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Hydroxychloroquine blood levels in stable lupus nephritis under low dose (2–3 mg/kg/day): 12-month prospective randomized controlled trial

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Abstract

Introduction

The American Academy of Ophthalmology (2016-AAO) recommended hydroxychloroquine (HCQ) dose not to exceed 5 mg/kg/day (real body weight). Recently, it was reported that prescribed 2016-AAO dose provided adequate HCQ levels for most lupus nephritis (LN) patients, with low flare risk. However, the minimum HCQ dose required to keep adequate levels is unknown.

Objectives

To evaluate if a further reduction in 2016-AAO dose (2–3 mg/kg/day) would sustain 12-month HCQ levels in LN patients with stable inactive disease.

Methods

Seventy-three stable LN patients under prescribed full HCQ 2016-AAO dose for ≥6 months and adequate baseline HCQ levels (≥613.5 ng/mL) were divided in two groups: reduced 2016-AAO dose (2–3 mg/kg/day), n = 32, and full 2016-AAO dose (5 mg/kg/day), n = 41. All patients were assessed at baseline, 3, 6, and 12 months. HCQ levels were measured by liquid chromatography-tandem mass spectrometry. Flare was defined as augment ≥ 3 in SLE Disease Activity Index-2000 and/or change in treatment. Rigorous clinical/laboratorial surveillance was performed.

Results

Prospective evaluation revealed for reduced 2016-AAO dose group a decrease of HCQ levels from baseline to 3 months (1,404.9 ± 492.0 vs. 731.6 ± 385.0 ng/mL, p < 0.01), and sustained levels at 6 months (p = 0.273) and 12 months (p = 0.091) compared to 3 months. For the full 2016-AAO dose group, a decrease occurred only from baseline to 12 months (1343.5 ± 521.5 vs. 991.6 ± 576.3 ng/mL, p < 0.001). Frequencies of patients with inadequate levels at 6 months was higher in reduced 2016-AAO group than full 2016-AAO dose (59% vs. 24%, p = 0.005), as well as at 12 months (66% vs. 32%, p = 0.002). Six-month and 12-month flare frequencies were comparable for both groups (p > 0.05).

Conclusions

Prescribed HCQ low-dose regimen (2–3 mg/kg/day) does not sustain, for most patients, 6- and 12-month adequate HCQ levels. Full 2016-AAO dose maintained HCQ levels way above this limit.

Trail registration

ClinicalTrials.gov: NCT03122431, registered on April 20, 2017

Key Points

• Reduced American Academy of Ophthalmology (2016-AAO) hydroxychloroquine (HCQ) dose (2–3 mg/kg/day, real body weight) is unable to sustain HCQ blood levels within the safe cut-off defined for flare risk.

• Full 2016-AAO dose (5 mg/kg/day) maintains a safe pattern of HCQ levels up to 12 months.

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Data availability

All data relevant to the study are included in the article, and the raw data will be provided to interested researchers whenever requested. The protocol was registered at ClinicalTrials.gov under number #NCT03122431.

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Acknowledgements

We are grateful to all the research subjects for their gentle collaboration. We thank Elaine P. Leon and Nicole Fontoura from Laboratório de Investigação Médica 17 (LIM17) and Paschoalina Romano and Valdemir M. Carvalho and Divisão de Laboratório Central (DLC)—Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil, for their support.

Funding

This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) [#2015/03756-4 to SGP, NEA, CAS and EB; #2017/03983-6 for the LC-MS/MS system; #2017/14352-7 to TNP; and #2019/17272-0 to LVKK] and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [#304984/2020-5 to CAS; #306879/2018-2 to EFB; and #305242/2019-9 to EB].

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Correspondence to Eloisa Bonfa.

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The present study was approved by the Local Ethical Committee (Ethics Committee for Research Projects Analysis of Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil) (#39705014.6.0000.0068), and a signed informed consent form was obtained from all research subjects.

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Zanetti, C.B., Pedrosa, T., Kupa, L.d.V.K. et al. Hydroxychloroquine blood levels in stable lupus nephritis under low dose (2–3 mg/kg/day): 12-month prospective randomized controlled trial. Clin Rheumatol 40, 2745–2751 (2021). https://doi.org/10.1007/s10067-021-05600-2

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