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Cited by 65Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsVenous Thromboembolism Diagnosis and Management

Association of Higher Hydroxychloroquine Blood Levels With Reduced Thrombosis Risk in Systemic Lupus Erythematosus

Open access
Petri, Michelle, Konig, Maximilian F., Li, Jessica, Goldman, Daniel W.·2021·Arthritis & Rheumatology
DOI 10.1002/art.41621PMC PMC8169526
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Abstract

Objective: Hydroxychloroquine (HCQ) has a primary role in the prophylaxis and treatment of systemic lupus erythematosus (SLE) and may be protective against thrombosis in SLE. Optimal weight‐based dosing of HCQ is unknown. This study was undertaken to examine the usefulness of HCQ blood monitoring in predicting thrombosis risk in a longitudinal SLE cohort. Methods: HCQ levels were serially quantified from EDTA whole blood by liquid chromatography–tandem mass spectrometry. The mean HCQ blood levels calculated prior to thrombosis or until the last visit were compared using t ‐tests between patients with and those without thrombosis. Pooled logistic regression was used to analyze the association between rates of thrombosis and HCQ blood level. Rate ratios (RRs) and 95% confidence intervals (95% CIs) were calculated. Results: In 739 patients with SLE, thrombosis occurred in 38 patients (5.1%). The mean ± SD HCQ blood level was lower in patients who developed thrombosis versus those who did not develop thrombosis (720 ± 489 ng/ml versus 935 ± 580 ng/ml; P = 0.025). Thrombosis rates were reduced by 13% for every 200‐ng/ml increase in the most recent HCQ blood level (RR 0.87 [95% CI 0.78–0.98], P = 0.025) and by 13% for mean HCQ blood level (RR 0.87 [95% CI 0.76–1.00], P = 0.056). Thrombotic events were reduced by 69% in patients with mean HCQ blood levels ≥1,068 ng/ml versus those with levels <648 ng/ml (RR 0.31 [95% CI 0.11–0.86], P = 0.024). This remained significant after adjustment for confounders (RR 0.34 [95% CI 0.12–0.94], P = 0.037). Conclusion: Low HCQ blood levels are associated with thrombotic events in SLE. Longitudinal measurement of HCQ levels may allow for personalized HCQ dosing strategies. Recommendations for empirical dose reduction may reduce or eliminate the benefits of HCQ in this high‐risk population.

AI snapshot

Written from the paper’s full text.

TL;DR

In the Hopkins Lupus Cohort, lower hydroxychloroquine (HCQ) whole blood levels were associated with incident thrombosis in systemic lupus erythematosus, with higher levels showing dose-dependent protection. The authors suggest HCQ blood-level monitoring may support personalized dosing, though the observational design limits causal inference.

Key findings

  • Among 739 patients with SLE over 2330 person-years, incident thrombosis occurred in 38 patients (5.1%), an overall rate of 16.3 per 1000 person-years; mean HCQ blood level was lower in those with thrombosis vs without (720±489 vs 935±580 ng/mL, p=0.025).
  • Thrombosis rates were reduced by 12% for every 200 ng/mL increase in the most recent HCQ blood level (rate ratio 0.87 [0.78, 0.98], p=0.025) and by 13% for mean HCQ blood level (rate ratio 0.87 [0.76, 1.00], p=0.056).
  • Thrombotic events were reduced by 69% in patients with mean HCQ blood levels >1068 ng/mL vs <648 ng/mL (rate ratio 0.31 [0.11, 0.86], p=0.024), remaining significant after adjustment (0.34 [0.12, 0.94], p=0.037).
  • Prescribed HCQ doses from 4.5 to 6.5 mg/kg did not predict HCQ blood levels (within-person rmcorr=0.01; between-person r=0.088).

Methods

  • Longitudinal Hopkins Lupus Cohort study of 739 patients with SLE meeting revised ACR or SLICC classification criteria; visits every 3 months, with inclusion requiring one or more HCQ blood levels and censoring after first thrombotic event or off HCQ due to retinopathy/intolerance.
  • HCQ levels were quantified from EDTA whole blood by liquid chromatography-tandem mass spectrometry, linear over 16–4000 ng/mL with coefficient of variation <3%; thrombotic events were recorded at visits and confirmed through medical record review and imaging.
  • A person-month dataset was analyzed with pooled logistic regression for thrombosis rate by mean and most recent HCQ blood levels, unadjusted and adjusted for age, ethnicity, lupus anticoagulant, low C3, and hypertension; t-tests and correlation coefficients were also used.

Limitations

  • Stated: observational design with potential confounding by unknown variables not included in modeling; single site, single rheumatologist; and small numbers of prospectively ascertained thrombotic events.
  • Stated: venous (p=0.0747) and arterial (p=0.1735) sub-analyses were not statistically significant due to lower power; the most recent HCQ level >1192 ng/mL had adjusted rate ratio 0.40 [0.16, 1.04], p=0.0614, just missing statistical significance.
  • Evident from the text: findings come from one cohort and no randomized dose-targeting intervention was performed, so the associations cannot establish causality.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/art.41621

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

5 of 15 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Prior retrospective and prospective studies have shown that hydroxychloroquine lowers the risk of arterial and venous thrombosis in systemic lupus erythematosus.

    “Multiple retrospective and a few prospective studies (3–13) have found that hydroxychloroquine (HCQ) reduces the risk of arterial and venous thrombosis.”
    Quote in the paperSubstantial claim3 of 10 sources checked
    • cites [3] Wallace DJ. Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus? Arthritis Rheum 1987; 30: 1435– 1436. 3435574 source
    • cites [4] Ho KT, Ahn CW, Alarcón GS, Baethge BA, Tan FK, Roseman J, Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events. Rheumatology 2005; 44: 1303– 1307. 16030085 source

      The Univariable analyses section reports that hydroxychloroquine use was protective against thrombotic events in the LUMINA cohort, which included arterial and venous events. But the Discussion says the association did not persist in the adjusted analysis. The paper also does not establish the claim's characterization of multiple retrospective and prospective studies finding a reduction. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [5] Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med 1994; 96: 254– 9. 8154514 source
    • cites [6] Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis 2009; 68: 238– 241. 18782792 PMC2875136 source

      The Results report that hydroxychloroquine use was associated with lower overall thrombosis risk in an SLE cohort. The Patients and Methods section includes arterial and venous events, but our copy does not report a separate hydroxychloroquine finding for each type. The Discussion describes this study as retrospective and says the association needs testing in prospective randomised trials, so this source does not establish the claim about prospective studies. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [7] Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010; 62: 863– 868. 20131232 source
    • cites [8] Hsu C-Y, Lin Y-S, Su Y-J, Lin H-F, Lin M-S, Syu Y-J, Effect of long-term hydroxychloroquine on vascular events in patients with systemic lupus erythematosus: a database prospective cohort study. Rheumatology (Oxford) 2017; 56: 2212– 2221. 29029334 source
    • cites [9] Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum 2009; 61: 29– 36. 19116963 source
    • cites [10] Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 2002; 41: 924– 9. 12154210 source

      The Discussion states that hydroxychloroquine reduces thrombosis risk in SLE patients, supporting the central point. It does not specify reduced risk for both arterial and venous thrombosis in SLE or identify the supporting studies as retrospective and prospective; this paper’s own study is cross-sectional. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [11] Sisó A, Ramos-Casals M, Bové A, Brito-Zerón P, Soria N, Muñoz S, Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus 2008; 17: 281– 8. 18413408 source
    • cites [12] Thrombosis Petri M. and systemic lupus erythematosus: the Hopkins Lupus Cohort perspective. Scand J Rheumatol 1996; 25: 191– 3. 8792794 source
  • Premisecitation

    Whole blood is preferred over plasma for measuring hydroxychloroquine because the drug binds to red blood cells and is sequestered in leukocytes.

    “Hydroxychloroquine blood levels are preferred over plasma levels due to binding of hydroxychloroquine to red blood cells and its lysosomal sequestration in leukocytes (28).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] Carlsson H, Hjorton K, Abujrais S, Rönnblom L, Åkerfeldt T, Kultima K. Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS-evaluation of whole blood, plasma, and serum as sample matrices. Arthritis Res Ther 2020; 22: 125. 32475347 PMC7261520 source

      The Conclusions (page unavailable) identify whole blood as the preferred matrix for hydroxychloroquine measurement. The Discussion (page unavailable) attributes its advantage to better reproducibility in patient samples; it does not establish red-blood-cell binding or lysosomal sequestration in leukocytes as the reasons for that preference. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingown data

    After adjustment, each 200 ng/mL increase in mean hydroxychloroquine blood level was associated with a thrombosis rate ratio of 0.87 (95% CI 0.76-1.00, p=0.056).

    “and by 13% for mean HCQ blood level (rate ratio 0.87 [0.76,1.00], p=0.056).”
    • Also stated in: § Target hydroxychloroquine blood level and risk of thrombotic events · plain
      “thrombosis rates were reduced by 13% for every 200 ng/mL increase in mean HCQ blood level (rate ratio 0.87 [0.76, 1.00], p=0.0559)”
    Quote in the paperSubstantial claim
  • Findingown data

    Low C3 was a confounder for thrombosis in univariate analysis (p=0.0173).

    “The most important confounders were hypertension (p=0.0176) and low C3 (p=0.0173).”
    Quote in the paperNot a substantial claim
  • Findingown data

    During follow-up, incident thrombosis occurred in 38 of 739 patients with SLE (5.1%).

    “In 739 patients with SLE, thrombosis occurred in 38 patients (5.1%).”
    • Also stated in: § Thrombotic events · plain
      “Incident thrombosis occurred in 38 patients (5.1%) during follow-up”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 10
  • May combine two claims. 6

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In a prospective study, the highest tertile of hydroxychloroquine blood levels predicted later retinopathy.

    “The highest tertile of hydroxychloroquine blood levels in the prospective study did predict later retinopathy, indicating a role in monitoring blood levels to reduce toxicity (25).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Petri M, Elkhalifa M, Li J, Magder LS, Goldman DW. Hydroxychloroquine blood levels predict hydroxychloroquine retinopathy. Arthritis Rheumatol 2020; 72: 448– 453. 31532077 PMC7050401 source

  • May combine two claims.

    Findingown data

    Venous and arterial thrombotic event subanalyses showed similar lower mean hydroxychloroquine blood levels but were not statistically significant due to lower power.

    “For the sub-analysis for venous (p=0.0747) and arterial thrombotic events (p=0.1735) the results were similar, but were not statistically significant (due to lower power).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A most recent hydroxychloroquine blood level above 1192 ng/mL was associated with a lower thrombosis rate (adjusted RR 0.40 [0.16,1.04], p=0.061), which did not reach statistical significance.

    “A mean whole blood level of greater than 1068 ng/mL and a most recent whole blood level of greater than 1192 ng/mL, as defined by tertiles, were protective against thrombosis in our cohort (adjusted rate ratio 0.34 [0.12, 0.94], p=0.0374 and 0.40 [0.16, 1.04], p=0.0614, respectively, with the latter p-value just missing statistical significance).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The overall thrombosis rate was 16.3 per 1000 person-years over 2330 person-years of follow-up.

    “This analysis was based on 2330 person years of follow up from 739 patients with SLE. Incident thrombosis occurred in 38 patients (5.1%) during follow-up, giving an overall rate of 16.3 per 1000 person years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Revised American Academy of Ophthalmology guidance limits hydroxychloroquine dosing to less than 5 mg/kg absolute body weight, based on the Kaiser-Permanente study.

    “The retrospective Kaiser-Permanente study was the basis for the revised American Academy of Ophthalmology (AAO) guidance to limit hydroxychloroquine dosing to less than 5 mg/kg absolute body weight (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology 2016; 123: 1386– 1394. 26992838 source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Thrombotic events were confirmed by medical record review and required objective imaging or other confirmation.

    “Venous (deep vein thrombosis, pulmonary embolus, superficial venous thrombosis, other venous thrombosis) or arterial (stroke, myocardial infarction, digital gangrene or other arterial thrombosis) were recorded at each visit according to the cohort protocol and confirmed through review of medical records.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Routine clinical integration of hydroxychloroquine blood level measurement offers an opportunity for personalized drug dosing and risk management beyond rigid empirical dosing recommendations in SLE.

    “Routine clinical integration of hydroxychloroquine blood level measurement offers an opportunity for personalized drug dosing and risk management beyond rigid empirical dosing recommendations in patients with SLE.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Hydroxychloroquine blood levels reflect hydroxychloroquine intake and tissue stores.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Additional limitations include single site, single rheumatologist, and small numbers of prospectively ascertained thrombotic events.

    “The additional limitations include the single site, single rheumatologist, and small numbers of prospectively ascertained thrombotic events.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Patients whose thrombotic event occurred before their first hydroxychloroquine measurement were excluded, and follow-up ended after the first thrombotic event.

    “Patients were excluded if their thrombotic event occurred prior to the first hydroxychloroquine measurement. Follow up for each patient was censored after the first thrombotic event.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analyses adjusted for age, ethnicity, lupus anticoagulant, C3, and hypertension.

    “after adjusting for age, ethnicity, lupus anticoagulant, C3, and hypertension.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    Hydroxychloroquine levels were measured from EDTA whole blood using liquid chromatography-tandem mass spectrometry, with linearity from 16 to 4000 ng/mL and a coefficient of variation below 3%.

    “Hydroxychloroquine levels were quantified from EDTA whole blood by liquid chromatography-tandem mass spectrometry as described by Chambliss et al, with measurements being linear over a range of 16 to 4000 ng/mL (29). The coefficient of variation was <3%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] 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. 23485647 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The observational study design has potential limitations including confounding by unknown variables not included in the modelling.

    “The observational study design has potential limitations. These include the potential for confounding by unknown variables that we did not include in our modelling.”
    Quote in the paperNot a substantial claim
12 of 12

  • The paper relies on this without support.

    Optimal weight-based dosing of hydroxychloroquine in SLE is unknown.

    “Optimal weight-based dosing of HCQ is unknown.”
    “Despite its widespread use since the 1950s (21), optimal dosing of HCQ in SLE is unknown.”

  • The paper relies on this without support.

    Hydroxychloroquine blood levels reflect hydroxychloroquine intake and tissue stores.

    “Hydroxychloroquine blood levels reflect hydroxychloroquine intake and tissue stores.”

  • The paper relies on this without support.

    The Kaiser-Permanente study used pharmacy dispensing records rather than prescribed dose, so its dose estimates are lower than actual prescribed doses.

    “The Kaiser-Permanente study, however, was based on pharmacy dispensing records and not on the prescribed dose (which is higher due to partial adherence).”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Most recent high blood-level tertile is called significantly protective despite a nonsignificant p-value

    Major

    The discussion says a most recent level above 1192 ng/mL conferred significant protection, but the results give p=0.0614 for that comparison and explicitly say it missed statistical significance.

  • Venous thrombosis percentage does not match the cohort size

    Minor

    Eighteen of 739 patients is 2.44%, which rounds to 2% at the stated whole-percent precision, not 3%.

    Reported 3 · recomputed 2.435724

  • Reduction per increase in the most recent HCQ level is stated as both 12% and 13%

    Minor

    The abstract reports a 12% reduction for the most recent blood level, whereas the discussion reports 13% for the same 200 ng/mL increase. The reported rate ratio of 0.87 corresponds to a 13% reduction.

  • AAO dosing limit uses conflicting definitions of body weight

    Minor

    The introduction describes the revised AAO limit as based on absolute body weight, while the discussion describes the new recommendation as based on ideal body weight.

4 of 4

Cites

Flagged first, then by citations

1 of the 39 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Sankhyan P, 2018, Hydroxychloroquine and the risk of thrombotic events in systemic lupus erythematosus patients: a systematic review and meta‐analysis [abstract], Arthritis Rheumatol, 70

Cited by

Sorted by citations

Related

Authors
Petri, M., Konig, M. F., Li, J., & Goldman, D. W.
Affiliations
Johns Hopkins University (US)
Corresponding author
Petri, Michelle
ORCID
Venue
Arthritis & Rheumatology
Publisher
Wiley
Published
2021-05-02
Volume
73
Issue
6
Pages
997-1004
ISSN
  • 2326-5191 (ISSN-L)
  • 2326-5205
DOI
10.1002/art.41621
PMC
PMC8169526
OpenAlex
W3120312887
Semantic Scholar
881fe05d9e80b659cde4603201452f71d006f446
Cited by
65
References
39
Citations by year
2026: 7 · 2025: 12 · 2024: 14 · 2023: 16 · 2022: 11 · 2021: 5
FWCI
7.10
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Arthritis & Rheumatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR069572, T32AR048522)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
Keywords
hydroxychloroquine, systemic lupus erythematosus, thrombosis, thromboprophylaxis, drug blood levels, therapeutic drug monitoring, individualized dosing, thrombosis risk prediction
MeSH terms
Adult, Chromatography, Liquid, Female, Fingers, Gangrene, Humans, Hydroxychloroquine

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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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