein 3 (GATA3) markers for Th1 and Th2 cells, respectively. RESULTS: Unilesional MF had a significantly higher level of expression of all members of the microRNA miR-17~92 cluster than early MF. Specifically, unilesional MF had a higher miR-17 level than early MF and inflammatory dermatoses. There was downregulation of the expression of phosphatase and tensin homolog (PTEN) and CREB1, known targets of miR-17~92 members; higher gene expression of interleukin-2 and interferon-γ; and a statistically lower average percentage of GATA3+ dermal cells (6·7% vs. 42·3%), were detected in unilesional MF compared with early MF. High immunoreactivity of CXCR3 was noted in both unilesional and early MF. CONCLUSIONS: Unilesional MF exhibits a microRNA profile distinct from that of conventional early MF, with a higher level of miR-17~92 members along with Th1 skewing. These findings suggest a robust reactive T-cell immune response in unilesional MF and might account for the localized nature of this disease.

The PROCLIPI international registry of early-stage mycosis fungoides identifies substantial diagnostic delay in most patients.

BACKGROUND: Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web-based data collection system for early-stage MF with legal data-sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in-built intelligence in the database system ensures accurate staging. OBJECTIVES: To develop a prognostic index for MF. METHODS: Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies. RESULTS: In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early-stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 12-90)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF. CONCLUSIONS: This confirmed early-stage MF cohort is being followed-up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex.

Grover disease and bullous pemphigoid: a clinicopathological study of six cases.

Grover disease (GD) is an idiopathic dermatosis that typically manifests as itchy papules over the trunk in middle-aged men. Bullous pemphigoid (BP) is an autoimmune bullous disease that affects older people. Not only are the two diseases easily distinguishable on clinical grounds, they are also characterized by differences in histopathology, pathogenesis and response to treatment Thus, the co-occurrence of these two conditions in the same patient is usually considered coincidental. In this report, we present a multicentre retrospective analysis of six patients who developed both GD and BP over a short period of time, and in all cases but one, GD preceded BP. We discuss the clinical and histopathological features of these patients, and the suggested mechanisms of the diseases. We conclude that GD might predispose to the development of BP.

Psychological stress and psoriasis: a systematic review and meta-analysis.

BACKGROUND: Psychological stress has long been linked with the exacerbation/onset of psoriasis. OBJECTIVES: To determine if antecedent psychological stress is associated with the exacerbation/onset of psoriasis. METHODS: A search of the PubMed, PsycINFO, Cochrane library and ClinicalTrials.gov databases was performed. Surveys evaluating beliefs about stress reactivity were analysed separately. Suitable studies were meta-analysed. RESULTS: Thirty-nine studies (32 537 patients) were included: 19 surveys, seven cross-sectional studies, 12 case-control studies and one cohort study. Forty-six per cent of patients believed their disease was stress reactive and 54% recalled preceding stressful events. Case-control studies evaluating stressful events rates prior to the exacerbation (n = 6) or onset (n = 6) of psoriasis varied in time lag to recollection (≤ 9 months to ≥ 5 years). Pooling five studies evaluating stressful events preceding onset of psoriasis gave an odds ratio (OR) of 3·4 [95% confidence interval (CI) 1·8-6·4; I2 = 87%]; the only study evaluating a documented stress disorder diagnosis reported similar rates between patients and controls (OR 1·2, 95% CI 0·8-1·8). Four studies evaluating stressful events prior to psoriasis exacerbation reported comparable rates with controls, whereas two found more frequent/severe preceding events among patients with psoriasis. A small prospective cohort study reported a modest association between stress levels and exacerbation of psoriasis (r = 0·28, P < 0·05). CONCLUSIONS: The association between preceding stress and exacerbation/onset of psoriasis is based primarily on retrospective studies with many limitations. No convincing evidence exists that preceding stress is strongly associated with exacerbation/onset of psoriasis.