Evaluation of disease activity and damage in different subtypes of cutaneous lupus erythematosus using the CLASI.

BACKGROUND: The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a scoring system for patients with cutaneous lupus erythematosus (CLE) to assess disease activity and damage. Objective The aim of this study was to evaluate whether the CLASI is a useful instrument which reflects the different subtypes of CLE comparably well in each parameter. METHODS: A total of 50 patients (42 female, 8 male) with different subtypes of CLE, including acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE) and LE tumidus (LET), from the Departments of Dermatology, University of Düsseldorf, Germany, and Danderyd Hospital, Stockholm, Sweden, were evaluated using the CLASI at one time point. RESULTS: The total CLASI activity score was significantly lower in patients with LET compared with ACLE (P<0.05) and CCLE (P<0.001), and the total CLASI damage score was significantly lower in patients with LET than with ACLE (P<0.05), SCLE (P<0.001) and CCLE (P<0.001). The erythema score and the scale/hypertrophy score were significantly lower in LET than in ACLE (P<0.05, both) and CCLE (P<0.05 and P < 0.001, respectively). The dyspigmentation score was lowest in patients with LET, differing significantly from ACLE (P<0.05), SCLE (P<0.05) and CCLE (P<0.001). The scarring/atrophy/panniculitis score was significantly higher in patients with CCLE in contrast to SCLE and LET (P<0.05 and P<0.001, respectively). CONCLUSION: These data characterize the CLASI as an overall useful instrument to analyse disease activity and damage in CLE. However, the CLASI does not give an accurate assessment of all disease subtypes; therefore, a revision of the CLASI with critical analysis of all parameters is recommended.

Reduction of regulatory T cells in skin lesions but not in peripheral blood of patients with systemic scleroderma.

OBJECTIVE: To determine the frequency and suppressive capacity of regulatory T cells (T(reg)) and their association with clinical parameters in patients with systemic scleroderma (SSc). METHODS: Peripheral blood from 25 patients with SSc, 15 patients with localised scleroderma (LS) and 29 healthy controls (HC) was studied. Analysis of CD4(+) forkhead box P3 (Foxp3)(+) and CD4(+)CD25(++)Foxp3(+) T(reg) subpopulations was carried out by flow cytometry and cell proliferation was quantified by (3)H-thymidine incorporation. Quantitative analysis of T(reg) was further performed in skin biopsies from 17 patients with SSc and 21 patients with LS using anti-CD4 and anti-Foxp3 monoclonal antibodies for immunohistochemistry. RESULTS: The frequency of CD4(+)Foxp3(+) and CD4(+)CD25(++)Foxp3(+) T(reg) in peripheral blood from patients with SSc was not significantly different from that of patients with LS or HC. The suppressive capacity of CD4(+)CD25(++) T(reg) in SSc was also found to be similar to that of HC. Phenotypic and functional data revealed no significant difference between the limited or diffuse form of SSc. Moreover, therapy with bosentan showed no significant effect on the frequency of T(reg) during the course of the disease. However, the frequency of T(reg) in skin lesions from patients with SSc or LS, determined as the percentage of CD4(+) cells expressing Foxp3 in the inflammatory infiltrate, was significantly reduced compared with other inflammatory skin diseases. CONCLUSION: These results indicate that although the authors found no defect in the frequency or function of peripheral T(reg) subpopulations, the reduction of CD4(+)Foxp3(+) T(reg) in the skin of patients with SSc may be important in the pathogenesis of the disease.

Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI): a modified outcome instrument for cutaneous lupus erythematosus.

BACKGROUND: In 2005, a scoring system (CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index) was developed for patients with cutaneous lupus erythematosus (CLE) to assess disease 'activity' and 'damage'. However, the CLASI does not give an accurate assessment of the severity in all disease subtypes. OBJECTIVES: The main objective of this study was to analyse critically the included parameters of the CLASI and to revise the activity and damage score taking into account various clinical features of the different subtypes of CLE. The revised CLASI (RCLASI) was also validated for use in clinical trials. Patients and methods A RCLASI was designed with regard to the anatomical region (i.e. face, chest, arms) and morphological aspects (i.e. erythema, scaling/hyperkeratosis, oedema/infiltration, scarring/atrophy) of skin lesions and evaluated by nine dermatologists who scored 12 patients with different subtypes of CLE to estimate inter- and intrarater reliability. RESULTS: Reliability studies demonstrated an intraclass correlation coefficient (ICC) for an inter-rater reliability of 0.89 for the activity score [95% confidence interval (CI) 0.79-0.96] and of 0.79 for the damage score (95% CI 0.62-0.92). The ICC for intrarater reliability for the activity score was 0.92 (95% CI 0.89-0.95) and the ICC for the damage score was 0.95 (95% CI 0.92-0.98). CONCLUSIONS: In the present study, a RCLASI was developed by experts, and reliability studies supported the validity and applicability of the revised scoring instrument for CLE. Thus, the RCLASI is a valuable instrument in multicentre studies and for the clinical evaluation of activity and damage in different disease subtypes.

Lupus erythematosus tumidus is a separate subtype of cutaneous lupus erythematosus.

Background Lupus erythematosus tumidus (LET) is a rare disease which was first described in 1909 but has not always been considered as a separate entity of cutaneous lupus erythematosus (CLE) in the international literature. Objectives To compare characteristic features of different subtypes of CLE and to analyse whether LET can be distinguished as a separate entity in the classification system of the disease. Methods The study involved 44 patients with CLE, including 24 patients with LET, 12 with discoid lupus erythematosus (DLE) and eight with subacute CLE (SCLE), from two centres in Germany. A core set questionnaire and an SPSS database were designed to enable a consistent statistical analysis. Results Location of skin lesions did not differ significantly between the CLE subtypes; however, the activity score was significantly lower in LET than in DLE (P < 0.01), and the damage score was significantly lower in LET than in SCLE (P < 0.01) and DLE (P < 0.01). Photosensitivity and antinuclear antibodies were confirmed to be different in LET compared with SCLE and DLE but without statistical significance. Moreover, histological analysis of skin biopsy specimens showed that abundant mucin deposition is significantly more present in LET compared with SCLE (P < 0.01) and DLE (P < 0.01) while prominent interface dermatitis and alteration of hair follicles were absent in LET. Conclusions Several significant differences were found between LET and other subtypes of CLE with regard to clinical, histological and laboratory parameters. These data strongly indicate that LET should be defined as a separate entity in the classification of CLE.

Development of a Core Set Questionnaire by the European Society of Cutaneous Lupus Erythematosus (EUSCLE).

A study group of the European Society of Cutaneous Lupus Erythematosus (EUSCLE) developed a Core Set Questionnaire for the evaluation of patients with cutaneous lupus erythematosus (CLE). The aim of the EUSCLE Core Set Questionnaire is to gain a broad and comparable data collection of patients with CLE from different European centers, to achieve consensus concerning evidence-based clinical standards for disease assessment, and to develop diagnostic and therapeutic guidelines. The authors designed the EUSCLE Core Set Questionnaire by including parameters considered most relevant for the evaluation of CLE and compiled from international literature, clinical praxis, and long-term experience with this disease. The compilation of the different parameters for the evaluation of CLE resulted in the 4-sided EUSCLE Core Set Questionnaire with six sections on patient data, diagnosis, skin involvement, activity and damage of disease, laboratory analysis, and treatment. Thus, the EUSCLE Core Set Questionnaire for CLE constitutes a useful tool for the collection and evaluation of epidemiological data from patients with this disease. It enables consistent statistical evaluation, exchange, and comparison of patient's data within several European countries and provides a set of guidelines for standardized diagnostic and therapeutic strategies in CLE.

The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. METHODS: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. RESULTS: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). CONCLUSION: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

[Current diagnosis of cutaneous lupus erythematosus]. / Aktuelle Diagnostik des kutanen Lupus erythematodes.

Cutaneous lupus erythematosus (CLE) is a disease with different subtypes and the new classification system includes acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), and intermittent CLE (ICLE). The broad spectrum of skin involvement and the possibility of systemic organ manifestations at the beginning and during the course of CLE require specific diagnostic procedures. Clinical assessment of the cutaneous manifestations is necessary along with a detailed patient's history. The diagnosis of CLE is confirmed by histopathology and immunofluorescence microscopy. Selective laboratory screening and additional diagnostic procedures depending on clinical symptoms are recommended. Photoprovocation tests can be performed to assess photosensitivity in patients with CLE and to support the diagnosis. Recently, a scoring system for the activity of the cutaneous manifestations in CLE has been developed and is now evaluated in several clinical studies. In this review, the classification and the characteristic clinical criteria of the different CLE subtypes as well as the current diagnostic possibilities are emphasized.

Aspartylglucosaminuria in a Canadian family.

Aspartylglucosaminuria (McKusick 208400) is a lysosomopathy associated with aspartylglucosaminidase (L-aspartamido-beta-N-acetylglucosamine amidohydrolase, EC 3.5.1.26) deficiency. It has been most frequently encountered in Finland, where the regional incidence may be as high as 1 in 3600 births. In North America it is very rare, having been reported in only 8 patients. We encountered 4 patients with aspartylglucosaminuria in a Canadian family of 12 siblings. The 4 siblings affected--2 brothers and 2 sisters--were apparently normal at birth; however, their developmental milestones, particularly speech, were slow, and they acquired only a simple vocabulary. Throughout life, there was a progressive coarsening of facial features; 3 had inguinal hernia and recurrent diarrhea; all became severely retarded and by the 4th decade showed evident deterioration of both cognitive and motor skills; 2 exhibited cyclical behavioural changes. Three of the siblings have died, at 33, 39 and 44 years of age. Two died of bronchopneumonia and 1 of asphyxiation following aspiration. In the urine of all 4 siblings, and in the 1 liver examined, we found 2-acetamido-1-N-(4-L-aspartyl)-2-deoxy-beta-D-glucosamine (GlcNAc-Asn) and alpha-D-mannose-(1,6)-beta-D-mannose-(1,4)-2-acetamido- 2-deoxy-beta-D-glucose-(1,4)-2-acetamido-1-N-(4-L-aspartyl)-2-deoxy-beta - D-glucosamine (Man2-GlcNAc2-Asn). Compared with the level of activity in controls, aspartylglucosaminidase activity was less than 2% in fibroblasts from 3 of the siblings, less than 0.5% in leukocytes from 1 sibling, and less than 1% in the liver of 1 sibling, whereas other acid hydrolase activities in these tissues were normal. Ultrastructural studies of skin showed that fibroblasts, endothelial cells and pericytes contained vacuoles with fine reticulo-floccular material. Glial and neuronal cells of the central nervous system showed similar inclusions as well as others composed of concentric or parallel membranous arrays intermingled with lipid droplets.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)-syndrome. Ultrastructural changes of mitochondria in cultured dermal fibroblasts of three patients.

Mitochondria of fibroblasts cultured from the skin obtained at biopsy from three patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)-syndrome, one of the autosomal recessive, heritable urea cycle disorders, were studied with appropriate controls ultrastructurally. The patients were two severely retarded 10- and 12-year-old boys, and a 22-year-old sister of the former whose mental status was at the low normal range; she never had motor impairments or seizures. The mitochondria, similar in all three patients, were increased in number, very long, branching and/or "looping," and tortuous. "Spurs" or "buddings" extended from their lateral surfaces and the terminal segments were often bulbous. Other unusual configurations were also present. In addition, giant forms with large diameter contained innumerable closely-packed and parallel cristae which traversed the entire width of these mitochondria; at times they assumed a "whirled" pattern. The mitochondrial matrix was usually of high electron density. These changes were not a feature of fibroblastic mitochondria of controls. Several changes resembled those of hepatic mitochondria in this disorder. All features are interpreted as an attempt at expanding the mitochondrial volume (via structural substratum) to compensate for the metabolic incompetence of these organelles (a block in transmembranous transfer of ornithine from hyaloplasm into mitochondria for conversion to citrulline).

Ciliated cultured dermal fibroblasts in a patient with hyperornithinemia, hyperammonemia and homocitrullinuria (HHH) syndrome.

Hyperornithinemia, hyperammonemia and homocitrullinuria (HHH)-syndrome is a rare autosomal recessive disorder of the urea cycle, probably caused by a defect in ornithine transport across the hepatic inner mitochondrial membrane. Single rudimentary cilia were present in approximately ten percent of post-divisional or dividing fibroblasts cultured from the skin of a patient with the HHH-syndrome, whereas no such organelles were observed in dermal fibroblasts cultured from normal controls. Since single rudimentary ("primary," "oligo," "solitary") cilia have been observed in a variety of cells in animals and men but the stimuli for their formation and their significance remain controversial, a brief report on their presence in the as yet unreported condition (HHH-syndrome) was considered of interest; hopefully, it might contribute to the ultimate unravelling of some of the unresolved problems. It is of note that unlike the author's previous findings of these unusual organelles in cells affected by a pathological process (atherosclerosis), the rudimentary cilia were observed in the present instance in dividing or postdivisional cells. The implications of these (and other) observations must await further work.

Cellular localization of metallothionein in human term placenta.

Cellular localization of metallothionein (MT) in placenta may provide information on its function as a metal binding protein. Rabbit antibodies to rat liver MT cross-reacted with human MT and were used to localize MT in human term placenta by avidin-biotin peroxidase technique. Serial sections (5 microns) were cut from paraffin-embedded placentae obtained at term from five normal women and incubated with rabbit antibodies to MT. Normal rabbit serum was used as a negative control. The slides were incubated with biotinylated swine anti-rabbit IgG (linking antibody) then with avidin-biotin horseradish peroxidase complex and developed with diaminobenzidine in hydrogen peroxide (0.03 per cent) substrate. The optimum staining of MT was obtained at a 1:800 antibody dilution. MT was identified in fetal amniotic cells, syncytial trophoblasts and villous interstitial cells, and in maternal decidual cells. The presence of MT at specific cellular sites suggests that it may regulate the transplacental transport of metals such as zinc, copper and cadmium. Since the level of cadmium is lower and that of zinc and copper higher in fetal than in maternal blood, this may suggest that placental MT may restrict cadmium while enhancing zinc and copper transport.