Purpose
To determine the impact of the revised academy guidelines on screening for hydroxychloroquine retinopathy.
Design
Retrospective, observational cohort study.
Methods
setting : Private practice of 29 doctors. study population : Total of 183 patients for follow-up and 36 patients for baseline screening. observation procedure : Review of charts, 10-2 visual fields (VFs), multifocal electroretinograms (mfERG), and spectral-domain optical coherence tomography (SD-OCT) images before and after the revised guidelines. main outcome measure : Rates of use of ancillary tests and clinical intervention, costs of screening, follow-up schedules, and comparative sensitivity of tests.
Results
New hydroxychloroquine toxicity was found in 2 of 183 returning patients (1.1%). Dosing above 6.5 mg/kg/d was found in 28 of 219 patients (12.8%), an underestimate because patient height, weight, and daily dose were not determined in 77 (35.1%), 84 (38.4%), and 59 (26.9%), respectively. In 10 of the 28 (35.7%), the dose was reduced, in 2 (7.1%) hydroxychloroquine was stopped, but in 16 (57.1%) no action was taken. The cost of screening rose 40%/patient after the revised guidelines. Fundus autofluorescence imaging was not used. No toxicity was detected by adding mfERG or SD-OCT. In no case was a 5-year period free of follow-up recommended after baseline screening in a low-risk patient.
Conclusions
Detection of toxic daily dosing is a cost-effective way to reduce hydroxychloroquine toxicity, but height, weight, and daily dose were commonly not checked. The revised guidelines, emphasizing mfERG, SD-OCT, or FAF, raised screening cost without improving case detection. The recommended 5-year screening-free interval for low-risk patients after baseline examination was ignored.
In 2011, an American Academy of Ophthalmology committee published revised guidelines concerning screening for hydroxychloroquine toxicity. Previous guidelines had been published in 2002. The 2011 guidelines recommend a baseline examination at onset of therapy that should include macular static perimetry (eg, the Humphrey 10-2 visual field [10-2 VF]) and at least 1 of multifocal electroretinography (mfERG), spectral-domain optical coherence tomography (SD-OCT), or fundus autofluorescence (FAF) if these latter 3 ancillary tests are available. If a patient has low risk for retinopathy, follow-up examinations were recommended beginning at 5 years of therapy. If a patient has high risk, follow-up examinations were recommended annually. It was recommended that daily doses should “be limited to 400 mg hydroxychloroquine…and that lower doses (in the range of 6.5 mg/kg/d of hydroxychloroquine…calculated on the basis of ideal body weight) be used for individuals who are of short stature.”
High-risk eyes are defined as those with duration of use >5 years, those with >1000 g total hydroxychloroquine consumption, >6.5 mg/kg/d daily dosing, increased age (with no cut point specified), concomitant renal or liver disease, or preexisting maculopathy.
The recommendation to add the 3 additional ancillary screening tests arose from a hope of detecting cases of hydroxychloroquine toxicity earlier, but in practice there are few data to test this premise. Moreover, most screening for hydroxychloroquine retinopathy is done by comprehensive ophthalmologists and optometrists. It is uncommon for these clinicians to obtain and interpret mfERG, SD-OCT of the macula, and FAF for other reasons, whereas they commonly obtain and interpret static perimetry in their care of glaucoma patients. Therefore, it is reasonable to ask how the recommendation to use these tests has succeeded in its implementation, considering their interpretational subtleties and the potential for artifacts. In addition, the revised guidelines could add to the cost of care. The purpose of the present study was to estimate the impact of the new guidelines on detection of hydroxychloroquine toxicity in actual practice, ophthalmologists’ actions relative to hydroxychloroquine treatment, and screening cost.
Methods
This was a retrospective, observational cohort study. Waiver of informed consent and waiver of HIPAA authorization was approved by the Presbyterian Hospital institutional review board. The revised guidelines were published in February 2011. The medical records of 219 patients undergoing hydroxychloroquine screening in a multispecialty ophthalmology practice of 26 ophthalmologists and 3 optometrists between May 3, 2011 and June 12, 2012 were reviewed using a prespecified template for the extraction of data. One hundred eighty-three of the 219 patients had been screened in previous years before the revised guidelines were published and then again after they were published. Therefore, in this subset the impact of the revised guidelines on screening practice could be isolated as the only variable that had changed. Thirty-six of the 219 patients were screened for the first time. Because SD-OCT and mfERG had not been used in this practice for hydroxychloroquine screening before publication of the revised guidelines (data not shown), analysis of this subset allowed determination of the impact of the revised guidelines on baseline examinations.
The list of patients was obtained by querying the electronic medical records for the practice using as a search term the International Classification of Diseases (ICD)-9 code V58.69. Data extracted from the charts included sex, age, diagnosis, date hydroxychloroquine was started, hydroxychloroquine dose and changes over time, ancillary tests used, height, weight, preexisting macular abnormalities, macular changes, recommended follow-up interval, and action taken by the ophthalmologist or optometrist.
Patient height and weight were self-reported. Top normal body weight was generally calculated from height by clinicians based on the National Heart Lung and Blood Institute table, but occasionally with a different formula. For the purposes of this paper, adjusted daily dosing means the daily dose divided by the lesser of the ideal body weight associated with the patient’s height or the actual body weight. Doses >6.5 mg/kg/d are referred to as “potentially toxic,” not because lower doses cannot be associated with maculopathy, but because of the acknowledged higher risk of doses in this range. In this paper, doses ≤6.5 mg/kg/d are referred to as “typically nontoxic,” not because doses in this range cannot be associated with maculopathy, but because they typically are not.
All of the recommended ancillary testing modalities mentioned in the revised guidelines were available in the practice if they were desired by the screening clinician. If 10-2 VF, mfERG, or SD-OCT were obtained, the studies were interpreted by the author and compared with the interpretation of the ordering clinician. Although FAF was available, no patient had this test. In patients receiving follow-up screening, the ancillary tests obtained after the publication of the revised academy guidelines were compared with those obtained before their publication.
The only ancillary tests considered for this study were 10-2 VF, mfERG, SD-OCT, and FAF. Some patients had color vision testing, fluorescein angiograms, time-domain OCT, and Amsler grid testing, but all of these tests have been shown to be insensitive for the detection of hydroxychloroquine toxicity and none are currently recommended. Some 10-2 VFs were obtained with a red test object and others with a white test object. For this paper, results from both 10-2 VF protocols have been pooled.
In the interpretation of mfERG in the context of hydroxychloroquine toxicity screening, various criteria for toxicity have been used, including critical values for amplitude, implicit time, and ring ratios. In this study, the criterion for toxicity used was an R1/R2 ratio >2.6. In interpreting the SD-OCT in the context of screening for hydroxychloroquine toxicity, various criteria have been used including perifoveal loss of the inner segment / outer segment junction and generalized macular thinning. We used loss of the perifoveal inner segment / outer segment junction and discontinuity of the RPE layer.
Costs for screening regimens were determined from Medicare reimbursements in North Carolina during 2011. Reimbursement for a comprehensive eye examination (Current Procedural Terminology [CPT] 92014), mfERG (CPT 92275), SD-OCT (CPT 92134), and 10-2 VF (CPT 92083) during 2011 were $112.15, $136.88, $43.01, and $81.17, respectively.
Results
Characteristics of the patients and eyes reviewed are listed in Table 1 . Of the 219 patients screened, 36 (16.4%) were for baseline examinations and 183 (83.6%) were for follow-up examinations. Women made up 91.3% (200/219) of those screened. Seventy-six percent (166/219) of patients took hydroxychloroquine for systemic lupus erythematosus or rheumatoid arthritis. Factors that place a patient at higher risk include preexisting macular disease, concomitant renal or liver disease, higher age, and duration of therapy greater than or equal to 5 years. Preexisting macular disease was present in 19.2% (84/438) of eyes, primarily as a manifestation of age-related macular degeneration. No patient had concomitant renal or liver disease. The age threshold at which risk of toxicity increases has not been defined, but 25% (55/219) of patients in this study were 70 years or older.
| Characteristic | Statistic |
|---|---|
| Type of screening examination a | |
| Initial hydroxychloroquine screening examination | 36 (16.4%) |
| Follow-up hydroxychloroquine screening examination | 183 (83.6%) |
| Age a | Median 62 y; IQR 50, 70; range 16, 90 |
| Women a (n, %) | 200 (91.3%) |
| Number of doctors screening patients | 29 (26 MDs, 3 ODs) |
| Number of patients screened/doctor | Median 8; IQR 4, 14 |
| Diagnosis of patients screened a | |
| Systemic lupus erythematosus | 87 (40%) |
| Rheumatoid arthritis | 79 (36%) |
| Other b | 53 (24%) |
| Macular descriptions c | |
| Normal | 354 (80.8%) |
| Drusen | 42 (9.6%) |
| RPE pigmentary changes | 25 (5.7%) |
| Microaneurysms and/or dot hemorrhages | 10 (2.3%) |
| Epiretinal membrane | 6 (1.4%) |
| Macular hole | 1 (0.2%) |
| Concomitant renal or liver disease a | 0 |
a Based on 219 patients screened.
b Nonspecific arthritis, dermatomyositis, granuloma annulare, polymyalgia rheumatica, psoriatic arthritis, sarcoidosis, Sjögren syndrome, scleritis, panniculitis.
Before publication of the revised guidelines, 180 of 183 patients (98.4%) returning for follow-up screening examinations had 10-2 VFs, and no patient had mfERG, SD-OCT, or FAF. After publication of the revised guidelines, 178 of 183 patients (97.3%) had 10-2 VFs, 86 of 183 (47.0%) had mfERGs, and 59 of 183 (32.2%) had SD-OCTs. For initial screening examinations after publication of the revised screening guidelines, 36 of 36 patients (100%) had 10-2 VFs, 17 of 36 (47.2%) had mfERGs, and 12 of 36 (33.3%) had SD-OCTs.
Follow-up appointments were equally divided between 6 and 12 months. No patient was scheduled for a 5-year follow-up–free interval after an initial screening examination even if the patient had low-risk characteristics as defined by the revised guidelines.
Of 183 patients undergoing follow-up screening examinations, 14 (7.7%) received an intervention by the screening clinician ( Table 2 ). For 12 of the 183 patients (6.6%), a dosage reduction was recommended to the prescribing physician based on dosing considered by the screening clinician to be in a toxic range; and for 2 patients (1.1%), cessation of hydroxychloroquine was recommended because of clinical toxicity discovered on the screening examination. Results of macular perimetry, mfERG, and SD-OCT tests for the 2 patients with hydroxychloroquine toxicity are shown in Figures 1 through 7 . For both patients with hydroxychloroquine toxicity, the macular static perimetry was abnormal ( Figures 1, 2, 4, and 7 ). No cases of hydroxychloroquine toxicity were detected by the addition of mfERG or SD-OCT to the screening regimen. The mfERG confirmed toxicity indicated by macular perimetry in Patients 1 and 2 ( Fig 3 and Fig 6 ) and the SD-OCT confirmed toxicity indicated by the 10-2 VF in Patient 2 ( Figure 5 ). Toxic daily dosing was present in 12 of 14 patients (85.7%). In 8 of these 12 (66.7%), the toxic dosing was based on the ideal body weight associated with height ≤63 inches. However, in 4 of the 12 patients (33.3%), the toxic dosing was based on an actual body weight that was less than the ideal body weight associated with height. That is, for asthenic patients, calculating dosing based on ideal body weight associated with height would have led to missing the presence of toxic dosing.
| Pt # | Action | Ex | Age (y) | Dur (y) | Ht (in) | Wt (lb) | ADD (mg/kg/d) | Cum Dose (g) | 10-2 VF | mfERG R1/R2 | SD-OCT | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OD | OS | OD | OS | OD | OS | |||||||||
| 1 | SHC | F | 87 | 17.2 | 64 | 118 | 7.5 | 2506 | Abn c | Abnl c | 2.63 | 1.23 | Nd | Nd |
| 2 | SHC | F | 65 | 8.3 | 62 | 180 | 6.7 | 1214 | Abnl | Abnl | Nd | Nd | Abnl | Abnl |
| 3 | RD | l d | 40 | 0 | 59 | 225 | 7.4 | 0 | N | N | Nd | Nd | N | N |
| 4 | RD | F | 77 | 8.4 | 63 | 112 | 7.9 | 1231 | N | N | Nd | Nd | Nd | Nd |
| 5 | RD | F | 57 | 4.7 | 61 | 112 | 7.9 | 681 | N | N | 1.83 | 1.61 | Nd | Nd |
| 6 | RD | F | 73 | 3.7 | 62 | 115 | 7.7 | 538 | N | N | 2.08 | 2.18 | Nd | Nd |
| 7 | RD | F | 58 | 7.7 | 62 | 175 | 6.7 | 1122 | N | N | 1.94 | 1.75 | N | N |
| 8 | RD | F | 58 | 15.7 | 62 | 150 | 6.7 | 2295 | Abnl | Abnl | Art | 1.46 | N | N |
| 9 | RD | F | 66 | 9.7 | nd | 105 | 8.4 a | 1419 | N | N | 2.17 | 1.90 | N | N |
| 10 | RD | F | 62 | 5.8 | 64 | 210 | 6.3 b | 846 | N | N | Nd | Nd | Nd | Nd |
| 11 | RD | F | 38 | 10.8 | 65 | 130 | 6.8 | 1580 | N | N | 1.92 | 1.86 | Nd | Nd |
| 12 | RD | F | 50 | 5.9 | 63 | 114 | 7.7 | 855 | N | N | 1.66 | 2.73 | N | N |
| 13 | RD | F | 74 | 4.9 | 64 | 147 | 6.3 b | 712 | N | N | 2.31 | 1.90 | N | N |
| 14 | RD | F | 58 | 4.9 | 67 | 134 | 6.6 | 719 | N | N | 1.27 | 1.37 | N | N |
| 15 | RD | F | 36 | 0.9 | 60 | 104 | 8.5 | 135 | N | N | 2.18 | 2.07 | N | N |
a Adjusted dosing calculated in this case based on the actual body weight alone.
b Dosing reduced by the clinician although adjusted daily dose was <6.5 mg/kg/d.
c Clinician used 24-2 rather than 10-2 VF.
d A 15th patient was seen for an initial examination only, but not for a follow-up examination.
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