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.

Continuing clinically severe vitamin D deficiency in Asians in the UK (Leicester).

Deprivational vitamin D deficiency began to be noted in immigrant Asians in the early 1960s. Although there have been suggestions that the level of this problem may be declining, we describe a number of clinical cases seen over a consecutive 3 1/2 year period. Musculoskeletal symptoms were the commonest though there were a variety of medical presentations requiring hospital referral. Most of the cases were Hindu vegetarians. There is likely to be significant underdiagnosis of this condition. In spite of the extensive medical, social and political attention this condition has received, our study shows that vitamin D deficiency continues to persist in certain Asians in a clinically florid fashion. An effective preventative policy is long overdue.

The three week sulphasalazine syndrome.

We report a 53-year-old man with sero-negative rheumatoid arthritis who developed a fever, rash and hepatitis 3 weeks after starting sulphasalazine therapy. This was associated with a T cell lymphocytosis, eosinophilia and evidence of classical complement pathway activation. He responded to high dose corticosteroids. This is a rare but characteristic reaction which is likely to be encountered by rheumatologists more frequently with the increasing use of sulphasalazine. It should be recognized promptly as it may be fatal and can be confused with other systemic diseases.

Primary pulmonary hypertension associated with systemic lupus erythematosus.

A 24-year-old West Indian woman with a four-year history of systemic lupus erythematosus presented with progressive dypsnoea due to primary pulmonary hypertension. Despite showing a response to vasodilators, these failed to control the condition. Her pulmonary hypertension increased in severity, eventually resulting in her death. We believe primary pulmonary hypertension to be an unusual complication of systemic lupus erythematosus. We suggest that this diagnosis should be considered in all patients with systemic lupus erythematosus and progressive dypsnoea, as optimum benefit can only be obtained by early institution of vasodilator therapy.

High prevalence of systemic disease and mortality in Asian subjects with systemic lupus erythematosus.

All patients with systemic lupus erythematosus (SLE) (American Rheumatism Association criteria with positive antinuclear antibody titre) and who attended any of the three general hospitals in Leicester over a 10 year period were ascertained using several complementary sources. Eighty seven subjects (26 Asian, 61 white) were identified. The estimated prevalence of SLE in Leicester is 0.4/1000 for Asian and 0.2/1000 for white subjects. Mean age of onset of the disease was 24 years in Asian and 31 years in white subjects, with both groups showing a female preponderance. Proteinuria (greater than 1 g/24 h) was noted in 15 (58%) Asian and 21 (35%) white subjects; neuropsychiatric disease in 10 (38%) Asian and 8 (13%) white subjects; myalgic symptoms with raised muscle enzymes in 9 (35%) Asian and 3 (5%) white subjects. Nineteen (73%) Asian subjects were positive for extractable nuclear antigens as well, at some stage of their disease, compared with 6 (10%) white subjects. Immunosuppressive treatment was required in 12 (46%) Asian and 12 (20%) white subjects, and deaths of seven Asian and five white subjects were attributed to SLE. These findings show that Asian subjects have a higher prevalence of SLE with greater systemic disease and mortality.

Relapsing polychondritis: an unusual cause of PUO in an Asian lady.

A case of pyrexia of unknown origin (PUO) in a 54-year-old Asian lady is described. She subsequently developed ocular and aural inflammation suggestive of relapsing polychondritis (RP) with immediate clinical improvement following steroid therapy. PUO is an unusual presenting feature of RP. The literature is reviewed and the clinical features of RP are discussed.

Large granular lymphocytosis associated with rheumatoid arthritis.

A 74 year old woman with rheumatoid arthritis, hepatosplenomegaly, neutropenia, and peripheral blood lymphocytosis is described. The lymphocytes had a large granular morphology and expressed a CD3+ CD8+ Leu7+ surface antigen phenotype. They did not have natural killer cell function. Southern analysis of the lymphocyte DNA using two restriction enzymes showed a rearranged pattern for the T cell receptor beta chain gene, indicating a monoclonal lymphoproliferation. Large granular lymphocytosis is a rare and heterogeneous phenomenon, which has become more clearly characterised through the application of molecular biology techniques. Most cases appear to be forms of T cell leukaemia with a chronic benign course. The association between rheumatoid arthritis and large granular lymphocytosis is emphasised.

Synovial fluid and plasma kinetics of repeat dose sustained action tiaprofenic acid in patients with rheumatoid arthritis.

Tiaprofenic acid is a potent non-steroidal anti-inflammatory drug which, in conventional tablet form, has been shown to be rapidly absorbed and eliminated from the plasma, while synovial fluid concentrations remain constant for at least 8 hours. Recently, a sustained action formulation of tiaprofenic acid has been developed to provide the patient with the convenience of a once daily dosage. The purpose of this study was to measure plasma and synovial fluid concentrations over a 24-hour period following repeated administration of the sustained action formulation, and thus determine the pharmacokinetic profile. Eight patients suffering from rheumatoid arthritis were included in this open study (of whom 3 were subsequently excluded from the analysis). All were hospital outpatients requiring aspiration of the knee joint. The patients received sustained action tiaprofenic acid in a dosage of 600 mg once daily for a period of 7 days. Plasma and synovial fluid samples were taken on the final treatment day at 0, 4, 8, 12, and 18 hours following administration of the last treatment dose. Areas under the concentration-time curves, maximum plasma and synovial fluid concentrations, times to maximum concentration, and apparent elimination half-lives are presented and the findings compared and discussed. The drug was found to be retained in both the plasma and synovial fluid over a 24-hour period. Synovial fluid concentrations exceeded plasma concentrations at 24 hours in 4 of the 5 patients who were analysed, while in the fifth patient the levels were very similar.

Chemonucleolysis of lumbar intervertebral disc prolapse with chymopapain: outcome after 1 year.

One hundred and one consecutive patients with lumbar disc prolapse were treated by chymopapain chemonucleolysis and their response and favourable pre-treatment criteria determined. Most improvement occurred within the first month, and one year after treatment outcome was judged satisfactory (excellent or good) in 71%. Individual patient characteristics associated with a satisfactory response were sciatica of greater severity than back pain (p = 0.005) and duration of symptoms less than 18 months (p = 0.03). Patients fulfilling 3 or 4 of four immediate pre-treatment clinical and radiographic criteria (sciatica more severe than back pain, reduced straight leg raising, neurological deficit, radiographic abnormality) had a satisfactory response more often than others (p less than 0.05). Reported success one year after surgery for disc prolapse is similar. Chemonucleolysis, however, requires less resources and does not preclude subsequent operation. Our results therefore suggest that it might be considered an alternative to surgery when conservative treatment has failed.

Phenytoin in rheumatoid arthritis.

In a prospective open study, 18 patients with active rheumatoid arthritis were treated with phenytoin (300 mg/day) for 32 weeks. Clinical assessments improved significantly and there was no relapse 8 weeks after drug withdrawal. Serum C-reactive protein, plasma viscosity and hemoglobin also improved but changes were not significant. Serum phenytoin concentrations were lower than anticipated. Side effects were mild and caused 2 patients to withdraw. Our observations and the known effects of phenytoin on the immune system and collagen metabolism suggest that further controlled studies using higher doses are warranted.

Treatment of chronic knee effusions with 90yttrium-correlation of in vitro radiation and chemical effects with clinical results at three and six months.

Twenty seven knees, mainly of rheumatoid patients, received intra-articular 90Y for chronic effusions; 24% were effusion-free at 6 months. In vitro chemical, radiation (32P-induced), and combined effects of cold (non-radioactive) yttrium and 32P on synovial fluid mononuclear cells, failed to show any significant correlation with subjective and/or objective clinical effects at 3 or 6 months. If 90Y exerts its therapeutic effect via these cells, it probably does so other than by a direct effect on mononuclear cell viability.

A controlled trial of tiaprofenic acid against indomethacin in patients with rheumatoid arthritis.

A multicentre double-blind crossover study of tiaprofenic acid 600 mg daily against indomethacin 75 mg daily was carried out in 68 patients with rheumatoid arthritis to compare short-term efficacy and tolerance. There were no significant differences in efficacy between the two treatments, but significantly fewer C.N.S. side-effects were associated with tiaprofenic acid treatment. Five patients withdrew during the course of the study due to side-effects and all were receiving indomethacin.