Background/Purpose Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disorder with a waxing and waning clinical course. Hydroxychloroquine (HCQ) is a well-tolerated and effective antimalarial medication which decreases disease flares and delays damage accrual in SLE. Additionally, a pre-disease study has shown that HCQ can potentially be a useful preventative therapy for delaying the onset of SLE. The exact mechanism by which HCQ might delay disease onset or flares is not well understood. One major obstacle of HCQ mechanistic studies is the confounding effects from other major immune modulating therapies used by SLE patients. Our goal is to elucidate the effects of HCQ on cellular changes and circulating soluble mediator concentration without the confounding effects of other major immunosuppressants (IS) in human lupus patients in vivo.

Methods As part of the Biomarkers of Lupus Disease (BOLD) study, 103 patients donated baseline blood samples of whom 41 had transient IM steroid therapy, then all IS and some hydroxychloroquine treatments stopped. Patients were followed until flare. Eligibility criteria included (> 4 ACR SLE classification  criteria and SLEDAI > 6 or BILAG ≥ 2 B or 1 A scores.. Cellular immunophenotyping and soluble mediators, including 52 cytokines, chemokines, and soluble receptors, were measured over time using xMAP multiplex technology and sandwich ELISA. Significant differences were determined using non-parametric tests. A longitudinal analysis was performed using mixed generalized linear models.

Results At baseline, SLE patients taking HCQ (n=27) had significantly lower levels of soluble TNFR I [median, 112.67 pg/mL; interquartile range (IQR), 103.5 -144.6 pg/mL] and TNFR II (median, 318.6 pg/mL; IQR, 266.8 – 374.8 pg/mL) compared to SLE patients not taking HCQ (n=10) (TNFR I, median, 186.63; IQR, 120.09-301.44; TNFR II, median 519.6; IQR, 332.16-641.00; p-value <0.05). In addition to the soluble TNFRs, SLE patients taking HCQ had significantly lower frequency of CD194hi Naïve B cells population (median, 1.54%; IQR, 0.15% - 5.48%) compared to SLE patients not taking HCQ (median, 5.57%; IQR, 2.03% - 13.19%; p-value < 0.05).  SLE patients that stayed on HCQ during the six month study (n=17) retained their low levels of TNFR II. Patients who had never taken HCQ or were taken off of HCQ (n=20) showed a significant reduction in their TNFR II  levels at the time of the next flare  (p-value <0.05).  TNFR II levels did remain higher than those observed in individuals that remained on HCQ.

Conclusion HCQ may contribute to disease suppression via an effective reduction in soluble TNF and other chemokine receptor levels. These findings suggest a likely focus for further patholophysiologic studies of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hydroxylchloroquine-use-is-associated-with-decreased-soluble-tnf-receptor-levels-in-sle-patient-samples/