2. Terapi Konjungtivitis alergi 2010

© 2010 Wichtig Editore - ISSN 1120-6721

Eur J Ophthalmol (2010; :5) 811-81820

811

ORIGINAL ARTICLE

INTRODUCTION

The term “allergic conjunctivitis” refers to a group of hyper-sensitivity disorders involving the eyelid, conjunctiva, and cornea, sharing a common pathogenesis.The allergic reaction is the response to the exposure to an environmental allergen binding an E immunoglobulin

on the surface of conjunctival mast cells, and causing an immediate release of histamine, which triggers the inflam-matory cascade with a release of other inflammatory mol-ecules (principally tryptase, prostaglandins, leukotrienes). Histamine is a major inflammatory molecule: binding to H1 receptors on the surface of many cells, it is responsible for ocular itching, the main symptom of allergic conjunctivitis

Treatment of allergic conjunctivitis: results of a 1-month, single-masked randomized study

Michele Figus1, Paolo Fogagnolo2, Stefano Lazzeri1, Federica Capizzi3, Mariachiara Romagnoli4,

Annalisa Canovetti1, Michele Iester5, Antonio Ferreras6, Luca Rossetti3, Marco Nardi1

1Department of Neurosciences, Ophthalmology, University of Pisa, Pisa - Italy 2G.B. Bietti Foundation–IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Roma - Italy 3Eye Clinic, San Paolo Hospital, University of Milano, Milano - Italy 4Ophthalmic Surgery, AOUP, Pisa - Italy 5Clinica Oculistica, Dept. of Neurological Sciences, Ophthalmology and Genetics, University of Genova, Genova - Italy 6Miguel Servet University Hospital, University of Zaragoza, Zaragoza - Spain

PurPose. To compare the effects of topical antiallergic eyedrops in relieving the signs and symptoms of patients with allergic conjunctival pathology.Methods. In this multicenter, single-masked, randomized study, 240 patients with signs and symptoms of allergic conjunctivitis were randomized to receive 1 of the following 8 treatments twice daily: cro-molyn sodium/chlorpheniramine maleate, diclofenac, epinastine, fluorometholone, ketotifen, levoca-bastine, naphazoline/antazoline, and olopatadine. Clinical signs and symptoms were evaluated by a masked operator using a 10-point scale at the moment of enrollment (day 0) and at weeks 1, 2, and 4. The percentage of patients achieving at least a small (at least 50% reduction of the total scale score) or a good (at least 75%) improvement of signs and symptoms was calculated at each visit. Tolerability was also evaluated as the duration of discomfort after instillation.results. All drugs gave some improvement in symptoms in more than 85% of cases. Epinastine and olopatadine obtained at least a good relief of symptoms in 37% and 33% of cases at week 1. At the end of the study, good improvement of symptoms was obtained in at least 70% of patients by epinas-tine, ketotifen, fluorometholone, and olopatadine, whereas a 75% improvement for signs was obtained only by fluorometholone and ketotifen. Naphazoline/antazoline induced higher discomfort compared to the other study treatments (p<0.0001). ConClusions. The efficacy of epinastine, ketotifen, and olopatadine in the treatment of allergic con-junctivitis was comparable to fluorometholone. Naphazoline/antazoline had lower tolerability than the other study treatments. (Eur J Ophthalmol 2010; 20: 811-8)

Key Words. Allergic conjunctivitis, Antihistamines, Mast-cell stabilizers, Steroids, Vasoconstrictors

Accepted: February 24, 2010

© 2010 Wichtig Editore - ISSN 1120-6721 812

Allergic conjunctivitis treatment

tine is an antihistaminic drug with good efficacy in reduc-ing itching and hyperemia after conjunctival provocation tests and in reducing symptoms in allergic inflammation (14). Ketotifen is a non-competitive, relatively selective an-tagonist of H1 histamine receptor. Its action includes in-hibition of inflammatory-mediator release from mast cells, basophils, and eosinophils; modulation of chemotaxis and degranulation of eosinophils; inhibition of platelet-activating factor and endothelial synthesis and expression of cellular adhesion molecules (15). Olopatadine is a strong inhibitor of mast cell degranulation and a selective histamine H1 recep-tor antagonist, to manage the itching, redness, chemosis, tearing, and lid swelling of the ocular allergic reaction (16). Epinastine is a molecule with high affinity for H1 receptors but it has also affinity for the H2, α1, α2, and 5 HT2 recep-tors (17). It is also endowed with a stabilizing action on mast cells, neutrophils, and eosinophils, preventing inflammatory molecule release and oxygen radical production (18).Although many clinical trials previously compared the ef-fects of few antiallergic drugs, a study addressing the ef-ficacy and tolerability of all available antiallergic treatments is needed. Thus, the purpose of our study was to com-pare the short-term response of the commercially available agents for the treatment of allergic conjunctival pathology.

MATERIALS AND METHODS

This study was conducted from April to September 2006 in 2 Eye Clinics: Santa Chiara Hospital, Pisa, Italy, and San Paolo Hospital, Milan, Italy. It adhered to the Declaration of Helsinki and to the laws for data protection. Informed consent was obtained from all participants. All patients referred to the centers with signs and symp-toms of allergic conjunctivitis were informed about the aims of the study and invited to participate. Inclusion crite-ria were 1) age > 18 years; 2) active allergic conjunctivitis; 3) positive history of allergic conjunctivitis since at least an allergic season; and 4) willingness to participate in the study. Exclusion criteria were 1) concomitant, not allergic ocular pathologies; 2) use of antiallergic treatment (topical or systemic) during the week before enrollment; 3) known hypersensitivity to components of study drugs, including benzalkonium chloride; 4) condition of pregnancy or lactat-ing for women; and 5) unwillingness to stop contact lens use for the study period.A total of 247 consecutive eligible patients were consid-

(1). Mast cell degranulation also induces activation of vas-cular endothelial cells and the expression of chemokines and adhesion molecules, which initiate the recruitment phase of inflammatory cells in the conjunctival mucosa, which leads to the ocular late-phase reaction (2). The late phase corresponds to the persistent clinical inflammation that characterizes allergic disease (3), and is characterized by mucosal infiltration by eosinophils, neutrophils, baso-phils, and T-lymphocytes (4). In addition, conjunctival and corneal epithelial cells and fibroblasts may worsen inflam-mation by expressing cytokines, chemokines, adhesion molecules, and factors that maintain local inflammation and lead to tissue remodeling (5-7).Ocular allergy comprises 2 main groups: the first includes the most frequent allergic conditions, i.e. seasonal (SAC) and perennial allergic conjunctivitis (PAC); the second in-cludes the less frequent chronic severe forms, i.e. vernal keratoconjunctivitis (VRK) and atopic keratoconjunctivitis (AKC), both of which may be complicated by corneal in-volvement (8).Clinical presentation of ocular allergy can be isolated or, more commonly, associated with rhinitis (50%), asthma (35%), atopic dermatitis (2%), or skin rash or angioedema (1%) (2). The severity of the disease ranges from mild to severe. While ocular allergy is associated with a reduced perception of quality of life even in the mild forms, severe, untreated ocular allergy may potentially result in impair-ment of visual acuity (8).Many molecules are available for the topical treatment of allergic conjunctivitis. Corticosteroids are effective anti-in-flammatory and immunosuppressive drugs but they should be used with caution due to side effects such as cataract, glaucoma, and corneal infections (9). Nonsteroidal anti-inflammatory drugs have a limited use in allergic conjunc-tivitis, although research shows that cyclo-oxygenase in-hibitors reduce conjunctival inflammation after arachidonic acid application. Mast-cell stabilizers inhibit degranulation of mast cells and prevent the release of histamine, leukot-rienes, and other inflammatory molecules (10). This preven-tive action requires an early (normally 4 weeks before the beginning of the allergic period) and prolonged treatment. These molecules do not have any significant side effects and, if properly used, they can spare steroid treatment also in the acute phase (11, 12). Local vasoconstrictors, such as sympathicomimetic amines, only have a symptomatic effect (13). Antihistamine eyedrops are also largely used for topical treatment of allergic conjunctivitis. Levocabas-


Figus et al

symptoms were evaluated: itching, burning, foreign body sensation, tearing, and photophobia. During the first visit, patients were asked to score their symptoms using a con-tinuous numeric scale from 0 to 10; a global score (ranging from 0 to 50) was calculated. If present, the duration of discomfort after eyedrops instillation was recorded using a scale from 0 (no discomfort) to 10 (a discomfort lasting for more than 30 minutes after instillation). At the end of each visit, all clinical information were col-lected by the data operator and sent to the coordinat-ing operator; so, they were not available to the clinical operator.

Primary outcome

We calculated the percentage of patients achieving at least a “small” or “good” improvement of signs and symptoms (see below for definitions) at each visit and during the whole study period.

Sample size calculation

The sample size was calculated to detect an intergroup (30 subjects per group) difference or efficacy (arbitrarily de-fined as 50% reduction of symptoms) of 25%, assuming a standard deviation of 10%.

Statistical analysis

All statistical analyses were calculated using SPSS (ver-sion 15.0; SPSS Inc., Chicago, IL) statistical software. The Kolmogorov-Smirnov test was applied to the data, which showed a normal distribution. Mean score at the beginning and the end of the study was compared in each group by means of t test for paired data.At follow-up visits, the global scores for signs and symp-toms were compared to baseline. A reduction of at least 50% of the global score was deemed a small improvement, whereas a reduction of 75% or more was deemed a good improvement. At each visit, the percentages of patients achieving at least a small or good improvement of signs and symptoms with each treatment were calculated and compared by means of Yates chi-square test corrected for continuity. Such percentages were plotted over time and area under the curve (AUC) of patients achieving at least a small or good improvement of both signs and symptoms was calculated to summarize the effect of the treatments.

ered for study participation; 7 patients did not agree to participate in the study owing to inability to adhere to the schedule visits. After baseline visit, 240 patients fulfilling inclusion and exclusion criteria were enrolled and random-ized to one of the 8 study groups (30 patients for each group): cromolyn sodium 4%/chlorpheniramine maleate 0.2%, diclofenac 0.1%, epinastine hydrochloride 0.05%, fluorometholone 0.2%, ketotifen fumarate 0.05%, levoca-bastine 0.05%, naphazoline 0.25/antazoline 5 mg/mL, and olopatadine hydrochloride 0.1%.During the study, each patient was followed by 2 operators: an unmasked data operator who explained the aims of the study to patients, collected informed consent, demograph-ics, and symptoms scales, and took care of randomization and prescription of study treatments; and an ophthalmolo-gist (clinical evaluator) performing all study visits and grad-ing the signs of the disease, who was masked to study treatment and patient demographics and symptoms.At the end of the baseline visit, the data operator commu-nicated the results of the visit to a coordinating operator (one for every center) who randomized patients by means of a list of random numbers using a 2-block randomization (seasonal and nonseasonal allergy) to minimize the differ-ences between groups. The randomization sequence was not available to any other operator.Industry involvement was absent in the design, conduct, and analysis of the study. Patients did not have to pay for any visit or medication (free samples provided by the com-panies were used). Patients were aware of the treatment they received. For drugs commercially available both as multidose and preservative free, only multidose formula-tion was used in order to avoid a possible intergroup vari-ability caused by the absence of preservative. Patients were instructed to start treatment the day after baseline visit and to use study treatment twice daily (8 aM and 8 PM); intervals of ±30 minutes were tolerated.Each patient was evaluated by the same ophthalmolo-gist at day 0 (enrollment), week 1, week 2, and week 4. At each visit, ophthalmologists addressed the following clinical signs: eyelid edema, eyelid hyperemia, conjunctival chemosis, conjunctival hyperemia, follicular reaction, cor-neal dysepithelization, and corneal ulcers. A continuous numeric scale ranging from 0 to 10 was used (0, absent; 3, mild; 6, moderate; 10, severe) for each sign, and a global score (ranging from 0 to 70) was calculated. Patients were given an autoevaluation test regarding symp-toms and discomfort at eyedrops instillation. The following



groups (ranging from 0.3±1.3 to 1.3±2.1, p>0.5), whereas diclofenac and naphazoline/antazoline showed less ef-ficacy in decreasing symptoms (4.0±2.8 and 3.3±2.3, re-spectively) compared to the other treatments (ranging from 0.7±0.9 to 2.3±2.3, p<0.05). All drugs induced at least a small improvement of both signs and symptoms in at least 85% of the study popula-tion (Tabs. III and IV). At week 1, the effect of diclofenac on symptoms was significantly less than any other eyedrop (0.32 vs 0.54-0.89, p<0.008), whereas no significant differ-ences were found for symptoms at weeks 2 and 4 and for signs during the whole study period. At week 1, epinas-tine, ketotifen, fluorometholone, and olopatadine induced at least a small improvement in symptoms in more than 70% of patients, while this percentage of improvements was obtained by all treatments for the signs. Epinastine, ketotifen, and levocabastine obtained the best AUC (0.80 or more) for at least small improvements of both signs and symptoms.When considering the percentages of patients achieving at least good improvements of symptoms and signs, less uniform patterns of efficacy were found (Tabs. V and VI). Relief of symptoms was obtained by epinastine and olo-patadine in 37% and 33% of cases at week 1, and these

RESULTS

At baseline, the groups had homogenous demograph-ics and distribution of the types of allergies (Tab. I). Mean scores for signs and symptoms were similar (p>0.05, t test for unpaired data); mean sign sum was 17.9±9.2 (range 14.6-20.4) and mean symptoms sum was 32.3±3.8 (range 29.2-34.1).The study was completed by 232/240 subjects (97%); 5 subjects interrupted the treatment due to burning, and 3 could not attend the visits for personal reasons. No sys-temic adverse events were reported.The discomfort at instillation of study eyedrops is reported in Table II. Naphazoline/antazoline induced significantly higher discomfort compared to the other study treatments (4.3±1.7 vs 2.7±1.3 or less, p<0.0001); 2 of 8 patients who discontinued the treatment were using naphazoline/antazoline. Ketotifen fumarate was the drug with the least discomfort (mean score 1.6±1.5, with discomfort less than few seconds in all subjects). All study treatments induced a statistically significant re-duction in mean scores for both signs and symptoms compared to baseline (p<0.0001, Tab. I). At the end of the study, the mean score for signs was similar in the study

TABLE I - DEMOGRAPHICS, DIAGNOSIS AT BASELINE, AND MEAN SCORES FOR SIGNS AND SYMPTOMS AT THE BEGIN-NING AND THE END OF THE STUDY

Cromolyn Diclofenac Epinastine Fluorometholone Ketotifen Levocabastine Naphazoline Olopatadine sodium 0.1% 0.05% 0.2% 0.05% 0.05% 0.25/antazoline 0.1% 4%/chlorpheniramine 5 mg/mL 0.2%

Patients No. patients 30 30 30 30 30 30 30 30 No. of discontinuations 0 0 1 2 1 1 2 1 Discontinuation due to burning 0 0 1 0 1 0 2 1 Discontinuation for inability to attend visits 0 0 0 2 0 1 0 0 Age, y 37±15 42±13 39±11 37±16 39±15 36±15 35±15 37±20 M/F 15/15 15/15 12/18 15/15 12/18 13/17 14/16 15/15Diagnosis Vernal 2 2 3 1 2 2 3 2 Seasonal 24 24 25 24 25 22 22 22 Giant-papillary 1 2 1 3 3 3 2 3 Atopic 1 2 1 1 0 0 1 1 Perennial 2 0 0 1 0 3 2 2 Mean score for signs at the beginning of the study ± SD 19.2±5.4 15.5±4.2 18.7±9.5 19.6±8.2 20.4±7.6 17.9±6.6 17.1±9.2 14.6±4.0 Mean score for symptoms at the beginning of the study ± SD 33.0±6.8 34.1±6.9 31.1±9.3 32.7±9.1 33.9±9.8 32.1±7.9 32.4±7.1 29.2±5.6 Mean score for signs at the end of the study ± SD 0.8±1.6 1.3±2.1 0.6±1.8 0.3±1.3 0.4±1.1 0.8±1.6 0.8±1.3 0.5±1.6 Mean score for symptoms at the end of the study ± SD 2.2±2.0 4.0±2.8 1.6±1.6 0.7±0.9 1.7±2.1 2.3±2.3 3.3±2.3 1.8±1.3


Figus et al

TABLE II - SIDE EFFECTS: MEAN SCORE OF DISCOMFORT AFTER INSTILLATION (MEAN ± STANDARD DEVIATION)

Cromolyn Diclofenac Epinastine Fluorometholone Ketotifen Levocabastine Naphazoline Olopatadinesodium 4%/ 0.1% hydrochloride 0.2% fumarate 0.05% 0.25/antazoline hydrochloridechlorpheniramine 0.05% 5 mg/mL 0.1% maleate 0.2% 2.2±1.6 2.7±1.3 2.0±1.5 1.8±1.4 1.6±1.5 2.5±1.5 4.3±1.7 1.9±1.9

TABLE III - PERCENTAGE OF PATIENTS SHOWING AT LEAST 50% IMPROVEMENT OF SYMPTOMS

Drugs Symptoms 1 week 2 weeks 4 weeks AUC

Cromolyn sodium 4%/chlorpheniramine maleate 0.2% 0.61 0.87 0.87 0.70Diclofenac 0.1% 0.32 0.74 1.00 0.61Epinastine hydrochloride 0.05% 0.85 0.96 0.96 0.81Fluorometholone 0.2% 0.89 0.93 0.93 0.80Ketotifen fumarate 0.05% 0.84 1.00 1.00 0.84Levocabastine 0.05% 0.70 1.00 1.00 0.80Naphazoline 0.25/antazoline 5 mg/mL 0.54 1.00 1.00 0.76Olopatadine hydrochloride 0.1% 0.79 0.88 0.88 0.74

AUC = area under the curve.

TABLE IV - PERCENTAGE OF PATIENTS SHOWING AT LEAST 50% IMPROVEMENT OF SIGNS

Drugs Signs 1 week 2 weeks 4 weeks AUC



TABLE V - PERCENTAGE OF PATIENTS SHOWING 75% OR MORE IMPROVEMENT OF SYMPTOMS

Drug Symptoms 1 week 2 weeks 4 weeks AUC





mast cell stabilizers (19). All the currently available topi-cal drugs are effective in decreasing the acute signs and symptoms of allergic conjunctivitis (20, 21). Our data on tolerability indicate that naphazoline/antazo-line is less tolerated than the other treatments, because it burned for more than 20 minutes after instillation in about 70% of patients. Two of 8 patients who discontinued the study were under treatment with naphazoline/antazoline. All the other treatments gave negligible discomfort at instil-lation, in particular ketotifen, fluorometholone, and olopa-tadine, which induced discomfort lasting for a few seconds in all subjects.Owing to the multicenter design, our study recruited an adequate number of patients with active ocular allergy; our results may reflect the real clinical efficacy of the treat-ments compared to other studies which used the conjunc-tival provocation test (22, 23). Also, owing to the 2-block randomization, all groups had similar characteristics for demographics and clinical findings.The absence of a control group is a potential limitation of the study. As a simple dilution of allergens may decrease signs and symptoms (24), using lubricating eyedrops as one of the investigational drugs might have been an op-tion. However, our intention was to compare clinically available antiallergy drugs, which we clearly showed to dif-fer in discomfort as well as in clinical effectiveness. Simple observation could be advisable, but we did not consider this option for ethical reasons. In conclusion, this study shows the efficacy of drugs acting with a double mechanism (both as competitive antagonists of histamine receptors and as mast-cell stabilizers), such as ketotifen, olopatadine, and epinastine. In particular, they

percentages were significantly higher than those obtained by cromolyn, diclofenac, levocabastine, and naphazoline/antazoline (p<0.02); at week 4, the improvement induced by diclofenac (0.26) was significantly less than the other treatments (0.61-0.87, p<0.03), apart from naphazoline/antazoline (0.54). For signs, no statistically significant dif-ferences were found at week 1, whereas fluorometholone and ketotifen achieved better results at weeks 2 and 4 (0.68 and 0.86, respectively, p<0.05). At the end of the study, good improvement of symptoms was obtained in at least 70% of patients by epinastine, ketotifen, fluorometholone, and olopatadine, whereas a 70% improvement in signs was obtained only by fluorometholone and ketotifen. Globally, an AUC >0.30 for both symptoms and signs was achieved by fluorometholone, ketotifen, and olopatadine; only fluo-rometholone obtained AUC>0.50.

DISCUSSION

This is a clinic prospective study comparing commercially available treatments for ocular allergy. All treatments were effective and induced at least a small improvement in symptoms and signs after 1-month follow-up. On the basis of our analyses, epinastine, fluorometholo-ne, ketotifen, and olopatadine were the treatments that provided the best relief of symptoms; fluorometholone and ketotifen obtained the best results for signs. Overall, di-clofenac showed less efficacy than the other molecules.Our results confirm the results of previously published meta-analyses. Limited evidence suggests that antihista-mines might have a faster therapeutic effect compared to

TABLE VII - PERCENTAGE OF PATIENTS SHOWING 75% OR MORE IMPROVEMENT OF SIGNS

Drug Signs

1 week 2 weeks 4 weeks AUC




Figus et al

Address for correspondence:Michele Figus, MD, PhDVia B. Buozzi, 1955045 Pietrasanta, LuccaItaly [email protected]

obtained very similar results to fluorometholone at each visit, without the well-known side effects of corticoster-oids. We cannot recommend the use of corticosteroids in the acute phase because, based on our data, this treat-ment did not guarantee a significant advantage during the first 1-2 weeks from presentation when compared to the above mentioned drugs. The topical ophthalmic solutions provided effective man-agement of allergic ocular signs and symptoms. Treatment preferences should therefore be based on convenience of use (with reduced frequency of instillation for some prepa-rations), patient preference, costs, and side effects.

The authors report no proprietary interest or financial support.

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