Old and new drugs used in rheumatoid arthritis: a historical perspective. Part 1: the older drugs.

Rheumatoid arthritis is the paradigmatic immune-mediated inflammatory arthropathy and may be of comparatively recent, New World origin. Apart from the symptom-relieving nonsteroidal anti-inflammatory drugs, whose natural congeners have been in use since antiquity for musculoskeletal pain and inflammation, only a dozen drugs or drug classes--the disease-modifying antirheumatic drugs--are currently in common use in rheumatoid arthritis. Development of these drugs has been a notable achievement of the 20th century. Some were developed serendipitously (glucocorticoids, antimalarials), some were the product of faulty reasoning (gold, D-penicillamine), and others were applied for plausible reasons but whose mechanism remains unproven (sulfasalazine, methotrexate, minocycline). A minority were originally applied on the basis of actions that remain germane to the pathophysiology of rheumatoid arthritis as currently understood (azathioprine, cyclosporine, leflunomide, infliximab, etanercept). Among the latter are the more recently introduced and effective agents. The practical use of these drugs is determined by efficacy-toxicity considerations, which have also driven the recent development of the cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs.

History of enteric coated sulfasalazine in rheumatoid arthritis.

Sulfasalazine was synthesized almost 50 years ago specifically to treat rheumatoid arthritis. At that time bacterial infection was believed to be an important factor in pathogenesis. The linkage of sulfapyridine and salicylate with an azobond was viewed as a method of combining antibacterial and antiinflammatory actions while minimizing gastric irritation. Early therapeutic results were encouraging, but the drug was discarded as an antirheumatic agent for 30 years, until its serendipitous rediscovery. Subsequent controlled trials have confirmed its efficacy, which may be related to sulfasalazine itself or to the sulfapyridine moiety.

Sulfasalazine: II. Some notes on the discovery and development of salazopyrin.

In summing up: salazopyrin is an effective drug, particularly in ulcerative colitis. Serious adverse effects are remarkably rare. Salazopyrin provoked an improvement in 75-80% of cases of UC. It is excellently adapted for long-term treatment and, in this respect, is clearly superior to corticosteroids. It prevents relapses, particularly if the dosage is increased. The main indication for corticosteroids in UC is for acute attacks early in the course of the disease and to influence allergic symptoms during the disease. For acute swelling of the rectum, local treatment with corticosteroids or salazopyrin is often effective. Adverse effects occur in about 15% of cases treated with salazopyrin. They are due primarily to hypersensitivity to the drug. With very few exceptions, they disappear spontaneously or are controlled by corticosteroids or by some other treatment. The allergic pulmonary changes may give rise to a modest dyspnea, which is not fatal. The cyanotic and the yellow-coloring of the skin are harmless side effects. As to sulfa crystals in the kidneys and the urine, for the most part, they can be avoided by simple treatment. Agranulocytosis is a rare complication in the course of treatment with salazopyrin. During the 35 yr that the drug has been used, only 14 cases have been published in the literature. Of this number, three have died, but the treatment of the agranulocytosis is known in only one of them. Nonpublished cases probably exist, but this number does not seem to be great in my experience. In comparison with many other drugs (certain chemotherapeutics and antibiotics), the frequency of serious side effects caused by salazopyrin is remarkably low.

Evolution of olsalazine.

Sulphasalazine was first produced nearly 50 years ago through the inspiration of a Swedish doctor, Dr Nanna Svartz. Later, in controlled trials, this compound was shown to reduce substantially the frequency of recurrent attacks of ulcerative colitis when used as long-term maintenance therapy. Studies into the metabolism of sulphasalazine have shown that, when taken orally, most of the ingested dose reaches the colon intact, and within the colonic lumen, bacteria split sulphasalazine into two breakdown products, sulphapyridine and 5-ASA. 5-ASA was shown to be the active therapeutic moiety while sulphapyridine served simply as a carrier. Olsalazine was developed to retain the property of sulphasalazine of reaching the colon intact, but also to liberate two molecules of 5-ASA with no residual carrier.