Dialogue: Antiplatelet effects of hydroxychloroquine in patients with systemic lupus erythematosus evaluated by the total thrombus-formation analysis system (T-TAS)

Abstract

Despite the improved overall survival in patients with SLE over the last decades, mortality risk is still increased compared with age-matched and sex-matched healthy controls and cardiovascular events are a major cause of death in patients with SLE.2 HCQ has been demonstrated to reduce mortality risk in patients with SLE by 45%,2 which might be in part related to the antithrombotic effects of HCQ next to other favourable effects regarding cardiovascular event risk such as reducing disease activity, flare rate and glucocorticoid dosage. Another limitation of the present study might be the overall very low disease activity reported from the 57 patients investigated, demonstrated by a median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score of 1 (IQR 0–2). Since SLE disease activity is an independent risk factor for cardiovascular events in SLE, additional studies on antiplatelet effects of HCQ using T-TAS in patients with moderate and high disease activity are needed. Furthermore, all subjects included in the study were of Asian background, and no data are currently available on differences in antiplatelet effects of HCQ between ethnic groups, while the response to drugs may be linked to genetic differences in ethnic/racial groups. [...]the study had a cross-sectional design and assessments of antiplatelet effects of HCQ using T-TAS were not related to the measurement of HCQ concentrations in whole blood.

Correspondence to Dr Irene E M Bultink; [email protected]

In the recent article entitled ‘Antiplatelet effects of hydroxychloroquine in patients with systemic lupus erythematosus evaluated by the total thrombus-formation analysis system (T-TAS)’, Hiraoka and colleagues¹ presented the results of an interesting cross-sectional study in 57 Japanese patients with SLE on dose-dependent antiplatelet effects of hydroxychloroquine (HCQ) as assessed using a new Total Thrombus-formation Analysis System (T-TAS). The reported advantage of using T-TAS is that this microchip-based flow chamber system is supposed to mimic physiological conditions in contrast to the commonly used platelet aggregation assay, a non-physiological test. The present study demonstrated a dose-dependent antiplatelet effect of HCQ using a prescribed HCQ dose per real body weight. The results of this study warrant further research into the antithrombotic effects of HCQ and the optimal HCQ dosing regimen to achieve that effect.

Despite the improved overall survival in patients with SLE over the last decades, mortality risk is still increased compared with age-matched and sex-matched healthy controls and cardiovascular events are a major cause of death in patients with SLE.² HCQ has been demonstrated to reduce mortality risk in patients with SLE by 45%,² which might be in part related to the antithrombotic effects of HCQ next to other favourable effects regarding cardiovascular event risk such as reducing disease activity, flare rate and glucocorticoid dosage.

The dose-dependent antiplatelet effect of HCQ assessed using T-TAS reported by Hiraoka and colleagues is a novel and interesting observation, but the study also has some limitations that have to be taken into account.

The authors categorised the 57 patients with SLE into two subgroups using a prescribed HCQ dosage of more or less than 5 mg/kg HCQ/real body weight and investigated T-TAS and pressure under the area curve for 10 min in these subgroups. However, non-adherence of patients with SLE to HCQ therapy is highly prevalent and a well-known problem in the treatment of patients with lupus.^{3 4} A study on HCQ treatment and adherence to therapy in 2936 European patients with SLE from 33 countries revealed that 17.3% of the patients reported skipping HCQ once a week or more often.³ Therefore, to draw conclusions on optimal HCQ dosages required to reach sufficient antiplatelet effects, supervised medication intake or use of special secured medication boxes should be performed.

Another limitation of the present study might be the overall very low disease activity reported from the 57 patients investigated, demonstrated by a median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score of 1 (IQR 0–2). Since SLE disease activity is an independent risk factor for cardiovascular events in SLE, additional studies on antiplatelet effects of HCQ using T-TAS in patients with moderate and high disease activity are needed.

Furthermore, all subjects included in the study were of Asian background, and no data are currently available on differences in antiplatelet effects of HCQ between ethnic groups, while the response to drugs may be linked to genetic differences in ethnic/racial groups.

Moreover, the study had a cross-sectional design and assessments of antiplatelet effects of HCQ using T-TAS were not related to the measurement of HCQ concentrations in whole blood.

Despite these limitations, the results of this study are promising. A large, international, multiethnic study comprising patients with SLE with high and low disease activity on the relationships between assessment of antiplatelet effects of HCQ using T-TAS, HCQ concentrations in whole blood, and the occurrence of future cardiovascular events will provide insight into the clinical relevance of the findings of the present study.

After more than four decades of research on the pathogenesis of cardiovascular disease in SLE, the exact risk factors and the relative contribution of and the interplay between thrombotic, atherosclerotic and inflammatory factors, and favourable and unfavourable drug effects are still not fully elucidated, and this hampers the further development of intervention strategies to prevent cardiovascular events in patients with SLE. Further research on the antithrombotic effects of HCQ, the cornerstone of SLE treatment and available in almost all countries of the world, should be strongly encouraged since reducing cardiovascular morbidity and mortality in patients with SLE is of major importance.

Ethics statements

Patient consent for publication

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Ethics approval

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Footnote

Contributors IEMB has written the manuscript and is the guarantor.

Funding The author has not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Commissioned; internally peer reviewed.

References

¹ Hiraoka D, Ishizaki J, Yamanouchi J, et al. Antiplatelet effects of hydroxychloroquine in patients with systemic lupus erythematosus evaluated by the total thrombus-formation analysis system (T-TAS). Lupus Sci Med 2024; 11: e001223. doi:10.1136/lupus-2024-001223

² Bultink IEM, de Vries F, van Vollenhoven RF, et al. Mortality, causes of death and influence of medication use in patients with systemic lupus erythematosus vs matched controls. Rheumatol (Oxford) 2021; 60: 207–16. doi:10.1093/rheumatology/keaa267

³ Osmani Z, Schrama TJ, Zacouris-Verweij W, et al. Hydroxychloroquine treatment in European patients with lupus erythematosus: dosing, retinopathy screening and adherence. Lupus Sci Med 2021; 8: e000478. doi:10.1136/lupus-2021-000478

⁴ Costedoat-Chalumeau N, Pouchot J, Guettrot-Imbert G, et al. Adherence to treatment in systemic lupus erythematosus patients. Best Pract Res Clin Rheumatol 2013; 27: 329–40. doi:10.1016/j.berh.2013.07.001