An American in Paris

Paris, a magnificent city that invariably dazzles, provided a grand stage for the 2008 EULAR Congress, an international meeting that grows continuously in size and prestige. People from all over the world gleefully flocked to the Paris edition, but, thankfully, English is the official language of the EULAR meeting. In the lecture rooms and corridors of the congress center, an American like me could feel at home. Outside on the streets of Paris, however, the going was tougher. Although I got an “A” in high school French, other than greeting people with bonjour, I was otherwise wordless in France’s mellifluous language. With my guidebook in hand as I strolled the tree-lined boulevards, I was unmistakable as a lost and bewildered tourist.

Despite speaking English virtually nonstop at EULAR, I had a French saying that kept circulating in my head: “Plus ça change, plus c’est la même chose.” The translation is simple: “The more things change, the more things are the same.” While this saying, with its cynical and world-weary view, may be true in many spheres of life, it is not true in rheumatology. Indeed, one of the main messages of this year’s EULAR congress (which will no doubt be reprised at the ACR meeting in San Francisco) is that things have changed in rheumatology—and I am talking big-time change.

Frequently, in medicine, improvements in clinical outcomes are gradual and incremental, with studies of tens of thousands of patients needed to show appreciable difference.

At present, in the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, change is not subtle and it is not small. Rather, the change is a massive transformation of a global scale. It is my firm belief that, if rheumatology is to flourish in the future, it has to acknowledge the ramifications of this change and set a brand new agenda. If we, as rheumatology providers, do not harness and channel this change, the survival of the specialty may become precarious.

RA: A (Formerly) Impossible Challenge

Consider one of the satellite symposia at EULAR entitled “Mission Possible: Remission in Rheumatoid Arthritis” (or something like that). The title is a clever play of words on the old TV show (and, I guess, a Tom Cruise movie). While I did not attend this symposium, I can imagine the thrust of the discussion and the overriding message that remission in RA is possible.

Thirty years ago, remission in RA would have been a dream or fantasy, a piece of science fiction rivaling those of the Frenchman Jules Verne, who spun tales about rockets to the moon and submarines under the seas. Furthermore, thirty years ago, investigators believed that new approaches to control RA would require drastic, even dangerous, interventions that would clobber the immune system and leave the patient near the brink of disaster.

In 1970s, when I started my career in rheumatology, the clinical trials sparking interest involved thoracic duct drainage, total lymph node irradiation, and plasmapharesis. Despite the extreme nature of these interventions, their efficacy was, in fact, limited. Coupled with emerging data that RA had a mortality rivaling that of certain malignancies, rheumatologists seemed poised for an even more aggressive treatment assault. The analogy with cancer treatment seemed strong as rheumatologists ventured to the use of high dose chemotherapy, broad-spectrum anti-lymphocyte antibodies, and other radical techniques to extirpate pathogenic T cells that were thought to drive the RA fire.

Knowing what havoc cancer treatment can wreak, it seemed inevitable that these approaches would have serious side effects and that more effective therapy would carry the same risk for harm that chemotherapy has in oncology. As an oncologist once told me when I fretted about the scorching toxicity of drugs for leukemia, “You can’t cure cancer with chicken soup.” It seemed that the same would be true for RA.

As a young investigator, I submitted a proposal to the NIH to assess patient acceptance of risk for new RA treatments by performing a standard gamble experiment. Basically, in this proposal, we would ask patients about the chance of death they would accept to get rid of their arthritis. Our question would be phrased as follows. “There is a treatment that can cure your arthritis but it could kill you. What chance of death from this treatment would you accept to be cured?” The other part of the research was to determine the demographic features and other factors (e.g, disease duration or severity) that would influence a patient’s decision.

At that point in history, I estimated that patients with RA would be willing to take less than a 5% chance of death to get cured. Other members of my division gave similar numbers, but the member of our faculty who was then recruiting patients for clinical trials for new RA treatments put the number five times higher. He was right. Indeed, his opinion was in accord with the existing literature indicating that RA patients would accept a 30% chance of dying to get rid of their disease. We never got funded for this grant (What else is new?) so I cannot verify these numbers, but I remain impressed by how bad RA must have been to make patients so desperate for relief.

RA Today: A Different Outlook

Fast-forward thirty years to Paris in 2008. Mission impossible has become mission possible with agents that are well tolerated, easy to administer, and seemingly quite safe, given their efficacy. Indeed, current therapy can lead to remissions rates, stringently defined, of over 50%, and combination therapy can literally stop erosion. Furthermore, as studies presented at EULAR demonstrated, disease modifying antirheumatic drug (DMARD) therapy can prevent the emergence of RA in patients with early signs of synovitis and that, in patients in remission, cessation of DMARDs may be possible.

These results are incredible and are a testament to several factors: the undaunted and pioneering work of rheumatology investigators; the remarkable development of targeted therapies by industry; and an unparalleled cooperation of clinical investigators, in academics and industry, throughout the world.

These accomplishments have produced striking benefits. The lives of patients with RA have been transformed and there is much to inspire both gratitude and pride.

Ce n’est pas la même chose.

In my next column, I will discuss the powerful implications of that statement for rheumatology today.

Dr. Pisetsky is physician editor of The Rheumatologist and professor of medicine and immunology at Duke University Medical Center in Durham, N.C.