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Our Amazing Progress - and More Within Rheumatology's Grasp


Image - Photo of Stephen A. Paget, MD, FACP, FACR
Stephen A. Paget, MD, FACP, FACR
Physician-in-Chief Emeritus, Hospital for Special Surgery
Stephen A. Paget Rheumatology Leadership Chair
In last month's Special Report, I discussed why we need to do better as physicians and as rheumatologists in recognizing and rapidly treating joint and autoimmune disorders -- to yield the best outcome and improved lives for our patients. (See A Call to Arms).

This month, my focus is all the good we have done - advances that have been made in the last 100 years, and particularly in the past 50 - and future challenges. The two reports are interconnected in many ways because, optimally, once we recognize medical problems and develop successful treatments for them, we would hope for rapid dissemination to all the people who need them.

In which disorders have we markedly enhanced the lives of many of our patients? How did (do) we define and measure that improvement? What advances in our knowledge led to those changes?

The infectious disorders that were plagues and diagnostic enigmas in the early part of the last century and that affected the musculoskeletal system to one degree or another included: tuberculosis, syphilis, rheumatic fever, septic arthritis, osteomyelitis, and polio. They came under control in the U.S. and elsewhere with the understanding of infectious agents and development of antibiotics, knowledge of the immune system and development of immunizations, and improvements in public health.

The quantum leap that was made with these disorders occurred because we were able to define their infectious etiology and develop specific antibacterial agents to control them. Here we are talking about cures, not the term "disease modification" that is employed when we discuss rheumatoid arthritis and systemic lupus erythematosus. Also, despite our impressive advances in infection control, the above-mentioned disorders still exist in population pockets in the U.S. and third-world countries where poverty reigns and social disorder exists.

In the latter part of the last century, AIDS/HIV - a disorder that at times affects the joints, muscles and vessels - was transformed from a rapidly and predictably deadly viral disease to a chronic one through extraordinary advances in infectious disease, virology, molecular biology, and immunology. Had HIV occurred in the setting of the scientific knowledge base of the 1950s, it might very well have spread like the influenza plague of 1918.

At about the same time, Lyme disease was defined as being caused by a tick-borne spirochete, responsive to antibiotics and easily detectable with the use of clinical and serological assessments. Interestingly, despite the fact that we know the organism that causes the disease and can, in most cases rid the patient of the offending B. burgdorferi that causes it, some patients develop a chronic, post-Lyme illness. This can mimic rheumatoid arthritis or fibromyalgia and appears to represent a "reactive," antibiotic-unresponsive response to the prior presence of the organism.

Advances in the management of gout came through much more focused scientific research than in other areas of rheumatology. Between 1960 and 1980, improved understanding of purine metabolism occurred, specific enzymatic events that caused hyperuricemia were unearthed, allopurinol (a xanthine oxidase inhibitor), was synthesized, and its optimal use in specific gout and kidney stone patient populations was defined.

With disorders such as rheumatoid arthritis and systemic lupus, we are still focused on unwinding their pathogeneses. Let's start with rheumatoid arthritis (RA), a disorder that when left untreated, invariably leads to some degree of joint damage and patient dysfunction. Thirty years ago, 10 to 20 patients were admitted to our hospital at any given time for the treatment of "RA unresponsive to outpatient care;" now we have none. Fifteen years ago, 25% of patients undergoing joint replacements had RA; now our orthopaedic surgeons see many fewer. Twenty to thirty years ago, rheumatologists commonly saw patients on their first visit presenting with joint deformities and damage, nodules on their elbows, and so-called extra-articular manifestations, such as pleurisy, blood vessel inflammation, nerve and neck damage; today, those are rare. Recent studies have even shown a lengthening of the life span of RA, compared to 30 years ago.

While we still have a long way to go, to what do we owe this amazing turn-around? First, we had to appreciate the true personality and destructive tendencies of untreated RA. Epidemiologic techniques revealed a disturbing picture of a systemic disorder that, left to its own devices, caused joint erosions within its first two years, caused 50% of patients to leave work permanently within 5-10 years after the onset of the illness, and shortened life by 5-10 years, mostly due to premature cardiovascular disease.

Once this was appreciated, a "war on RA" began, similar to the one waged against cancer many years ago. The war consisted of a profound change in physician, scientist and pharmaceutical industry "mind sets" about RA, in which early, aggressive treatment became mandatory. With RA seen as a "medical emergency," the scientific community went into overdrive to find more effective and safer treatments. From these profound changes in focus and interest arose a paradigm shift in treatment, in which the strongest of our medications (disease modifying anti-rheumatic drugs, or the so-called DMARDs) were used first and in combinations, and the weakest (nonsteroidal anti-inflammatory drugs, or NSAIDs) were relegated to a background position. Further, while we had thought that DMARDs were more toxic NSAIDs, we found that just the opposite was true.

The advances in patient benefits came about "on the watch" of methotrexate and its combination with other DMARDS. The improvements came way before the development of the newer and more powerful biologic agents - anti-TNF medications, such as etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). These benefits are attributable to the war mentality. From our experience with anti-TNF agents over the past four years, these amazing drugs have added a quantum leap to the advances generated during the methotrexate generation of therapy - and they have done so in a safe manner. And these drugs are simply "the beginning of the beginning" of such focused, effective biologic medications that have arisen from amazing scientific and technologic advances. While these drugs are costly ($13,500/year) and their side effect profile has yet to be fully written, they give great hope for the future.



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