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The Great Debate: Plaquenil - Choosing Safety over Efficacy?

I am usually thrilled to offer Plaquenil as one of the safer  therapy options to my patients with lupus and other autoimmune conditions. Unfortunately, on many occasions, once we go into detailed discussion of the potential side effects with the patient,  the issue of hydroxychloroquine eye toxicity casts a cloud over  overall optimistic view of Plaquenil. Not once or twice a patient of mine would come back for a follow up worried or even stop their treatment after visiting their ophthalmologist. As per ophthalmology guidelines published in JAMA  the dose of hydroxychloroquine shall not exceed 5 mg/kg/d for all patients, which is lower than a standard 200 mg bid for most. So what’s the right way to go? Do we lower the dose and sacrifice efficacy or shall we not follow the guidelines assuming that benefits outweigh risks. Today’s great debate addressed the issue of Plaquenil eye toxicity and dose adjustment.
 
As per French multicenter PLUS trial, although lower blood Plaquenil levels were associated with higher SLE activity, adjusting the dose did not decrease frequency of flares at 7 months follow up.
 
On the other hand, multiple studies on Plaquenil compliance conclude majority of lupus patients are not compliant with their hydroxychloroquine regimen. As per one of the studies [1]  85% of the patient were not compliant with daily plaquenil regimen. Study concluded that theoretically one would need to prescribe a mean of 11.1 mg/kg of plaquenil in order to have 5 mg/kg collected at the pharmacy. 
 
In a course of the debate Dr. James T. Rosenbaum from Oregon Health & Science University and Legacy Devers Eye Institute strongly advocated adherence to the guidelines of the American academy of ophthalmology as follows:
  • max dose of HCq shall not exceed 5 mg/kg actual weight
  • Obtain baseline and screen annually at 5 years
  • OCT and visual fields are the mainstay of screening
  • Other screening methods: autofluorescence or ERG
Dr. Rosenbaum provided significant evidence supporting the guidelines. Many studies presented in his presentation suggest that 5.2 -9.7% of the patients ( depending on the study) develop hydroxychloroquine retinopathy with long term use of the medication. In one of the studies from South Korea [2] eye toxicity was seen with average dose of Plaquenil as low as 284 mg/ daily. 
 
Based on a British study[3], over half of individuals on HCQ are treated with higher than dose suggested by the  guidelines. 
Finally the issue of potential cardiac toxicity was brought up, where conduction defects and AFib were main concern. One of the studies associated HCQ with increase risk of heart failure ( HR 3.61, CI 1.23-10.63), ( ABST2145 Increased Risk of Heart Failure with Prolonged Use of Hydroxychloroquine in Patients with Rheumatoid Arthritis, presented at this meeting). 
 
On the other hand, Dr. Michelle Petri from the Johns Hopkins University School of Medicine argued that current hydroxychloroquine dose guidelines are not appropriate. In her review of the guidelines Dr. Petri noted that from the publications itself “.. it is no clear that there is any truly ‘safe’ dosage for long duration of use”.
 
By using tamoxifen related eye toxicity as an example, Dr. Petri argued that in certain cases benefit outweighs the risk and our concern about higher doses of HCQ is often driven by our fear of blindness. Dr. Petri referred to the results of the  study in prevalence of blindness in a cohort of rheumatologic patients treated with hydroxychloroquine by Dr. Singh et al. As per this study, blindness was associated with diagnoses other than HCQ toxicity in majority of the patients ( 27% stroke, 18% diabetic retinopathy etc). In this study only 3/31 patients had signs of HCQ toxicity. Dr. Petri stressed that even though long term risk is there, we shall also think of short term benefits of HCQ in controlling active disease. While dose reduction over time to prevent toxicity might be appropriate, it is not always safe for the patient to lower the dose early in the course of the disease, especially if manifestations of the disease are severe and not optimally controlled otherwise. As per nested case-controlled study conducted by Dr. Petri in 1995, renal involvement occurs in 36% of the SLE patients in the first year and SLE patients on HCQ less likely to develop new renal involvement (OR 0.35). It was reminded to us that HCQ is the only medication that improves survival in SLE. At the conclusion of her presentation Dr. Petri suggested that with the use of new monitoring technologies and measuring blood HCQ levels, use of Plaquenil can be relatively safe and beneficial in the dose of 6.5 mg/kg ( no more than 400 mg/ daily). 
 
From this truly great debate I learned that there are pros and cons in both approaches but at the end of the day it is about weighing risk and benefit ratio, monitoring closely and deciding on case by case basis. While guidelines are there to guide us, the decision has to be made by the care team and the patient for the patient's’ best benefit. 
 
References:
1. Dynamic Patterns and Predictors of Hydroxychloroquine Nonadherence Among Medicaid Beneficiaries With Systemic Lupus Erythematosus
Candace H Feldman et al. Semin Arthritis Rheum. 2018 
2. Frequency and Clinical Characteristics of Hydroxychloroquine Retinopathy in Korean Patients with Rheumatologic Diseases
Doo-ri Eo, Min Gyu Lee, [...], and Sang Jin Kim. J Korean Med Sci. 2017 Mar; 32(3): 522–527.Published online 2017 Jan 23.
3. Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines. April M. Jorge, Ronald B. Melles, Yuqing Zhang, Na Lu, Sharan K. Rai, Lucy H. Young, Karen H. Costenbader, Rosalind Ramsey-Goldman, S. Sam Lim, John M. Esdaile, Ann E. Clarke, M. B. Urowitz, Anca Askanase, Cynthia Aranow, Michelle Petri and Hyon Choi. Arthritis Research & Therapy201820:133

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