Association of Corticosteroid Use with Incidence of Central Serous Chorioretinopathy in South Korea

Supplementary Online Content

Rim TH, Kim HS, Kwak J, Lee JS, Kim DW, Kim SS. Association of corticosteroid use with incidence of central serous chorioretinopathy in South Korea. JAMA Ophthalmol. Published online August 9, 2018. doi:10.1001/jamaophthalmol.2018.3293

eMethods. Steroid Exposure and Central Serous Chorioretinopathy eTable 1. Steroid use between 2002 and 2010 and Central Serous Chorioretinopathy. eTable 2. Incidence of central serous chorioretinopathy according to amount of oral steroid exposure (n=394,788) eTable 3. Medical departments responsible for the prescription of corticosteroids in 2002 eTable 4. Thirty most frequent diagnoses associated with the prescription of corticosteroids in 2002 eTable 5. Prevalence of central serous chorioretinopathy per 10,000 individuals during 2011–2015 in South Korea

This supplementary material has been provided by the authors to give readers additional information about their work.

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SUPPLEMENTARY MATERIALS

eMethods Steroid Exposure and Central Serous Chorioretinopathy

The Korean National Health Insurance Service (KNHIS) controls all medical costs accrued by beneficiaries, medical providers, and the government. Therefore, almost all medical data (including diagnostic codes, prescription drugs, procedures performed, and personal information) are centralized in large databases. The KNHIS and medical providers exchange all cost-related healthcare information using electronic codes of the Korean electronic data interchange (KEDI) (e.g., the KEDI code for “Visual Field Examination [Automated]” is E6691, and for “Cosopt; Merck and Co., Inc.” is 655500390 [E09060211]). Each South Korean resident is assigned a unique identification number at birth, and this number is used by the KNHIS to identify each individual. Thus, health care claims data are not omitted or duplicated. Moreover, the currently used second version of NHIS-National Sample Data was developed for research purposes, resulting in improved integrity and reliability of the data following data cleansing by NHIS. Therefore, we believe that the drug information included in our study is highly accurate. Drug exposure is difficult to analyze using claims data. In a previous Taiwanese study, steroid exposure was defined as repeated prescriptions for any steroid administered by the oral route in 2 consecutive months. From the data in Figure 1 in the main manuscript, it is difficult to evaluate the risk of central serous chorioretinopathy (CSCR) with recent steroid use only because former use also affects the incident CSCR. For example, the risk of CSCR has actually risen due to past intravenous use, which can be misinterpreted as having been caused by recent topical use.

There are methods for drug analysis in the clinical setting. However, in a retrospective case-control study, it is difficult to control surveillance bias when we are using claims data. To prospectively analyze as much data as possible, we searched for steroid use according to route of administration between 2002 and 2010 and summarize our findings in eTable 1. The incidence and hazard ratio for the incidence of CSCR since 2011 are estimated. This analysis assumes that the patterns of steroid use until 2010 will be similar to those after 2010. This is inaccurate; however, it is still useful for determining the overall association. The information on steroid use was identified based on dosage forms (oral administration, topical application, injections or parenteral preparations, and eye drops) and type of corticosteroid, including fludrocortisone, betamethasone, dexamethasone, methylprednisolone, triamcinolone, prednisolone, prednisone, hydrocortisone, and cortisone.

eTable 1 shows the risk of CSCR according to the dosage form. In terms of route of administration, no association (adjusted hazard ratio [HR] 1.01) was observed between use of steroid eye drops and CSCR, and a borderline association (adjusted HR 1.30, 95% confidence interval [CI] 0.96–1.77) was observed between topical application only and CSCR. The risk of CSCR increases in subjects who took a steroid orally, which is the most common route (adjusted HR 1.37, 95% CI 1.16 –1.62) and in subjects who took oral steroids orally and used them topically (adjusted HR 1.44, 95% CI 1.22–1.69). The incidence of CSCR was highest among individuals who have been used steroids via injection or parenteral steroid preparations at least once (7.0 cases of CSCR per 10,000 person-years, 95% CI 3.2–15.6). However, the wide CI indicates a less precise finding.

In order to evaluate the dose-dependent association between steroid use and CSCR, we extracted never steroid users and oral only steroid users from the data (n=394,791). eTable 2 shows the incidence of CSCR according to amount of oral steroid administration. A trend of increasing HR values for cases of CSCR with increasing dose of prednisolone or an equivalent dose was observed

In our main paper, the classification shows that the incidence of CSCR is relatively high in individuals who used steroids between 2010 and 2015 (HR, minimum 1.54, maximum 2.15 in eTable 1), and some subjects used steroids after development of CSCR. Therefore, the actual effect may be greater than this.

In conclusion, the use of steroids in the real world is very complex in terms of type, route, and duration. Therefore, it is difficult to precisely define steroid exposure in the real world and compare the incidence of CSCR in each defined subgroup. Based on the assumption that past patterns of use persist in the future, we searched for steroid use from 2002 to 2010, and the data obtained show that the risk of CSCR is highest among those who received intravenous corticosteroids at least once. This analysis is based on an arbitrary assumption, so caution is needed when interpreting this finding.

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To evaluate the rationale behind the prescription of corticosteroids, we examined the medical departments prescribing the medications and the diagnoses of individuals receiving corticosteroids using an explorative analysis for all claims in 2002. A total of 808,199 claims were filed for the prescription of corticosteroids out of a total of 5,194,582 claims from 979,390 subjects. More than 50% of corticosteroids were prescribed by the departments of internal medicine or dermatology (eTable 3). A total of 3,194 diagnoses were included, with the 30 most frequent diagnoses provided in eTable 4.

We defined prevalent cases as those with least one eye clinic visit per calendar year. Thus, this approach considered uveitis as an episodic CSCR rather than a chronic disease. This conservative definition of prevalence includes patients who might need a check-up for CSCR or other ophthalmic problems each calendar year, and thus might be informative for ophthalmologists. To include all patients with CSCR based on this approach, we included patients diagnosed with CSCR from 2011 to 2015. The annual prevalence was calculated based on the total number of cases per year and the total population that qualified for NHIS-NSC on the first day of January of each year. Period prevalence and annual prevalence per 10,000 persons were estimated during 2011–2015 (eTable 5).

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eTable 1. Steroid use between 2002 and 2010 and Central Serous Chorioretinopathy.

Corticosteroid use between 2002 and 2010 Injection or Oral Eye drop External parenteral N (%) Person-year CSCR Incidence (95% CI) Hazard Ratio (95% CI) No use 169,378 (19.5) 803,741 232 2.9 2.5 - 3.3 1 (reference) Any use √ or √ or √ or √ 699,561 (80.5) 3,314,027 1191 3.6 3.4 - 3.8

Dosage Forms √ 15,113 (1.7) 70,287 18 2.6 1.6 - 4.1 √ 33,752 (3.9) 158,717 52 3.3 2.5 - 4.3 √ √ 5,242 (0.6) 24,220 7 2.9 1.4 - 6.1 √ 223,204 (25.7) 1,058,625 379 3.6 3.2 - 4.0 √ √ 51,547 (5.9) 241,668 106 4.4 3.6 - 5.3 √ √ 277,553 (31.9) 1,321,016 449 3.4 3.1 - 3.7 √ √ √ 91,380 (10.5) 430,958 174 4.0 3.5 - 4.7 ( √ or √ or √ ) √ 1,770 (0.2) 8,536 6 7.0 3.2 - 15.6

Total 868,939 (100.0) 4,117,768 1423 3.5 3.3 - 3.6

CI, confidence interval; CSCR, central serous chorioretinopathy. Inhaled corticosteroids were considered external use; intra-articular injections were included in the injection or parenteral use group.

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eTable 2 Incidence of central serous chorioretinopathy according to amount of oral steroid exposure (n=394,788)

Analyses Never ≤20 mg PL or >20 mg PL or steroid user equivalent dose equivalent dose Subjects (n) 169,713 110,486 114,589 Total follow-up (person-years) 805,281 522,608 544,809 Cases of CSCR (n) 232 177 203 Incidence (n/10,000 person-years) 2.9 3.4 3.7 Hazard ratio (95% CI) 1 (reference) 1.30 (1.06–1.58) 1.43 (1.18–1.74) P-value 0.01 <0.001 P for trend <0.001 CI, confidence interval; CSCR, central serous chorioretinopathy; PL, prednisolone

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eTable 3. Medical departments responsible for the prescription of corticosteroids in 2002

Code Department Number (%) 00 General physician 3967 (0.5) 01 Internal medicine 166935 (20.7) 02 Neurology 2333 (0.3) 03 Psychiatry 525 (0.1) 04 General Surgery 13853 (1.7) 05 Orthopedic Surgery 37719 (4.7) 06 Neurosurgery 3447 (0.4) 07 Chest Surgery 1304 (0.2) 08 Plastic surgery 31 (0.0) 09 Anesthesiology and Pain Medicine 909 (0.1) 10 Obstetrics and Gynecology 3970 (0.5) 11 Pediatrics 113022 (14.0) 12 Ophthalmology 71156 (8.8) 13 Otolaryngology 86366 (10.7) 14 Dermatology 251356 (31.1) 15 Urology 23140 (2.9) 16 Radiology 1218 (0.2) 17 Radiation Oncology 45 (0.0) 18 Pathology 66 (0.0) 19 Laboratory Medicine 289 (0.0) 20 Tuberculosis Department 818 (0.1) 21 Rehabilitation 1033 (0.1) 22 Nuclear Medicine 103 (0.0) 23 Family Medicine 22997 (2.8) 24 Emergency Medicine 1232 (0.2) 25 Occupational Medicine 361 (0.0) 26 Preventive Medicine 1 (0.0) 99 Missing 3 (0.0) 808199 (100.0)

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eTable 4. Thirty most frequent diagnoses associated with the prescription of corticosteroids in 2002

Diagnostic code Disease Freq. % L239 Allergic contact dermatitis, unspecified cause 46502 (5.8) L23 Allergic contact dermatitis 28014 (3.5) J209 Acute bronchitis, unspecified 24142 (3.0) J304 Allergic rhinitis, unspecified 18161 (2.2) J039 Acute tonsillitis, unspecified 16902 (2.1) L238 Allergic contact dermatitis due to other agents 16827 (2.1) L500 Allergic urticaria 15975 (2.0) J459 Asthma, unspecified 15759 (1.9) J00 Acute nasopharyngitis [common cold] 15209 (1.9) J20 Acute bronchitis 14888 (1.8) L20 Atopic dermatitis 14200 (1.8) J03 Acute tonsillitis 13711 (1.7) L209 Atopic dermatitis, unspecified 12528 (1.6) J029 Acute pharyngitis, unspecified 12374 (1.5) J069 Acute upper respiratory infection, unspecified 10158 (1.3) L309 Dermatitis, unspecified 10081 (1.2) H101 Acute atopic conjunctivitis 9074 (1.1) J310 Chronic rhinitis 8650 (1.1) L208 Atopic neurodermatitis 8194 (1.0) B300 Keratoconjunctivitis due to adenovirus 8015 (1.0) J02 Acute pharyngitis 7954 (1.0) J45 Asthma 7851 (1.0) J060 Acute laryngopharyngitis 7774 (1.0) J303 Other allergic rhinitis 6880 (0.9) L259 Unspecified contact dermatitis, unspecified cause 6879 (0.9) L249 Irritant contact dermatitis, unspecified cause 6827 (0.8) L50 Urticaria 6791 (0.8) B_ Masked diagnosis due to privacy policy 6664 (0.8) L509 Urticaria, unspecified 6648 (0.8) L21 Seborrheic dermatitis 6548 (0.8) Others 418019 (51.7) Total 808199 (100.0)

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eTable 5. Prevalence of central serous chorioretinopathy per 10,000 individuals during 2011–2015 in South Korea

Both Sexes Men Women Male Year Persons n Prevalence (95% CI) Persons n Prevalence (95% CI) Persons n Prevalence (95% CI) to female ratio 2011 808,741 444 5.5 5.0 - 6.0 399,682 336 8.4 7.5 - 9.3 409,059 108 2.6 2.2 - 3.2 3.2 2012 818,136 469 5.7 5.2 - 6.3 404,496 347 8.6 7.7 - 9.5 413,640 122 2.9 2.5 - 3.5 3.0 2013 827,172 491 5.9 5.4 - 6.5 409,153 381 9.3 8.4 - 10.3 418,019 110 2.6 2.2 - 3.2 3.6 2014 836,381 514 6.1 5.6 - 6.7 414,073 396 9.6 8.7 - 10.5 422,308 118 2.8 2.3 - 3.3 3.4 2015 845,263 618 7.3 6.8 - 7.9 418,669 457 10.9 9.9 - 12.0 426,594 161 3.8 3.2 - 4.4 2.9

Overall 827,139 507 6.1 5.9 - 6.4 409,215 383 9.4 9.0 - 9.8 417,924 124 3.0 2.7 - 3.2 3.1 CI, confidence interval

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