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The Role of Hydroxychloroquine Blood Levels in SLE

Mar 14, 2016 11:40 am

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

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, (

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.  

Conclusion

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.

References

1.         Alarcón GS, McGwin G, Bertoli AM, Fessler BJ, Calvo-Alén J, Bastian HM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis. 2007;66(9):1168-72. doi: 10.1136/ard.2006.068676. PubMed PMID: 17389655; PubMed Central PMCID: PMCPMC1955128.

2.         Fessler BJ, Alarcón GS, McGwin G, Roseman J, Bastian HM, Friedman AW, et al. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 2005;52(5):1473-80. doi: 10.1002/art.21039. PubMed PMID: 15880829.

3.         Sutton EJ, Davidson JE, Bruce IN. The systemic lupus international collaborating clinics (SLICC) damage index: a systematic literature review. Semin Arthritis Rheum. 2013;43(3):352-61. doi: 10.1016/j.semarthrit.2013.05.003. PubMed PMID: 23786872.

4.         Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: update of therapeutic options part I. J Am Acad Dermatol. 2011;65(6):e179-93. doi: 10.1016/j.jaad.2010.06.018. PubMed PMID: 20739095.

5.         Williams HJ, Egger MJ, Singer JZ, Willkens RF, Kalunian KC, Clegg DO, et al. Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus. J Rheumatol. 1994;21(8):1457-62. PubMed PMID: 7983646.

6.         Kasitanon N, Fine DM, Haas M, Magder LS, Petri M. Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus. 2006;15(6):366-70. PubMed PMID: 16830883.

7.         Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas--a randomized trial. Diabetes Res Clin Pract. 2002;55(3):209-19. PubMed PMID: 11850097.

8.         Cairoli E, Rebella M, Danese N, Garra V, Borba EF. Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect. Lupus. 2012;21(11):1178-82. doi: 10.1177/0961203312450084. PubMed PMID: 22641182.

9.         Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132(12):1453-60. doi: 10.1001/jamaophthalmol.2014.3459. PubMed PMID: 25275721.

10.       Costedoat-Chalumeau N, Pouchot J, Guettrot-Imbert G, Le Guern V, Leroux G, Marra D, et al. Adherence to treatment in systemic lupus erythematosus patients. Best Pract Res Clin Rheumatol. 2013;27(3):329-40. doi: 10.1016/j.berh.2013.07.001. PubMed PMID: 24238690.

11.       Füzéry AK, Breaud AR, Emezienna N, Schools S, Clarke WA. A rapid and reliable method for the quantitation of hydroxychloroquine in serum using turbulent flow liquid chromatography-tandem mass spectrometry. Clin Chim Acta. 2013;421:79-84. doi: 10.1016/j.cca.2013.02.018. PubMed PMID: 23485647.

12.       Munster T, Gibbs JP, Shen D, Baethge BA, Botstein GR, Caldwell J, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46(6):1460-9. doi: 10.1002/art.10307. PubMed PMID: 12115175.

13.       Durcan L, Clarke WA, Magder LS, Petri M. Hydroxychloroquine Blood Levels in Systemic Lupus Erythematosus: Clarifying Dosing Controversies and Improving Adherence. J Rheumatol. 2015;42(11):2092-7. doi: 10.3899/jrheum.150379. PubMed PMID: 26428205; PubMed Central PMCID: PMCPMC4630115.

14.       Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2010;62(6):775-84. Epub 2010/06/11. doi: 10.1002/acr.20133. PubMed PMID: 20535788.

15.       Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):415-22. Epub 2011/02/05. doi: 10.1016/j.ophtha.2010.11.017. PubMed PMID: 21292109.

16.       Durcan L, Clarke WA, Magder LS, Petri M. Hydroxychloroquine blood levels in SLE: clarifying dosing controversies and improving adherence. Journal of Rheumatology. 2015.

17.       Costedoat-Chalumeau N, Amoura Z, Hulot JS, Aymard G, Leroux G, Marra D, et al. Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus. Ann Rheum Dis. 2007;66(6):821-4. doi: 10.1136/ard.2006.067835. PubMed PMID: 17324970; PubMed Central PMCID: PMCPMC1954674.

18.       Julian LJ, Yelin E, Yazdany J, Panopalis P, Trupin L, Criswell LA, et al. Depression, medication adherence, and service utilization in systemic lupus erythematosus. Arthritis Rheum. 2009;61(2):240-6. doi: 10.1002/art.24236. PubMed PMID: 19177526; PubMed Central PMCID: PMCPMC2875189.

19.       Bruce IN, Gladman DD, Urowitz MB. Factors associated with refractory renal disease in patients with systemic lupus erythematosus: the role of patient nonadherence. Arthritis Care Res. 2000;13(6):406-8. PubMed PMID: 14635317.

20.       Petri M, Perez-Gutthann S, Longenecker JC, Hochberg M. Morbidity of systemic lupus erythematosus: role of race and socioeconomic status. Am J Med. 1991;91(4):345-53. PubMed PMID: 1951378.

21.       Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(10):3284-90. doi: 10.1002/art.22156. PubMed PMID: 17009263.

22.       Francès C, Cosnes A, Duhaut P, Zahr N, Soutou B, Ingen-Housz-Oro S, et al. Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. Arch Dermatol. 2012;148(4):479-84. doi: 10.1001/archdermatol.2011.2558. PubMed PMID: 22508872.

23.       Costedoat-Chalumeau N, Galicier L, Aumaitre O, Frances C, Le Guern V, Liote F, et al. Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study). Ann Rheum Dis. 2013;72(11):1786-92. Epub 2012/11/13. doi: 10.1136/annrheumdis-2012-202322. PubMed PMID: 23144449.

 

Disclosures
The author has received research/grant financial support on this subject

Michelle Petri, MD, MPH is the director of the Hopkins Lupus Center and Professor of Medicine. The Hopkins Lupus Cohort is a longitudinal cohort of SLE patients funded by NIH; it currently includes over 2,000 patients. The major outcome measures are prediction of disease activity, prevention of organ damage, and improvement in quality of life. The cohort has made important contributions to the understanding of corticosteroid toxicity in SLE, the preventive role of hydroxychloroquine and the pathogenesis of accelerated atherosclerosis. The center also participates in clinical trials (playing an important role in the development of belimumab for SLE) and NIH-funded studies of the genetics of SLE, autoantibodies in SLE, and single cell studies of lupus kidney biopsies (the AMP project).

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