Prevalence of Steroid-Induced Cataract and Glaucoma in Chronic Obstructive Pulmonary Disease Patients Attending a Tertiary Care Center in India

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1 original clinical study Prevalence of Steroid-Induced Cataract and Glaucoma in Chronic Obstructive Pulmonary Disease Patients Attending a Tertiary Care Center in India Tirupati Nath, MS, FMRF,* Subham Sinha Roy, MBBS,* Himanshu Kumar, MS,* Rachit Agrawal, MBBS,* Santosh Kumar, MD, FCCP, FNCCP, and S. K. Satsangi, MS* Purpose: Exposure to corticosteroids is known to be associated with an increased risk of cataract and glaucoma. This study was undertaken to determine the prevalence of steroid-induced cataract and glaucoma in patients with chronic obstructive pulmonary disease (COPD) and to assess a dose-response relationship between them. Design: This was a prospective observational study. Methods: We identified all COPD patients aged 50 years or older, with minimum steroid exposure of 4 months and on inhaled corticosteroids from March 0 to March 015. Average daily dose of inhaled corticosteroids was defined as low (1 50 μg), medium ( μg), and high ( μg) using fluticasone propionate equivalents. Results: We screened 405 COPD patients, of which 48 were dropouts. We identified 58 cataract and glaucoma patients with a prevalence of 1.4% and 3.9%, respectively. We also observed a dose-response relationship with the highest prevalence of cataract (39.%) and glaucoma (4.8%) at daily doses of μg fluticasone propionate equivalents. Conclusions: It is evident that higher doses and longer duration of inhaled corticosteroid in COPD patients are associated with a higher prevalence of cataract and glaucoma. Key Words: steroid-induced cataract, steroid-induced glaucoma, chronic obstructive pulmonary disease (Asia-Pac J Ophthalmol 017;1:8 3) Cataract and glaucoma have been the leading causes of blindness worldwide. Age-related cataracts are responsible for 51% of world blindness, or approximately 0 million people. 1 Glaucoma is the second leading cause of blindness worldwide. It was estimated that 1 million people worldwide would have glaucoma by 010 and 8.4 million will be bilaterally blind from the disease. The increasing use of corticosteroids in various medical conditions also increases the steroid-related complications of ocular concern, particularly steroid-related cataract and glaucoma, constituting the global burden of visual impairment worldwide. Steroid use is the fourth leading risk factor for secondary cataract and accounts for 4.7% of all cataract extractions. 3 The link between steroid use and the development of posterior subcapsular cataract (PSC) was first reported in 190 by Black et al. From the *Upgraded Department of Ophthalmology and Department of Tuberculosis and Chest Diseases, S. N. Medical College, Agra, India. Received for publication January 0, 01; accepted May, 01. The authors have no funding or conflicts of interest to declare. Reprints: Subham Sinha Roy, MBBS, Room No. 0, PG Boys Hostel, S. N. Medical College, Agra 800, India. subhamsinharoy@gmail.com. Copyright 017 by Asia Pacific Academy of Ophthalmology ISSN: DOI: 10.08/APO.011 Steroid-induced glaucoma is a form of secondary open-angle glaucoma occurring as an adverse effect of corticosteroid therapy. 4 It is usually associated with topical steroid use, but it may develop with oral, intravenous, inhaled, and periocular steroid administration by causing a decrease in aqueous outflow facility. The association of steroids and glaucoma was first established in 1950 when systemic administration of the adrenocorticotrophin hormone was shown to increase intraocular pressure (IOP). 5 However, there is no literature available from the Indian subcontinent on the development of steroid-induced cataract and glaucoma in relation to inhaled corticosteroid use. The purpose of our study was to determine the prevalence of inhaled steroid-induced glaucoma and cataract in patients with chronic obstructive pulmonary disease (COPD) attending a tertiary care center and also to find a dose-related response of steroid-induced cataract and glaucoma in COPD patients. materials and methods Our study was conducted with the approval of our local ethics committee and in accordance with the tenets of the Declaration of Helsinki. Written consent was obtained from all study subjects. All known cases or diagnosed cases of COPD as per criteria adopted and standardized by WHO-GOLD 011, who were aged 50 years or older and had received steroid therapy for at least 4 months during a period of 1 year from March 0 to March 015, were included. Already diagnosed cases of glaucoma or cataract before steroid intake; any other cause of glaucoma and cataracts other than steroids; and any other cause of diminution of vision, namely retinal pathology, corneal pathology, uveitis, and so on were excluded from our study. Apart from ocular pathologies, COPD patients with other comorbidities such as diabetes mellitus, hypertension, and prescribed steroid therapy for other systemic illness, which could lead to a confounding bias in our study, were also excluded. We divided all the COPD patients meeting the inclusion criteria into 3 groups based on duration and daily dosage of inhalational fluticasone propionate or its equivalent as mild, moderate, and high dosages. Details regarding dosage and duration are presented in Table 1. In our study, mainly fluticasone propionate and budesonide were prescribed as inhaled steroids in combination with long-acting beta agonist. The maximum prescribed daily dosage of fluticasone is 500 μg twice daily, and budesonide is 70 μg twice daily. All the study subjects underwent detailed examination including history, thorough anterior and posterior segment evaluation using slit lamp biomicroscopy, automated visual field testing for subjects with best-corrected visual acuity better than /0 in the better eye using the 30- test pattern on Humphrey Visual Field Analyzer (Carl Zeiss Meditec, Banglore, India), gonioscopy, 8 Asia-Pacific Journal of Ophthalmology Volume, Number 1, January/February 017

2 Asia-Pacific Journal of Ophthalmology Volume, Number 1, January/February 017 Steroid-Induced Cataract and Glaucoma Table 1. Distribution of Patients by and Dosage of Inhalational Steroids Inhalational Dosage of Fluticasone Propionate or Equivalent Moderate dosage, μg/d indirect ophthalmoscopy, and disc evaluation using a +90 D Volk lens (New Delhi, India). Statistical Analysis All statistical analyses were conducted using GraphPad In- Stat Version 3 for Windows (GraphPad Software Inc, San Diego, California). RESULTS A total of 405 subjects diagnosed with COPD in the Tuberculosis and Chest Disease Department who were on inhaled corticosteroids were examined for steroid-induced cataract and glaucoma during the study period. Of these, 48 subjects dropped out during the study period. The subjects comprised 53 (70.87%) men and 104 (9.13%) women [mean (SD) age, 4.1 (8.0) years; age range, 5 85 years], with a male-to-female ratio of.43:1 (Fig. 1). In this study, 37.5% of cases were aged 51 0 years, 38.38% were 1 70 years, 18.1% were years, and.1% were years. The maximum number of women was in the group aged 51 0 years (5.88%), and the highest number of men was recorded in the group aged 1 70 years (41.50%). The age-sex distribution of the study population is shown in Table and Figure 3. Of 357 COPD patients, 58 patients had steroid-induced cataract, including 4 men and 1 women. The overall prevalence of steroid-induced cataract was found to be 1.4% (Fig. ). Bilateral cataract was present in 11.7% of the population, whereas another 4.48% had unilateral cataract. We observed that men in our study had a higher prevalence of steroid-induced cataract (18.18%) than women (11.53%). The prevalence of steroid-induced cataract increased significantly with age from 10.5% among those aged 51 to 0 years to 7.7% among those aged 80 years or older. The prevalence of steroid-induced cataract with demographic details is shown in Table 3. The prevalence of steroid-induced cataract was higher in the group of patients taking moderate ( μg/d fluticasone propionate or its equivalents) to high doses ( μg/d fluticasone propionate or its equivalents) of inhaled corticosteroids (ICS) on a daily basis: 3.75% (n = 19) and 39.5% (n = 3), respectively. No cataract was found in patients taking low doses (1 50 μg/d fluticasone propionate or its equivalents) of ICS, even for more than 1 year s duration. The lowest prevalence rate (3.44%) was found in the group taking a high dosage of inhalational steroids for 4 to months, whereas the highest prevalence rate (39.5%) was observed in the group taking a high dosage of ICS for more than 1 year. Figure 4 and Table 4 depict the dose-response relationship. In our study, the overall prevalence of steroid-induced glaucoma was found to be 3.9%, including 11 men and 3 women (Fig. 4). Fifty-seven subjects had IOP greater than mm Hg and out of these, patients developed steroid-induced glaucoma with glaucomatous disc changes and field defects. The total number of patients with ocular hypertension was 43 (1.04%). The percentage of the population who had only glaucoma was 1.40%, and the percentage of the population who had only steroid-induced cataract was 13.7%, whereas the percentage of the population who had both steroid-induced cataract and glaucoma was.5%. Twenty-six patients had a positive family history of glaucoma. Considering the demographic profile of the study population, it was found that the highest prevalence of steroid-induced glaucoma (.57%) was in the age group of 1 to 70 years, whereas the lowest prevalence rate (1.50%) was noticed in the age group of 51 to 0 years. The prevalence of steroid-induced glaucoma with demographic details is shown in Table 5. We also observed that men in our study had a higher prevalence of steroid-induced glaucoma (4.34%) than women (.88%). Of patients diagnosed with steroid-induced glaucoma, none were in the group receiving 4 to months of steroid therapy even at a high dose. The highest prevalence (n = ; 4.85%) was noticed in the group receiving a high dosage of inhalational therapy for more than 1 year s duration. The lowest prevalence rate (n = ;.8%) was observed in the group of patients taking moderate to high doses for months to 1 year. Even patients taking Table. Age-Sex Distribution of the Study Population Men (n = 53) Women (n = 104) Total (n = 357) figure 1. Sex distribution of the study population (30.83) 105 (41.50) 51 (0.15) 19 (7.50) 55 (5.88) 3 (30.7) (13.4) 3 (.88) 133 (37.5) 137 (38.38) 5 (18.1) (.1) 9

3 Nath et al Asia-Pacific Journal of Ophthalmology Volume, Number 1, January/February 017 figure. Prevalence of steroid-induced cataract and glaucoma. figure 3. Age-sex distribution of the study population. moderate doses of inhalational steroids for more than 1 year showed a prevalence rate of 8.57% (n = 4). Details of the doseresponse relationship of steroid-induced glaucoma are shown in Figure 5 and Table. Twenty-five eyes of patients were diagnosed with steroidinduced glaucoma. Three eyes showed advanced glaucomatous cupping with significant field changes, and all of them were taking high doses of steroid therapy ( μg/d fluticasone propionate or its equivalents) for more than 1 year. Seventeen of those 5 eyes were in the group taking steroid therapy for more than 1 year. Ten eyes had normal cup-disc ratio with arcuate field defects, and 3 eyes showedmoderate glaucomatous cupping (Table 7). forms of steroid preparations (oral, topical, depot injections, intravitreal, etc.) can induce complications in eyes depending on the mode of administration, frequency of application, and duration of use. In our study, we evaluated the effect of inhaled corticosteroids on COPD patients based on the duration of therapy and dosage of each patient. However, there have been few large-scale studies conducted in the past to determine the association of inhaled corticosteroids with the development of PSC and steroid-induced glaucoma. Cumming et al reported in their study that the use of ICS is associated with the development of PSC and nuclear cataracts. In their study of 354 patients aged 49 to 97 years, they found that the use of ICS at any time was associated with a significantly increased prevalence of nuclear cataracts [relative prevalence, 1.5; 95% confidence interval (CI), ] and PSC (relative prevalence, 1.9; 95% CI, 1.3.8). Higher cumulative lifetime doses of beclomethasone were associated with higher risks of PSC. The highest prevalence (7%) of PSC was among subjects whose lifetime dose of beclomethasone was more than 000 mg (relative prevalence, 5.5; 95% CI, ). In our study of 357 COPD patients, we also observed a positive association between ICS and PSC, with a prevalence of 1.4% after adjusting for diabetes mellitus, systemic hypertension, and other systemic illness. Additionally, a positive dose-response relationship was observed between the dosage of inhaled steroids and the prevalence of steroid-induced cataract, with the highest prevalence (39.5%) found in the group taking inhaled fluticasone propionate or its equivalents DISCUSSION Steroid use and its adverse effects on eyes in the form of cataract, glaucoma, and raised IOP is a proven fact to date. Various Table 3. Association of Steroid-Induced Cataract With Sociodemographic Characteristics (Age Groups) No. Subjects Examined No. Steroid-Induced Cataract Patients Prevalence (%) Overall % 15.3%.15% 7.7% 1.4% figure 4. Dose-response relationship of steroid-induced cataract. 30

4 Asia-Pacific Journal of Ophthalmology Volume, Number 1, January/February 017 Steroid-Induced Cataract and Glaucoma Table 4. Dose-Response Relationship of Steroid-Induced Cataract Inhalational Dosage of Fluticasone Propionate or Equivalent Total No. Cataract Patients Moderate dosage, μg/d (3.44%) 5 (8.%) 9 (15.51%) 19 (3.75%) 3 (39.5%) 58 in daily doses ranging from 500 to 1000 μg/d for more than 1 year s duration. In our study, the inhaled steroids prescribed to the patients were mainly fluticasone propionate and budesonide. No beclomethasone was prescribed to any of the subjects in the study population. Similarly, Smeeth et al 7 reported that high doses of ICS used for prolonged periods were associated with an increased risk of cataract formation. There was a dose-response relationship, with the adjusted odds ratio increasing from 0.99 (95% CI, ) at daily doses up to 400 μg to 1.9 (95% CI, ) for daily doses greater than 100 μg. The association was also stronger with increasing duration of use. In contrast to our study, Miller et al 8 found that a fluticasone propionate/salmeterol fixed-dose combination or other ICS exposure was not associated with increased odds of cataracts or glaucoma, nor was a dose-response relationship observed in this population-based nested case-control study of COPD patients in the United Kingdom. Few studies have been conducted on children and young adults to evaluate the effect of ICS on crystalline lens. Simons et al 9 performed slit lamp examinations of the lenses of 9 young patients with asthma who had used inhaled corticosteroids for an average of 5 years, and none had any evidence of cataract. Tinkelman et al 10 found no cataracts in 108 children treated with inhaled beclomethasone for 1 year. Nassif et al 11 identified 1 PSC among 3 children treated with inhaled corticosteroids for an average of 1.3 years. In our study, the prevalence of steroid-induced glaucoma was 3.9%. Fifty-seven subjects had IOP greater than mm Hg, and patients developed steroid-induced glaucoma with field and optic nerve head changes. Of 57 subjects, patients had a positive family history of glaucoma, whereas of patients with steroid-induced glaucoma had a positive family history of glaucoma. In contrast to our study, Mitchell et al 1 reported an association between ICS use and glaucoma among patients with a family history of glaucoma or elevated IOP. The highest prevalence (4.85%) was noticed in the group receiving heavy doses of inhalational therapy ( μg/d fluticasone propionate or its equivalents) for more than 1 year. Age and sex also have an impact in the causation of ocular morbidity from inhaled steroids, as is evident from our study. The prevalence of steroid-induced cataract increased significantly with age from 10.5% among those aged 51 to 0 years to 7.7% among those aged 80 years or older. Similarly, the highest prevalence of steroid-induced glaucoma (.57%) was in the age group of 1 to 70 years. Regarding sex predilection, male preponderance was found both in steroid-induced cataract and glaucoma. In steroid-induced cataract subjects, men had a higher prevalence of steroid-induced cataract (18.18%) than women (11.53%). Similarly, the prevalence of steroid-induced glaucoma was higher in men (4.34%) compared with women (.88%). The major limitation of our study was the failure to obtain a detailed history of oral corticosteroids used by a limited number of subjects in the study population and to analyze their role in the development of steroid-induced cataract and glaucoma. Secondly, the number of subjects with COPD and the duration of our study were too small to draw definite conclusions. It is evident from our study that higher doses and longer duration of inhaled corticosteroid in patients with COPD are associated with a higher prevalence of cataract and glaucoma. These Table 5. Association of Steroid-Induced Glaucoma With Sociodemographic Characteristics (Age Groups) No. Subjects Examined No. Steroid-Induced Glaucoma Patients Prevalence (%) Overall %.57% 3.08% 4.54% 3.9% figure 5. Dose-response relationship of steroid-induced glaucoma. 31

5 Nath et al Asia-Pacific Journal of Ophthalmology Volume, Number 1, January/February 017 Table. Dose-Response Relationship of Steroid-Induced Glaucoma Inhalational Dosage of Fluticasone Propionate or Equivalent Total No. Glaucoma Patients Moderate dosage, μg/d (.8%) (.8%) 4 (8.57%) (4.85%) Table 7. Relationship Between of Steroid Therapy and Cup-Disc Ratio Cup-Disc Ratio of Steroid Therapy Normal Mild (up to 0.5) Moderate (0. 0.7) Advanced (>0.8) 4 mo mo 1 y >1 y data should be considered together with results from other observational studies in relation to corticosteroid therapy to obtain a clearer understanding of the long-term benefit-risk profile (risk of cataracts and glaucoma) of inhaled corticosteroid containing products in the treatment of COPD REFERENCES World Health Organization. Prevention of blindness and visual impairment. Priority eye diseases: cataract. Available at: causes/priority/en/index1.html. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 010 and 00. Br J Ophthalmol. 00;90: 7. Jobling AI, Augusteyn RC. What causes steroid cataracts? A review of steroid-induced posterior subcapsular cataracts. Clin Exp Optom. 00; 85:1 75. Dada T, Konkal V, Tandon R, et al. Corneal topographic response to IOP reduction in steroid induced glaucoma with VKC. Eye. 005;5:1 19. McLean JM. Use of ACTH and cortisone. Trans Am Ophthalmol Soc. 1950;48:93 9. Discussion. Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med. 1997;337:8. 7. Smeeth L, Boulis M, Hubbard R, et al. A population based case-control study of cataract and inhaled corticosteroids. Br J Ophthalmol. 003;87: Miller DP, Watkins SE, Sampson T, et al. Long-term use of fluticasone propionate/salmeterol fixed-dose combination and incidence of cataracts and glaucoma among chronic obstructive pulmonary disease patients in the UK General Practice Research Database. Int J Chron Obstruct Pulmon Dis. 011;: Simons FE, Persaud MP, Gillespie CA, et al. Absence of posterior subcapsular cataracts in young patients treated with inhaled glucocorticoids. Lancet. 1993;34: Tinkelman DG, Reed CE, Nelson HS, et al. Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics. 1993;9: Nassif E, Weinberger M, Sherman B, et al. Extrapulmonary effects of maintenance corticosteroid therapy with alternate-day prednisone and inhaled beclomethasone in children with chronic asthma. J Allergy Clin Immunol. 1987;80: Mitchell P, Cumming RG, Mackey DA. Inhaled corticosteroids, family history, and risk of glaucoma. Ophthalmology. 1999;10: