Imbalanced IL-1B and IL-18 Expression in Sézary Syndrome.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.

Erythroderma (exfoliative dermatitis). Part 2: energy homeostasis and dietetic management strategies.

Erythroderma (exfoliative dermatitis) is associated with important metabolic changes that include an enhancement in energy expenditure. The key components to total energy expenditure (TEE) include basal metabolic rate (~68% of TEE), physical activity (~22% of TEE) and thermic effect of food (~10% of TEE). In the erythrodermic state, there are likely multiple contributors to the increase in basal metabolic rate, such as 'caloric drain' resulting from increased evaporation of water from enhanced transepidermal water loss, increased activity of the cardiovascular system (including high-output cardiac failure), increased nonshivering thermogenesis and hormonal changes such as hypercortisolaemia. A change in the patient's level of physical activity and appetite as a result of ill health status may further impact on their TEE and energy consumption. In Part 2 of this two-part concise review, we explore the key constituents of energy homeostasis and the potential mechanisms influencing energy homeostasis in erythroderma, and suggest much-needed dietetic management strategies for this important condition.

NRF2 Augments Epidermal Antioxidant Defenses and Promotes Atopy.

Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2-related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1α. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.

Exploring the in situ expression of vascular endothelial growth factor and endoglin in pemphigus foliaceus variants and pemphigus vulgaris.

BACKGROUND: Erythroderma is a severe manifestation of pemphigus foliaceus (PF), a blistering disease mediated by IgG autoantibodies against desmoglein 1. Increasing evidence supports the contribution of angiogenic mediators in the pathogenesis of erythroderma. OBJECTIVE: To evaluate the in situ expression of vascular endothelial growth factor (VEGF) and endoglin in patients with PF with erythroderma. METHODS: Formalin-fixed paraffin-embedded skin samples obtained from patients with erythrodermic PF (n = 19; 12 patients with endemic PF), non-erythrodermic PF (n = 17), pemphigus vulgaris (PV; n = 10), psoriasis (n = 10) and healthy individuals (HI; n = 10) were processed in an automated immunohistochemistry platform utilizing anti-VEGF and anti-endoglin as primary antibodies. Reactivity was evaluated both manually (0 = negative; 1+ = mild; 2+ = intense) and through an automated microvessel analysis algorithm. RESULTS: Vascular endothelial growth factor expression in erythrodermic PF was higher than in non-erythrodermic PF (P = 0.034) and in HI (P = 0.004), and similar to psoriasis (P = 0.667) and PV (P = 0.667). In non-erythrodermic PF, VEGF positivity was similar to HI (P = 0.247), and lower than psoriasis (P = 0.049) and PV (P = 0.049). Both erythrodermic and non-erythrodermic PF presented similar endoglin expression (P = 0.700). In addition, endoglin positivity during erythrodermic PF was similar to psoriasis (P = 0.133) and lower than PV (P = 0.0009). Increased expression of in situVEGF suggests that healing processes are triggered in response to tissue damage led by autoantibodies in PF, especially during erythroderma. Reduced endoglin positivity suggests that an unbalanced angiogenesis may occur during erythrodermic PF. Further studies may help to confirm if the regulation of VEGF and endoglin expression in patients with PF can contribute to control the healing process and enable disease remission. CONCLUSION: Overexpression of VEGF in erythrodermic PF as well as in PV and psoriasis points out a dysregulated repair process in severe forms of these diseases and suggests VEGF and endoglin could act as prognostic markers and future therapeutic targets to enable proper healing in PF.

Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides.

Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.

Differential expression of TOX by skin-infiltrating T cells in Sézary syndrome and erythrodermic dermatitis.

BACKGROUND: The histopathologic differentiation between Sézary syndrome (SS) and erythrodermic dermatitis may be extremely difficult. In this immunohistochemical study, it was investigated if thymocyte selection-associated high mobility group box protein (TOX) and C-MYC can be used as additional diagnostic markers to differentiate between SS and erythrodermic dermatitis. METHOD: Paraffin-embedded skin biopsies from 15 SS patients and 17 erythrodermic dermatitis patients were stained and scored for TOX or C-MYC expression. RESULTS: Strong nuclear staining for TOX in more than 50% of skin-infiltrating T cells was observed in 13 of 15 (87%) SS cases, whereas erythrodermic dermatitis cases showed weak nuclear staining in 11-50% (median: 25%) of the T cells; strong nuclear staining as found in SS was never observed in erythrodermic dermatitis. No significant differences in C-MYC expression between SS and erythrodermic dermatitis were found. In most patients of both groups, percentages of C-MYC positive-cells varied between less than 10 and 25% of skin-infiltrating T cells. CONCLUSION: Our results suggest that strong expression of TOX in more than 50% of skin-infiltrating T cells in erythrodermic skin is a useful marker in the differentiation between SS and erythrodermic dermatitis, whereas staining for C-MYC does not contribute to differential diagnosis.

Erythrodermic Leukemia Cutis in a Patient With Pre-B-Cell Acute Lymphoblastic Leukemia.

The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. The authors present an exceptional case of erythroderma secondary to pre-B-cell lymphoblastic leukemia cutis, with diagnostic findings on biopsy.

Homozygous deletion of six genes including corneodesmosin on chromosome 6p21.3 is associated with generalized peeling skin disease.

BACKGROUND: Peeling skin syndrome (PSS) is a rare autosomal recessive form of ichthyosis showing skin exfoliation. PSS is divided into acral and generalized PSS, and the latter is further classified into non-inflammatory type (PSS type A) and inflammatory type (PSS type B). PSS type B is now called peeling skin disease (PSD). Different loss-of-function mutations in the corneodesmosin (CDSN) gene have been reported to cause PSD. OBJECTIVE: The aim of this study was to determine genetic basis of disease in a 14-year-old Japanese patient with PSD. METHODS AND RESULTS: Immunohistochemical study showed lack of corneodesmosin (CDSN) in the skin, and standard PCR for genomic DNA failed to amplify CDSN product, suggesting CDSN defect. Multiplex ligation-dependent probe amplification and genomic quantitative real-time PCR analyses detected large homozygous deletion of 59,184bp extending from 40.6kb upstream to 13.2kb downstream of CDSN, which included 6 genes (TCF19, CCHCR1, PSORS1C2, PSORS1C1, CDSN and C6orf15). The continuous gene lost did not result in additional clinical features. Inverted repeats with 85% similarity flanking the deletion breakpoint were considered to mediate the deletion by non-homologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication. Parents were clinically unaffected and were heterozygote carriers of the same deletion, which was absent in 284 ethnically matched control alleles. We also developed simple PCR method, which is useful for detection of this deletion. CONCLUSION: Although 5 other genes were also deleted, homozygous deletion of CDSN was considered to be responsible for this PSD.

Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B).

BACKGROUND: Atopic dermatitis (AD), Netherton syndrome (NS) and peeling skin syndrome type B (PSS) may show some clinical phenotypic overlap. Corneodesmosomes are crucial for maintaining stratum corneum integrity and the components' localization can be visualized by immunostaining tape-stripped corneocytes. In normal skin, they are detected at the cell periphery. OBJECTIVE: To determine whether AD, NS, PSS and ichthyosis vulgaris (IV) have differences in the corneodesmosomal components' distribution and corneocytes surface areas. METHODS: Corneocytes were tape-stripped from a control group (n=12) and a disease group (37 AD cases, 3 IV cases, 4 NS cases, and 3 PSS cases), and analyzed with immunofluorescent microscopy. The distribution patterns of corneodesmosomal components: desmoglein 1, corneodesmosin, and desmocollin 1 were classified into four types: peripheral, sparse diffuse, dense diffuse and partial diffuse. Corneocyte surface areas were also measured. RESULTS: The corneodesmosome staining patterns were abnormal in the disease group. Other than in the 3 PSS cases, all three components showed similar patterns in each category. In lesional AD skin, the dense diffuse pattern was prominent. A high rate of the partial diffuse pattern, loss of linear cell-cell contacts, and irregular stripping manners were unique to NS. Only in PSS was corneodesmosin staining virtually absent. The corneocyte surface areas correlated significantly with the rate of combined sparse and dense diffuse patterns of desmoglein 1. CONCLUSION: This method may be used to assess abnormally differentiated corneocytes in AD and other diseases tested. In PSS samples, tape stripping analysis may serve as a non-invasive diagnostic test.

Psoriasiform pemphigus foliaceus: a report of two cases.

Pemphigus foliaceus (PF) represents an autoimmune blistering disease characterized by the disruption of epidermal intercellular adhesion proteins. Clinical findings include superficial crusted erosions in a seborrheic distribution; however, the disease can rarely present as an exfoliative erythroderma. Histopathologic findings include acantholysis with cleavage within the granular layer. Direct immunofluorescence studies show intercellular IgG and complement deposition. We present two patients, to our dermatology department, with a previous diagnosis of psoriasis, with an exfoliative erythroderma, which ultimately proved to be because of PF based on histopathological features, direct immunofluorescence results and levels of antibodies against desmoglein 1. Both patients responded well to oral prednisone and rituximab. This variant of PF should be entertained in both the clinical differential diagnosis of psoriasiform erythroderma and in the microscopic differential diagnosis of psoriasiform epidermal hyperplasia with focal acantholysis, particularly in patients for whom the clinical history is not classic for psoriasis or for whom conventional psoriasis therapies have not proven beneficial.

Dislodgeable stratum corneum exfoliation: role in percutaneous penetration?

BACKGROUND: Stratum corneum (SC) readily dislodgeable exfoliation could affect percutaneous absorption and thus influence treatment and toxicological effects. Urea, a classical enhancer, is absorbed less than 1% in vivo in man and might be a useful marker to quantify chemical-drug exfoliation. This study develops a simple model utilizing washing and tape-stripping to quantify surface loss of chemicals topically applied on human skin and estimate the extent of chemical-drug SC exfoliation. METHODS: Urea, 10% as a model hydrophilic chemical marker, was applied to human skin on identical sites (5 cm(2)/area with 1.8 mg/cm(2) urea) in vitro and in vivo. At time points 0, 4, and 6 h, the area was washed, rubbed, and stripped five times with cellophane tape. Quantitative urea was performed by colorimetric assay. RESULTS: The data of the in vitro protected non-exfoliating model, as the control, showed no statistical difference between 0-, 4-, and 6-h recovery (P > 0.05). In the air-exposed model in vivo exfoliation in man, the recovery decreased from 98.8 ± 3.7% to 93.9 ± 6.8% in 4 h and 86.4 ± 3.0% in 6 h (P = 0.02). In the cloth-covered model in vivo, the recovery decreased from 99.4 ± 5.8% to 84.9 ± 5.3% in 4 h (P = 0.04), which reached 73 ± 2.8% within 6 h (P = 0.007). CONCLUSIONS: This study suggests that urea, measured with washing, rubbing, and tape-stripping, can be used as a possible chemical-drug SC readily dislodgeable exfoliation and friction rubbing metric. In addition, this might help to determine the rule of skin exfoliation in dermatopharmacologic and dermatoxicologic assessment.

Histopathologic diagnosis of lymphomatous versus inflammatory erythroderma: a morphologic and phenotypic study on 47 skin biopsies.

Erythroderma may be secondary to a cutaneous T-cell lymphoma (CTCL) and various other erythrodermic inflammatory dermatoses (EID), and their histopathologic distinction is often difficult. The aim of this study was to determine if morphological parameters, namely: the presence of b-catenin, and JunB (previously shown to be expressed by CTCL cells), the epidermal CD8:CD3 ratio, and CD30 expression may help in the histopathologic diagnosis of erythroderma, especially in differentiating CTCL and EID. We retrospectively reviewed a series of 47 skin biopsies from patients with erythroderma (18 CTCL and 29 EID). The diagnosis of each case was established using clinical, biological and histopathologic data. After a blind assessment of the hematoxylin--eosin--safran stained slides, a correct diagnosis of the underlying cause of erythroderma was made only in 31% of cases. A correct differential diagnosis between lymphoma and EID was done with certainty in 57% of cases. Various morphologic and phenotypic parameters were then recorded and we compared their frequency in the CTCL versus the EID group. With the exception of atypical lymphocytes, the moderate to high density of dermal infiltrates and Pautrier microabcesses, only found in CTCL, no morphologic parameter was found to be specific of CTCL, although single lymphocytes epidermotropism, telangiectasias, and slight lymphocytic dermal infiltrate were significantly more frequent in EID. A low (<10%) CD8:CD3 ratio in the epidermal lymphocytic infiltrate and dermal CD30+ lymphocytes were significantly more frequent in CTCL. JunB expression by lymphocytes was specific of CTCL, but was inconstant in our series (17%). We found ß-catenin expression in a minority of cases from both the CTCL and EID groups. Among EID, dermal suprapapillary thinning was specific of psoriasis. Neutrophils exocytosis and edema of papillary dermis were significantly more frequent in psoriasis, and spongiosis was more frequent in eczema. In conclusion, few morphological and phenotypical parameters are helpful in making a differential diagnosis between erythrodermic CTCL and EID using paraffin embedded skin biopsies.

Early skin biopsy is helpful for the diagnosis and management of neonatal and infantile erythrodermas.

BACKGROUND: Erythrodermas are often life-threatening conditions in infants. Determination of the underlying cause is crucial. Microscopic changes in adult erythroderma lack specificity. OBJECTIVE: To determine if an early skin biopsy is helpful for the diagnosis of neonatal and infantile erythroderma. METHODS: Seventy-two patients admitted for erythroderma in the first year of life were retrospectively included. One hundred and eleven skin biopsies (12-year period) were examined by 3 pathologists blinded to the clinical diagnosis, and classified into atopic dermatitis, immunodeficiency (ID), psoriasis, Netherton syndrome (NS), ichthyosis, other. From year 2000, LEKTI antibody was performed when NS was suspected. Pathological diagnosis was then compared with clinical diagnosis. RESULTS: The final diagnosis was made in 69.3% of the cases. In 57.6%, pathological diagnosis was in accordance, and in 11.7%, it was in accordance, but other diagnosis had also been proposed. For ID, sensitivity and specificity were 58.5 and 98.5%, respectively. Before year 2000, NS was frequently misdiagnosed with psoriasis, but with the use of LEKTI antibody, sensitivity and specificity were 100%. CONCLUSION: Skin biopsy is helpful for etiologic diagnosis of early erythroderma of infancy, particularly in ID and NS, the most severe diseases. Consequently, these results justify an early systematic skin biopsy for a better and earlier management.

[Intralesional and anatomopathologic features of psoriatic erythroderma]. / Erythrodermie psoriasique: caracteristiques anatomopathologiques et intralesionnelles.

BACKGROUND: Psoriasis is a chronic inflammatory cutaneous disorder. It is marked by aberrant epidermal and dermal expression of cytokines. AIM: Evaluate the expression of proinflammatory cytokines in a particular severe form of psoriasis the psoriatic erythroderma. METHODS: We focused on intra-lesional cytokine gene expression in cutaneous biopsies of lesional site and their correspondent non lesional skin. On the whole, four healthy volunteers and thirty six patients were included in this study. Among these, three had a psoriatic erythroderma. Assuming that local production of cytokines may be approached by mRNA cytokine quantification, the expression of alpha tumour necrosis factor (TNFalpha) and interleukin-8 (IL-8) was analyzed by reverse transcription and real time quantitative polymerase chain reaction. RESULTS: Under expression of all selected molecules in psoriatic erythroderma lesions was contrasted with the data obtained in the other psoriatic lesion forms witch revealed that ratios had significantly increased in lesional skin compared with non lesional one. However, at anatomy-pathology analysis, inflammatory infiltrate in psoriatic erythroderma was classical poor and no specific of this disease, such as the case of our three patients. This could explain the drop of intra-lesional inflammatory mediators. CONCLUSION: The paradoxal low levels of proinflammatory cytokines in psoriatic erythroderma are an original and important result.

Neonatal and infantile erythroderma: a clinical and follow-up study of 42 cases.

Erythroderma in neonates and infants is a frequently encountered problem in the daily practice of pediatric dermatology. The objective of this study was to determine the frequency of various causes of this clinical entity, as well as which clinical and laboratory findings are useful in the differentiation of these causes, and to assess the evolution of this disease in this age group. Forty-two patients with erythroderma under 1 year of age were included in this study. A follow-up period of 3-5 years was completed. The study was performed in the Department of Dermatology, Al-Sadr and Alhakeem teaching hospitals and a private section in Najaf governorate, Iraq during the period 1998-2006. The diagnosis was made at an average of 3 months after the onset of the disease. The underlying causes included seborrheic dermatitis in 21.4%, atopic dermatitis in 14.3%, different types of Ichthyoses in 31.5%, psoriasis in 4.7%, pityriasis rubra pilaris in 2.4%, Staphylococcal scalded skin syndrome in 7.14%, Netherton syndrome in 4.7%, immune deficiency syndromes in 4.8% and undetermined erythroderma in 9.5% of the patients. Of 29 cases, histopathological examination of skin biopsy showed non-specific features in 58.7% and could confirm the diagnosis in 41.3% cases. The prognosis was poor with a mortality rate of 26.2% and severe dermatoses persisted in 60% of the survivors. It is difficult to make the etiological diagnosis of neonatal erythroderma from the first examination. Associated immune deficiency should be suspected if the condition associated with skin indurations, severe alopecia, failure to thrive and/or have infectious complications. The prognosis is poor especially in those with immune deficiency or a chronic persistent course.

On the diagnosis of erythrodermic cutaneous T-cell lymphoma.

Erythrodermic cutaneous T-cell lymphoma (E-CTCL) is the cause of less than 5% of all cases of generalized erythroderma. A methodical evaluation of skin, blood, and lymph node samples using standard histology, immunohistochemistry (IHC), flow cytometry (FC), and molecular analysis for evidence of a dominant T-cell clone has been recommended in a recently published diagnostic algorithm. In this commentary, the author discusses available information regarding the role of these diagnostic methods for the diagnosis of E-CTCL with emphasis on personal observations regarding skin IHC and polymerase chain reaction (PCR)-based molecular studies as adjunct diagnostic studies on a series of 55 patients with erythrodermic mycosis fungoides and 50 patients with Sézary syndrome compared to 50 patients with extensive benign inflammatory skin disease. The conclusions are (1) IHC of the skin does not reliably differentiate E-CTCL from benign simulants, (2) presence of phenotypically abnormal T cells in the blood or expanded subsets of CD4+CD7- or CD4+CD26- cells by FC is particularly helpful as a diagnostic study, (3) the presence of an identical T-cell clone in the skin and blood also is a specific diagnostic criterion for E-CTCL, but exceptions may occur, and (4) the PCRgamma-denaturing gradient gel electrophoresis technique appears to be more reliable than PCRgamma-single-stranded conformational polymorphism for diagnostic purposes.

Erythroderma with lichenoid granulomatous features induced by erythropoietin.

The increasing use of new drugs in cancer therapy, especially growth factors, hormones, and chemotherapies resulted in several reports of unusual skin eruptions. We studied a patient with erythroderma who had received erythropoietin because of myeloma with tumor anemia. The histological features were characterized by a lichenoid, focally granulomatous infiltrate with predominance of histiocytes. It is important for dermatopathologists to recognize this interesting pattern induced by erythropoietin.