Patient-centered endpoints, novel biomarkers, and long-term outcomes of high impact chronic pain in sickle cell disease: Sickle Pain Related Impact (SPiRIt-2) Study - ABSTRACT Sickle cell disease (SCD) is a rare inherited multi-system blood disorder that affects about 100,000 persons in the US, almost all of whom are Black or African American. Most adults with SCD experience chronic pain (CP), i.e., pain on most days of the month for 6 months or more, and poor outcomes. SCD CP is further complicated by progressive end-organ damage, premature mortality, and enduring disparities in pain care. Given individual variability in the impact of CP, the National Pain Strategy conceptualized CP with substantial restriction of participation in work, social, or self-care activities as High-Impact Chronic Pain (HICP). We have, for the first time, examined HICP in SCD. Our work in three cohorts, including the pilot Sickle Pain Related Impact (SPiRit) study has shown that HICP is a high-risk CP phenotype in SCD, distinct from mild-bothersome CP (MBCP), and that HICP may be a dynamic state. Thus, we do not know who is at risk for sustained HICP and long-term risk of poor outcomes (Gap 1), and who to prioritize for treatment intensification and for resource limited and high-risk intensive therapies (e.g., gene therapy, hematopoietic cell transplant). Identifying risk factors for sustained HICP is also crucial as they are potential intervention targets to reduce disability (Gap 1). Lack of patient-centered endpoints to assess the efficacy and impact of interventions for SCD CP is another gap; current SCD clinical trial endpoints do not consider the perspective of, or preferences for pain endpoints among persons with lived experience of SCD CP (Gap 2). Further, there are no blood-based biomarkers specific to SCD CP that complement self-reported pain, which hinder regulatory approval of new SCD treatments (Gap 3). Our work has set the stage to address these critical gaps in a definitive way in an observational longitudinal study, SPIRit2. In SPiRIt2, we will follow 300 adults with SCD CP every 6-months for 2 years (Timepoints T1-T5). To identify persons at sustained high-risk, we propose a novel longitudinal risk group classification based on overall frequency of HICP or MBCP; higher frequency of HICP relative to MBCP will be considered ‘overall high-risk’, and higher frequency of MBCP (or no CP) relative to HICP will be considered ‘overall low-risk’. We propose three specific aims: In Aim 1, we will examine the long-term temporal stability of HICP, risk factors and long-term outcomes of HICP in SCD. In Aim 2, we will identify preferences for pain-related endpoints for interventional clinical trials among persons with SCD CP. In Aim 3, we will identify proteomic biomarkers of HICP, pain outcomes, and central sensitization in SCD. Completion of aims will shift paradigms with an evidence-based framework for future interventions for SCD CP thereby improving patient outcomes, and will translate beyond SCD to the study of HICP. The PI and investigator team have research and clinical expertise in SCD, SCD CP, longitudinal studies, patient reported outcomes, psychology, qualitative science, decision science, plasma-based proteomics, quantitative sensory testing, and biostatistical expertise in pain to complete the proposed aims.
