Steroids enable aggressive treatment of ocular inflammatory disease
Ophthalmic steroids remain the go-to treatment for ocular inflammation associated with eye disease and surgical trauma despite adverse side effects such as elevated IOP and cataract formation.
Used alone or in conjunction with other pharmacologic or surgical treatments and in widely varied dosing regimens, steroids have proven to be effective in treating internal and external ocular inflammation.
“I believe that we’re expanding our role in the use of topical steroids,” Edward J. Holland, MD, OSN Cornea/External Disease Board Member, said. “For many years, we were taught never to use long-term steroids. Now, we’re seeing the value, especially with the many different types of steroids we have, that we’re seeing indications for long-term steroids.”
The availability of new steroids allows clinicians to tailor treatment to patient needs, according to John D. Sheppard, MD, MMSc.
“As a result, treating inflammation has become less of a knee-jerk and much more of a designer effort on the part of the clinician to match the needs of their patients to their disease,” Dr. Sheppard said. “For me, that’s really exciting. I think the indications for control of inflammation are ever-broadening.”
Image: Donnenfeld ED
In addition, steroid-related complications such as cataract and glaucoma can be treated.
“Inflammation is so much worse than the treatable conditions of cataract or glaucoma. It is really important to emphasize inflammation control as our No. 1 priority,” Dr. Sheppard said. “Certainly, a significant number of patients may develop complications, but those are all amenable to surgical intervention or even pharmacologic intervention.”
Lotemax (loteprednol ophthalmic suspension 0.5%, Bausch + Lomb) is safe for the topical treatment of corneal and intraocular inflammation, Dr. Holland said. It is a good choice as an anti-inflammatory because of its efficacy and safety profile, and it has few side effects.
“The IOP response is less than 2% of patients instead of 8% as seen with other strong steroids,” Dr. Holland said. “In addition, I have not seen a cataract develop despite chronic use in many patients.”
“Loteprednol seems to be the most versatile agent because it’s good for induction as well as maintenance therapy targeting a wide variety of conditions, including both intraocular inflammation and ocular surface inflammation,” Dr. Sheppard said.
“The steroids such as loteprednol have all the efficacy on the ocular surface of prednisolone acetate, with a drastic reduction in side effects,” Eric D. Donnenfeld, MD, OSN Cornea/External Disease Board Member, said. “We can use these steroids more commonly, control inflammation more aggressively and have less side effects overall. … I like to use loteprednol because it has a much lower incidence of steroid-associated intraocular pressure rise.”
Another steroid, Durezol (difluprednate ophthalmic emulsion 0.05%, Alcon), has proven to be effective in treating ocular surface disease, corneal inflammation and intraocular inflammation. It has strong anti-inflammatory effects, Dr. Holland said.
Edward J. Holland
He said difluprednate is his steroid of choice for patients with uveitis, complicated cataracts such as intraoperative floppy iris syndrome, cases requiring iris rings or iris retractors, patients with prolonged phaco time and patients with vitreous loss.
“I have also found difluprednate very effective in the management of cystoid macular edema,” he said.
Dr. Donnenfeld also said that difluprednate is the steroid to turn to for high-risk patients.
“However, in addition to that, we’re using Durezol on almost all of our cataract surgeries because the patient’s visual potential returns faster and there’s less macular edema, even in routine cases when used with a nonsteroidal. So, we’re very high on using that steroid,” he said.
Dr. Donnenfeld and colleagues have completed research showing that difluprednate can result in clearer corneas, better visual acuity and less macular thickening in cataract patients.
“I think this is an important paper to show that high-dose pulse steroids can really reduce inflammation and improve quality of vision quickly after surgery,” Dr. Donnenfeld said.
Dr. Sheppard said that difluprednate is also effective in addressing hypotony in some patients by virtue of its IOP-raising properties.
“I have a wide variety of patients with chronic uveitis and ciliary body compromise or shutdown, so they have chronic low pressure,” he said. “In these cases, difluprednate is very useful to try to bring the pressure up to an acceptable level such that the macula functions properly. The macula doesn’t function very well in hypotonus eyes at around 8 mm Hg or lower.”
Contraindications and combination agents
Dr. Sheppard said that all steroids are contraindicated in patients with Acanthamoeba infection and fungal infections of the eye. In fact, steroids can worsen fungal infections.
“Using the example of fungal keratitis, even taking one drop of steroid a day will create a marked prolongation of that infection,” Dr. Sheppard said. “Your inclination is to make the redness go away, but it’s far better to let the antifungal antibiotic agent completely eradicate this organism, and only when you’re 100% sure that the fungus is dead would you allow the use of steroids to limit scarring if the infection has produced axial involvement of the cornea.
“Interestingly, cyclosporine given topically (Restasis, Allergan) possesses anti-fungal properties and may allow at least a modicum of steroid-free inflammation control in the context of sight-threatening fungal keratitis.”
Combination agents such as Zylet (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension, Bausch + Lomb) or Tobradex (tobramycin and dexamethasone ophthalmic suspension USP, Alcon) are ideal for simultaneously addressing infection and inflammation, Dr. Sheppard said.
“Good agents combine antibiotics and steroids,” he said. “Combination drugs are very useful agents for conditions in which you know the steroid is not contraindicated and the antibiotic may be efficacious, including hypersensitivity marginal keratitis or acute blepharoconjunctivitis.”
Induction, maintenance and pulse treatments
Dr. Sheppard described the benefits of a staged approach to steroid dosing.
“I like to use an induction and maintenance philosophy,” he said. “The induction is with a powerful agent that may have a greater degree of side effects. The maintenance is with a safe and sustainable agent that’s effective for the condition once it’s brought completely under control.”
An example of staged administration is the induction of difluprednate followed by loteprednol as a maintenance agent, Dr. Sheppard said.
“In the case of acute scleritis, systemic agents are often used but create a wide variety of side effects, even gastritis or renal insufficiency, in the case of an oral nonsteroidal,” he said. “But giving a patient difluprednate or Durezol in the very early stages may be effective in controlling the scleritis, precluding oral therapy. Then maintenance can be sustained on loteprednol.
“Another example is induction of dry eye therapy with loteprednol, followed by long-term therapy with Restasis. This approach reduces side effects with both agents, yet provides a much more rapid resolution of signs and symptoms,” Dr. Sheppard said.
Long-term steroids are indicated for patients with chronic immune stromal keratitis from herpetic viral infection. Many such patients have been undertreated with steroids, Dr. Holland said, and loteprednol can be a good choice for these patients.
“But what we find is that long-term maintenance of topical steroids tends to reverse scarring and neovascularization and improve visual acuity,” he said.
Dr. Donnenfeld also noted the value of topical steroids in mitigating corneal damage and vision loss.
“Not using steroids can cause visual decrease, which results in patients having permanent corneal damage that can only be improved with a high-risk keratoplasty,” he said. “I don’t think we use enough steroids for ocular surface disease.”
Short-term, high-dose pulse steroids more effectively treat inflammation and spur fewer adverse side effects than prolonged lower doses, Dr. Donnenfeld said.
“When I have a problem, I like to hit it hard with steroids, control the inflammation and get out quickly. I’d much rather use pulse dosing every hour or two for the first day or two and taper off quickly rather than see a patient take chronic steroids,” he said.
Dr. Donnenfeld and colleagues initiate pulse steroid treatment 1 hour before cataract surgery and continue it every 15 minutes intraoperatively.
“Our line of thinking is that the corneal endothelium is neuroectoderm, just like brain tissue,” he said. “And just like a neurosurgeon would use high-dose pulse steroids in a patient with brain trauma, we are pre-treating the cornea before surgery, suppressing inflammation and protecting the endothelium so that we get better results with our surgery.”
Douglas J. Rhee, MD, OSN Glaucoma Board Member, said that the added strength and less frequent dosing of difluprednate may enhance patient compliance, a major concern among ophthalmologists.
Douglas J. Rhee
“We may be able to use [difluprednate] less often, and with that we might get improved compliance, and with improved compliance, better results,” Dr. Rhee said.
Diabetic retinopathy study
A recent study offered insight into the role of intravitreal steroids in treating macular edema from diabetic retinopathy.
Members of the Diabetic Retinopathy Clinical Research Network (DRCR.net) compared outcomes from 1-mg or 4-mg intravitreal injections of triamcinolone acetonide and focal/grid photocoagulation. Results showed that rates of progression were lower in the 4-mg triamcinolone group than in the 1-mg triamcinolone and laser groups.
However, laser therapy improved visual acuity more effectively than either steroid group, with a lower incidence of IOP changes or cataract, the study authors reported.
“But in reality, it doesn’t say steroids don’t work because they worked quite well for macular edema early on,” Carl D. Regillo, MD, OSN Retina/Vitreous Board Member, said. “It’s just that laser seemed to work better in the long run. But [it] was only marginally better. The steroids did work to some degree. … We’re thinking of [steroids] as an adjunct to laser therapy. But laser should be considered the gold standard, primary therapy for diabetic edema. At this time, for diabetic macular edema, it’s laser first and then consider others as add-ons down the line if laser alone doesn’t achieve complete resolution of the edema.”
Useful potential add-on treatments for diabetic macular edema also include anti-VEGF agents such as Lucentis (ranibizumab, Genentech) or Avastin (bevacizumab, Genentech) by intravitreal injection.
In addition, the DRCR.net conducted a study on laser therapy in combination with steroids and anti-VEGF agents. Results are expected to be released later this year, Dr. Regillo said.
Steroids and glaucoma
Attention to elevated IOP resulting from steroid use is critical to prevent or mitigate glaucomatous damage, whether glaucoma is the primary condition or a steroid side effect, Dr. Rhee said.
“Everything is individualized,” he said. “There’s not a magic IOP number for everybody. It’s going to vary based on the current status of the optic nerve, the patient’s current status and the value of the [intraocular] pressure. … It depends on any past history of glaucoma and how high the pressure is. Obviously, if there’s a past history of glaucoma or the pressure is very high, then the tolerance for non-surgical management is going to be lower. In other words, intervene earlier.”
A mild steroid should be used after canaloplasty and Trabectome (NeoMedix), Dr. Rhee said.
“You want to use a milder steroid for those procedures, like Vexol (rimexolone, Alcon) or FML (fluorometholone, Allergan),” he said. “For the postoperative management of laser iridotomy, laser iridoplasty, trabeculectomy and tube shunt surgery, Pred Forte (prednisolone acetate, Allergan) is pretty much going to be your first-line agent. Other factors may make you deviate from it in favor of either weaker or stronger steroids.
“The management of postoperative inflammation following laser trabeculoplasty is highly varied with no standard; clinicians range from using a strong steroid, like prednisolone acetate, to a weak steroid, a nonsteroidal anti-inflammatory, to nothing. Our experience with difluprednate is still too recent to know exactly where it fits in the management of glaucoma patients.”
Laser therapy and shunt implantation procedures are efficacious for many patients who experience IOP elevation after steroid treatment for ocular inflammation, Dr. Sheppard said.
“I’ve found that selective laser trabeculoplasty is a very effective procedure to control moderate degrees of glaucoma in patients who have inflammation,” he said. “In the case of severe inflammatory glaucoma, patients generally respond very well to shunt procedures to ultimately control their glaucoma, coupled with long-term judicious steroid maintenance therapy.” – by Matt Hasson
- Bell NP, Karp CL, Alfonso EC, Schiffman J, Miller D. Effects of methylprednisolone and cyclosporine A on fungal growth in vitro. Cornea. 1999;18(3):306-313.
- Bressler NM, Edwards AR, Beck RW, et al; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide and focal/grid photocoagulation. Arch Ophthalmol. 2009;127(12):1566-1571.
- Sheppard JD, Donnenfeld ED. Topical loteprednol 0.5% induction therapy improves topical cyclosporine emulsion tolerability in chronic dry eye disease. Invest Ophthalmol Vis Sci. 2008;49:E-Abstract 99.
- Eric D. Donnenfeld, MD, can be reached at OCLI, 2000 North Village Ave., Rockville Centre, NY 11570; 516-766-2519; fax: 516-766-3714; e-mail: email@example.com. Dr. Donnenfeld is a consultant for Allergan, Alcon, Bausch + Lomb and Sirion.
- Edward J. Holland, MD, can be reached at Cincinnati Eye Institute, 580 South Loop Road, Edgewood, KY 41017; 859-331-9000; e-mail: firstname.lastname@example.org. Dr. Holland is a consultant for Alcon and Bausch + Lomb.
- Carl D. Regillo, MD, can be reached at Retina Service, Wills Eye Institute, 840 Walnut St., Suite 1020, Philadelphia, PA 19107; 215-264-3159; fax: 610-856-7787; e-mail: email@example.com. Dr. Regillo is a consultant for Genentech and AMO. He receives research grants from Genentech, Alimera, Allergan, Alcon and Regeneron.
- Douglas J. Rhee, MD, can be reached at Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02144; 617-573-3670; fax: 617-573-3707; e-mail: firstname.lastname@example.org. Dr. Rhee is a paid consultant for Alcon, Allergan and Santen.
- John D. Sheppard, MD, MMSc, can be reached at Virginia Eye Consultants, 241 Corporate Blvd., Norfolk, VA 23502; 757-622-2200; fax: 757-622-4866; e-mail: email@example.com. Dr. Sheppard is an advisor and does research work for Alcon, Bausch + Lomb and Allergan.