Exploration of circulating metabolic signature of erythrodermic psoriasis based on LC-MS metabolomics.

Erythrodermic psoriasis (EP) is a rare and life-threatening disease, the pathogenesis of which remains to be largely unknown. Metabolomics analysis can provide global information on disease pathophysiology, candidate biomarkers, and potential intervention strategies. To gain a better understanding of the mechanisms of EP and explore the serum metabolic signature of EP, we conducted an untargeted metabolomics analysis from 20 EP patients and 20 healthy controls. Furthermore, targeted metabolomics for focused metabolites were identified in the serum samples of 30 EP patients and 30 psoriasis vulgaris (PsV) patients. In the untargeted analysis, a total of 2992 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed significant difference between groups. After screening, 98 metabolites were found to be significantly dysregulated in EP, including 67 down-regulated and 31 up-regulated. EP patients had lower levels of L-tryptophan, L-isoleucine, retinol, lysophosphatidylcholine (LPC), and higher levels of betaine and uric acid. KEGG analysis showed differential metabolites were enriched in amino acid metabolism and glycerophospholipid metabolism. The targeted metabolomics showed lower L-tryptophan in EP than PsV with significant difference and L-tryptophan levels were negatively correlated with the PASI scores. The serum metabolic signature of EP was discovered. Amino acid and glycerophospholipid metabolism were dysregulated in EP. The metabolite differences provide clues for pathogenesis of EP and they may provide insights for therapeutic interventions.

T helper 2 polarization in senile erythroderma with elevated levels of TARC and IgE.

BACKGROUND: Some cases of senile erythroderma tend to be diagnosed as senile atopic dermatitis (AD) based on elevated levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). However, there are few studies that describe the detailed characteristics of senile erythroderma and senile AD. OBJECTIVE: We examined the association of erythroderma with AD. METHODS: In this retrospective observational study, 68 patients over 65 years of age who presented with erythroderma at Osaka University Hospital were enrolled. Patient data were collected through medical records and descriptive statistics. RESULTS: 47% of the patients were classified as having idiopathic erythroderma and 53% as having secondary erythroderma. In both idiopathic and secondary senile erythroderma patients, serum IgE and TARC levels were elevated. 84% of idiopathic erythroderma patients fulfilled the Japanese Dermatological Associations criteria for AD; however, only 4 patients were finally definitely diagnosed with senile AD. CONCLUSION: Many senile erythroderma patients showed AD-like symptoms due to T helper 2 polarization.

Skin-homing Th2/Th22 cells in papuloerythroderma of Ofuji.

Papuloerythroderma of Ofuji (PEO) appears to be a T cell-mediated skin disease; however, the pathogenesis of PEO remains unclear. We report two cases of PEO and examine cytokine production and expression of skin-homing receptors in circulating T cells in the patients. The percentages of interleukin 4 (IL-4)-, IL-13- and IL-22-producing CD4+ and CD8+ T cells were markedly higher in the circulation of patients with PEO than in those of healthy subjects. The expression of both cutaneous lymphocyte antigen (CLA) and CC chemokine receptor 4 (CCR4) were significantly upregulated in the circulating CD4+ and CD8+ T cells. Moreover, serum levels of thymus and activation-regulated chemokine (TARC), a chemoattractant for CCR4, were increased. The number of IL-4-, IL-13- and IL-22-producing T cells, expression of CLA and CCR4 by T cells, and serum TARC levels significantly decreased after complete remission of PEO. These results suggest that skin-homing Th2/Th22 cells may play a role in the pathogenesis of PEO.

The surface morphology of human B lymphocytes as revealed by immunoelectron microscopy.

Surface immunoglobulins (sIg) were detected on human lymphocytes by immunoelectron microscopy with peroxidase-conjugated antibodies. Blood, marrow, and thymus cells from normal individuals and patients with lymphoproliferative disorders were examined. Samples were fixed before exposure to specific reagents. Normal lymphocyts with detectable sIg, i.e. B lymphocytes, were characterized by a villous surface; nonlabeled blood lymphocytes and thymocytes were smooth cells. Intermediate cells were also found which in sections appeared moderately villous and labeled, thus identified as B lymphocytes. Further evidence for a relationship between villous surface and sIg was given by the finding of a few lymphocytes with polar concentration of labeled microvilli. In chronic lymphocytic leukemia patients, most cells exhibited a villous surface with parallel variations of the number of microvilli and of anti-immunoglobulin-binding capacity. However, some labeled smooth blastic cells were also observed. On the other hand, abnormal lymphocytes from Sézary's syndrome which could exhibit segments of villous membrane had no detectable sIg. This study confirms that in most cases human B lymphocytes have a characteristic surface appearance and that the detection of sIg in normal lymphocytes correlates with the presence of microvilli.

Prognostic Significance of Serum Copper in Patients With Cutaneous T-cell Lymphoma.

BACKGROUND: Serum copper has been reported to be increased in various cancers, including lymphoma. The purpose of the present study was to investigate the clinical and prognostic importance of serum copper levels in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Serum copper was measured in 60 men and 38 women with mycosis fungoides (MF) and 14 men and 3 women with erythrodermic CTCL (6 with Sézary syndrome) consecutively evaluated from July 1980 to June 1985. RESULTS: A greater than normal copper level was present in nearly 20% of patients and was associated with an increased risk of disease progression and shortened disease-specific survival for patients with patch or plaque phase MF, but not for those with tumor phase MF or erythrodermic CTCL. In contrast, the serum lactate dehydrogenase level and neutrophil/lymphocyte ratio were not significantly associated with prognosis in our patient cohort. CONCLUSION: The reason for the association between the high serum copper levels and adverse prognosis is unknown. We hypothesized that interleukin-6 is secreted primarily by non-neoplastic cells at MF skin sites, leading to release of copper by the liver. Local production of interleukin-6 at the lesion sites might conceivably also promote neoplastic cell progression by stimulation of the STAT3 pathway. Further studies on the relationship between activated tumor-associated macrophages, serum copper levels, interleukin-6, or C-reactive protein and prognosis might be informative.

Papuloerythroderma-like cutaneous involvement of a CD62L- subclone of T-cell prolymphocytic leukemia.

We report the case of an 88-year-old Japanese man with erythrodermic involvement of T-cell prolymphocytic leukemia (T-PLL). He had a history of pharyngeal diffuse large B-cell lymphoma successfully treated with polychemotherapy including cyclophosphamide and epirubicin, 6 years before the current illness. He presented with numerous reddish, coalescing, flat-topped papules on the trunk and extremities, sparing the skin folds of the abdomen, the features of which mimicked those of papuloerythroderma. Immunohistochemistry showed perivascular and epidermotropic infiltration of CD3+ CD4+ T cells in the cutaneous lesion. However, flow cytometric analysis revealed that the skin infiltrating T cells were negative for surface CD4, and that CD3+ CD4- CD8- cells made up 92% of the T-cell fraction of peripheral blood. The circulating atypical T cells had a round or oval nucleus and prominent nucleoli, and the deletion of chromosomes 6q, 13 and 17. These cytological profiles were consistent with those of T-PLL and distinct from those of Sézary cells. The same T-cell clone was detected in the cutaneous lesion and peripheral blood, but the expression of CD62L was absent in the skin infiltrates and present in the circulating cells. No specific mutation was detected in STAT3 or STAT5B. Although low-dose oral etoposide had a beneficial effect on the skin rash, a fatal crisis of marked leukocytosis (169 × 103 /µL) occurred 19 months after the illness onset. CD62L-leukemic cells of T-PLL may infiltrate the skin to form papuloerythroderma-like cutaneous lesions.

Omenn syndrome: a rare case of neonatal erythroderma.

Omenn syndrome is a severe combined immunodeficiency characterized by erythroderma, hepatosplenomegaly, lymphadenopathy and failure to thrive, with activated oligoclonal T lymphocytes and an absence of circulating B cells.A 3 day-old boy presented with a congenital erythroderma. Investigations revealed a marked neutropenia and lymphopenia and the absence of a thymus. Genetic studies showed RAG 1 mutations. He was successfully treated with an HLA identical bone marrow transplantation. Omenn syndrome is a rare severe combined immunodeficiency. Most cases are due to mutations in the RAG genes with autosomal recessive transmission. Our observation is original because of an incomplete clinical presentation. During the course of the disease, the child had no failure to thrive, no organomegaly and no recurrent infection. Immunodeficiency must be excluded in every case of neonatal erythroderma and an immunological assessment should be performed without delay.

Phenotypic analysis of circulating T-cell subset and its association with burden of skin disease in patients with chronic actinic dermatitis: a hematologic and clinicopathologic study of 20 subjects.

BACKGROUND: Chronic actinic dermatitis (CAD) is a recurrent photosensitive dermatitis that occurs predominantly on sun-exposed areas with unknown etiology. In severe cases, it may present with erythroderma, which is clinicopathologically analogous to cutaneous T-cell lymphoma. Typically, inflammatory infiltrates in the skin lesions are mainly CD8+ reactive T cells. However, hematologic characteristics of CAD have not been fully elucidated. METHODS: Twenty patients with CAD ranging in age from 45 to 86 years (median, 64), including 17 males and three females (M/F ratio, 5.7), were examined. All patients were phototested for UV light. In addition, seven of the 20 patients with extensive eruption were also tested for visible light. All biopsy specimens were obtained from the CAD eruptions (n = 25 lesions). Histopathologic and immunohistochemical studies were performed. Furthermore, flow cytometric analysis was performed to determine the CD4/8 ratio using peripheral blood mononuclear cells of 13 of the 20 patients. RESULTS: In 11 of the 20 patients (55%), the eruption was localized to sun-exposed areas. Skin-infiltrating T cells were CD8-dominant in the CAD eruption. Three patients (15%) showed erythroderma with a reduced CD4/8 ratio (median, 0.7) of peripheral mononuclear cells. As for treatment, eight of the 20 patients (40%) required oral cyclosporine in addition to topical therapies. Subsequently, the reduced CD4/8 ratio was normalized after treatment in two of the three patients with erythroderma. CONCLUSIONS: We considered that there appeared to be a relationship between the reduced CD4/8 ratio of circulating T cells (hematologic burden) and the affected area (skin burden).

Thymoma-associated multi-organ autoimmunity: A case of graft-versus-host disease-like erythroderma complicated by Good syndrome successfully treated by thymectomy.

Thymoma-associated multi-organ autoimmunity disease (TAMA) is a rare paraneoplastic disorder, clinicopathologically similar to graft-versus-host disease (GVHD). Many reported cases follow a difficult course; half of them die from serious infectious diseases subsequent to immunosuppression induced by chemotherapy for unresectable thymoma, or intensive therapies including systemic steroids for complicating autoimmune diseases and GVHD-like symptoms. We report a patient whose skin symptoms were improved subsequently to total thymectomy. The patient also presented with hypogammaglobulinemia, which led to the diagnosis of complicated Good syndrome. Taking account of her immunodeficient condition, antibiotics and i.v. immunoglobulin were administrated promptly on onset of bacterial pneumonia, which was successfully treated. According to a review of the published work, treatments with systemic steroids for skin symptoms have limited effects and may contribute to serious infection. Our case indicates that successful treatment of thymoma itself may lead to the amelioration of the disease. The management priority should be given to the treatment of thymoma and the control of subsequent immune abnormality other than GVHD-like erythroderma.

Diagnostic value of T-cell receptor beta gene rearrangement analysis on peripheral blood lymphocytes of patients with erythroderma.

Differentiation between Sézary's syndrome (SS) and benign forms of erythroderma may be extremely difficult. In this study T-cell receptor beta (TCR beta) gene rearrangement analysis was performed on peripheral blood lymphocytes (PBL) from 32 patients with erythroderma, including 10 patients with SS, three patients with another type of cutaneous T-cell lymphoma, and 19 patients with a benign form of erythroderma. The aim of this study was to define the sensitivity and specificity of this technique in the diagnosis of SS. Clonal TCR beta gene rearrangements were found in eight of 10 patients with SS, one T-CLL patient, one of two patients with erythrodermic mycosis fungoides, and only one of 19 patients from the benign group. In the two "false-negative" cases of SS clonal TCR beta gene rearrangements were detected in PBL obtained during follow-up. The results indicate that TCR beta gene rearrangement analysis on PBL is a sensitive and highly specific technique, that may contribute significantly to the differential diagnosis of patients with erythroderma. However, because both "false-positive" and "false-negative" results may occur, the results of gene-rearrangement analysis should always be considered in conjunction with clinical, histologic, and immunophenotypical data.

Diagnostic criteria in Sézary's syndrome: a multiparameter study of peripheral blood lymphocytes in 32 patients with erythroderma.

In order to define additional diagnostic criteria for the early diagnosis of Sézary's syndrome (SS), peripheral blood lymphocytes of 32 patients with erythroderma, including 8 patients with SS, 4 patients with erythrodermic mycosis fungoides, 14 patients with an erythroderma on the basis of atopic or chronic dermatitis, and 6 patients with erythrodermic psoriasis, were investigated by computer-assisted morphometry. The degree of nuclear indentation, expressed as the nuclear contour index (NCI), was measured on electron micrographs. The mean NCI and the percentages of cerebriform mononuclear cells (CMC), defined by a NCI greater than or equal to 6.5, were calculated. In addition, the percentages of lymphocytes, T and B cells, and the distribution of T-cell sub-populations as defined by Fc-receptors (T mu, T gamma) and monoclonal antibodies (OKT3, OKT4, OKT8, HLA-DR) were determined. Statistical analysis showed as most discriminating parameters for the differentiation between SS and benign forms of erythroderma: high percentages of lymphocytes (50% or more), an expanded OKT3+, OKT4+ population with an OKT4/OKT8 ratio greater than 10, a mean NCI value greater than or equal to 5.5, the presence of more than 20% CMC, as well as the presence of cells with a NCI greater than or equal to 11.5. The total leukocyte and lymphocyte counts, as well as the percentages of B, T, T mu, and T gamma cells had limited value for the early diagnosis of SS.

Utility of flow cytometry immunophenotyping and DNA ploidy studies for diagnosis and characterization of blood involvement in CD4+ Sézary's syndrome.

BACKGROUND AND OBJECTIVES: The exact immunophenotypic criteria for the identification of Sézary cells in the blood are still poorly defined. DESIGN AND METHODS: We analyzed the immunophenotype and DNA cell content of blood T cells in a series of 18 consecutive cases of Sézary's syndrome (SS), 21 normal individuals and 10 patients with reactive erythroderma, and correlated them with molecular and morphological findings. RESULTS: Phenotypically abnormal CD3+/TCRalphabeta+/CD4+ T cells were found in all SS patients but in none of the reactive erythroderma cases; small diploid, or less frequently hypodiploid Sézary's cells coexisted with large nearly tetraploid Sézary's cells in some cases. The most frequent phenotypic aberrations consisted in decreased expression of CD3/TCRalphabeta (94%), CD4 (94%), CD7 (100%) and/or CD2 (83%). In addition, Sézary's cells were constantly CD28+ and CD5+ and they did not express natural-killer associated (NKa) antigens. Phenotypic heterogeneity was a common finding and phenotypic changes over time were frequently observed. In contrast to what was found in patients with reactive erythroderma, flow cytometry analysis of the T-cell receptor (TCR) repertoire revealed a major TCR-Vbeta expansion in all SS cases. INTERPRETATION AND CONCLUSIONS: The presence of CD28+/CD5+/NKa-/CD4+ T cells expressing abnormally low levels of CD3, TCRalphabeta, CD4, CD7 and/or CD2 would support the diagnosis of SS in patients with erythroderma. Further analyses on larger series of patients are necessary in order to cover less frequent phenotypic patterns, establish the preferential usage of specific TCR-Vb families and investigate the specificity of these phenotypic abnormalities for diagnosing SS.

Leukemic erythroderma with elevated plasma IL-3 and hyperhistaminemia: in situ expression of IL-3 mRNA in leukemic cells.

We report a case of chronic myelogenous leukemia (CML) with pruritic erythroderma. Hyperhistaminemia, elevated level of plasma interleukin-3 (IL-3), and moderate basophilia were noted in this case. His skin manifestation was resistant to topical corticosteroid therapy and exacerbated in parallel with leukocyte count, plasma histamine and IL-3 levels. To identify localization and production of IL-3 in our case, we performed in situ hybridization on peripheral blood cells and skin biopsy specimen, and detected IL-3 mRNA in myelogenic cells in both specimens.

Acute erythroderma as an exclusion criterion for idiopathic CD4+ T lymphocytopenia.

BACKGROUND: Idiopathic CD4+ T lymphocytopenia is defined as a CD4+ T lymphocytopenia of less than 0.3 x 10(9)/L that is not associated with human immunodeficiency virus, other immunodeficiency, or immunosuppressive therapy. The associated clinical course and laboratory findings are variable. We describe a subset of patients whose peripheral CD4+ T-lymphocytopenia was transient, and suggest a pathomechanism for this phenomenon. OBSERVATIONS: We describe three patients with cutaneous T-cell lymphoma, atopic dermatitis, or psoriasis in whom acute erythroderma was concomitant with a peripheral CD4+ T lymphocytopenia that normalized after resolution of the erythroderma. Immunoperoxidase staining of skin biopsy specimens and quantitative estimation of CD4+ T lymphocytes in the cutaneous and peripheral blood compartments demonstrated that the peripheral CD4+ T lymphocytopenia in these cases most probably resulted from sequestration of CD4+ T lymphocytes in the skin. The skin of an erythrodermic patient appears capable of sequestering 10(10) to 10(11) CD4+ T lymphocytes, whereas the peripheral blood compartment contains in the range of 10(9) CD4+ T lymphocytes. CONCLUSIONS: We propose that CD4+ T lymphocytopenia can occur as a result of acute erythroderma of multiple causes and that acute erythroderma associated with transient CD4+ T lymphocytopenia be considered as an exclusion criterion for idiopathic peripheral blood CD4+ T lymphocytopenia.

The diagnostic value of morphometry on blood lymphocytes in erythrodermic actinic reticuloid.

BACKGROUND: As the differential diagnosis of erythrodermic actinic reticuloid vs Sézary syndrome (SS) can be very difficult, we examined the value of the nuclear contour index (NCI) on blood lymphocytes as the criterion for differential diagnoses. The NCI is defined as the nuclear parameter divided by the square root of the nuclear area. Three different parameters were studied: mean NCI, percentage of cells with an NCI of 6.5 or greater, and the highest NCI. These indexes were studied on blood lymphocyte samples obtained from 10 patients with erythrodermic actinic reticuloid and were compared with the findings in 10 patients with other benign forms of erythroderma and in seven patients suffering from SS. RESULTS: The patients with erythrodermic actinic reticuloid differed significantly from the group with SS regarding the percentage of cells with an NCI of 6.5 or greater and the highest NCI, but not when the mean NCI was considered. All three parameters revealed nonsignificant results for erythrodermic actinic reticuloid compared with other benign forms of erythroderma. The group with SS differed significantly from the patients with other benign forms of erythroderma regarding all three parameters. By combining three morphometric criteria (mean NCI, > or = 5.5; > 30% lymphoid cells with an NCI of > or = 6.5; and highest NCI, > or = 11.5), all patients with erythrodermic actinic reticuloid or other benign forms of erythroderma and six of the seven patients with SS were correctly classified. CONCLUSION: Our data indicate that assessment of the NCI on peripheral blood lymphocytes is of value in the differential diagnosis of erythrodermic actinic reticuloid vs SS.

Serum soluble interleukin 2 receptor levels in erythrodermic cutaneous T-cell lymphoma correlate with response to photopheresis-based treatment.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) comprises a spectrum of presentations, including erythroderma, pruritus, lymphadenopathy, and circulating atypical lymphocytes. Photopheresis is an extracorporeal treatment in which white blood cell concentrates are subjected to UV irradiation when the serum methoxypsoralen level is above 50 ng/mL. Of patients with CTCL, those with erythroderma have been most responsive to this therapy. In some conditions, including certain malignant hematologic neoplasms, serum soluble interleukin 2 receptor levels (SIL2R) correlate with disease activity. We sought to determine whether serum SIL2R levels correlated with disease activity in six erythrodermic patients with CTCL treated primarily with photopheresis. We measured SIL2R levels in five patients with stage III or greater erythrodermic CTCL and one with stage IIa CTCL. We compared SIL2R values with clinical course, skin scores, CD4/CD8 ratios, peripheral white blood cell counts, and Sézary cell counts, using Pearson correlation coefficients. OBSERVATIONS: The SIL2R levels correlated with clinical course and skin scores, even when controlled for other factors noted above. CONCLUSION: Data preliminarily suggest that serum SIL2R levels may be useful indicators of disease activity in erythrodermic CTCL patients treated with photopheresis.

Distribution of T-cell subpopulations in the peripheral blood of patients with erythrodermic psoriasis.

In the present study the percentages of T cells and T-cell subsets, as defined by Fc receptors and monoclonal antibodies (OKT3, OKT4, OKT8, HLA-DR) were determined in the peripheral blood of 12 patients with psoriasis, including six patients with erythroderma and 6 with active, but limited disease. The patients with erythroderma were studied before treatment and 4-8 weeks following. The mean percentages of E-rosette-forming cells and T-cell subsets reactive with the monoclonal antibodies OKT3, OKT4 and OKT8 were within normal limits, as were the percentages of T mu-cells, irrespective of the extent or activity of the disease. The mean percentage of T gamma-cells was reduced in the patients with untreated erythrodermic psoriasis but not in the patients with limited disease. Comparison of the T gamma values in the erythroderma group before and after therapy showed a slight, but statistically significant increase (P less than 0.03). These results indicate a direct relationship between the T gamma deficit and the extent of skin involvement, and argue against a primary suppressor T-cell defect in psoriasis vulgaris.

Circulating Sézary cells. A new preparatory method for their identification and enumeration.

Although Sézary cells are not specific for the Sézary syndrome, the enumeration of these circulating abnormal lymphoid cells is important in the evaluation of patients with mycosis fungoides, Sézary syndrome, and benign dermatoses that might be confused with these entities. Various techniques have been developed for this purpose, but none of the techniques have been widely accepted as practical and accurate. We describe a new method of preparing blood specimens for the identification and enumeration of circulating Sézary cells. Peripheral blood was separated on a density gradient and the mononuclear cell fraction was embedded in plastic. Semithin sections were cut, stained for alpha-naphthyl acetate esterase, and examined by light microscopy. We found that the percentage of Sézary cells correlated well with the clinical diagnosis of Sézary syndrome in the subjects who were studied.

Clinical significance of serum adenosine deaminase activity in patients with mycosis fungoides.

Adenosine deaminase is one of the key enzymes in purine nucleotide degradation. This enzyme exists in most of the human tissues and the activity is high in lymphatic tissues, especially in T lymphocytes. Elevated adenosine deaminase activity in T cell leukemia has been reported, and its inhibitor, deoxycoformycin, has been developed as an antitumor agent. In some types of leukemia, serum adenosine deaminase activity increases in accordance with the severity of the disease. Although mycosis fungoides rarely involves peripheral blood, tumor cells do invade the skin. In order to evaluate the clinical significance of adenosine deaminase in mycosis fungoides, adenosine deaminase activity was measured in sera of 15 patients with mycosis fungoides at various stages. The mean enzyme activity was 23.2 IU/l, which was high with statistical significance compared with healthy controls (P < 0.001). Nine of twelve patients in the plaque stage (T2N0M0, IB) showed higher adenosine deaminase activity than did the normal population. The mean adenosine deaminase activity in sera in the patients in the plaque stage (T2N0M0, IB) was as high as 19.0 IU/l (range 13.7-21.4) with statistical significance compared with healthy control (P < 0.001). Three tumor stage patients without visceral involvement (T3N0M0, IIB) showed higher levels of adenosine deaminase activity (19.7, 21.5, 24.4 IU/l). An erythrodermic patient (T4N0M0, III) also had a high adenosine deaminase activity 28.4 IU/l. Two tumor stage patients with organ involvement (T3N0M1, IVB) exhibited extremely high adenosine deaminase activity (60.9, 32.2 IU/l). The adenosine deaminase activity in sera showed a tendency to become higher with the extension of the stages.(ABSTRACT TRUNCATED AT 250 WORDS)