Hydroxychloroquine (Plaquenil) Update

The antimalarials—Aralen (chloroquine, Sanofi) and Plaquenil (hydroxychloroquine, Sanofi)—are widely used in rheumatologic care, particularly for rheumatoid arthritis and systemic lupus erythematosus. Since prescribing doctors are generally aware of the retinotoxic potential of these drugs, patients are usually requested to see an eye doctor for baseline evaluation and follow-up surveillance.

plaquinilMost patients are placed on Plaquenil, the slightly less toxic of the two. The usual dosage is two 200mg tablets per day. This is generally a "safe" dose for patients having a lean body weight of at least 135 lbs. The generally-regarded safe dosage is 6.5mg/kg/qd, thus the 135 lb. safety threshold. When a person's lean body weight is less than 135 lbs., the prescribing doctor should consider reducing the total daily dose. In patients weighing less than 135 lbs., it may require the gentle counsel of the eye doctor to bring this potentially touchy issue to the prescribing doctor's attention. Just as many eye doctors still use timolol 0.5% bid, so too do many rheumatologists continue to prescribe Plaquenil at 200mg bid—regardless of the patient's lean body weight. We all need to become more precise prescribers.

New Insights into Hydroxychloroquine (Plaquenil) Retinotoxicity

Two new articles1, 2 further refine our understanding of the retinotoxic risks of Plaquenil usage, and also provide new insights into patient evaluation and follow-up care.

It is well understood that hydroxychloroquine (HCQ) has the potential to cause irreversible central vision loss. It is standard-of-care for patients being treated with HCQ to have a baseline retinal evaluation within a few months of initiation of therapy.

Since there is no known means available to diagnose toxic damage before some minor permanent damage has occurred, it is critical to assess risk factors for HCQ toxicity, thoroughly educate our patients, and perform appropriate screening measures in a timely manner. Known risk factors are:

  • Daily dosage of HCQ exceeding 6.5mg/kg (that is, a daily dosage not to exceed 400mg in patients having a lean body weight of < 135lbs.)

  • Obesity. We stress here that HCQ is not absorbed into adipose tissue. This means that an obese person who weighs 160lbs may be considered within the "safe" zone, but their lean body weight may be only 120lbs, which poses an increased relative risk. We have communicated this critical issue of lean body weight to our referring rheumatologists and dermatologists, and have asked them to assess the lean body weight of each of their HCQ patients and make this information known to us, so that we can more accurately assess the risk for retinotoxicity. The formula for women (the vast preponderant gender prescribed HCQ) is: 1.07 x weight – 1.48 x (wt2/100 x height in meters2). As mathematically-challenged individuals, you can appreciate why we chose to place the burden of lean body weight determination on the shoulders of the prescribing physician! After all, they must know this information in order to properly prescribe the medicine.

  • Duration of use longer than 5 years. It is now more firmly established that duration of exposure (i.e., cumulative dose) portends more retinotoxic risk than daily intake. In fact, prevalence of toxic expression is quite limited within the first 5 years of use, and the risk "increased sharply after 5-7 years to approximately 1%." So, it appears that initial screening during the first 5 years of therapy can be rationally relaxed in those patients not having significant risk factors, but beginning about Year 5, as dosage accumulates, more frequent (usually annually) assessments should be performed.

  • Renal or hepatic functional impairment. Compromised kidney and/or liver function can lead to increased accumulation of HCQ in the tissues, so that the health status of these organs should be assessed by the prescribing physician.

  • Age >60 years. "Patients older than 60 years, and with a duration of treatment greater than five years appear to be at greater risk for retinal toxicity."

  • Preexisting retinal disease. It stands to reason that any clinically significant retinomacular tissue compromise could place these delicate tissues at increased risk from HCQ exposure. Such patients may have a contraindication to HCQ use, or at least a lower dose should be tried.

Most physicians, in our vast experience, prescribe the usual 400mg q day dosage. However, because of this drug's long residence time in the blood and tissues, the clinical effects build up slowly. This unique pharmacology allows for intermediate dosing, which is easily achieved by varying the daily dosage. "For example, 300mg daily results from taking 200mg and 400mg on alternate days." It was stated in a 2002 article3 that: "These drugs are typically prescribed by internists, rheumatologists, and dermatologists who may not be fully aware of the ophthalmic implications." Another 2002 article4 stated: "Under circumstances of proper dosing, screening could be rationally discontinued." While this is probably true for almost all patients, there may be a few patients who are indeed properly dosed, yet because of individual idiosyncrasies and variability, may still develop toxicity.

So how do we evaluate patients for early toxic effects? It must be stressed that no mechanism exists to detect ocular damage from HCQ before it occurs. We can only try to detect such damage at its earliest manifestation. Functional compromise occurs before any ophthalmoscopically visible changes can be seen. The Gold Standard has been, and continues to be, a central 10-degree visual field test to look for repeatable central and paracentral scotomas. As with any other visual field test, one must bear in mind that there can be a lot of subjective variability; thus if there are any suspicious defects, a second visual field test should be performed within a few weeks to determine if the same defects are still present. The Amsler grid is supra-threshold, and is of no value in the setting of HCQ screening. We use the Humphrey visual field 10-2 test for all of our HCQ patient evaluations.

New, as of 2011, is the addition of one or more objective assessments, such as spectral domain OCT, multifocal electroretinogram, and fundus autofluorescence. Of these, the most practical and most accessible is the SD-OCT, and it is our recommended instrumentation. These spectral domain scans can reveal localized thinning in the parafoveal region. (The earlier generation, time-domain instruments, do not have the resolution to enable meaningful quantification of these crucial retinal tissues.) It is thought that these objective assessments may even be a bit more sensitive to tissue compromise than the 10-2 visual field test.

In summary, it is of paramount importance to inform HCQ patients of the remote (<1%) chance of a problem. Furthermore, it should be stressed that it is in detecting the earliest possible expression of damage that further, irreversible vision loss can be prevented. The patient should understand that risk is extremely low during the first five years of HCQ therapy, but that continued use beyond five to seven years confers an increasing risk (up to about 1%) for retinomacular tissue damage.

Bottom line: assess vision, baseline macular abnormalities, 10-2 visual field testing with a white target, and if at all possible, try to obtain a paramacular scan with an SD-OCT. Then follow these patients probably annually, particularly after five years of drug exposure.

1 Michaelides, M., et al. "Retinal Toxicity Associated with Hydroxychloroquine and Chloroquine." Arch. Ophthalmic. Vol. 129, No. 1 January, 2011

2 Marmor, M. F., et al. "Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy." Ophthalmology, Vol. 118, No. 2, February, 2011

3 Marmor, M. F., et al. "Recommendations of Screening for Chloroquine and Hydroxychloroquine Retinopathy." Ophthalmology, Vol. 109, No. 7, July, 2002

4 Browning, D. J. "Hydroxychloroquine and Chloroquine Retinopathy: Screening for Drug Toxicity." AJO, Vol. 133, No. 5, May, 2002

Evaluating the Plaquenil patient. The literature discusses a variety of approaches in assessing patients sent in for Plaquenil evaluations. In keeping with our modus operandi of clinical simplicity, here's our protocol. It's as simple as 1-2-3-4.

  1. Best visual acuity.
  2. Dilated ophthalmoscopic examination of the macular and paramacular tissues.
  3. Zeiss-Humphrey visual field 10-2 testing (using standard white stimulus).
  4. Spectral domain OCT nerve fiber layer analysis (if possible)

Posterior pole photodocumentation is optional if the macular tissues are completely normal. If the macular tissues are not completely normal at baseline, obtain fundus photography in order to maximize monitoring for any changes that may occur in these tissues in the future. In the event of suspicious RPE findings (or changes), additional retinal evaluations my be indicated..

Frequency of follow-up. This is a difficult call, and is commonly influenced by the number of years of HCQ exposure. It is also dependent, to some degree, on how the prescribing doctor has portrayed the risk of ocular side effects to the patient.

plaquinel-picFor newly treated patients with normal baseline findings and a lean body weight well above 135 lbs., we recommend annual visits. Obviously, the less the patient weighs (below 135 lbs.), the closer we tend to schedule the follow-up visits. We do all we possibly can to get the prescribing physician to reduce therapy in these situations. As noted above, there is an inverse relationship between the patient's weight (below 135 lbs.) and our persistence in educating and encouraging the prescribing physician to reduce the patient's daily dose of Plaquenil. Our primary approach here is to send the doctor copies of authoritative articles supporting our recommendation.

It is always a challenge for us to make clinical care simple because of the numerous confounding variables, such as the patient's anxiety level, status of the macular tissues at baseline, expectations of the referring physician, years of cumulative exposure, dosage, weight,
etc. In almost all clinical circumstances, patient management must be plaquenil-eye1individualized.

In all of our years of clinical practice, we have seenexceedingly few patients who demonstrated maculopathy, and those had been chronically overdosed for several years. We have seen no cases of toxicity when the 6.5mg/kg/qd threshold was honored; however, in biological systems, there are no absolutes.


Plaquenil Form (.pdf file - updated 3/16/17)