Y. Soma

Measurement of anticardiolipin antibodies by ELISA using β2-glycoprotein I (β2-GPI) in systemic sclerosis

In order to determine the prevalence and clinical significance of β2‐GPI‐dependent anticardiolipin antibodies (β2‐GPI/aCL) in patients with systemic sclerosis (SSc), serum samples from 80 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), and 120 healthy control subjects were examined by ELISA using purified β2‐GPI. IgG isotype β2‐GPI/aCL was present in eight of 80 patients with SSc (10%), and the presence of β2‐GPI/aCL IgG was significantly correlated with the presence of isolated pulmonary hypertension (PH). Furthermore, levels of β2‐GPI/aCL IgG were significantly correlated with levels of mean pulmonary arterial pressure. These data suggest that IgG isotype β2‐GPI/aCL might be a serological indicator of the severity of PH in patients with SSc.

Elevated plasma endothelin levels in systemic sclerosis.

Endothelin is a novel potent vasoconstrictor peptide produced mainly by endothelial cells. Thrombomodulin is a high-affinity thrombin receptor on vascular endothelial cells that plays an important role as a natural anticoagulant. In this study, we measured plasma levels of endothelin and thrombomodulin in patients with systemic sclerosis or Raynauds disease. Plasma levels of endothelin and the ratio of thrombomodulin to creatinine were significantly increased in patients with systemic sclerosis compared with normal controls, and there was a positive correlation between these two indicators (r=0.615, P=0.004). Moreover, plasma levels of endothelin were significantly higher in patients with diffuse systemic sclerosis than in patients with limited systemic sclerosis. In contrast, plasma levels of endothelin in patients with Raynauds disease were not significantly increased. These results suggest that increased plasma levels of endothelin and thrombomodulin may reflect microvascular damage in systemic sclerosis.

Clinical evaluation of scleroderma spectrum disorders using a points system

We have established a new diagnostic method using a points system to evaluate patients with early scleroderma and those with scleroderma spectrum disorders (SSD). To examine the clinical usefulness of this method, it was applied to a total of 215 cases including 97 patients with scleroderma, 32 with SSD, 28 with presumed primary Raynauds phenomenon (RP) and 58 with other connective tissue disorders (CTD). A total score was obtained for each patient as the sum of the following five factors: (1) extent of skin sclerosis (maximum, 10 points); (2) pulmonary changes (maximum, 4 points); (3) antinuclear antibodies (maximum, 5 points); (4) pattern of Raynauds phenomenon (maximum, 3 points); and (5) nailfold bleeding (maximum, 2 points). Of the 97 scleroderma patients, 86 (89%) had 9 or more points, and of the 32 SSD patients, 28 (88%) had 5 to 8 points. In contrast, all patients with presumed primary RP and 54 of 58 (93%) patients with other CTD had 0 to 4 points. These data suggest that this diagnostic method is very useful not only for clinical evaluation of SSD, but also for the differentiation of scleroderma and SSD from other CTD and primary RP.

Increased levels of circulating intercellular adhesion molecule-1 in patients with localized scleroderma

BACKGROUND Intercellular adhesion molecule-1 (ICAM-1) is important in immune-mediated mechanisms, and its circulating form (cICAM-1) may be an indicator of immune activation. Localized scleroderma is accompanied by various immunologic abnormalities. OBJECTIVE We investigated whether the serum level of cICAM-1 in patients with localized scleroderma was elevated and was correlated with the clinical or serologic features of this disease. METHODS Serum cICAM-1 levels were determined by an enzyme-linked immunosorbent assay in 48 patients with localized scleroderma, in 20 patients with systemic sclerosis, and in 20 healthy control subjects. RESULTS Serum levels of cICAM-1 were significantly higher in patients with localized scleroderma than in the healthy control subjects. These levels correlated with the number of lesions, the number of involved areas, levels of antihistone antibody IgM, and levels of soluble interleukin 2 receptor. CONCLUSION The results suggest that immune activation may be a factor in localized scleroderma.

Coexistence of Morphea and Systemic Sclerosis

While the association of morphea and systemic sclerosis (SSc) is considered to be a rare condition, we observed well-demarcated sclerotic skin changes indistinguishable from morphea in 9 of 135 SSc patients who visited our clinic during the last decade. We consider this rate of incidence (6.7%) to be high enough to consider morphea to be one of the skin involvements of SSc. There was a significantly (p < 0.01) higher incidence of morphea in males (3 of 5) than in females (6 of 130). Only 3 of 111 SSc patients positive for antinuclear antibody (ANA) also showed morphea, whereas 6 of 9 patients negative for ANA showed morphea (p < 0.01). Although the mechanism underlying the development of morphea in SSc patients remains unknown, our observations suggest a heterogeneous pathogenesis related to SSc gender and ANA type.

Serum concentration of procollagen type I carboxyterminal propeptide in systemic sclerosis

The serum level of procollagen type I carboxyterminal propeptide (P1CP), which has been used as an index of collagen synthesis in patients with various fibrotic diseases during the active stage, was measured using enzyme-linked immunosorbent assay in 61 patients with systemic sclerosis (SSc) and in 21 control subjects. The mean P1CP level in the SSc patients was significantly higher than in the normal controls (mean ± SD, 326 ± 319 vs 128 ± 87 ng/ml; p<0.005). In 36% of the SSc patients, the serum P1CP level was significantly elevated more than two standard deviations above the mean control value. The mean serum P1CP level in patients with diffuse SSc was significantly higher than in those with limited SSc (411 ± 373 vs 255 ± 199 ng/ml; p<0.05). In addition, the SSc patients with elevated serum P1CP levels showed a significantly greater incidence of lung fibrosis and joint involvement than those with normal P1CP levels (p<0.005 and p<0.05, respectively). These results suggest that the serum P1CP level is a useful indicator of the severity of disease in SSc patients.

Response of scleroderma fibroblasts to various growth factors

SummaryAbnormal growth regulation in lesional skin fibroblasts may be related to scleroderma pathogenesis. We report on the abnormal response of cultured fibroblasts derived from sclerotic lesions to various growth factors. We investigated the responses of skin fibroblasts (10 strains) and normal fibroblasts (9 strains) to the growth factors as PDGF, TGF-Β1, EGF and basic FGF. Experiments were conducted during the proliferation and confluent stages. PDGF, EGF and basic FGF stimulated fibroblast growth during the proliferation and confluent stages, but the response of scleroderma fibroblasts was significantly lower than that of normal fibroblasts. TGF-Β1 slightly stimulated confluent fibroblast growth and inhibited proliferating fibroblasts, and the response of scleroderma fibroblasts exceeded that of normal fibroblasts. The decreased response to growth-stimulating factors observed in scleroderma fibroblasts suggests that cultured fibroblasts derived from scleroderma lesions were already senescent because they have been activated by growth-stimulating factors and repeatedly divided in vivo. Thus, abnormal growth regulation of skin fibroblasts may be partially related to the pathogenesis of scleroderma.

Increased serum levels of soluble vascular cell adhesion molecule-1 and soluble E-selectin in patients with polymyositis/dermatomyositis

Background Elevated levels of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) and soluble E‐selectin (sE‐selectin) have previously been reported in patients with various inflammatory diseases, but not in patients with polymyositis/dermatomyositis (PM/DM). Objectives To determine serum levels and significance of sVCAM‐1 and sE‐selectin in patients with PM/DM. Patients and methods Serum samples from 36 PM/DM patients, 30 patients with systemic sclerosis and 25 healthy control subjects were examined using specific enzyme‐linked immunosorbent assay systems.  Results The serum levels of sVCAM‐1 in the PM/DM patients were significantly higher than those in the healthy controls. The elevated serum sVCAM‐1 levels were correlated with the values of elevated erythrocyte sedimentation rate and elevated serum hyaluronate levels in the PM/DM patients. The serum sE‐selectin levels in the PM/DM patients were also significantly higher than those in the healthy controls. The elevated serum sE‐selectin levels were correlated with the incidence of elevated creatine kinase activities. The concentrations of serum sE‐selectin were correlated with the serum tissue inhibitor of metalloproteinase‐1 concentrations in the PM/DM patients (r = 0·53).  Conclusions These results suggest that serum sVCAM‐1 and sE‐selectin levels might be useful for detecting disease activity in patients with PM/DM.

Diagnostic significance of nailfold bleeding in scleroderma spectrum disorders

BACKGROUND The early detection of scleroderma spectrum disorders (SSD) is important. OBJECTIVE Our purpose was to determine the prevalence of nailfold bleeding in SSD. METHODS We examined patients for nailfold bleeding in the following three groups: (1) 81 patients with SSD including 50 patients with scleroderma, 10 with mixed connective tissue disease, and 21 with Raynauds phenomenon having specific antinuclear antibody (ANA); (2) 99 patients with other connective tissue diseases or primary Raynauds phenomenon; and (3) 200 patients with common skin diseases. RESULTS The frequency of nailfold bleeding was significantly higher in SSD (75.3%) than in other connective tissue diseases (12.1%) and in controls (3.0%). The presence of nailfold bleeding in two or more fingers showed a 98.3% specificity for SSD. Among the patients with SSD, the incidence of nailfold bleeding in scleroderma, mixed connective tissue disease, and Raynauds phenomenon with specific ANA was similar. Nailfold bleeding strongly correlated with the presence of anticentromere antibody. CONCLUSION The presence of nailfold bleeding is useful for the early detection of SSD.

Early Detection of Scleroderma Spectrum Disorders in Patients with Raynaud’s Phenomenon

Fifty patients with the chief complaint of Raynauds phenomenon (RP) presented at our scleroderma clinic from March to December 1990. Physical examination, routine laboratory tests (blood, urine and chest X-ray), determination of the pattern of RP, antinuclear antibody (ANA) tests and examination for nailfold bleeding were performed. Three patients were diagnosed as having systemic sclerosis sine scleroderma, 15 patients as having RP with positive anticentromere antibody and 6 patients as having an incomplete form of mixed connective tissue disease. Thus, a total of at least 24 patients out of 50 (48%) were shown to have a scleroderma spectrum disorder. A definite RP pattern (triphasic or biphasic and bilateral), positive ANA and positive nailfold bleeding were strongly correlated statistically, suggesting that these are simple useful findings for the early detection of scleroderma spectrum disorders in patients with RP. We expect that there are many undiagnosed patients with an early-stage scleroderma spectrum disorder in the general population.