Auranofin (SK&F) in early rheumatoid arthritis: results from a 24-month double-blind, placebo-controlled study. Effect on clinical and biochemical assessments.

In a 2-year, randomized, double-blind Nordic multicentre trial, auranofin was compared with placebo in early (disease duration less than or equal to 2 years), active rheumatoid arthritis (RA). Efficacy and safety were analysed in 67 patients receiving auranofin and 65 receiving placebo. Life table analysis demonstrated a significantly higher withdrawal rate due to insufficient therapeutic effect in the placebo group, whereas more patients dropped out due to side effects in the auranofin group. More auranofin than placebo patients (35 vs. 24) completed the 2 years. Clinical and inflammatory activity improved in both groups, but consistently more so in the auranofin group, in spite of the greater consumption of local steroids and NSAIDs in the placebo group. The most frequent side effects leading to withdrawal in the auranofin group were cutaneous and gastrointestinal reactions. The study demonstrated that most patients exhibit improvement in clinical signs and symptoms and about half of all patients with early RA continue to take auranofin for at least 2 years.

Plasma amino acids in rheumatoid arthritis.

Plasma amino acid concentrations have been investigated in 12 female patients with rheumatoid arthritis (RA), who were hospitalized for two 14-day periods, one of which included 7 days of total fasting, whereas the other served as control period with normal food intake. All medical treatment was stopped on admission to the hospital. Plasma amino acid levels were repeatedly determined during both periods. Another group, consisting of 8 healthy volunteers, also underwent total fasting, for 6 days. The response to food deprivation with regard to plasma amino acid levels was compared with that in the RA patients. The results obtained from the control period were compared with those derived from age and sex matched healthy controls. RA disease was not characterized by a typical amino acid pattern. Major increases were seen in the concentrations of taurine, aspartate, glutamate, glycine, 1-methyl histidine, isoleucine and arginine. Rather smaller yet significant elevations could be observed in the levels of cystein, threonine, serine, citrulline, methionine and leucine. The only amino acid to show a lowered concentration was alpha-aminobutyrate. Most of the alterations induced by fasting were similar to those in healthy volunteers. An exception was the levels of taurine, which evidenced in RA patients a further increase during starvation, not observed in healthy volunteers, and valine which exhibited, a smaller increment than that apparent in healthy controls. The increase in sulphur-containing amino acids might be interpreted as a sign of an enhanced glutathione (GSH) catabolism, whereas the differing metabolic behaviour of branched chain amino acids (BCAA) suggests a specific reaction of valine in RA disease, similar to that in other catabolic diseases.

Cyclic nucleotides and catecholamines in rheumatoid arthritis.

A controlled cross over study on the effect of fasting on cyclic nucleotide and catecholamine excretion was carried out in 12 female RA patients. They were hospitalized during a control and fasting period. The fasting period started with 3 days of habituation to hospital conditions, followed by 7 days of total fasting. Thereafter followed 3 days of realimentation. The control period was in every respect identical with the fasting period, with the exception of food intake. All medication was stopped when the patients were admitted to the hospital. The urinary concentrations of cAMP, cGMP, E and NE were monitored daily. The clinical status of the subjects was evaluated every second day using Ritchie's clinical index. Clinical and laboratory measures of inflammatory activity remained unaltered during the control period, but improved significantly during fasting. Excretion of cAMP and cGMP was low during the control period when compared with published normal levels. The cAMP/cGMP ratio in urine was normal, however. The urinary levels of E and NE were normal in the control period, but increased significantly during fasting. Excretion of cAMP decreased during fasting, while urinary cGMP levels decreased initially, but rose to prefasting levels towards the end of the fast. The cAMP/cGMP ratio increased during the first days of the fast, with a maximum on days 2 and 3. This increment coincided in time with the greatest rate of improvement in clinical joint activity.

Cyclic nucleotides in rheumatoid arthritis.

Cyclic 3',5'-adenosine monophosphate (cAMP) and cyclic 3',5' guanosine monophosphate (cGMP) may influence important regulatory mechanisms in the rheumatoid inflammatory process. It has been claimed that fasting improves the condition of the patient with rheumatoid arthritis (RA). The present study was designed to measure cAMP in plasma and urine cGMP in urine in medically untreated RA patients. 12 female patients were investigated in a cross-over study during a control and a fasting period. They received no other drugs than analgesics during these periods. Levels of plasma and urinary cAMP found during the control period were somewhat lower than previously reported. However, the ratio cAMP/cGMP in urine was 10 to 1 which is reported to be normal. Clinical and laboratory variables of inflammatory activity were significantly improved during the 7-day fasting period. The ratio of cAMP/cGMP in urine was significantly increased on days 2-4 and coincided in time with the maximum of clinical improvement. Cyclic AMP concentrations were lowered both in plasma and urine during fasting. This is in contrast to fasting in normal and obese subjects reported in previous studies.

The effect of fasting on plasma cyclic adenosine-3', 5'-monophosphate in rheumatoid arthritis.

Cyclic adenosine-3', 5'-monophosphate (cAMP) may influence important mechanisms in the inflammatory process, and fasting has been claimed to be clinically beneficial in rheumatoid arthritis (RA). A study was therefore designed to measure the concentrations of plasma cAMP in RA patients not undergoing drug treatment during a control and a fasting period. Twelve female RA patients were hospitalized for two 14-day periods and investigated in a crossover study. Clinical and laboratory variables of inflammatory activity were assessed during both periods. During the control period the concentrations of cAMP in plasma were slightly below the lower normal limit, with no significant change throughout the period. The clinical and laboratory variables of inflammatory activity were unchanged during the same period. In the fasting period, the prefasting level of plasma cAMP was significantly higher than on the corresponding day in the control period. During 7 days of total fasting the plasma cAMP concentrations decreased significantly. The clinical and laboratory variables of inflammatory activity decreased significantly from the start to the end of fasting. High prefasting plasma cAMP concentrations were associated with improvement in clinical inflammatory activity. A decrease in plasma cAMP concentrations during fasting in RA patients is in contrast to the findings in obese and healthy subjects previously reported.

Cyclic nucleotides in joint fluid in rheumatoid arthritis and in Reiter's syndrome.

Levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) have been investigated in joint fluid in inflammatory arthropathies. A disturbed balance between cAMP and cGMP due to a depressed level of cAMP was found in rheumatoid arthritis (RA) and Reiter's syndrome, in comparison with patients with osteoarthritis. No correlation could be demonstrated between the absolute levels of cAMP or cGMP and the degree of local inflammatory activity, white cell count, or lysosomal enzyme activity in the joint fluid. Intra-articular injection of epinephrine showed just as good an effect on local pain as betamethasone (Cellestona), but the steriod reduced the swelling more effectively. An increase in intracellular levels of cAMP at 20 min was observed following injection of epinephrine with a slight change in cGMP. Intra-articular injection of dibutyryl-cAMP (db-cAMP) produced a marked easing of local pain and swelling in each of the 4 patients so treated. It is concluded that stimulation of the beta-adrenergic system or injection with db-cAMP may be beneficial in rheumatoid inflammation.

Levels of prostaglandins F2 alpha and E2 and thromboxane B2 in joint fluid in rheumatoid arthritis.

Prostaglandin F2 alpha (PGF2 alpha), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) levels were determined by radioimmunoassay (RIA) in knee joint fluid in two groups of patients with classical or definite rheumatoid arthritis (RA). One group had no treatment for one week prior to the study. The second group consisted of patients who developed acute exudative arthritis despite the use of various non-steroidal anti-inflammatory drugs (NSAID). The main metabolites of PGF2 alpha in plasma and urine were measured in the untreated group. The conclusion to be drawn from this study are: 1) Treatment with NSAID effectively lowers PGF2 alpha and PGE2 and TXB2 levels in joint fluid. 2) Signs and symptoms of arthritis may persist in spite of lowered levels of PGF2 alpha and PGE2 in the joint fluid. 3) The main metabolites of PGF2 alpha in plasma and urine are above the low-normal limit in untreated patients. 4) The ratio TXB2/PG was low in untreated patients, suggesting that the thromboxane pathway is quantitatively minor in rheumatoid joint inflammation.