Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension.

OBJECTIVE: To investigate the usefulness of hydroxychloroquine (HCQ) dose-loading to increase the percentage of responders or rate of response in treating rheumatoid arthritis (RA). METHODS: Two hundred twelve patients with early RA (mean duration 1.5 years) were enrolled in a 24-week trial. Patients were stabilized with 1,000 mg naproxen/day and then began a 6-week, double-blind trial comparing treatment with HCQ at 400 mg/day (n = 71), 800 mg/day (n = 71), and 1,200 mg/day (n = 66), followed by 18 weeks of open-label HCQ treatment at 400 mg/day. RESULTS: All patients had mild, active disease at the time of initiation of HCQ treatment (31-43% rheumatoid factor positive; no previous disease-modifying antirheumatic drugs; mean swollen joint count 8.6-10.4). Based on the Paulus criteria, response during the 6-week double-blind portion of the study was 47.97%, 57.7%, and 63.6% in the 400 mg/day, 800 mg/day, and 1,200 mg/day groups, respectively (P = 0.052). Discontinuations for adverse events were dose related (3 in the 400 mg/day group, 5 in the 800 mg/day group, 6 in the 1,200 mg/day group). Most involved the gastrointestinal (GI) system, with the background naproxen treatment possibly contributing. Ocular abnormalities occurred in 17 of 212 patients (8%) but were not dose related. CONCLUSION: Dose-loading with HCQ increased the degree of response at 6 weeks in this group of patients with early, predominantly seronegative RA. Adverse GI events were dose related, while adverse ocular events were not.

Gallstones, cholecystectomy, and colorectal cancer.

PURPOSE: To examine the controversial association of gallstones, cholecystectomy and colorectal cancer. Methodologic explanations for the association include ascertainment bias, unequal diagnostic testing, and necropsy selection bias. Necropsy screening, which eliminates unequal diagnostic testing and ascertainment bias and reduces necropsy selection bias, was used to study this controversy. METHODS: Adult necropsies at the University of Kansas Medical Center from 1950 to 1984 were reviewed. Patients with colorectal cancer, gallstones, or who had cholecystectomy during life were excluded. The remaining patients were those in whom neither colorectal cancer nor gallstones were suspected during life (reducing selection bias). The occurrence of gallstones and colorectal cancer among these individuals was then determined (reducing ascertainment bias and unequal diagnostic testing). RESULTS: Of 7485 persons receiving necropsy, 239 had colorectal cancer diagnosed during life and an additional 604 had gallstones or cholecystectomy, leaving 6642 patients available for study. Overall, no association between colorectal cancer and gallstones was found. In women, gallstones were associated with colorectal cancer; 6/447 (1.3%) with gallstones had colorectal cancer compared with 11/2259 (0.4%) without gallstones who had colorectal cancer, p = 0.048, odds ratio 2.78 (95% CI 0.84-8.25). A stronger association was found between right-sided colorectal cancer and gallstones (odds ratio 6.79, 95% CI 1.14-46.46). CONCLUSIONS: These data suggest an association between gallstones and colorectal cancer among women. Gallstones may indicate patients at higher risk for colorectal cancer. Studies associating cholecystectomy with colorectal cancer may be explained--not by ascertainment bias--but, rather, by susceptibility bias. The reason for the cholecystectomy (gallstones) may be the correct association and not the cholecystectomy itself.