Biomedical subjects
Publications and source records attributed to G P Rodnan.
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.
Fifty-eight patients with progressive systemic sclerosis (PSS) were evaluated clinically and by biopsy of the minor salivary glands of the lips for the presence of Sjögren's syndrome. Clinical findings included dry eyes in 38%, dry mouth in 32%, parotid enlargement in 4%, and an abnormal Schirmer's test in 34%. Histologic changes in lip biopsies included lymphocytic infiltrates characteristic of Sjögren's syndrome in 17 individuals (29%). In 19 (33%) there was periglandular and intraglandular fibrosis (PSS-fibrosis) without significant inflammation, an alteration characteristic of PSS per se. In the remaining 22 patients (38%) with PSS, no abnormality was found. Of those with PSS and Sjögren's syndrome, 53% had serum antibodies to SS-A and/or SS-B, while only 1 patient with a normal biopsy had either of these antibodies. Anti-SS-A and anti-SS-B were not detected in patients with glandular fibrosis alone. The mortality rate of the PSS-fibrosis group was higher due to a variety of severe internal manifestations related to PSS. Antibodies to SS-A and SS-B are useful serologic markers of the presence of Sjögren's syndrome in patients with PSS.
Capillary microscopy was performed on 19 patients with eosinophilic fasciitis. These patients were compared with 13 individuals with progressive systemic sclerosis (scleroderma). Capillary patterns were normal in 16 of 19 (84%) eosinophilic fasciitis patients; 3 exhibited either borderline or nonspecific changes, and none showed a definite scleroderma pattern. In contrast, characteristic nailfold capillary changes, consisting of both dilatation and loss of capillaries, were present in 11 of 13 (85%) scleroderma patients; the remaining 2 showed scleroderma-type abnormalities of only 1 finger and were, therefore, classified as borderline. These results suggest that capillary microscopy may help to distinguish these 2 disorders.
Three different in vitro assays--immunofluorescence with monoclonal anti-T cell reagents, enumeration of T gamma cells, and nonspecific suppressor cell function--were used for the analysis of suppressor lymphocytes in the circulation of 28 patients with progressive systemic sclerosis (PSS, scleroderma) and 20 normal individuals. Both OKT8+ and T gamma lymphocytes were significantly reduced (P less than 0.001 and P less than 0.02, respectively) in patients with PSS compared with controls. The OKT4/OKT8 ratio was increased (P less than 0.02). However, the mean suppressor cell index (SCI) of 1.9 (range 0.4-6.6) for patients with PSS was not significantly different (P greater than 0.05) from the SCI of 2.9 (range 1.2-14) for controls. Eleven of the patients had depressed suppressor cell function as indicated by the index value of less than 1.2. In only 5 of these patients, simultaneously measured T gamma and OKT8+ cells were reduced and OKT4+ lymphocytes were concomitantly increased. There were no significant correlations between the numbers of T gamma or OKT8+ cells and the SCI in patients and controls. Neither depressed suppressor cell function nor the OKT4+/OKT8+ ratio greater than 4.2 (greater than 2 SD of normal) in the patients could be related to other immunologic findings, to disease duration and severity, or to involvement of internal organs. These results suggest that depressed suppressor cell activity and immunoregulatory T cell imbalance in PSS may not be directly related to the pathogenesis of the disease.
This paper reports the experiences of our group with 68 patients with progressive systemic sclerosis (PSS) admitted to hospitals of the University of Pittsburgh Health Center between 1955 and 1981 with scleroderma renal crisis (SRC). The onset of SRC was characterized by four features, namely, onset or aggravation, usually abrupt, of arterial hypertension; appearance of Grade III or IV retinopathy; elevations of peripheral renin activity to at least twice the upper limit of normal; and rapid deterioration of renal function within a period of less than one month. Over 90% of our patients in whom these criteria could be determined had at least three of them present with the onset of SRC. Management of these patients during the first 15 years of this period was uniformly ineffective. Before 1971, no patients lived longer than a year; usual survival ranged from 1 to 3 months. With the advent of renal dialysis and the more effective treatment of severe hypertension, along with the utilization of bilateral nephrectomy in selected anuric patients, some improvement in longevity was achieved. However, only in the past few years have we accumulated a group of 11 patients who have survived for longer than one year. The clinical characteristics of the onset and progression of SRC suggest the sudden imposition of severe stress such as cold or an autoimmune insult affecting vulnerable arteries and arterioles. The renal damage becomes self-perpetuating with extremely high renin activity causing further rise in blood pressure and additional renal and systemic vascular damage. Progress in the last few years seems to have been achieved primarily by the advent of pharmacologic agents that specifically block the effect of angiotensin II by inhibiting the angiotensin I converting enzyme. When diagnosis is prompt and the condition is treated as an emergency with these compounds, we and others have found that normal renal function can be restored in a number of patients. The result is a considerably brighter outlook for patients with this previously rapidly fatal complication of progressive systemic sclerosis.
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.
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.
Fibroblast monolayers were established by explant culture of dermis from seven patients with early, rapidly advancing PSS (scleroderma) and from six normal individuals. Net GAG synthesis was measured as [3H]glucosamine incorporation into the polymer and also as total uronic acid accumulation in the cultures. Cultures from patients with PSS accumulated up to fivefold more GAG than did normal cultures. Evidence suggests that this is a result of increased synthesis rather than decreased degradation. PSS cultures simultaneously accumulated increased amounts of CSP as well as GAG. Data obtained from studies of several monolayers, followed for as many as 10 generations, show that the difference between PSS and normal cultures can be propagated. The total quantity of GAGs was increased in PSS cultures, and there were differences in the distribution of individual GAGs on a percentage basis in PSS and normal cell cultures. GAG, as well as collagen, may be important in the development of connective tissue thickening and induration in scleroderma.
Punch biopsies of skin were obtained from the forearms of 3 patients with progressive systemic sclerosis with diffuse scleroderma before and after treatment for 1 year or more with D-penicillamine. While on therapy, each patient studied had demonstrated a marked reduction in skin thickening. Collagenase-sensitive protein and glycosaminoglycan accumulation were measured in fibroblast cultures derived from these biopsies. No differences were observed pre- and post-treatment. We conclude that although D-penicillamine may exert its effect in vivo on connective tissue synthesis, maturation and/or turnover, fibroblasts remaining in the thinned dermis retain their potential for increased synthesis of connective tissue.
Serum immune complexes were measured in 92 patients with progressive systemic sclerosis, and elevated levels were found as follows: Raji cell assay 72% (59% after pronase treatment of Raji cell), agarose gel electrophoresis 52%, and C1q binding 24%. Forty-three (47%) had abnormal results on two or more of these tests, but only 17 (18%) had normal results by all three assays. Computer-assisted analysis of immune complex results and extensive clinical and laboratory data compiled on these patients revealed that the patients with abnormal Raji cell assays more often had diffuse scleroderma, tendon friction rubs, and positive serum antinuclear antibody tests than did patients with negative results on Raji cell assays. Individuals with immune complexes detected by C1q binding had evidence of pulmonary involvement and positive serum rheumatoid factor more frequently than did patients whose C1q tests were negative.
Serum immune complexes were measured in 22 patients with eosinophilic fasciitis, 8 of whom had serial determinations. Elevated levels were found by Raji cell radioimmunoassay in 14 (64%) patients, by agarose gel electrophoresis in 13 (59%), and by C1q agglutination-inhibition in 9 (41%). Elevated levels by Raji cell assay were present more frequently at times of active disease [17 of 22 sera (77%)] than at times of inactive disease [2 of 24 (8%) (P less than 0.0005)] and were more closely correlated with disease activity than were eosinophilia, hypergammaglobulinemia, or increased erythrocyte sedimentation rate.
Serum eosinophil chemotactic activity was determined by the Boyden chamber technique in 20 patients with eosinophilic fasciitis. Increased eosinophil chemotactic activity (greater than 125% of background) was found in all 20 patients (mean 297% +/- 129), whereas sera of 20 controls with systemic sclerosis and diffuse scleroderma had increased eosinophil chemotactic activity in only 6 (30%) instances (mean 96% +/- 47, P less than 0.001). Although serum eosinophil chemotactic activity decreased over time in all 8 eosinophilic fasciitis patients studied longitudinally, this activity returned to normal in only 3, all of whom received prolonged courses of corticosteroids. Preliminary data suggest the existence of a eosinophilotactic serum factor common to patients with eosinophilic fasciitis.
Patients with progressive systemic sclerosis (PSS; scleroderma) were typed for the HLA-A, -B, and -DR antigens. No significant differences in the frequencies of any HLA-A or -B antigen were found. In the subgroup of patients with PSS and diffuse scleroderma (PSS-DS), the frequency of Bw35 was increased (0.30 vs 0.17 in controls; p less than 0.005, corrected P greater than 0.2). Although patients with PSS-DS also had an increased frequency of DR1 antigen (0.27 vs 0.12 in local controls; P less than 0.005, corrected P less than 0.05), no association between Bw35 and DR1 antigens could be detected. We found no increase in the frequencies of the DR3 or DR5 antigens in patients with PSS. However, in a subset of PSS patients with pulmonary fibrosis, an increase in DR3 and a decrease in DR4 antigens (P less than 0.005) were observed. Serum antibodies to centromere occurred more frequently in DR1-positive than DR/-negative patients (0.46 vs 0.18; P less than 0.005). This study of a large number of patients with PSS failed to confirm previously reported associations of PSS with the HLA-B8/DR3 haplotype of HLA-DR5 antigen.
The sensitivity of peripheral blood lymphocytes to E-type prostaglandin-mediated inhibition of lymphokine secretion was examined in 3 groups of individuals; normal controls, hospitalized patients, and patients with progressive systemic sclerosis (PSS, scleroderma). Leukocytes were stimulated by a polyclonal T-cell activator, phytohemagglutinin, and the release of the lymphokine, leukocyte migration inhibitory factor (LIF), was measured in the presence or absence of exogenous PGE2 using a direct agarose droplet migration inhibition technique. Leukocytes of scleroderma patients were found to be hyporesponsive to E-type prostaglandin (i.e., lymphokine secretion by these cells was not inhibited at concentrations of PGE2 between 2.8 X 10(-8) and 2.8 X 10(-5) M). In addition, a marked sex difference in PGE responsiveness was found to exist among normal controls, whereby females were hyporesponsive during the latter half of the menstrual cycle. It is possible that this deficit may facilitate, in part, the development of connective tissue diseases in women of childbearing age. The inability to suppress lymphokine production and arrest persistent immune reactivity, coupled with the known ability of lymphokines to augment fibroblast collagen production, offers a a reasonable explanation for the accumulation of tissue collagen in scleroderma.
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In a retrospective study on progressive systemic sclerosis, we compared 73 patients who had received D-penicillamine therapy for a minimum of 6 consecutive months with 45 patients who had not received this drug. All patients had diffuse sclerodermatous skin changes and early disease (less than 3-years duration). D-Penicillamine was prescribed for an average of 24 months (range, 6 to 68 months) with a maximum daily dose of 500 to 1500 mg (median, 750 mg). During a mean follow-up interval of 38 months, the degree and extent of skin thickness, determined on physical examination, decreased considerably more in the patients treated with D-penicillamine than in patients in the comparison group (p = 0.07). The rate of new visceral organ involvement was reduced in patients treated with D-penicillamine, especially for the kidney (p = 0.01). Patients treated with D-penicillamine had a greater 5-year cumulative survival rate (88% versus 66%, p less than 0.05). Therapy with colchicine (23 patients) or immunosuppressive agents (26 patients) was not associated with these improvements.
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