Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis.

OBJECTIVES: To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA). METHODS: We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity. RESULTS: Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group. CONCLUSIONS: In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.

A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee.

The primary objective of this study was to investigate structural changes, as measured by joint space narrowing (JSN), within the knee joint during treatment with intra-articular sodium hyaluronate (HA) of molecular weight 500-730 kDa in patients with osteoarthritis (OA) of the knee. Patients received a weekly intra-articular injection of either 20 mg2/ml HA or a 2 ml vehicle placebo (saline) for three weeks. This course was repeated twice more at four-monthly intervals. Concomitant treatment with analgesics or NSAIDs was allowed. The primary efficacy measure was the reduction in mean joint space width (JSW) of the medial compartment at 52 weeks. A total of 408 patients were randomised and 319 completed the one-year study (HA: n=160, placebo: n=159); 273 of the 319 were included in the primary analysis. Analysis of variance on these 273 patients did not show a statistically significant difference between the two treatment groups. However, there was a significant difference in response to treatment in terms of the baseline JSW (p=0.01), indicating that outcome of treatment may depend on-baseline JSW. Therefore, a subgroup analysis by baseline JSW was conducted. This compared patients with a JSW >4.6 mm with those with a JSW <4.6 mm. In those with radiologically milder disease at baseline and receiving HA, the JSN was significantly reduced compared with placebo (p=0.02). In patients with radiologically more severe disease there was no difference in JSN between the two treatments. Although, in this one-year study, no overall treatment effect was seen, those with radiologically milder disease at baseline had less progression of joint space narrowing when treated with HA.

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.

The outcome of knee synovitis in early arthritis provides guidelines for management.

The aim of the study was to examine the clinical outcome of patients presenting to an early arthritis clinic with synovitis of the knee. The patients were assessed at presentation for evidence and pattern of joint inflammation. These patients were then reassessed at 3, 6 and 12 months and thereafter annually to determine clinical outcome. One thousand six hundred and thirty-three consecutive referrals were examined, 903 of whom had early synovitis. One hundred and thirty had knee synovitis at presentation, of whom 73 fulfilled ACR criteria for rheumatoid arthritis (RA) during the study. All 73 presented with a symmetrical polyarthritis that included the small joints and had persistent disease at 1 year. Of the remaining 57 patients, 61% of those presenting with an oligoarthritis and 33% with a polyarthritis (including knee synovitis) were in remission at 1 year. None of those presenting as a monoarthritis of the knee had inflammation at 1 year or fulfilled ACR criteria for RA at any time. It was concluded that patients presenting with knee synovitis in the absence of a small joint polyarthritis usually have a benign course following standard therapy. No patient who presented with monoarthritis developed RA. Knee synovitis as part of a polyarthritis (even when not fulfilling ACR criteria) probably justifies disease-modifying antirheumatic drug at presentation.

Microemulsion formulation of cyclosporin (Sandimmun Neoral) vs Sandimmun: comparative safety, tolerability and efficacy in severe active rheumatoid arthritis. On behalf of the OLR 302 Study Group.

OBJECTIVE: To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral) and the original CyA formulation (Sandimmun), in patients with severe active rheumatoid arthritis (RA), over a 12-month period. METHODS: In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients' assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals. RESULTS: Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients' assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups. CONCLUSION: These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.

Single-blind randomized controlled trial of an educational booklet for patients with chronic arthritis.

Consecutive new attendees at a rheumatology clinic were randomly allocated to one of three groups. All groups received routine care, but one received no other intervention, one an educational booklet on arthritis and one the booklet plus instruction from a health professional. Prior to intervention, all groups had similar knowledge. Nottingham Health Profile (NHP) and Health Assessment Questionnaire (HAQ) score. After 6 weeks, the knowledge score was significantly increased in both groups given the booklet, but not in the control group. The group instructed by a health professional showed no greater increase than the group given the booklet alone. Increased knowledge was not associated with improved clinical status and no group showed a significant change in NHP or HAQ scores. Nearly all patients said they found the booklet useful.

Effects of antiinflammatory drugs on the progression of osteoarthritis of the knee. LINK Study Group. Longitudinal Investigation of Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis.

OBJECTIVE: To compare the rate of radiographic progression in knee osteoarthritis (OA) comparing indomethacin with placebo and tiaprofenic acid with placebo. METHODS: Rate of radiographic progression of OA of the knees was studied in 812 patients randomized double blind parallel group study at 20 rheumatology clinics in the United Kingdom and analyzed sequentially. Patients received either indomethacin 25 mg three times daily, tiaprofenic acid 300 mg twice daily, or matched placebo. All had access to paracetamol as a rescue analgesic. Joint space narrowing was measured by a 6 point grading scale, using radiographs taken with a standardized technique at recruitment and annually thereafter. RESULTS: Three hundred and seventy six patients completed at least one year of study medication and therefore contributed evaluable results. More than twice as many patients showed deterioration in the indomethacin group as in the placebo group; of 170 available patients at the 3rd interim analysis, 40 of 85 receiving indomethacin had deteriorated compared to 19 of 85 receiving placebo, a statistically significant difference (p = 0.009). No statistically significant difference (p = 0.308) was found between tiaprofenic acid and placebo at the 7th interim analysis, the conclusion of the study. CONCLUSION: Indomethacin increased the rate of radiological deterioration of joint space in patients with OA of the knee; tiaprofenic acid did not.

Signal changes in the intervertebral discs on MRI of the thoracolumbar spine in ankylosing spondylitis.

Contrary to standard teaching in magnetic resonance imaging (MRI), recent reports have documented calcification appearing as areas of increased signal intensity (SI) on T1-weighted images. Intervertebral disc calcification is a frequent finding on radiographs in chronic ankylosing spondylitis (AS). This study was performed to investigate the appearance of variable degrees of disc calcification in MRI. Thirty-six patients with AS of variable duration underwent an MRI scan of the thoraco-lumbar spine and the MR appearances, particularly of the discs, were compared with plain radiographs. Increased SI of the discs on T1-weighted images were found in 17 of 36 patients, occurring over a range of disc levels, and correlating with disc calcification on the radiographs in 78% of cases. This group tended to be older and have a longer duration of disease than those with normal appearing discs. Four different patterns of increased signal within the discs termed Type A (marginal), Type B (annular), Type C (central) and Type D (solid) were identified. In those with less than six discs involved Type A was the most common pattern. In those with more than six discs involved Type D was the most common pattern, suggesting a progression of disc involvement with more advanced disease. Although these findings will not affect the management of the disease, they do highlight the recently described phenomenon of calcification appearing as increased SI on T1-weighted images, likely to be related to the surface area of the calcium crystal. This should lead to the consideration of calcium in the differential diagnosis of increased SI on T1-weighted images. End-plate marrow changes were a relatively frequent finding in this study but did not correlate with the signal changes seen within the discs; in a number of cases they related to variable degrees of bony bridging.

Increased prevalence of poor sulphoxidation in patients with rheumatoid arthritis: effect of changes in the acute phase response and second line drug treatment.

A minority of normal subjects have an impaired ability to oxidise sulphur, which is associated with an increased risk of side effects when they receive sulphur containing drugs. In 114 patients with rheumatoid arthritis a greatly increased prevalence of poor sulphoxidation was found in 82 (72%) patients compared with 70/200 (35%) healthy controls, 45/121 (37%) controls matched for age, and 4/35 (11%) of the normal aged general population. In a longitudinal study of 37 patients there was no significant alteration in sulphoxidation status after the introduction of a second line drug or with marked changes in the acute phase response. It seems, therefore, that the poor sulphoxidation status in patients with RA is not an epiphenomenon and may be an important factor in determining the clinical features of rheumatoid disease.

Endogenous sex steroid levels in women with generalised osteoarthritis.

Epidemiologic and clinical observations have suggested a relationship between generalised osteoarthritis (GOA) and hormonal and menopausal factors in women. We explored the hypothesis that postmenopausal women with GOA have altered sex hormone status compared with control women. We studied 112 women (mean age 64) with GOA. Controls were 151 women (mean age 54) from the general population without clinical evidence of hand or knee OA. All women were postmenopausal. Serum was assayed by RIA for testosterone, oestradiol, sex hormone binding globulin (SHBG), and dyhydroepiandrosterone sulphate (DHEAS). Because of the differences in mean ages, the results were compared according to equal age groups divided on the basis of tertiles. SHBG was lower in the GOA group, reaching significance in the middle group 53-61 years (58.0 vs 67.9 nmol/l p less than 0.05). Testosterone was slightly higher in GOA women aged under 53. No consistent differences were seen in the older age group or for the other sex steroids. These preliminary data suggest that middle-aged women with GOA have lower circulating SHBG levels. This implies that higher circulating free oestrogens and androgens are present suggesting a role in the aetiopathogenesis of GOA.

Inner ear deafness in Wegener's granulomatosis.

Autoimmune deafness represents a heterogeneous group of disorders in which there is though to be inner ear and/or middle ear damage mediated by various immunological abnormalities. We describe a patient with Wegener's granulomatosis in whom there was evidence of significant inner ear damage caused by vasculitis, which was completely reversed by cyclophosphamide and prednisolone. We propose that Wegener's granulomatosis is a cause of autoimmune deafness.

Sulphasalazine in psoriatic arthritis: a double-blind placebo-controlled study.

Sulphasalazine (SASP) is now accepted as an effective slow-acting antirheumatic drug for treating active rheumatoid arthritis (RA), but has not been previously evaluated in psoriatic arthritis. An earlier open study suggested that it was well tolerated and potentially beneficial. The present double-blind placebo-controlled trial of 30 patients has now confirmed its efficacy. Greater improvement occurred in those patients on active treatment than on placebo, with more benefit being detected in those patients with the symmetrical polyarticular but seronegative pattern of arthritis associated with a high acute-phase response. SASP was stopped in 26% because of side-effects but these were mild. No exacerbation or remission of psoriasis was observed. Further studies are in progress to determine the degree of efficacy of SASP in different clinical subgroups of psoriatic arthritis.

A pharmacokinetic study of the active metabolite of nabumetone in young healthy subjects and older arthritis patients.

We have performed a detailed pharmacokinetic study of the plasma concentrations of the major active metabolite of nabumetone, 6-methoxy-2-naphthylacetic acid (6 MNA), attained after a single dose and during chronic administration comparing the results of a group of young healthy volunteers with those of a group of elderly arthritic patients. The latter had higher peak plasma concentrations of 6 MNA and slower rates of elimination but there is no tendency for the drug to accumulate unpredictably in the old. Disease activity also influences plasma concentration, those with more active disease, and lower serum albumin concentrations had lower AUC values.

Treatment of psoriatic arthritis with sulphasalazine: a one year open study.

Sulphasalazine (SASP) has recently become established as an effective treatment for active rheumatoid arthritis (RA), but has not previously been used in psoriatic arthritis in which remission-inducing drugs have proved disappointing. In this one year open study, 34 patients with active psoriatic arthritis were treated with sulphasalazine. An overall favourable clinical response was observed in 23 patients (67%). Nine patients (26%) achieved a very good therapeutic response and these either had arthritis associated with spondylitis or the symmetrical type of joint disease. Evaluation at 3, 6 and 12 months showed a significant improvement in inflammatory indices including a reduction in the C-reactive protein level and ESR. The drug was well-tolerated and side-effects were mild. Eight patients (23.5%) stopped the drug because of reactions and one patient with a rash was successfully desensitised. Fifty-three percent continued the drug into the second year. No apparent exacerbation of the psoriasis was observed. These results suggest that sulphasalazine is a safe and potentially effective drug in the treatment of psoriatic arthritis. A double-blind placebo-controlled trial has been set up to determine its true efficacy.