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Lower the Thermostat - the Heat is Too High: Winning the Battle and the War


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

The above graph tells the whole story. Unless we as rheumatologists learn to and how to "turn and keep down the heat” related to the inflammatory processes that burden our patients, we relegate them to the cumulative, attendant types of collateral damage to which they are subject. Years of unopposed, uncontrolled active inflammation, at any level, is detrimental and begets many life-shortening and life-altering effects. The point of therapeutic opportunity is at the beginning of the disease process.

If we were discussing most infections, the inflammatory thermostat triggered by the infection would be turned off completely by the institution of antibiotics. Historically, certain uncontrolled infections, such as chronic tuberculosis or osteomyelitis, could lead to amyloidosis, a disorder caused by unopposed, chronic serum amyloid A protein (SAA) bombardment. This secondary type of amyloidosis is an example of one of the many types of collateral damage that occurs in the setting of chronic inflammation, whether due to tuberculosis – or rheumatoid arthritis. Antibiotics now control nearly all infections and limit the overall impact of the inflammatory process instigated by the infectious process to a very few days. Just imagine if this infectious burden lasted for years, an unlikely eventuality because most uncontrolled infections cannot be tolerated by a human.

Fortunately, diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) decrease the quality of life more than its duration. However, during the many years of being "bathed” in one degree of inflammation or another, patients with those disorders pay the price for a lack of a known etiology and a magic bullet like an antibiotic. There is probably a genetic predeterminism regarding how a given person’s body responds to a given level of inflammation, and each person probably has its threshold point at which the inflammation spills over to affect other tissues and physiologic processes negatively.

Similar disease burdens exist with high blood pressure (HBP), atherosclerosis, diabetes, Helicobacter pylori infection of the stomach, and hepatitis C. Each of these, if left un- or under-treated, can eventually lead to severe consequences, such as stroke, renal failure or congestive heart failure in the case of HBP; myocardial infarction and abdominal aortic aneurysm due to atherosclerosis; microangiopathy with neuropathy, eye and kidney disease in diabetes; ulcer, bleeding or lymphoma when it comes to H. pylori; and mixed cryoglobulinemia and hepatocellular carcinoma with hepatitis C. Just as we have learned not to allow those disorders to go under treated, we have learned similar lessons regarding chronic musculoskeletal and autoimmune disorders.

Having learned these facts, where are we in our therapeutic evolution regarding diseases such as RA, SLE, ankylosing spondylitis, and scleroderma?

We are farthest along with RA, because of the fruits of our epidemiologic studies of the disease and our immunological and technologic advances. However we cumulatively limit the level of inflammation, be it with disease-modifying drugs, corticosteroids, NSAIDs, or mechanical or physical therapeutic measures, or combinations of these modalities, our patient is better off. Improvement in any RA outcome you choose has been demonstrated with drugs such as methotrexate, and further movement towards an eventual infectious paradigm will occur with biologic agents.

In SLE, much of the progress regarding mortality and morbidity has been related to improvements in general medical care rather than new treatments focused directly at SLE. Antibiotics, anti-hypertensives, cholesterol-lowering statins, anti-smoking campaigns, improvements in dialysis technology and transplant immunology have all had a profound impact on mortality – from a 50% five-year survival in 1954 to a 93% 10-year survival and 70% 20-year survival in 1995. Certainly, the development of a more enlightened approach to the use of steroids, specifically the employment of lower doses of steroids for shorter periods of time, has allowed the physician to "get in and get out” more rapidly without leaving major, steroid-related fall-out for the patient. The use of pulse steroids has helped as well because, while not totally free of side effects, industrial-strength pulses of steroids for only one to three days more profoundly re-sets the inflammatory thermostat in a way that smaller doses do not. Intravenous cyclophosphamide has clearly improved the outcome of one of the main scourges of SLE, diffuse proliferative glomerulonephritis, but this is not invariable, is associated with many major side effects, and more effective, predictable and focused therapies are essential. Our understanding of the immunopathogenesis of SLE is improving significantly. Many the new therapies that arise from this expanded understanding are in the pipeline. They sure to move SLE therapy forward in the same quantum manner that RA and psoriatic arthritis therapy has moved in the past 10 years.

Heretofore, anklylosing spondylitis has been one of the therapeutic stepchildren of rheumatology. Patients were, in many ways, left on their own, relegated to being treated with NSAIDs and exercises because no therapy, including methotrexate or sulfasalazine, appeared to have a disease-modifying impact on spinal inflammation. That has all changed with the advent of tumour necrosis factor blockers such as infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). Impressive clinical and radiological results bode well for these drugs as first-line therapy in this disease.

And then there is scleroderma. Here, the inflammatory and immunological paradigm has not seemed to fit with regard to finding effective therapies to change the natural history of this disease. Angiotensin converting enzyme inhibitors had a profound impact upon the previously poor outcome of "malignant” scleroderma, with its malignant hypertension, renal ischemia, microangiopathic hemolytic anemia and arrhythmias. Oral cyclophosphamide (Cytoxan) and pulse steroids seem to be effective in the setting of early, non-fibrotic alveolitis. New endothelin-blocking drugs such as bosentan (Tracleer) are now saving lives -- and improving the quality of life -- in pulmonary hypertension. Prostaglandin inhibitors have helped to prevent finger damage in those with severe vasospasm due to Raynaud’s phenomenon. And, acid pump inhibitors have improved living with the esophageal disease of PSS.

However, the hope of d-penicillamine and relaxin has fallen by the wayside, and we need a new pathogenic and therapeutic paradigm in order to move along at the rate of RA. Perhaps, tissue growth factor (TGF) beta inhibitors will help to arrest the profibrotic nature of scleroderma and avoid the inexorably downhill course of scarring in the lungs, GI tract and skin and the vasculopathy that makes scleroderma such a frustrating and frightening disease for patient and physician.

What is the future? One hopes that new therapies for all chronic inflammatory disorders will be able to "cure” them as we can infectious disorders – stop them in their tracks -- and that the outcome for our patients will be more like the graph below than the one above.


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