Treating the Ocular Component of Allergic Rhinoconjunctivitis and Related Eye Disorders

Leonard Bielory, MD; C. H. Katelaris, MD; Susan Lightman, FRCP, FRCOphth, PhD; Robert M. Naclerio, MD

Disclosures
In This Article

Treatment Options for Ocular Allergy

A range of treatment options are available for the control of ocular allergy symptoms, some of which may obviate pharmacologic interventions ( Table 1 ). Allergen avoidance is implemented by minimizing patient contact with the allergens to which they are sensitive; however, the eyes present a large surface area and thus it is often impossible or at least impractical to avoid ocular exposure to airborne allergens. Allergens can also be diluted and removed from the ocular surface through lubrication with artificial tears (saline combined with a wetting and viscosity agent); however, the unit-dose packaging required for sterility makes these products expensive, and they do not treat the underlying allergic response. Cold compresses are another nonpharmacologic intervention that may provide relief from ocular symptoms.

When avoidance and nonpharmacologic strategies do not provide adequate symptom relief, pharmacologic treatments may be applied topically ( Table 2 ) or given systemically to diminish the allergic response. For example, the H1 topical antihistamine levocabastine hydrochloride is effective in rapidly relieving ocular inflammation when administered topically to the eye.[47,48] However, a limited duration of action necessitates frequent dosing of up to 4 times per day,[49] and topical antihistamines may be irritating to the eye, especially with prolonged use. Because atopy has been shown to be related to a fivefold increase in symptoms during allergy seasons, patients who use contact lenses should consider the use of soft daily-disposable lenses for comfort.[50] A small percentage of patients may have to discontinue the use of contact lenses during acute periods.

Combination treatments using decongestants with antihistamines have been shown to be more effective,[51] and are administered to the eye as drops up to 4 times daily. Decongestants (oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, and naphazoline hydrochloride) act primarily as vasoconstrictors and are effective in reducing erythema[51]; however, adverse effects include burning and stinging on instillation, mydriasis, and rebound hyperemia or conjunctivitis medicamentosa with chronic use.[52] Therefore, these treatments are suitable only for short-term symptom relief, and are not recommended for use in narrow-angle glaucoma patients.

Mast-cell stabilizing medications (cromolyn sodium 2% or 4%, lodoxamide tromethamine 0.1%, nedocromil sodium 2%) can also be applied topically to the eye, and may be suitable for more severe forms of conjunctivitis. However, for mast-cell stabilizers to be effective, the mast cell has to be de-activated before the allergic reaction is triggered, thus they require a loading period during which they must be applied before the antigen exposure. Compliance is, therefore, an important factor because frequent regular dosing before an allergic reaction can become difficult for patients to adhere to. Cromolyn sodium is used in several types of conjunctivitis, including forms of AC; however, studies have shown only marginal effectiveness compared with placebo.[53,54,55] Lodoxamide tromethamine is more potent than cromolyn sodium in the prevention of histamine release in animal models,[56] and has been shown to provide relief from the symptoms of VKC.[57] Nedocromil sodium has also been shown to be more potent than cromolyn sodium.[58,59]

In contrast to classical mast-cell stabilizers, the topical antihistamine mast-cell stabilizers have a dual mode of action: they inhibit mast-cell degranulation while competitively blocking histamine binding to H1 receptors, thus providing rapid allergic symptom relief through antihistamine action. As a result of this more rapid action, compliance is likely to be greater compared with that of the pure mast-cell stabilizers. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are possible candidates for treating the symptoms of SAC. The only NSAID currently approved for SAC is ketorolac tromethamine 0.5%, which works on the arachidonic acid cascade and is effective in reducing ocular itching. However, as is the case for several classes of topical ocular treatments, NSAIDs are also known to cause discomfort on instillation,[60,61,62] which may affect patient compliance.

The more severe variants of conjunctivitis, including AKC, VKC, and GPC, can be controlled by topical corticosteroids (loteprednol etabonate 0.2% and rimexolone 0.1%), which are also effective in the treatment of acute and chronic forms of AC.[63,64,65,66]. Corticosteroids administered via eye drops are associated with serious adverse events when administered over long periods, including increased intraocular pressure (IOP) and cataract formation, and these agents are therefore appropriate for short courses (up to 2 weeks); however, if needed for longer durations, an eye examination should be carried out, including baseline assessment of cataracts and IOP.[8]

The topical ocular treatments described above share common limitations that arise from the mode of administration. Many adults have poor tolerance of eye drops, and they are particularly difficult to administer in a sterile manner when patients suffer from arthritis or tremors, or when used in pediatric practice. Since eye drops are cleared rapidly from the eye, efficacy and duration of action may be reduced, necessitating frequent administration and increasing expense. Moreover, compliance is a major issue in the use of eye drops,[67,68] which may be exacerbated by allergies that affect multiple systems. Patients may need to use a nasal treatment plus oral antihistamines, and topical creams and inhalers. It may be beneficial to reduce the number of agents used regularly by a patient through the use of immunotherapy, and orally or nasally administered allergy treatments that are effective against ocular symptoms.[69]

The efficacy of immunotherapy against ocular symptoms precipitated by conjunctival antigen challenges was originally demonstrated in 1911,[70] and this well-established method may be considered for the long-term control of AC. Although some more recent studies have focused on nasal rather than ocular symptoms,[71] others have confirmed the efficacy of immunotherapy against ocular symptoms.[72,73,74,75,76,77] However, immune responses to allergen administration are not predictive of the effectiveness of the therapy,[78] and the therapy itself can produce systemic reactions, the incidence and severity of which vary dependent on the type of allergen administered.[79] Traditionally, immunotherapy has involved subcutaneous administration of allergen solution; however, newer sublingual immunotherapy (SLIT) provides a more convenient option. SLIT requires further evaluation for ocular allergy relief; it has been shown to control ocular signs and symptoms,[80,81,82] although ocular symptoms may respond less well than nasal symptoms.[83]

Oral antihistamines (cetirizine hydrochloride, desloratadine, fexofenadine hydrochloride, and loratadine) are commonly used for the therapy of nasal and ocular allergy symptoms. These newer second-generation antihistamines are recommended in preference to first-generation antihistamines because they have a reduced propensity for adverse effects such as somnolence.[8] Loratadine has been shown to have a protective effect in conjunctival provocation tests,[84] and desloratadine[85] and fexofenadine hydrochloride[86,87] have been found to significantly reduce ocular symptoms of SAR in placebo-controlled studies. In addition, cetirizine has demonstrated efficacy against symptoms of AC in conjunctival provocation tests;[88,89] however, a double-blind placebo-controlled trial showed no impact on ocular symptoms of perennial allergic rhinitis (PAR).[90] Second-generation antihistamines can, however, induce ocular drying,[91,92] which may impair the protective barrier provided by the ocular tear film and thus actually worsen allergic symptoms. It has therefore been suggested that the concomitant use of an eye drop may treat ocular allergic symptoms more effectively.[31] Indeed, ketotifen fumarate plus desloratadine,[93] and olopatadine hydrochloride plus loratadine[94] have been shown to be more effective than either antihistamine alone as a result of the local effect of the topically applied agent. In addition, one trial has shown that eye irritation was significantly reduced by an antihistamine preparation that had been formulated for intranasal application (azelastine hydrochloride).[95] However, these results have been inconsistent because eye watering was significantly reduced compared with placebo by twice-daily (but not once-daily) application of azelastine hydrochloride in 1 trial,[96] but was not significantly reduced in another.[95]

Intranasal corticosteroids (INS) are highly effective for treating nasal symptoms of AR,[8] but the evidence that they may also be effective for the treatment of ocular symptoms is inconsistent. Currently, the mechanism by which intranasal treatments act on ocular symptoms is not known. Potential mechanisms include improved drainage of ocular secretions resulting from a reduction of edema and inflammation around the lower end of the nasolacrimal duct, and a decrease in neuronal reflex activity. It is well established that allergen challenges to one side of the nasal cavity lead to nasal secretion in the contralateral cavity via a neurologic reflex.[97,98,99,100,101] Nasal challenges have also produced ocular itching in 90% of patients in 1 study,[102] and ocular symptoms in approximately 20% in another,[103] suggesting that ocular symptoms may be induced by a nasal-ocular reflex (Figure 4). It may be the case that INS inhibit the nasal-ocular component of ocular allergy symptoms, but not the direct ocular component.

Routes of ocular allergy therapy administration. Nasal therapy may act on afferent nerve fibers to reduce the stimulation of ocular inflammation by efferent nerves in the hypothesized naso-ocular reflex. CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs; SLIT, sublingual immunotherapy; SCIT, subcutaneous immunotherapy.

The variation in effectiveness of INS on ocular symptoms may therefore be the result of varying levels of affinity for nasal receptors. Systemic effects are unlikely with these agents as they have low bioavailability and rapid first-pass metabolism leading to low plasma levels.[104,105] Thus, the amount of an intranasal steroid available in the eye for a direct therapeutic effect is miniscule. Passage of agents from the nose to the eye via the nasolacrimal duct has also been shown to be unlikely.[106] A number of large clinical trials have investigated the ocular efficacy of INS in allergic patients; a meta-analysis of 16 randomized controlled trials showed that INS were more effective against several nasal symptoms of AR than oral antihistamines, and also found no difference in efficacy against AR ocular symptoms between the treatment classes.[107] Similar conclusions were drawn by a systematic review that determined that 9 of 10 AR studies showed no difference in efficacy for ocular symptoms between INS and oral antihistamines, while 1 study showed superiority of the oral antihistamine.[108] In contrast, pooled efficacy data from 7 multicenter, randomized, double-blind, placebo-controlled studies have shown that the INS fluticasone propionate 200 mcg once daily provides effective relief of ocular symptoms associated with SAR.[22] In accordance, a randomized, double-blind, parallel group study conducted at 14 investigative sites showed that fluticasone propionate 200 mcg once daily significantly decreased the ocular symptoms score compared with vehicle placebo[21]; however, other placebo-controlled trials found no effect of fluticasone propionate on eye symptoms in adults[109] or children[110] with SAC.

Another nasally administered corticosteroid, triamcinolone acetonide, has also been shown to have efficacy against ocular symptoms; however, only 1 placebo-controlled trial showed a statistically significant improvement,[111] and these findings have not been consistent.[112] Similarly, a pooled analysis of 4 studies found that mometasone furoate 200 mcg once daily may also provide relief from ocular symptoms in patients with SAR.[23,113] In a recent study,[114] ciclesonide did not have a significant effect on non-nasal symptoms, or the eye symptom domain of the RQLQ.

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