Getting Uveitis Under Control — Quickly

BY ALEXANDRE DE SAINT SARDOS, MD, AND ERIC SUHLER, MD

As ophthalmologists, it can be easy to settle into a routine of cataracts, glaucoma and age-related macular degeneration that often make up the bulk of a comprehensive practice. As physicians, however, the uveitis cases we see offer us a chance to return to our more comprehensive medical roots by working up patients and treating them in a manner that has more traditionally been associated with internal medicine.

It's an exciting time to be involved in uveitis management. The SUN criteria have offered us a means of describing uveitis in a more standardized manner, facilitating dialogue and enabling research in a field peppered with atypical disease.¹ Recent clinical trials as well as innovations in rheumatologic therapies offer us more and safer choices for patients, and there are many promising new therapies on the horizon. The surge of intravitreal injections in treating retinal disease and the evolution of intraocular implants and innovative methods of drug delivery has also inspired curiosity regarding the intraocular use of many systemic immunosuppressants.

Patients with uveitis typically consult for three reasons: to find out what they have, why they have it, and how to treat it. What follows is a brief overview of these three elements of diagnosing and treating uveitis.

History & Physical

A complete uveitis history usually begins with a waiting-room questionnaire that is expanded upon with the physician encounter. Almost every organ system and element of the history can provide clues that point toward a particular diagnosis, so being thorough is essential and a good questionnaire will keep a busy clinician from skipping any details.

Corneal sensitivity testing prior to topical anesthesia and evaluation of the irides for transillumination defects may suggest a viral origin. Conjunctival nodules or enlarged lacrimal glands might suggest sarcoidosis. The type and distribution of keratic precipitates may also orient the astute examiner. Gonioscopy and a detailed look at the iris and pupillary margin may show distinctive nodules, synechiae or even foreign bodies. Proper fundus visualization remains essential even in the photophobic eye. This is even more important with the advent of local steroid injections in a potentially infected eye.

The SUN workgroup has given us an important tool by standardizing the nomenclature with which we categorize uveitis and the images by which we grade vitreous haze.¹ As an example: iritis with vitreous cell, snowballs, macular edema and peripheral vasculitis might previously have been categorized by uveitis experts in many differing ways, including anterior and posterior uveitis, or panuveitis, but is now termed by acclamation as anterior and intermediate uveitis.

Diagnostic Testing

Ancillary tests such as B-scan ultrasonography and ultrasonic biomicroscopy can be useful in uveitis cases with dense cataracts and those suspicious for foreign bodies, residual lens material and other potential masquerade syndromes. Traditional tools such as fluorescein angiography and ERG are still very useful, but OCT and multifocal ERG are playing an increasingly important role. MRI continues to play a role in cases suspected for multiple sclerosis or lymphoma.² Color photos and visual fields are crucial in following pathologies such as birdshot chorioretinopathy, which may progress slowly and subtly.

How best to determine the etiology of the uveitis depends largely on where the history and physical orient us. With a few standard exceptions, diagnostic tests should almost always be focused on the most likely culprits for the disease. This strategy attempts to avoid the pitfalls of false positives. The standard exceptions are traditionally tuberculosis and syphilis, which — while rare in the eye — are great mimickers, easily tested for and potentially contagious or curable. An RPR, FTA-ABS, chest X-ray and tuberculin skin test are routine for almost all patients in a uveitis work-up and typically required prior to any systemic immunosuppression.

Treatment of Non-infectious Uveitis

The goal of treatment is to suppress the immune system sufficiently to improve vision, prevent additional damage to the eye and make the patient comfortable as quickly as possible, while minimizing side effects by using the least amount of medicine necessary. The three classes of treatment for non-infectious uveitis are topical, local and systemic. New developments in each category are covered below.

Topical Therapy

Frequent use of 1% prednisolone acetate eye drops paired with a cycloplegic and bedtime steroid ointment are favored for the initial short-term treatment of most cases of unilateral idiopathic sudden-onset acute anterior uveitis. Durezol (difluprednate), a newly approved topical steroid from Sirion Therapeutics, has been suggested to be a more potent eye drop for similar indications and has recently been approved to decrease postoperative eye pain and inflammation.³

It has not been clearly shown which cycloplegic is best to prevent or undo posterior synechiae. While some may be concerned that atropine may result in a Urrets-Zavalia⁴ type reaction leading to a fixed dilated pupil or feel that a short-acting cycloplegic may provide the repeated motion necessary to break existing synechiae, there is presently no evidence to promote one cycloplegic over another. There is little role for topical or systemic NSAIDs in the management of uveitis.

Local Therapy

It should be apparent within the first two weeks of intense usage if drops will be sufficient to control uveitis. In the anterior segment, success is related to a decrease in symptoms, improvement in vision, diminished redness, breakup of synechiae and reduction in the number of cells per high-powered field. Flare is less relevant and often persists regardless of control, due to alteration of the blood-iris barrier. By contrast, in the posterior segment, haze is the most important measure of active inflammation and cells may persist in the vitreous long after the uveitis has been stabilized.

In the acute setting, when drops are deemed insufficient, a subconjunctival shot of beta- or dexamethasone and lidocaine is relatively low risk. It may provide the patient some relief (albeit short term) and respite from a frequent drop regimen. Injections can also be advantageous in less compliant patients and in those already undergoing surgery.

Peribulbar, sub-Tenon's and intravitreal Kenalog are frequently used to treat uveitis and related CME, particularly in unilateral disease not responding to drops. For many unilateral cases we initially favor a 1 cc peribulbar or sub-Tenon's triamcinolone acetonide injection (40 mg/ml). OCT would typically guide our treatment in cases being injected for macular edema. If the macula is not flattened sufficiently, a second periocular injection or an intravitreal injection (0.1 cc of triamcinolone acetonide 40 mg/ml) would be our next step.

Because it has been specifically approved for use in the eye, preservative-free Triesence (Alcon Pharmaceuticals) would be our intraocular steroid of choice. Given the results of the recent SCORE trial, it may be interesting to see if 0.025 cc or 1 mg might be as effective as 4 mg in the uveitic eye.⁵ If intravitreal Kenalog or high-dose oral steroids do not improve the CME on OCT even for a short while, and there is no tractional component or active inflammation, there is probably little else to be done. Poor acuity that persists despite a significant improvement of CME on OCT may be the result of longstanding damage to the macula. If, on the other hand, anatomic and subsequent visual improvement can be achieved even temporarily with any of the aforementioned solutions, the patient may benefit from systemic steroid-sparing agents or a Retisert implant.

While all steroid injections risk causing glaucoma and cataracts, there is no single best injection type for all cases.^6-8 Peribulbar injections may cause undesirable adipose lid changes, and sub-Tenon's injections may cause ptosis or prove awkward for the uninitiated. Neither depot can be easily removed should the need arise. Intravitreal injections risk causing a retinal detachment, vitreous hemorrhage or endophthalmitis, so an explanation and justification of the risks for the proposed technique is mandatory. With corticosteroid therapy, it is essential that compliance with follow-up and IOP verification be maintained.

Bevacizumab (Avastin), an anti-VEGF, has proven very useful in management of neovascular complications of many eye diseases, including uveitis.^9,10 While anti-VEGFs may offer a safer alternative to intravitreal Kenalog in treatment of certain cases of uveitic CME, their duration of action may limit their usefulness. Intravitreal methotrexate has recently shown some promise as a potentially new tool in the uveitic arsenal for lymphoma, uveitis and macular edema due to uveitis, and may be especially useful in steroid responders.¹¹

• Steroid implants. Retisert and Ozurdex are sustained corticosteroid release devices that are, respectively, surgically implanted or injected into the eye.

Retisert (Bausch & Lomb) is a small fluocinolone acetonide (0.59 mg) intravitreal implant surgically implanted in the uveitic eye. The implant is felt to be effective for approximately 30 months, at which point another may be implanted. There is a 100% cataract rate with Retisert and a 37% chance of needing glaucoma surgery. While these rates may seem alarming, cataract or glaucoma are also known risks of uncontrolled uveitis, and the outcomes of these surgeries may be much improved with the inflammatory control this implant affords. The implant is costly, but the health benefits of being able to discontinue systemic immunosuppressants (and the attendant cost of long-term immunosuppressive medications) make it an attractive choice for many.

Ozurdex, a new implant from Allergan, is a 0.7 mg dexamethasone slow-release pellet recently approved for use in eyes with macular edema caused by venous occlusive disease. It is injected through the pars plana with an included 22-gauge needle applicator. During the initial studies, three out of 421 patients required laser or surgical glaucoma management and 25% had elevated IOP within the first six months. The improvement in visual acuity and its duration of action appear similar to the results obtained with the IVK injections of the SCORE trial. Its duration of action in a uveitic eye remains to be quantified.

• Laser ablative therapy for pars planitis tends to be favored over cryotherapy in cases with peripheral neovascularization or significant snow banks not responding to more conventional therapy.^12,13 Cryotherapy is more inflammatory than laser ablation, but both can decrease or eliminate the need for systemic medication in select cases and in many circumstances only cryotherapy is possible.¹³

Systemic Therapy

• Prednisone is one of the least expensive and most effective means of decreasing eye inflammation, but its long term use is limited by an extensive and potentially serious side effect profile. While every case is unique, we use an initial 0.5-1mg/kg daily dose. For symptomatic heartburn, we prescribe an H2 inhibitor or PPI. When used long term, we add calcium and vitamin D supplementation in addition to conducting bone density testing in those at greater risk for osteoporosis. Caution must be taken to avoid an overly rapid taper; we typically aim to reduce the dose of steroid by half each month initially, but must be re-evaluated based on response, recurrences, or toxicity. In severe cases, with intra ocular surgery, or in conjunction with intravenous infliximab therapy, we administer intra venous solumedrol. Systemic corticosteroid therapy can rapidly cause surprisingly high IOP elevations which must be monitored.^14,15

• Steroid-sparing agents are typically used to reduce or eliminate the need for prednisone and avoid its unfortunate side effects. Like prednisone, all increase the risk of infection and some also augment the chances of malignancy.¹⁶

Pregnancy is contraindicated with many of these medications and routine blood work must be verified at least every two months. Patients are recommended to stop their immunosuppressants should they acquire an infection, and attenuated seasonal vaccines are highly encouraged. If one is not effective, another may be tried or sometimes added to combination therapy regimes to control significant inflammation. Due to the enormous variation in both patients and pathologies, trial and error has a greater role than we might hope in managing complex uveitic cases.

• Methotrexate, a folic acid analog and anti-metabolite, inhibits DNA replication. It has greater bioavailability as a weekly subcutaneous injection but many patients averse to needles prefer the pill form (7.5 to 25 mg weekly). It requires concomitant folic acid (1 mg) the remaining six days of the week and begins working after about six weeks. Methotrexate is an effective means of controlling uveitis on its own or in conjunction with other immunosupressants.^17-20

It is popular due to its low cost and high tolerability but does require baseline hepatitis serology as well as liver function tests, metabolic panel and complete blood count every two months. Alcohol and pregnancy are contraindicated, and many patients experience weakness and GI disturbances the day following the injection, with hair loss, blood count suppression, and allergic response less common.

• Mycophenolate mofetil (Cellcept) and azathioprine (Imuran). Cellcept is usually taken twice daily at daily doses of 2-3 g with half doses usually given the first week. A generic version is now available; following methotrexate, it is probably our next most popular steroid-sparing agent. It has high oral bioavailability when taken on an empty stomach and requires two weeks before any effects are noted.

While there have been no clinical trials of Cellcept to treat uveitis, a chart review of 106 patients indicates GI upset, headache and fatigue as the more common complaints.²¹ It is an effective immunosuppressant and steroid-sparing agent, and seems to cause less GI disturbances than its cousin azathioprine (Imuran). Imuran is often given as 100 to 150 mg daily (1 to 2.5 mg/kg daily) and had been found in a small RCT to decrease the incidence of flare-ups in Behçet's disease and retrospectively to have moderate effectiveness as a steroid-sparing agent for uveitis.^22,23 Both require regular bloodwork, including LFTs.

• Cyclosprine A (Neoral) and tacrolimus (Prograf), both T-cell inhibitors, are effective agents for certain uveitis patients. Cyclosporine is typically prescribed as 3-5mg/kg daily in divided doses and requires at least one month to become effective. It has been shown to be as effective as and to function synergistically with prednisone in the treatment of uveitis.^24,25 Patients on cyclosporine require blood pressure monitoring in addition to routine blood work. This drug sometimes causes hirsutism, gingival hyperplasia, neuro pathies, renal toxicity and hypertension. A more recent study has shown that while tacrolimus, dosed from 0.03-0.08 mg/kg (usually 2 to 4 mg bid), does have a narrow therapeutic range that requires monitoring, it seems to be as effective as cyclosporine with a more favorable safety profile.²⁶

A novel calcineurin inhibitor, voclosporin (Luveniq), recently reported results from a large, placebo-controlled, dose ranging, randomized clinical trial, and was found to be effective in the treatment of active posterior uveitis and in allowing steroid tapering in patients with quiescent disease. Application for FDA approval is pending, with targeted drug availability in 2010.

• Cyclophosphamide (Cytoxan) and chlorambucil (Leukeran) are alkylating agents long used as antineoplastics as well as in rheumatic disease. Cytoxan (1 to 2 mg/kg/day) has been found effective in systemic vasculitides including Wegener's granulomatosis and SLE. It may be effective for intractable uveitis and vasculitides, but is not routinely used due to the risk of hemorrhagic cystitis and bladder cancer.^27,28 Chlorambucil has a slower onset of action than cyclophosphamide but has no risk of hemorrhagic cystitis and is therefore preferable for those patients with bladder toxicity. Both drugs require careful monitoring of the WBC count and urine analysis, and have been shown to be effective in the treatment of intractable uveitis.^29,30

• Remicade (Infliximab) and Humira (Adalimumab) are two anti-TNF alpha monoclonal antibodies that have gained popularity as treatments for uveitis.^31,32 Both medications were developed for use in rheumatic diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. They are expensive and typically require special approval from insurers prior to use for the eyes.

Remicade has been shown effective in certain refractory uveitides, particularly in Behçet's disease.^33,34 It is given as a series of intravenous infusions. Infusion reactions including anaphylaxis are diminished with the concomitant use of anti-histamines and analgesics. There are many serious side effects associated with the use of anti-TNF alpha antibodies, including worsening of congestive heart failure, demyelinating disease, lupus-like illness, and severe infections.³⁵ It remains to be seen whether uveitis patients treated with TNF inhibitors are at greater long term risk for malignancy, with evidence from the rheumatology literature and one retrospective cohort study in uveitis suggesting potential increased risk.¹⁶

Humira, a fully human anti-TNF antibody, may be easier to use than Remicade, as it is administered as a subcutaneous injection of 20-40 mg at one- to two-week intervals. It has also been shown to be effective in refractory uveitis and there are several reports of patients successfully treated with Remicade for their uveitis making a positive transition to Humira.^36-38 Humira has been found particularly useful in pediatric uveitis, especially those patients with JIA.^32,39 It also appears to reduce by half the chance of flare-ups in patients receiving the medication for their ankylosing spondylitis.⁴⁰

• Interferon alpha-2a at daily subcutaneous doses of 3 to 6 million IU has been shown in small case series to be effective and well tolerated for a variety of types of uveitis as well as CME due to non-infectious uveitis, especially in Behçet's disease.^41,42

• In the pipeline: Biologics being developed and used for systemic inflammatory disease include B-cell blockers (rituximab), T-cell costimulation blockers (abatacept), and blockers of interleukin or interleukin receptors 1 (anakinra), 6 (tocilizumab), 11 (efalizumab), 17 (AIN457), and 12/23 (ustekinimab), among others. Many of these have been or will be studied for ocular inflammatory disease in the future.

Summary

The armamentarium of those treating uveitis is rapidly expanding, due in part to more recent clinical trials and in part to our unique position to benefit from innovations in both the retinal drug delivery and rheumatic realms. As ophthalmologists, we are fortunate to be able to both diagnose and manage these interesting and appreciative patients either solely or in conjunction with rheumatologists, retinal specialists and uveitis specialists. OM

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