October 2010




Treating vexing VKC cases

by Vanessa Caceres EyeWorld Contributing Editor


Ophthalmologists find severe allergic condition can be hard to treat

Two typical cases of vernal keratoconjunctivitis.

Source: Jodi Luchs, M.D.

It can be hard to watch a young patient with vernal keratoconjunctivitis (VKC) suffer through the symptoms, said John D. Sheppard, M.D., professor of ophthalmology, microbiology, and immunology, Eastern Virginia Medical School, Norfolk, Va. "Some of these kids are wheezing, their eyes are puffy, and their nose is dripping. They look horrendous," Dr. Sheppard said.

However, treating VKC can be difficult because there are no uniform diagnostic and treatment criteria, said Sunil Kumar, M.D., Toronto Western Hospital, Toronto, lead author of a review paper on VKC published in the May issue of Current Allergy and Asthma Reports. Although at its best VKC is an annoyance, at its worst it can cause permanent visual impairment.

Patients with VKCmany of whom are children or young adultsmay initially appear to be seasonal or perennial allergy patients, Dr. Kumar wrote. However, VKC patients are distinguished by the presence of large papillae. Signs of VKC usually appear in the conjunctiva and cornea and include large papillae on the tarsal surface of the upper lid and bulbar conjunctiva and Horner-Trantas dots (yellow-white points on the limbal conjunctiva), Dr. Kumar wrote. Punctate epithelial keratitis, epithelial macroerosions, shield ulcer, and corneal vascularization are other signs of VKC, he added.

VKC treatment

Once diagnosed, ophthalmologists must approach VKC patients with a variety of possible treatments, as no particular treatment seems to best serve all patients.

"Despite extensive progress in the field of VKC pharmacotherapy, thus far, no single medication is enough to treat the entire multifaceted pathophysiology of VKC," Dr. Kumar wrote. "Currently available drugs are merely palliative and do not extinguish the complex immune process initiating and perpetuating the allergic ocular surface inflammation." Because of this, VKC often returns once therapy stops.

Of course, avoiding factors that trigger VKC, such as sun, wind, and allergens, is the first step, said Andrea Leonardi, M.D., department of neurosciences, ophthalmology unit, University of Padua, Italy.

Patients and, when applicable, their parents, should also be told about the causes of VKC, the disease duration, and its possible complications, Dr. Leonardi said.

In addition to avoidance and cold compresses, common drugs to treat VKC are vasoconstrictor and nonspecific histamine blocker combination drops, nonspecific histamine receptor blockers, mast cell stabilizers, H1-receptor blockers, systemic antihistamines, dual- or multiple-action drugs, nonsteroidal anti-inflammatory drugs, topical or supratarsal injection corticosteroids, immunomodulators, and antimetabolites (mitomycin-C).

Read on to find out how ophthalmologists use some of these medications most effectively.

Mast cell stabilizers and antihistamines

Just as with seasonal ocular allergies, mast cell stabilizers and antihistamines are popular options to treat VKC.

The mast cell stabilizer sodium cromoglycate is usually a go-to choice for Dr. Kumar.

"In children with mild VKC limited to bulbar conjunctiva, I prefer to start with sodium cromoglycate. Selective antihistamines are the second line of defense," he said.

If the patient had two previous episodes of seasonal VKC, Dr. Kumar prefers starting sodium cromoglycate a week before allergy season begins and then continuing it for six weeks. "If symptom control is suboptimal, I substitute sodium cromoglycate with dual-action drugs," he said.

According to Dr. Kumar's review article, mast cell stabilizers "act primarily by stabilizing mast cell membranes and prevent degranulation, probably by blocking calcium channels. The efficacy of [mast cell stabilizers] in the control of symptoms and prevention of exacerbation has been demonstrated by many studies."

Dr. Leonardi agrees that mast cell stabilizers and antihistamines are a reasonable approach.

"It appears that the combined treatment with topical drugs that inhibit mast cells and block the effects of histamine, such as olopatadine [Patanol, Alcon, Fort Worth, Texas] and drugs that reduce eosinophil activation, such as lodoxamine [Alomide, Alcon] and spaglumic acid, and systemic antihistamines can be used as standard treatment," he said.


Although most ophthalmologists would agree that long-term high-dose steroid use is not a good idea, they do add that some tapered usage might be necessary with VKC.

For example, a low-dose steroid like Alrex (loteprednol etabonate 0.2%, Bausch & Lomb, Rochester, N.Y.) can "put out the fire and be continued long term" in moderate to severe VKC patients, said C. Stephen Foster, M.D., clinical professor of ophthalmology, Harvard Medical School, Boston.

"Topical corticosteroids must be added as pulse therapy when inflammation is not controlled," Dr. Leonardi said. In fact, he finds topical steroids to be the most effective drugs for moderate to severe VKC and atopic keratoconjunctivitis (AKC) and has used them in two thirds of his VKC and AKC patients. However, Dr. Leonardi cautions against prolonged or repeated use of steroids.

Dr. Kumar uses modified steroids in patients with superficial punctuate keratitis involving the upper two thirds of the cornea with moderate to severe bulbar or palpebral VKC. (He also uses dual-action drugs and lubricating eye drops in these patients.) He prescribes steroids for patients with vernal shield ulcer, along with mast cell stabilizers and lubricating eye drops.

"Short periods of frequent instillation of steroids (preferably modified steroids with a better side effect profile) followed by maintenance of palliation by a dual-action drug or an H1-receptor blocker is an effective and safe strategy," Dr. Kumar wrote in his review article. Steroids should not be used as a first-line defense against VKC or for a prolonged, unsupervised period of time due to the risk of steroid-induced cataracts and glaucoma, Dr. Kumar added.

Ophthalmologists also must consider alternatives for patients who are poor responders to steroids. This has sparked a greater interest in immunomodulators like cyclosporine.


Although its use is off-label, cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan, Irvine, Calif.) is piquing the interest of ophthalmologists who have patients who are poor steroid responders. Others like it simply because it seems to help control VKC in their patients.

"I think the cyclosporine is safe, and I use it for both chronic allergies such as AKC and VKC as well as dry-eye related problems," said Esen K. Akpek, M.D., associate professor of ophthalmology, and director, Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University, Baltimore.

"I have found a beneficial role for Restasis in the treatment of severe VKC with or without a shield ulcer," Dr. Kumar said.

Dr. Foster calls topical cyclosporine the "sexiest" new treatment for severe allergies. Interestingly, he has seen systemicnot topicalcyclosporine make a significant difference in the lives of patients with eczema. However, these same patients cannot try topical cyclosporine in clinical trials for their AKC, as they are already on the systemic form of the drug. "In poor responders or when only prolonged steroids are effective, my choice is topical cyclosporine (0.5% to 2%), which significantly ameliorates the signs and symptoms of moderate to severe VKC and AKC without side effects," Dr. Leonardi said. However, he still prefers steroids when there is active corneal involvement.

A number of studies are showing good clinical results with cyclosporine in VKC, such as the report from D. Shii and co-investigators in Japan, published in Current Eye Research last year. They found that cyclosporine eye drops "inhibited fibrosis and inflammatory cell infiltration by the suppression of Th2 cytokine production in repeatedly antigen-challenged conjunctiva without affecting the early-phase reaction."

Italian investigators, led by R. Tesse, published results in the March issue of Pediatric Allergy and Immunology that found 197 children with severe VKC who were treated long term with cyclosporine 1% had faster improvement of ocular signs and symptoms compared with other patients. A PubMed search of "VKC" and "cyclosporine" yields approximately 20 relevant studies.

More trials are needed to determine the optimum concentration of cyclosporine needed to treat VKC, Dr. Kumar reported in his review.

Future treatments

In addition to cyclosporine, other new treatment options are attracting attention.

Dr. Leonardi sometimes uses tacrolimus 0.1% or 0.03%, a dermatologic ointment, applying it externally or into the fornix in a small number of patients with severe allergic conjunctivitis, and he has found that it reduces signs and symptoms. Tacrolimus is approved by the U.S. Food and Drug Administration (FDA) for treating dermatitis; the FDA added a black box warning to the ointment last year due to a possible increased risk for cancer, according to the FDA website.

Dr. Foster agrees that certain topical skin applications are under-recognized for use in VKC patients.

A poster at this year's Association for Research in Vision and Ophthalmology (ARVO) meeting evaluated tacrolimus eye drops (Talymus ophthalmic suspension 0.1%, Senju Pharmaceutical, Osaka, Japan) to treat AKC and VKC. On average, at the cessation of treatment, the drops were instilled 1.3 times a day, according to Y. Satake, Tokyo Dental College, Ichikawa, Japan, and co-investigators. All 10 patients had complete resolution with no giant papillary formation at cessation, but seven patients experienced a recurrence of allergic inflammation at a mean of four weeks. Six of the seven had to resume the use of tacrolimus. Rituximab, an anti-CD20 monoclonal antibody, may have a role in some CD4 cell-mediated diseases, including severe allergic conjunctivitis, Dr. Leonardi said. Rituximab has proven effective for lymphoma and some auto-immune diseases.

Finally, Dr. Sheppard has found that some VKC patients respond well to 5 mg of oral daily Singulair (montelukast sodium, Merck, Whitehouse Station, N.J.). Singulair is a leukotriene receptor antagonist usually used in allergy and asthma patients. It can provide some relief without drying effects, he said.

Editors' note: Dr. Akpek has received research grants from Allergan (Irvine, Calif.). Dr. Sheppard has financial interests with Alcon (Fort Worth, Texas), Allergan, Bausch & Lomb (Rochester, N.Y.), and Vistakon (Jacksonville, Fla.). Drs. Foster, Kumar, and Leonardi have no financial interests related to their comments.

Contact information

Akpek: 410-955-5494, esakpek@jhmi.edu
Foster:617-621-6377, sfoster@mersi.us
Kumar: sunkaru79@hotmail.com
Leonardi: andrea.leonardi@unipd.it
Sheppard: 757-622-2200, docshep@hotmail.com

Treating vexing VKC cases Treating vexing VKC cases
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