Linear scleroderma. Clinical spectrum, prognosis, and laboratory abnormalities.

The clinical features and natural history of linear scleroderma in 53 patients and the laboratory tests helpful in the management of this disease are described. No patient had Raynaud's phenomenon or signs of systemic connective tissue disease in a mean follow-up of 10 years. Blood eosinophilia (greater than 300 cells/mm3) was present in half the patients, usually those with clinically active disease rather than inactive disease (p less than 0.02). An elevated serum IgG level correlated with the presence of joint contractures (p less than 0.02). Antinuclear antibodies, commoner in patients with extensive and prolonged disease, were present in 31% and 46% of patients whose sera were tested on mouse kidney and HEp-2 cells, respectively. Antibodies to single-stranded DNA, present in 50% of patients, were associated with extensive disease, joint contractures (p less than 0.001), and active disease of greater than 2 years' duration (p less than 0.001). Discordance in immune reactivity indicates that at least three serum autoantibodies exist in these patients: antibodies to single-stranded DNA and antinuclear antibodies with homogeneous and nucleolar immunofluorescence patterns.

Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis.

Pulmonary hypertension (PHT) occurred in 59 (9%) of 673 systemic sclerosis patients seen between 1963 and 1983. In 30 patients, all with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), the pulmonary hypertension was isolated, i.e., independent of other pulmonary or cardiac conditions. In 20 patients, isolated PHT was demonstrated by cardiac catheterization. All had normal or only mildly decreased lung volumes, and mild or no pulmonary interstitial fibrosis on chest roentgenogram. In comparison with 287 CREST syndrome patients without PHT, these 20 patients had markedly reduced diffusing capacity for carbon monoxide (DLCO) (mean 39% of predicted normal). In 6 patients, the low DLCO antedated clinical evidence of PHT by 1-6 years. At autopsy there was marked intimal fibrosis with hyalinization and smooth muscle hypertrophy in the small- and medium-sized arteries, without significant parenchymal fibrosis or inflammation. Patients with isolated PHT did not respond favorably to vasodilators and had a very poor prognosis, with a 2-year cumulative survival rate of 40%. A DLCO less than 45% of predicted in the absence of pulmonary interstitial fibrosis may be an important predictor of the subsequent development of isolated PHT.

Persistence of scleroderma-like phenotype in normal fibroblasts after prolonged exposure to soluble mediators from mononuclear cells.

Supernatants of mononuclear cells (MNC-SN) were shown to increase synthesis of glycosaminoglycan (GAG) by cultured normal dermal fibroblasts. Fibroblasts from the skin of patients with progressive systemic sclerosis (PSS, scleroderma) were hyporesponsive. We exposed fibroblasts outgrowing from explants of normal adult skin to MNC-SN for up to 30 generations in culture. MNC-SN were obtained by incubating normal MNC with concanavalin A. Four experimental, 4 normal control, and 3 PSS control lines were passaged by trypsinizing and splitting the cultures 1:2 every 7 days. At the third and fifth passages, portions of the experimental fibroblasts were removed from MNC-SN, then passaged in medium alone. Cell counts, assays for GAG, and electron microscopy were performed and increases in GAG after brief reexposure to MNC-SN were determined at the third, fifth, and eighth passages. In normal dermal fibroblasts, baseline GAG production, measured by 3H-glucosamine uptake, was low and increased as much as 15 times after reexposure to MNC-SN. In contrast, production was high in both experimental and PSS lines, and increases after reexposure to MNC-SN were consistently small. This PSS-like behavior persisted in experimental fibroblasts removed from MNC-SN at the third and fifth passages. Growth of experimental and scleroderma fibroblasts was slower than that of control fibroblasts. Ultrastructurally, both scleroderma and experimental dermal fibroblasts differed from normal fibroblasts by their oval cellular shape, indentations in nuclear membrane, numerous organelles and bundles of microfilaments, prominent Golgi, and intranuclear inclusions. These experiments indicate that normal adult dermal fibroblasts subjected to MNC-SN in vitro acquire a scleroderma-like phenotype that persists for many generations.

The effect of D-penicillamine on pulmonary findings in systemic sclerosis.

D-penicillamine has been used for the treatment of systemic sclerosis for 2 decades. Forty-four systemic sclerosis patients who received a mean dose of 636 mg of D-penicillamine for 2.3 years and 48 untreated patients, who had repeat pulmonary function tests performed after a mean of 3.5 and 4.8 years, respectively, were evaluated. There were no significant changes in the vital capacity or the forced expiratory volumes during this time in either group. However, the diffusing capacity for carbon monoxide improved from 76% of predicted to 87% of predicted in D-penicillamine-treated patients. Untreated patients changed slightly, from 73% of predicted to 76% of predicted. When multiple logistic regression analysis was used to account for factors which could have biased treatment comparisons, the improvement related to use of the D-penicillamine was significant (P less than 0.05). This improvement in the D-penicillamine-treated patients was associated with no further progression of dyspnea or fibrosis on chest radiograph, as well as reduced skin thickening. These data suggest that D-penicillamine may be useful in the treatment of systemic sclerosis that involves the lung; however, further studies are needed.

Pulmonary involvement in systemic sclerosis (scleroderma).

One hundred sixty-five nonsmoking systemic sclerosis patients were evaluated by pulmonary function testing. Restrictive lung disease and an isolated reduction of the diffusing capacity of carbon monoxide were the most frequent abnormalities. Patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias) had a similar frequency and severity of pulmonary involvement compared with the patients who had diffuse scleroderma. CREST syndrome patients with restrictive lung disease rarely had the anticentromere antibody and had more skin and joint involvement of their hands, compared with other CREST syndrome patients. Dyspnea and rales were most commonly found in patients with restrictive lung disease. Fibrosis, shown on chest radiograph, and pulmonary function abnormalities correlated poorly with each other. Dyspnea was associated with restrictive disease, and rales were more commonly found in patients with fibrosis. Patients with a restrictive abnormality had the worst prognosis, with a 5-year survival rate of 58%, although death from pulmonary causes was uncommon. Comparison of these nonsmoking patients with 137 scleroderma patients who smoked, seen during the same time period, revealed more frequent and severe obstructive changes in smokers. Smoking patients with restrictive lung disease had more severe disease than nonsmoking patients. The single breath diffusing capacity for carbon monoxide was significantly decreased in the patients who smoked compared with the nonsmokers. These data confirm that pulmonary function abnormalities are common in patients with systemic sclerosis including CREST syndrome. Smoking appears to have an additive deleterious effect on pulmonary function and should be strongly discouraged.

Soluble mediators from mononuclear cells increase the synthesis of glycosaminoglycan by dermal fibroblast cultures derived from normal subjects and progressive systemic sclerosis patients.

Dermal fibroblast cultures from patients with progressive systemic sclerosis (PSS) synthesize up to 5 times more glycosaminoglycan (GAG) than normal cultures. In an in vitro model of fibroblast-lymphocyte interactions, we show that the supernatants of activated mononuclear cells (MNC) modulate GAG synthesis, as measured by the incorporation of 3H-glucosamine into GAG following incubation of the confluent fibroblast monolayers with active supernatant preparations. GAG accumulation was selectively increased up to 18 times in normal dermal fibroblast cultures. Cell viability was not affected, and 3H-thymidine uptake and cell numbers were depressed in cultures treated with the supernatants. In contrast to normal dermal fibroblast cultures, PSS fibroblasts responded to MNC supernatants by only a 1-2-fold increase in GAG. Supernatants of concanavalin A-activated PSS MNC had higher stimulatory activity than those of normal MNC. Supernatants made with MNC that had been depleted of monocytes on Sephadex G-10 columns were only minimally stimulatory. The GAG-stimulatory supernatants modulated the synthesis, but not the degradation of GAG. Gel filtration on a calibrated Sephadex G-100 column indicated the presence of stimulatory activity in both the 50,000 and 15,000 molecular weight fractions. These activities were trypsin-sensitive, but had different susceptibilities to heat. The active column fractions also contained interleukin-1 activity, as shown in an assay measuring proliferation of mouse thymocytes. Like our factors, interleukin-1 preparations increased GAG in normal and PSS dermal fibroblasts. Products of activated MNC may modulate normal and pathologic processes in human skin.

Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease.

Eighty-seven patients diagnosed as having primary Raynaud's phenomenon (Raynaud's disease) were reexamined after this symptom had been present for a mean of 8.8 years (range 2.0-34.5). One or more additional clinical feature(s) suggesting an underlying connective tissue disease were found in 12 patients (14%) at first evaluation, and in 23 (26%) by the last evaluation. The most frequent findings were puffy fingers (10 patients), digital tip pitting scars (8 patients), and digital tip ulcerations (6 patients). Distal esophageal hypomotility and/or decreased pulmonary diffusing capacity for carbon monoxide were found in 12 patients. Only 4 individuals (5%) developed clear evidence of a connective tissue disease, and in all cases, the diagnosis was the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome variant of systemic sclerosis. This condition became obvious 8-17 years after the onset of Raynaud's phenomenon. One or more serologic test values were initially abnormal in 2 of these CREST syndrome patients, as well as in 12 patients who continued to have primary Raynaud's phenomenon at the last evaluation. The combination of puffy fingers, digital pitting scars, and serum anticentromere antibody, all consistent with CREST syndrome, occurred in a small group of patients. None of the 78 patients whose serologic tests were repeated during followup had a change in the serologic profile. These results suggest that only a small proportion of patients with primary Raynaud's phenomenon develop one of the connective tissue diseases during the first decade after onset. When such a disorder does appear, systemic sclerosis with the CREST syndrome variant is the most likely eventual diagnosis.

Products of activated mononuclear cells modulate accumulation of collagen by normal dermal and scleroderma fibroblasts in culture.

Supernatants of human mononuclear cells activated with concanavalin A contain soluble factors that modulate accumulation of collagen in human dermal fibroblasts in culture. The supernatants decreased collagen accumulation by 67% in normal fibroblast lines and by greater than 80% in lines established from skin of patients with scleroderma. Collagen was measured by incorporation of 3H-proline into collagenase-sensitive protein. The inhibitory activity of collagen was optimal after a 24-hour incubation of confluent fibroblast monolayers with unfractionated mononuclear cell supernatants. Kinetic studies of this response showed a delay in accumulation of collagen-sensitive protein in supernatant-treated cultures. The 3H-thymidine uptake and fibroblast cell count and viability were only minimally altered. Noncollagen protein was inhibited by 30% to 40%. The presence of serum in fibroblast cultures did not affect this activity. The inhibitory factors were produced by purified T-lymphocyte subpopulations. Supernatant inhibitory activity was present after removal of monocytes from mononuclear cell cultures. By gel filtration on Sephadex G-100, active supernatants fractionated into at least three peaks of activity with molecular weight of 50,000, 30,000, and 15,000 daltons. Interleukin 1 might be one of the factors in mononuclear cell supernatants that modulates production of collagenase-sensitive protein in human dermal fibroblasts. Factors modulating collagen-sensitive protein are important in processes leading to excessive accumulation of the connective tissue and fibrosis in certain diseases.

Myocardial function and perfusion in the CREST syndrome variant of progressive systemic sclerosis. Exercise radionuclide evaluation and comparison with diffuse scleroderma.

Myocardial function and perfusion were evaluated in 22 patients with progressive systemic sclerosis with the CREST syndrome using exercise and radionuclide techniques, pulmonary function testing, and chest roentgenography. The results were compared with a similar study of 26 patients with progressive systemic sclerosis with diffuse scleroderma. The prevalence of thallium perfusion abnormalities was similar in the groups with CREST syndrome and diffuse scleroderma, (64 percent versus 77 percent), but the defects were significantly smaller in the CREST syndrome (p less than 0.01). Reperfusion thallium defects in the absence of extramural coronary artery disease were seen in 38 percent of patients with diffuse scleroderma. This finding was not seen in any of the patients with the CREST syndrome. In diffuse scleroderma, abnormalities of both right and left ventricular function were related to larger thallium perfusion defects. In the CREST syndrome, abnormalities of left ventricular function were minor, were seen only during exercise, and were unrelated to thallium perfusion defects. Abnormal resting right ventricular function was seen in 36 percent of the patients with the CREST syndrome and was associated with an isolated decrease in diffusing capacity of carbon monoxide. It is concluded that the cardiac manifestations of the CREST syndrome are distinct from those found in diffuse scleroderma. Unlike diffuse scleroderma, abnormalities of left ventricular function in the CREST syndrome are minor and are unrelated to abnormalities of coronary perfusion. Right ventricular dysfunction in the CREST syndrome appears to be primarily related to pulmonary vascular disease.

Serum amyloid A protein concentration in progressive systemic sclerosis (scleroderma).

Serum amyloid A protein (SAA) concentrations were determined in 62 patients with progressive systemic sclerosis (PSS). Forty-seven patients had normal or slightly elevated SAA levels (less than 1000 ng/ml = micrograms/l), while 15 patients had moderately to markedly elevated SAA levels, similar to those observed in active rheumatoid arthritis (RA) (greater than or equal to 1000 ng/ml = micrograms/l). Five patients with PSS had SAA levels corresponding to those observed in amyloidosis secondary to RA. High SAA was associated with more severe skin thickening and diminished cumulative survival at five years. The rarity of amyloidosis secondary to PSS is unlikely to be related to an intrinsic defect in SAA production.

Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations.

Mononuclear cells (MNC) present in the dermis of the forearm and in the blood of patients with progressive systemic sclerosis (PSS) were quantified and analyzed for subsets using monoclonal antibodies. The findings were correlated with cutaneous and systemic features of the disease. Total T lymphocytes and their subsets, B cells, and macrophages were enumerated in the skin samples of 21 patients with PSS. The dermal MNC infiltrates consisted mostly of activated T lymphocytes with a mean T helper/T suppressor (T4/T8) ratio of 2.4 +/- 1.3 SD. Few B1-positive or T6-positive cells (macrophages) were observed. There was no correlation between the skin or blood T4/T8 ratios and the degree of skin thickening. On histologic examination, 58 of 115 (50%) untreated patients with PSS had prominent dermal MNC infiltration. Significant correlations between the degree of MNC infiltration and both the degree (P less than 0.05) and progression (P less than 0.05) of skin thickening were observed. No correlations with other systemic disease features of PSS were noted. These results suggest that cutaneous T lymphocytes may play a role in mediating dermal sclerosis in PSS.

Factors predicting development of renal involvement in progressive systemic sclerosis.

Renal involvement or "scleroderma renal crisis" developed in 60 patients with progressive systemic sclerosis evaluated at the University of Pittsburgh during the period from 1972 to 1982. Forty-seven of these patients had progressive systemic sclerosis with diffuse scleroderma, representing 18 percent of persons with progressive systemic sclerosis and diffuse scleroderma evaluated during this time period. Ten additional patients did not have truncal scleroderma but were suspected of having incompletely developed diffuse scleroderma. Only three patients were classified as having progressive systemic sclerosis with the CREST syndrome. Renal crisis was observed early in the course of the illness, a mean of 3.2 years after onset. During May and June, this complication developed in fewer patients than expected. Thirty-six patients who had diffuse scleroderma and renal involvement after their initial Pittsburgh evaluation were compared with 212 who had diffuse scleroderma without renal involvement during follow-up. The patients with renal involvement had a shorter mean disease duration at the time of their first evaluation (2.4 versus 4.2 years, p less than 0.05) and less frequently had digital pitting scars (29 versus 54 percent), but no other significant clinical, laboratory, or serologic differences were noted. Data available for 31 patients with renal involvement during the six months preceding the onset of renal disease were analyzed. Blood pressure, serum creatinine, urine protein and red blood cells, and plasma renin levels were similar in these patients and the 212 patients without renal involvement. More patients with renal involvement had anemia or clinical evidence of cardiac involvement during this period compared with the patients without renal involvement. During the 12-month period prior to renal involvement, seven of 16 (44 percent) patients with such involvement had an impressive increase in skin thickening on physical examination compared with only 23 of 180 (14 percent) patients without renal involvement at any time during their course. Thus, the subset of patients with diffuse scleroderma who show rapid progression of their skin thickening early in the illness with development of anemia, pericardial effusion, or congestive heart failure have a high risk of "scleroderma renal crisis."

Surface proteins of scleroderma fibroblasts in culture.

Scleroderma skin fibroblasts, as examined by a lactoperoxidase-iodine labeling technique, lack a surface associated protein of apparent molecular weight 120,000 daltons present in normal skin fibroblasts and contain 2 proteins 74,000 and 59,500 daltons, which are absent in normal-fibroblasts. Relative concentrations of several other cell surface proteins also appear to be different in these fibroblasts.

Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis.

Anticentromere antibody (ACA) was found in the serum of 4 (3%) of 120 patients with progressive systemic sclerosis with diffuse scleroderma and in 69 (49%) of 141 with progressive systemic sclerosis with the CREST syndrome variant. The 69 CREST syndrome patients with ACA were compared with the 72 CREST syndrome patients without ACA. The former were older at the onset of symptoms and significantly more frequently female (97% versus 78%, P less than 0.01). Those with ACA more often had telangiectasiae of the digits (93% versus 75%) and calcinosis (55% versus 22%). These differences were also present after the groups were stratified according to duration of disease. Cutaneous involvement was similar in both degree and extent in the 2 groups; 20% of CREST patients both with and without ACA had forearm skin thickening. Pulmonary interstitial fibrosis on chest roentgenogram and restrictive disease on pulmonary function testing were significantly less frequent in the ACA patients. Gastrointestinal involvement, pulmonary arterial hypertension, and cardiac abnormalities were similar in both groups, and there has been no difference in survival between CREST syndrome patients with and without ACA. Tissue typing studies revealed a significant association between ACA and HLA-DR1.

Physiologic abnormalities of cardiac function in progressive systemic sclerosis with diffuse scleroderma.

To investigate cardiopulmonary function in progressive systemic sclerosis with diffuse scleroderma, we studied 26 patients with maximal exercise and redistribution thallium scans, rest and exercise radionuclide ventriculography, pulmonary-function testing, and chest roentgenography. Although only 6 patients had clinical evidence of cardiac involvement, 20 had abnormal thallium scans, including 10 with reversible exercise-induced defects and 18 with fixed defects (8 had both). Seven of the 10 patients who had exercise-induced defects and underwent cardiac catheterization had normal coronary angiograms. Mean resting left ventricular ejection fraction and mean resting right ventricular ejection fraction were lower in patients with post-exercise left ventricular thallium defect scores above the median (59 +/- 13 per cent vs. 69 +/- 6 per cent [P less than 0.025], and 36 +/- 12 per cent vs. 47 +/- 7 per cent [P less than 0.025], respectively). We conclude that in progressive systemic sclerosis with diffuse scleroderma, abnormalities of myocardial perfusion are common and appear to be due to a disturbance of the myocardial microcirculation. Both right and left ventricular dysfunction appear to be related to this circulatory disturbance, suggesting ischemically mediated injury.

Clinical spectrum of connective tissue disease after cosmetic surgery. Observations on eighteen patients and a review of the Japanese literature.

Connective tissue disease has been reported to occur following cosmetic surgery with injection of the foreign substances paraffin and silicone (human adjuvant disease). The clinical findings in 18 such patients and a review of 28 additional cases from the Japanese literature are presented. The patients were classified into 2 major groups: group I consisted of 24 patients with definite connective tissue disease--12 with scleroderma, including 8 with progressive systemic sclerosis (PSS), 6 with rheumatoid arthritis, 5 with systemic lupus erythematosus, and 1 with polymyositis; group II consisted of 22 patients with human adjuvant disease with some symptoms, signs, and laboratory abnormalities suggestive, but not diagnostic of a connective tissue disease. The occurrence of PSS is approximately three-fold greater than expected for all women believed to have undergone such surgery, and PSS developed primarily in individuals injected with paraffin. Prolonged exposure to the injected substance may play a role in the induction of these immunologic disorders.

Pulmonary function in progressive systemic sclerosis. Comparison of CREST syndrome variant with diffuse scleroderma.

The pulmonary function and chest roentgenograms were evaluated in 88 patients with the CREST syndrome variant of progressive systemic sclerosis (PSS or scleroderma). Seventy-two percent of the patients had abnormal pulmonary function. An isolated decrease in diffusing capacity was the most common abnormality noted, followed by restrictive abnormalities and airway obstruction. Chest roentgenograms revealed interstitial infiltrates consistent with pulmonary fibrosis in 33 percent. When compared to a contemporaneous group of 77 patients with PSS and diffuse scleroderma, patients with the CREST syndrome had similar abnormalities on pulmonary function testing and chest roentgenogram. However, patients with the CREST syndrome had a lower mean diffusing capacity despite a higher mean vital capacity; this combination of findings suggests primary pulmonary vascular disease. Calcified granulomata were identified significantly more often in PSS-CREST patients, while superior rib notching occurred exclusively in patients with PSS and diffuse scleroderma. The CREST variant of PSS is associated with frequent roentgenographic and pulmonary function abnormalities similar to those seen in PSS with diffuse scleroderma.