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Cited by 101Systemic Lupus Erythematosus ResearchSystemic Sclerosis and Related DiseasesVasculitis and related conditions

Hydroxychloroquine Use Is Associated with Lower Odds of Persistently Positive Antiphospholipid Antibodies and/or Lupus Anticoagulant in Systemic Lupus Erythematosus

Open access
BRODER, ANNA, PUTTERMAN, CHAIM·2013·The Journal of Rheumatology
DOI 10.3899/jrheum.120157PMC PMC3768146
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Abstract

Objective.: Antiphospholipid antibodies (aPL) play an active role in the pathogenesis of the antiphospholipid syndrome (APS). Primary prevention in APS may be aimed at decreasing existing elevated aPL levels, or preventing high aPL titers and/or lupus anticoagulant (LAC) from developing in the first place. Hydroxychloroquine (HCQ) has been shown in retrospective studies to decrease aPL titers in laboratory studies, and to decrease thrombosis risk in patients with systemic lupus erythematosus (SLE). We investigated an association between HCQ use and persistent aPL and/or LAC in SLE. Methods.: We identified all patients over 21 years old with SLE from an urban tertiary care center who had aPL and LAC measured on at least 2 occasions at least 12 weeks apart. We defined the presence of persistent LAC+ and/or at least 1 aPL ≥ 40 U [immunoglobulin A (IgA), IgG, or IgM] as the main outcome variable. Results.: Among 90 patients included in the study, 17 (19%) had persistent LAC+ and/or at least 1 aPL ≥ 40 U. HCQ use was associated with significantly lower odds of having persistent LAC+ and/or aPL ≥ 40 U (OR 0.21, 95% CI 0.05, 0.79, p = 0.02), adjusted for age, ethnicity, and sex. Conclusion.: This is the first study to show that HCQ use is associated with lower odds of having persistently positive LAC and/or aPL. Data from this study provide a basis for the design of future prospective studies investigating the role of HCQ in primary and secondary prevention of APS.

AI snapshot

Written from the paper’s full text.

TL;DR

In a retrospective study of 90 SLE patients, hydroxychloroquine use was associated with lower odds of persistently positive lupus anticoagulant and/or antiphospholipid antibodies ≥40 units (OR 0.21, 95% CI 0.05–0.79, p=0.02). The authors conclude this exploratory finding provides a basis for future prospective studies of HCQ in primary and secondary prevention of antiphospholipid syndrome.

Key findings

  • Among 90 patients, 17 (19%) had persistent LAC+ and/or at least one aPL Ab ≥40 units.
  • HCQ use was lower in the persistent aPL/LAC positive group than in the comparison group: 11 (65%) vs 65 (89%), p=0.02.
  • In logistic regression adjusted for age, ethnicity, and gender, HCQ use was associated with lower odds of persistent LAC+ and/or aPL Abs ≥40 U: OR 0.21 (95% CI 0.05, 0.79), p=0.02.
  • For persistently positive LAC and/or moderate/high Sapporo criteria aPL Abs, HCQ use was associated with OR 0.24 (0.06, 0.94), p=0.04, and Hispanic ethnicity with OR 4.2 (1.0, 16.7), p=0.04; no association was observed for other immunosuppressives or prednisone.

Methods

  • Retrospective study at Montefiore Medical Center including all adult SLE patients by ACR criteria who had LAC, anticardiolipin, anti-beta2 glycoprotein I, and antiphosphatidylserine antibodies measured at least twice, at least 12 weeks apart, between January 2006 and May 2012.
  • Main outcome was persistent LAC+ and/or at least one aPL Ab (IgA, IgG, or IgM) ≥40 units; medication exposure was defined as ever having been on the medication.
  • Bivariate comparisons and logistic regression adjusted for age, ethnicity, and gender were performed using STATA 12.0; no adjustments were made for multiple comparisons in this exploratory study.

Limitations

  • Stated in the paper: retrospective design and sample size; differential selection, differential and non-differential misclassification, disease activity, and medication dosage, duration, and compliance; causal relationship between HCQ use and aPL/LAC positivity could not be established in this cross-sectional study; the study was not designed or powered to evaluate whether HCQ decreased aPL Ab levels.
  • Evident from the text: single-center urban tertiary care sample, exploratory analysis without multiple-comparison adjustment, medication exposure defined as ever use, and race/ethnicity analyzed as self-reported categories with over 90% of non-Hispanics being African-American.

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

Integrity signals

Registry

Crossref · 10.3899/jrheum.120157

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 18 cited sources checked · 1 supported · 1 flagged · accuracy not yet measured

  • Interpretationown data

    This was the first study to report that hydroxychloroquine use is associated with lower odds of persistently positive lupus anticoagulant and/or antiphospholipid antibodies.

    “This is the first study to show that HCQ use is associated with lower odds of having persistently positive LAC and/or aPL Abs.”
    • Also stated in: § Discussion · hedged
      “However, this is the first study to show that HCQ use may be associated with lower odds of having persistently positive LAC and/or aPL Abs in SLE, and, therefore, may be beneficial in primary prevention.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] source

      The Results report no difference in hydroxychloroquine use between patients whose anticardiolipin antibody titres decreased, increased, or remained stable. The Discussion explicitly says the authors found no relation between hydroxychloroquine treatment and change in titre, rather than an association with lower odds of persistent positivity. Page numbers were not provided for these passages. (LLM, conf=0.91)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingown data

    Hydroxychloroquine use was associated with lower odds of persistently positive lupus anticoagulant and/or moderate-to-high Sapporo criteria antiphospholipid antibodies, with an odds ratio of 0.24 (95% CI 0.06-0.94), p=0.04.

    “Similarly, persistently positive LAC and/or moderate/high Sapporo criteria aPL Abs (aCL IgG or IGM, or anti-b2GPI IgG or IgM) (10) were associated with HCQ use, OR 0.24 (0.06, 0.94), p=0.04”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] source

      The citation follows the description of persistently positive LAC and Sapporo-criteria antibodies. In Patient selection (page unavailable), the guideline says a positive lupus anticoagulant result must be repeated more than 12 weeks later, supporting the persistence requirement. Our copy does not establish the stated moderate-to-high antibody criteria or report an association with hydroxychloroquine, the odds ratio, or its p-value. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Findingown data

    Hispanic ethnicity was associated with higher odds of persistently positive lupus anticoagulant and/or moderate-to-high Sapporo criteria antiphospholipid antibodies, with an odds ratio of 4.2 (95% CI 1.0-16.7), p=0.04.

    “and Hispanic ethnicity, OR 4.2 (1.0, 16.7), p=0.04 (Table 3).”
    • Also stated in: § Discussion · boosted
      “We also showed that Hispanic ethnicity was associated with higher odds of persistent Sapporo criteria aPL Abs and/or LAC compared with non-Hispanics (predominantly African-Americans).”
    Quote in the paperNot a substantial claim
  • Findingown data

    After adjustment for age, ethnicity, and gender, hydroxychloroquine use was linked to significantly lower odds of persistently positive lupus anticoagulant and/or antiphospholipid antibodies at or above 40 units, with an odds ratio of 0.21 (95% CI 0.05-0.79), p=0.02.

    “HCQ use was associated with significantly lower odds of having persistent LAC+ and/or aPL Abs ≥ 40 U, OR 0.21 (95% CI 0.05, 0.79) p=0.02, adjusted for age, ethnicity, and gender.”
    • Also stated in: § Results · plain
      “HCQ use was associated with significantly lower odds of having persistent LAC+ and/or aPL Abs ≥ 40 U (IgA, IgG or IgM), OR 0.21 (95% CI 0.05, 0.79) p=0.02.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the subgroup of SLE patients not taking immunosuppressants (n=49), hydroxychloroquine use was associated with an odds ratio of 0.17 (95% CI 0.03-0.88), p=0.03 for persistently positive lupus anticoagulant and/or Sapporo criteria antiphospholipid antibodies at or above 40 units.

    “When we limited our analysis to a subgroup of SLE patients who were not on immunosuppressives, presuming less severe SLE (n=49), HCQ was associated with the OR (95%CI) of 0.17 (0.03, 0.88), p = 0.03 of LAC+ and/or Sapporo criteria aPL Abs ≥ 40 units”
    Quote in the paperSubstantial claim
  • May combine two claims. 8
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Premisecitation

    Before this study, only one published study had examined the relationship between hydroxychloroquine and antiphospholipid antibodies, in a secondary analysis, and it found no association.

    “However, only one published study to date evaluated the association between HCQ and aPL Abs in a secondary analysis with a negative result (6).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] source

      The Results report no association between hydroxychloroquine use and changes in anticardiolipin antibody (aCL) titres, and the Discussion says the study was not primarily designed to test that relationship. Our copy does not establish that this was the only published study to examine the association, and its negative finding concerns aCL titres specifically rather than all antiphospholipid antibodies. The indexed passages provide no page numbers. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Lupus anticoagulant results were reported as positive or negative by the MMC laboratory following International Society on Thrombosis and Hemostasis guidelines.

    “LAC was reported as positive or negative (LAC+/LAC−) by the MMC laboratory in accordance with the guidelines of the International Society on Thrombosis and Hemostasis (9).”
    Quote in the paperSubstantial claim1 of 1 sources checked

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

    Findingown data

    More than 90% of non-Hispanic patients were African-American, which matched the center's overall racial and ethnic distribution.

    “Over 90% of non-Hispanics were African-American, reflecting the overall racial/ethnic distribution in our center.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither age nor gender showed an independent association with persistently positive lupus anticoagulant and/or antiphospholipid antibodies.

    “Age and gender were not independently associated with persistent LAC/aPL Abs.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Median hydroxychloroquine duration was 49 months (IQR 31-61) in the persistently positive group and 36 months (IQR 19-56) in the comparison group, with p=0.6.

    “The median (IQR) duration of HCQ use was 49 (31, 61) months in the aPL/LAC positive group, and 36 (19, 56) months in the comparison group, p=0.6.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Few patients changed from positive to negative or from negative to positive for antiphospholipid antibodies and/or lupus anticoagulant.

    “The number of patients who converted from aPL and/or LAC positive to negative, or from negative to positive, was small.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The link between Hispanic ethnicity and higher odds of positive antiphospholipid antibodies and/or lupus anticoagulant had not been reported before.

    “While it was previously reported that LAC was more prevalent in Caucasians (15), the association between Hispanic ethnicity and the higher odds of positive aPL and/or LAC has not been previously reported.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Under the two-hit hypothesis, antiphospholipid antibodies are required for a prothrombotic state.

    “According to the two-hit hypothesis, the presence of antiphospholipid antibodies (aPL Abs) is necessary to create a prothrombotic state (1st hit).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] source
    • cites [2] source

  • May combine two claims.

    Study design and conductown data

    The persistently positive group and the comparison group did not differ in age, gender, comorbidity scores, hydroxychloroquine duration, or disease duration.

    “The two groups were similar with respect to age, gender, co-morbidity scores, HCQ duration, and disease duration.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The exploratory analysis did not adjust for multiple comparisons.

    “No adjustments were made for multiple comparisons in this exploratory study.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    Antiphospholipid antibodies are probably influenced by several demographic and SLE-related factors.

    “It is likely that aPL Abs are affected by multiple demographic and SLE-specific factors.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Earlier work reported that lupus anticoagulant was more common in Caucasians.

    “While it was previously reported that LAC was more prevalent in Caucasians (15), the association between Hispanic ethnicity and the higher odds of positive aPL and/or LAC has not been previously reported.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

  • May combine two claims.

    Study design and conductown data

    Comparing patients who used hydroxychloroquine with those who did not, no differences were found in demographics, disease duration, Charlson Comorbidity Score, or medications.

    “When we compared patients on HCQ (HCQ+) with patients not on HCQ (HCQ−), no differences were observed with respect to demographics, disease duration, Charlson Co-morbidity Score (11), or medications.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] source

  • Classified as probably not a substantial claim.

    Premisecitation

    Current recommendations advise hydroxychloroquine for SLE patients with persistent moderate-to-high antiphospholipid antibodies or positive lupus anticoagulant for primary prevention (grade 1B to 2B), based on its other benefits in SLE and thrombosis.

    “HCQ treatment is currently recommended for SLE patients with persistent moderate-high aPL Ab or LAC+ for primary prevention (grade 1B to 2B recommendation) based on the other beneficial effects of HCQ in SLE (12, 13) and thrombosis (14).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] source
    • cites [13] source
    • cites [14] source

  • May combine two claims.

    Premisecitation

    Antiphospholipid antibodies by themselves are insufficient for thrombosis and can remain for a long period before a second hit triggers the thrombotic event.

    “However, aPL Abs alone are not sufficient, and may persist for a long time before the 2nd hit results in the actual thrombotic event (1, 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] source
    • cites [2] source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The study was not designed or powered to determine whether hydroxychloroquine lowered antiphospholipid antibody levels.

    “However, while our study was not designed or powered to evaluate whether HCQ decreased aPL Ab levels, the information learned from this study may be used to design prospective studies to evaluate this important question.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The study included only patients meeting ACR criteria for SLE and conducted several sensitivity analyses that gave consistent results.

    “However, we included only patients who satisfied ACR criteria for SLE, and performed several sensitivity analyses with consistent results.”
    Quote in the paperNot a substantial claim
17 of 17

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Authors
BRODER, A., & PUTTERMAN, C.
Affiliations
Albert Einstein College of Medicine (US)
ORCID
Venue
The Journal of Rheumatology
Publisher
The Journal of Rheumatology
Published
2012-08-01
Volume
40
Issue
1
Pages
30-33
ISSN
  • 0315-162X (ISSN-L)
  • 1499-2752
DOI
10.3899/jrheum.120157
PMC
PMC3768146
OpenAlex
W2116291585
Cited by
101
References
15
Citations by year
2026: 1 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 10 · 2019: 7 · 2018: 11 · 2017: 7 · 2016: 10 · 2015: 6 · 2014: 15 · 2013: 9 · 2012: 2
FWCI
7.00
Type
journal article
Language
en
Open access
Locations
  • The Journal of Rheumatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vasculitis and related conditions
Keywords
hydroxychloroquine, antiphospholipid antibodies, lupus anticoagulant, systemic lupus erythematosus, antiphospholipid syndrome, thromboprophylaxis, immunosuppressive therapy
MeSH terms
Adult, Female, Humans, Hydroxychloroquine, Lupus Erythematosus, Systemic

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