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.

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.

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.

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).

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.

Oxidative stress and leukocyte migration inhibition response in cutaneous adverse drug reactions.

BACKGROUND: Cutaneous adverse drug reactions (CADRs) may either be immunological or non-immunological. The precise mechanisms, however, are largely obscure. Other concomitant mechanisms may amplify and/or contribute to the severity and duration of a reaction. One such mechanism could be oxidative stress, a state of imbalance between reactive oxygen species, and their subsequent detoxification by antioxidants. AIMS: (a) to assess the oxidative stress status in the blood of cutaneous drug reaction patients by assaying for reduced glutathione (GSH) and malondialdehyde (MDA) levels, (b) to determine the leukocyte migration inhibition (LMI) response in these patients in response to the suspected drug (s), and (c) to look for the association between oxidative stress parameters and LMI. METHODS: Ethical committee approval was obtained for this study. Fresh venous blood samples were obtained from the patients of CADRs (group A) during the acute phase of reaction and healthy control subjects (group B). MDA levels, a measure of oxidative lipid damage, and reduced GSH levels, a measure of anti-oxidant capacity, were assayed in the blood samples of both groups using spectrophotometry. LMI response was measured by challenging the patients' peripheral blood mononuclear cells with the suspected drug to confirm immunological perturbation. RESULTS: Totally 66 participants, 33 cases in group A and equal number of controls in group B, were studied. The mean MDA levels were found to be raised (P < 0.001), but GSH levels were significantly reduced in group A when compared with group B (P = <0.001). LMI response against drug(s) was performed in 33 cases (group A), out of which 25 cases showed a positive LMI response as follows: fixed drug eruption (10/25), SJS (5/25), urticaria (3/25), exfoliative dermatitis (2/25), morbilliform rash (2/25), erythroderma (1/25), vasculitis (1/25), and dapsone syndrome (1/25). The mean MDA levels were found to be significantly higher in the LMI positive CADRs (P < 0.001) when compared with LMI-negative ones, while no significant difference was seen for GSH (P = 0.100). Furthermore, there was a significant positive correlation between MDA levels and LMI response (r = 0.831, P < 0.001). On the other hand, a negative but statistically insignificant correlation was found between GSH and LMI response (r = -0.248, P = 0.271). CONCLUSION: CADR patients were found to be under oxidative stress based on MDA and GSH levels in the peripheral blood. There is a significant positive correlation of LMI response (against the causative drug) with MDA levels, which strongly associates oxidative stress with the immunopathogenesis in CADRs.

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.

Expression pattern of chemokine receptors and chemokine release in inflammatory erythroderma and Sézary syndrome.

BACKGROUND: Erythroderma can be caused by inflammatory dermatoses or cutaneous T-cell lymphoma. Even if chemokines and their receptors are involved in the skin-selective lymphocyte recruitment, their role in inflammatory erythroderma is yet unclear. OBJECTIVE: To evaluate the chemokine release (TARC, MDC, IP-10) and to define the expression pattern of Th1- (CCR5, CXCR3) and Th2-related (CCR4) chemokine receptors in inflammatory erythroderma and Sézary syndrome (SS). MATERIALS AND METHODS: Flow cytometry has been carried out on both circulating and skin-infiltrating T lymphocytes; serum chemokine levels have been evaluated using ELISA techniques. RESULTS: CCR4, CCR5 and CXCR3 were expressed on about 40% of peripheral blood lymphocytes and on the majority of skin-infiltrating lymphocytes in the inflammatory erythroderma patients, whereas the leukemic CD4+CD26- subpopulation in SS was characterized by a high CCR4 expression without a concurrent increase in CCR5 or CXCR3. TARC, MDC and IP-10 serum levels were significantly increased in both erythrodermic and SS patients. CONCLUSIONS: Our results confirm that SS is a Th2 disorder with a selective expression of CCR4, whereas inflammatory erythroderma shares an overexpression of both Th1- and Th2-related chemokine receptors, suggesting an activation of different pathways driving reactive lymphocytes to the skin.

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.

"High-dose" UVA1 therapy of widespread plaque-type, nodular, and erythrodermic mycosis fungoides.

BACKGROUND: UVA1 (340 to 400 nm) was found to be effective in the treatment of early-stage mycosis fungoides (MF). OBJECTIVE: The purpose of this study was to assess the efficacy of UVA1 phototherapy for widespread plaque-type, nodular, and erythrodermic MF. METHODS: Thirteen patients (8 with stage IB, 4 with IIB, and 1 with III MF) received 100 J/cm(2) UVA1 daily until remission. Four patients also had lesions inaccessible by UVA1 that were considered control lesions. Immunocytologic studies of skin infiltrates and circulating T cells were done before and after the therapy. RESULTS: Eleven patients showed complete clinical and histologic responses. Two patients had a partial improvement. Unirradiated control lesions never improved. Serious short-term side effects were not recorded. Circulating CD4(+)/CD45RO(+) and CD4(+)/CD95(+) lymphocytes were significantly reduced by the therapy. CONCLUSION: UVA1 therapy is an effective and well-tolerated treatment for advanced MF. The therapeutic relevance of the effects on circulating lymphocytes remains to be established because lesions in nonexposed cutaneous areas did not respond.

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.

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.

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.

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.

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)