What's Race Got to Do With It? CRP Levels in Immune Mediated Skin Diseases: Considerations for Hidradenitis Suppurativa

Currently, there is a lack of racial/ethnic heterogeneity in research databases, exposing a systematic issue in studies exploring inflammation-mediated diseases, such as hidradenitis suppurativa (HS). HS is a chronic inflammatory skin condition that disrupts normal structure and functioning of terminal hair follicles, resulting in the formation of recurrent abscesses, nodules, and sinus tracts within intertriginous regions. Studies have described higher serum levels of inflammation-mediated C-reactive protein (CRP) in patients with HS, a disease that predominantly affects skin of color (SOC) populations. Herein, we explore the role of CRP levels in the context of HS disease presentation, management, and psychosocial implications in SOC patients to determine existing disparities in research studies.


INTRODUCTION
Skin of color (SOC) refers to individuals of African, Asian, Native American, Middle Eastern, and Hispanic backgrounds (1). According to the 2020 United States (US) Census, these persons collectively constitute nearly half of the population (2). Among the US and United Kingdom (UK) populations, the Black community accounts for 13.4% of 328 million and 3.3% of 56.1 million, respectively (3). Despite being one of the largest minority groups in both countries, this population is marginally included in research.
A recent article by Nagar et al. revealed higher serum levels of inflammation-mediated C-reactive protein (CRP) in UK populations composed largely of older, Black females. Notably, the sample included only 6,456 (0.1%) Black subjects and 426,842 (98.5%) White subjects (4). Compared to census demographics reported during the same time period (2006)(2007)(2008)(2009)(2010)(2011), this sampled population underrepresents Black communities (3). Their findings suggest that socioenvironmental factors play a consequential role in explaining these disparities. Yet, the lack of racial/ethnic heterogeneity in their dataset demonstrates a systematic issue in studies exploring inflammation-mediated diseases. This fundamental representation gap limits our understanding of disease biomarker influence on inflammatory skin conditions that disproportionately affect minority patients.
CRP is an acute phase reactant produced by the liver during inflammation. With pro-inflammatory and anti-inflammatory properties, CRP is essential in the clearance of foreign antigens and damaged cells (5). Traditionally, it has been used as a biomarker for infectious and cardiovascular events (6), but various studies also demonstrate a correlation between CRP levels and disease severity in inflammatory skin conditions (7-9) such as HS (10). Research shows that socioeconomic and psychosocial factors likely contribute to variations in CRP levels between Blacks and Whites. Low-income status and smoking activity contributed most to elevated CRP levels among older Black males, whereas obesity mainly contributed to elevated CRP levels in older Black females (11). Moreover, self-reported daily and lifetime discrimination by Blacks/African Americans (AA) correlated with increased CRP levels (12).
Here, we highlight the limited correlative research on CRP in SOC HS patients to address this population's existing health disparities and poor psychosocial outcomes. The present study found that though differences in CRP levels have been related to HS severity, there is paucity of research exploring its correlation to race in the disease. Our aim is to encourage dialogue about the underrepresentation of Blacks/AA within CRP as well as HS investigations, underscoring the need for diversity in clinical and biomedical studies to produce generalizable data and results.

HIDRADENITIS SUPPURATIVA
HS is a chronic inflammatory skin condition that disrupts normal structure and functioning of terminal hair follicles. It is characterized by the formation of recurrent abscesses, nodules, and sinus tracts in intertriginous regions, with severe complications including soft tissue infection, lymphedema, and sepsis (13)(14)(15). Although the pathogenesis is not entirely understood, studies show that HS is three times more prevalent in Blacks/AA compared to Whites (16,17). Yet, there is a scarcity of diverse representation in research examining CRP's role in inflammatory diseases despite its strong association and increased levels in SOC patients. Quantitative evaluation has revealed higher CRP levels among HS patients than matched controls, independent of BMI and smoking status (10,18). Moreover, CRP levels were found to be an independent predictor of Hurly Stage III, the most severe form of the disease (19). In patients with moderate-tosevere HS, Adalimumab treatment led to significant improvement in the clinical inflammatory load. These patients also showed reductions in serum CRP levels from baseline following treatment (20). All of these studies account for various predisposing factors, such as smoking status, obesity (BMI), gender, and age while neglecting to consider race (10,19,21). Table 1 shows a summary of the information extracted from these studies. Though several studies suggest CRP as a potential biomarker for HS, the scarcity of representation of SOC in such studies prevents the generalizability of this data. Monitoring race in studies such as these can further explain extenuating aspects that cause minority patients to be affected by common disease processes differently.
Oversight of this inequality maintains and exacerbates existing psychosocial outcomes of Black HS patients. These communities report a lower health-related quality of life, which is attributed to debilitating chronic pain, poor mental health and diminished self-sufficiency (35)(36)(37)(38). Phenotypic manifestations, including disfiguring nodules with malodorous discharge, perpetuate social stigma, low self-esteem and self-isolation. This is implicated in the disproportionate rates of depression, anxiety, substance use, and suicidal ideation among this population (37,(39)(40)(41)(42)(43). Interestingly, patients with major depressive disorder exhibit increased peripheral blood concentrations of CRP (44,45), and elevated CRP levels predict resistance to standard antidepressant therapies (44,46,47). Black/AA patients are more likely to have severe HS with elevated CRP levels (48,49). Thus, neglecting these communities hinders quality of life while deepening existing disparities (49,50).

DISCUSSION
Inflammatory skin conditions like HS have distinct features in SOC populations, and CRP is a commonly utilized biomarker that is linked to disease activity. Compared to individuals without disease, CRP levels are significantly elevated in individuals with HS. Despite the vast evidence of more severe disease manifestations among Black populations, there is a gross underrepresentation of racial minorities throughout clinical and biomedical research even in diseases that disproportionally affect SOC patients.
Addressing the racial disparity in clinical and biomedical research studies, databases, and biorepositories is therefore critical to reducing the disease burden experienced by SOC patients. Researchers should accurately report race/ethnicity data and establish race-matched healthy controls. Understanding mediators of inflammatory skin diseases among Black patients may reveal pertinent risk factors and optimal therapeutic strategies. This will inform tailored interventions to appropriately address the aforementioned psychological  burdens, as this lack of diversity has culminated in poorer outcomes among vulnerable populations. While limitations associated with inadequate diversity in data collection have been established, little has been done to revolutionize change. Therefore, it is imperative that academic researchers prioritize racial/ethnic diversity during patient recruitment as well as biospecimen collection and analysis.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article material. Further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS
CO, JW, CI, PI, and AB identified the gap in the field and conceptualized the overarching idea. CO, JW, CI, and PI collected and summarized the data from literature searches and drafted the manuscript. RK, JP, GO, and AB provided critical review and revised this manuscript. All authors contributed to the article and approved the submitted version.

FUNDING
The publishing of this work was supported by the Skin of Color Society Career Development Award (ASB). The symbol * represents missing data.