A randomized, double-blind, crossover comparison of the efficacy and safety of oral controlled-release tramadol and placebo in patients with painful osteoarthritis.

OBJECTIVE: To compare the efficacy and safety of controlled-release (CR) tramadol (Zytram XL, Purdue Pharma, Canada) and placebo in patients with painful osteoarthritis. METHODS: Patients underwent analgesic washout for two to seven days before random assignment to 150 mg daily of CR tramadol or placebo, and were titrated weekly to 200 mg, 300 mg or a maximum of 400 mg once daily. After four weeks, patients crossed over to the alternate treatment for another four weeks. Plain acetaminophen was provided as a rescue analgesic. All patients who completed the crossover study were eligible to receive open label CR tramadol for six months. RESULTS: Seventy-seven of 100 randomly assigned patients were evaluable for efficacy. CR tramadol resulted in significantly lower visual analogue scale pain intensity scores (37.4+/-23.9 versus 45.1+/-24.3, P=0.0009). Western Ontario and McMaster Universities osteoarthritis index subscale scores for pain (189.0+/-105.0 versus 230.0+/-115.4; P=0.0001) and physical function (632.4+/-361.3 versus 727.4+/-383.4; P=0.0205) were significantly better with CR tramadol. Total pain and disability (22.8+/-14.5 versus 27.2+/-14.8; P=0.0004), and overall pain and sleep (104.7+/-98.0 versus 141.0+/-108.2; P=0.0005) scores in the Pain and Sleep Questionnaire were significantly lower for CR tramadol. Short-form 36 Health Survey scores were significantly better during CR tramadol treatment for the pain index (38.8+/-10.8 versus 35.6+/-9.0; P=0.0100), general health perception (46.5+/-11.2 versus 44.4+/-11.6; P=0.0262), vitality (43.1+/-13.2 versus 40.2+/-13.7; P=0.0255) and overall physical components (40.8+/-8.9 versus 37.8+/-7.7; P=0.0002). CR tramadol treatment was preferred by 55.8% of patients (P=0.0005) versus 20.8% and 23.4% of patients who chose placebo or had no preference, respectively. These improvements were sustained for up to six months, and 86.5% of patients reported at least moderate benefit from CR tramadol during long-term treatment. CONCLUSION: CR tramadol is effective for the management of painful osteoarthritis.

The effect of low dose methotrexate on bone density.

OBJECTIVE: High dose methotrexate (MTX) has been linked with bone loss in oncology patients. However, it is unclear whether longterm low dose MTX used in the treatment of inflammatory arthritis is associated with bone loss. We compared the effect of low dose MTX on bone density in prospectively recruited patients with rheumatoid arthritis (RA) and psoriasis/psoriatic arthritis (Ps/PsA). METHODS: Thirty RA patients and 30 Ps/PsA patients taking MTX were compared to controls not taking MTX (30 with RA, 27 Ps/PsA). Bone mineral density (BMD) of the radius, lumbar spine, trochanter, and femoral neck was measured using Lunar dual energy x-ray absorptiometry. Student t tests were used to detect differences in bone density (using Z scores) of the MTX group versus controls for both the RA and Ps/PsA groups. Analysis of covariance was used to examine for confounders including disease duration, disease activity, age, and sex. RESULTS: BMD of the radius/femoral neck/trochanter did not differ significantly between the MTX treated groups and controls when analyzed by Z scores. The mean difference between the MTX group and controls of the femoral neck was 0.040 (95% CI -0.40, 0.12) and 0.060 (95% CI -0.30, 0.15) for the RA and Ps/PsA groups, respectively. The absolute BMD of the lumbar spine (L2-L4) was higher in the RA MTX group than in controls. Analysis of covariance did not reveal an effect of study group on bone density. CONCLUSION: This study suggests that low dose MTX does not have a negative effect on bone density, at either cortical or trabecular sites.

Conversion of patients with rheumatoid arthritis from the conventional to a microemulsion formulation of cyclosporine: a double blind comparison to screen for differences in safety, efficacy, and pharmacokinetics.

OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) may be converted, on a milligram-to-milligram basis, from conventional cyclosporin A (CyA, Sandimmun) to the microemulsion formulation (Neoral) with maintenance of longterm safety, and to compare cyclosporin A (CyA) pharmacokinetics between formulations. METHODS: In this double blind, multicenter, parallel group study, 51 patients receiving stable conventional CyA maintenance treatment were randomized to continue conventional CyA (n = 27) or to convert to CyA microemulsion (n = 24) and were monitored for 52 weeks. Trough blood CyA levels were measured before and at intervals after conversion. CyA steady-state area under the curve was assessed one week before and 2 and 6 weeks after randomization in 15 patients in each treatment arm. CyA trough levels and pharmacokinetic results remained unknown to investigators throughout the study. CyA doses were titrated as necessary on the basis of clinical evaluation and disease activity assessments. RESULTS: Initial mean daily doses were 3.5 mg/kg/day (conventional CyA) and 3.3 mg/kg/day (CyA microemulsion) and did not change significantly during the study. The mean bioavailability of CyA from the microemulsion formulation was 23% higher than from conventional CyA. Replicate assessments indicated a more reproducible pharmacokinetic profile with CyA microemulsion. The overall incidence and nature of adverse events and changes in vital signs and laboratory variables were similar in both groups. No clinically relevant differences in efficacy were found between treatments. No loss of efficacy and no tolerability problems occurred after conversion from conventional to microemulsion CyA. CONCLUSION: Existing CyA dosing guidelines, formulated for conventional CyA, are suitable for longterm CyA microemulsion therapy of patients with RA. These results indicate the pharmacokinetic advantages of the microemulsion formulation.

Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: an open-label extension study. The Methotrexate-Cyclosporine Combination Study Group.

OBJECTIVE: To determine whether the clinical benefit and favorable safety profile previously noted with the combination of cyclosporine (CSA) and methotrexate (MTX) given for 24 weeks in patients with rheumatoid arthritis (RA) would be maintained for a further 24 weeks, and whether the addition of CSA in patients who had previously been randomized to receive placebo + MTX would result in clinical benefit. METHODS: Eligible subjects from the initial study (weeks 0-24), in which the addition of placebo or CSA to MTX therapy was compared in patients with RA that was partially responsive to MTX, were enrolled. Patients who had received CSA + MTX continued this regimen for a further 24 weeks (weeks 24-48) (group 1; n = 48), and patients who had initially received placebo + MTX now received CSA + MTX for 24 weeks (weeks 24-48) (group 2; n = 44), in an open-label extension study. The primary outcome measures were the number of tender joints, number of swollen joints, physician and patient global assessments, pain, functional disability as measured by the modified Health Assessment Questionnaire, and erythrocyte sedimentation rate. RESULTS: Of the 92 patients enrolled, 80 (87%) completed the extension study. In patients in group 1, the clinically and statistically significant improvement in response outcomes previously noted at week 24, ranging from 25% to 50%, was maintained through week 48. In patients in group 2, the addition of CSA resulted in significant clinical improvement. By week 48, most outcome measures in group 2 patients were similar to those in group 1 patients. CSA treatment resulted in a small increase in serum creatinine levels, but only 1 patient was withdrawn from the study for this reason. CONCLUSION: The clinical improvement previously observed in patients treated with the CSA + MTX combination for 24 weeks was maintained for 24 subsequent weeks, without serious adverse effects, and was also observed in the patients whose treatment was switched from placebo + MTX to CSA + MTX.

Impact of patient with patient interaction on perceived rheumatoid arthritis overall disease status.

To determine whether patient interaction impacts on perceived disease severity and ability to cope with rheumatoid arthritis (RA) forty RA patients were assessed using joint counts, clinician global assessment, patient global assessment (PGA), VAS pain scale and Health Assessment Questionnaire (HAQ). All participants had six one-on-one conversations about their disease activity and the effect of RA on their lives. Follow-up questionnaires asked about recall of pre-conversation PGA; post-conversation PGA; change in PGA; and change in ability to cope as a result of the conversations. 87.5% of the questionnaires were returned. Pre- and post-conversation PGA were statistically reliable; PGA score improved (P = 0.004); 60.0% of participants felt their ability to cope with their disease improved as a result of this interaction. RA patients benefit from sharing information with like patients. Support groups may be an integral part of treatment strategy in patients with RA.

Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group.

BACKGROUND: Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement. METHODS: In a six-month randomized, double-blind trial, we compared combination therapy with cyclosporine (2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals) and methotrexate (at the maximal tolerated dose) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment. The primary outcome measure was the change in the number of tender joints. RESULTS: The mean (+/- SD) dose of cyclosporine at the final treatment was 2.97 +/- 1.02 mg per kilogram per day. As compared with the placebo group, the patients in the treatment group had a net improvement in the tender-joint count of 25 percent, or 4.8 joints (95 percent confidence interval, 0.7 to 8.9; P = 0.02), and in the swollen-joint count of 25 percent, or 3.8 joints (95 percent confidence interval, 1.3 to 6.3; P = 0.005); improvement in overall disease activity as assessed by the physician (19 percent, P < 0.001) and the patient (21 percent, P < 0.001); and improvement in joint pain (23 percent, P = 0.04) and in the degree of disability (26 percent, P < 0.001). The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group (P = 0.006). Thirty-six patients (48 percent) in the cyclosporine group and 12 patients (16 percent) in the placebo group (P < 0.001) met the 1993 criteria for improvement of the American College of Rheumatology (more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables). Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study; 2 patients in the cyclosporine group died, 1 from viral pneumonia and the other in a motor vehicle accident. Serum creatinine concentrations increased by a mean of 0.14 +/- 0.27 mg per deciliter (12 +/- 24 mmol per liter) in the cyclosporine group and by 0.05 +/- 0.19 mg per deciliter (4 +/- 17 mmol per liter) in the placebo group (P = 0.02). CONCLUSIONS: In a six-month study, patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinically important improvement after combination therapy with cyclosporine and methotrexate. Side effects were not substantially increased. Long-term follow-up of patients treated with this combination is needed.

A multicenter study of nabumetone and diclofenac SR in patients with osteoarthritis.

OBJECTIVE: To conduct the first Canadian study of the comparative efficacy and safety of nabumetone and diclofenac SR in patients with primary osteoarthritis (OA) of the hip, knee and shoulder. METHODS: Nabumetone 1000-1500 mg po daily was compared to diclofenac SR 100-150 mg po daily in a 6-month, double blind, randomized, controlled, multicenter, parallel trial. Initial starting doses were nabumetone 1000 mg daily and diclofenac SR 100 mg daily, with optional subsequent one-level dose titration permitted after 2 weeks on lower dose up to 1500 mg nabumetone and 150 mg diclofenac SR. The primary outcome measures were overall pain and disease activity as assessed by physician and patient. Secondary efficacy measures included tenderness, swelling, limitation of motion, duration of morning stiffness, acetaminophen consumption, physician and patient global assessment, and patient evaluation of efficacy and tolerability. Following an initial screening visit and a 2 to 7 day nonsteroidal antiinflammatory drug free washout period (i.e., randomization), patients were assessed at Weeks 2, 8, 14, 20, and 26. RESULTS: In all, 382 patients [nabumetone (n = 192), diclofenac SR (n = 190)] participated in the trial. Improvement in all efficacy variables was noted, but there was no statistically significant difference between drugs. Significantly fewer (p = 0.01) patients reported upper gastrointestinal (GI) adverse experiences in the nabumetone group. Significantly fewer (p < 0.04) patients withdrew from the study for adverse experiences in the nabumetone (14%) than the diclofenac SR (23%) group, particularly from upper abdominal pain (p < 0.04) and dyspepsia (p = 0.02). Three patients treated with diclofenac SR and none with nabumetone developed upper GI ulcers or bleeds. The number of patients experiencing clinically important elevations in transaminases (p < 0.04) or BUN/creatinine (p < 0.03) was significantly lower in the nabumetone group. CONCLUSION: Nabumetone is efficacious and well tolerated in patients with OA of the hip, knee or shoulder. In this group of patients it was similar in efficacy and superior in tolerability to diclofenac SR.

A comparative study of signal versus aggregate methods of outcome measurement based on the WOMAC Osteoarthritis Index. Western Ontario and McMaster Universities Osteoarthritis Index.

OBJECTIVE: To compare signal versus aggregate measurement strategies using the VA3.0S version of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis (OA) Index. METHODS: Seventy patients with OA of the knee were asked to identify a signal item for each of the 3 dimensions of the WOMAC OA Index at baseline and termination of a 12-week, double blind, randomized, controlled trial. RESULTS: The signal method detected statistically significant alterations in health status at relatively small sample sizes and with a relative efficiency close to or at unity. In addition to a low prevalence of deterioration in nonsignal items, we observed some inconsistency in signal selection. CONCLUSION: Signal methods of measurement may provide an alternative approach to outcome measurement provided issues of nonsignal deterioration and the consistency of signal selection can be addressed.

Patient compliance with tenoxicam in family practice.

This study evaluated factors that may influence patient compliance and also confirmed tolerability and efficacy of tenoxicam in routine clinical practice. Compliance in 1809 patients was evaluated over a 4-week period by physician pill-counts, patient assessment cards, and, for a subpopulation, by electronically monitored pill vials. In addition, physicians documented patient improvement and side effects after 2 weeks and after 4 weeks of therapy; patients reported satisfaction with therapy and side effects on a weekly basis. A total of 399 physicians provided data on 1809 patients, of whom 84.3% had osteoarthritis, 12.6% had rheumatoid arthritis, and 3.2% had ankylosing spondylitis. The typical patient was a woman (64.9%), white (91.2%), in her 50s (mean age, 57.9 years), with a duration of osteoarthritis of at least 1 year (72.3%). High and similar compliance rates were achieved by patients regardless of age, gender, or diagnostic category. Patient and disease characteristics were similar between compliant and noncompliant patients. Most patients (81.1%) experienced improvement of symptoms after 4 weeks of treatment. A low incidence of side effects (12.6%) was reported, with no significant differences observed among patients with respect to age, gender, or diagnostic category. Product characteristics, such as tolerability, efficacy, and dosing regimen, are more significant factors of compliance than patient or disease characteristics. Tenoxicam's tolerability and clinical effectiveness were confirmed in patients with arthritis in routine clinical practice settings.

The effects of comprehensive home physiotherapy and supervision on patients with ankylosing spondylitis--an 8-month followup.

OBJECTIVE: Our previous randomized clinical trial showed a 4-month home physiotherapy program was effective for patients with ankylosing spondylitis. This followup study reports on 22 control patients who received the previously withheld treatment and 24 experimental patients who received followup treatment as needed. METHODS: The primary outcome measure was spinal mobility measured by fingertip-to-floor distance using a portable measuring device specially designed and validated for this study. RESULTS: Following treatment, fingertip-to-floor distance did not change in control patients (P2 = 0.145). Between 4 and 8 months, fingertip-to-floor distance did not change in experimental patients (P2 = 0.143); however, initial improvement achieved was maintained. The experimental group at 4 months was better than the control group at 8 months (P2 = 0.038). CONCLUSION: The home physiotherapy treatment program must be delivered as rigorously as it was in the initial trial to be effective. The benefit from this treatment program can be maintained with very little intervention.

Therapeutic value of colchicine in the treatment of patients with psoriatic arthritis.

OBJECTIVE: To test the hypothesis that colchicine is an effective treatment of psoriatic arthritis. METHODS: Twenty five patients with psoriatic arthritis were entered into a two centre, double blind, crossover study of 23 weeks' duration comparing the therapeutic effect of colchicine (0.6-1.8 mg/day) with placebo. RESULTS: No significant difference was noted between colchicine or placebo treatment for the primary outcome measure (Lansbury joint count) or any of the seven secondary outcome measures. No change in the psoriasis was noted during active or placebo treatment. Adverse clinical effects were reported more often during treatment with colchicine (14 patients) than with the placebo (four patients), resulting in the early withdrawal of three patients receiving colchicine from the trial. Increased creatine kinase values, without weakness, occurred during treatment with colchicine (five patients) and placebo (four patients). CONCLUSIONS: In conclusion, our study did not provide evidence that colchicine is of therapeutic value in the treatment of psoriatic arthritis.

A multicenter study of tenoxicam and diclofenac in patients with osteoarthritis of the knee.

OBJECTIVE: To conduct the first Canadian study of the comparative efficacy and safety of tenoxicam and diclofenac in patients with primary osteoarthritis (OA) of the knee. METHODS: Tenoxicam 20 mg per os once daily (po od) was compared to diclofenac (Voltaren) 50 mg per os 3 times a day (po tid) in a 12-week, double blind, randomized, controlled, multicenter, parallel trial. The primary outcome measure was the pain dimension of the WOMAC OA Index. Following an initial screening visit and a 3 to 7 day NSAID-free washout period (i.e., baseline), patients were assessed at Weeks 2, 4 and 12; assessments including some 15 efficacy variables and safety variables. RESULTS: Ninety-eight patients [tenoxicam (n = 48), diclofenac (n = 50)] participated in the trial. Statistically significant (p < or = 0.05) improvements in all 3 dimensions of the WOMAC OA Index and six efficacy variables were noted in both treatment groups. No significant between drug differences were noted on any efficacy variable. Significantly fewer patients reported adverse events in the tenoxicam group (21 vs 33, p = 0.03). CONCLUSION: Tenoxicam is efficacious and well tolerated in patients with OA of the knee. In this group of patients it was similar in efficacy and superior in tolerability to diclofenac 150 mg/day (50 mg tid). Thus the benefit/risk ratio of tenoxicam was superior to that of diclofenac in this study.

Minimum important difference between patients with rheumatoid arthritis: the patient's perspective.

OBJECTIVE: To determine the point at which differences in clinical assessment scores on physical ability, pain and overall condition are sufficiently large to correspond to a subjective perception of a meaningful difference from the perspective of the patient. METHODS: Forty patients with a diagnosis of rheumatoid arthritis participated in an evening of clinical assessment and one-on-one conversations with each other regarding their arthritic condition. The assessments included tender and swollen joint counts, clinician and patient global assessments, participant assessment of pain and the Health Assessment Questionnaire (HAQ) on physical ability. After each conversation, participants rated themselves relative to their conversational partner on physical ability, pain and overall condition. These subjective comparative ratings were compared to the differences of the individual clinical assessments. RESULTS: In total there were 120 conversations. Generally participants judged themselves as less disabled than others. They rated themselves as "somewhat better" than their conversation partner when they had a (mean) 7% better score on the HAQ, 6% less pain, and 9% better global assessment. In contrast, they rated themselves as "somewhat worse" when they had a (mean) 16% worse score on the HAQ, 16% more pain, and 29% worse global assessment. CONCLUSIONS: Patients view clinically important differences in an asymmetric manner. These results can provide guidance in interpreting results and planning clinical trials.

Efficacy and tolerability of enteric-coated naproxen in the treatment of osteoarthritis and rheumatoid arthritis: a double-blind comparison with standard naproxen followed by an open-label trial.

One hundred and twenty-three patients with osteoarthritis (n = 50) or rheumatoid arthritis (n = 73) were enrolled in a 6-week, double-blind, randomized, controlled, parallel trial comparing enteric-coated naproxen with standard naproxen. Ninety-eight patients subsequently entered a 20-week, open-label trial of enteric-coated naproxen. The study demonstrated that naproxen in both its standard formulation and its new enteric-coated formulation is a highly effective form of therapy for osteoarthritis and rheumatoid arthritis. The tolerability profiles of the two formulations were similar in terms of the types of complaints reported. It is concluded that enteric-coated naproxen is an efficacious and well-tolerated formulation for the treatment of osteoarthritis and rheumatoid arthritis.

Open-label tolerability study of enteric-coated naproxen in the treatment of osteoarthritis and rheumatoid arthritis.

Two hundred and ninety-six patients were enrolled in a 6-month, open-label tolerability study of enteric-coated naproxen in patients with rheumatoid arthritis (n = 174) and osteoarthritis (n = 122). Thirty percent of the patients were greater than 65 years of age. Under standard clinical prescribing conditions, enteric-coated naproxen 500 mg twice daily and 375 mg twice daily demonstrated an acceptable tolerability profile that was not different from what one would expect with standard naproxen.

A non-cytotoxic suppressor of immunoglobulin synthesis and secretion by B cells of normal humans and patients with rheumatoid arthritis and systemic lupus erythematosus.

A factor secreted by thymocytes of immunized rabbits totally suppressed both the initiation of, and ongoing synthesis and secretion of, lectin (PWM)-induced synthesis of IgM and IgG immunoglobulins by the circulating B lymphocytes of normal humans, and of twenty consecutive patients with rheumatoid arthritis and twelve consecutive patients with systemic lupus erythematosus. The suppressor factor, referred to as human Ig synthesis/secretion suppressor factor or HISSF, is not HLA restricted in its activity and is not cytotoxic to the circulating human mononuclear cells (B cells, T cells, Null cells and monocytes). It was demonstrated that T cells precultured with HISSF were transformed into suppressor cells which, when added to fresh cultures of autologous B cells, suppressed the synthesis and secretion of IgM and IgG. On the basis of its suppressive and non-cytotoxic properties in vitro, HISSF may be an effective immunosuppressant in the treatment of patients with autoimmune diseases.

Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis.

144 patients with severe rheumatoid arthritis from six centres were randomised to receive oral cyclosporin or placebo for 6 months. The initial daily dose of cyclosporin was 2.5 mg/kg, which was increased cautiously with monitoring of serum cyclosporin levels and creatinine; the mean stabilisation dose was 3.8 mg/kg. There were significant improvements in the cyclosporin-treated patients compared with the controls in the major outcomes of reduction of active joints (23% improvement), pain (24%), and functional status (16%); global improvement was 27%. In the cyclosporin group serum creatinine increased by a mean of 15.6 mumols/l and mean arterial blood pressure by 6.27 mmHg; these increases were controlled in all but 2 patients by dose adjustment without withdrawal from the study.

The effects of comprehensive home physiotherapy and supervision on patients with ankylosing spondylitis--a randomized controlled trial.

Fifty-three patients with ankylosing spondylitis (AS) were randomly allocated; 26 experimental patients received physiotherapy and disease education, 27 control patients received neither. The primary treatment outcome was change in spinal mobility measured at 4 months by fingertip-to-floor distance. Experimental patients had more improvement in fingertip-to-floor distance (p2 less than 0.004) and in function (p2 less than 0.001) than control patients. Physiotherapy with disease education is effective in the treatment of patients with AS.

Acute gastrointestinal manifestations of systemic lupus erythematosus.

Systemic lupus erythematosus is a common multisystem disorder of young women, and gastrointestinal symptoms are a frequent clinical manifestation. There is serious danger that appropriate therapy may be delayed in the patient with an acute abdomen when systemic lupus erythematosus is not considered as a cause. This paper describes four patients with acute abdomen as a manifestation of systemic lupus erythematosus. They responded dramatically and without complication to steroid therapy. The symptoms recurred in one patient but responded to plasmapheresis and intravenous administration of cyclophosphamide. The other gastrointestinal manifestations of systemic lupus erythematosus and their pathogenesis are discussed. Management requires consideration of systemic lupus erythematosus as the cause of acute abdomen, paracentesis for culture and treatment with high doses of steroids with or without broad-spectrum antibiotics. If there is no notable improvement within 24 hours laparotomy should be performed.