As an autoimmune disease, people naturally think that glucocorticoid and /or immunosuppressants may have therapeutic effort on PBC. In the previous studies of UDCA combined with glucocorticoid or immunosuppressant17,18, part of studies may indicate that it is effective, but limited by the sample size, observation time and population. different results also contradict each other, and most of the literatures were published a long time ago. Therefore, we conducted this retrospective study in PBC patients receiving UDCA monotherapy and combination therapy.
To carry out our study, it is necessary to estimate the outcome of treated patients. We used different models to predict the prognosis as accurately as possible. According to Paris II standard, patients after UDCA treatment for one year were judged by ALP, AST and bilirubin levels, which were divided into two groups: good response group and poor response group, but there was a defect that the prognosis of each patient could not be predicted 15. Therefore, we used the GLOBE score system to collect indicators after UDCA treatment for one year to estimate the survival time without liver transplantation 16. The clinical value of this score in Chinese patients also has been verified 19.
In the present study, although the main biochemical indicators such as ALT, AST, GGT in the combination therapy group show a downward trend than UDCA monotherapy group there is no significant difference in the one-year response rate between the three groups based on the Paris II standard, suggesting that the addition of glucocorticoids and/or immunosuppressants to UDCA cannot significantly improve the one-year efficacy. The long-term survival rate of patients was judged based on GLOBE score, GLOBE score > 0.3 means that the long-term survival rate is lower than the matched general population 16. The study found that although there was no significant difference between combined therapy and UDCA monotherapy, triple therapy may improve the long-term survival rate of patients.
Glucocorticoids are widely used in inflammatory diseases, and their biological effects are mediated by glucocorticoid receptors antagonizing proinflammatory transcription factors 20. In recent years, it has been suggested that glucocorticoids are effective in the treatment of cholestatic liver diseases, which may be related to the inhibition of bile acid synthesis and the promotion of bile acid reabsorption. Additionally, researchers have found that glucocorticoids can inhibit the production of bile acids by inhibiting the expression of CYP7A1, the rate limiting enzyme of bile acid synthesis 21, and can increase the top dependency bile acid sodium transporters (Asbt) expression to stimulate the absorption of bile acid and liver cells in the ileal the basolateral bile transporter (Ntcp) expression to increase liver bile acid intake 21,22. Immunosuppressants are commonly used in the treatment of autoimmune diseases. Different drugs play different roles to regulate the immune response of the body. Generally speaking, on the one hand, it can reduce the number of lymphocytes by inhibiting the proliferation and activation of lymphocytes; on the other hand, it can inhibit the function of lymphocytes by inhibiting cytokines. Therefore, triple therapy may play a more effective role through different mechanisms of action between drugs.
Our study found that compared with monotherapy, triple therapy has few benefits for PBC patients in one year, but may improve the long-term survival rate of patients. For this seemingly contradictory conclusion, it may be caused by the disease characteristics of PBC itself. Although PBC is considered to be an autoimmune disease, it shows more damages related to free bile acid and secondary cholestasis. At present, some scholars believe that PBC is caused by the secretion defect of bicarbonate produced by biliary system23. In conclusion, immunosuppressive therapy has no effect or little effect on PBC, and there are adverse reactions. Therefore, the current guidelines do not recommend the use of immunosuppressive therapy 1. Although there was no significant difference in IgG level among the three groups, we can see that the median IgG level in group C (18.9) is higher than that in group A (16.40) and B (15.55), suggesting that the disease may continue to progress into variant syndrome, which may partly explain why the long-term survival rate of triple therapy will increase. In addition to the characteristics of pathogenesis, PBC is often associated with extrahepatic autoimmune diseases. Floreani made statistics on 361 cases of PBC patients during 1975–2012, and found that 221 patients (61.2%) had at least one kind of extrahepatic autoimmune disease 24, a study from China also showed that about half of the population with AMA positive had autoimmune diseases 25, but whether this is related to the increased long-term survival rate needs further study.
Some patients with PBC may overlap the characteristics of AIH, and there are two kinds of characteristics of autoimmune liver diseases at the same time, which is called overlap syndrome (OS). However, it is difficult to accurately judge and classify OS in clinical practice. Therefore, the International Autoimmune Hepatitis Group (IAIHG) recommends the use of variant syndrome to describe patients with two disease characteristics 26. If PBC patients are accompanied with abnormal examination results, such as elevated IgG, it should be suspected whether there is variant syndrome 27. According to Paris standard, IgG higher than 2 ULN is the diagnostic standard of variant syndrome 28. The levels of IgG in 79 patients with high IgG were analyzed, there were 74 patients whose IgG level was higher than 1 ULN, and 5 patients were more than 2 ULN. Compared with UDCA monotherapy group, there was no significant difference in one-year efficacy of combination therapy for PBC patients with high IgG, suggesting that the clinical benefit of combined therapy is not obvious compared with UDCA monotherapy treatment. Although it is considered that variant syndrome is a potential population sensitive to immunosuppressive therapy, we should pay close attention to the IgG level of patients to prevent the over diagnosis of variant syndrome and avoid unnecessary immunosuppressive treatment. Since the number of cases greater than 2 ULN is too small, no statistical analysis was conducted.
Although UDCA combined with glucocorticoid or immunosuppressants may have few clinical benefits for PBC patients, other combined treatment options need to be considered for patients with poor clinical response to UDCA monotherapy. Therefore, early detection of patients with poor response to UDCA alone is an urgent problem to be solved in clinical practice. Previous studies have shown that age and gender 29, biochemical indicators 30 are the influencing factors of UDCA treatment response. According to Paris II standard, patients were divided into good response group and poor response group. Comparing the clinical data of the two groups at the beginning of treatment, it was found that compared to the good response group, the poor response group has higher percentage of male patients, the levels of IgG, GGT, ALP, TBIL at baseline were higher, and the levels of ALB and PLT were lower. Cholestasis is the key link in the pathogenesis of PBC, GGT and ALP are the enzyme markers of bile duct injury, and TBIL reflects the degree of cholestasis. The increase of the above indicators indicates that the degree of cholestasis is more serious, while the decrease of platelet and albumin levels can partly reflect the decline of liver function, which may explain the poor response results in mechanism. The above-mentioned risk factors and different treatment regimens were included in the multivariate logistic regression analysis. It was found that high ALP, low ALB and PLT were the risk factors affecting the response to treatment. Our patients have no statistical difference in age, which is different from the previous study , which may be due to the young patients' neglect of disease symptoms leading to the bias of the included population and the small number of patients. Although the elevated level of IgG has not reached the diagnostic criteria of variant syndrome, this study still suggests that the elevated IgG level is related to poor response, and may be related to the characteristics of AIH, which needs further verification.
Our research has three main limitations. First of all, the number of patients treated with combination therapy was small. Only when patients go to other departments or have other diseases can they use glucocorticoid or immunosuppressants. Therefore, relatively few patients meet the inclusion criteria. At the beginning of the study, we further divided the double therapy group into UDCA combined with glucocorticoid or immunosuppressant group. However, there was no difference between the two groups in terms of baseline data and prognosis. Considering that the number of patients in the two groups was small, a comparison was made for the combination.
Secondly, we used the Paris II standard and GLOBE score to judge the prognosis of patients receiving combined treatment, which were only verified in PBC patients who received UDCA treatment for one year. However, the researchers found that the actual survival rate of UDCA combined with bezafibrate was higher than that estimated by GLOBE score . Whether UDCA combined with glucocorticoid or immunosuppressive therapy also underestimated the survival rate needs further study.
Finally, the analysis was a retrospective study with a low level of evidence.