Round 20: Why a Rheumatologist needs to Understand Uveitis

By: James T. Rosenbaum, MD

Oregon Health & Science University

Dr. Rosenbaum has no significant financial interest or relationships to disclose.

Release Date: March 20, 2009
Expiration Date: January 1, 2011

For CME credit,TAKE POST-TEST & EVALUATION

I am a card-carrying Rheumatologist who had no intention of ever studying eye diseases. Despite my best intentions, I have spent the last 25 years studying uveitis. It is some of that experience that I want to share with you this morning.

Objectives:

  • Express an overview of uveitis.
  • Explain differential diagnosis of uveitis, and how a rheumatologist should select laboratory tests to treat uveitis.

Overview of Uveitis

The New England Journal of Medicine (NEJM) has Clinicopathological Conferences (CPCs) every week, and sometimes those CPCs involve the eye and cases of uveitis. In 2002, there was a case of a 28-year-old woman with ocular inflammation, fever and headache. This particular case had three discussants. One of the discussants was Dr. Grayson (an editor of the NEJM) because there were some pulmonary findings. He missed completely the importance of the ocular inflammation. Another discussant, neurologist Marty Samuels was very smart about the eye inflammation, and gave a differential diagnosis of uveomeningitic inflammation and knew this was sarcoidosis. Sarcoidosis is a bilateral uveal disorder that is unresponsive to corticosteroid therapy. Commonly, problems that do not respond to anti-inflammatories are infections, not inflammations. This turned out to be a B-cell lymphoma. B-cell lymphomas account for about 1% of the patients in my uveitis clinic. The NEJM loves the differential diagnosis of mediastinal lymphadenopathy. There are only a couple of entities that cause mediastinal and hilar lymphadenopathy; sarcoidosis is one of these entities. This case had to be sarcoidosis, uveitis hilar lymphadenopathy and interstitial lung disease, although the pathologist, when he was done discussing the case, said: “It could be TB, it could be sarcoid, and it could be both.”

In another case with mediastinal lymphadenopathy, this time with vitreous hemorrhage, the discussant said: “this is a classic case of a retinal vasculitis known as Eel’s disease.” Among my 2,000 patients with uveitis, I only have two with Eel’s disease—I did not know what a classic case represented, but this was a classic case of Eel’s disease.

The last case is a 63-year-old woman with bilateral maxillary sinus opacification and mediastinal lymphadenopathy. This patient had an anterior uveitis. The discussant from Massachusetts General said, “The symptoms of iritis and anterior uveitis are eye pain, redness, blurred vision, and floating.” However, there is the subset of juvenile arthritis where the patient has iritis with no pain and no redness, so that is quite variable. Blurred vision is also quite variable. Floaters would indicate some vitreous inflammation, which is not an anterior uveitis, but an intermediate or posterior uveitis. The discussants said that in 80% of cases, iritis has no known cause. In my clinic, and virtually any uveitis center around the world, it is 30%, not 80%. Then the remainder may be caused by sarcoidosis and that is absolutely true.

Syphilis accounts for about 0.2% of iritis; Tuberculosis accounts for about 0.2% of iritis; and rheumatoid arthritis has essentially no association with iritis at all, unless there is a scleritis and some associated changes. Because 70% of the cases you can account for and you got the one that is about 5% and the other is less than 1%, they gave one is wrong, they obviously left out the main disease that is associated with anterior uveitis, which is ankylosing spondylitis.

The discussant was an otolaryngologist (Remember, this is maxillary sinus opacification), and the ENT doctor said: “We should resist looking at problems through narrow-angled lenses, especially from subspecialties,” although ironically I think that is exactly what they have done. It’s a little discouraging to me that an expert like NEJM or a journal that represents such expertise would have so many things incorrect.

One expert who gets it right is the author Robin Cook, an ophthalmologist who trained at Massachusetts Eye & Ear. Robin Cook writes formulaic novels about medicine and science. He recently wrote a novel about a CDC investigator named Marissa Blumenthal. The heroine in the novel Outbreak is similar to the heroines of all Robin Cook novels: she is beautiful, she is brilliant, and she knows everything in the world. In the novel, an ophthalmologist says to our heroine at a cocktail party, “Some of the rare viruses like Ebola and even the AIDS virus have been localized in tears and the aqueous humor. Some of them even cause anterior uveitis.” “Oh,” said Marissa, nodding as if she understood. Actually, she had no idea what anterior uveitis was.

I think that is a far more accurate description of the world’s knowledge of uveitis, especially internal medicine knowledge of uveitis in NEJM. Although this is accurate, it is also upsetting to me because I am sure that most people who read this do not realize how very funny and accurate it truly is.

Laboratory Research to Understand the Immune Response

Figure 1

Fig 1. The eye is an unbelievably elegant structure. It is about 2.5 cm in a human from front to back. It has a clear avascular area at the front called the cornea. The back (the retina) is an extension of the brain. You can imagine that the diseases that will cause anterior inflammation such as iritis or iridocyclitis tend to be different from the diseases that affect the back of the eye, such as retinal choroiditis, chorioretinitis, or a pan-uveitis when the entire uveal track is involved.

Uvea is the Latin word for grape. Somehow, the early anatomists thought that if they peeled off the sclera, which is the outer layer of the eye and the cornea; there was a grape-like structure underneath. The uvea, therefore, is sandwiched here between the brain and retina, and the outer part; that includes the choroid, the iris, and the ciliary body; any portion of the uveal track could get inflamed.

When anterior uveitis starts suddenly, it causes a red eye. Posterior uveitis does not necessarily cause a red eye. Insidious onset of uveitis does not necessarily cause a red eye. Some forms of uveitis are associated with a red eye.

Differential diagnosis for red eye:

  • anterior uveitis
  • conjunctivitis
  • episcleritis
  • iritis
  • corneal inflammation
  • acute closed-angle glaucoma

An ophthalmologist has the privilege of using a biomicroscope called a slit-lamp biomicroscope that allows the ophthalmologist to see the process of inflammation. What are the hallmarks of inflammation? Leukocyte migration and altered vascular permeability.

The space between the cornea and the lens is the anterior chamber. A blood aqueous barrier such as the blood-synovial barrier protects the anterior chamber. The anterior chamber fluid is aqueous humor. When it is normal, it should have virtually no protein, like CSF, and there should be no white cells in it. As far as that beam of light is concerned, it is passing through a vacuum. When the blood-aqueous barrier is disrupted (because of an iris inflammation which means anterior uveitis), leukocytes can be seen. You can see white cells responding. You also see a haze that is referred to as flare; it indicates that there is an increase of protein in the aqueous humor because the beam of light is now going to something particular. Basically, vascular permeability can be measured non-invasively with a slit-lamp.

Figure 2

Fig 2. (A), The mouse is receiving continuous gas anesthesia, and he has injected rodamine into the tail veins, which is a fluorescent dye that is taken up by nucleated cells. Then he is able to project digit-type images of the iris circulation under the computer screens. This procedure is exploiting what an ophthalmologist or an optometrist has in every day practice: looking at the inflammatory process. (B), This is the pupil of the mouse’s eye. (C), This is the iris. Rodamine was injected into the tail veins. This is a completely normal eye. Every once in a while you see a little flick of white going through, that is a leukocyte – a cell that has taken up the rodamine dye. There is nothing to impede or slow down the flow of these cells. If you inject bacterial endotoxin into the eye, there is a tremendous inflammatory response.

Neutrophils

When the inflammatory response is photographed, there are lots of white cells that line up along these vessels (arrested), and some of the white cells are tumbling along. They are rolling, probably a selective mediated process. Some of the white cells are invading the tissue. This is standard, real-time interval microscopy that dozens of laboratories around the world have performed on the mesentery, on the cheek pouch, on the trachea. Many different tissues can be used to study this. The advantage of the eye is that you do not need to do any surgical manipulation in order to see the tissue. If we compare how we see in vivo with the in vitro, we see a very good resolution.

Figure 3

Fig 3. This is a study where we use CXCR2 knockout. CXCR2 is a receptor for the IL-8 family of cytokines. The mouse actually has no IL-8 but it has homologues. When you inject a controlled mouse with endotoxin, you wait six hours; all the little dots represent neutrophils that have been dated. If you do conventional histology, you can find the neutrophils. I think you actually see them better in vivo.) If you knockout CXCR2 you get a few neutrophils, but they are markedly reduced.

Figure 4

Fig 4. A huge advantage to studying the eye (if you want to try to understand the inflammatory process) is that you do not need to do any surgical manipulation of the tissue. That allows us to do time-lapse imaging. This is a very complex migration. If we randomly put triangles at the origin of a number of these different neutrophils, and trace where they go over 90 minutes, you can see that some of them seem to wander in a random fashion. The T cells seem to wander in a lymph node, somewhat randomly. There are other cells that are clearly tracking in a nearly linear fashion, or wander and then go linearly. This is a very complex migration. Because it is very complex, it is more difficult to study and manipulate than to see what changes it, although that is what we are trying to do.

The neutrophil is amphibious, and what is controlling its migration inside the lumen of a vessel is very different, perhaps, from what controls its migration in a tissue plane. Movement of a neutrophil in tissue is a fundamental, biological process that we really do not understand because we do not have a way to study it. We hope we will better understand it through imaging technology like this, and then try to change the migration.

Antigen-presenting cells

Most immunologists think that neutrophils are the dumb infantry and not very exciting—that a targeted immune response is much more important. The eye facilitates understanding of that aspect of the immune response. If you take a foreign protein like ovalbumin and inject it in the eye, and tag it with a fluorescent dye, what you see initially is a sea of red. However, once there is a turnover of the aqueous humor, the red washes away, and three hours after an anterior chamber injection, you see that the ovalbumin protein has been taken up by this network of cells within the iris. These are phagocytic cells and presumably are antigen-presenting cells. Certainly, some of them have an elegant dendritic form morphology. Many of them are aligned along the vessels as if they want to communicate with whatever is going by along the vessel.

The ocular immune response is both the same and different from the immune response elsewhere in the body. The eye, for example, has no lymphatics inside the eye. This is true of the brain as well. There is a lot of TGF-beta in the aqueous humor and other immunosuppressant factors. There is a phenomenon where if you put a soluble antigen into the eye, you tend to suppress a T cell response, although you get a soluble immune response. Even though the eye does not want to get inflamed (its immune privilege), it still has this incredibly dense network of sentinel cells picking up foreign antigen. You can also do what we call in vivo immunohistology.

Figure 5

Fig 5. We have outlined the vessel here by taking dextran that we tagged with flouorescein; then we outlined this cell with an antibody to CD11-B. This is a dendritic form-type cell that is right adjacent to the vessel.

You all know the dogma that antigen-presenting cells, dendritic cells pick up antigen, but they communicate to the T cell in the lymph node. Therefore, if you get a tetanus toxoid vaccine, your antigen-presenting cells will eat that antigen and over the next 48 hours by the lymphatic change their cell surface expression, change their function, get to the lymph node and talk to a T cell.

We have done a little bit of imaging in the skin using the ear. When we put fluorescent micro-beads into the mouse’s skin, individual beads are in motion six hours after that injection. This is consistent with the idea that those beads have been ingested and the antigen-presenting cells are in motion. If you look at 12 hours after injection, cells are moving, and some seem to take all, as if the antigen-presenting cell has found a lymphatic. What would happen if you did the same experiment in the eye, a tissue with no lymphatics? The picture is very different. Every once in a while some of the fluorescent protein is in motion, and a cell in motion. However, for the most part, the antigen-presenting cells in the iris are completely stable. They are not going anywhere at all, very different from the antigen-presenting cells in the skin. That correlates very nicely with an experiment done in my lab by a post-doctoratal student. Ovalbumin in red and beads in green were simultaneously injected.

Figure 6

Fig 6. When done in the skin (ear) and then dissecting the lymph node (a little submandibular lymph node), either six hours, 24 hours, or 96 hours after the injection, both the soluble protein and the beads make it to that subcapsular space, then they migrate into the central part of the lymph node over time. (Left), When done in the anterior chamber of the eye, the soluble protein is able to make it out through a pathway called the uvuoscleral path. However, the beads have to get ingested (they are two microns in size.), and they are too big to make it through that little bit of uveosleral outflow. It gets to the conjunctiva that does have lymphatics and then the beads go along with the idea that those antigen-presenting cells in the eye really do not move. Soluble protein makes it out, but particular antigens do not make it out. We never see the green beads make it into the lymph node over the next four days.

CD11c is a good marker for dendritic cells. The cornea has a lot of dendritic formed cells even though it is avascular. Cornea is a very important tissue immunologically because it can be the target of inflammatory response as in RA, and because it is the most frequently transplanted tissue in the world, and T cells are important in rejection. Some of the dendritic cells—and there is heterogeneity among dendritic cells—move, and other cells do not move their cell bodies, but they wave their arms (which has also been reported in the CNS) as if they are sampling what is going on.

Figure 7

Fig 7. We also can take out tissue and look at it ex vivo. This is using a mouse that has GFP on lysozyme, so that monocytes and macrophages are inflamed. The mouse was injected with endotoxin, so there are many cells in the iris. It was also injected with Dextran. It stayed within the vessels; but it also got outside the vessels, and there are some phagocytic cells. There are two populations of cells—rapidly moving cells consistent with the neutrophil, and stationary cells consistent with an antigen-presenting cell.

T Cells

It would be useful if we could better understand how these antigen-presenting cells talk to T cells. There are a couple of groups around the country using a twofold type microscopy and getting very elegant pictures in lymph nodes and thymus about that communication. I do not know of anyone doing a great job looking at this communication at a site of inflammation. How much a T cell needs to talk to an APC at the site of inflammation, how much of that is antigen-specific, how much is non-specific; is the T cell like a bee, fleeting from antigen-presenting cells to antigen-presenting cell? These are all open questions. However, we think that we have the tools to start to ask and answer those questions.

We have looked in the cornea, and used the DO-11.10 mouse whose T cells are transgenic for a peptide derived from ovalbumin. We can take a DO-11.10 spleen, label it with a red dye (CMTMR), put it back into the mouse. Then we inject green ovalbumin into the cornea or into the iris, get the antigen-presenting cells labeled as we have done here, and see how the T cells interact. Several of the T cells do not seem to care about the antigen-presenting cells. Then there is one T cell that really seems to be in intimate contact with the antigen-presenting cell. This T cell moves in what seems to be a targeted, purposeful way toward that antigen-presenting cell. A lot of the T cells are completely stationary. We are still trying to unravel this: why are some T cells moving while other T cells are not? What if we look at T cells that are ovalbumin-related? Are there other antigen-presenting cells present? There are, but they do not have ovalbumin—how do they influence in the migration? I think there are a lot of open-ended questions, but we hope that we have the tools to start looking at that.

Figure 8

Fig 8. In this model, you can take the tissue out, do a confocal imaging, and then separate out that confocal image to can get a three-dimensional picture. In this case, the T cells labeled green, and the antigen-presenting cell had red ovalbumin. This is from an iris in one of our models. It really is a very intimate relationship that presumably allows a lot of communication. I hesitate to call this a synapse because we have not done the staining to define the synapse; however, presumably this is an immune synapse in vivo.

Figure 9

Fig 9. To an extent, we can do this in the human eye. This is scleritis. Scleritis has a close association with severe arthritis and rheumatoid vasculitis. Using a confocal microscope with no dyes at all, looking at the superficial vessels in individuals with conjunctivitis we can see these leukocytes rolling and sticking along these vessels when they are inflamed. Rolling and sticking is a phenomenon that we can study well in mice and hamsters, but not so easily in people because vessels are not so accessible. However, the eye is a good exception. We hope to study this phenomenon further.

Factors used to Classify Uveitis

As I said from the outset, uveitis is not a usual topic for a rheumatologist to discuss. It is sort of a daunting topic to most internist rheumatologists. It is a little intimidating. Uveitis can be better understood if you think about the subsets of uveitis:

  • Location
  • Onset
  • Symmetry
  • Continuity
  • Complications
  • Keratic precipitates
  • Response to therapy

Tubulointerstitial Nephritis and Uveitis

Tubulointerstitial Nephritis and Uveitis (TINU) is a distinct form of uveitis. It accounts for about one percent of the patients in my database of 2,000 patients. The patients who develop TINU are usually very characteristic. First of all, the uveitis is almost always bilateral. It is an anterior uveitis with sudden onset that tends to be persistent, but it can go away. In terms of the renal disease, the patients are usually systemically ill. They have fever, arthalgias, their SGOT is one and a half times normal; they are anemic—I have seen some with a sedimentation rate of 100. Their creatinine can be normal, or their creatinine can be 10; it is quite variable. The renal disease can precede the eye disease by a couple of months. Rarely, the eye disease comes first and then the renal disease.

TINU is a very distinctive entity. It is an entity that most people are not familiar with. However, it is probably a lot more common than we think because renal disease can be self-limited and you can miss it. Then you see these patients coming in with a systemic illness. They get worked up for vasculitis, etc. The answer is often just in doing a simple urinalysis and showing the white cells. If I take all comers with uveitis in my clinic, 1.3% have TINU. However, if I focus only on my patients who have a sudden onset bilaterally anterior uveitis, eight percent have TINU. If I focus on those who have a sudden onset bilateral anterior and are less than 20 years of age, more than 1/5 have TINU. It tends to be a female disease; therefore, among the women with bilateral sudden onset under 20 years of age, one quarter have TINU. That is basically true of almost any particular type of uveitis you want to talk about.

HLAB27 associated uveitis

For rheumatologists, the most important entity is HLAB27 associated uveitis. HLAB27 associated uveitis is incredibly consistent. It has a sudden onset; it affects only one eye at a time; pressure tends to decrease; and is often a very severe inflammation that usually resolves within two months. If you look in that subset, sudden onset unilateral, often recurrant, anterior uveitis—the majority of those patients are HLAB27 positive.

Differential diagnosis of uveitis

There is a huge differential for uveitis. There are infections, like CNV, tuberculosis, Lyme disease (rarely). There are patients who have ocular syndromes that are just confined to the eye. Many of these patients get labeled as having idiopathic uveitis. It is presumably immunologically-mediated. Some of these patients need immunosupression. The syndromes have wonderful names like birdshot choreoretinopathy, which has a HLA association with A29; that is 95% of the patients. There is also an entity called pars planitis. There are also masquerade syndromes such as B cell lymphoma, which seems to mimic uveitis.

Suspected immune-mediated causes of uveitis

  • Ankylosing spondylitis
  • Behçet´s disease
  • Drug or hypersensitivity reaction
  • Familial granulomatous synovitis
  • Inflammatory bowel disease
  • Interstitial nephritis
  • Juvenile idiopathic arthritis
  • Multiple sclerosis
  • NOMID
  • Psoriatic arthritis
  • Reactive arthritis
  • Relapsing polychondritis
  • Rheumatic fever
  • Sarcoidosis
  • Sclerosing cholangitis
  • Systemic lupus
  • Vasculitis
  • Vogt-Koyanagi-Harada Syndrome

This list includes the B27-related diseases such as AS and reactive arthritis. Forty percent of patients with either AS or reactive arthritis would develop a sudden onset unilateral anterior uveitis at some point in the course of the disease. As many as 70-80% of patients with Behçet’s disease will get uveitis; it is characteristically a vasculitis. It characteristically starts as an anterior uveitis and may subside. Recurrent episodes tend to march towards the back of the eye so that all portions of the eye can be involved, and you get a pan uveitis. Drugs are not a common cause of uveitis; however, there are one or two drugs that commonly cause uveitis, such as rifabutin. That can cause a very severe uveitis in about 30% of users.

Familial granulomatous synovitis is a disease that was first described by Doug Jabs, who is here at Hopkins in the Eye Department. Some people call it Jabs syndrome. Outside of Baltimore it is called Blau syndrome. Both Crohn’s disease and colitis are associated with uveitis about two to five percent of the time. The classic eye finding with MS is optic neuritis, but MS accounts for one percent of the patients in my uveitis clinic. It has a clear association with uveitis. Neonatal onset multisystem inflammatory disease (NOMID) is an autoinflammatory disease. It is the first cousin to MS, and it responds unbelievably to Anakinra®. About seven percent of patients with psoriatic arthritis get uveitis. Relapsing polychondritis can do a lot of things in the eye. Rheumatic fever has been associated with uveitis occasionally. Sarcoids are a very important cause of uveitis. Lupus is a very rare cause of uveitis, as are the major vasculitides.

Figure 10

Fig 10. This is a patient with an unilateral sudden onset anterior uveitis. I actually can tell from the photograph that this is uveitis because the pupils are asymmetrical. With the sudden onset of anterior uveitis, there is a spasm of the ciliary muscles, and the pupil will contract a little bit. Someone who looks like this has a very high likelihood of being HLAB27 positive.

About 80% of the time an HLAB27 positive patient with anterior uveitis has an associated spondyloarthritis. It is unusual to have sudden onset anterior uveitis, HLAB27 positive, and not have spondyloarthropathy, but it occurs. Non-granulomatous refers to the shape of the cells deposited on the cornea. Generally, it goes away completely in a couple of months. Only one eye is involved, but when it recurs, it may recur in the other eye. The pressure goes down. Herpes simplex is in a differential recurrent anterior uveitis, and in that one the pressure goes up. About 80% of patients in North America who have hypopian uveitis are HLAB-27 positive.

AAU = 76 sib pairs (blue); AS = 244 sib pairs (red)

Figure 11

Fig 11. My lab has done a genome wide screen on HLAB-27 associated uveitis (blue line), restricted to the phenotype of sudden onset unilateral recurrent anterior uveitis. We were able to identify 76 pairs from around the world, and to compare that with the screen from the North America Spondylitis Consortium, looking at AS (red line). Many of the patients had AS, but not all. Sometimes, one sibling would have AS and the other would not. If you look at the genome screen from the North America Spondylitis Consortium, there is a huge hit on the sixth chromosome where you see the HLA locus. There are some other signals as well with the AS screen in red. We found a huge signal on the ninth chromosome that you do not see much of when only looking at the AS, and a small signal on the first chromosome as well. I am hoping that the fine mapping will soon be complete so we know which of the hundred genes is actually responsible. There about 20 type-1 interferon genes; interferon therapy has been associated with causing uveitis. Type-1 interferon therapy in Europe is being used to treat Behçet’s associated uveitis. I am betting that it is a type-1 interferon gene. Of course, type-1 interferons have also been associated with SLE.

Figure 12

Fig 12. The other systemic disease that Rheumatologists need to know about is sarcoidosis vis-à-vis uveitis. Above are data nearly 30 years old from Duke.

Based on these data, sarcoidosis presents asymptomatically. Back in 1978, the usual way that sarcoidosis was picked up was to be found on a film with no symptoms. The lung and eye symptoms tied at about a fifth of patients who present with either ocular or pulmonary symptoms. Sarcoidosis does not present as joint disease very often. In order to get joint disease on the slide, I had to combine it with skin and CNS. An ophthalmologist often has an opportunity to initially diagnose sarcoidosis. Sarcoidosis is like Louis Carroll’s Cheshire cat. The cat stays in the tree with a smile and other parts disappear. That is the same as sarcoidosis in the eye. Remember the NEJM data that said in 80% of cases, iritis has no known cause? And I said that the number is actually 30%? A lot of what we consider to be idiopathic uveitis, or uveitis that does not have an obvious systemic disease may be sarcoidosis where the pulmonary has resolved. Sarcoidosis can cause choroid retinal scars. In fact, when using an indirect ophthalmoscope after seeing this peripherally, it appears to be pathopnemonic sarcoidosis. We will routinely do a chest CT scan on patients who come to the clinic with uveitis, and after doing a thorough history we cannot identify a pigeon hole, a niche, or a diagnostic category for that uveitis. If we do not suspect that the patient has spondyloarthropathy, inflammatory bowel disease, Behçet’s disease, relapsing polychondritis, or anything else, we will look for sarcoidosis.

We think that a chest CT is better than a routine chest X-ray. This is based on data that has come out of the Cleveland Clinic. In this study, they had females aged 61 to 83 with chronic uveitis of unknown etiology, and they found adenopathy in 57% and confirmed it with a biopsy in the majority. Our experience is that many patients will not have an adenopathy seen on a routine film, but they will have it if you look on a CT. Portland has the smallest African American population for any American city of over one million, yet five and a half percent of my patients have sarcoidosis.

Systemic diseases most commonly associated with retinal vasculitis

  • Sarcoidosis
  • Behçet’s disease
  • Multiple sclerosis
  • Vogt-Koyanagi-Harada syndrome

One of the classic ocular manifestations of sarcoidosis is a retinal vasculitis. These are “candle wax drippings” in a patient with active sarcoidosis. As a rhuematologist, I do not conceptualize sarcoidosis as a vasculitis. However, if you ask any ophthalmologist in the world, they will tell you that sarcoidosis is a vasculitis. The point is that retinal vasculitis is an incredibly misunderstood term.

Example: A rheumatologist from Seattle called me about a patient with Wegener’s disease. The patient had lost an eye from orbital disease, which is known to happen with Wegener’s. The patient had been treated with cyclophosphamide. This particular patient had a positive ANCA, then the ANCA became negative. Everything was sailing along when the patient began to have some visual difficulties. He went to the ophthalmologist, and the ophthalmologist said: “Oh, retinal vasculitis!” The ophthalmologist was right. The Wegener’s patient had developed a retinal vasculitis in a setting of what seemed to be quiescent Wegener’s. The rheumatologist said: “What do I do?” What was very clear, was that the ophthalmologist was describing a herpetic-type of infection causing retinal vasculitis. The treatment was to reduce the immunosupression and treat with something in the acyclovir family. There is a real communication problem in ophthalmologist talking to internists and rheumatologists about retinal vasculitis. It turns out that the classic vasculitides such as polyarteritis, Wegener’s and Churg-Strauss disease can cause retinal vasculitis, but they almost never do. I do not think I have ever seen a case of PAM-associated retinal vasculitis, but I definitely see sarcoidosis, Behçet’s disease, MS, and possibly BKH-associated vasculitis, at least a choroidal vasculitis.

Lupus. Of my 2,000 patients who have uveitis, I think two have lupus. The most common ocular manifestation of lupus is dry eye. The second most common is what we call retinal vasculopathy, which manifests as cotton wool spots. About 14% of patients with lupus will get cotton wool spots. A cotton wool spot is indicative of local retinal ischemia. It is often associated with anti-phospholipid antibodies, but not always. However, you do not see the kind of abnormal fluorescent angiogram with the sheathing typically in lupus. You might, but it is not common.

Blau Syndrome

Blau syndrome is incredibly rare because there are three billion base pairs that make up your genome. If you change one of those base pairs, you have a 100% chance of developing uveitis. If that is not a clue to the pathogenesis of uveitis, I do not know what it is. We do not fully understand that clue because we do not fully understand why HLAB27 predisposes to uveitis either. The histopathology of Blau syndrome is non-necrotizing granuloma, just like sarcoidosis. Tammy Martin and Carlos Rosé in Delaware have setup an international registry for these patients. It is very clear that the majority of patients with early-onset sarcoidosis actually have Blau syndrome with adnovum mutation.

The gene responsible for Blau is known. The gene is called CARD15/NOD2. The CARD15/NOD2 gene has three domains. It has two caspase recruitment domains. The caspases are vital intracellular enzymes. Caspase-1 is involved in activating interleukin-1. Caspase-9 is very involved in apoptosis. There are also these nucleotide-binding domains that allow oligomerization of the gene. These are where the mutations are found that are responsible for Blau syndrome. The other genes that have nucleotide-binding domains include the genes that are responsible for NOMID, the IL-1 determined disease. The third part of the NOD2 gene includes leucine. There are about 600 proteins in the body that have a lot of leucine. But immunologists ought to know about one particular set of genes that have the proteins, that have leucine, and those are the toll receptors. The immune system is vitally dependent upon proteins that have leucine. It is the leucine that recognizes the bacterial and viral products. It is very clear now that the NOD2 acts like an intercellular toll receptor. The ligand for the leucine in NOD2 is muramyl dipeptide. This is a two-amino acid sequence that is common to every bacterial cell wall that is known. It turns out that there are mutations in the leucine that are associated with a very different granulomatous disease: Crohn’s disease. Same gene mutation here, you get uveitis, arthritis, dermatitis granulomas. Mutations here are not 100% guaranteed to develop granulomas in your bowel and elsewhere, but you are predisposed to it. It is a huge risk factor. How a bacterial sensor might lead to that, obviously, is a fascinating question, especially since Crohn’s is clearly a disease related to bacteria.

Laboratory Tests

Conducting a history will do an adequate job in working up a patient with uveitis. If nothing turns out by history, a syphilis serology and a chest X-ray or CT will work. When treating the patient, there is a role for systemic immunosuppresants for a small subset, and you communication with about the use of those drugs with the ophthalmologist is necessary.

Summary

  • Uveitis is an obscure disease to most rheumatologists;
  • Rheumatologists can play a vital role in the evaluation and management of patients with uveitis.
  • Understanding ocular inflammatory disease provides insight into other inflammatory diseases.

For CME credit,TAKE POST-TEST & EVALUATION

Updated: August 16, 2012

Arthritis Center

About Arthritis Center

Founded in 1998, the Arthritis Center at Johns Hopkins is dedicated to providing quality education to patients and healthcare providers alike.