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Skeletal findings in progressive systemic sclerosis (scleroderma).

Radiographs were reviewed of the chest, hands, and feet of 55 patients with progressive systemic sclerosis. These patients had been selected so as to exclude overlap syndromes, particularly mixed connective tissue disease. Soft tissue changes included flexion deformities, generalized or localized atrophy, and dystrophic calcifications. While resorption of distal phalanges was the most common bony change, osteolysis in other sites (feet, ribs, and mandibles) was also frequent. Twelve of 55 patients showed radiographic evidence of inflammatory arthritis, ranging from isolated to generalized joint destruction, that could not be attributed to overlap with rheumatoid arthritis or mixed connective tissue disease.

Adult↗

Association of polar amino acids at position 26 of the HLA-DQB1 first domain with the anticentromere autoantibody response in systemic sclerosis (scleroderma).

HLA class II alleles (detected by DNA typing) were determined in 116 Caucasians with systemic sclerosis positive and negative for anticentromere autoantibodies (ACA). Significantly increased frequencies of HLA-DR5(DRw11) (P = 0.009) and the Dw13(DRB1*0403, *0407) subtypes of DR4 (probability corrected, Pc = 0.005) were seen in ACA positive patients, and HLA-DR1 and DRw8 were also increased. These findings appeared to reflect linkage disequilibrium of DR5(DRw11) and many DR4(Dw13) haplotypes with HLA-DQw7 and DR1 with DQw5. In fact, the presence of a DQB1 allele having a polar glycine or tyrosine at position 26 of the DQB1 first domain versus a hydrophobic leucine accounted for 100% of ACA positive Caucasian systemic sclerosis patients compared to 69% of the ACA negative SS patients (P = 0.0008) and 71% of Caucasian controls (P = 0.0003) as well as all 7 ACA patients of non-Caucasian background. Furthermore, the genotype frequency of DQB1 alleles lacking leucine at position 26 was 73% in ACA positive SS patients, compared to 42% of ACA negative patients (P = 1.2 x 10(-5)) and 38% of controls (P = 5.8 x 10(-7)). These data, then, suggest that the second hypervariable region of the HLA-DQB1 chain may form the candidate epitope associated with the ACA response.

Alleles↗

[Prostaglandins in the pathogenesis of various systemic diseases of the connective tissue].

A study was made of the content of prostaglandins E, A, F2 alpha and malonic dialdehyde (MDA) in the blood plasma and urine of patients with systemic lupus erythematosus, systemic scleroderma, rheumatoid arthritis and healthy persons. The levels of plasma and urine prostaglandins and MDA were significantly elevated in systemic lupus erythematosus and rheumatoid arthritis, and in systemic scleroderma they did not differ from those in normal. The ratio of pressor and depressor prostaglandins in systemic lupus erythematosus and rheumatoid arthritis did not change, and in systemic scleroderma there was a strong shift to pressor prostaglandins. Change in the content and ratio of prostaglandins and MDA in systemic diseases of connective tissue was suggestive of differences of pathogenetic effects of these mediators in some diseases of this group.

Adult↗

[Scintigraphic diagnosis of esophageal involvement in systemic sclerosis (scleroderma)].

Motor function disturbances (MFD) of the esophagus occur in the majority (90%) of patients with systemic sclerosis. We have tested the diagnostic value of esophagus scintigraphy in 20 patients with systemic sclerosis (12 CREST and 8 with diffuse form) and 18 controls (11 normals and 7 with pyrosis and/or regurgitation), in order to establish sensitivity, specificity, effects of body posture, and use of a liquid or solid meal in the evaluation of MFD of the esophagus. The patients drank 4 ml of fruit juice marked with 500 microCi of 99mTc-sulfur-colloid and afterwards 10 g of an equally marked and scrambled egg. Pictures were made with a Gamma-Camera until 180 s. Radioactivity was plotted against time and separately analysed for the upper, middle and distal esophagus. 65% of the systemic sclerosis patients had dysphagia and 70% had abnormal barium meal transit in the esophagus. The scintigrams were altered in all the patients with systemic sclerosis (p less than 0.001). Sensitivity using fluids was 95%, and specificity was 89%; with solid food 100% and 50%, respectively. Tests done in the upright position showed a better clearance of the esophagus in patients with systemic sclerosis and control patients, with loss of sensitivity. The qualitative analysis yielded little benefit to the reported results. The quantitative analysis under use of 2 indices (total transit time and clearance rate) permitted a clear distinction among patients and control individuals with and without upper digestive symptoms in the first 15 s of the test. The esophagus scintigraphy is a simple, quantitative and very sensitive method for the diagnosis of MFD of the esophagus in patients with systemic sclerosis.

Adult↗

Concurrent linear scleroderma and systemic lupus erythematosus: a report of two cases.

Two patients with linear scleroderma (en coup de sabre) developed systemic lupus erythematosus (SLE). This association has been well documented in only one previous case. The presence of high titer antibodies to ribonucleoprotein (RNP) initially led to the diagnosis of the mixed connective tissue disease. Development of more serious clinical involvement and antibodies to Sm (case 1) or native deoxyribonucleic acid (nDNA) (case 2) helped establish a diagnosis of SLE. Use of these studies in the differential diagnosis of systemic rheumatic diseases is disucssed briefly. The presence of anti-RNAP antibodies in patients with localized scleroderma may herald a more serious rheumatic disease.

Adult↗

Specificity and sensitivity of esophageal motor abnormality in systemic sclerosis (scleroderma) and related diseases: a cineradiographic study.

Using cineradiography, we studied esophageal peristalsis in patients with suspected systemic sclerosis and related diseases, and in patients without known esophageal disease who had been referred for upper gastrointestinal series. Patterns of peristaltic abnormality were identified, and specificity and sensitivity values calculated. Esophageal aperistalsis was 100% specific, and consistently weak peristalsis after all, swallows was 88% specific for systemic sclerosis. Specificity decreased to 70% in patients over age 60. Abnormal peristalsis after some, but not all, swallows had only 52% specificity. Consistently abnormal peristalsis (absent or diminished) was 67% sensitive for scleroderma. Although a high sensitivity value (87%) for cineradiography can be obtained by considering any peristaltic abnormality as a sign of scleroderma, this is achieved at the price of an undesirably high number of false positives (specificity 40%).

Adolescent↗

Association of HLA-DR5 (DR11) with systemic sclerosis (scleroderma) in Mexican patients.

OBJECTIVE: To study the association between Major Histocompatibility Complex (MHC) haplotypes and systemic sclerosis (SSc) in Mexican mestizo patients. METHODS: Class I, II and III MHC antigens were determined in 41 Mexican mestizo patients with SSc, 113 of their first degree relatives, and 85 ethnically matched controls. The significance of differences between patients and controls was tested by chi-square analysis with Yates' correction. RESULTS: Frequencies of HLA-DR5 and HLA-DRw52 were found to be higher in SSc patients compared to ethnically matched healthy controls (p = 0.007, RR = 3.31; 95% confidence interval: 1.3-8.3 and p = 0.04, RR = 2.4; 95% confidence interval: 1.0-5.7, respectively). Sequence-specific oligotyping in DR5 positive individuals showed that 10 out of 41 patients had the DRB1*1104 subtype (24.3%) as compared to only 6 of the 85 healthy controls (7.0%) (p = 0.01, RR = 4.25). Subdividing patients according to their clinical features showed a significant increase of HLA-DR5 in diffuse (p = 0.013, RR = 3.89, 95% confidence interval: 1.27-12.0) and limited scleroderma (p = 0.0008), but not in the CREST syndrome. Segregation analysis obtained from the families showed that in the patients, DR5 was mostly part of the [HLAB35;DR5] haplotype as opposed to healthy controls. CONCLUSION: These data support the role of DR5 (DRB1*1104) in the genetic susceptibility to develop scleroderma in Mexican patients and also sustain the notion of genetically determined clinical subgroups of SSc.

Base Sequence↗

Adhesion of peripheral blood mononuclear cells to vascular endothelium in patients with systemic sclerosis (scleroderma).

OBJECTIVE: Perivascular infiltrates in skin, subcutaneous tissue, and internal organs are a characteristic feature of early systemic sclerosis (SSc). We studied the first step of migration of peripheral blood mononuclear cells (PBMC) through the vessel wall to the extravascular space, i.e., adhesion of PBMC to endothelial cells (EC), in patients with various forms of SSc (limited scleroderma, diffuse scleroderma, and the transitional form). METHODS: Radioisotope-labeled patient PBMC were coincubated with umbilical cord EC in vitro, and the percentage adhesion was measured. RESULTS: Adhesion of PBMC to EC was markedly decreased, while adhesion of isolated active rosette-forming cells (ARFC) was significantly increased, in SSc patients compared with healthy controls. Decreased adhesion of PBMC to EC was found to correlate with a diminished percentage of ARFC in the peripheral blood. Preincubation of PBMC from healthy donors with interleukin-2 (IL-2) enhanced their adhesion to EC, while preincubation of PBMC from SSc patients with this cytokine resulted in a decrease in adhesion in 10 of 14 individuals. IL-1, interferon-gamma, and transforming growth factor beta had no significant effect on adhesion of SSc patient PBMC to EC. Differences in adhesion of PBMC to EC among the SSc subgroups were not significant. CONCLUSION: Our findings suggest that in SSc, activation of subpopulations of PBMC leads to their enhanced adhesion to vascular endothelium in vivo and to migration of these cells to the extravascular space, resulting in the elimination from the peripheral blood of those PBMC with high ability to adhere to EC.

Adult↗

A syndrome resembling human systemic sclerosis (scleroderma) in MRL/lpr mice lacking interferon-gamma (IFN-gamma) receptor (MRL/lprgammaR-/-).

MRL/lpr mice develop a systemic autoimmune disease characterized by autoantibodies and inflammatory lesions in various organs. The main cause of early mortality is glomerulonephritis. We previously found that MRL/lprgammaR-/- mice are protected from glomerulonephritis and have an increased life span compared with their MRL/lprgammaR+/+ littermates. We now carried out a histopathological study of a selection of organs of MRL/lprgammaR-/- mice. Mice were killed as soon as they showed clinical signs of disease. In the majority of animals skin lesions were the first apparent pathology. Mononuclear cell infiltrates were frequent in skin, lungs and kidneys, and they occurred also in liver, salivary glands and heart. In infiltrated areas there was an abnormal accumulation of bundles of collagen. In the lungs of MRL/lprgammaR-/- mice, and occasionally in other organs, small and middle-sized arteries and veins showed intimal proliferation, resulting in a narrowed lumen. Alveolitis was widespread. Mononuclear cell infiltrates and excessive production of collagen in the skin and several visceral organs, thickening of vascular intima and autoantibodies are characteristic features of human systemic sclerosis. Thus, MRL/lprgammaR-/- mice might represent a model for that disease.

Age Factors↗

Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association.

To examine the possible relationship between cardiac and skeletal muscle disease in systemic sclerosis, we reviewed computerized records of 1095 consecutive patients with systemic sclerosis. One hundred eighty three (17%) had skeletal myopathy. Thirty-nine (21%) of the 183 fulfilled criteria for myocardial disease, compared with 90 (10%) of the 912 without myopathy (p < 0.0001.) Nineteen (10%) of the 183 had clinical CHF compared with 38 (4%) of the remainder (p < 0.002.) Fifteen (8%) of the patients with myopathy died of cardiac causes compared with 27 (3%) of the 912 without myopathy (p < 0.002.) Twenty-five patients with coexistent myopathy and myocardial disease, in the absence of other identifiable contributing causes, were identified. This group was characterized by a high incidence of cardiac conduction abnormalities (60%) and by the severity of the myocardial dysfunction and arrhythmias, both atrial and ventricular that they experienced. Eighteen of these 25 patients died; 12 (67%) died suddenly. Eight of the 18 (44%) had intractable CHF, which directly contributed to their deaths. Myocardial fibrosis was the predominant histologic abnormality at autopsy. However, autopsy of a patient who died in the context of acute "myocarditis" showed severe myocytolysis with contraction band necrosis but without inflammation or fibrosis; this is consistent with possible ischemically mediated injury. We conclude that skeletal and cardiac muscle disease in systemic sclerosis are associated. Patients with myopathy are at increased risk for CHF, sustained symptomatic arrhythmias, and cardiac death, particularly sudden death.

Adolescent↗

Predictors of survival in 171 patients with systemic sclerosis (scleroderma).

Predictors of survival were determined in 171 patients with systemic sclerosis by univariate analysis, and the Cox proportional hazards model using both cross sectional data at entry into the follow-up and time-dependent follow-up data. Clinical and laboratory data were evaluated from 1982 to the end of 1993. The presence of diffuse scleroderma, kidney and cardiac involvements were unfavourable prognostic signs in both the univariate analysis, and the Cox proportional hazards models. The Cox model, using the variables detected at study entry, indicated that pericarditis, and anaemia were bad prognostic signs. Analysis with time dependent data has not been reported in systemic sclerosis. The appearance of pigmentation disturbances, anaemia, and respiratory failure during the follow-up also caused a poor prognosis of the disease by the Cox model. In the stepwise selection models, diffuse scleroderma, internal organ manifestations including renal, and cardiac involvements were predominantly selected as the most unfavourable factors for survival. As to the extent of skin involvement and internal organ manifestations, the general behaviour of the disease seems to be similar throughout the world. The early appearance of pericarditis and pigmentation disturbances at study entry are bad prognostic signs.

Adult↗

HLA-DR antigens in progressive systemic sclerosis (scleroderma).

Typing at the HLA-DR locus was performed in 125 North American white patients with progressive systemic sclerosis (PSS). We could not confirm associations of PSS with the HLA-DR5 antigen or the HLA-B8/DR3 haplotype. A weak association of the DR1 antigen and PSS with diffuse scleroderma (27.5% vs 11.5% in local controls (corrected p less than 0.05) was observed. HLA-DR1 was significantly associated with the presence of anticentromere antibodies (p less than 0.05), and this combination was found more frequently in individuals with the CREST syndrome variant of PSS. This study failed to identify a clear-cut association between PSS and a genetic factor linked to the major histocompatibility complex.

Adolescent↗

Polyneuropathy as initial manifestation of systemic sclerosis (scleroderma).

We report the first case of a young female patient who developed a sensory-motor polyneuropathy, without any skin or internal involvement characteristic of SSc, but with a serological positivity of antitopoisomerase I antibodies. After 4 years she developed a rapid skin tightening with lung involvement, in a full blown picture of the diffuse subset of SSc. The case suggests that the peripheral nervous system deserves more attention, in particular in the earliest phase of SSc.

Adult↗

Cutaneous and subcutaneous inflammatory sclerosis syndromes.

Systemic scleroderma and localized scleroderma (morphea) show comparable changes on skin biopsy specimens, and a distinction has often been made on the basis of Raynaud's phenomenon, organ involvement, and laboratory abnormalities characteristically seen in systemic scleroderma. Critical evaluation not only of patients with localized scleroderma but also of those with eosinophilic fasciitis, morphea profunda, and acral pansclerotic morphea has disclosed Raynaud's phenomenon, organ involvement, and laboratory abnormalities typical of systemic scleroderma in a small percentage of patients. Histologically, all five conditions show similar inflammation and sclerosis of the skin, the primary difference being the depth at which these changes occur. These conditions may possibly be related, and the clinical and laboratory differences observed may result from variations in depth, nature, and intensity of the cutaneous and subcutaneous inflammatory sclerosis.

Child↗

Scleroderma and occupational exposure to hand-transmitted vibration.

OBJECTIVES: To determine whether occupational exposure to hand-transmitted vibration is a risk factor for scleroderma (systemic sclerosis, SSc), two case-control studies were conducted in the provinces of Trento and Verona, northeastern Italy. METHODS: In the Trento study, 21 patients with a diagnosis of either systemic or localised scleroderma were recruited from those admitted to all hospitals of the province from 1 January 1976 to 31 December 1991. For each case, two age- and gender-matched controls were selected. In the Verona study, cases included 55 patients diagnosed with SSc and clinically followed at the rheumatology clinic of the local university hospital between 1 January 1997 and 30 June 1999. The controls included 171 subjects frequency-matched by gender and age group. In both studies, all subjects were interviewed by structured questionnaire containing items on personal characteristics, smoking and drinking habits, use of medicines, occupational history and complete medical history. Women were also investigated about silicone implants and cosmetic surgery. Jobs and job tasks involving the use of vibratory tools, with or without concomitant exposure to silica dust in mining and non-mining occupations, were carefully investigated. A minimum criterion of 6 months was required for exposure duration. RESULTS: In the Trento study, men with scleroderma were more likely than controls to have had exposure to hand-transmitted vibration (odds ratio (OR) 1.5, 95% confidence interval (95% CI) 0.1-74.1) or silica dust (OR 5.2, 95% Cl 0.5-74.1), but the association was not significant. The scleroderma patients were miners or stone workers who had operated jackhammers and rock drills. In the Verona study, a greater, although not statistically significant, odds of SSc was observed in men exposed to hand-transmitted vibration (OR 2.4, 95% CI 0.4-14.0) and in women exposed to silica (OR 2.4, 95% Cl 0.4-15.5). The SSc patients with vibration exposure were machinery operators or metal workers who had used grinders and impact wrenches. CONCLUSIONS: Our case-control studies did not show a significant association between scleroderma and hand-transmitted vibration, with or without concomitant exposure to silica dust. Owing to the rarity of the disease and the small number of cases in the present studies, a genetic susceptibility to connective tissue disorders in SSc patients with occupational exposure to hand-transmitted vibration and/or silica cannot be ruled out.

Case-Control Studies↗

[3H]Thymidine labeling of dermal endothelial cells in scleroderma.

The purpose of this study was to estimate [3H] thymidine labeling of endothelial cells of skin capillaries in localized scleroderma (LS) and systemic scleroderma (SS). Skin specimens from 14 patients with SS, 5 with LS, and 9 matched controls were studied by in vitro autoradiography. Capillaries from patients with SS showed a statistically significant increase in endothelial cell labeling when compared to vessels from controls (p less than 0.0005).

Adult↗

Silica and trichloroethylene-induced progressive systemic sclerosis.

Several environmental factors and chemicals have been described as being able to induce systemic scleroderma and scleroderma-like diseases. The present work reports 2 male patients with progressive systemic sclerosis and pulmonary silicosis. Both patients had occupational histories of exposure to silica and one of them of handling trichloroethylene as a degreasing agent. The clinical and analytical findings could not be distinguished from those present in idiopathic systemic scleroderma with the exception of interstitial images with calcified hilar lymph nodes in the chest X-ray suggestive of pulmonary silicosis.

Adult↗