pharmacology - How did Sulfasalazine become a disease-modifying treatment for rheumatoid arthritis?

Sulfasalazine has been around for about fifty years, starting as an antibiotic. More recently it is used as a disease-modifying anti-rheumatic drug (DMARD, see also arthritis.org). While biologics (biopharmaceuticals) are becoming more widespread in early treatment of some types of RA, Sulfasalazine has a known safety profile and is inexpensive. Sulfasalazine is on the World Health Organization's Model List of Essential Medicines. See section 17.3, Anti-inflammatory medicines.

Wikipedia says:

The mechanism of action is not clear, but it appears that sulfasalazine and its metabolites have immunosuppressive, antibacterial, and anti-inflammatory effects.[refs] It also appears to inhibit the cystine-glutamate antiporter.[ref]

Why was this "old antibiotic" tested as an anti-inflammatory medicine? Is the situation similar to Minoxidil where a "side-effect" turned out to have significant medical value? What is the evidence (if any) that sulfasalazine has a disease-modifying effect in the treatment of RA - that it actually slows down the progress of the disease rather than just temporarily reduce symptoms?

Answer

Question 1:

Why was this "old antibiotic" tested as an anti-inflammatory medicine?

A 2016 publication by the Department of Medicine at both Imperial College Healthcare Trust, and Hammersmith Hospital (both in the UK), titled, "Rheumatoid Arthritis Treatments: A Historical Perspective", states:

"Sulfasalazine: After NSAIDs and Gold, Sulfasalazine (SSZ) is the third oldest drug class that is still available to use as a treatment of RA. In 1938, SSZ was the first drug to be synthesized specifically for RA. The consensus at the time was that RA was the result of infection and accordingly Svartz et al developed the DMARD, SSZ (originally known as salicylazosulfapyridin) by combining the anti-inflammatory, salicylic acid, with the antibacterial sulfapyridine by an azo bond."

Also, according to a publication by the Department of Medicine at Princeton:

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.

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Question 2:

What is the evidence (if any) that sulfasalazine has a disease-modifying effect in the treatment of RA - that it actually slows down the progress of the disease rather than just temporarily reduce symptoms?

A 1995 publication conducted by Adis International affiliates states:

The efficacy of sulfasalazine in RA noted in many noncomparative studies has been confirmed in placebo-controlled trials and comparisons with other disease-modifying antirheumatic drugs (DMARDs). Sulfasalazine therapy produces significant improvements in many clinical and laboratory parameters associated with the disease, including erythrocyte sedimentation rate (ESR), Ritchie articular index (RAI) or number of swollen joints, grip strength and duration of early morning stiffness (EMS).