Article

Systemic therapy for non-infectious uveitis

A guide to options, dosing and data.

When managing a patient with uveitis, it is essential to promptly initiate the appropriate treatment.

The critical first step to determining that treatment is to consider possible infectious causes (always including syphilis) as well as masquerade syndromes. When infection and malignancy have been ruled out, corticosteroids are the mainstay of initial treatment for uveitis.

While many cases of anterior uveitis may respond to steroid drops, topical treatment alone is often inadequate for uveitis involving the posterior as well as some severe cases of anterior uveitis. For such cases, current options include regional steroids (subconjunctival or intravitreal triamcinolone, Ozurdex dexamethasone insert, Retisert fluocinolone implant) or systemic treatment. Systemic treatment is often indicated for uveitis which is bilateral, severe, recurrent or associated with systemic inflammation.

Here is our analysis of these available uveitis therapies.

First up: Oral corticosteroids

In most cases of non-infectious uveitis that require systemic treatment, oral corticosteroids are the first-line agents. They are effective for rapid control of the inflammation. In addition to the ophthalmic side effects of glaucoma and cataract, oral steroids, such as prednisone, can lead to systemic side effects: hyperglycemia, dyslipidemia, hypertension; osteoporosis and fractures; immunosuppression and gastric reflux, among many others. Given these potentially serious side effects, it is crucial to follow the current recommended treatment guidelines. These guidelines, outlined by Jabs et al,1,2 were used in the prospective randomized Multicenter Uveitis Steroid Treatment (MUST) trial.3 The guidelines advise the introduction of an immunosuppressive agent in cases that respond inadequately to corticosteroids alone and transition to a steroid-sparing agent for patients who need long-term therapy.

The initial dose of prednisone is 1 mg/kg/day or less, up to 60 mg/day. This initial dose should not be used longer than a month; longer use has been associated with a significantly increased risk of complications, specifically aseptic necrosis of the femoral head. If the inflammation does not start to respond to 60 mg/day within a few weeks, an immunosuppressive agent should be added.

Once the inflammation is under control, prednisone should be tapered gradually. If the inflammation recurs at a dose of 10 mg/day or more of prednisone, the dosage should increase to double the dosage at which the flare occurred; again, addition of an immunosuppressive agent should be considered.

The immunosuppressive agents may take one to two months to take effect, so corticosteroid tapering should proceed slowly. Patients whose disease is controlled with less than 10 mg/day of prednisone (with or without an immunosuppressant) may be able to safely continue prednisone long term if needed.

STEROID-SPARING OPTIONS

The range of choices in steroid-sparing immunosuppressive medications — traditionally antimetabolites, T-cell inhibitors and alkylating agents — has expanded with the more recent addition of biologics. Each of these medication categories has its risks and benefits the physician must consider along with patient-specific characteristics. Many ophthalmologists find it useful to collaborate with a rheumatologist to prescribe and monitor immunosuppressive agents. The ideal treatment duration for immunosuppressive therapy hasn’t been addressed in a prospective clinical trial, but the general consensus in the uveitis community is to have at least two years of quiescence on treatment before trying to taper.

Antimetabolites

The antimetabolites, including methotrexate and mycophenolate mofetil, are often first-line agents for steroid-sparing systemic treatments due to their relatively favorable side-effect profile. T-cell inhibitors, including cyclosporine and tacrolimus, can be associated with hypertension and nephrotoxicity. Alkylating agents, including cyclophosphamide and chlorambucil, are used for uveitis associated with severe systemic disease, such as granulomatosis with polyangiitis. Side effects include pancytopenia, hemorrhagic cystitis and malignancies.

Biologics

More recently, biologic agents have been proven useful for non-infectious uveitis. Several small studies have demonstrated the efficacy of infliximab (Remicade) for Behcet’s disease. The VISUAL I and II trials showed benefit of adalimumab (Humira) for patients with active and inactive non-infectious intermediate, posterior or panuveitis requiring systemic prednisone.3,4 Patients receiving adalimumab (80 mg loading dose followed by 40 mg every other week) were half as likely to fail steroid taper than those receiving placebo. Use of adalimumab was also associated with an approximately doubled time to treatment failure as compared to the placebo group. Based on the VISUAL I and II studies, the FDA expanded the exisiting 9 indications for adalimumab in 2016 to also include non-infectious intermediate, posterior and panuveitis.

The main side effects of biologics are increased susceptibility to infection; less common complications may include increased risk of malignancy and demyelinating disease. Given the association of intermediate uveitis with multiple sclerosis, an MRI of the brain should be considered prior to starting biologics for a patient with intermediate uveitis.

Treatment MUSTs

The MUST trial compared systemic anti-inflammatory therapy to sustained-release corticosteroid implants for non-infectious uveitis affecting the posterior segment. This longitudinal study showed that although local therapy led to faster control of inflammation, the systemic medication group had better visual acuity outcomes after seven years. The implant therapy eyes had statistically significantly higher rates of complications related to IOP and cataracts,7 while the systemic therapy group had a significantly higher rate of infections requiring treatment.5,6

The seven-year results of the MUST Study demonstrated the safety and efficacy of systemic treatment of non-infectious uveitis affecting the posterior segment.4 The current treatment recommendations for utilizing immunosuppressants to keep corticosteroid exposure within safe limits ensure the most effective and safest possible care.

Conclusion

Many options help to systemically manage uveitis patients. Fortunately, these include more steroid-sparing options that can help keep the disease under control while minimizing side effects. OM

References

  1. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513.
  2. Jabs DA, Akpek EK. Immunosuppression for posterior uveitis. Retina. 2005;25:1-18.
  3. Jaffe GJ, Dick AD, Brezin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med 2016;375:932-943.
  4. 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 multicenter, double-masked, randomized, placebo-controlled phase 3 trial. Lancet 2016;388(10050):1183-92.
  5. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, Holbrook JT, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011 Oct;118:1916-1926.
  6. The Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study Research Group. Association between long lasting fluocinolone acetonide intravitreous implant vs. systemic anti-inflammatory therapy and visual outcomes at seven years among patients with intermediate, posterior, or panuveitis. JAMA. 2017;317:1993-2005.
  7. Sheppard JD, Nguyen QD, Usner DW, Comstock TL, for the Fluocinolone Acetonide Uveitis Study Group. Post-cataract outcomes in patients with noninfectious posterior uveitis treated with the fluocinolone acetonide intravitreal implant. Clin Ophthalmolo. 2012;6:79-85.

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