The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis of the knee: a randomized placebo-controlled trial.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat osteoarthritis (OA), though their long-term efficacy is uncertain. We report a comparison of the symptomatic responses to therapy with tiaprofenic acid, indomethacin and placebo over 5 yr. METHODS: A parallel-group, randomized, single-blind trial of patients with knee OA recruited 812 patients from 20 centres; 307 patients received tiaprofenic acid (300 mg b.d.), 202 indomethacin (25 mg t.d.s.) and 303 matching placebo for up to 5 yr. At the end of the parallel-group study, patients receiving tiaprofenic acid or placebo entered a 4-week blinded cross-over study of tiaprofenic acid or placebo, both given for 2 weeks. Assessments were at baseline, 4 weeks, then at 6-month intervals for up to 5 yr in the parallel group study and at 2-week intervals in the cross-over study. They comprised pain scores, duration of morning stiffness, patients' global assessments, paracetamol consumption, adverse reactions, withdrawals and functional outcomes. RESULTS: There were significant falls in overall pain scores in patients receiving NSAIDs compared with placebo at 4 weeks in the parallel-group phase. Thereafter there were no advantages favouring active therapy. In the cross-over phase, pain scores were significantly lower in patients receiving tiaprofenic acid than placebo. Patients who had been receiving long-term tiaprofenic acid showed significant rises in their pain scores when receiving placebo therapy and vice versa. Adverse events were reported by 61% of patients receiving tiaprofenic acid, 63% on indomethacin and 51% on placebo. Potentially severe side-effects were rare; for example, there were only three cases of gastrointestinal bleeding on NSAIDs. The pattern of withdrawal was similar in patients taking NSAIDs and placebo in the parallel-group study; at 48 weeks 53% of the patients remained on tiaprofenic acid, 50% on indomethacin and 54% on placebo. CONCLUSIONS: NSAIDs significantly reduce overall pain over 4 weeks. This short-term responsiveness is retained, and even after several years of therapy with tiaprofenic acid pain scores increased over 2 weeks when it was changed to placebo. Our results do not show long-term benefits from the use of NSAIDs in OA and the majority of patients had persisting pain and disability despite therapy.

Differential metabolism of 25-hydroxyvitamin D3 by cultured synovial fluid macrophages and fibroblast-like cells from patients with arthritis.

Differential metabolism of 25-hydroxyvitamin D3 (25(OH)D3) has been shown for macrophages and fibroblast-like cells (possibly synoviocytes) cultured for two to 50 days after isolation from the synovial fluid of 12 patients with various forms of inflammatory arthritis. Macrophages synthesised the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the synthesis of which was increased by bacterial lipopolysaccharide, a known macrophage activating factor. In contrast, fibroblast-like cells formed 24, 25-dihydroxyvitamin D3 (24,25(OH)2D3), synthesis of which was stimulated by 1,25(OH)2D3 and inhibited by lipopolysaccharide. The synthesis of 1,25(OH)2D3 and 24,25(OH)2D3 by macrophages and fibroblast-like cells respectively was inhibited by ketoconazole, indicating that both hydroxylases are dependent on cytochrome P-450. Mean (SEM) synovial fluid and serum 25(OH)D3 concentrations were 16.7 (1.7) and 22.2 (2.6) ng/ml and those of 1,25(OH)2D3 were 29.4 (4.8) and 43.3 (4.0) pg/ml respectively. In most cases concentrations were lower in synovial fluid than in paired serum samples, but in two patients 1,25(OH)2D3 concentrations were greater in synovial fluid than in serum, suggesting local synthesis within the affected joints.

Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis.

The extrarenal synthesis of 1,25-dihydroxyvitamin D [1,25-(OH)2D] is a characteristic of activated macrophages and has been demonstrated to occur in vitro in synovial fluid macrophages from patients with inflammatory arthritis. To examine whether such synthesis occurs in vivo, 19 patients with rheumatoid arthritis, 5 patient controls, and 5 healthy controls received a challenge oral dose of 250 micrograms 25-hydroxyvitamin D3 (25-OHD3) and the serum 1,25-(OH)2D3 response was measured. The median rise in serum 1,25-(OH)2D3 was significantly greater (22 pg/ml) in the rheumatoid patients compared to either of the control groups (8 pg/ml), although the increase in precursor 25-OHD3 was similar in all groups. The serum 1,25-(OH)2D concentration did not rise above the normal upper limit in any of the control subjects but exceeded the normal range in 8 of the rheumatoid patients. Extrarenal 1,25-(OH)2D synthesis is substrate dependent, unlike renal 1 alpha-hydroxylation, which is homeostatically controlled. Excessive 1,25-(OH)2D3 synthesis in the rheumatoid group on raising the 25-OHD3 concentration is indicative of nonrenal production of the hormonal metabolite. Further evidence for substrate-dependent extrarenal synthesis came from measurements of 25-OHD and 1,25-(OH)2D in paired serum and synovial fluid samples from 19 patients with inflammatory arthritis, including 15 with rheumatoid arthritis. Synovial fluid 1,25-(OH)2D was usually present at a lower concentration than serum 1,25(OH)2D, with which it was strongly correlated (Kendall's R = 0.46, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Wegener's granulomatosis presenting during first trimester of pregnancy.

We describe a case of Wegener's granulomatosis in a lady who presented acutely with pulmonary haemorrhage, fever and breathlessness during her early pregnancy. She responded well to aggressive medical treatment.

A multicentre double-blind comparison of auranofin, intramuscular gold thiomalate and placebo in patients with psoriatic arthritis.

The efficacy and safety of the oral gold compound auranofin and intramuscular gold thiomalate have been compared in a placebo-controlled, double-blind, four-centre trial in 82 patients with psoriatic arthritis requiring remittive drug therapy. There were statistically significant falls in Ritchie articular index, visual analogue pain score and ESR at 12 and 24 weeks following i.m. gold but no significant changes in the auranofin group. Intramuscular gold was safe and more effective than auranofin as a second-line, suppressive antirheumatic agent for patients with psoriatic arthritis when followed for 6 months.

Anti-DNA antibody in serum measured by radioimmunoassay (Farr technique). Description of method and recommended procedure.

Anti-DNA antibody determination in serum is increasingly used because it supports the diagnosis of systemic lupus erythematosus (SLE) with high selectivity. The present work evaluates several of the technical variables of the Farr radioimmunoassay for anti-DNA antibody determination and describes a recommendable procedure, emphasizes the most important sources of error and gives the range of normal blood donors and a group of hospital patients without SLE.

Production of leucocyte migration inhibitory factor (LIF) in infectious mononucleosis. Spontaneous release and lack of response to concanavalin A.

The spontaneous release of LIF from blood lymphocytes was studied in patients with infectious mononucleosis. Mononuclear cells were separated from the blood and cultured for 22 hr, and LIF activity in the supernatant was determined. Supernatants depleted of LIF activity by means of anti-LIF antibodies or by treatment at 80 degrees C for 30 min were employed as controls; these two methods gave essentially similar results. In nine out of eighteen patients, spontaneous LIF production was demonstrated during the acute stage of the illness; this was not seen in any of the normal persons studied. 6 weeks later, spontaneous LIF production had ceased in most patients. Concanavalin A stimulated all normal lymphocytes to LIF production, but in sixteen out of seventeen patients with infectious mononucleosis this response was absent or diminished. At the follow-up study 6 weeks later, the lymphocyte response to concanavalin A was still suppressed.

Some immunological parameters in rheumatoid arthritis from India.

The present study describes the immune status of 41 patients with rheumatoid arthritis from India. The results showed a high level of immunoglobulins, normal levels of C3, less proportion of seropositivity (54%) than that reported from the west and 26% having antinuclear antibody in their serum. T lymphocyte proportion in the blood was found to be low in acutely ill patients only. Mantoux and streptokinase-streptodornase skin tests for delayed hypersensitivity were positive only in about 50% of that of controls. However, all the patients could be sensitized to DNCB. For testing the humoral antibody response TAB vaccine was given. The levels of antibody produced against O and H antigens of "Salmonella typhi" were comparable in patients and controls. However, the level of IgM rose significantly in the patients in comparison to that of controls. The cause of this, at least partially, was found to be due to a very significant rise of rheumatoid factor after TAB vaccine in the patients. Also 3 out of 8 patients converted to a seropositive state after TAB vaccination. Controls did not show the development of rheumatoid factor.

In vitro modulation of human leucocyte migration and migration inhibitory factor (LIF) activity by cyclic 3',5'-AMP and cyclic 3',5'-GMP.

The effects of cyclic 3', 5'-AMP (cAMP) and cyclic 3', 5'-GMP (cGMP) on the in vitro migration of human peripheral blood leucocytes under agarose and on the activity of leucocyte migration inhibitory factor (LIF) was studied. Leucocyte migration was not influenced by dibutyryl cAMP, while the dibutyryl derivative of cGMP significantly stimulated cell migration (1 x 10(-5)M). LIF-treated leucocytes partially escaped migration inhibition in the presence of dibutyryl cAMP (greater than or equal to 1 x 10(-6)M), while dibutyryl cGMP was inefficient. If the parent compounds cAMP and cGMP were tested, almost similar results would be obtained, although at higher concentrations of the drugs. These results represent initial experiments with a view to investigating the possible role of cyclic nucleotides in the expression of LIF activity.