Understanding the “Red” Eye

At an industry-sponsored symposium held in conjunction with the American College of Allergy, Asthma and Immunology 2003 Annual Meeting, three leaders in the treatment of ocular allergies presented the newest information on the keys to differentiating between types of conjunctivitis, categories of ocular inflammation with emphasis on etiology and mast cell involvement and optimal care for conjunctival inflammatory disorders. Topics covered included mechanisms of action in hypersensitivity reactions, making the differential diagnosis between conjunctival allergies and other ocular diseases and differences in the actions and responses to
available classes of medication.

This program was supported by an unrestricted educational grant from Alcon Laboratories, Inc.

Categories of Ocular Inflammation, Etiology and Mast Cell Involvement

Hypersensitivity reactions can be divided into four categories no matter where they are occurring, including the eye. Type I reactions (immediate hypersensitivity reactions) involve immuno-globulin E (IgE)–mediated release of histamine and other mediators from mast cells and basophils. Type II reactions (cytotoxic hypersensitivity reactions) involve immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies bound to cell surface antigens, with subsequent complement fixation. Type III reactions (immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation. Finally, Type IV reactions (delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T-cells rather than by antibodies. (Table 1)

“The mechanism for these reactions involve T-cells, macrophage and dendritic cell interactions,” said Dr. Lanny Rosenwasser, MD, Professor of Medicine at the University of Colorado Health Sciences Center in Denver. “While at one time the conjunctiva and other eye organs were thought to be immunologically privileged, it’s becoming clear that even in Type-1 hypersensitivity, underlying cell-based immunity leading to T-cell responses play a significant role.”

The T-lymphocyte provides the specificity for the allergen or antigen, but it is dependent on macrophages and dendritic cells (DC) for full expression. The DC is the most potent of the antigen-presenting cells (APC). Their major role is to capture an invader in the mucosa and present it to the T-cells to initiate the reaction. They come from the same linage as macrophages and require cytokine growth factors to develop from the precursors. Among the operative cytokines are granulocyte macrophage colony-stimulating factor (GM-CSF), Interleukin (IL)-3, IL-4, IL-1 and tumor necrosis factor (TNF).

As with most immune cells involved in generating inflammation and immunity in the eye, there is clearly a differentiation in the APCs. Dendritic cells help precursor T-cells differentiate into TH-1 or TH-2 cells depending on the types of cytokines they have been exposed to.

“There are many ways that T-cells can be eliminated from reactions and that becomes a strategy for treating many kinds of allergic reactions,” said Dr. Rosenwasser. “It is possible to anergize the T-cells and make them unresponsive by exposing them to certain cytokines.”

For example, there are proteins on the surface of DCs and T-cells such as Fas and Fas ligand. These activate apoptosis and trigger cell death. (Table 2)
Cytokines produced by mast cells have been identified as being present in seasonal allergic and perennial allergic conjunctivitis. Cytokines are small
glycoproteins with unique receptors, often synergize for optimal function and have overlapping and/or redundant functions.

“This is very good in terms of providing host defense, but makes it harder to devise therapeutic strategies,” said Dr. Rosenwasser. “Very often
eliminating only one cytokine is not enough to have an effect and maybe whole classes of cytokines will have to be stopped.”

Cytokines themselves have receptor systems that are involved and activated in these processes. One of the ways to potentially manipulate cytokines would be to take common receptors that might have an impact on a whole set of cytokines and find ways to selectively inhibit them based on the receptor’s structure.

Another strategy looks at ways to influence the cytokines involved in eosinophil differentiation. Dr. Rosen-wasser suggested focusing on common beta chains on Il-3, Il-5 and GM-CSF receptors.

Researchers are looking at many other ways to intervene at different levels of the response. For example, GM-CSF and transforming growth
factor-beta (TGF) can inhibit mast cell differentiation. Stem cell factor is important in mast cell differentiation and the release of histamine. Basophil release can be impacted leading to changes in IgE response and histamine release. Strategies to interfere with cytokines have been shown to influence eosinophil production and migration.

“Whether these strategies actually influence development or progression of diseases remains to be seen,” said Dr. Rosenwasser.

Chemokines are small molecular weight cytokines involved in the activation and attraction of inflammatory cells, especially neutrophils, eosinophils and basophils. There are four families, each with a wide variety of receptors. The alpha and beta families are well defined and the genes for their expression are well known. Two other families have only one member.

The role of cytokines and T-cells in IgE production is to promote T- and B-cell interactions and to produce IL-4 and –13 that stimulates production of IgE by the B-cells. There are others, such as TGF-beta and interferon gamma that inhibits this switch. IL-12 and –18 indirectly down-regulate IgE by changing the balance of TH-1. This increases production of interferon gamma and blunts the effects of IgE.

Il-4 is an important inducer of TH-2 differentiation while Il-12 and -18 serve the same function for induction of TH-1. IL-4 and –13 share receptors, however, only IL-4 can induce TH-2 cells. Similarly, IL-12 and –18 share some functions, but only –18 can activate both TH-1 and TH-2 cells.

“Altering the balance between these cells that produce cytokines that influence allergic reactions would be a useful strategy to treat allergic conjunctivitis,” said Dr. Rosenwasser.

Keys to Differentiating Conjunctivitis

It is estimated that 23 million people who are currently taking medication for systemic or nasal allergies also have ocular allergies. Of those, only about 3 million get a prescription eye drop, averaging two bottles each.

“What’s interesting is that there were over 40 million bottles of over-the-counter anti-allergy eye drops sold during 2002, roughly two bottles for each of these people as well,” said David Granet, MD, Associate Professor of Ophthalmology and Pediatrics at the University of California in San Diego Medical School. “There are literally millions of people who are already on allergy medication treatments that are not getting help from a physician for their ocular allergies.”

Part of the problem is that the other symptoms may overwhelm the issue of how badly their eyes are bothering them. Another is that allergists
do not often ask their patients about eye-related problems.

“What worries the allergist most about the eye is the one, one-hour lecture you had on the subject in medical school,” said Dr. Granet. “The one that discussed blindness, so people get worried about treating the eyes inappropriately.”

He suggests checking the vital signs of the eye, with vision being the first. There should not be significant loss of vision with routine allergic conjunctivitis.
Next, check the reflexes. A simple ophthalmoscope shined into the eye will elicit a red reflex bilaterally. If on only one side, then it is not likely allergy
related.

When taking a general history, do not forget to ask about redness or discharges. If the patient complains of redness that goes away when allergy
season ends, it is not likely an infection. The type and color of any discharge is another distinguishing factor. Assess for anything that happened around the time the problems were first noticed to rule out trauma or chemical exposures.

Check for eye movement — it should be normal with allergic conjunctivitis. Also, since allergies tend to happen in both eyes, when symptoms are seen in only one, a more in-depth assessment is in order. Follow-up is important with all medications. If the person is treated for allergic conjunctivitis and does not show response in a few days, then go looking for other things.

“Think about having the patients fill out a simple form when they arrive in the office to bring out eye symptoms they might otherwise forget to mention,” he said. “I bet you will find many of your patients with allergic conjunctivitis or related concerns are among the 20 million not being treated by allergists, ophthalmologists or primary care physicians.”

In the eyes, the major preformed player in allergic conjunctivitis is histamine. However, the mast cell in the eye is structurally different from what is seen in lungs, nasal mucosa or small intestines. That means that medications from one area cannot be used to treat the other since the cells are not identical.

“The quickest way to diagnose seasonal allergic conjunctivitis (SAC) is to look at the underside of the conjunctiva on the lid,” noted Dr. Granet. “Normal conjunctiva looks smooth, like a Zamboni has just finished resurfacing the ice rink. If it is bumpy, you are looking at SAC, with the proper historical context.”

The best way to treat allergic conjunctivitis is to avoid the allergen. One tip suggested by Dr. Granet and largely overlooked is having patients wash their hair before going to sleep. This eliminates allergens that havebuilt up over the course of the day, are deposited on the pillow and then in their eyes when the patient rolls over.

The second suggestion is to tell patients not to rub their eyes. The mechanical irritation alone will trigger an allergic response that is made worse by irritants on their hands.

Medication treatment is often indicated. Dr. Granet and others did a study of persons taking steroid nasal sprays and comparing a non-sedating oral
antihistamine to an eye drop. They found that not only did the eye drop impact on the ocular relief of symptoms score; it was better for nasal symptoms as well (Lanier BQ, et al. Clin Ther. 2002; 24: 1161).

The final consideration is cost. The Medical Letter did a comparison and found that newer drugs, such as ketotifen or olopatadine are actually cheaper than older medications that are dosed four-times-a-day and require an additional mast cell stabilizer or antihistamine (Medical Letter Consultants. Med Lett Drugs Ther. 2000;42:39).

Dr. Granet noted that if there is reason to suspect something other than allergies are causing the conjunctivitis, differential diagnosis should be aggressively pursued. For instance, giving steroids, a perfectly acceptable treatment for SAC, can actually cause holes in the tissues of the eyes if the proper diagnosis was viral conjunctivitis.

He also stressed that allergists should remember that SAC does not mean that other problems cannot be presenting. For instance, rubbing the eyes because of the itching associated with allergies is a great vector for introducing bacteria from the hands and causing a superinfection.

“Ophthalmologists would never think of giving an antibiotic pill that would be absorbed systemically with relatively little getting to the eye,” said Dr. Granet. “This is also a great paradigm for allergic disease.”

Optimal Care for Conjunctival Inflammatory Disorders

“I think it is important that we start thinking about the therapies we have and focus on which therapies target which mediators,” said Stanley Fineman, MD, Clinical Associate Professor of Medicine at the Emory School of Medicine in Atlanta. “We have a number of different choices when we prescribe and need to match the medication’s actions with the patient’s needs.”

The first class to consider is the topical decongestant. Most available over-the-counter, these medications include phenylephrine, tetrahydrozoline and oxymetazoline and function by vasoconstriction. They are often combined with antihistamines. The main therapeutic concern with this group is the
potential for rebound, as in similar medications used in the nose. These also are contraindicated for use in patients with glaucoma.

“The question then becomes which is better, oral or topical administration?” said Dr. Fineman. “Oral H-1 antagonists work in the eye, although they are not quite as effective because there is a blood/ocular membrane. Topical agents seem to work better and you get faster response by dropping the medication right into the eye.”

A study by Lanier, et al. compared the itching scores following an allergen challenge with either ketotifen or desloratadine. They found that the desloratadine alone works, but not nearly as well as the topical ketotifen. Another trial comparing olopatadine and laratadine showed clearly that the former was superior over a week-long period (Lanier BQ, et al. Ann Allergy Clin Immunol. 2001;86:641). (Figure 2)

There are a number of options available to the physician wanting to prescribe antihistamine eye drops. Emedastine and levocabastine were both found to be effective in controlling itching over a season in patients with allergic conjunctivitis. Emedastine treatment was shown to have slightly better improvement (Verin P, et al. Am J Ophthal. 2001;131: 691).

“Another model that has proven useful in evaluating allergy treatments for the eye is the conjunctival allergen challenge (CAC),” said Dr. Fineman. “Like allergy testing in the early 1900s, you put a drop of the allergen in the eye followed by the medication.”

Ahluwalia and colleagues used this model to assess treatment with levocabastine or nedocromil. They found a modest differential in improvement of symptoms with the nedocromil (Ahluwalia P, et al. J Allergy Clin Immunol. 2001;108:449).

“These researchers also found that different cytokines are targeted by specific medications,” said Dr. Fineman. “There were increases in both histamine and prostaglandin D2 (PGD-2) concentrations following allergen challenge in the CAC model.”

The group found that nedocromil effectively blocked the release of both histamine and PGD-2 compared to levocabastine. Levocabastine did not block them as well. When they looked at mean E-selectin and intercellular adhesion molecule 1 (ICAM), though, nedocromil was superior.

Orfeo and colleagues completed a CAC study comparing nedocromil and emedastine in the control of local reactions in those with allergic conjunctivitis. Both helped lessen redness and itching (Orfeo V, et al. Eur J Ophthalmol. 2002; 12:262).

Another class of medications useful in eye allergy treatment are the mast cell stabilizers. They prevent the release of histamine and preformed mediators while inhibiting eosinophil chemotactic factor release. Among the approved medications are lodoxamine, nedocromil and pemirolast.

“Most of these have a short duration of action, are approved for use in children and are in pregnancy Category B,” said Dr. Fineman. “Nedocromil is indicated for twice-a-day dosing; the rest are limited by having to be taken up to four times a day.”

Yanni and his group looked at results of a one-minute allergen challenge. Cromolyn, nedocromil, and pemirolast all inhibited histamine release and were basically the same following the IgE challenge (Yanni JM, et al. Ann Allergy Asthma Immunol. 1997;79:541).

“The dual action agents are those I think we should use the most for allergic conjunctivitis,” he said. “The beauty is that they have both antihistamine and mast cell stabilizing effects giving us two for the price of one. The three primary drugs are azelastine, ketotifen and olopatadine.”

Studies have shown all three were significantly better than placebo in relieving different symptom clusters associated with allergic conjunctivitis. There were differences found, however, in comparison studies.

A trial by Kempuraj and colleagues looked at patients given either azelastine or olopatadine and their impacts on mediator release. Both inhibited IL-6 and tryptase release. The azelastine was more potent, although both effectively blocked anti-IgE. Using mast cells from the umbilicus, they noted a post-IgE challenge release of the vacuoles. But when treated with azelastine or olopatadine, there is not as much granule release (Kempuraj D, et al. Ann Allergy Asthma Immunol. 2002;88:501).

Another study used cultured human mast cells (CHMC) to study the effects of olopatadine on TNF-alpha. There was a significant correlation between
concentration of the drug and mediator inhibition (Cook E, et al. Ann Allergy Asthma Immunol.2000;84:504).

Ketotifen has also been studied. An open controlled study by Abelson and others included a number of symptoms such as itching, burning, redness, and tearing. All were improved by treatment with the medication (Abelson MB, et al. Arch Ophthalmol. 2003;121:626).

They also did biopsies and looked at the number of cell in stainings for CD-29 and eotaxin. The bottom line was that you did get suppression of eotaxin and CD-29 over time.

“There are a number of comparison trials available to help evaluate medications in this group,” noted Dr. Fineman. “Some studies use the CAC model and some use patients during the allergy season.”

Aguilar studied patients during their allergy season and found there was an advantage to using olopatadine compared to ketotifen. A similar advantage was reported by Berdy, et al. using the CAC model (Aguilar A. Acta Ophthalmol Scand Suppl. 2000;230:52; Berdy GJ, et al. Clin Ther. 2000;22:826).

Another group compared results of administering olopatadine, nedocromil and placebo. Again the advantage went to olopatadine, probably related to it having both an antihistamine and mast cell stabilizing effect. Others have shown olopatadine to have better results when compared with azelastine and the mast cell stabilizers.

“Immunotherapy is another modality that should be considered in these patients,” stressed Dr. Fineman. “A group of 11 studies published by Len Bielory shows a definite benefit to utilizing immunotherapy.

“The bottom line is that there are a number of options for the treatment of allergic conjunctivitis,” he continued. “Topical therapy is most efficient, but the physician must consider all the patient’s symptoms when treating allergic disease.”

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