Maria Blaszczyk

Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin

The molecular and cellular mechanisms that maintain proper collagen homeostasis in healthy human skin and are responsible for the dysregulated collagen synthesis in scleroderma remain primarily unknown. This study demonstrates that Fli1 is a physiological negative regulator of collagen gene expression in dermal fibroblasts in vitro and in human skin in vivo. This conclusion is supported by the analyses of mouse embryonic fibroblasts from Fli1(-/-), Fli1(+/-), and Fli1(+/+) mice. In cultured human and mouse fibroblasts Fli1 expression levels are inversely correlated with the collagen type I expression levels. These in vitro observations were validated in vivo. In healthy human skin Fli1 protein is expressed in fibroblasts and endothelial cells. Significantly, absence of Fli1 expression in individual fibroblasts correlates with elevated collagen synthesis. In contrast to healthy skin, Fli1 protein is consistently absent from fibroblasts and significantly reduced in endothelial cells in clinically involved scleroderma skin, which correlates with enhanced collagen synthesis in systemic sclerosis skin. This study supports the role of Fli1 as a suppressor of collagen transcription in human skin in vivo. Persistent down-regulation of Fli1 in scleroderma fibroblasts in vivo may directly contribute to uncontrolled matrix deposition in scleroderma skin.

Subacute cutaneous lupus erythematosus versus systemic lupus erythematosus: Diagnostic criteria and therapeutic implications

BACKGROUND The nosologic position of subacute cutaneous lupus erythematosus (SCLE) is controversial. More than four American Rheumatism Association (ARA) criteria for systemic lupus erythematosus (SLE) are found in a proportion of patients diagnosed as having SCLE; thus such cases could be classified as SLE. OBJECTIVE Our purpose was to determine whether ARA criteria for SLE are helpful in differentiating SCLE from SLE and whether cutaneous and visceral changes, immunologic findings, and photosensitivity provide a basis for diagnosis of SCLE. METHODS A cohort of 143 patients (79 with SCLE, 58 with SLE, and six with overlapping features of SCLE and SLE) was studied clinically, histologically, and immunologically as well as by phototesting. The patients were observed for up to 10 years, and the course of the disease and response to therapy were evaluated in each group. RESULTS SCLE differed from SLE by cutaneous changes, significantly less frequent kidney involvement, serositis and arthritis, and the rare presence of double-stranded DNA, U1RNP, and Sm antibodies characteristic of SLE. Ro(SS-A) and La(SS-B) antibodies were detected with similar frequency, and photosensitivity was not related to the presence of Ro antibody. In contrast, photoreproduction (appearance of LE lesion in irradiated area) was significantly more frequent in patients with SCLE. The course of SCLE in older patients was less severe than in younger patients, and aggressive therapy was usually not required. CONCLUSION Patients with SCLE (although the majority fulfill more than four ARA criteria for SLE) show significant differences from those with SLE in terms of cutaneous and visceral involvement, immunologic findings, photosensitivity, course of the disease, and the requirement for therapy. Therefore SCLE should be recognized as a separate subset. However, cases of overlapping SLE and SCLE suggest a close relation.

Scl 70 antibody—a specific marker of systemic sclerosis

Scl 70 antibodies were tested for in 107 patients with systemic sclerosis: 68 with acrosclerosis and 39 with diffuse scleroderma. Anticentromere antibodies (ACA) and other antinuclear antibodies (ANA) were tested for by indirect immunofiuorescence on HEp‐2 cells. Positive results for Scl 70 antibodies were obtained in 77percnt; of cases of diffuse scleroderma and 44percnt; of acrosclerosis. ACA and Scl 70 antibodies were found to be mutually exclusive. If acrosclerosis cases positive for anticentromere antibodies are excluded, the percentage of acrosclerosis cases positive for Scl 70 was 63percnt;. ACA were found to be a marker of a benign, abortive subset of acrosclerosis with almost no cutaneous involvement (CREST), whereas Scl 70 did not discriminate between acrosclerosis and diffuse scleroderma. On HEp‐2 cells Scl 70 positive sera gave a characteristic, fine speckled, almost homogeneous nuclear staining pattern.

IMMUNOSUPPRESSANTS IN THE TREATMENT OF PEMPHIGUS

The results are presented of parenteral treatment with methotrexate (12·5 mg. twice a week) in 19 cases of various forms of pemphigus; small doses of corticosteroids (usually 8–32 mg. daily) were given in addition. Two other cases, both of pemphigus erythematosus, were treated with azathioprine.

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

OBJECTIVE Activation of Smad1 signaling has recently been implicated in the development of fibrosis. The goal of the present study was to gain further insights into activation of the Smad1 pathway in fibrosis in systemic sclerosis (SSc) and to determine whether this pathway is targeted by the antifibrotic drug imatinib mesylate. METHODS Levels of phosphorylated Smad1 and total Smad1 were examined in SSc and control skin biopsy samples by immunohistochemistry and in cultured fibroblasts by Western blotting. Activity of the CCN2 promoter was examined by a luciferase reporter gene assay. Interactions of Smad1 with the CCN2 promoter were examined by in vitro and in vivo DNA binding assays. Expression of the nonreceptor tyrosine kinase c-Abl and Smad1 was blocked using respective small interfering RNA. RESULTS Total and phosphorylated Smad1 levels were significantly elevated in SSc skin biopsy samples and in cultured SSc fibroblasts and correlated with elevated CCN2 protein and CCN2 promoter activity. DNA binding assays demonstrated that Smad1 was a direct activator of the CCN2 gene. Small interfering RNA-mediated depletion of Smad1 in SSc fibroblasts normalized the production of CCN2 and collagen. Imatinib mesylate blocked activation of the Smad1 pathway in transforming growth factor beta-stimulated control fibroblasts and reversed activation of this pathway in SSc fibroblasts. Likewise, blockade of c-Abl abrogated activation of the Smad1 pathway in SSc fibroblasts. CONCLUSION Our findings demonstrate that activation of Smad1 signaling occurs in a subset of SSc patients and contributes to persistent activation of SSc fibroblasts. Demonstration that the Smad1/CCN2 pathway is blocked by imatinib mesylate further clarifies the mechanism of the antifibrotic effects of this compound. This study suggests that SSc patients with activated Smad1 signaling may benefit from imatinib mesylate treatment.

Phototests in patients with various forms of lupus erythematosus

ABSTRACT: Responses to ultraviolet B (UVB; 290–320 nm) were tested in 227 patients with main forms of lupus erythematosus (LE): discoid LE (OLE), discoid disseminated LE (DOLE), systemic LE (SLE), and subacute cutaneous LE (SCLE). Four parameters were evaluated: minimal erythema dose (MED), its distribution, persistence of erythema, and photoreproduction of lesions. Patients with LE differed considerably from controls in their UVB reactivity. In addition, there were significant differences between various LE forms, even after a single UV exposure. Lowered MED in comparison to controls was observed most frequently in SLE patients (64.4%) and least frequently in OLE patients (32.1%). Prolonged persistence of erythema induced by 1–2 MED was a constant finding in SCLE. In SLE and DOLE, it was observed in more than 80% of patients, and in OLE in 56.7% of examined cases. Photoreproduction of lesions after single UVB exposure was observed most frequently in SCLE (62.5%) and only in 10% of OLE patients.

Scleroderma-like disorders.

Scleroderma-like disorders are widely disparate conditions mimicking either systemic sclerosis or cutaneous localized scleroderma, not infrequently displaying features of both. Some are exclusively sclerotic, some scleroatrophic with prevailing sclerosis or atrophies. The recognition of scleroderma-like disorders is of practical importance because by establishing the cause of the disease, it is possible to introduce an effective therapy, as in scleredema Buschke or scleredema diabeticorum, sclerodermiform porphyria, Borrelia burgdorferi-induced sclerodermiform acrodermatitis atrophicans, sclerodermiform phenylketonuria, drug-induced conditions, and so on. Scleroderma-like disorders strongly suggest that the pathogenesis of skin sclerosis and internal involvement may be divergent, and of various causes. Some of them, such as atrophoderma Pasini-Pierini or progressive facial hemiatrophy, frequently overlapping with scleroderma, make the differentiation very difficult, if at all possible, and the diagnosis is often arbitrary. Some, as sclerodermiform graft-versus-host reaction, point to the autoimmune origin of scleroderma. The amply-covered congenital sclerodermiform conditions present a large spectrum of still not widely known and extremely heterogeneous syndromes, associated with numerous anomalies and/or malignancies.

Atrophoderma Pasini-Pierini is a primary atrophic abortive morphea.

BACKGROUND There are divergent opinions whether atrophoderma Pasini-Pierini (APP) is a nosologic entity or a primary atrophic morphea. OBJECTIVE Since usually single cases are reported without a long-term follow-up the present study was performed in order to elucidate the natural history of the disorder. METHODS We followed a large series of 139 patients, 91 adults and 48 children, for 4-30 years (mean over 10 years). RESULTS APP was found to be 6 times more frequent in females and not uncommon in children (10% of our series of localized scleroderma). At some time during the follow-up period, indurations appeared in the central parts of the lesions in 17% of the patients, and in 22% they coexisted with morphea plaques outside the atrophies. The histological pattern was similar to morphea at the stage of atrophy. No case developed full-blown morphea. CONCLUSION APP appears to be an abortive morphea, in which the indurations failed to develop. The differentiation from morphea is of practical importance because of different management and prognosis.

Diagnostic importance of immunofluorescence in oral bullous diseases and lupus erythematosus

Immunofluorescent tests have proved to be of diagnostic importance for pemphigus, bullous pemphigoid, cicatricial pemphigoid, systemic lupus erythematosus, and discoid lupus erythematosus. Immunofluorescence test procedures, necessary specimens, and test findings have been reviewed as aids to dentists in the utilization and interpretation of these tests for the study of oral lesions.

Anticentromere antibody: an immunological marker of a subset of systemic sclerosis

Our clinical and immunological studies of 114 cases of systemic sclerosis, 54 of Raynauds disease and 46 of other connective tissue diseases, centered on the diagnostic and prognostic significance of anticentromere antibodies (ACA). The ACA occurred in 21 of 84 patients with acrosclerosis, in four of 54 patients with Raynauds disease but in none of 30 patients with diffuse scleroderma or transitional form, acrosclerosis‐diffuse scleroderma, or 46 cases of other connective tissue diseases. The ACA‐positive patients had no contracture or immobilization of the fingers, the indurations and/or indurative oedema were confined to fingers and usually no other types of ANA were detected. However, systemic involvement and the course of the disease were comparable in ACA‐negative and ACA‐positive acrosclerosis patients.