THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Definition of reactive arthritis may require expansion

Robert Inman, MD
Robert Inman, MD

A Sunday State-of-the-Art Lecture will cover the latest findings related to reactive arthritis, including the biological mechanisms that link microbial factors to arthritis and some of the management implications.

Emerging findings suggest that current definitions of reactive arthritis are probably too restrictive. Multiple forms of arthritis share important characteristics with reactive arthritis, and many seem to be related to infectious disease in some fashion.

“Where reactive arthritis, by definition, is an arthritis that is preceded by a pre-existing infection, there are also other forms of arthritis in which microbial factors may set the stage for initiating and perpetuating the inflammation,” said Robert Inman, MD, Professor of Medicine at the University of Toronto and Director of The Spondyloarthritis Research Consortium of Canada. “Ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease all invoke some alteration in the host-microbial balance in the gastrointestinal tract.”

It’s overly simplistic to think that all reactive arthritis is a reaction to microbial infection, said Dr. Inman, who will present State-of-the-Art Lecture Reactive Arthritis: 2017 Update from 1:00 – 2:00 pm in Room 6 A.

“Arthritic reactions to checkpoint inhibitors used in cancer immunotherapy would be a good example,” he said. “Other examples would be genetic alterations where there is an inherited dysfunction in immune regulation with an inappropriate down regulation of normal controlling factors, say IL-1 receptor antagonists, that give rise to a chronic inflammatory joint disease that is probably independent of a microbial trigger. The factors that can initiate and perpetuate noninfectious chronic arthritis is a much broader range of possibilities than just microbial triggers.”

There is also a growing sense that 19th century rheumatology, which categorized arthritis as a reaction to microbial infection, likely held a kernel of truth. Removing the infection source through tonsillectomies, high colonic enemas, or dental extractions was overly aggressive, but the appropriate use of antibiotics has been shown to truncate the course of reactive arthritis induced by chlamydia infection.

The successful use of antibiotics to stop some forms of arthritis also raises questions about the functional differences between reactive arthritis and septic arthritis.

Chlamydia-induced reactive arthritis is culture positive and can respond to antibiotic treatment. Yet reactive arthritis induced by gastrointestinal infection is generally culture-negative and does not respond to antibiotic treatment.

“The fact that antibiotics can seem to accelerate clearance of chlamydia-
induced arthritis suggests that maybe there are antigenic organisms persisting in the joints or elsewhere in the body in the case of other reactive arthritis,” Dr. Inman suggested. “That is interesting in terms of how we think of the pathogenesis of reactive arthritis generally.”

Another factor suggesting a microbial origin for gut-associated reactive arthritis is the detection of mucosal associated invariant T (MAIT) cells in the joints of patients with ankylosing spondylitis. MAIT cells are usually resident in the lamina propria of the gastrointestinal tract but are present and expanded in synovial fluid sampled from patients with ankylosing spondylitis.

Integrins, a class of surface proteins, typically direct MAIT cells and other cells to the appropriate tissue. A specific family of integrins trafficks MAIT cells in circulation back to the gut lamina propria.

“Under normal circumstances, MAIT cells are in the GI tract, but in some chronic rheumatic diseases, they end up mislocating into the joints,” Dr. Inman said. “That speaks to the presence of a gut-joint interface in immunity and to what extent these trafficking molecules are dysregulated.”

Another question mark is the recent discovery that the genetic signatures of T cell receptors seen in reactive arthritis are reminiscent of T cell receptors seen in ankylosing spondylitis. The immune response seen in reactive arthritis with an identified microbial trigger is very similar to the immune response in ankylosing spondylitis, which does not have a known microbial trigger.

“In some ways, recent developments in the biology and genetics of reactive arthritis have brought us full circle, back to the microbial origin theories of rheumatic disease. We are coming back to where we started in rheumatology and getting to know the place for the first time,” Dr. Inman said.