Vision is one of our most precious senses. The ability to see enriches our lives and helps us appreciate our world. Therefore, protecting our vision is a crucial part of maintaining our health and well-being. Surprisingly, the eye can also provide insight that might help us better understand the cause of ankylosing spondylitis (AS).
Sometimes we forget that axial spondyloarthritis (axSpA), a broad category of diseases that includes AS, is not confined to the spine or joints. The eyes, skin, and bowel are common targets for disease activity associated with AS. Sometimes even the heart or lungs are affected. But the eye is the most commonly involved part of the body other than the joints.
One large genetic study concluded that in their lifetimes, more than 50 percent of people with AS will have at least one episode of acute anterior uveitis, the medical term for inflammation inside the front of the eye. The name uveitis comes from the Latin word, uvea, for grape— because anatomists thought that the inside of the eye was shaped like a grape. The front or anterior portion of the uvea is the iris, which gives the eye its blue, brown, green, or hazel color. You might also hear uveitis referred to as iritis; anterior uveitis and iritis mean the same.
Sudden attacks of iritis cause pain, redness, and sometimes loss of vision (but if diagnosed promptly and treated appropriately, permanent visual loss can usually be avoided or minimized). The eye may feel tender and become sensitive to light. Episodes usually resolve with treatment in a few days. A common treatment is prednisolone eye drops. Drops to dilate the iris might also be prescribed. Occasionally prednisone by mouth is recommended for a short period, or a form of cortisone can be injected near the eye—just as a painful joint may require a local injection. The ability to work is often impaired during episodes of iritis. Some patients seek strategies such as the drug sulfasalazine to prevent recurrent attacks or to minimize damage from attacks. Some with AS find the iritis more distressing than the joint disease, and make medication choices based on what may best control both the eye inflammation and the joint disease.
Why does eye inflammation co-exist with spinal inflammation? Could the eye help us understand why AS occurs?
A remarkable paper appeared in the journal, Nature, in December, 2022 (Yang et al., Nature, 612:771, 2022). It reported a seminal advance in the understanding of AS. It represented an international collaboration involving Stanford, Oxford, Washington University at St. Louis, and scientists in Moscow. It listed 19 authors as contributors. It relied heavily (but not exclusively) on insights gained from the eye.
Before I explain what the publication reported, I need to provide some background, which some readers may find unnecessary. Each of us relies on our immune system to protect us from infections. The immune system has several components, including white blood cells that circulate throughout the body. These white blood cells are like the Coast Guard. They are on patrol, on the lookout, and prepared to rush to the rescue. Some of these white blood cells are called lymphocytes. The two major divisions of lymphocytes are T cells, which are educated in the thymus gland, and B cells, which are educated in the bone marrow. T cells and B cells have proteins on their surface—proteins that allow them to recognize very specific targets, so they can act like a guided missile and cause minimal collateral damage while doing their work. The target is called an antigen. If we knew the identity of that antigen, we would have a major tool to use to understand why a particular disease occurs.
Although the immune system is essential for life, it can sometimes make a mistake that results in disease. Dozens of diseases like rheumatoid arthritis, systemic lupus, Crohn’s disease, and multiple sclerosis are immune system diseases. These diseases are often termed “autoimmune disease,” meaning that the immune system is attacking our bodies in error. In some instances like rheumatoid arthritis, this is undoubtedly the case. But the immune system is also poised to respond to many other antigens, such as microbes (like viruses and bacteria), allergens (like pollen), and foreign bodies (like a splinter of wood beneath our skin). A disease caused by the immune system should be labeled “immune-mediated” rather than “autoimmune” if the immune system is targeting something foreign to the body, such as a micro-organism. Are axSpA—and therefore AS—autoimmune diseases, or should they more appropriately be labeled immune-mediated?
The Nature paper suggests both labels are correct. The team of authors collected fluid from the inflamed joints of people with AS, and fluid from the eye from AS patients with acute anterior uveitis. They then employed technology to analyze the antigens recognized by the T cells that were present in these samples from the eye and the joint. This sophisticated technology has only existed for a few years.
Their work provided several original observations. First, some T cells had increased in number. This is called clonal expansion, and it suggests that an antigen was stimulating the T cells. Second, some T cells were recognizing parts of a protein that occurs naturally in the iris. This is consistent with the conclusion that axSpA is an autoimmune disease. But other T cells were recognizing antigens that were present in bacteria. This would argue that axSpA is better called an immune-mediated disease. Many bacteria including E. Coli, Shigella, Salmonella, and Klebsiella express this antigen. Some of these bacteria are known to cause reactive arthritis, another disease within the axSpA family. And finally, there was overlap between what the T cells responded to, either in the joint or in the eye. This would suggest that understanding why the immune system attacks the eye would help to explain the joint disease, and vice-versa.
Great science represents an advance while providing a platform to ask further questions. For example: Which comes first, the immune response to bacteria, or the immune response to one’s own body? My hunch is that the bacteria are more likely the trigger, and the body is similar enough to the bacteria to become a target as well. My theory is that in trying to respond to the bacteria, the joints become attacked as innocent bystanders.
Other questions also await further study: Why does the eye disease come and go, while the joint disease is usually more persistent? What precipitates the onset of eye inflammation, i.e. why is it not there all the time? If the inflammation inside the eye is an autoimmune attack, why does this inflammation resolve? And perhaps most important, how can these observations translate into ways to prevent or treat AS?
Maybe you thought the eye only exists so that we can see. Now you know the eye exists so that science can better understand AS. I’m joking, of course. However, you can rest assured that there’s more to vision than meets the eye.
James T. Rosenbaum, MD is Senior Vice President for Research at Corvus Pharmaceuticals in Burlingame, CA. He is a rheumatologist who has also been the Chair of the Legacy Devers Eye Institute, making him arguably the world’s only practicing rheumatologist to chair a department of ophthalmology. He is a longtime member of SAA’s Medical and Scientific Advisory Board.
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