Strategies for Managing Uveitis, Part 1: Initiating Treatment in Adults

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The approach to evaluating and managing noninfectious uveitis is confusing for many ophthal­mologists, especially with the growing array of biologic agents that are poten­tially effective for suppressing intraoc­ular inflammation. Clinical trials tend to focus on the efficacy and safety of individual agents; less is written about real-world experiences with these thera­pies in clinical practice.

Gary N. Holland, MD, of the Jules Stein Eye Institute at University of Cali­fornia, Los Angeles (UCLA), discussed this subject with Nisha Acharya, MD, MS, of the Francis I. Proctor Founda­tion at University of California, San Francisco; John D. Fitzgerald, MD, PhD, MBA, of the Rheumatology Divi­sion, Department of Medicine, David Geffen School of Medicine at UCLA; Debra A. Goldstein, MD, of the Fein­berg School of Medicine at Northwest­ern University in Chicago; and John H. Kempen, MD, MPH, PhD, MHS, of Massachusetts Eye and Ear and the Schepens Eye Research Institute in Boston.

In this first part of a four-part series, the experts share advice on initiating uveitis therapy in adults. Part 2 will in­clude tips for maintaining disease con­trol during treatment and will appear in the next issue of EyeNet. The final two installments, dealing with children, will appear in subsequent issues.

Newly Diagnosed Uveitis

Dr. Holland: When a patient first pres­ents to you with newly diagnosed or uncontrolled uveitis, and infection is ruled out, what is your initial approach to control intraocular inflammation?

Dr. Goldstein: In general, I start with corticosteroids of some sort, but the approach depends on the type of uveitis. For acute anterior uveitis, my first line of therapy would be aggressive topical steroids. For persistent birdshot chorioretinitis, I would be planning for immunosuppression potentially pre­ceded by a transition period on oral or implanted corticosteroids. If the patient presents with active anterior uveitis, I usually give prednisolone acetate 1%; however, for very severe uveitis in an adult patient, I would use difluprednate.

Dr. Kempen: I think difluprednate is valuable if there is little concern about cataract development, such as in perioperative inflammation after cataract surgery. I also give difluprednate if induction with 1% prednisolone acetate is not effective.

Dr. Acharya: I agree. My go-to drug is 1% prednisolone acetate, but some patients have sensitivity or discomfort of the ocular surface because this agent is a suspension that can feel gritty. In such cases, I would give preservative-free dexamethasone (0.1%). I reserve difluprednate for patients with severe inflammation, nonresponse to prednis­olone acetate 1%, or macular edema. I think difluprednate has better pene­tration into the back of the eye, but it necessitates careful monitoring of IOP. We usually see patients seven to 10 days after starting any corticosteroid treatment, and we continue to monitor IOP at frequent intervals throughout treatment.

I rarely use low-potency topical cor­ticosteroids; they tend to be insufficient for controlling active inflammation. I also generally avoid having patients on a maintenance corticosteroid.

Dr. Goldstein: For patients with panuveitis or posterior uveitis, there is evidence that intravitreally administered corticosteroids are more effective than sub-Tenon or posterior sub-Tenon corticosteroids.¹ On the other hand, sub-Tenon triamcinolone acetonide avoids the risks of vitreous hemorrhage, endophthalmitis, and retinal detach­ment. In practice, many patients with posterior segment inflammation have had very good response to posterior sub-Tenon triamcinolone acetonide, so that is what I try first, especially for those expected to have chronic uveitis. If that approach doesn’t work and I want to use local corticosteroids, I would give them intravitreally. If I need to quickly suppress inflammation, such as in active serpiginous choroiditis or Behçet disease prior to starting immu­nosuppression, I would use an intravitreal steroid such as a dexamethasone implant (Ozurdex), which will release drug for 14-16 weeks, the period of time when immunosuppressive agents will have their onset of action.

Dr. Kempen: I agree. If it’s clear that the disease will be chronic, then systemic therapy can be useful. If the goal is controlling inflammation before the immunosuppressive therapy takes effect, then the dexamethasone implant may be sufficient. We have evidence from the POINT trial that efficacy is greater with intravitreous corticosteroids, but posterior sub-Tenon delivery tends to work well too.¹

Dr. Goldstein: We need to choose a duration of therapy that is compatible with the duration of disease. I would never repeatedly inject intravitreal dexamethasone implants as long-term therapy; they would be reserved for breakthrough macular edema or as a bridge before systemic immunosup­pression. The exceptions are cases of macular edema that occur intermittently for decades; I treat these patients with posterior sub-Tenon triamcinolone acetonide every few months, with or without systemic immunosuppression.

ANTERIOR UVEITIS. A woman with anterior uveitis at presentation. In addition to 3+ anterior chamber cells, she has granulomatous (“mutton-fat”) keratic precipitates. Initial treatment consisted of hourly prednisolone acetate 1% while awake.

TB Testing Before Treatment

Dr. Holland: Do you test patients for latent tuberculosis (TB) before start­ing any drugs?

Dr. Fitzgerald: We typically test for latent TB before initiating any biologics or JAK inhibitors but not for the oral antimetabolites or for cyclosporine or tacrolimus.

Initiating Immunomodulatory Therapy

Dr. Holland: How long do you treat with corticosteroids before deciding to start immunosuppression, and what is your approach for starting immunomodulatory therapy?

Dr. Acharya: Several scenarios justify moving forward with systemic immu­nosuppression. Cases tend to involve diseases with chronic, progressive posterior uveitis or panuveitis that will require long-term therapy, such as birdshot chorioretinopathy, retinal vas­culitis, or multifocal choroiditis. I start corticosteroid-sparing therapy soon after such conditions are diagnosed—within a couple weeks of starting corticosteroids—because we know that immunosuppressive therapies can take many months to show effectiveness.

Dr. Holland: In general, we use corti­costeroids to gain control of inflamma­tion, and immunomodulatory therapy to maintain that control. Long-term, high-dose corticosteroid treatment is not appropriate for management of chronic disease.

Dr. Acharya: I fully agree. If we aren’t certain that a patient will need long-term therapy, then I give corticoste­roids, monitor for a response, and then taper the dosage. If the inflammation recurs, that would be an indication to start steroid-sparing therapy.

Dr. Goldstein: My choice of initial immunomodulatory therapy is based on several factors, including patient age, comorbidities, and how quickly the immunosuppression is needed. Al­though antimetabolites are less costly, they generally take three to five months to show an effect. If a patient has poten­tially blinding disease, I will start with a biologic, often adalimumab because it is FDA-approved for uveitis.

I usually avoid giving methotrexate to adults; I find that it’s not tolerated as well as mycophenolate mofetil. For anyone of childbearing age, I avoid both methotrexate and mycophenolate mofetil. I would instead start with a biologic in those patients because bio­logic agents are safer during pregnancy.

Dr. Acharya: The FAST (First-Line Antimetabolites as Steroid-Sparing Treatment) uveitis trial was designed to directly compare effectiveness of oral methotrexate and oral mycophenolate mofetil for intermediate, posterior, or panuveitis.² The primary outcome was steroid-sparing control at six months. We found that about 67% of those on methotrexate had steroid-sparing control at six months, versus about 57% in the mycophenolate mofetil group, but that difference was not significant. The takeaway was that the drugs were comparable.

Methotrexate typically is given once weekly, but we used a high dosage and quick escalation in the FAST trial, reach­ing daily regimens of 25 mg of metho­trexate or 3 g of mycophenolate mofetil within two weeks. We allowed dose reduction for intolerance, and approxi­mately 19% of patients on methotrexate did require a dose reduction, and that rate was higher than for mycophenolate mofetil. About 14% of those on meth­otrexate had liver function abnormali­ties, compared with roughly 7% in the mycophenolate mofetil group; in both groups, these events generally were not serious.

Dr. Kempen: I led an observational comparison study of methotrexate and mycophenolate, with an outcome measure of “time-to-success.”³ Results showed that mycophenolate mofetil took effect faster and therefore out­performed methotrexate. However, methotrexate eventually had an effect. And in light of FAST findings showing that methotrexate was escalated more rapidly and seemed to perform better than mycophenolate mofetil, I consider methotrexate as first-line, particularly when cost is a concern. I think the right strategy for a slow-acting drug is to start with a higher dose.

The Rheumatology Perspective

Dr. Holland: What should ophthalmologists be thinking about, from a medical standpoint, when choosing among the antimetabolites?

Dr. Fitzgerald: As rheumatologists, we generally start methotrexate at 15 mg, once weekly, and try to reach 20 mg. We don’t usually go as high as 25 mg orally because of tolerability and absorption issues; we often will give methotrexate subcutaneously if we need a higher dosage. Split dosing is another option to help with tolerability, as long as the full dose is consumed within a 24-hour period. We monitor complete blood counts, including white blood cell differentials and platelet counts, as well as liver function test results, for patients on methotrexate, starting three to four weeks after initi­ation and continuing at three-month intervals thereafter. We also check for previous hepatitis exposure. We coun­sel patients about concurrent alcohol use, but this is no longer a strict contra­indication. I explain to patients that the liver has to clean the methotrexate, so if it has to clean the alcohol also, there is an increased risk of experiencing side effects. Fatty liver is probably the most common comorbidity that contributes to my choice of therapy.

Mycophenolate mofetil is associ­ated with gastrointestinal intolerance, so many rheumatologists will titrate it slowly; it usually takes a month of weekly escalations to reach 2 or 3 g. For cyclosporine, we monitor creatinine and blood pressure. For azathioprine, we check thiopurine methyltransferase (TPMT) to make sure the patient can metabolize the drug. An overarching concern with these antimetabolites is safety during pregnancy.

Dr. Goldstein: The FDA lists azathi­oprine in pregnancy category D, but there is some evidence that azathio­prine is safe in pregnancy.

Dr. Fitzgerald: We give azathio­prine often, particularly in patients with lupus, and many of them are of childbearing age. There are a lot of data showing that azathioprine is safe in pregnancy.⁴ The American College of Rheumatology also provides infor­mation on the use of other rheumatic medications during pregnancy and lactation on its website.⁵

Dr. Acharya: I rarely prescribe cyc­losporine or tacrolimus anymore. I rely on the antimetabolites and TNF inhib­itors or other biologics. Biologics seem to be reasonably safe during pregnancy.

Dr. Goldstein: Cyclosporine adds so little to our therapeutic array now that we have biologics. I don’t prescribe cyclosporine at all anymore.

Dr. Holland: We don’t use cyclosporine often either. It can be very effective for control of uveitis, but the side effects of hypertension and renal toxicity are major concerns.

Dr. Goldstein: I’ve continued azathio­prine in patients who have come to me already on it, and I have transitioned patients from another antimetabolite to azathioprine if they’re planning on pregnancy and are not going to be on a biologic. Otherwise, I don’t use azathioprine.

Dr. Acharya: I do the same. When it comes to uveitis, experience favors methotrexate and mycophenolate over azathioprine, in large part because of the rate with which azathioprine is discontinued for intolerance.⁶

Low-Dose Steroid Extension

Dr. Holland: What is your approach for a patient who has started immu­nomodulatory therapy, but seems also to need continued low-dose topical corticosteroid to maintain disease control? Would you continue the corticosteroid or consider adding a second immunosuppressant?

Dr. Goldstein: We need to think about treatment in the context of the patient’s age. For a 70-year-old with sarcoidosis, myriad comorbidities, and no glaucoma, I would rather potentially accelerate cataract development with long-term topical steroids than risk hypertension and liver disease by tak­ing the patient off steroids too soon. My approach in a pediatric patient would be very different.

Dr. Acharya: I agree. Depending on the patient’s situation, continuing a low-dose topical corticosteroid can be safe, but frequent IOP monitoring becomes crucial because the pressure can increase at any time, even in some­one who is not considered a steroid responder.

Dr. Kempen: Yes, our outcomes data show that the steroid-responder status is relative; a patient can become a steroid-responder after years of IOP stability on steroids. We are slightly less concerned about continuing steroids in a pseudophakic patient, because cata­ract development is not a concern, and pseudophakia also is associated with a lower risk of IOP elevation.

Dr. Goldstein: When discussing with patients why periodic IOP monitoring is needed while they’re on steroids, I use an analogy of a shower drain progressively getting clogged with soap scum and hair; eventually, the water stops draining properly. The trabecular meshwork needs to be like a clean drain to clear the intraocular fluid and avoid elevated IOP.

Dr. Holland: It’s important to be aggressive at the onset of the disease. With uveitis, we want to prevent com­plications rather than treat compli­cations. I agree that the ultimate goal should be to discontinue corticoste­roids, but I also think low-dose topical corticosteroids can have some effect on anterior segment inflammation when used in addition to immunosuppres­sion, and one should weigh the risks and benefits of extending the duration of a corticosteroid versus adding a second immunosuppressant. We should also be mindful of the issue of potential nonadherence to eyedrops and the fact that patients sometimes don’t have their monitoring bloodwork done while on systemic treatments.

Dr. Acharya: I think those concerns underscore the point that risk-benefit discussions with patients are crucial when managing uveitis. Also, we should recognize that therapeutic decision-making can change over time for any given patient. That’s just the nature of our specialty.

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1 Thorne JE et al for the Multicenter Uveitis Ste­roid Treatment Trial Research Group. Ophthal­mology. 2019;126(2):283-295.

2 Rathinam SR et al for the FAST Research Group. JAMA. 2019;322(10):936-945.

3 Gangaputra SS et al for the SITE Cohort Re­search Group. Am J Ophthalmol. 2019;208:68-75.

4 Natekar A et al. Can Fam Physician. 2011;57(12):1401-1402.

5 https://rheumatology.org/pregnancy-rheumatic-disease. Accessed May 3, 2023.

6 Pasadhika S et al. Am J Ophthalmol. 2009;148(4): 500-509.

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Dr. Acharya is the Elizabeth C. Proctor Distin­guished Professor at the F.I. Proctor Foundation and Departments of Ophthalmology, Epidemi­ology and Biostatistics at UCSF and Director of the Uveitis and Ocular Inflammatory Disease Service. Relevant financial disclosures: AbbVie: S.

Dr. Fitzgerald is Clinical Professor of Medicine, David Geffen School of Medicine at UCLA and Staff Physician with the Veterans Affairs Greater Los Angeles Healthcare System. Relevant financial disclosures: None.

Dr. Goldstein is Magerstadt Professor of Oph­thalmology at Northwestern University Feinberg School of Medicine in Chicago. Relevant financial disclosures: None.

Dr. Holland is Distinguished Professor of Oph­thalmology and Jack H. Skirball Chair in Ocular Inflammatory Diseases, David Geffen School of Medicine at UCLA, and member of the Jules Stein Eye Institute at UCLA. Relevant financial disclosures: None.

Dr. Kempen is Professor of Ophthalmology, part-time at Harvard Medical School, Director of Epidemiology and Senior Scholar at Massachu­setts Eye and Ear and the Schepens Eye Research Institute in Boston. Relevant financial disclosures: Betaliq: PS; Massachusetts Eye and Ear: E; Nation­al Eye Institute: S; Sight for Souls: S; Tarsier: PS.

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