An evidence-based approach to prescribing NSAIDs in musculoskeletal disease: a Canadian consensus. Canadian NSAID Consensus Participants.

OBJECTIVE: To make recommendations for the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) in primary care practice, particularly for patients at high risk for NSAID-induced complications. OPTIONS: The use of misoprostol to prevent gastrointestinal ulceration and other unwanted NSAIDs effects was considered. The role of cyclooxygenase-2 (COX-2) versus COX-1 inhibiting agents was also examined. OUTCOMES: Reduction of complications associated with long-term use of NSAIDs. EVIDENCE: Evidence was gathered in late 1995 from published research studies and reviews. Position papers were prepared by faculty and advisory board members and discussed at the Canadian NSAID Consensus Symposium in Cambridge, Ont., Jan. 26 and 27, 1996. VALUES: Recommendations were based on randomized, placebo-controlled clinical trials (level I evidence) and case-control studies (level II evidence) involving NSAID use when such evidence was available. When the scientific literature was incomplete or inconsistent in a particular area, recommendations reflect the consensus of the participants at the symposium (level III evidence). Physicians were recruited from across Canada for their expertise in rheumatology, gastroenterology, epidemiology, gerontology, family practice, and clinical and basic scientific research. BENEFITS, HARMS AND COSTS: Although a reduction in complications due to inappropriate NSAID use should reduce costs of additional investigations, admissions to hospital and time lost from work, definitive cost analysis studies are not yet available. RECOMMENDATIONS: Currently, no NSAID is available that lacks potential for serious toxicity; therefore, long-term use of NSAIDs should be avoided whenever possible, particularly in high-risk patients (e.g., those who are elderly, suffer from hypertension, congestive heart failure, renal or hepatic impairment or volume depletion, take certain concomitant medications or have a history of peptic ulcer disease) (level I evidence). If NSAIDs are to be used in patients with gastric or nephrotoxic risk factors, the lowest effective dose of NSAID should be used (level III evidence); NSAIDs that are weak COX-1 inhibitors may be preferred (level II evidence). In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications (level I evidence). However, the clinical judgement of the practising clinician must always be part of any therapeutic decision. VALIDATION: These recommendations are based on the consensus of Canadian experts in rheumatology, gastroenterology and epidemiology, and have been subjected to external peer review.

The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone.

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.

Assessment of salsalate, a nonacetylated salicylate, in the treatment of patients with arthritis.

This study evaluated physicians' use of the occurrence of tinnitus as a tool to establish the optimal dosage of salsalate, a nonacetylated salicylate, in patients with arthritis treated in routine clinical practice. The use of printed educational materials to improve compliance was also studied prospectively. A total of 782 patients were enrolled in this 3-week study by 95 general practitioners in an office setting. Of the 771 assessable patients, 90.0% had osteoarthritis, 9.7% had rheumatoid arthritis, and 0.3% had both types of arthritis. Most patients experienced improvement of symptoms after 3 weeks of treatment. There were no differences in the rates of improvement at the first and third weeks of treatment between patients with osteoarthritis and patients with rheumatoid arthritis. In addition, duration of arthritis had no effect on rates of improvement. Rates of patient satisfaction tended to increase over the study period. Rates of patient satisfaction did not differ significantly at the first and third weeks between patients who did not receive printed educational materials and whose who did not. Treatment was discontinued in 234 patients (30.4%) because of side effects. The most frequent reasons for discontinuation were gastrointestinal symptoms (n = 102; 13.2%) and tinnitus (n = 52; 6.7%). The clinical effectiveness and safety of salsalate were confirmed in patients with arthritis in routine clinical practice settings.

Disseminated zygomycosis associated with systemic lupus erythematosus.

We describe a 36-year-old patient who had systemic lupus erythematosus (SLE) and died of disseminated zygomycosis. There was rapid progression of his SLE, leading to suspicion of superimposed infectious disease, but the actual cause of his multiorgan failure was not recognized until after death. The manner in which systemic fungal infection may mimic SLE is discussed.

A comparison of flurbiprofen and naproxen in the treatment of rheumatoid arthritis: a Canadian multi-centre study.

A 6-week double-blind, parallel controlled, randomized study was carried out to compare the efficacy and tolerability of 100 mg flurbiprofen twice daily with 375 mg naproxen twice daily in patients with rheumatoid arthritis. One hundred and six patients from five centres were evaluable; 52 from the flurbiprofen group and 54 from the naproxen group. Evaluation of the primary efficacy parameters demonstrated no difference in efficacy between the treatment groups. In general, the results of evaluation of the secondary efficacy parameters also supported similar improvement for both treatment groups. The overall incidence of adverse clinical/laboratory experiences was similar between the treatment groups. Five patients, 3 flurbiprofen and 2 naproxen-treated, discontinued the study, all because of gastro-intestinal intolerance.

Reactive arthritis associated with Clostridium difficile enteritis.

Reactive arthritis of one or more peripheral joints developed after an enteric infection with Clostridium difficile in 2 adult patients. Other reactive signs such as conjunctivitis, mucous membrane lesions and urethritis were absent. One patient had the HLA-B27 antigen. Short term followup showed a benign course of the arthritis. Three other cases of arthritis associated with C. difficile were reviewed.

Osteoarthrosis.

Osteoarthrosis is a common disorder of synovial joints, seen most often in older patients. The joints affected most commonly are the knee, hip, hands and the first metatarsophalangeal joint. Involvement of other joints such as the ankle, wrist and shoulder is uncommon, and suggests a secondary etiology. Although osteoarthrosis may be present in many joints, symptoms are usually evident in one or two joints at the most. The three main symptoms are pain, morning stiffness and a tendency for the affected joint to gel with immobility. Treatment includes rest; weight loss; physiotherapy; aids such as canes, shoe lifts, and elastic knee supports; and judicious use of anti-inflammatory medications.

Granulomatosis vasculitis in the syndrome of diffuse fasciitis with eosinophilia.

Two patients had an illness with clinical features of the syndrome of diffuse fasciitis with eosinophilia. The histologic findings in both patients showed granuloma formation in association with prominent vasculitis, in addition to other previously reported histologic features. The findings in these two cases raise the possibility that this syndrome should be classified with the vasculitides rather than as a variant of scleroderma.

Nonarticular rheumatism.

Nonarticular rheumatism refers to a group of conditions characterized by musculoskeletal aches and pains which do not arise from joints. A number of different entities are considered under this definition. They are classified either as generalized conditions which include polymyalgia rheumatica, fibrositis and aches and pains NYD, or localized conditions which include the enthesopathies: tendonitis, epicondylitis and fasciitis, tenosynovitis and bursitis. The treatment of most of these conditions is expectant, because they tend to be self-limiting and improve despite therapeutic interventions. The exception is polymyalgia rheumatica, which requires low dose steroids for a varying period of time-sometimes years.

Crossover comparison of benoxaprofen and naproxen in rheumatoid arthritis.

This multicenter double-blind clinical trial compared the efficacy and safety of benoxaprofen and naproxen in the treatment of rheumatoid arthritis. The studies followed a crossover design which provided 6 wk therapy with each of the 2 study drugs. Benoxaprofen at a single daily dose of 600 mg compared favorably to naproxen, 750 mg, administered in 2 equally divided doses. All efficacy results indicated slightly more improvement with benoxaprofen although the difference between the 2 drugs was not significant. Side effects were generally mild and only 1 patient discontinued benoxaprofen therapy because of a reactivation of a duodenal ulcer.

Drug trial in rheumatoid arthritis: a new design.

The comparative efficacy and safety of naproxen and ibuprofen were studied in 64 patients with rheumatoid arthritis. A new trial design with three aspirin periods interspersed during the study was used. By passing a smooth curve through the values obtained for the various measures of disease activity during the aspirin periods, one could calculate the difference between what would have been expected on aspirin therapy and what was found during therapy with the two trial drugs. These differences, or "incremental values," allowed each patient's variations to be analyzed individually, thus eliminating the necessity of assuming that a patient's disease was constant. Napoxen and ibuprofen were comparable in efficacy to each other and to aspirin, but both drugs caused significantly less severe side effects than aspirin. Although analysis of the incremental values showed essentially the same results as a standard analysis of the raw data with only a modest increase in sensitivity in this particular study, the novel trial design may prove useful in future drug studies in patients with rheumatoid arthritis and other chronic but fluctuating diseases.