A long-term five-year randomized controlled trial of hydroxychloroquine, sodium aurothiomalate, auranofin and penicillamine in the treatment of patients with rheumatoid arthritis

OBJECTIVE: To compare the efficacy of hydroxychloroquine, penicillamine, sodium aurothiomalate and auranofin in the treatment of active rheumatoid arthritis over a period of 5 yr. METHOD: Five hundred and forty-one patients with definite or classical rheumatoid arthritis were entered into an open randomized controlled trial with a flexible dose regimen designed to reflect clinical practice. Decisions to stop treatment with any one of the disease-modifying anti-rheumatic drugs (DMARDs) were based on an agreed trial protocol which defined criteria for adverse reactions and therapeutic failure. The managing physicians' decisions were confirmed in a separate monitor clinic. RESULTS: The proportion of patients who remained on their first DMARD or who were in remission at 5 yr was 53% for penicillamine, 34% for sodium aurothiomalate, 31%, for auranofin and 30% for hydroxychloroquine (P < 0.001). In patients who stayed on their first DMARD, all groups showed a 30-50% improvement in C-reactive protein, erythrocyte sedimentation rate, Ritchie Index and joint stiffness, and a deterioration in their Larsen score. There was no evidence of physician bias to explain the larger proportion of patients remaining on penicillamine for 5 yr. CONCLUSION: Despite the increased popularity of sulphasalazine and inmmunosuppressives, the drugs in this study continue to be used worldwide. The natural history of rheumatoid arthritis requires long-term follow up to establish drug efficacy. Evidence is needed as to whether the newer regimens will prove to be more effective and safer in the longer term than the commonly prescribed DMARDs. The data from this trial will provide a reference for comparison with future studies.     

Institute of Rheumatology and progress of antirheumatic therapy

The paper deals with the achievements of the Institute of Rheumatology in antirheumatic therapy, among them there are methods of objective assessment of antirheumatic drugs, the first use of antimalarials in the treatment of chronic rheumatic fever, discovery of immunodepressive properties of these drugs, specification of the mechanism of action of several NSAIDs. Antilymphocytic globulin, salazopyridazine and the alkylating drug dopan were used for the first time in therapy of rheumatic diseases. Administration of the most potent NSAIDs diclofenac or indomethacin to patients with acute rheumatic fever proved to be as effective as prednizolone. Special attention is paid to the combination treatment of rheumatoid arthritis with NSAIDs. The concurrent administration of aurannofin and methotrexate was shown to cause a more rapid development of clinical improvement than monotherapy with either drug. A combination of gold aurothiomalate and hydroxychloroquine and that of low doses of D-penicillamine and cyclophosphamide had no advantages over monotherapy. Revealing the therapeutical potential of antibodies to interferon-gamma in the treatment of rheumatic arthritis and psoriatic arthritis was the most important achievement of recent years. These studies open new vistas for anticytokine treatment of rheumatic diseases.     

Effect of postexercise carbohydrate supplementation on muscle glycogen repletion in trained sled dogs

OBJECTIVE: To evaluate the effect of immediate postexercise carbohydrate supplementation on muscle glycogen (MG) repletion during the first 4 hours of recovery in sled dogs. ANIMALS: 24 Alaskan Huskies. PROCEDURE: Dogs were assigned to 1 of 3 treatment groups, and a muscle biopsy specimen was obtained 1 hour before and immediately (group A) or 4 hours (groups B and C) after a 30-km run. Immediately after exercise, dogs in group A and group C were given water; dogs in group B were given a glucose polymer solution (1.5 g/kg of body weight) in water. RESULTS: At 4 hours after exercise, MG concentration was significantly greater in group-B than in group-C dogs; the value in group-C dogs was not different from the value in group-A dogs immediately after exercise. Assuming similar rates of glycogen depletion between treatment groups, during the first 4 hours of recovery, group-B dogs replaced 49% of the glycogen used during exercise. Plasma glucose concentration was significantly greater in group-B than in group-A and group-C dogs at 100 minutes after exercise. CONCLUSIONS: Immediate postexercise carbohydrate supplementation in sled dogs leads to increased glucose concentration, which in turn promotes more rapid rate of MG repletion in the first 4 hours of recovery than is observed in dogs not given supplements. CLINICAL RELEVANCE: For dogs running in multiple heats on a single day or over several consecutive days, immediate postexercise carbohydrate supplementation may promote more rapid and complete recovery between bouts of exercise.     

A new approach to assessing rheumatoid arthritis (RA) disease activity using the American College of Rheumatology core set of disease activity measures for RA trials--a multi-center study

To characterize the American College of Rheumatology core set of disease activity measures for rheumatoid arthritis (RA) clinical trials (ACR core set measures) and the ACR definition of improvement of RA (ACR improvement definition), we studied 42 Japanese patients with active RA who were treated with DMARDs including mizoribine. Each patient's disease activity was assessed at the time of enrollment to the study and after 24 weeks using the ACR core set measures as well as the physical global assessment through the conventional measures. Twenty-five (60%) patients were discerned as showing improved by physicians through the conventional measures. This decision appeared to be based on improvement in Lansbury activity index (LAI) and C-reactive protein (CRP) value. Twelve of the 25 "improved" patients satisfied the ACR improvement definition. The 12 patients showed significant improvement in "outcome" measures including patients assessments of pain, disease activity, and physical function, compared to the 30 patients not satisfying the ACR definition. However, no significant differences were observed between these two groups in "process" measures including LAI, tender joint count, swallen joint count, or CRP value. In conclusion, the ACR core set measures including both process and outcome measures have potential to reflect clinical important changes on "real life" of patients with RA.     

Clinical and radiographic outcomes of rheumatoid arthritis patients not treated with disease-modifying drugs

OBJECTIVE: To compare the radiographic and clinical features of rheumatoid arthritis (RA) patients who were not given disease-modifying antirheumatic drugs (DMARDs) with those of RA patients who were followed up and treated with DMARDs at a rheumatology clinic. METHODS: The population of this case-control study includes a series of RA patients who immigrated to Israel from the previous Union of Soviet Socialist Republics and who were treated only with nonsteroidal antiinflammatory drugs. Control patients who were followed up and treated with DMARDs at our rheumatology clinic were matched by sex, disease duration, number of actively inflamed joints, and the presence of serum rheumatoid factor. The outcome measures were the number of deformed and radiographically damaged joints. Radiographic damage was evaluated by the methods of Steinbrocker and Sharp. RESULTS: The study population consisted of 22 RA patients (15 women, 7 men) who were not treated with DMARDs and 22 patients (15 women, 7 men) who were treated with DMARDs. The mean disease duration was 16.2 years for the study patients and 14.3 years for the controls. Compared with the matched controls, RA patients who were not treated with DMARDs were found to have a significantly higher mean number of deformed joints (13.8 versus 7.2), a higher mean number of damaged joints (24.4 versus 15.5), and a higher overall damage score by the Sharp criteria (146.1 versus 65.7). CONCLUSION: RA patients who were not given DMARDs had a 1.57-fold increased number of radiographically damaged joints and a 2.22-fold increased overall Sharp damage score compared with patients who were treated with second-line agents.     

Auranofin inhibits the induction of interleukin 1 beta and tumor necrosis factor alpha mRNA in macrophages

Gold compounds are widely used in the treatment of rheumatoid arthritis, but their mechanisms of action remain unclear. We demonstrate here that auranofin (AF) (0.1-3 microM), but neither the hydrophilic gold compounds aurothiomalate (ATM) and aurothioglucose nor methotrexate or D-penicillamine, inhibits the induction of interleukin 1 beta and tumor necrosis factor (TNF) alpha mRNA and protein by either zymosan, lipopolysaccharide (LPS), or various bacteria in mouse macrophages. The auranofin-mediated inhibition of the induction of TNF-alpha mRNA was stronger than that of interleukin (IL) 1 beta mRNA. AF, but not the other drugs, also inhibited zymosan-induced mobilization of arachidonate. The fact that AF inhibited the induction of mRNA for both these proinflammatory cytokines, irrespective of which stimulus was used, may indicate that it affects some common signal transduction step vital to their induction.     

A comparison of two surgical techniques for preparation of rats with chronic bile duct cannulae for the investigation of enterohepatic circulation

Two surgical biliary cannulation procedures for study of enterohepatic circulation in chronically cannulated rats were compared in a randomized study. Control rats (group A) had only a jugular vein cannula and no laparotomy, whereas experimental group-B rats additionally had the bile duct cannulated at two locations, one for collecting bile from the liver and the other for returning bile into the duodenum. Experimental group-C rats had the jugular vein cannula as well as the bile duct cannula for collecting bile, but the duodenal wall was cannulated for returning bile to the intestine. Several physiologic and biochemical indicators were monitored daily after surgery, including body weight, bile flow rate, and plasma concentrations of bilirubin and creatinine, and activities of glutamate-pyruvate transaminase (GPT) and lipase. Overall duration of survival of group-B rats was shorter than that of group-A rats (P < 0.05), whereas no difference was found between groups A and C. Group-B rats had higher bilirubin concentration than did controls (P < 0.05), whereas group-C rats did not. Group-B rats had higher plasma lipase activity than did rats of the other two groups, and this analyte was more variable in group-B rats. Rats of groups B and C had high GPT activity after surgery (P < 0.05). A statistically significant loss of body weight was associated with group-B rats over 8 days after surgery and for group-C rats over 2 days after surgery, after which body weight stabilized in group-C rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Herring lateral pillar classification for prognosis in Perthes disease. Late results in 49 patients treated conservatively

We reviewed the radiographs of 49 patients with Perthes' disease at the stage of fragmentation and also after the end of skeletal growth to assess the value of the lateral pillar classification of Herring. The average age of the patients at diagnosis was 7 years 6 months and the mean follow-up was 24 years. Ten of the 11 Herring group-A hips showed good reconstruction of the femoral head. There were good results in group-B hips when the patients were less than nine years of age at diagnosis. All 11 group-C patients showed hip deformity at follow-up. The Herring classification provides a valid long-term prognosis in Perthes' disease, although age at diagnosis is also an important prognostic factor. The classification is relatively easy to apply, is reliable, and requires only an anteroposterior radiograph taken during the fragmentation stage of the disease.     

Adverse reactions to D-penicillamine after gold toxicity

The incidence of adverse reactions to D-penicillamine in 155 patients with rheumatoid arthritis was analysed and compared with their history of adverse reactions to gold. Out of 125 patients who took only D-penicillamine, 45 developed side effects from the drug, whereas of 27 patients with a history of gold toxicity, 18 also reacted adversely to D-penicillamine. All patients who took D-penicillamine within six months after an adverse reaction to gold developed side effects from D-penicillamine. Fourteen patients developed similar adverse reactions to D-penicillamine and gold, and the interval between treatments in this group was significantly shorter (p less than 0.01) than in those who developed either differing adverse reactions to both drugs or no reaction to D-penicillamine after treatment with gold. An interval exceeding six months between treatment with gold and treatment with D-penicillamine in patients who have developed adverse reactions to gold apparently reduces the risk of adverse reactions to D-penicillamine.     

Spinal clonidine fails to provide surgical anesthesia for transurethral resection of prostate. A dose-finding pilot study

To investigate the effects of disease modifying antirheumatic drugs (DMARDs) and DEX on production of IL-1 beta, IL-6 and TNF-alpha, synovial cells were observed after IL-1 beta administration in vitro. Materials and Methods: Synovial tissue was obtained aseptically from 8 rheumatoid arthritis patients during joint surgery. The dissected tissue was treated with collagenase and adherent cells were passaged before using as samples. They were stimulated with IL-1 beta (1 ng/ml) and cultured with DMARDs and DEX in serum-free media. After 24 hours' incubation, the production of IL-1 beta, IL-6 and TNF-alpha in the supernatants was measured. Results: DEX inhibited the production of IL-6. GST inhibited the production of IL-1 beta and IL-6. Conclusion: DEX and GST may modulate the disease activity by inhibiting the cytokine production from synovial cells.     

Pharmacokinetics, enantiomer interconversion, and metabolism of R-apomorphine in patients with idiopathic Parkinson''s disease

Disease-modifying antirheumatic drug (DMARD) therapy is now clearly accepted as the primary treatment for rheumatoid arthritis, with an increasing emphasis on use of combination therapy. Data on combination therapy have highlighted the difficulties in performing these studies and the large number of patients required to produce meaningful results. Combination studies have focused on use of rapidly decreasing high-dose steroids as a part of the combination and emphasize the importance of using patients with early rheumatoid arthritis. Even with relatively aggressive use of DMARDs, the majority of patients develop erosions. Adverse reactions to DMARDs continue to concern clinicians, although evaluation of the frequency of these events has led to a reappraisal of previously accepted monitoring strategies in some cases. For example, it may not be cost-effective to subject patients on antimalarials to regular review by an ophthalmologist because of the low frequency of serious eye defects. Studies have also identified risk factors for the development of pulmonary toxicity in association with methotrexate. That DMARDs are effective in treating rheumatoid arthritis is beyond question-just how effective they are and what combinations of DMARDs will show improved efficacy will provide data for the next annual review.     

Double-blind study of a multivitamin complex supplemented with ginseng extract

To remedy the deterioration in quality of life in large cities, the addition of ginseng root extract to a multivitamin base appears to produce a promising dietary supplement. The aim of the present study was to compare the quality-of-life parameters in subjects receiving multivitamins plus ginseng with those found in subjects receiving multivitamins alone. The study was comparative, randomized and double-blind, and it involved 625 patients of both sexes divided into two groups taking one capsule per day for 12 weeks. Group A received vitamins, minerals, trace elements and ginseng extract G115 (Pharmaton Capsules) while group B received vitamins, minerals and trace elements (multivitamin capsules) only. The resulting quality-of-life was assessed by a standardized 11-item questionnaire, validated by the Medical School of the National Autonomous University of Mexico (UNAM). Of the 625 patients recruited, 124 were excluded from the study due to lack of compliance with the treatment, so that 338 patients in group A and 163 patients in group B completed the study. By the end of the study, the 4th of the monthly assessments showed that both the group-A and the group-B treatments had induced a significant increase in the quality-of-life index, the change being 11.9 points for Pharmaton Capsules in group A which was significantly superior to the 6.4 average increase with the group-B capsules containing multivitamins alone. Group A showed significant improvement in every one of the 11 questionnaire items, whereas group B did not show significant improvement in any of these items. Significant increases in body weight and in diastolic blood pressure were recorded in the group B treated with the multivitamin alone. Adverse effects of the capsules were minimal in both groups. This study has demonstrated that Pharmaton Capsules were more effective than the multivitamin capsules alone in improving the quality-of-life in a population subjected to the stress of high physical and mental activity.     

Hepatic manifestations of Wilson's disease: frequency and pattern in Saudi patients

Seven symptomatic patients with Wilson's disease have so far been diagnosed at King Khalid University Hospital (KKUH), Riyadh, over the last six years. On family screening, another three asymptomatic patients were found to be affected. Five of the symptomatic patients had clinical features of liver disease on initial presentation and was preceded by renal dysfunction in another patient. The remaining patient presented with neurological features. Six patients had Kayser-Fleisher ring. Abnormal liver function tests were found in half of the patients. Ceruloplasmin was reduced in 7 of 10 patients. Serum copper and urinary copper estimations were most useful diagnostic laboratory tests. Morphological alteration was found in all 9 patients who had a percutaneous liver biopsy. All patients were treated initially with D-penicillamine and clinical response was noted in seven, of whom one developed neurological manifestations while receiving the treatment. D-penicillamine was replaced by zinc sulfate in 3 patients who developed thrombocytopenia. The data suggest that Wilson's disease may not be rare in Saudi Arabia. For early detection and prompt treatment, the disease should be suspected under appropriate clinical circumstances especially in young patients with liver diseases. Close relatives of such index patients should be routinely screened.     

Effect, on renal function, of a product rich in polyunsaturated fatty acids: results obtained in subjects with chronic renal failure caused by nephroangiosclerosis

Subjects with renal chronic failure were studied. Four patients were treated with 2,5 mg/Kg of phosphatidylcholine, a drug with an high content of polyunsatured fatty acids. The drug's effects, studied during three successive 30 min. Clearance periods, were the same as in healthy subjects, i.e.: a statistically significant increase of: urine flow, renal blood flow, glomerular filtration rate and sodium excretion. In other 6 patients, administration of i.v. lysine acetylsalicylate (10,5 mg/Kg) caused a decrease of the parameters under study, that were increasing for a previous dose of phosphatidylcholine and made ineffective another administration of this drug. If the thesis is assumed that in normal subjects phenomena may be referred to the local synthesis of PG, then the authors believe that the potential synthesis capacity of these substances is not compromised in chronic renal failure.     

Sex differences in energy intake and expenditure

Four patients with rheumatoid arthritis developed heavy proteinuria after five to 12 months of treatment with D-penicillamine. Light microscopy of renal biopsy samples showed minimal glomerular capillary wall thickening and mesangial matrix increase, or no departure from normal. Electron microscopy, however, revealed subepithelial electron-dense deposits, fusion of epithelial cell foot processes, and evidence of mesangial cell hyperactivity. Immunofluorescence microscopy demonstrated granular capillary wall deposits of IgG and C3. The findings were similar to those in early membranous glomerulonephritis, differences being observed however in the results of staining for the early-acting complement components C1q and C4. It is tentatively concluded that complement was activated by the classical pathway.     

Transfection of the gene for B7-1 but not B7-2 can induce immunity to murine malignant mesothelioma

A 56-year-old female with rheumatoid arthritis was admitted because of bilateral hip pain. In a few months of her hospitalization, a relatively abrupt renal dysfunction was emerged besides complement breakdown, and renal biopsy revealed crescentic glomerulonephritis. Immunofluorescence study showed peripheral granular deposits of IgG, IgM, and C3 in the glomeruli. Cresents were predominantly composed of macrophages and glomerular epithelial cells. Amyloid nephropathy, renal vasuculitis, and association of other collagen vascular diseases were negligible for the causative factor. It was suggested that immune complexes were formed in the glomeruli, in which both humoral and cellular immune responses were to be induced, that brought cescents formation in the lesions. Crescentic glomerulonephritis in patients with rheumatoid arthritis is rare and a possible pathogenetic mechanisms involved in the development of renal dysfunction are discussed with the special reference to immune complex-induced inflammation.     

Prognostic value of progressive decrease in serum cholesterol in predicting survival in Child-Pugh C viral cirrhosis

BACKGROUND: The identification of cirrhotic patients with low life expectancy is an open clinical problem. Hypocholesterolemia is frequently found in severe chronic hepatic insufficiency because the liver is the most active site of cholesterol metabolism, but poor information is available on its precise prognostic value. We evaluated the prognostic role of hypocholesterolemia in patients with advanced liver cirrhosis. METHODS: Serial serum cholesterol concentrations of 34 patients with virus-induced cirrhosis, from the first appearance of Child-Pugh class C to death, were considered. To compare survival functions, we established three base-line cholesterol cut-off points (150, 125, and 100 mg/dl) and stratified patients into groups A and B, with base-line cholesterol levels lower and higher than each cut-off value, respectively. RESULTS: Cholesterolemia decreased progressively in all patients. At the 100 mg/dl cut-off point all group-A patients died within 17 months, whereas 75% of group-B patients were alive at 24 months (P < 0.0001). Moreover, cholesterolemia was significantly correlated with cholinesterase, indirect bilirubin, and total bilirubin at entry time and immediately before death. No correlation was observed between cholesterol and these variables when stratified for the Child-Pugh score. CONCLUSIONS: Base-line serum cholesterol levels lower than 100 mg/dl identify a subgroup of Child-C cirrhotic patients with high mortality risk within a 2-year follow-up. The prognostic importance of cholesterolemia may also be deduced by the significant correlation with other well-established indicators of survival.     

Viability in human heart valves prepared for grafting

Oral administration of synthetic D-penicillamine to rats induces alterations of the renal mesangium, apparently without involvement of immune mechanisms. Alterations of mitochondria, especially enlargement, were seen in the proximal tubular epithelium. These results are discussed in the light of recent findings in "penicillamine" nephritis and diseased human kidneys in general.     

Exacerbation of congestive heart failure after administration of polyethylene glycol-electrolyte lavage solution

OBJECTIVE: To report a patient with exacerbation of congestive heart failure after administration of polyethylene glycol-electrolyte lavage solution (PEG-ELS). METHODS: A MEDLINE search was performed, using the terms congestive heart failure (CHF), gastric lavage, colonoscopy, irrigation, and gastroparesis, of English-language articles published from January 1980 through January 1995, as well as review of pertinent articles' bibliographies. CASE SUMMARY: A 45-year-old white woman with left ventricular systolic dysfunction and diabetic gastroparesis received 4 L of a PEG-ELS as preparation for colonoscopy. Within 24 hours she presented to the emergency department with shortness of breath and increased bilateral lower extremity edema. She was admitted and treated with intravenous furosemide therapy. After aggressive diuresis her symptoms returned to baseline and she was discharged. DISCUSSION: The literature search revealed no report of a patient requiring hospitalization as a result of sodium and water retention after bowel preparation with PEG-ELS. CHF is not considered a contraindication to the use of this solution; however, most studies that included patients with heart failure did not describe the degree of left ventricular dysfunction. Our patient's severe CHF, in combination with chronic renal insufficiency, resulted in significant retention of sodium and water. CONCLUSIONS: Patients with severe left ventricular dysfunction and chronic renal insufficiency who are being considered for procedures that necessitate bowel cleansing with PEG-ELS may be at risk for sodium and water retention and exacerbation of CHF.     

Nonoliguric acute renal failure associated with a low fractional excretion of sodium

Measurement of the fractional excretion of sodium has been recommended as a useful clinical tool in evaluating acute renal failure. Six patients with nonoliguric acute renal failure had a fractional excretion of sodium less than or equal to 1.0%; these patients had severe liver dysfunction, which suggested a sodium-avid state. A review of the literature showed that in patients with other sodium-avid states (congestive heart failure, nephrotic syndrome, and burns) the fractional excretion of sodium was frequently less than or equal to 1.0%. The fractional excretion of sodium is thus a less useful diagnostic test in patients whose clinical state makes them sodium avid.