Friday, 16 Nov 2018

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Hydroxychloroquine Dosing: the Great Debate

Rheumatologists tend to be a conservative bunch of people. We’re law abiding and we (mostly) follow guidelines. Which is fine when they are in the best interests of our patients, but what do we do when we fundamentally disagree?

I have been following some of the literature in Ophthalmology over the past few years in which it has been suggested that the risk of retinal toxicity is much higher than we had previously thought. The new guidelines issued from the American association of Ophthalmologists suggested dosing below 5mg/kg total body weight replacing previous guidelines of dosing below 6.5mg/kg ideal body weight. They recommended screening at baseline, at five years and annually thereafter. They also specified that OCT should be part of the retinal screening programme. Their guidelines were based on 3,482 Kaiser Permanente patients taking HCQ for at least 5 years.

On Sunday, Dr. Michelle Petri argued passionately that in patients with SLE there is a very strong reason NOT to adopt these guidelines. On Tuesday afternoon she presented the results of a study in which her unit carried out assays of HCQ blood levels. She found that most of those who were taking doses greater than 5mg/kg/d HCQ did not have increased drug levels. Dr Costedoat-Chalumeau had presented data suggesting that in a survey of over 10,000 patients over 85% were non adherent but Prof Petri thinks that there may also be genetic influences. She did find evidence that the highest tertile of blood levels were associated with an increased risk of retinopathy. She also found that retinopathy was actually more common in obese patients BMI >35 rather than those with a BMI <25. In addition, she confirmed older concerns that patients over the age of 60 are at higher risk and should be considered for reduced dosing. Prof Petri presented powerful arguments to remind us of the health benefits of HCQ in SLE which reduces mortality by over 50% both from reduced cardiovascular disease and reduced Lupus flares. She showed data from her Lupus cohort (475 patients) in John Hopkins – in this group who have retinopathy screening as standard, the risk of retinopathy stayed steady at 2-3% for the first 15 years before climbing to an 11% rate at 16-20 years and 9% >21 years. So I think we can conclude that the hard data provided by Professor Petri will give us pause for thought before we reduce the dose in our patients with moderate to severe SLE.

Of course, many physicians also have large numbers of patients on HCQ for rheumatoid arthritis, and in this group it is much harder to defend maintaining patients on high doses of HCQ for prolonged periods. We have recently looked at HCQ dosing as a quality improvement project in our practice and found around 20% needed to have a dose reduction to come down to the new guideline dosage level of 5mg/kg/d. There were four posters on this topic that caught my eye.

Abstract 1181: Dr Goel (California) used a registry to examine the dosage of HCQ given to 162 patients with SLE. They found that 41% were on doses greater than 5mg/kg. 23 patients were on greater than 6mg/kg and 6 were on more than 7mg/kg. Only 26 patients in this cohort were not being prescribed HCQ.

Abstract 1243: Dr Jessee (Duke Uni) undertook a Quality improvement (QI) project to improve compliance with dosing guidelines for HCQ. Over two thirds of the prescribers interviews said they had little or no concern about the new guidelines. Almost a quarter of prescribers had seen a patient suffer an adverse clinical outcome after reducing HCQ dosage. They analysed 1218 encounters where HCQ was prescribed, and two thirds of patients were taking a dose of 400mg/kg. Most patients had SLE (39%), followed by RA (27%) and UCTD (16%). They found that at the start of the project 27% were on doses in excess of 5mg/kg, reducing to 17% after the QI project began. Perhaps reassuringly, ‘non compliance’ with the dosing guidelines was greatest in the group with SLE.

Abstract 1244: Dr Kaeley (Jacksonville) assessed 436 patient records on an EHR. They found that 24% of patients were being prescribed doses greater than 5mg/kg/day. Twenty patients were on greater than 7mg/kg/day. When they reviewed records a year later they found that the number of patients receiving doses had fallen to 17% (this was a much smaller subset of the original total).

Abstract 1246: Dr Shaukat (Albany) reported very similar findings from a chart review of 248 records. They found that an eye exam had only been documented in only 49% of cases reviewed – only four of seven patients ‘overdosed’ on HCQ had an eye exam. They also reported that one patient had developed retinal toxicity and had been taking 7.5mg/kg/d.

So what are the take-home messages for the practicing clinician? I think that Hydroxychloroquine is a great drug, but over the years I have seen three patients develop retinal damage in spite of adherence to the ‘old’ guidelines. I think that this is a good topic for a QI project: where we decide to continue dosing above the guidelines we need to document our discussion with the patient and our reasons for doing so. We also need to make sure that these patients are being screened strictly by the guidelines: Professor Petri’s patients are all being carefully screened and drug levels monitored (a luxury not available to us). I will certainly be very cautious about reducing dosage in patients with moderate to severe SLE, but I will be much more ready to do so in my RA patients in whom other excellent alternatives are available.

I hope that this summary is of some interest to you. The opinions expressed here are my own, and I would encourage you to examine the issues from other perspectives on

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