Rheumatoid arthritis: clinical considerations in diagnosis and management.

Advances in the understanding of the immune response, in immunogenetics, and in better identification of microbial agents that produce arthritis have made possible more accurate diagnosis of rheumatoid arthritis. Epidemiologic study of groups of rheumatoid patients and their response to therapy has provided a broader perspective of the disease's course and management. Therapy must be guided by the acute or chronic phase of the disease and must embrace chemical, psychologic, and physical modalities to achieve the goals of pain relief and the restoration of immune balance. Rheumatoid arthritis can no longer be considered benign since it impairs the duration as well as the quality of life. Therapy should be aggressive depending upon the predictors of more destructive disease.

Reappraisal of the use of methotrexate in rheumatic disease.

Methotrexate has been available for clinical use since 1951. Initially, it was utilized as a chemotherapeutic agent, but it has since been widely used in the treatment of such nonmalignant disorders as psoriasis and, more recently, experimentally in psoriatic arthritis and polymyositis. Its mechanism of action is imprecisely understood but it appears to involve both anti-inflammatory and immunosuppressive effects. Controlled pilot studies are underway using methotrexate in patients with severe rheumatoid arthritis.

An overview of the long-term safety experience of nabumetone.

Safety data have been gathered in US clinical trials of nabumetone on 1912 patients from August 1981 to May 1988. Dosing in the double-blind trials was 100 mg at bedtime, but in open-label trials patients could increase the dosage of nabumetone to 1500 or 2000 mg if required. Adverse experiences reported in the double-blind and open-label studies that were considered related to nabumetone treatment, or of unknown origin, occurred most commonly in two body systems: the body as a whole, and the digestive system. Incidence rates greater than 10% for adverse experiences categorised by preferred term occurred in the 'body as a whole' category for abdominal pain, and in the digestive system for diarrhoea and dyspepsia. Dosage increases to 2000 mg appeared to cause a dose-related increase in diarrhoea. In the long term studies, gastrointestinal ulcers have been confirmed in 13 (0.7%) patients. Hepatic and renal function was well preserved in patients treated with nabumetone. Overall, only 7 nabumetone-treated patients (0.4%) showed a marked elevation in both ALT (SGPT) and AST (SGOT). Two nabumetone-treated patients showed marked elevations in renal parameters, serum creatinine and blood urea nitrogen. Overall, nabumetone was well tolerated, and the adverse experience profile was clinically acceptable and presented no unusual or unexpected patterns.

New perspectives of secondary and tertiary therapy for rheumatoid arthritis.

Rheumatoid arthritis continues to be recognised as a disorder with a variable prognosis, but recent studies have emphasised its potential for shortening life span. Epidemiological, genetic, and natural history studies have helped to identify patients who are at risk for the development of more aggressive disease earlier in their clinical course, and rheumatologists are willing to be more aggressive in their treatment now as their armamentarium expands. Earlier separation of drugs into anti-inflammatory and immunomodulatory agents becomes irrelevant as these concepts change and drugs fulfil both definitions. Sequences of therapy continue to be dictated by the potential of toxicity and generally follow rather than precede disease progression. The addition of several new agents to the algorithms of therapy against rheumatoid arthritis raises questions about their effects and place in therapeutic regimens, especially as concerns auranofin, sulphasalazine, methotrexate and cyclosporin. Combination therapy is currently at the end of the drug line, but the therapeutic horizon beckons with the potential of biological agents aimed at the restoration of immune balance.

Resolve: methotrexate is the drug of choice after NSAIDs in rheumatoid arthritis.

This article, in favor of the resolution that methotrexate (MTX) is the drug of choice after nonsteroidal antiinflammatory treatment, develops the following four points. MTX is an effective treatment of rheumatoid arthritis. MTX is easy to administer and to monitor for effectiveness and safety. MTX has demonstrated a therapeutic to toxic ratio that exceeds that of other second-line antirheumatic drugs. MTX has the potential to impair disease progression.

Worldwide clinical safety experience with diclofenac.

Data from more than 100,000 patients in foreign and United States trials provide substantial evidence of diclofenac's safety and tolerability. Adverse experiences were infrequent and generally mild or transient. In United States short-term trials, the frequency and severity of side effects compared favorably with rates for placebo, aspirin, and other NSAIDs. The drop-out rate for therapeutic reasons (adverse effects or lack of efficacy) was lower for diclofenac than for any of the comparative treatments. In long-term trials, diclofenac has been taken safely for a year or more. The incidence of adverse experiences reported for older patients (greater than or equal to 65 years) treated with diclofenac did not generally differ from that reported for younger patients. No significant differences in the incidence of hepatic problems were detected between diclofenac and other active treatments in U.S. trials. Finally, foreign post-marketing data on adverse experiences show that diclofenac is one of the safest agents of its kind for the treatment of a broad range of rheumatic conditions.

Prognostic staging for therapy of rheumatoid arthritis.

An attempt should be made to predict the most likely course of individual disease when a patient is first diagnosed as having rheumatoid arthritis (RA). Such a prediction can be called prognostic staging for therapy. While no specific marker will accomplish this accurately, the summation of demographic, genetic, historical, physical, laboratory, radiologic, and scanning data may be used to make a reasonable estimation of outcome. The use of immunogenetic typing is the newest technique that can help identify patients likely to develop more serious disease. Once patients are identified as having probable aggressive disease, that is, beyond stage I, combination therapy should be initiated. Goals of therapy should include the prevention and/or interference of progression of radiologic erosions, as well as functional improvement as measured by life-style and productivity.

Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis.

Low dose pulse MTX was associated with the development of pancytopenia in six patients with RA. Two patients died. Factors implicated in the occurrence of this complication were renal impairment in five patients, medication errors by two patients, preexisting marrow injury from occult alcoholism in one patient, and an apparent idiosyncratic reaction to the drug in another. Medication errors were associated with the use of five or more medications, and the unusual schedule of administration of low dose MTX may also have been contributory. From a consideration of the clinical pharmacokinetics of MTX, we suggest other factors that may predispose to the occurrence of marrow toxicity: the presence of hypoalbuminemia, interactions between MTX and other protein bound or weakly acidic drugs, and the repetitive dosing schedule of low dose MTX. Based on our experience, patients with impaired renal function (creatinine greater than or equal to 2.0 mg/dL) should not receive MTX. Renal function should be monitored regularly during treatment with MTX, and blood counts should be observed carefully if a new drug is added or substituted. A 5 mg test dose of MTX before initiating weekly therapy may identify patients with severe hypersensitivity to the drug. The potential risks of using MTX in a patient unwilling to accept blood products should be acknowledged and discussed with the patient. Furthermore, we recommend the use of leucovorin if pancytopenia occurs, even if low or undetectable serum levels of MTX are present.

The treatment of acute gout with naproxen.

The effectiveness of naproxen in the management of acute gouty arthritis was assessed in an open study of 20 patients. These patients were selected on the basis of their clinical presentation of characteristic acute arthritis associated in 19 with concomitant hyperuricemia. There were 17 men and three women varying in age from 35 to 89 years. The first 12 patients were treated with 600 mg naproxen initially, followed by 300 mg every 8 hours for the first 48 hours and then tapered or discontinued depending upon their clinical response. The last eight patients received a loading dose of 750 mg naproxen, followed by 250 mg every 8 hours for a duration of 72 hours before tapering the drug. The response of 15 of the 20 was either excellent or good, while the response was fair in three and poor in two. Poor responders had been failures in other regimens or were treated late in the course of their attack. The higher loading dose was associated with more rapid and satisfactory remission. No significant undesirable side effects were observed. On the basis of this study, naproxen was found effective in alleviating the inflammation of acute gout.

The selection of a nonsteroidal antiinflammatory drug. Is there a difference?

The availability of an ever expanding number of nonsteroidal antiinflammatory drugs (NSAID) relates to their utility for the treatment of a broad spectrum of disorders. Both the efficacy and adverse effects of NSAID relate primarily to their antiprostaglandin mechanism of action, prostaglandin inhibition. At full antiinflammatory doses, there is little evidence to support a rank order of effectiveness. The major differences among NSAID are their half-lives and safety profiles. With newer agents the emphasis is on safety, especially with respect to gastrointestinal irritation. Acknowledgment of inherent drug differences with respect to pharmacology and safety enhances tolerability by the patient and increases the likelihood for continued drug therapy.

Short term efficacy of methotrexate in the treatment of rheumatoid arthritis.

Methotrexate is easily administered, widely accepted by patients, and has a rapid therapeutic effect. With careful attention to known risk factors, such as alcoholism, diabetes, obesity, and renal disease, it is a useful agent for the treatment of refractory rheumatoid arthritis (RA). Although rheumatologists have been using methotrexate in the treatment of RA for some time, controlled studies have been needed to establish the safety and efficacy of this agent. This paper will review the findings of the Cooperating Clinics of the American Rheumatism Association, as well as other studies that have investigated the short term efficacy of methotrexate.

Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial.

To assess the relative efficacy of methotrexate (MTX), azathioprine (AZA), and their combination in the treatment of rheumatoid arthritis (RA), a double blind, prospective, multicenter, controlled trial was carried out. Two hundred nine patients with active RA were treated with escalating doses of MTX (5-15 mg/week), AZA (50-150 mg/day), or combination (5/50-7.5/100) with opportunity to increase dosage at 6 week intervals. Patients were evaluated for clinical and laboratory improvement and assessed for radiologic progression at 48 weeks. One hundred ten patients remained on the initial, randomly assigned therapy. Response was defined as 30% or greater improvement in at least 3 of 4 variables, and occurred in the following: 38% on the combination arm, 26% on AZA, and 45% on MTX (p = 0.06). A trend for decreased radiologic progression was seen in the MTX group. Adverse experiences and treatment termination occurred more frequently in the combination and AZA arms relative to the MTX group. The most frequent causes for treatment discontinuations were lack of effectiveness, gastrointestinal adverse effects and liver enzyme elevation. This study establishes that the combination of MTX and AZA in the dosages employed is not associated with more toxicity than treatment with single agents, but enhanced efficacy is not seen. A trend toward decreased radiographic progression was noted in the MTX treated patients.

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.

Long-term clinical evaluation of suprofen and aspirin in patients with osteoarthritis.

The safety and efficacy of suprofen 200 mg q.i.d. and aspirin 650 mg q.i.d. in the treatment of chronic pain due to osteoarthritis were compared in a double-blind, randomized, parallel group study over a 12-week period. Suprofen was comparable to aspirin in the relief of pain and improvement in activity impairment. Results of ocular examination, laboratory data, and vital signs examinations indicated no clinically significant changes for suprofen. No serious side effects were reported by either group.

Methotrexate: a perspective of its use in the treatment of rheumatic diseases.

MTX has been available for clinical use since 1951, and although it is widely accepted as a chemotherapeutic agent, its use in nonmalignant disorders has been sporadic and not well documented. Its mechanism of action is imprecisely understood but appears to involve both anti-inflammatory and immunosuppressive effects. The most extensive use of MTX in benign conditions has been in the treatment of psoriasis and more recently in psoriatic arthritis as well as polymyositis, sarcoid, and Reiter's syndrome. In addition, pilot studies have been carried out using MTX in patients with resistive RA. We have used MTX in 67 patients with severe RA. Maintained on oral pulse treatment schedule at 7.5 to 15.0 mg/week, approximately 75% had an improved global response with a significant decrease in active joints and ESR. Thirty-three patients have remained on therapy for periods of less than 1 year to more than 10 years. Thirty-four have discontinued treatment: 11 because of inefficacy, five with gastrointestinal complaints, three because of liver function abnormalities, and eight because of apprehension. Two patients died of neoplasm. Of the potential side effects of this agent, hepatotoxicity remains a serious consideration. We treat with attention to risk factors and rely on liver function tests to alert us to increased risk. There are data to suggest that a cumulative dose of MTX beyond 1.5 gm needs tissue surveillance. MTX appears to provide safe and effective treatment in resistive RA but requires further definitive trails.