Acupuncture Ameliorates Heightened Inflammatory/Immune Responses Accompanied with Improvement in Clinical Outcomes in Patients with Sickle Cell Disease

Background: Pain is a life-long challenge for patients with sickle cell disease (SCD). Systemic inflammation and altered immune function have been associated with the pathogenesis of persistent pain in SCD. Acupuncture has shown significant promise in relieving SCD pain in both preclinical and clinical studies. However, our understanding of the immune mechanisms by which acupuncture improves clinical pain symptoms of SCD, remains unexplored. This study aimed to examine whether acupuncture can ameliorate the heightened inflammatory/immune responses and the potential relationship with the improvement of clinical outcomes in patients with SCD. Methods: The study cohort consisted of 40 patients with SCD aged 14-73 years (23 female, 58%) enrolled in our ongoing parent RCT(ClinicalTrials.gov Identifier: NCT05045820), in which the participants are randomized to receive 5 weeks of verum or sham acupuncture, followed by 12 months of follow-up assessments.Inflammatory/immune responses were profiled by multiplex immunoassays that simultaneously quantified 80 inflammatory cytokines/chemokines/growth factors (referred to as cytokines thereafter) and 18 autoantibodies in plasma samples from the patients with SCD before and after the treatment. In addition, peripheral blood mononuclear cells (PBMCs) were used to profile changes in immune cell phenotypes by flow cytometry. Clinical outcomes were assessed by patient-reported outcomes (PROs). We evaluate pain intensity and interference, as well as physical dysfunction, using the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Questionnaire. Neuropathic pain symptoms are assessed using the PainDETECT Questionnaire. Depression is evaluated using the Hospital Anxiety and Depression Scale (HADS). Pain-related quality of life (QoL) is evaluated using the Pediatric Quality of Life Inventory (PedsQL). Statistical analysis was performed using GraphPad Prism with Wilcoxon test and Spearman's correlation. P < 0.05 was considered significant. Pleasenote: As our clinical trial remains ongoing and blinded, we are presently unable to definitively attribute observed effects solely to the verum treatment or the sham treatment. For these interim analyses, we pooled the data from the verum and sham groups and determined whether inflammatory/immune profiles and various clinical outcomes were modulated by the treatments. Results: Following treatments, plasma concentrations of 11 inflammatory mediators (Eotaxin-2, CCL23, IL-1α, IL-3, IL-6, IL-10, IL-21, I-TAC, TRAIL, TSLP, and CD30), 3 autoantibodies (SSA/Ro52, PCNA, Ku), and immune activation markers (PD-1 on B cells, %CD69+ NK cells, and CD38 on mucosal-associated invariant T cells) were significantly downregulated or showed a notable down-regulation trend. Consistent with our previousresults, pain intensity and interference, physical dysfunction, and depression were attenuated, along with improved pain-related QoL. Most importantly, the alleviated pain detection, pain interference, pain intensity, depression, or physical dysfunction strongly correlated with reduced levels of multiple inflammatory/immune markers (CCL23, IL-6, I-TAC, CD30, Ku, HLA-DR on B cells, and PD-1+ B cells). Conclusion: Our preliminary results suggest that acupuncture treatment is effective in reducing proinflammatory/immuneresponses that is associated with improved pain and emotional distress in patients with SCD.