Association between Inflammatory Cytokines and Liver Functions in Rheumatoid Arthritis Patients

Background: Rheumatoid arthritis (RA) is associated with abnormal liver tests, and the medications used for RA are often hepatotoxic. Therefore, this study aimed to investigate an association between pro-inflammatory and anti-inflammatory cytokines and liver function tests in RA patients. Methods: In this descriptive cross-sectional study, 88 RA patients were included, 84 of them were women and 4 men, aged 21–81 years. Serum interleukin-10 (IL-10), interleukin-17 (IL-17), Osteopontin (OPN) were measured and liver function tests were conducted. Results: The frequency of RAwas higher among adults aged>41 years (72 [81.8%]) than young adults aged ≤41 years (16 [18.2%]). RA was more common in women (84 [95.5%]) than in men (4 [4.5%]) – approximately 21:1-fold. Young adults had higher abnormal IL-10 than adult RA patients (OR = 3.72, p-value 0.044). Abnormal IL-17 (OR = 5.67, p-value 0.034) was found to be increased in young-adult RA patients. No association was observed between age and OPN and between the duration of disease and IL-10, IL-17, and OPN. Similarly, no association was noted between the types of treatment and IL-10, IL-17, and OPN, nor between IL-10, IL-17, OPN and liver parameters (AST, ALT, ALP, ALB, TP, and GGT). Conclusion: Pro-inflammatory and anti-inflammatory cytokines are not associated with abnormal liver functions, as has been demonstrated in RA patients.


Introduction
Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease. Although the prevalence of RA is lower globally (0.5-1%), it is associated with socioeconomic burden and higher risk of mortality rate [1]. Recent studies have demonstrated that the treatments used for RA improved outcome, and also accounts as a risk for hepatic complications [2]. The adverse effects of RA treatments include asymptomatic elevations of liver enzyme, fibrosis, and sometimes fatal hepatic necrosis [3]. On the other hand, liver disorders have been noted in untreated RA patients [4].
Increasing amounts of interleukin-10 (IL-10), a potent anti-inflammatory cytokine [5], can be detected in the synovium of RA patients. Additionally, considering that the activity of RA cannot be attenuated by IL-10 administration [6], many researchers suggest that IL-10 plays an important role in chronic liver diseases [7]. Interleukin-17 (IL-17), a proinflammatory cytokine, is upregulated in many autoimmune diseases such as RA; high levels of IL-17 have been reported to be produced in different samples of RA [8,9]. Some investigators suggest that IL-17 plays a key role in many liver diseases and is also associated with the progress of the disease [10][11][12]. Osteopontin (OPN) is a proinflammatory cytokine that induces RA [13][14][15], and included in many liver diseases, despite its role in liver problems are still controversial [16]. Therefore, this study was carried out to find out the association between pro-inflammatory, anti-inflammatory cytokines and liver function tests among RA patients.

Materials and Methods
This descriptive cross-sectional hospital-based study was conducted on 88 RA patients percentages. Chi-square test was used to determine the level of significance (P-value of 0.05 was considered to be statistically significant).

Results
RA is more common in adults (72 [ Also, abnormal IL-17 (OR = 5.67, p-value 0.034) was found to be increased in young adult RA patients while no association was seen between age and OPN (OR = 2.67, p-value 0.144; Table 2). Furthermore, no association was reported between the duration of the disease and IL-10, IL-17, and OPN with p-values 0.410, 0.176, and 0.502 and OR 0.77, 0.37, and 1.30, respectively (Table 3). Similarly, no association could be derived between the types of treatment and IL-10, IL-17, and OPN with p-value 0.246, 0.286, and 0.351 and OR 1.53, 2.21, and 0.65, respectively (Table 4). Pearson's correlation analysis revealed that there were no association between IL-10, IL-17, OPN and liver parameters (AST, ALT, ALP, ALB, TP, and GGT; Table 5).

Discussion
Abnormal liver functions were observed in RA patients. The researchers further attributed the abnormality to immune aggregations and others justified it by drugs toxicity. Accordingly, this study was carried out to assess whether the pro-inflammatory or anti-inflammatory cytokines are associated with liver functions in RA patients.
The current study revealed that there is no association between interleukins and liver function tests. In fact, abnormal liver tests were noted in patients with RA [17]. Concurrent with many previous studies, the frequency of RA is higher in elderly subjects [18,19]. A possible explanation might be that the protective mechanisms in elderly population are  decreased, resulting in decreased immunotolerance and decreased cytokines synthesis and T cells proliferation [20]. The demographic data indicated that the prevalence of RA was found to be 21-fold higher in women than in men. In contrast to a previous study in Sudan, the female-to-male ratio was 9:1 [21]. Since the change in sex hormones after  puberty is associated with high prevalence of RA in women, a woman's immune system is potentially more reactive than that of a man. The current study reports that young adults are more likely to have abnormal IL-10 and IL-17. However, these results disagree with previous studies [22,23]. No association was found between age and OPN level.
Concurrent with this finding, a relationship between age and OPN has been previously reported [24]. Similar to other results, no associations between IL10, IL17, OPN levels and the duration of disease have been demonstrated [22,23,25]. Despite reducing IL-17 after the use of steroids therapy, IL-10 was increased [26]. The present study revealed no associations between IL-10, IL-17, OPN levels and the types of treatment. It has become clear that steroids directly modulate the pro-inflammatory cytokine or suppress cytokines-producing cells [26,27].

Conclusion
The data of present study shows that women are at a higher risk to have RA. Moreover, young adult RA patients are more likely to have abnormal IL-10 and IL-17. Furthermore, pro-inflammatory and anti-inflammatory cytokines are not associated with abnormal liver functions as has been demonstrated in RA patients.