Clinical significance of serum bilirubin in primary Sjögren syndrome patients

Abstract Objective The purpose of our research was to demonstrate the clinical significance of serum bilirubin in primary Sjögren syndrome patients (pSS). Patients and methods A total of 116 patients with primary Sjögren syndrome and 138 matched individuals were included in our study. The laboratory parameters of patients with pSS and healthy controls were retrospectively analyzed. Results Serum total bilirubin, direct bilirubin, and indirect bilirubin were significantly reduced (P < .001, P = .001, P < .001) while ESR was significantly increased (P < .001) in patients with pSS when compared with healthy checkup individuals. Statistically, the AUC in patients with pSS is as follows: TBIL = 0.77, P < .001, cutoff value = 7.96; DBIL = 0.617, P = .001 cutoff value = 2.2; and IBIL = 0.786, P < .001 cutoff value = 4.5. Furthermore, our study revealed that TBIL, DBIL, and IBIL were significantly negativity related to ESR (r = −.406, P < .001; r = −.206, P = .026; r = −.429, P < .001). Interestingly, multiple linear regression analysis showed that when adjusted for sex, age, ALT, and AST, the levels of TBIL, DBIL, and IBIL in patients with pSS were independently correlated with ESR. Conclusions This study found that the levels of serum bilirubin were reduced and the inflammatory marker was elevated in patients with pSS. Additionally, serum bilirubin was negatively related with ESR and TBIL, DBIL, and IBIL can be used in the clinical diagnosis and follow‐up visits of the patients with pSS.

of pSS is related to genetic, environmental, and immunological basis, the exact cause is still unknown. 5 Previous studies had showed that pSS is related to some inflammatory cytokines such as interleukin-10 (IL-10), interleukin-17(IL-17), interferon-γ, and interleukin-37 (IL-37), 1,6-8 but they are too expensive to routine inspection.
As the final decomposition product of heme metabolism, functions of serum bilirubin not only in the endogenous strong antioxidant but also in anti-inflammation and immunosuppression provide significant protection for many diseases. Previous studies have discovered that the concentration of bilirubin was reduced in migraine, cardiovascular disease, and Crohn's disease patients. [9][10][11] Furthermore, serum bilirubin also plays a crucial role in autoimmune diseases, such as rheumatoid arthritis (RA), polymyositis (PM), and systemic lupus erythematosus (SLE). [12][13][14] Despite the fact that a variety of studies have demonstrated that the levels of bilirubin were related to inflammatory disease but there still no study shows the correlation between pSS and bilirubin, this study investigated the relation between the levels of bilirubin and patients with pSS.

| PATIENTS AND ME THODS
From June 2015 to June 2019, 116 patients with pSS who diagnosed in the First Affiliated Hospital of Guangxi Medical University (Guangxi, China) were included in our study. Patients with pSS were diagnosed according to international standards. 15 Additionally, 138 sex and age-matched individuals who went to our hospital for healthy checkup at the same time were served as healthy controls.
Patients with obesity, smoking, acute or chronic inflammatory diseases, cardiovascular disease, concomitant with other autoimmune diseases, anti-inflammatory drugs and painkillers treatment in the recent month, and liver damage caused by diseases were ruled out our study.

| Statistical analysis
The software of Statistical Product and Service Solutions (SPSS, version 24) was used for statistical analysis. We applied the Kolmogorov-Smirnov test to distinguish the normality of the data, and P > .1 was regarded as normal distribution data. Normal distribution data were compared by independent Student's t test and described by means

| RE SULTS
The characteristics of patients with pSS and healthy individuals are shown in Table 1. Sex and age have no statistically significant differences between patients with pSS and healthy individuals.

| D ISCUSS I ON
As far as we know, we are the first to report the relationship between the concentration of bilirubin and patients with pSS. We discovered that the concentration of bilirubin was significantly lower in patients with pSS than healthy individuals. Furthermore, our results showed that the levels of bilirubin have high diagnostic value in pSS and were negatively correlated with ESR.
Oxidative stress (OS) is caused by the excessive production of highly active molecules such as reactive nitrogen species (RNS) and reactive oxygen species (ROS), the degree of oxidation exceeds the scavenging of oxides, and the oxidation system and the antioxidant system are out of balance and lead to tissue damage, 16 which is one of the mechanisms of various diseases such as SLE, RA, and pSS. [17][18][19] Bilirubin is a type of tetra pyrrole pigment, which mainly comes from All in all, our study demonstrated that the levels of bilirubin were reduced in patients with pSS and negatively related to ESR.
Furthermore, the levels of bilirubin have high diagnostic value in primary Sjögren syndrome. Interestingly, we found that TBIL, DBIL, and IBIL were independently associated with ESR in patients with pSS.
Therefore, we speculate that the decrease of serum bilirubin in patients with pSS was caused by inflammation.
However, there are numerous shortcomings in this study. Firstly, this is a retrospective analysis and the sample size is relatively small.
Secondly, analysis of the correlation between bilirubin and other inflammatory cytokines such as IL-17, interferon-γ, IL-10, and IL-37 were not made. Lastly, comparison of the concentration of bilirubin before and after treatment in patients with pSS is required for further observation.