Gerald P. Rodnan

D-Penicillamine Therapy in Progressive Systemic Sclerosis (Scleroderma): A Retrospective Analysis

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.

Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma).

Severe pulmonary hypertension without pulmonary fibrosis occurred in 10 patients with the CREST syndrome (calcinosis, Raynauds phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), reputedly a benign variant of progressive systemic sclerosis. Time from the initial symptom, Raynauds phenomenon, to the recognition of pulmonary hypertension was as long as 40 years. Pulmonary hypertension and increased pulmonary vascular resistance was shown in all patients. Autopsy examination in three of six deaths attributable to pulmonary hypertension showed intimal proliferation with myxomatous change in the small- and medium-sized pulmonary arteries similar to changes in the digital arteries of patients with scleroderma and Raynauds phenomenon, and interlobular renal arteries of those with scleroderma kidney. It is concluded that the CREST syndrome is not entirely benign but may be complicated, after a long clinical course, by progressive pulmonary vascular obliteration, pulmonary hypertension, and death in the absence of significant pulmonary fibrosis.

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.

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.

The Association of Progressive Systemic Sclerosis (Scleroderma) with Coal Miners' Pneumoconiosis and Other Forms of Silicosis

Excerpt Progressive systemic sclerosis (PSS or scleroderma) occurs in men engaged in many kinds of work, and until recently there has been little reason to suspect that this disease might be prefer...

Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases.

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.

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 Raynauds 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.

Effects of food, fast and alcohol on serum uric acid and acute attacks of gout

Abstract The interrelationship of the effects of brief periods of fasting and of alcohol on uric acid metabolism has been investigated in nine gouty patients and in two normouricemic subjects. There were appreciable elevations in serum urate concentration after one and two day fasts, which were accompanied by increases in both serum beta-hydroxybutyrate and blood acetoacetate. The rise in serum urate could be accounted for in most cases by a diminution in the urinary output of uric acid, which was presumably the result of inhibition, by the elevated ketone levels, of urate excretion by the tubules. The administration of from 68 to 100 gm. of ethyl alcohol together with a low purine diet produced only minor changes in serum urate levels and urinary excretion of uric acid. Larger doses of alcohol (112 to 135 gm.) given with food led to significant increases in blood lactate concentration, diminution in urinary uric acid output and hyperuricemia. When the same (smaller) amounts of alcohol which had been found to be without effect on serum urate levels were taken during brief periods of fasting, there was an elevation in serum urate levels which was slightly greater than that observed after fasting alone. This was accompanied by greater increases in blood lactate than observed after the administration of alcohol with food, and greater increases in serum beta-hydroxybutyrate than observed after an equivalent period of fasting alone. It appears that the combination of fasting and ethyl alcohol may be additive or mutually potentiating with respect to the effects of each of these factors on uric acid metabolism. Eight of the nine patients experienced one or more acute attacks of gout during the course of these studies. In the majority of cases the onset of the attack appeared to be related to rapid fluctuations in serum urate levels induced by fasting or by fasting together with alcohol ingestion. Serum urate levels tended to remain stable during and immediately after these attacks, giving little or no indication of the changes which had preceded the onset of acute gouty-arthritis. Although treatment with probenecid in two cases produced the expected uricosuria, it did not prevent the increase in serum urate induced by fasting and alcohol. The patient with gout should be cautioned to avoid prolonged fasting and other situations which produce rapid changes in serum urate concentration. However, our gouty patients do not go out to fast, but to drink. Unfortunately the alcoholic bout often continues in the absence of food, thus resulting in a combination of metabolic changes which often lead to an acute attack.

Thyroid disease in progressive systemic sclerosis: increased frequency of glandular fibrosis and hypothyroidism.

A series of patients with fatal progressive systemic sclerosis was reviewed with regard to pathologic, clinical, and serologic evidence of thyroid disease. Histologic evidence of severe fibrosis of the thyroid gland was found significantly more frequently in 56 progressive systemic sclerosis cases (14%) compared to an age and sex matched control autopsy series (2%) from the same institution. Based on determination of serum free thyroxine, free triiodothyroxine (T3), thyroid stimulating hormone, and reverse T3, 27 patients were classified as euthyroid (11), euthyroid sick (9), and hypothyroid (7). Patients with hypothyroidism more frequently had subcutaneous calcinosis. Raynauds phenomenon, esophageal hypomotility, sclerodactyly, and multiple telangiectasias (the CREST syndrome variant of progressive systemic sclerosis); all thyroid glands from the hypothyroid patients had fibrosis, but lymphocytic infiltration was an infrequent finding. Six hypothyroid patients had high titers of serum antithyroid antibodies, suggesting autoimmune thyroid disease. Thyroid gland fibrosis and hypothyroidism, possibly of autoimmune pathogenesis, are thus frequent and often unsuspected findings in progressive systemic sclerosis.

Quantitative measurement of gastrointestinal blood loss: I. The use of radioactive Cr51 in patients with gastrointestinal hemorrhage

Abstract 1.1. A method for quantitating the amount of blood lost in the feces by means of erythrocytes labeled with radioactive sodium chromate is described. The maximum amount of blood lost by normal subjects is 1.2 ± 0.5 ml., with a range of 0.3 to 2.0 ml. of whole blood per day. 2.2. The sensitivity of the qualitative benzidine dihydrochloride test to hemoglobin in aqueous solution has been compared with the sensitivity to hemoglobin in homogenized stools. It was found that the sensitivity of the test was approximately 100 times greater for hemoglobin in aqueous solution than for hemoglobin present in the stools. 3.3. The use of the Cr 51 technic for quantitating blood loss from the gastrointestinal tract, combined with intestinal intubation for localizing the level of bleeding, has been tested in nine cases in which there was difficulty either in establishing that the anemia was due to blood loss or in localizing the level of bleeding by x-ray studies. In eight of the nine cases these technics were of aid in arriving at the correct diagnosis. In one case the interpretation of the Cr 51 and intubation data was not substantiated by the findings at operation.