The Origins of Rheumatoid Arthritis


When considering the evidence, it appears that rather than it being a discrete clinical entity with a unique cause, rheumatoid arthritis (RA) is likely a syndrome that represents a common endpoint for a number of different causative agents.

When considering the evidence, it appears that rather than it being a discrete clinical entity with a unique cause, rheumatoid arthritis (RA) is likely a syndrome that represents a common endpoint for a number of different causative agents.

Although published in 2009 in Open Access Rheumatology Research and Reviews, it remains a poignant review of the search for the origins of rheumatoid arthritis. Led by Alan P. Hudson, Ph.D., of Wayne State University, Detroit, Dr. Hudson and colleagues present a review of the evidence for rheumatoid arthritis looking at causative theories from environmental factors to genetic predisposition. They goal was to demonstrate that rheumatoid arthritis is a common endpoint as a result of many possible origins.

“RA as a common clinical endpoint for differing initiating factors and pathogenic mechanisms is supported by the many different clinical manifestations that encompass the diagnosis of RA,” the authors wrote.


The first know description of rheumatoid arthritis dates back to the early eighteen hundreds. With millions of sufferers worldwide, rheumatoid arthritis imposes a heavy burden on patients leading to functional disability and loss of productivity.

Rheumatoid arthritis is a chronic progressive disease most often presenting as symmetrical pain and swelling in the small joints of the hands and feet. While systemic features can accompany joint inflammation the primary goal is to treat quickly and aggressively in an attempt to prevent long-term joint damage.

One reason it is difficult to pinpoint a single cause in early rheumatoid arthritis is that the clinical picture in the early stages is extremely diverse and heterogeneous leading to missed diagnoses and delays in treatment.


Rheumatoid arthritis strikes as many as one percent of North Americans and puts patients at higher risk for death compared to the general population. Women are far more likely to develop rheumatoid arthritis then men and this fact has long been investigated in an effort to determine its significance.

Even after extensive investigation the pathogenesis of rheumatoid arthritis remains unclear although inflammation leading to joint damage possibly as a result of autoantibody and immune complex interaction is the leading theory.

The diagnostic utility of anti-citrullinated protein antibody assays and the presence of T-cell and B-cell abnormalities lend support for autoimmunity as a key pathogenic feature in rheumatoid arthritis.


While it is known that autoimmunity is involved in the pathogenesis of rheumatoid arthritis it is unclear if a loss of tolerance to self-tissue is causative or merely a feature of the larger syndrome. In any case, proliferation of inflammatory immune cells in the joints is a primary characteristic of rheumatoid arthritis.

NEXT PAGE:  The case for infection as cause


The idea that infectious agents may play a strong causative role in rheumatoid arthritis is widely believed by many rheumatologists. The literature provides evidence for this theory and suggests that multiple organisms may play a role in the pathogenesis of rheumatoid arthritis if not representing the primary causative stimulus.

Molecular mimicry is when T-cells become activated by proteins from infectious organisms which are similar to the host organism and has gained a great deal of traction in the rheumatology community as a potential way infection may lead to rheumatoid arthritis.

Further support for infection as a contributor in rheumatoid arthritis is found in the high levels of anti-Epstein Barr antibodies found in patients with the disease.

No single organism or group of organisms are likely the cause of rheumatoid arthritis because none are ubiquitous geographically, persistent in humans, capable of eliciting an immune response and present only in diseased tissue and not in healthy controls. Since all of these requirements are necessary, the authors conclude that infection is likely only one contributor in the development of rheumatoid arthritis.


There exist strong evidence supporting the role of genetic susceptibility in rheumatoid arthritis. However, many things including environmental factors, smoking, lifestyle choices, and infection can affect genetic predisposition. Relatives of patients with rheumatoid arthritis are more likely to develop the disease.

The genetic contribution to the development of rheumatoid arthritis is estimated to be between fifty and sixty percent with two specific mutations accounting for most of the increased susceptibility. While there are clearly genetic contributions to rheumatoid arthritis, no single variant has been identified that causes the disease.

The authors believe that examining disease-related genes in other related pathologic conditions such as systemic lupus erythematosus may provide important clues to the role of genetics in rheumatoid arthritis.


There are good evidence environmental factors such as diet, smoking, and alcohol consumption play a role in developing rheumatoid arthritis. Smoking and eating red meat increase the risk of rheumatoid arthritis while drinking alcohol seems to be protective.

The role of hormones in both pathogenesis and protection from rheumatoid arthritis are compelling since women are affected disproportionally and generally protected during pregnancy and breastfeeding.

“It follows from the observations reviewed above that neither infection nor specific single or multiple genetic attributes can be held uniquely responsible for the initiation and maintenance of RA pathogenesis. In turn as suggested by us and others, some combination of genetic attributes with infectious agent(s) or other environmental factor(s) must constitute the etiologic basis for that pathogenic process,” the authors wrote.

While autoimmunity and inflammation are easily implicated in the pathogenesis and progression of rheumatoid arthritis, the disease itself appears to be a common clinical endpoint for a multitude of initiating factors. Not only do many factors contribute to the etiology of rheumatoid arthritis, they appear to do so differentially in individual patients.

In any case, stepping back and looking at rheumatoid arthritis as an endpoint resulting from many possible starting points will allow researchers to look upon data with fresh eyes and may lead to meaningful new therapeutic strategies in the future.


Jessica A Stanich, John D Carter, Judith Whittum-Hudson, Alan P Hudson. "Rheumatoid arthritis: Disease or syndrome? Open Access Rheumatology Research and Reviews," Open Access Rheumatology Research and Reviews2009:1 179–192.

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