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The Comanagement of Uveitis Patients

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A healthy 17-year-old student, John, noticed sudden onset of floaters in his right eye. After they continued to get worse over the next month, he saw an ophthalmologist. Upon seeing bleeding in the retina, the ophthalmologist referred the young man to a retina specialist, who sent him for a second opinion to another retina specialist. This second retina specialist diagnosed retinal vasculitis and vitritis in addition to the retinal hemorrhages and edema. Given the inflammatory findings, the patient was ultimately transferred to a uveitis specialist. This sequence of events is not uncommon in uveitis. In this case, there were appropriate and rapid referrals such that it was only a few weeks from the time John saw the first ophthalmologist until he saw the uveitis specialist. In other cases, delays may increase the risk of vision loss.

When seeing a newly referred uveitis patient, it is important to keep an open mind and to start fresh to get the diagnosis, and thus the treatment course, correct. First, take a thorough history from the patient, including an extensive review of systems (a uveitis questionnaire is helpful), past medical history, and exposure history. Next, do a detailed ocular exam as well as a selected physical exam based on the review of systems. The complete history and exam will lead to your initial differential, which will determine which labs and testing to order. In all cases, it is important to test for syphilis. Keep in mind that, if the patient is already on steroids or other immunosuppressives, the exam may reveal a misleadingly low level of inflammation. In John’s case, no additional history was revealed, but the exam revealed arteritis and retinal whitening that were not previously noted. A serologic work-up revealed a positive fluorescent treponemal antibody absorption (FTA-ABS) test but a negative rapid plasma reagin test and no other indication of infection. He was referred to an infectious disease specialist who confirmed that the FTA-ABS test was a false positive. At this point, the patient was started on systemic prednisone and rheumatology was consulted for comanagement of steroid-sparing immunosuppressives. After a full evaluation revealed no evidence of Behcet disease, initial treatment with methotrexate was recommended. They continued to follow the patient as the methotrexate dose was escalated in response to the results of the eye exams. When the retinal vasculitis remained active despite the maximal dose of methotrexate as well as local ocular steroid injections, John was started on subcutaneous adalimumab every 2 weeks as well.

As this case highlights, many uveitis patients see multiple providers. When coordinating care, the key is communication.

Elizabeth A. Atchison, MD, is a vitreoretinal surgery fellow at Rush University Medical Center and Illinois Retina Associates, S.C., in Chicago. Pauline T. Merrill, MD, is the uveitis section director at Rush University and a vitreoretinal surgeon with Illinois Retina Associates, S.C. Dr. Atchison reports no related disclosures. Dr. Merrill reports research support and advisory board membership with Santen and Abbvie; research support from Clearside Biomedical, Eyegate, and Alimera; and personal fees from Allergan. Reach Dr. Atchison at elizabethatchison@gmail.com. Editor’s note: This article is featured in a journal club episode of Straight From the Cutter’s Mouth: A Retina Podcast. Listen to the episode at www.retinapodcast.com .

RHEUMATOLOGY

For the comanaging rheumatologist, it is imperative that the ophthalmologist clearly communicate the diagnosis for the patient’s initial visit and what role you would like the rheumatologist to play. If the rheumatologist is not familiar with uveitis, it may be worthwhile to update him or her on the systemic options often used for uveitis treatment. Traditional steroid-sparing systemic options include the antimetabolites methotrexate and mycophenolate mofetil, which are often the first-line agents due to their relatively favorable side effect profile. Cyclosporine and tacrolimus are calcineurin inhibitors that can be associated with hypertension and nephrotoxicity. Cyclophosphamide and chlorambucil are alkylating agents that are used for uveitis associated with severe systemic disease, such as granulomatosis with polyangiitis. Their side effects include pancytopenia, hemorrhagic cystitis, and malignancies.

Newer systemic treatment options for uveitis include biologic agents. Adalimumab is a tumor necrosis factor-alpha inhibitor indicated for use in many inflammatory conditions, including rheumatoid arthritis, psoriasis, and Crohn disease. The VISUAL I and II trials showed significant benefit of adalimumab (Humira; AbbVie) for patients with active and inactive, respectively, noninfectious intermediate, posterior, or panuveitis requiring systemic prednisone.1,2 Patients receiving adalimumab were half as likely to fail a steroid taper as those receiving placebo. Use of this injectable medication was also associated with an approximately doubled time to treatment failure as compared with the placebo group. In 2016, based on the VISUAL I and II studies, the US Food and Drug Administration expanded the indications of adalimumab to include noninfectious posterior uveitis. Intravenous infliximab is often used off label to treat severe noninfectious uveitis.

After the initial visit, communication shifts to the current inflammatory state. Is it well controlled, or are there signs of persistent inflammation? We recommend that, if such communication is via note, there be a special section that summarizes what the rheumatologist needs to know. In cases of persistent inflammation, a new or additional agent may need to be added.

PULMONOLOGY

For patients with sarcoidosis, the comanagement may be with a pulmonologist who can help determine if there are pulmonary issues beyond any abnormalities on chest imaging; pulmonary function tests may reveal a decreased diffusing capacity. The pulmonologist may also manage systemic treatment, which may include oral prednisone, methotrexate, azathioprine, infliximab, or adalimumab.

INFECTIOUS DISEASE

For many cases of infectious uveitis, an infectious disease specialist may provide valuable input. This may be to evaluate further the possibility of an infectious disease vs a false positive (such as syphilis in our patient) or to treat the underlying cause. In the case of syphilis, the infectious disease specialist not only can help facilitate staging of the patient’s disease with a lumbar puncture, but also can help with the mandatory reporting of syphilis and partner treatment as needed. With syphilis or some cases of acute retinal necrosis, it may be helpful to remind the treating physician that these cases often require the more intense intravenous antimicrobial dosing that neurosyphilis or encephalitis due to herpes simplex or varicella zoster requires.

PRIMARY CARE

When oral steroids are indicated, the patient’s primary care physician may be needed to help monitor and control side effects. Not only can patients have elevated blood pressure and blood glucose from the steroids, but steroids can increase the risk of stroke or heart attack by 20% and the risk of fracture by 80%.3 Additionally, the primary care provider may need to monitor and/or provide referrals to specialists for additional issues from the underlying disease.

CATARACT SURGEONS

In addition to outside specialists, the uveitis patient also may be seeing multiple ophthalmologists. Compared with age-matched patients, those with posterior uveitis are 10 times more likely to have blindness or low vision, twice as likely to have glaucoma, 3 times as likely to have cataract, and 12 times more likely to have a retinal detachment.4 An oft-cited general rule is that the patient’s uveitis should be well controlled for 3 months before cataract surgery.5 Additionally, in the setting of cataract extraction, depending on the underlying cause of the uveitis, there may be a high risk of reactivation of the underlying disease. One-third of patients with ocular toxoplasmosis will reactivate within 4 months of cataract surgery, so suppression with oral antibiotics should be considered.6 Conversely, those with Fuchs heterochromic cyclitis tend to have good cataract surgery outcomes even with persistent anterior chamber cell.7 The taper of topical and/or oral steroids after surgery may need to be extended, depending on the individual case.

GLAUCOMA SPECIALISTS

Patients with uveitis have an increased risk of glaucoma not only from the uveitis itself but also from steroid exposure. Overall, about 1 in 5 uveitis patients will develop glaucoma.8 Those with Fuchs heterochromic uveitis, Posner-Schlossman syndrome, juvenile idiopathic arthritis, and uveitis secondary to herpetic disease are at a particularly high risk for developing glaucoma. Management begins with topical agents. Although prostaglandin analogs have been reported to be associated with an increased risk of inflammation, they may be safely used in uveitic glaucoma after the inflammation is controlled. Systemic carbonic anhydrase inhibitors may also be helpful. Peripheral iridotomies should be performed in any cases of pupillary block or narrow angles. Selective laser trabeculoplasty is preferred over argon laser trabeculoplasty due to its lower level of associated inflammation. In cases in which nonsurgical treatments are inadequate, glaucoma drainage implants may have a higher incidence of success than trabeculectomy for patients with uveitic glaucoma, particularly in young patients.8

CONCLUSION

Uveitis patients can have an added level of complexity due to the number of providers involved with their care. Frequent visits with multiple specialists may be an additional burden for these relatively young patients, who are often trying to juggle full-time work and family commitments as well as their challenging eye disease. Clear communication between providers can help facilitate care and optimize patient outcomes. RP

REFERENCES

  1. Jaffe GJ, Dick AD, Br├ęzin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375(10):932-943.
  2. Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388(10050):1183-1192.
  3. Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respir Med. 2009;103(7):975-994.
  4. Dick AD, Tundia N, Sorg R, et al. Risk of ocular complications in patients with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Ophthalmology. 2016;123(3):655-662.
  5. Van Gelder RN, Leveque TK. Cataract surgery in the setting of uveitis. Curr Opin Ophthalmol. 2009;20(1):42-45.
  6. Bosch-Driessen LH, Plaisier MB, Stilma JS, Van der Lelij A, Rothova A. Reactivations of ocular toxoplasmosis after cataract extraction. Ophthalmology. 2002;109(1):41-45.
  7. Tejwani S, Murthy S, Sangwan VS. Cataract extraction outcomes in patients with Fuchs’ heterochromic cyclitis. J Cataract Refract Surg. 2006;32(10):1678-1682.
  8. Siddique SS, Suelves AM, Baheti U, Foster CS. Glaucoma and uveitis. Surv Ophthalmol. 2013;58(1):1-10.