We appreciate the comments of Drs. Galland and Clark. The space constraints of my brief editorial precluded an in-depth review of all aspects of the subject, and their comments provide useful insights into the historical and scientific background in which the recent controlled clinical trials of minocycline were done.

Dr. Galland hypothesizes that rheumatoid arthritis is caused by sensitization to bacterial antigens, the absorption of which through the intestinal mucosa is enhanced by NSAID-induced hyperpermeability and inflammation of the bowel. He also suggests that the benefit of minocycline is caused by its antibacterial action on the gut flora. This is an interesting and rational hypothesis, but proving it by comparing the changes in intestinal lactulose permeability and stool leukocyte counts with the changes in clinical measures may be difficult because of the relative insensitivity of the clinical measures, the modest proven clinical benefit of minocycline, and the large placebo response rate noted in the trial by Tilley and colleagues [1].

We knew of Dr. Thomas McPherson Brown's seminal work in this field but were not aware of his favorable report on tetracycline to the Seventh International Congress in Rheumatic Diseases in 1949, the published reports in 1949 and 1951, or the gorilla studies in 1970. We apologize for the inadvertent omission of Dr. Clark as an author in our reference 4. We await the results of the pilot study of intravenous antibiotic agents now being done at Duke University. Considerable additional clinical and basic research is needed to fully evaluate and exploit the leads developed by Drs. Brown, Clark, and others.