A Short History of Rheumatoid Arthritis Therapeutics

Why did you want to become a rheumatologist? For me, the decision wasn’t hard. As a medical resident, reading electrocardiograms at 2 am—or at 2 pm for that matter—didn’t appeal to me. Endocrinology seemed to lack any complexity; a simple look at lab tests either meant the patient was or was not hypothyroid. I lacked the passion for inserting endoscopes into any orifice. I had whittled my choices to a few remaining possibilities, and then I experienced a defining medical moment. I am referring to those clinical experiences that can immediately transform you and set you on your career path.

It happened during my junior residency year. I was in charge of a moderately busy medical ward consisting of older patients battling pneumonias or a flare of their chronic obstructive pulmonary disease brought on by exposure to the fierce winds and endless snowfalls of January in Montreal. It was there that I met Michael.

Dr. Koch isolating the Rinderpest virus in his laboratory.

Michael (name has been changed) was a delightful adolescent male, at least 40 years younger than any of my other patients. He had a long history of systemic juvenile arthritis. His illness began when he was five and it never let up. I was shocked to learn that he was nineteen years old; his growth had been stunted by his disease, leaving him no taller than about 4 feet 5 inches. His cherubic, slate grey face with undersized mandibles displayed the ravages of too many years of prednisone and gold therapies. He had already undergone several orthopedic procedures and one of them, his knee replacement, had become infected.

He was admitted for a lengthy stay consisting of surgery, followed by a prolonged course of antibiotics, followed by more surgery. Yet Michael’s resilience and determination to get better never wavered. He was upbeat and cheerful to a fault. Many years later, I learned that this personality trait was a common characteristic among rheumatoid arthritis (RA) patients, especially those with more severe disease. Yet what struck me most about Michael’s care was his treatment with gold, specifically intramuscular gold shots given every two weeks.

Origins of Gold Treatment

Like so many stories in medicine about the origins of particular therapies, this one gets a bit confusing. Many Europeans claim credit for the idea of using gold to treat RA. In fact, it seems that just about every country in the European Union lays claim to having been the “first” to discover the benefits of this mineral therapy. In a wonderful review of the topic published in 1945 by Dr. Thomas Fraser of Glasgow, the author traces the origins of gold therapy to 1890 when Dr. Heinrich Hermann Robert Koch (of Koch Postulates fame) first described the benefits of gold in inhibiting the in vitro growth of the tubercle bacillus.

In the early part of the twentieth century, many physicians considered tuberculosis (TB) to be responsible for a host of chronic diseases, including RA. Since heavy metal therapy was considered to be useful in treating TB, it made sense to use gold to treat the deforming arthritis thought to be “related” to TB. In 1914, Dr. Holger Møllgaard introduced the concept of intravenous gold to treat TB, and in 1926, Drs. Frederic Lewy and Rudolf Freund observed the benefits of a new gold compound, solganal, in treating streptococcoal infections. That same year, Dr. Ingemar Hedenius reported favorable results using gold to treat septic polyarthritis.

By most accounts, the French rheumatologist Jacques Forestier is credited with being the first to publish a favorable clinical study of gold in RA in 1932. Working in a hospital in Aix-Les-Bains, the site of the ancient Roman baths in France, he completed a reasonably well-designed study of 48 patients. His conclusion that, “it [gold] may be regarded as the best chemical for the treatment of rheumatoid arthritis,” held sway for the next several decades.

The popularity of gold salt therapy was aided by the relatively slow progress of rheumatology research over the next several years. Then Philip Hench and his colleagues at the Mayo Clinic in Rochester, Minn., made a remarkable set of observations. The story begins on April Fools Day of 1929, when a 65-year-old patient of his with RA told him a remarkable story. After four years of relentless disease, he abruptly went into remission after developing the sudden onset of jaundice. The jaundice lasted five weeks, but the RA did not relapse until several weeks after the jaundice disappeared.

Over the next fifteen years, Dr. Hench observed this similar phenomenon in sixteen other patients. He began to suspect that the “ameliorating effect of pregnancy,” which many clinicians had previously observed, “was analogous to, if not identical with, that which may occur during jaundice and that the same agent might be responsible for both, although the mechanism for developing the chemical agent might be different.” The Mayo group noted this phenomenon in other diseases as well, including psoriatic arthritis, asthma, hay fever, and myasthenia gravis. They concluded that there must be a substance X that provided group-specific rather than disease-specific benefits. Working with his Mayo colleagues Dr. Charles Slocumb and the biochemist Edward Kendall, they concluded that this mystery compound could be derived from the adrenal cortex.

Based on this assumption, they began treating a number of patients with a variety of adrenal and bile salt extracts, but they failed to achieve any breakthroughs. In January 1941, they decided to administer compound E, or 17-hydroxy 11-dehydrocorticosterone, to patients with RA. This compound increased the resistance of animals against reactions to typhoid vaccine, and it had been observed that these vaccines could induce striking but transient remissions of RA.

The only problem was they lacked a sufficient supply to administer to patients. So, as Hench noted, “I recorded this idea in my pocketbook.” It took seven years for the actual experiment to take place. In 1948, the first patient, who had longstanding refractory RA, was treated with 100 mg of the compound daily, and by the third day she had dramatically improved. The rest is history—Hench and Kendall shared the 1950 Nobel Prize with Tad Reichstein, an organic chemist in Basel who had simultaneously described the chemical composition of cortisone. Perhaps equally amazing to this story is the speed with which the Nobel Prize was awarded. To be precise, the ceremony in Stockholm occurred less than 27 months after the first patient was treated in Rochester and 19 months after the authors had presented their data to a public forum for the first time.

Modern RA Treatment

Flash forward to the late 1970s. Rheumatologists still believed in pyramids. We were stuck in the era of treating RA damage after the fact. There were no effective strategies to prevent damage. If there was a concept diametrically opposite to the current paradigm of treating to target, then this was it and the ’70s was its heyday. A rheumatology mentor of mine described his role then as being similar to the relief pitcher of the baseball team trailing by five runs who is brought in to keep the score respectable (European and Canadian readers can replace “pitcher” with football and hockey goaltender, respectively!).

It took methotrexate to shake us out of our complacency. Its precursor, aminopterin, had been regarded as a potent inhibitor of connective tissue proliferation. This effect was thought to mimic the pharmacologic effect of the newly discovered corticosteroids. Interestingly, Richard Gubner, a cardiologist at Kings County Hospital in Brooklyn, N.Y., first reported the use of aminopterin in patients with RA or psoriatic arthritis in 1951. Despite its potential for use in the rheumatology population, the next generation compound, methotrexate, did not gain widespread use for another thirty years. Four randomized clinical trials published in 1984–85 demonstrated the beneficial effects of methotrexate when administered to patients with established disease who had failed to respond to other therapies in use at the time, such as gold salts and D-penicillamine.

The 1980s were also notable for the explosive pace of immunology research using newly developed technologies. Dr. Lloyd Old (who died in November 2011) and colleagues at Memorial Sloan-Kettering Cancer Center in New York City previously had demonstrated an endotoxin-induced serum factor that could cause tumor-cell necrosis. They named it tumor necrosis factor, or TNF. Others identified a homologous factor, termed “cachetin,” which was thought to be responsible for the wasting seen in hosts with certain cancers or infections.

Bruce Beutler, the 2011 co-winner of the Nobel Prize in Physiology or Medicine for his work in toll-like receptors, showed that passive immunization with rabbit antiserum or purified immunoglobulin raised against murine TNF–protected mice from the lethal effects of bacterial lipopolysaccharide. Simply stated, these investigators believed they had discovered a potential therapy to protect the host against septic shock.

A small start-up biotechnology firm invested heavily in the development of a therapeutic monoclonal antibody to bacterial lipopolysaccharide, provisionally named “centoxin,” intended for the treatment of sepsis. Jan Vilcek, MD, working at NYU Langone Medical Center in New York City, had recently recruited to his lab a talented postdoctoral scientist, Junming Le, whose expertise lay in the newly developed science of monoclonal antibody technology. (Georges Kohler and Cesar Milstein had recently been awarded the Nobel Prize in 1984 for their work in developing this technology.) One of the antibodies, A2, not only bound to TNF with high affinity and selectivity, but also showed a potent neutralizing activity against TNF, which suggested that it might have therapeutic potential.

As mouse antibodies were known to be unsuitable for long-term therapeutic application, the company developed a chimeric antibody, cA2, by joining the variable region of the original mouse antibody A2 with human immunoglobulin G1 sequences. However, clinical trials proved to be a disaster. The antibody had no benefit in treating sepsis. In 1992, the U.S. Food and Drug Administration (FDA) denied approval for centoxin, plunging the start-up company, Centocor, into a financial crisis.

Fortunately, Drs. Marc Feldmann and Ravinder Maini at the Kennedy Institute of Rheumatology in London persuaded Centocor to provide them with enough cA2 to conduct a small open clinical trial in patients with RA. The results of this study were dramatic, showing both considerable relief of the severity of clinical symptoms and substantial decrease in inflammatory markers in the blood. Thus, cA2 became the first TNF-blocking agent to be successfully used in humans. Six years of clinical trials ensued before the FDA approved cA2 (by then re-baptized infliximab, or Remicade) for RA and Crohn’s disease.

Looking back at the evolution of RA therapeutics, it is easy to suggest that serendipity played a major role in drug development. No doubt most great discoveries require some proper alignment of the stars, but I would argue that many of the breakthroughs occurred because of the careful diligence of the investigators. They often followed false leads, but kept their minds open to all the possibilities.

What happened to Michael? Unfortunately, the therapeutic revolution arrived too late to prevent the damage that required so many surgeries to repair. However, the biologics allowed him to completely wean off his dreaded prednisone. Michael’s current rheumatologist tells me that he is grateful for these small victories.

Taking care of Michael had a profound effect on my career choice. Thirty years ago, we could not effectively treat rheumatoid arthritis. I think that luck or fate determined patient outcomes more than our treatments. But all that has changed. We have not yet achieved a cure for rheumatoid arthritis, but we are getting so much closer to that target.

Dr. Helfgott is physician editor of The Rheumatologist and associate professor of medicine in the division of rheumatology, immunology, and allergy at Harvard Medical School in Boston.