Looking back: one hundred years in rheumatology.

A clinician's experience in 1906 evaluating and managing a new patient with inflammatory polyarthritis would be very different compared with today. While common conditions of inflammatory polyarthritides such as rheumatoid arthritis or systemic lupus were known, the clinician's ability to establish a specific diagnosis would be based solely on his clinical acumen and without much benefit of laboratory tests such as the rheumatoid factor or antinuclear antibody, as early precursors of these tests were not even described until the 1940s. Radiological imaging may have been possible, but was only reported by Sir Wilheim Roentgen in 1895 and was likely not widely available in physicians' offices. If an anti-inflammatory drug was prescribed, a relatively new drug called aspirin was available commercially and the patient would likely receive treatment with an antimicrobial as it was "common knowledge" that infections were the likely cause of the "atrophic" arthritides including rheumatoid arthritis. Since antibiotics as we know them today were still a quarter of a century from discovery, a clinician would resort to heavy metals, arsenical products or even antisera to treat suspected infections, In a few short years, clinicians would report on their experience with gold salts to treat "mycobacterial" infections, the putative cause of rheumatoid arthritis. While the reliance on parenteral gold salts to treat rheumatoid arthritis would dominate the twentieth century as an effective form of therapy, the original rationale to kill mycobacteria would no longer be maintained. If the antimicrobial therapy was ineffective, a clinician may resort to removing the tonsils, appendix or gallbladder to eradicate the source of the infection, or treat the patient with colonic lavage to wash out the precipitating organisms.

In the early part of the twentieth century, the more meaningful advances in rheumatology were primarily diagnostic. Improved diagnoses came about through better classification of the rheumatic diseases and a better understanding of the underlying mechanisms responsible for these diseases. The recognition of a pre-existing streptococcal infection in acute rheumatic fever (ARF) and a dysenteric infection in Reiter syndrome spawned a new classification of reactive arthritis, and in the case of ARF, identified an effective way to reduce the incidence of ARF through effective treatment of streptococcal infections. The discovery of the rheumatoid factor, antinuclear antibodies and later the association of HLA-B27 and ankylosing spondylitis helped clinicians correctly identify and diagnose rheumatoid arthritis from systemic lupus erythematosus from the seronegative spondyloarthopathies. Their discoveries helped eliminate several erroneous and misleading categories of conditions previously known as rheumatoid variants, rheumatoid spondylitis and atypical rheumatoid arthritis. The many "criteria of classification" which were developed for several complicated diseases like rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis were a significant step forward in establishing clinical trials to identify effective therapeutic interventions. Early reports of large clinical therapeutic studies generated criticism about the diagnostic homogeneity of the patient population being studied. Finally, in the second half of the twentieth century, the elucidation of the immune system's complexity and its importance and role in the rheumatic disorders led to the development of effective therapeutic strategies for these and other important diseases in the twentieth century, including AIDS.

Once these conditions could be better classified and diagnosed, and the immune system better understood, effective therapeutic strategies could be developed and tested. In the mid-twentieth century, using the most effective therapeutics available at the time, a treatment pyramid for rheumatoid arthritis was very popular but was later turned upside down as statistically-powered clinical studies helped identify even more effective strategies. While gold salts dominated the treatment of rheumatoid arthritis in the last one hundred years, it was through statistical analysis that methotrexate was found to be superior and gold salts nearly abandoned in the last decade. As the mysteries of the immune system were teased away, effective therapies were proposed, developed and tested to reduce the role of B lymphocytes in rheumatic diseases, tumor necrosis factor (TNF) in inflammatory conditions, and a variety of cell surface markers and cytokines to develop "smart-weapons" to control inflammation. Today we have effective available therapies to neutralize the impact of TNF on inflammation, and have additional therapies in study to block cytokines and cells with specific cell surface proteins.

Advances in rheumatology over the past century have been remarkable and can be divided simply into two categories: 1) improvements in diagnosis including a better comprehension of the pathophysiology, and 2) advances in treatment. Over the last one hundred years, these improvements have evolved in spurts and with the exception of the introduction of gold salt therapy; the diagnostic advances or improved understanding of the pathophysiology typically preceded successful therapeutic progress. This observed sequence of events, improved diagnosis or a better understanding of pathophysiological mechanisms followed by improved therapies, helps project how advances in the next one hundred years will proceed. As we unlock the mystery and complexity of rheumatic diseases, we will identify, develop and produce specific targeted therapies for these diseases. In addition, we will likely refine our diagnosis of several diseases like rheumatoid arthritis or systemic lupus erythematosus with heterogeneous clinical presentations as we discover each is likely to be more than one disease. Finally, we have not even begun to understand and effectively manage our most common rheumatic condition, osteoarthritis, and develop effective therapies to combat what now seems like an impossible challenge: resisting the natural changes of time. As we understand how aging affects us on a cellular and molecular level we will be able to develop effective therapeutic strategies. One hundred years from today, clinicians will look back in amazement at how primitive our "state-of-the-art" practice is, in much the same way we now view clinicians in 1906 managing polyarthritis--at least we hope so!

A man can succeed at almost anything for which he has unlimited
enthusiasm.
--Charles Schwab

Dennis W. Boulware, MD

From the Division of Clinical immunology and Rheumatology, University of Alabama at Birmingham. Birmingham, AL.

Reprint requests to Dennis W. Boulware, MD, Professor of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL. Email: [e-mail]