Hydroxychloroquine is the cornerstone of the medical management of systemic lupus erythematosus (SLE). It has been shown in multiple SLE populations to associate with improved survival (1-3) and specifically has been found to be effective in the treatment of cutaneous disease(4), arthritis(5), with an augmenting effect on the efficacy of mycophenolate mofetil in the management of nephritis(6) amongst other positive health effects(7, 8).
Hydroxychloroquine is a safe, non-immunosuppressive therapy with good tolerability. However, there are increasing concerns about retinopathy, in particular, in light of new screening methods, which are thought to have increased sensitivity(9). There is also significant controversy surrounding how to best dose this medication, with some advocating dosing based on actual body weight (capped at 400 mg per day), whilst others are in favor of calculating the daily dose based on ideal body weight. A further challenge in SLE is medication adherence(10), which is especially pertinent given that immunosuppression is often increased without the knowledge about whether baseline medications are being taken.
Hydroxychloroquine blood levels can be quantified by high performance liquid chromatography (11), which is a widely available means of measuring drug concentrations. It is also possible to measure serum levels but for reasons of pharmacokinetic stability and reliability, whole blood is preferable (12).
Here, we review the available literature, with a particular focus on the recent findings in the Hopkins Lupus Cohort (13), regarding the clinical utility of hydroxychloroquine blood levels in helping to clarify some of the above issues.
Hydroxychloroquine dosing is important to ophthalmologists as well as rheumatologists due to the drug’s rare association with retinopathy(14). At present, there is no data which links hydroxychloroquine blood levels with retinal toxicity. The known risk factors for the development of ocular deposition include duration on therapy, cumulative dose and renal function(9).
The American Academy of Ophthalmology (AAO) advises weight-based dosing of 6.5 mg/kg, with an upper limit of 400 mg/day. Exceptions are individuals of short stature and obese patients, for whom the AAO advises calculating dosage based on ideal body weight for height(15). The high prevalence of obesity amongst our patients mean that there is significant confusion regarding the most appropriate means of calculating daily hydroxychloroquine doses.
Uncertainty also exists regarding the best means of screening for retinal abnormalities. Current AAO guidelines advise monitoring beyond the dilated retinal examination and automated visual field testing, in an attempt to identify toxicity early and include one or more of the following: spectral domain optical coherence tomography (SD-OCT), multifocal electroretinogram (mfERG), and fundus autofluorescence (FAF)(15). The sensitivity and specificity of these tests are not yet known for hydroxychloroquine related retinal toxicity. There is a high rate of baseline abnormalities, in particular in those who are elderly or have comorbid disease, which make the changes challenging to interpret. Another issue is that SLE itself associates with the presence of retinal abnormalities, adding further to the complexity of deciphering these tests.
Regarding the dosing of hydroxychloroquine, we advocate the use of a weight based dosing regimen with a cap at 400 mg per day, except in the case of renal insufficiency, when the dose should be reduced to 200 mg per day and for those on dialysis, who should take their hydroxychloroquine, 200 mg three times per week. To evaluate the performance of this regimen, we followed patient’s hydroxychloroquine blood levels and found that blood levels were not significantly different when individuals were stratified by either BMI, actual or ideal body weight(16). Specifically, addressing those who were obese (BMI over 30, 215/686 individuals) and those of short stature, (<60 inches, 66/686 individuals) there were no differences demonstrated in terms of hydroxychloroquine blood levels.
We consider this supportive of dosing based on actual body weight (6.5 mg per kg with a cap at 400 mg per day). From a practical perspective, this means the daily dose should be reduced, from 400 mg per day, for those weighing less than 61 kg (134lbs).
Hydroxychloroquine Blood Levels and Adherence
As with most chronic diseases, medication adherence in SLE is a challenge(10, 17), which associates with poor clinical outcomes. More outpatient visits and emergency room use has been reported in those who had adherence issues(18) and patient factors have been deemed the main reason for renal impairment in individuals with SLE who went on to develop chronic renal insufficiency (19). In our cohort poor physician global assessment of compliance and patient attendance at routine outpatient appointments were associated with bad outcomes(20).
Identification of poor adherence, by objective measures, means that this problem can be addressed and, as we have demonstrated, impacted upon(16). In our cohort, up to 44% of patients did not take their most important medication as prescribed, based on sub-therapeutic blood levels. With counseling and repeated measurement, the proportion of patients within the therapeutic range increased to 80%. This is an important clinical message as it established the baseline level of medication adherence, but also showed that this could be improved upon through repeated measurement and patient communication.
What is also salient is that the majority of literature points towards improved SLE disease activity with the attainment of therapeutic levels of hydroxychloroquine(13, 21, 22), although one clinical trial, in which levels were increased to target, yielded disappointing results (23). In the case where patients present with a flare in disease activity, the identification of non-adherence is a crucial clinical issue, which should influence subsequent decisions regarding immunosuppression.
Hydroxychloroquine blood levels in routine clinical care grant us the opportunity to identify non-adherence and impact upon it to improve SLE disease activity and potentially avoid more toxic immunosuppressive regimens.
Insufficient data exist presently, regarding whether these blood levels will be instructive in identifying individuals at higher risk of retinal toxicity. Our results support the prescription of hydroxychloroquine based on actual (capped at 400 mg per day) rather than ideal body weight and did not demonstrate differences in blood levels in those who were obese or short stature.
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