Injectable Gold Research Articles

Life table analysis of treatment episodes with disease-modifying anti-rheumatic drugs in rheumatoid arthritis

To evaluate the utility of therapy with all the major disease-modifying anti-rheumatic drugs (DMARDs) in long-term treatment, 1666 DMARDs treatment episodes were analyzed using 5-year life tables. In total, all treatment episodes attributable to DMARDs remained in less than 20% of the patients up to 60 months. As for the prevalence of patients remaining in the follow-up study, those receiving methotrexate (MTX) were the most common, those receiving injectable gold compound (GST), bucillamine (BU), andd-penicillamine (DP) were higher than those receiving actalit (ACT) and sulfasalazine (SASP), and those receiving mizoribine (MZR), lobenzarit (CCA), and auranofin (AF) were least. The treatment terminations for inefficacy in BU, DP, and SASP increased slowly over 36 months. For all drugs but GST and MTX, the life table curve of terminations for toxicity became horizontal over time. The prevalence of terminations for toxicity in MTX increased even after 48 months. The long-term utility of DMARDs therapy for RA is unsatisfying. MTX was the most useful, and GST, BU, DP, and SASP were relatively useful. Relapse of the disease occurred with BU, DP, and SASP. We need to observe patients closely for the appearance of side effects throughout the prescription period of MTX irrespective of the duration of treatment.

Basic therapeutic combination therapy in chronic polyarthritis: an overview

Therapy of rheumatoid arthritis with a combination of several disease-modifying drugs aims towards better control of the disease than achievable by monotherapy. Based on a broad variety of clinical studies, revealing more or less positive results, several combinations have been suggested: the inclusion of cyclosporin into combinations with methotrexate, the inclusion of sulfasalazine into combinations with methotrexate, the combined use of two chemotherapeutic substances, including methotrexate, azathioprine and cyclophosphamide, the inclusion of chloroquine derivatives into such or other combinations, and the combination of methotrexate with injectable gold. The validity of some of the studies is affected by high drop out rates and by the unknown influence of concomitant therapy with corticosteroids. Our own beneficial experience with the triple combination of methotrexate with azathioprine and chloroquine in 21 patients with refractory rheumatoid arthritis is summarized.

Injectable gold for rheumatoid arthritis.

To estimate the short-term benefit and risk of side-effects of injectable gold for rheumatoid arthritis. We searched the Cochrane Musculoskeletal Group trials register, and Medline, up to July 1997, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). The search was complemented with bibliography searching of the reference list of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles. Randomized clinical trials (RCT) comparing injectable gold against placebo in patients with rheumatoid arthritis were included. Methodological quality of the RCTs was asessed by two reviewers (MS, BS) (kappa=1.0). Rheumatoid arthritis outcome measures were extracted by two reviewers from the publications for the 6 month endpoint. Sufficient data was obtained to conduct a pooled analysis of the number of swollen joints, physician global assessment, patient global assessment and erythrocyte sedimentation rate (ESR). Results were analyzed as standardized weighted mean differences for swollen joints and global assessments and weighted mean differences for ESR. Toxicity was evaluated with pooled odds ratios for withdrawals. Heterogeneity was estimated using a chi-square test. Fixed effects models were used throughout. Four trials and 415 patients were included. A statistically significant benefit was observed for injectable gold when compared to placebo. The standardized weighted difference (effect size) between gold and placebo for the number of swollen joints was -0.5, translating into a percentage change of 30% in favour of gold adjusted for placebo. Statistically significant differences were also observed for ESR and patient and physician assessments. Twenty two percent of the treated patients withdrew from toxicity compared to 4% of controls (OR=3.9 - 95%Cl: 2.1 - 7.2). Although its use can be limited by the incidence of serious toxicity, injectable gold has an important clinically and statistically significant benefit in the short term treatment of patients with rheumatoid arthritis.

Salmonella Urosepsis Complicated by Metastatic osteomyelitis of the Chest Wall.

Although tens of thousands of Salmonella infections occur annually in this country, most involve the gastrointestinal tract with involvement of the urinary tract being quite infrequent.1-3 I would like to report a case of urosepsis due to Salmonella with eventual development of metastatic osteomyelitis of a rib that proved refractory to treatment. A 59-year-old Latin American male who resided in the Texas Rio Grande Valley presented to an emergency room with inability to void, having first noted a decreased urinary stream and dribbling a few months earlier. In-and-out bladder catheterization yielded 700 cc of urine, and he was sent out on co-trimoxazole one double-strength tablet twice daily. The patient returned within several hours, again unable to void, and a Foley catheter was inserted draining 1100 cc of urine. The patient was admitted for further evaluation. Past history was notable for long-standing inflammatory arthritis treated with injectable gold, hydroxychloroquine and nonsteroidal anti-inflammatory agents. He had previously undergone left shoulder replacement and synovectomy of both knees. Diabetes mellitus was diagnosed 6 years earlier and treated with oral hypoglycemic agents. The patient denied any gastrointestinal complaints. Examination was notable for a temperature of 102.4 degreesF and obvious sequelae of long-standing rheumatoid arthritis. The abdomen was entirely benign, but rectal examination revealed an enlarged, nontender prostate. White blood cell count was 11,200/mm3. Urinalysis revealed 10-12 white blood cells per high power field and 15-20 red blood cells per high power field. Two blood cultures from admission grew Salmonella species sensitive to all antibiotics. Urine cultured at the time of admission remained sterile. The patient was treated initially with tobramycin and ciprofloxacin and was changed to ceftriaxone 1 g intravenously every 12 hr when the Salmonella was identified. Ultrasound examination confirmed an enlarged prostate but disclosed no ureteral or renal abnormalities. Intravenous pyelogram also revealed the enlarged prostate but was otherwise unremarkable. On the ninth hospital day a transurethral resection of the prostate (TURP) was performed with histologic evidence of abscesses containing acute inflammatory cells in the resected tissue. The tissue itself was culture negative. He gradually defervesced and completed a 14-day course of parenteral therapy. The patient did well for about 6 months at which point he developed anterior chest wall pain for which he applied a heating pad. A second degree burn developed which ulcerated and began to drain. Culture revealed Salmonella species with a similar sensitivity pattern as the previous isolate. Local care as well as courses of oral ciprofloxacin and chloramphenicol failed to eradicate the drainage. The patient underwent surgical excision of the sinus tract 11 months after the initial bacteremia. Surgical specimens again grew Salmonella. Unfortunately, neither this nor the previous chest wall isolate was saved for further analysis. The area continued to drain and bone scan was consistent with osteomyelitis of the left sixth rib. Ceftriaxone 2 g intravenously per day was begun. The following month (16 months after the initial bacteremia) the patient underwent extensive debridement of the anterior chest wall with removal of the sixth and seventh ribs, and closure via a pectoralis myocutaneous flap. Forty-eight hours postoperatively, the patient suffered an acute myocardial infarction and expired. Postmortem revealed severe coronary artery disease. No additional focus of Salmonella infection was found.

Injectable gold compounds: an overview.

Injectable gold compounds have enjoyed widespread, but occasionally controversial, use in rheumatoid arthritis since the 1920s. This overview examines the data from controlled trials and longer-term observational studies. We conclude that gold is equivalent to other widely used second-line agents in terms of efficacy. Toxicity profiles are similar, apart from methotrexate. It is most efficacious and toxic in the first 2 yr of treatment. There appears to be a dose-response relationship for both efficacy and toxicity. Gold is one of the few agents that decreases the rate of progression of erosions (RR 0.38, 95% CI 0.23-064). Gold compounds, therefore, have a definite place in the rheumatologist's armamentarium, but further research is required to determine optimal monitoring regimes as well as the role of maintenance therapy and combination therapy.

A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma

BACKGROUND: Previous clinical studies have demonstrated that injectable gold salts and the oral gold compound, auranofin, possess significant steroid-sparing effects in the treatment of asthma. OBJECTIVES: The objectives of this investigation were to determine whether auranofin could reduce oral corticosteroid requirements and to evaluate the safety of auranofin in the treatment of chronic corticosteroid-dependent asthma. METHODS: Patients with asthma were eligible if they required at least 10 mg of prednisone per day for control and prevention of asthma exacerbations. Two hundred seventy-nine patients with chronic corticosteroid-dependent asthma (requiring ≥ 10 mg/day) were randomized to receive auranofin, 3 mg twice daily, or placebo during an 8-month clinical trial, which was divided into three phases including: a 4-week baseline period (phase I), a 6-month double-blind treatment and steroid reduction period (phase II), and a 4-week posttreatment observation period during which steroid and auranofin doses or placebo doses were maintained at levels achieved by the end of phase II (phase III). The primary efficacy variable was “therapeutic success” or reduction of daily corticosteroid use by 50% or more. RESULTS: The proportion of patients in the auranofin group achieving therapeutic success (41%) was significantly higher than that in the placebo group (27%) ( p = 0.01). This effect was greatest in patients requiring 10 to 19 mg of oral prednisone per day at baseline ( p < 0.001). In all treated patients, including those who did and did not complete the trial, significant reduction (≥50% of baseline) in oral corticosteroid dosage was achieved in the auranofin group (60%) compared with the placebo group (32%) ( p < 0.001). There were no significant differences between treatment groups in symptoms, concomitant medication use, or lung function. Mean serum total IgE levels decreased significantly from baseline in the auranofin group (-44.63 IU/ml) compared with the placebo group ( p = 0.001). Gastrointestinal and cutaneous adverse events were greater in the auranofin group. CONCLUSIONS: Auranofin demonstrated a steroid-sparing effect without concomitant worsening of symptoms or lung function and appeared to be more effective in patients dependent on 10 to 19 mg of prednisone per day. Therefore this study has demonstrated that auranofin is useful as a steroid-sparing agent in the treatment of chronic corticosteroid-dependent asthma. (J A LLERGY C LIN I MMUNOL 1996;98:317-24.)

MULTIPLE-OUTCOME META-ANALYSIS OF CLINICAL TRIALS

When several clinical trials report multiple outcomes, meta-analyses ordinarily analyse each outcome separately. Instead, by applying generalized-least-squares (GLS) regression, Raudenbush et al. showed how to analyse the multiple outcomes jointly in a single model. A variant of their GLS approach, discussed here, can incorporate correlations among the outcomes within treatment groups and thus provide more accurate estimates. Also, it facilitates adjustment for covariates. In our approach, each study need not report all outcomes nor evaluate all treatments. For example, a meta-analysis may evaluate two or more treatments (one 'treatment' may be a control) and include all randomized controlled trials that report on any subset (of one or more) of the treatments of interest. The analysis omits other treatments that these trials evaluated but that are not of interest to the meta-analyst. In the proposed fixed-effects GLS regression model, study-level and treatment-arm-level covariates may be predictors of one or more of the outcomes. An analysis of rheumatoid arthritis data from trials of second-line drug treatments (used after initial standard therapies prove unsatisfactory for a patient) motivates and applies the method. Data from 44 randomized controlled trials were used to evaluate the effectiveness of injectable gold and auranofin on the three outcomes tender joint count, grip strength, and erythrocyte sedimentation rate. The covariates in the regression model were quality and duration of trial and baseline measures of the patients' disease severity and disease activity in each trial. The meta-analysis found that gold was significantly more effective than auranofin on all three treatment outcomes. For all estimated coefficients, the multiple-outcomes model produced moderate changes in their values and slightly smaller standard errors, to the three separate outcome models.

MULTIPLE‐OUTCOME META‐ANALYSIS OF CLINICAL TRIALS

When several clinical trials report multiple outcomes, meta-analyses ordinarily analyse each outcome separately. Instead, by applying generalized-least-squares (GLS) regression, Raudenbush et al. showed how to analyse the multiple outcomes jointly in a single model. A variant of their GLS approach, discussed here, can incorporate correlations among the outcomes within treatment groups and thus provide more accurate estimates. Also, it facilitates adjustment for covariates. In our approach, each study need not report all outcomes nor evaluate all treatments. For example, a meta-analysis may evaluate two or more treatments (one ‘treatment’ may be a control) and include all randomized controlled trials that report on any subset (of one or more) of the treatments of interest. The analysis omits other treatments that these trials evaluated but that are not of interest to the meta-analyst. In the proposed fixed-effects GLS regression model, study-level and treatment-arm-level covariates may be predictors of one or more of the outcomes. An analysis of rheumatoid arthritis data from trials of second-line drug treatments (used after initial standard therapies prove unsatisfactory for a patient) motivates and applies the method. Data from 44 randomized controlled trials were used to evaluate the effectiveness of injectable gold and auranofin on the three outcomes tender joint count, grip strength, and erythrocyte sedimentation rate. The covariates in the regression model were quality and duration of trial and baseline measures of the patients' disease severity and disease activity in each trial. The meta-analysis found that gold was significantly more effective than auranofin on all three treatment outcomes. For all estimated coefficients, the multiple-outcomes model produced moderate changes in their values and slightly smaller standard errors, to the three separate outcomes models.

Effects of Second-line Drugs on the Progression or Regression of Rheumatoid Nodules

Second-line drugs may have different effects on nodules than on synovitis. In this study, we have begun to evaluate the effects of these agents on rheumatoid nodules. The appearance, progression, or regression of rheumatoid nodules were studied in an open series of 119 patients with rheumatoid arthritis (RA) seen at an academic center over the last 20 years. Fifty-six of these patients had nodules during a mean period of observation of 5.4 years. During this time, 1-5 second-line drugs were taken. Our population had a higher prevalence of nodules (47%) than did patients in most previously reported series. New nodule formation and nodule progression were most often associated with methotrexate (n = 21, 68%) but were also noted during use of gold salts (n = 6, 18%) and hydroxychloroquine (n = 3, 8%). Nodule regression and even complete resolution of nodules was most often observed with hydroxycholoroquine (n = 14, 36%) and with sulfasazine (n = 6, 32%) and injectable gold (n = 5, 14%). Changes in nodules occurred without consistent relation to synovitis. Second-line drugs that may modify the articular aspects of RA may exert varying effects on nodules. These very different effects, if confirmed, suggest important differences in drug mechanisms of action on this basic manifestation of RA.

The total costs of drug therapy for rheumatoid arthritis

We created a model to estimate the total medication costs of treating patients with rheumatoid arthritis with 6 second-line agents for the first 6 months of treatment. Drug costs were obtained from a survey of pharmacies; monitoring costs were calculated from utilization information obtained in a survey of rheumatologists; toxicity costs were obtained using decision trees to represent the evaluation and treatment of potential toxicities. Monitoring and toxicity costs were estimated using costs from the Boston University Medical Center or, for hospitalizations, using appropriate diagnosis-related group categories. The sum of the 3 components determined the total medication costs. The least expensive medication was penicillamine, at $10.62/week, and the most expensive was injectable gold, at $30.89/week. In terms of monitoring costs, methotrexate had the highest costs associated with necessary laboratory tests and office visits. Hydroxychloroquine had the lowest monitoring costs for office visits, and oral gold had the lowest for laboratory costs. Hematologic toxicities were the largest component of toxicity costs for all 6 medications, and renal toxicities were costly for patients taking oral gold, penicillamine, and injectable gold. Total medication costs revealed oral gold as the least expensive medication and injectable gold as the most expensive. The combination of monitoring and toxicity costs accounted for more than 60% of the total costs for all medications except injectable gold. In all cases, the cost of treating toxicities was the smallest of the 3 components. When calculating the costs of drug therapy, it is important to consider not only the price of the drug, but also the costs of monitoring and treating the toxicities that might occur. Failure to do so will result in underestimating the true costs of treatment with these medications.

Changing Therapy from Injectable Gold to Auranofin with Rheumatoid Arthritis

Changing Therapy from Injectable Gold to Auranofin with Rheumatoid Arthritis

Randomized trial of switching rheumatoid arthritis patients in remission with injectable gold to auranofin

This prospective unblinded 24-month-study compared the therapeutic value of oral gold with injectable gold to maintain rheumatoid arthritis (RA) patients in clinical remission and prevent the progression of erosive disease. Forty-six patients with definite RA in remission with injectable gold were randomized into two groups: a control group, continued on maintenance injectable gold (Solganal, aurothioglucose, 50-100 mg, intramuscularly, 2 to 4 weeks); and an experimental group, switched to oral gold (6-9 mg auranofin by mouth daily). Only 29% of the original 24 oral gold patients remained on assigned treatment at 24 months compared with 64% of the injectable gold group. By six months, over one-half of the oral gold patients had electively stopped their randomized therapy. Sixty-seven percent of the oral gold patients had adverse reactions, mostly gastrointestinal complaints, compared with one proteinuria in the injectable gold group. The oral gold group experienced significantly more deterioration in all the primary measures of treatment effect over the follow-up period. At the termination of the trial, 88% of the group had increases of 5 or more points in radiographic scores suggesting progression of erosive disease compared with only 29% of the control group. These data suggest that oral gold is not an effective substitute for injectable gold in maintaining remission in rheumatoid arthritis.

Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials.

Preferred drugs for rheumatoid arthritis (RA) should be those that have maximal efficacy with the least toxicity. We evaluated the efficacy and toxicity tradeoffs for drugs frequently used in the treatment of RA. We updated 2 metaanalyses of published clinical trials, by adding trials published through 1990 and trials of azathioprine (AZA). We tested 3 different definitions of efficacy, each plotted against 3 different toxicity measures, for antimalarial drugs, methotrexate (MTX), auranofin, injectable gold, D-penicillamine, sulfasalazine (SSZ), AZA, and placebo. Efficacy measures included composite efficacy (a combination of joint count, grip strength, and erythrocyte sedimentation rate), tender joint count alone, and a measure based on how many patients dropped out due to inefficacy. Toxicity measures were the proportion dropping out due to toxicity, the same dropouts with side effects weighted for severity using a modification of a published toxicity index, and the proportion with severe toxicities (defined as a score of at least 7 of 10 on the toxicity index). The latter were usually organ toxicities (e.g., cytopenias and renal involvement). All 9 efficacy/toxicity tradeoff plots suggested that MTX and antimalarial drugs had the highest efficacy relative to toxicity. MTX scored among the most efficacious of the drugs and, of these, had the least toxicity. Antimalarial drugs, though showing only moderate efficacy, had the lowest toxicity rate of all the drugs. SSZ scored close to MTX but was, in general, slightly more toxic. In the short-term context of clinical trials, antimalarial drugs and MTX have the best efficacy/toxicity tradeoffs and may, therefore, be the preferred drugs.

Pharmacological Management of Juvenile Rheumatoid Arthritis

The goals of pharmacotherapy in juvenile rheumatoid arthritis (JRA) are to suppress chronic synovitis which causes potential cartilage destruction and deformities, to control the systemic effects of inflammation (including growth retardation and nutritional deficits), relieve pain and limit psychological impact of disease. Currently available methods include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, salicylates, naproxen, tolmetin, ibuprofen and indomethacin; disease modifying antirheumatic drugs (DMARDs) such as oral and injectable gold salts, hydroxychloroquine, penicillamine, oral and injectable methotrexate, and sulfasalazine; oral (daily or on alternate days), intravenous pulse or intra-articular corticosteroids; immunosuppresants, including cyclophosphamide, chlorambucil, cyclosporin, and azathioprine; and gammaglobulin and other experimental therapies. Over the past 10 years, rheumatologists have adopted more aggressive pharmacological treatment of JRA. As time progresses and the safety of certain drugs such as methotrexate and sulfasalazine becomes clearer, wider and earlier use of these agents can be expected. Still the approach to treatment is a 'step by step' one, starting with the classical NSAIDs and ending with the DMARDs as needed.

Plasma cell stomatitis-pharyngitis in cats 40 cases (1973-1991)

Summary Clinical signs, laboratory findings, and treatment results of 40 cats with the histologic diagnosis of plasma cell stomatitis-pharyngitis are discussed. Median age was 7.1 years, with no discernable sex predilection. Anorexia and difficulty prehending food were the most common clinical signs. Hyperproteinemia with associated hyperglobulinemia was the most common laboratory finding. Of various treatments, administration of corticosteroids or injectable gold (aurothioglucose) proved most effective in controlling the clinical signs.

Audit of full blood count monitoring in patients on longterm gold therapy for rheumatoid arthritis

The use of injectable gold in the treatment of rheumatoid arthritis (RA) is hampered by the high incidence of adverse reactions of which myelotoxicity is potentially the most serious. Regular full blood count (FBC) monitoring prior to each injection, a practice which requires much time and effort, has never been fully evaluated. Of 154 patients who were started on gold and followed by the lifetable method for up to 10 years, five patients were withdrawn from treatment because of myelotoxicity, thrombocytopenia in all cases: the two most serious cases occurred early at 3 and 7 months after starting treatment; three mild cases occurred at 17, 37 and 60 months, were of slow onset and reversed spontaneously. Clearly, FBC monitoring is justifiable in the first two years of treatment when the incidence of adverse reaction is highest. Further investigation is required to justify this practice after two years of uncomplicated treatment.

Requiem for Gold?

Letters1 June 1991Requiem for Gold?Luis Fernandez-Herlihy, MDLuis Fernandez-Herlihy, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-114-11-993_3 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editors:The time has come to stop the use of injectable (or any other) gold in the treatment of adult rheumatoid arthritis. The recent report by Epstein and colleagues (1) on the apparent ineffectiveness of parenteral chrysotherapy is highly significant. Since the first reports of the use of gold therapy in rheumatoid arthritis, 64 years ago, its efficacy has been hotly debated and its toxicity has been amply documented. A recent study (2) found that of six commonly used second-line drugs for the treatment of rheumatoid arthritis (methotrexate, injectable gold, D-penicillamine, sulfasalazine, auranofin, and antimalarials), injectable gold had...

Meta-analysis: Auranofin is the least effective and injectable gold is the most toxic of second-line drugs for rheumatoid arthritis

Source Citation Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum. 1990 Oct;33:1449-61.

Exacerbation of Psoriasis by Chrysotherapy

To the Editor.— Psoriatic arthritis typically consists of psoriatic skin and nail changes concomitant with asymmetrical, pauciarticular joint disease. The primary therapeutic modality advocated for joint involvement is the administration of an anti-inflammatory medication. Many patients with moderate to severe psoriatic arthritis receive a disease-modifying agent such as injectable gold (chrysotherapy). Although dermatitis occurs in 15% to 25% of patients receiving gold therapy, 1 the ability of chrysotherapy to exacerbate psoriasis has not been proven; neither a major review of drug-induced psoriasis 2 nor a standard textbook of dermatology 3 lists gold as a precipitant. We describe a patient with sparsely distributed, long-standing psoriasis who developed diffuse psoriasis shortly after the initiation of intramuscular gold sodium thiomalate, and review the English literature from 1969 to 1990 for reports of possible gold-induced psoriasis, aided by a Medline search. Report of a Case.— A 54-year-old white man was seen with a 14-year

The comparative efficacy and toxicity of second‐line drugs in rheumatoid arthritis results of two metaanalyses

We performed 2 metaanalyses of placebo-controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX), injectable gold, D-penicillamine (DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs, the second-line drugs most commonly used to treat rheumatoid arthritis (RA). For the efficacy study, we applied a set of inclusion criteria and focused on trials which provided information on tender joint count, erythrocyte sedimentation rate, or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest, and for each drug, we combined the treatment groups. For each outcome, results showed that AUR tended to be weaker than other second-line drugs. The results of the 3 outcome measures were synthesized into a composite measure of outcomes, and AUR was significantly weaker than MTX (P = 0.006), injectable gold (P less than 0.0001), DP (P less than 0.0001), and SSZ (P = 0.009) and was slightly, but not significantly, weaker than antimalarial agents (P = 0.11). We also found heterogeneity among antimalarial agents, in that patients treated with chloroquine did better than those treated with hydroxychloroquine. We found little difference in efficacy between MTX, injectable gold, DP, and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g., AUR) second-line drugs. None of the reported interdrug comparative trials we reviewed were this large. For the toxicity study, our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug. Overall, 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P less than 0.05) and higher total dropout rates (P less than 0.01) than any other drug; 30% of gold-treated patients dropped out because of side effects versus 15% of all trial patients. Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus, of the commonly used second-line drugs, AUR is the weakest, and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)