Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis.

The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radiological joint damage in rat adjuvant arthritis (AA) and on urinary collagen cross-link excretion in patients with RA. In the animal study, adjuvant arthritis was induced in male Lewis rats. From day 7 onward, high-dose TEA (500 mg/kg body weight, once daily) or placebo was administered orally. Study groups consisted of TEA-treated normal rats (C + TEA), placebo-treated normal rats (C + plac), AA rats treated with TEA (AA + TEA) or with placebo (AA + plac). To monitor joint destruction, urinary collagen cross-link excretion (pyridinoline, HP; deoxypyridinoline, LP) was measured by high-performance liquid chromatography at days 14 and 21. Radiological evaluation of joints was performed at day 21. In the patient study, TEA was administered to nine patients with RA as adjuvant medication (approximately 20 mg/kg body weight, three times daily) for 12 weeks. Urinary HP and LP excretion levels were measured before and during TEA treatment, and 4 weeks after the cessation of TEA treatment. In AA + TEA rats, a significant reduction of HP and a tendency towards a reduction of LP excretion were found compared with AA + plac rats (P < 0.05), at day 14, whereas the HP/LP ratio did not change. No difference was observed in HP, LP excretion, HP/LP ratio and radiological damage score between the TEA- and placebo-treated AA rats at day 21. In RA patients, a significant reduction of HP and LP excretion was found during the TEA treatment period (P < 0.05). After the cessation of TEA treatment, HP and LP excretion increased towards baseline levels. No effect on disease activity was observed. The plasmin antagonist TEA reduced the excretion of collagen pyridinoline cross-links in both experimental and rheumatoid arthritis. As such, this study not only supports the involvement of the plasminogen activation system in the destructive phase of arthritis, but also suggests a beneficial effect of therapeutic strategies directed against inhibition of matrix proteolysis.

Specific interleukin-1 inhibitor in serum and urine of children with systemic juvenile chronic arthritis.

Interleukin-1 (IL-1) activity and inhibition were studied in serum and urine from nine patients with systemic juvenile chronic arthritis (S-JCA). In afebrile patients IL-1 activity was normal or high. Serum from two afebrile S-JCA patients taken during a period of severe disease activity had an enhancing effect on the activity of exogenous IL-1. Secondary amyloidosis subsequently developed in one of these patients. In contrast, in febrile patients' serum and urine IL-1 activity was low, apparently reflecting the presence of a strong inhibitor of IL-1 activity measured by the inhibition of prostaglandin E2 production by synovial cells. This inhibition was greatest at the time of peak temperature, suggesting the possibility of feedback regulation during fever. This novel identification in S-JCA of a specific IL-1 inhibitor that competes at the IL-1 receptor level may be an important step in the understanding of the pattern of fever and the evaluation of disease in patients with S-JCA.

5-Thiopyridoxine in rheumatoid arthritis: clinical and experimental studies.

Twelve patients with rheumatoid arthritis who had failed to respond to or developed side effects preventing further use of penicillamine were given 5-thiopyridoxine (5-TP). These patients were compared with 48 patients with similar indications randomly assigned to placebo or penicillamine. Both 5-TP and penicillamine were superior to placebo, and the effectiveness of the two active drugs was similar. Both produced a gradual amelioration of symptoms and signs of the disease accompanied by reduction in erythrocyte sedimentation rate, rheumatoid factor titer, and immunoglobulins. Nine patients on 5-TP were able to continue treatment with good control of the disease for at least 18 months. Toxic effects included rashes, proteinuria, loss of taste, and mouth ulcers. Patients who had developed a particular side effect with penicillamine did not necessarily do the same with 5-TP. This is the second mercaptan compound which has suppressive effects on the clinical and laboratory features of rheumatoid arthritis. Because of their similarities, 5-TP and penicillamine were studied in various experimental systems in an attempt to find some common biochemical or pharmacologic action. Among the properties studied were the effects on copper, vitamin B6 metabolism, dermal collagen, and mixed disulfide formation. Results with animal models of inflammation were also examined. The only common action was enhancement of the secondary lesions of adjuvant arthritis.

[Calcium, phosphorus, hydroxyproline and nitrogen in inflammatory joint diseases]. / Zum Studium des Calciums, Phosphors, Oxyprolins und Stickstoffs bei entzündlichen Gelenkerkra nkungen

The elimination of calcium, phosphorus, hydroxyproline and nitrogen was studied in 127 patients with inflammatory joint diseases and )6 healthy controls for 4 days. On the third day, 186 mg of calcium was administered intravenously. Provoked hypercalciuria tests were made in 35 males, 116 females with rheumatiod arthritis (RA), 18 males with ankylosing spondylitis (ASp), 8 postinfectious arthritis (PA) and 18 healthy controls (C). In 120 patients comparison was made between the ratios of eliminated P/hydroxyproline, Ca/hydroxyproline and P/Ca with regards to the results obtained in healthy controls. The kinetics of 47Ca were studied in 7 males with ASp and 4 C. The ratios Ca/P in serum and P/Ca in urine were studied in the same patients and compared with 21 C. The results show that the bone symptomatology of PA manifests itself by elimination of elevated amounts of all of the indicators studied, especially phosphorus. In RA there may be considerable oscillations of flow of urine due to the perspiration of patients. RA differs from decompensated coxarthrosis and gonarthrosis in that the patients eliminate significantly less calcium and phosphorus. Corticosteroids stimulate the elimination of hydroxyproline. Younger patients with RA (25-44) show changes compatible with osteoporosis, older females (45-64) display changes similar to those seen in osteomalacia, the oldest female patient (65-84) appear to have insufficient binding capacity for calcium. The hyposthesis is proposed that at the disease onset RA is characterized by an extremely marked syndrome of osteopathy. ASp is characterized by significantly reduced elimination of hydraxyproline, higher metabolic pool of calcium, lower elimination of calcium in urine and faeces and lower accretion to bone.