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    Strategies for Managing Uveitis, Part 2: Treatment of Adults With Chronic Disease

    By Gary N. Holland, MD, with Nisha Acharya, MD, MS, John D. Fitzgerald, MD, PhD, MBA, Debra A. Goldstein, MD, and John H. Kempen, MD, MPH, PhD, MHS
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    Treatment for chronic nonin­fectious uveitis may involve corticosteroids, antimetabolites, biologics, or a combination of agents. The best therapeutic regimen for a giv­en patient can be complex and evolve over the course of disease. Decisions about treatment should be informed by patient characteristics as well as by expert experience and opinion. For cli­nicians whose patients lack consistent access to uveitis specialists, long-term disease control can be elusive. In this second of a multipart series, Gary N. Holland, MD, of the Jules Stein Eye Institute at University of California, Los Angeles (UCLA), discusses this topic 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.

    Antimetabolite Monotherapy

    Dr. Holland: For a patient on an antimetabolite as monotherapy, when do you expect to see an effect, and how long do you wait before concluding that a particular drug is not working and the regimen needs to be changed?

    Dr. Kempen: The response to an antimetabolite can take a long time, potentially six months even with high initial dosing. Tumor necrosis factor (TNF) inhibitors are probably the better option if you need rapid disease control, but antimetabolites are more cost-effective.

    Dr. Holland: In my experience, we can usually tell whether the treatment is going to be successful by three months, even if it hasn’t reached the maximum effect by then.

    Dr. Acharya: In a typical scenario requiring a modification of treatment, the patient is on an antimetabolite, usually methotrexate or mycopheno­late mofetil, and you’re tapering the concurrent corticosteroid and finding that the inflammation is worsening. My approach in this situation has been to continue the antimetabolite and add a TNF inhibitor, usually adalimumab.

    There is some risk of anti-drug antibody development during long-term adalimumab treatment, but the risk is lower on combination therapy that includes an antimetabolite. That has been shown in the literature on ankylosing spondylitis.1 If the patient cannot tolerate the antimetabolite, I would transition to monotherapy with adalimumab, but my preference is the dual therapy.

    Dr. Fitzgerald: I also use methotrex­ate concurrently to prevent anti-drug antibodies.

    Chimeric infliximab poses an even greater risk for development of anti-drug antibodies than adalimumab. I talk with patients about methotrexate being like “an insurance policy” to protect the TNF inhibitor. With uveitis, it seems that there are few proven alternatives available when there is loss of response to adalimumab or infliximab. There­fore, trying to prevent loss of efficacy by anti-drug antibodies is important.

    External photo of the eye of a sarcoidosis patient with multifocal choroiditis.
    SARCOIDOSIS-ASSOCIATED UVEITIS. Multifocal choroiditis in a patient with a confirmed diagnosis of systemic sarcoidosis. This image was originally published in the ASRS Retina Image Bank. Henry J. Kaplan, MD and Niloofar Piri, MD, University of Louisville, Louisville, Ky. Sarcoidosis Choroiditis. Retina Image Bank. 2013;Image number 4885. ©The American Society of Retina Specialists.

    Combination Therapy

    Dr. Holland: In combination therapy, is it ever appropriate to use multiple drugs from the same category?

    Dr. Fitzgerald: In patients with rheumatoid arthritis, we have experi­ence using two antimetabolites, but it is not a common strategy for treatment of uveitis. Methotrexate plus cyclospo­rine or a TNF inhibitor would be more logical combinations for treatment of uveitis. We’ve been cautious about combining biologics, in part based on results of studies involving patients with rheumatoid arthritis. They showed that combining a TNF inhibitor with an interleukin-1 agent yielded no greater efficacy than single agent therapy and it increased the risk of infection.2,3

    Dr. Holland: Treatment in some of the studies you mentioned included etanercept, a TNF inhibitor generally believed not to be effective for treatment of uveitis, but the studies do illustrate the problems associated with using two biologic agents at the same time.

    I think most uveitis specialists accept the fact that each of the antimetabo­lites are fully effective in only about 60%-70% of patients; thus the need for combination therapies comes up often. If the response with one drug is not ad­equate, I generally would add a biologic agent rather than combining metho­trexate with mycophenolate mofetil.

    Malignancy Concerns

    Dr. Holland: How do you manage patient concerns about the possibility of malignancy occurring with these drugs?

    Dr. Fitzgerald: We do discuss malig­nancy risks with patients, but the risks are quite low. We primarily see lym­phoma associations, particularly B-cell cancers. The lifetime lymphoma risk in the general population is approximately 5%, so a 5% risk on treatment is usually acceptable to patients. It’s not clear if disease severity is a contributor to malignancy risk.

    Dr. Kempen: In our ongoing large-scale cohort study lasting nearly 20 years, known as the Systemic Immuno­suppressive Therapy for Eye Diseases (SITE) Cohort study, we are finding that the common immunosuppressants are not linked to higher risk of death in general or death from cancer, nor does there appear to be an appreciable increase in cancer incidence in most scenarios for patients with eye inflam­mation who take these drugs.4

    10 Take-Home Points

    1. Noninfectious uveitis should be treated early and ag­gressively to prevent complications and preserve sight.
    2. Inflammation should be suppressed initially with corticosteroids. In cases of chronic uveitis, corticoste­roid-sparing immunosuppressive agents should be used to maintain long-term suppression of inflammation.
    3. Methotrexate has traditionally been the initial drug used by uveitis specialists for long-term treatment of noninfectious uveitis. If methotrexate is ineffective, con­traindicated for medical reasons, or not tolerated, myco­phenolate mofetil has generally been the next drug to be tried. There is growing interest, however, in biologics as first-line agents for treatment of uveitis.
    4. An immunomodulatory agent should be used for at least three months before assuming that it is not effective.
    5. If there is no evidence that the initial drug has had a therapeutic effect after maximizing the dose (or if it is not tolerated), switch to another agent. If there has been a beneficial effect of the initial drug, but inflammation has not been completely suppressed, consider supplement­ing the initial drug with a second agent, generally from a different class of drug. The combination of methotrexate and a tumor necrosis factor (TNF) inhibitor is the most commonly used combination.
    6. If one can taper topical corticosteroid to 1 or 2 drops daily and maintain control of chronic anterior uveitis, continuation of topical corticosteroid at this frequency may be an acceptable alternative to systemic treatment in some patients; however, the patients must be followed closely for intraocular pressure rise or progression of lens opacities. Periodic attempts to taper and stop the corticosteroid should be made. A risk/benefit analysis is important in deciding between low-dose topical therapy alone or initiating systemic immunosuppression.
    7. TNF inhibitors are the most common biologics to be used in the treatment of uveitis and are effective in most cases, but they may eventually lose their effect, requiring dose escalation. Using an antimetabolite with TNF inhibi­tors may prolong the effectiveness of the biologic.
    8. Laboratory tests should be obtained on a regu­lar basis to monitor for toxicity of immunosuppressive agents. Tests include complete blood counts (including leukocyte differential and platelet count) and a compre­hensive metabolic panel. Additional tests may be war­ranted, depending on the specific agent being used. Both the patient’s ophthalmologist and rheumatologist should ensure that tests have been ordered and reviewed.
    9. Systemic immunosuppression is generally continued for two years after control of uveitis is achieved, if the therapy is tolerated medically. Stopping earlier is associ­ated with a higher rate of disease relapse. Therapy should be tapered before stopping completely, with close obser­vation, in case there is a relapse of inflammation during the taper.
    10. Exacerbations of anterior uveitis during immuno­suppressive therapy can often be suppressed with short courses of topical corticosteroid. Exacerbations do not necessarily call for a change in the systemic treatment.

    Managing Exacerbations

    Dr. Holland: If a patient’s uveitis has been controlled for several months, but an exacerbation of anterior segment inflammation occurs, do you consider that exacerbation to be a failure of the drug regimen? Such exacerbations are often associated with an upper respiratory infection or vaccination. How do you manage the exacerbation?

    Dr. Goldstein: I would treat the ante­rior segment inflammation with a short course of topical steroids and see if we can return to where we were. I wouldn’t consider a mild exacerbation with intercurrent illness as a sign that the drug has failed. However, if the exacerbation is severe or persists, or if such exacerba­tions are frequent, then I would think the drug has failed.

    Dr. Holland: When we encounter this situation, usually the drug regi­men that the patient has been on will continue to control the disease once the exacerbation has been suppressed with a short course of corticosteroids.

    Nonresponse to a Biologic

    Dr. Holland: When therapy with a TNF inhibitor fails, what’s your next step?

    Dr. Goldstein: That depends on the disease you are treating. If a patient with retinal vasculitis who is on a TNF inhibitor has no response to it, I would switch to tocilizumab.5,6 If the patient has scleritis or an orbital pseudotumor, we have data that rituximab may be a good second-line drug.7,8 The caveat is that we don’t have comparisons of any of these drugs for any of these diagno­ses. I think that we have more anecdot­al evidence favoring tocilizumab for vasculitis and rituximab for scleritis.

    Dr. Holland: That’s true. We don’t have enough high-quality data to guide second-line drug selection in these settings with confidence. Nevertheless, based on the experience we do have, to­cilizumab is my next go-to agent. I have not found abatacept to be effective. It should be mentioned, though, that in some cases, switching from one TNF inhibitor to another TNF inhibitor will regain control of inflammation.

    Dr. Acharya: Unfortunately, patients with the most severe disease are those who tend to be nonresponders to TNF inhibitors, and it’s difficult to make a general comment on their response to second-line therapies such as tocilizumab. I’ve increasingly been using JAK inhibitors when TNF inhibitors fail. Beyond those, I would try local therapy, such as a steroid implant.

    Discontinuing Treatment

    Dr. Holland: Once uveitis is controlled, how long do you continue treatment before attempting to stop? What are your strategies for discontinuing treatment?

    Dr. Acharya: This is an area that deserves further study, and the decision needs to be made on a patient-by-pa­tient basis. We have some retrospective evidence that the longer the uveitis is controlled, the greater the likelihood that the medication can be discontin­ued without disease recurrence.9

    Dr. Fitzgerald: Randomized cessation studies involving patients with rheu­matoid arthritis have been conducted. In a randomized trial of patients in remission on combination therapy with methotrexate and a TNF inhibitor, discontinuation of methotrexate with continued TNF-agent monotherapy re­sulted in fewer reactivations than when the TNF agent was discontinued with continued methotrexate monotherapy.10

    Dr. Goldstein: Depending on the diagnosis, I may taper the medication very gradually. You have to consider the consequences of discontinuing medication. For example, if serpiginous choroiditis is threatening the fovea, im­munosuppressive therapy should never be stopped.

    Dr. Fitzgerald: We only consider stopping therapy when there is disease control without steroids. Methotrex­ate takes two to three months to start working and at least a month to stop working, so I generally taper the dos­age from 15 mg to 7.5 mg and make monthly decisions thereafter on wheth­er to continue tapering it. We have no data on tapering TNF inhibitors beyond their indication, although it has been the practice of some clinicians to extend the interval between injections or in­fusions before stopping treatment alto­gether. These agents should not be used on an intermittent, as-needed basis.

    Dr. Kempen: Our group has found relatively low rates of remission, defined as no disease activity when the patient is off systemic (and local) anti-inflammatory drugs. For chronic anterior uveitis, the remission rate was about 40% by five years, and the rate was even lower for intermediate uveitis and scleritis.11 We found that if the dis­ease arose recently, it is more likely to remit. For instance, if the uveitis started six months ago and is controlled, it may be reasonable to consider stopping therapy after one year. However, as ter­tiary specialists, we often don’t see pa­tients until they’ve had the disease for many years, which makes recurrence more likely, if treatment is stopped.

    ___________________________

    1 Ducourau E et al. RMD Open. 2020;6:e001047.

    2 Genovese MC et al. Arthritis Rheum. 2004;50(5):1412-1419.

    3 Weinblatt M et al. Ann Rheum Dis. 2007;66(2):228-234.

    4 Kempen JH et al. BMJ. 2009;339:b2480.

    5 Karaca I et al. Eye (Lond). Published online Nov. 28, 2022.

    6 Uludag G et al. Ocul Immunol Inflamm. Pub­lished online Dec. 21, 2022.

    7 Suhler EB et al. JAMA Ophthalmol. 2014;132(5):572-578.

    8 Ng CC et al. J Ophthalmic Inflamm Infect. 2021;11(1):23.

    9 Kalinina Ayuso V et al. Am J Ophthalmol. 2011;151(2):217-222.

    10 Curtis JR et al. Arthritis Rheumatol. 2021;73(5):759-768.

    11 Sobrin L et al for the Systemic Immuno­suppressive Therapy for Eye Diseases Co­hort Study Research Group. Ophthalmology. 2020;127(6):826-834.

    ___________________________

    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.

    For full disclosures and the disclosure key, see below.

    Full Financial Disclosures

    Dr. Acharya AbbVie: S.

    Dr. Fitzgerald Arthritis Foundation: S; National Institutes of Diabetes and Digestive and Kidney Diseases: S.

    Dr. Goldstein None.

    Dr. Holland None.

    Dr. Kempen Betaliq: PS; Massachusetts Eye and Ear: E; National Eye Institute: S; Sight for Souls: S; Tarsier: PS.

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