Daniel E. Furst

Rational use of disease-modifying antirheumatic drugs.

SummaryThe currently available, most frequently used disease-modifying antirheumatic drugs (DMARDs) include auranofin, azathioprine, D-penicillamine, gold sodium thiomalate, hydroxychloroquine, methotrexate (amethopterin) and sulphasalazine. Controlled trials of these agents are reviewed to compare their relative efficacy and tolerability.Tender joint counts decreased with all drugs, as did joint swelling (measured as the percentage of patients with ≥ 50% improvement in joint swelling). Tender joint count decreased by 8 to 57% in drug-treated patients, compared with 3 to 30% (1 study exceeded this degree of placebo response) in the placebo groups. The ratio of drug to placebo improvement usually averaged greater than 2. A 50% improvement in joint swelling occurred in between 15 and 65% of drug-treated patients. Time to onset of response varied from.6 weeks (with methotrexate) to as long as 18 months (some patients on hydroxychloroquine). The remission rate was inconsistent and unusual in controlled studies (5 to 7%), but very high in some open studies (e.g. 43%). While up to 8% of patients on DMARDs stopped therapy secondary to unsatisfactory therapeutic response (with 1 exception) up to 43% of placebo patients discontinued therapy for this reason. The ratio, of dropouts for unsatisfactory therapeutic response for DMARD compared to placebo was less than 1 in 16 of 22 studies, and it was usually less than 0.5.Laboratory data examined include ESR, rheumatoid factor (RF), immunoglobulins and radiographic data. Ratios of decreases in ESR, comparing drug and placebo, were usually greater than 2. ESRs decreased from 3.6 to 27 mm/h, with gold sodium thio-malate, auranofin and methotrexate being most effective relative to placebo. RF decreased by ≥ 2 tube dilutions in 15 to 53% of the DMARD groups but also decreased in up to 26% of placebo patients, with ratios of drug: placebo usually greater than 2. Immunoglobulins tended to decrease with DMARDs but the data are fragmentary.Radiographic evidence that a drug slows the rate of bony damage is strong evidence that it is a DMARD. These data, however, are not easily available because measurement of bony damage is insensitive and difficult. The best evidence of radiographic efficacy exists for gold, although the data are not uniform even here. Studies with other DMARDs suffer from lack of convincing control populations, methodological failures or small numbers, although trends exist showing that azathioprine and D-penicillamine (and perhaps sulphasalazine and methotrexate) may also slow bony deterioration.The other side of efficacy, of course, is tolerability. By examining dropouts resulting from adverse effects, it was discovered that hydroxychloroquine, sulphasalazine and auranofin were the best tolerated DMARDs, while D-penicillamine appeared most toxic. Finally, a clinically reasonable, although not scientifically or statistically exact, method for comparing DMARDs was developed. This approach was developed a priori and resulted in the following conclusions: (a) for efficacy, gold sodium thiomalate and methotrexate were generally equivalent, D-penicillamine and azathioprine were marginally less effective, and hydroxychloroquine, sulphasalazine and auranofin were equal and less effective than the others; (b) on the other hand, hydroxychloroquine, azathioprine and methotrexate caused the least dropouts due to adverse reactions during these 6- to 12-month studies, while auranofin and sulphasalazine were equal and slightly less well tolerated; D-penicillamine and gold sodium thiomalate were most toxic.

Development of a Composite Outcome Measure for Systemic Sclerosis RelatedInterstitial Lung Disease

OBJECTIVE While systemic sclerosis-related interstitial lung disease (SSc-ILD) trials predominantly use forced vital capacity (FVC) as the primary outcome, combining individual outcomes may lead to a more comprehensive measure of treatment response and minimize the risk of type 1 error. The present analysis aimed to develop a composite outcome measure to assess treatment response in SSc-ILD patients. METHODS We used data from the Scleroderma Lung Study I (SLS-I) to create the composite outcome measure. SLS I was a multi-institutional, double-blind clinical trial, in which 158 patients with SSc-ILD were randomized to receive either oral cyclophosphamide (CYC) (titrated to 2.0 mg/kg once daily) or matching placebo for one year. To select the variables for inclusion in the composite outcome, we first performed a univariate analysis using all of the outcome variables measured in SLS I. We subsequently combined the variables with significant treatment effects (p<0.05) in a principal component analysis (PCA) to assess the difference between treatment groups. These variables included the FVC% predicted, computer-based score for quantitative lung fibrosis in the zone of maximum fibrosis (QLF-ZM) from thoracic high-resolution computer tomography (HRCT) scans, transitional dyspnea index (TDI), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at 12 months. RESULTS Of the 158 patients, 82 had complete outcome data and were included in this analysis. There were no significant differences in baseline characteristics between the 82 patients included in this analysis and the remaining 76 patients. The regression model with the first principal component for FVC% predicted, QLF-ZM, TDI and HAQ-DI as the composite outcome demonstrated a significant treatment effect favoring cyclophosphamide (Estimate 0.7 [SE 0.2]; p=0.005). Eliminating FVC% predicted from the composite outcome model did not change the overall treatment effect (Estimate 0.8 [SE 0.2]; p=0.004). CONCLUSION The CYC treatment effect observed from using the composite outcome of FVC% predicted, QLF-ZM, TDI and HAQ-DI was stronger than the effect observed using FVC% predicted alone. These findings suggest that combining patient-reported outcomes with structural and physiologic outcomes into a single outcome may serve as a more robust measure of treatment response compared with FVC alone in SSc-ILD trials.