Uveitis and Other Eye Conditions in Rheumatology Patients

Interviews with Experts


Sergio Schwartzman, MD

Associate Attending Physician, Hospital for Special Surgery
Associate Professor, Weill Cornell Medical College
Clinical Director, Inflammatory Arthritis Center of Excellence


  1. Types and symptoms of uveitis
  2. Associated disorders
  3. Specialist care
  4. Patient evaluation and differential diagnosis
  5. Treatment
  6. Evaluating anti-TNF agents for uveitis

Dr. Paget:  It is a pleasure today to introduce today Dr. Sergio Schwartzman, a Clinical Associate Professor of Medicine at the Weill Medical College of Cornell University. Dr. Schwartzman is a superb rheumatologist, but also has a an interest in inflammatory diseases of the eye, an important focus for our patients who develop these types of problems.

Dr. Schwartzman, why is the eye important to a rheumatologist and to a primary care physician?

Types and symptoms of uveitis

Dr. Schwartzman: Although autoimmune diseases of the eye are relatively uncommon, when they occur they clearly have a very important impact on morbidity and, at times, mortality. Further, effects secondary to some of the medications that are used to treat them can at times be very important. Various types of autoimmune disease affect the eye. By far and away, the most common is uveitis. Uveitis is a disease that has many clinical features and is separated into three types:

  • anterior uveitis, in which the iris and the ciliary body are involved
  • intermediate uveitis, and
  • posterior uveitis, in which the choroid and the retina are predominately involved.

There can be an overlap, and there are conditions in which there is involvement of all of the chambers - what we call pan-uveitis. The symptoms of these different manifestations differ somewhat, but again, they can overlap.

In anterior uveitis, photophobia, eye tearing and occasional eye pain occur. Vision is not dramatically impaired, but can be impaired if this condition becomes chronic. In intermediate uveitis, patients complain of floaters or occasional decreased visual acuity. In posterior uveitis, you have similar symptoms with a decrease in visual acuity.

We also know that uveitis can exist as an independent disease or as an illness that is associated with other autoimmune diseases which the rheumatologist frequently sees.

Associated disorders

Dr. Paget: Could you give some examples of disorders that the rheumatologist deals with that are most characteristically associated with uveitis?

Dr. Schwartzman: Sure. About half of the time, uveitis occurs as an independent disease. The remaining 50% of cases of uveitis can be associated with other illnesses. It is very important, however, before we consider rheumatic diseases, to exclude infectious illnesses such as CMV, herpes, toxo, TB, and syphilis, and to exclude malignant diseases. Lymphoma can effect the eye in a way that may mimic uveitis.

The most common diseases that a rheumatologist sees that result in uveitis are ankylosing spondylitis, juvenile rheumatoid arthritis, Behcet's disease, and all of the HLA B-27 associated seronegative spondyloarthropathies.

Dr. Paget: What about the vasculitides that we deal with, such as Wegener's and polyarteritis nodosa?

Dr. Schwartzman: Those don't tend to result in uveitis. They can, however, affect the eye, as can lupus and antiphospholipid antibody syndrome. These tend to predominate to a somewhat greater extent in the retina, but can affect the eye as well in other areas.

Specialist care

Dr. Paget: Is it absolutely mandatory to have an ophthalmologist involved in the care of somebody with these types of problems?

Dr. Schwartzman: It is not only critical to have an ophthalmologist involved, but I think it's critical to have an ophthalmologist who is familiar with autoimmune diseases and involved in the care of these types of patients. The rationale for this is that when one determines therapy, the barometer for deciding how aggressive to be is clearly the ophthalmological examination. One can actually quantify uveitis by counting cells through the slit lamp (high magnification eye microscope). The numbers of cells present reflect the activity of the disease.

Dr. Paget: So there are probably two different types of people: those who are sent to you by an ophthalmologist, and those whom you are already treating who develop a problem and may be sent to an ophthalmologist. Is there a different algorithm of care and evaluation in each one of those?

Dr. Schwartzman: I think the algorithm is relatively similar. However, there is an important difference. Most of the patients that we detect as having autoimmune disease affecting the eye tend to have relatively mild eye disease and established systemic autoimmune disease. The most common condition is ankylosing spondylitis, where as many as 20-40% of patients who have that disease will at some point in their lives experience anterior uveitis; in that circumstance, the uveitis is relatively mild. It is short-lived. It's unilateral, and it is treated with topical agents.

The patient that the ophthalmologist refers to us for care, however, is usually a patient that can have one of many diseases affecting the eye, but one that has been resistant to therapies that the ophthalmologist is comfortable with.

The ophthalmologist does not have the experience that we as rheumatologists have treating with these very aggressive immunosuppressive agents. So I would say that the clinical experience is different. The algorithm, which is not really developed - although it is something that potentially would be helpful on this group of diseases - is relatively the same.

Patient evaluation and differential diagnosis

Dr. Paget: For the primary care physician and the rheumatologist out there, what does the evaluation consist of? Obviously, you do a complete history and physical, because you need to rule out the systemic diseases and comorbidities. Are there specific tests that you do on people with "unknown" causes of uveitis?

Dr. Schwartzman: I think that the preliminary evaluation, in addition to the careful history and physical exam, would require the following: a PPD (purified protein derivative skin test), syphilis serologies, chest x-ray, and routine laboratory tests. I think that at times we need a little bit more of an extensive type of diagnostic work-up. In certain circumstances, dictated by the careful history and physical exam, a more extensive work up needs to be undertaken. For example, if a patient has a history of bloody diarrhea, an evaluation for colitis needs to be done.

Dr. Paget: Two disorders that you haven't mentioned as yet, Lyme disease and sarcoidosis, are often discussed with regard to the differential diagnosis of uveitis. How common are those, and do you evaluate those patients for the presence of those disorders?

Dr. Schwartzman: I think Lyme disease can clearly cause uveitis. It is one of the infectious etiologies, and there are probably at least 10 diseases that we can name that are infectious and can cause uveitis, but it is very uncommon. Sarcoidosis is somewhat more common. The pattern is relatively pathognomonic. These patients develop bilateral pan-uveitis. It can have a nodular type of pattern that is sometimes noted. If the history is suggestive, clearly a diagnostic evaluation for these conditions needs to be carried out.

Treatment

Dr. Paget: So, once you have made the diagnosis, whether you've seen them initially or they've been referred by an ophthalmologist, what are the parts of the armamentarium that you have available, from the mildest to the most significant, with regard to controlling this potentially blinding problem?

Dr. Schwartzman: I think your point about the blinding issue is important to recognize. Although I've mentioned that uveitis is a relatively uncommon disease, even for the ophthalmologist to see, it accounts for 10% of significant visual loss in the United States. So it has a very high degree of morbidity. In addition, some of the agents that we use to treat this, which we will discuss, can result in further morbidity. Cataracts and glaucoma are not infrequent in patients with uveitis secondary to steroids.

In terms of our armamentarium, cycloplegic agents and topical steroids are really the first line and, in most patients with uveitis, that will usually be successful in treating the disease, particularly anterior uveitis. Posterior uveitis, chronic uveitis, and intermediate uveitis generally require a more aggressive approach. The current recommendations are that systemic steroids be utilized first -- prednisone at a dose of 1 mg per kilogram, which is then adjusted based on what the ophthalmologist sees. If the ophthalmologist sees rapid improvement, one is relatively safe in tapering the steroid slowly.

In patients who don't respond to corticosteroids, there isn't an established, agreed-upon paradigm. However, there are certain medications that we utilize commonly. These include Methotrexate, Mycophenolate, Azathioprine, and Cyclosporin. Cyclophosphamide (Cytoxan) has been used to treat uveitis both orally and systemically, and pulse steroids - that is, 1 gram of methylprednisolone (Medrol) a day for three days in a row - has also been used. These two therapies are less frequently used today.

Although gammaglobulin and several biological therapies have been used experimentally for the treatment of chronic “resistant” uveitis, the greatest emphasis over the last 8 years has been on the use of anti-TNF agents.

Evaluating anti-TNF agents for uveitis

Dr. Paget: What are the anti-TNF agents you are talking about?

Dr. Schwartzman: Although all three of the anti TNF agents - etanercept, infliximab and adalimumab - have been used to treat resistant uveitis, it is now clear that only the monoclonal antibodies - infliximab and adalimumab - are efficacious. Clearly, etanercept should not be used to treat this group of diseases.  Further, surprisingly and disturbingly there has been a recent paper published in Ocular Immunology and Inflammation on etanercept-associated inflammatory eye disease where several cases of inflammatory eye disease may have been precipitated paradoxically by etanercept. 

Dr. Paget: Now, would these be for everyone with uveitis, so as to improve the overall outcome in that 10% of patients with blindness caused by uveitis, or is that just a subset of people who are refractory to the prior medications you are talking about?

Dr. Schwartzman: I think that is a very good question. The answer is, we don't yet know. Infliximab and adalimumab are not currently first line therapies for resistant uveitis. I can tell you that the way the studies are being organized is similar to the studies that were done for biological agents in rheumatoid arthritis. The first group of patients who are being subjected to these agents are patients who have been resistant to all other therapies for uveitis. My sense is that if biologics work in uveitis in the same way that we have seen in rheumatoid arthritis, we will likely see the same pattern of treatment as in rheumatoid arthritis; and that pattern, as you know, is that biologics are beginning to be used much earlier in treating patients with rheumatoid arthritis. I think that the same pattern will occur in uveitis. Interestingly, infliximab was recently approved in Japan for Behcet’s-associated uveitis.

Dr. Paget: So we will try to profile people, and if they have certain characteristics that make it seem as though they are moving towards the blindness potential, we might very well act earlier, just like in rheumatoid arthritis with a person with aggressive disease that may eventuate a joint replacement.

Dr. Schwartzman: That's correct. I think we will have similar types of problems in terms of prognosticating which patients are more likely to develop blindness and visual impairment. For example, we know that patients with pan-uveitis or posterior uveitis are more difficult to treat. And I think that those factors, whether they be clinical or ultimately genetic, will be defined as we move forward.

Dr. Paget: And what do you see for the future -- more biologics, using them in combinations?

Dr. Schwartzman: I think that the current approach is to use them in combination with an immunosuppressive agent such as methotrexate or mycophenolate. As this field expands, my hope is that we will have more specific agents. There are animal models of uveitis in which cytokines have been identified which can probably promulgate uveitis, and in those studies there have been high levels of TNF, but there have been other cytokines as well.

I suspect that in some patients with uveitis there will be one or two cytokines that drive the disease, whereas in other patients, the cytokine profile may be completely different. It is going to be difficult to sample that from the eye, but I think there may be a better approach from a genetic perspective.

Dr. Paget: Thank you very much, Dr. Schwartzman.


Dr. Schwartzman was interviewed by Dr. Stephen A. Paget, Physician-in-Chief Hospital for Special Surgery

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