The liver is an exocrine gland that is frequently involved in SS, and PBC is an autoimmune liver disease that is most frequently associated with SS [12]. Our study found that patients with liver injury caused by SS combined with PBC were more prone to cirrhosis, consistent with previous reports [3, 13]. Apart from conventional factors such as increased levels of liver enzymes and PBC-specific autoantibodies, this study demonstrated some other laboratory risk factors of PBC in patients with SS, including elevated IgM levels, ACA positivity, high ANA titer, and cytoplasmic ANA pattern. These results may aid in the early screening and diagnosis of PBC in patients with SS, especially for patients in the early stage of PBC without elevated ALP levels or those with negative AMA.
We found that the elevated IgM level was an independent risk factor for SS in patients with PBC, suggesting that clinicians should pay attention to IgM at an early stage of the disease. IgM is the primary immunoglobulin involved in the early immune response, and in patients with PBC, it is synthesized at high levels through T and B cell activation, reflected in higher serum concentrations [14–18]. Although there is a disorder in the peripheral B cell population of patients with SS [19], the abnormality of IgM mainly exists in the labial gland tissue [20], while immunological dysregulation in serum is related to IgG- rather than IgM-producing clones [21]. In addition, SS-associated autoantibodies (anti-SSA and anti-SSB) are reportedly IgG1-dominant [22, 23]. However, the specific AMAs of PBC are predominantly IgG2 and IgG3 [24, 25]. The present study found that in patients with SS ± PBC, the levels of IgG3, IgG3/IgG, IgG2, and IgG2/IgG were higher compared to those in patients with SS; however, the levels of IgG1/IgG were lower in patients with SS ± PBC than those in patients with SS. We speculated that there was a switch between immunoglobulin subtypes in the combined group, which may be involved in the pathogenesis of comorbidities.
ACA has also been detected in patients with various autoimmune diseases. Previous literature reported that 4.7% of patients with SS and 30% of patients with PBC were ACA-positive, and ACA-positive patients had common clinical features [26–28]. This study found that 31.1% of patients with SS ± PBC were ACA-positive, which was higher than 6.1% in the SS group. This result was consistent with the literature that reported ACA as a marker of SS combined with PBC [26, 29]. However, both groups had a similar prevalence of anti-SSA, anti-SSB, and anti-Ro52 antibodies, which was most likely attributable to SS.
ANA is a standard test used for the differential diagnosis of autoimmune diseases [30]. To the best of our knowledge, the cytoplasmic pattern of ANA indicates the existence of AMA, thus favoring the diagnosis of PBC [30, 31]. It has been reported that 59% of patients with SS display cytoplasmic pattern positivity, and patients with autoimmune disease and cytoplasmic pattern positivity exhibit hepatic involvement [32]. Our study found that 85.4% of patients with SS ± PBC had a cytoplasmic pattern, which was similar to the 62.2–85.7% of patients with PBC reported in the literature [31, 33] but higher than the 57.14% (4/13) of patients with SS ± PBC in the literature [33]. This may be due to the low case numbers in the literature, and the characteristic pattern of AMA (cytoplasmic granular type AC-21) was not separated from other cytoplasmic patterns in our study, which might have led to an overestimation of the results.
According to international recommendations, the ANA titer is mainly used to diagnose autoimmune diseases [34]. The literature reported no difference in ANA titers between SS and SS with PBC [13]. However, our study found that the ANA titer (≥ 1:10000) of patients with SS ± PBC was higher than that of those with SS. Previous studies reported that the ANA titers of 26.9% (83/309) of patients with SS and 40.1% (55/137) of patients with PBC were higher than 1: 1000 [31, 32]. Yang et al. reported that patients with PBC had higher ANA titers [35]. We speculated that the concomitant occurrence of SS and PBC might enhance the immune response, leading to higher antibody positivity.
In routine clinical practice, ALT and AST are the most frequently assessed liver enzymes, whereas ALP and GGT are less frequently available [36]. In addition, because of the high cost and unavailability in many clinics and hospitals, laboratory tests for autoimmune liver disease-specific autoantibodies cannot be widely applied to every patient with SS. These risk factors have great significance in reminding physicians to use further specific investigations for early PBC detection and diagnosis in patients with SS.
Our study has some limitations. This was a retrospective single-center study. Our study did not record the response to treatment in either group, and the clinical data were not strictly matched, which may have led to deviations in the results.