Efficacy and safety of latanoprost in eyes with uveitic glaucoma

Transcription

1 Graefes Arch Clin Exp Ophthalmol (2009) 247: DOI /s GLAUCOMA Efficacy and safety of latanoprost in eyes with uveitic glaucoma Nikos N. Markomichelakis & Agori Kostakou & Ioannis Halkiadakis & Sonia Chalkidou & Dimitrios Papakonstantinou & Gerasimos Georgopoulos Received: 4 November 2008 / Revised: 31 December 2008 / Accepted: 5 January 2009 / Published online: 28 January 2009 # Springer-Verlag 2009 Abstract Background To compare the efficacy and safety of latanoprost against a fixed combination of dorzolamide and timolol in eyes with elevated intraocular pressure (IOP) or glaucoma and anterior or intermediate uveitis. Methods Fifty-eight patients with anterior or intermediate uveitis and elevated IOP or glaucoma presented or followed up in the Ocular Inflammation and Immunology Service of General Hospital of Athens were randomly assigned to receive treatment either with latanoprost (30) or with dorzolamide/timolol (28). The main outcome measures were inflammatory relapses and IOP response to treatment. Results Ten patients (34%) in the latanoprost group and sixteen patients (57%) in the dorzolamide/timolol group experienced relapses of anterior uveitis (p=0.93). There was no statistical difference between the two groups in respect of inflammatory relapses (p=0.21). Twenty-one patients were followed up before starting latanoprost. The number of recurrences of anterior uveitis per patient per year before treatment with latanoprost was 0.82 ± 1.2. The rate of The authors have no proprietary interest in any aspect of this study. N. N. Markomichelakis (*) : A. Kostakou Ocular Immunology and Inflammation Service, Department of Ophthalmology, General Hospital of Athens, 106 Kykladon Street, Ag. Paraskevi, Athens 15341, Greece marnik@gna-gennimatas.gr A. Kostakou : I. Halkiadakis : S. Chalkidou Ophthalmiatrion Athinon, Athens Eye Hospital, Athens, Greece D. Papakonstantinou : G. Georgopoulos Department of Ophthalmology, Medical School, University of Athens, Athens, Greece relapses per patient per year after starting latanoprost was 0.39 ±0.7 for these patients (p=0.038). After 1 year of treatment, intraocular pressure was dropped from 27.8 ± 8.4 mmhg to 18.6 ± 5.3 mmhg (p<0.001) in the latanoprost group and from 28.2 ±8.1 mmhg to 22.6 ±10.1 mmhg (p< 0.001) in the dorzolamide/timolol group. Four patients during treatment with latanoprost and five patients during treatment with dorzolamide/timolol developed macular edema. Conclusion Latanoprost is safe and equally effective to a fixed combination of dorzolamide and timolol in the treatment of uveitic glaucoma. Keywords Glaucoma. Latanoprost. Anterior uveitis. Dorzolamide. Timolol Introduction Glaucoma is a common and potentially devastating complication of uveitis [1, 2] and remains a considerable therapeutic challenge despite the availability of many medical treatments. A clinician has to deal with the destructive effect of chronic or recurrent inflammation on the outflow pathway compounded by the hypertensive influence of corticosteroid medications. Medical therapy may not be as well tolerated in uveitic glaucoma as in other types of glaucoma [2]. Any surgical intervention in an eye with active inflammation is associated with a high risk of failure, whereas the success rate of surgical interventions performed even in non-inflamed eyes declines with time [3]. The place of prostaglandin analogues in the treatment of uveitic glaucoma is not clarified. The role of prostaglandins as mediators of inflammation is well-known. Early studies using large quantities of prostaglandins infused into animal eyes led to ocular inflammation with breakdown of the

2 776 Graefes Arch Clin Exp Ophthalmol (2009) 247: blood-aqueous barrier [4]. Further research in human subjects found that latanoprost had no significant effect on the permeability of the blood-aqueous barrier in phakic eyes [5, 6]. Prostaglandin analogs however, have been reported to induce recurrent uveitis, to provoke macular edema, to activate herpetic eye disease, or to induce a paradoxical increase in intraocular pressure (IOP) in eyes with uveitic glaucoma [7 11]. Schumer and colleagues reviewed this topic, with particular attention to the relationship between cystoid macular edema (CME) and topical prostaglandin medications [12]. They considered CME and iridocyclitis as putative but unproven side effects of prostaglandin analogues, due to a lack of evidence from double-masked, controlled rechallenge studies. Several randomized, double-masked, controlled clinical trials failed to establish a causal relationship between prostaglandin analogue use and these putative side effects [13 20]. However, investigators have proposed that caution should be exercised when considering the use of these drugs in patients with risk factors for CME and iridocyclitis. The fixed combination of dorzolamide and timolol is widely used to lower IOP in uveitic glaucoma. Today, there are no data to support the possibility that this combination promotes intraocular inflammation. Furthermore, it is equally effective to latanoprost in primary open angle glaucoma [18 20]. The purpose of our study was to compare the efficacy and safety of latanoprost with those of a fixed combination of dorzolamide and timolol in eyes with elevated IOP and anterior or intermediate uveitis. Methods All patients with anterior or intermediate uveitis and increased IOP >24 mmhg or glaucoma requiring treatment presented or followed up in the Ocular Inflammation and Immunology Service of General Hospital of Athens G. Gennimatas from the year 2000 to 2007 were included in this study. Approval for the study was obtained from the Ethics Committee of Athens General Hospital. Patients were randomly assigned to receive either latanoprost or a fixed combination of dorzolamide and timolol at the beginning of the study. Patients with angle closure, posterior forms of uveitis, macular edema or prior ocular surgery were excluded from the study. A comprehensive medical and ophthalmologic history, including an extensive review of systems, was obtained from each patient during the initial consultation. The ophthalmologic examination performed at every visit included best-corrected visual acuity, biomicroscopy, gonioscopy, tonometry, and indirect ophthalmoscopy in all patients. Anterior segment and fundus photography, visual fields, fluorescein angiography OCT, and ultrasonography were performed when indicated. We reviewed the medical records for sex prevalence, age at onset of anterior or intermediate uveitis and unilateral or bilateral involvement. If anterior segment inflammation was present we collected the following data: information concerning the extent of intraocular inflammation, the status of the macula and the type of topical or systemic medication used to control their uveitis. Τhe Standardization of Uveitis Nomenclature (SUN) Working Group grading scheme was used for anterior chamber cell and flare assesment [21]. Recurrence of anterior uveitis was defined as anterior segment activity with cells 1+. All patients were treated according to the degree of intraocular inflammation using a stepladder steroid-sparing therapeutic algorithm. Patients with anterior uveitis were initially treated with topical corticosteroids; periocular corticosteroids were used for severe recurrent attacks of inflammation (+4 cells), and for CME. Patients with intermediate uveitis were treated only if the visual acuity was less than 20/30 with periocular corticosteroids. Long-term systemic nonsteroidal anti-inflammatory drugs (NSAIDs) were used if active inflammation recurred with attempted topical steroid withdrawal, and to prevent recurrence of inflammation. Short-course systemic corticosteroids were given if the inflammation could not be controlled with previous therapy. Patients with sarcoidosis, juvenile rheumatoid arthritis, multiple sclerosis and Adamantiades-Behcet disease received treatment for the underlying disease. Systemic immunosuppressive agents were used in patients in whom previous therapeutic strategies had failed. Patients with herpetic keratouveits received specific antiviral therapy. CME was verified with OCT and treated as previously described [22]. Ocular hypertension was defined as IOP above 24 mmhg on more than two examinations, without visual field defects. The diagnosis of uveitic glaucoma was made when visual field defects were present. Patients were examined 1, 3 and every 6 months after commencing treatment and when needed in the meantime. To minimize the effects of diurnal variations, IOP measurements were taken at approximately the same time in the morning at each visit. The following information was collected: status of uveitis, IOP, adverse effects, need for additional medicine or surgery. Patients with at least 1 year of follow-up were included in the present study. The primary outcome parameters were IOP control and rate of relapses before and after initiation of latanoprost.we also compared the frequency of relapses of patients using latanoprost with that for patients using a fixed combination of dorzolamide and timolol. Statistical analysis One eye of each patient was used for analysis. In bilateral cases the eye with the higher IOP at diagnosis was

3 Graefes Arch Clin Exp Ophthalmol (2009) 247: included. Data were analyzed using SPSS 11.0 for Windows. All the parameters analyzed were tested for normality using one-sample Kolmogorov-Smirnov statistics. A two-factor mixed repeated measures analysis of variance was conducted to compare each of the parameters assessed. The subject group was the between subject factor with two levels (latanoprost and fixed combination), and the time factor was the within subject factor. The Mann-Whitney test, Wilcoxon signed ranks test and Pearson chi-square test were used, whenever appropriate, in order to determine if a statistical difference existed between groups. Results Our study included 58 patients who were randomly assigned to two groups. The first group (group A) consisted of 30 patients who were treated with latanoprost, and the second group (group B) consisted of 28 patients who received treatment with a fixed combination of dorzolamide and timolol. Patients characteristics are presented in Table 1. The mean duration of treatment was 16.1 ± 9 months for the latanoprost group and 18.6 ± 12 months for the group treated with the fixed combination of dorzolamide and timolol (p=0.12). Inflammatory relapses Ten patients (34%) in group A and sixteen patients (57%) in group B experienced relapses of anterior uveitis (Pearson chi-square=3.319, p-value=0.93). In group A, 21 patients (70%) were followed up in the Ocular Inflammation and Immunology Service. Mean follow-up was 38 ± 17 months. The number of recurrences of anterior uveitis (AU) per patient per year before treatment with latanoprost was 0.82 ± 1.2. The rate of relapses per patient per year after starting latanoprost was 0.39 ± 0.7 for these patients (Wilcoxon signed ranks test: p=0.038) and 0.41 ± 0.6 for the whole group. The period between onset of treatment with latanoprost and exacerbation of anterior uveitis varied from 68 to 315 days. In all cases, anterior segment activity resolved with topical steroid drops. Latanoprost was discontinued in two patients because they developed CME. Five patients had herpetic keratouveitis and received latanoprost. One patient developed CME, and latanoprost was stopped. The remaining four did not develop any inflammatory relapses during treatment. For group B, the rate of annual relapses was 0.56 ± 0.74 during treatment with the fixed combination of dorzolamide and timolol. In this group, increase of activity of AU occurred between 28 and 280 days from the institution the Table 1 Demographic and clinical characteristics of the study population Patients on latanoprost (n = 30) Patients on combination of dorzolamide and timolol (n = 28) P Age (years) 39.4± ± Male/Female 17/13 11/17 Laterality Unilateral Bilateral 10 4 Anatomical location of uveitis Anterior Intermediate 9 10 Diagnosis Undefined anterior uveitis 9 9 HLA-B27 associated uveitis 6 1 Juvenile idiopathic arthritis 1 1 Herpetic keratouveitis 5 7 Undefined intermediate uveitis 6 6 Sarcoidosis 3 Multiple sclerosis 1 Adamantiades-Behcet disease 3 Visual acuity (Snellen lines) 7.6 (2.4) 8.6 (2.6) 0.43 IOP (mmhg) 27.8 (8.5) 28.2 (8.1) 0.3 Glaucoma status Ocular hypertension 10 4 Glaucoma 20 24

4 778 Graefes Arch Clin Exp Ophthalmol (2009) 247: combination. There was no statistically significant difference between the two groups in the frequency of anterior uveitis bouts (Mann-Whitney test: p=0.214). Intraocular pressure control The IOP for the group of latanoprost was reduced after one month of application from ± 8.4 mmhg to 23.9 ± 10.7 mmhg (p=0.026). For the fixed combination, these numbers were 28.2 ± 8.1mmHg before treatment and 19.8 ± 7.8 mmhg (p=0.001) after 1 month. After 1 year of treatment, these numbers were 18.6 ±5.3 mmhg for group A and 22.6 ± 10.1 mmhg for group B. Using a repeated measures analysis, we conclude that there is no significant difference between the two groups at any time point during the study (F (1, 56)= 0.217; p-value=0.643) (Fig. 1). Response to treatment, in terms of reduction of IOP over 20% from baseline to month 3 therapy, was achieved in 18 patients of group A and 16 patients of group B. There is no statistical difference in responders between the two groups (Pearson chi-square=0.049, p-value=0.82). Six patients in the latanoprost group (group A) and four patients in the dorzolamide/timolol group (group B) had active anterior segment inflammation at the time of inclusion in the study. Topical steroids were instituted apart from the antiglaucomatous agent in each group. In the 1- month follow-up, inflammation subsided in nine patients. At the same time, there was a lowering IOP effect (>20%) in four patients of group A and in two patients of group B, whereas all except one achieved IOP control in their second Group Xalatan Cosopt visit (2-month follow-up). One patient discontinued latanoprost because he developed CME. After the third month, a second medicine (brimonidine) was added or surgery (tube shunt) was performed in six patients of group A and four patients of group B. These eyes were excluded from analysis after the change of the treatment scheme. The post treatment (1 year) best corrected visual acuity was 8.6 ± 2.4 Snellen lines for group A and 8.4 ± 2.8 Snellen lines for group B. There is no significant difference in visual acuities before and after treatment (p=0.39). Adverse effects Four patients (13.3%) developed CME, 1, 4, 9 months and 1 year respectively after starting latanoprost. The first patient with history of idiopathic iritis was started on latanoprost while having activity (+2 cells) in his anterior chamber. One month later, he still had anterior segment inflammation, although of lower grade, and he developed CME. Latanoprost was stopped, and his macula returned back to normal. The other two patients had a history of intermediate uveitis and CME, prior to treatment with latanoprost. They were treated accordingly, but latanoprost was not discontinued. The fourth patient had a history of herpes simplex virus (HSV) anterior uveitis. After discontinuation of latanoprost, his macula returned back to normal. In group B, five patients (17.8%) developed CME between 3 and 9 months after starting fixed combination of dorzolamide and timolol. Two of them had bilateral CME. Both of them had a history of intermediate uveitis. Two had a history of HSV associated anterior uveitis and one of Adamantiades-Behcet disease. IOP (mm Hg) Baseline 1st month 3rd month Time of visit 6th month 12th month Fig. 1 Intraocular pressure of latanoprost (Xalatan) and dorzolamide timolol (Cosopt) groups during follow-up Discussion The management of uveitic glaucoma requires a difficult balance between effective control of inflammation and adequate IOP-lowering in order to prevent ocular complications. Prostaglandin analogues are effective and safe in treatment of most primary and secondary forms of glaucoma, but they are relatively contraindicated in the inflammatory type, because of an association with anterior uveitis and CME [11]. In terms of safety, our study did not find any significant difference in inflammatory relapses between latanoprost and the fixed combination of dorzolamide and timolol. There are several studies evaluating the effect of prostaglandin analogues in the blood aqueous barrier. Alm and Stjernschantz [13] and Camras [14] reported no association of latanoprost with anterior uveitis. Watson and Stjernschantz [15] and

5 Graefes Arch Clin Exp Ophthalmol (2009) 247: Warwar et al. [8] reported a low-grade activity in the anterior chamber in the form of flare or a few cells in a small number of patients. Those patients, however, suffered from other forms of glaucoma and did not carry any history of prior ocular inflammation. Smith et al. [9] reviewed the records of a small group of 13 patients with previous history of uveitis, and reported that three (23%) developed delayed, mild exacerbation of anterior segment inflammation with latanoprost treatment. This is in accordance with our study, which found that 34% of patients in latanoprost group developed inflammatory relapses. Fechtner et al. [7] reported four cases of anterior uveitis associated with the use of latanoprost. Three of their patients had a history of prior incisional ocular surgery. They concluded that latanoprost may be relatively contraindicated in patients after ocular surgery. Sacca et al. [10] reported three cases of relapse of anterior uveitis in patients with history of inflammatory glaucoma treated with latanoprost. A recent retrospective study by Chang et al. [23] is in agreement with our study that prostaglandin analogues are not associated with an increased rate of inflammatory relapses. Furthermore, they indicated that prostaglandin analogues are not associated with increased risk of CME. In contrast with the earlier study, however, at least one of our patients with no prior history of CME developed CME during treatment. Latanoprost was stopped, and CME resolved. Nevertheless, no difference in development of CME between patients receiving latanoprost and the fixed combination was noticed. Results of our study indicate that despite the known association between latanoprost use and reactivation of HSV [24 26], latanoprost may be used with relative safety in patients receiving oral antiviral prophylaxis [27 28]. Only one among the five patients with herpetic keratouveitis developed inflammation after treatment with latanoprost. These results, however, should be interpreted with caution because of the small sample size. In terms of efficacy, latanoprost was as effective as the fixed combination of dorzolamide and timolol over 1 year of treatment. This is in agreement with previous studies comparing the two treatments in other types of glaucoma [18 20]. Nonetheless, a significant number of non-responders in both medications was noticed. Forty percent of patients receiving latanoprost and 50% of patients receiving the fixed combination did not achieved 20% IOP reduction. Previous studies reported a 56-70% of responders to latanoprost among patients with other types of glaucoma [29 30]. The lack of response of patients with uveitic glaucoma to latanoprost was first reported by Smith and coworkers [9]. According to their study, IOP of patients with active uveitis was not responsive to latanoprost. They suggested that an inflamed uvea may inhibit the uveoscleral outflow. Contrary to this assumption, our study indicated that latanoprost was effective in controlling IOP in patients with active uveitis. In these patients, however, inflammation was controlled after starting latanoprost because of the concurrent administration of the antinflammatory agents. Thus, no definite conclusion can be extracted about the effectiveness of latanoprost in eyes with persistent inflammation. Our study suggested that the IOP-lowering effect of the fixed combination is also highly variable in uveitis. It is possible that the IOPlowering effect of antiglaucomatous medication varies according to the activity of inflammation and also the main mechanism by which uveitis leads to elevated IOP. Steroid responders may have a different response to treatment to that for patients with inflammation of the angle. Our study has several limitations, and our results should be interpreted with caution. Patients with posterior uveitis who are prone to development of CME were not included in our study. Eyes with prior ocular surgery were also not included. Another potential confounding factor is the diurnal effect on IOP. Although we tried to schedule appointments at the same time of the day, this was not always possible. In conclusion, this study suggests that latanoprost and possibly other prostaglandin analogues are not contraindicated in patients with uveitic glaucoma as initially suggested. Given the difficulty in management of inflammatory glaucoma, prostaglandin analogues may be a useful extra tool in the hands of clinicians for managing this special category of patients. However, their IOP-lowering effect is highly variable, and should still be used cautiously in uveitic patients with a history of CME or patients with herpetic keratouveitis not receiving prophylaxis. References 1. Kok H, Barton K (2002) Uveitic glaucoma. 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