To our knowledge, this study included the largest cohort of patients with pSS with HC. Their demographic characteristics and treatment outcomes are presented (Table 1). Approximately, 25.33% of patients with pSS had HC, and were more likely to have decreased WBC counts compared with those with NC (4.51 vs. 5.12, p < 0.001). Additionally, we demonstrated that HC is a marker of disease activity when applied across the entire cohort of patients with pSS, as HC is associated with the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI) score. However, to our knowledge, this is the first study to demonstrate that HC is a marker of pSS activity, thus suggesting the measurement of C3 and C4 levels to assess and monitor the condition of patients with pSS. Several candidates of risk factors in univariate analyses were found; of those, leukopenia, elevated IgG, renal involvement, and nervous system involvement were significantly related to HC development in patients with pSS, as observed in a multivariate analysis.
In this study, we found a prevalence of low C3 and C4 levels of 22.82% and 8.71%, respectively, which are similar to those of previous studies. Especially, Baldini et al.16 detected low C3 and C4 levels in 15.3% and 11.1% of 1,115 patients, respectively. Jordán-González et al.17 found low C3 and C4 levels in 9.57% and 13.83% of 94 patients, respectively, while Lin et al.18 reported low C3 and C4 levels in 14.4% and 16.5% of their participants, respectively. The different ethnicity, cohort size, disease severity degrees, and cut-off levels of the complement assays used may be attributed to the different prevalence of HC observed in these studies. Therefore, these results suggested that complement consumption may contribute to the pSS etiopathogenesis.
Several previous studies have explored the potential role for abnormal complement activation in pSS. Especially, Zadura, et al. found that with the widespread autoantibody production, the C4BP levels decreased in parallel with the C3 and C4 levels in active patients with pSS, which suggested that disturbed complement regulation may contribute to pSS pathogenicity19. Interestingly, Sudzius et al. reported that the serum C4d level was significantly lower in anti-SSA/SSB Ab seropositive than in seronegative patients with pSS and was also correlated with the C4 and anti-SSB Ab levels and the κ/λ ratio. They proposed that the C4d level can be an appropriate marker of complement activation in patients with pSS with Abs20. Evans et al. reported the presence of positive staining for C9 around the tubular basement membranes in patients with pSS-TIN (Tubulointerstitial nephritis, TIN)21. Moreover, Xia et al. performed a retrospective study and investigated the prevalence and localization of C4d deposits in renal biopsy tissues of patients with pSS. They found that glomerular C4d deposition was observed in all patients with pSS-related membranous nephropathy (MN) and suggested a role for the mannan-binding lectin pathway of complement activation in patients with pSS-related MN22. With the evidence of the complement system in vivo activation, these results suggested that complement consumption affects pSS pathophysiology. Therefore, the presence of HC in patients with pSS may signify the presence of disease activity. This is consistent with our findings, which demonstrated a significant higher ESSDAI score in patients with pSS-HC.
Our main aim was to demonstrate the relationship of HC with its role in pSS and its prognostic parameters. Jordán-González1 et al. found that pSS patients with low C3 levels were more likely to have leukocytoclastic vasculitis (44.4% vs. 8.2%, p = 0.010) and interstitial lung disease (33.3% vs. 1.2%, p = 0.002) and be exposed to rituximab treatment (22.2% vs. 2.4%, p = 0.045) than those with normal C3 levels17.
An increased interest in pSS-associated renal disease raised over the last few years. Specifically, the scientific interest focused on whether decreased complement in patients with pSS is associated with kidney involvement. In our study, HC was more commonly found in patients with renal disease than in those in other groups, which is in line with previous findings23,24. However, this finding was contradicted by other studies. Especially, Zhao et al. found that hypokalemic paralysis, assumed to be a surrogate of renal damage, did not show any association with low complement25. Moreover, Yang et al. published a retrospective study, which included 103 patients with pSS who had undergone kidney biopsy. Interestingly, no significant differences were observed between patients with and without renal disease26. Combined with the pathological findings, it was suggested that complement activation may have contributed to Sjogren’s nephritis development.
Nervous system involvement, ranging from the peripheral nervous system to the CNS, is known to be multifaceted and possibly underestimated in pSS. Neurological disease may arise many years before pSS diagnosis and was found to contribute to damage in patients with pSS. Our study is one of the first to report that nervous system involvement is a potential risk factor for HC in patients with pSS. Besides, we found that there was a relationship between the incidences of nervous system involvement and HC, which is consistent with the findings by Ye et al., who found that patients with pSS with neurological involvement showed reduced C3 levels (p < 0.05). Additionally, low C3 level was found to be a potential risk factor for neurological involvement in younger patients with pSS27. Moreover, arising data supported that the complement system may facilitate various neuroinflammation activities28,29. Because of the evidence indicating that the complement levels play key roles in driving multiple nervous pathologies, the complement system may be a potential therapeutic target for treating brain injury in patients with pSS21,30.
The complement system plays a pivotal role in SLE development, and previous data reported that patients with pSS with low complement levels are more likely to develop SLE. In a retrospective study including 55 patients with Sjogren’s syndrome-onset SLE (SS/SLE), Yunjiao et al. revealed that these patients showed a significantly higher frequency of low complement levels (C3, 54.5% vs. 12.7%; C4, 41.8% vs. 7.3%, p = 0.000). Additionally, low C3 and C4 levels were independent risk factors of SS/SLE development (low C3 levels, RR (Relative risk, RR) = 9.659, p = 0.000; low C4 levels, RR = 6.035, p = 0.007)31. In our study, four patients developed SLE during the follow-up period, which supported our notion that the patients with pSS with HC should be monitored carefully, as they are highly likely to develop SS/SLE.
Although the mechanisms underlying lymphoma pathogenesis in patients with pSS have not been well identified, low C3/C4 levels may help improve the survival of autoreactive B-cells in such patients and further, through mutations, increase the risk of lymphoid malignancy occurrence32,33. HC was thought to be associated with lymphoma development and worse prognosis in patients with pSS14,16,34,35. In our study, it is noteworthy that such patients with HC usually presented hypergammaglobulinemia, anemia, leukopenia, and, especially, lymphocytopenia at the time of pSS diagnosis, indicating that these conditions are strong predictors of lymphoma development. In accordance with previous reports, we confirmed the preponderance of high risk of lymphoma development in the HC group.
However, our study has several limitations. First, the study has a retrospective design. Second, we had no information regarding the cryoglobulin status. Especially, because of the lack of routine evaluation of cryoglobulin in our patients, we were unable to investigate their cryoglobulin status at the time of diagnosis. Therefore, we cannot exclude the possibility that patients with HC could also have cryoglobulinemia. To address this issue, a future study analyzing the predictive value of cryoglobulinemia in Chinese patients with pSS is required. Third, in this study, potential clinical factors in estimating the prognosis, such as changes in the C3/C4 levels, were not well evaluated. Further prospective studies with a larger number of patients with pSS are needed.
In conclusion, we confirmed that low complement levels are associated with renal and neurologic manifestations in patients with pSS. It is noteworthy that such patients with HC usually presented hypergammaglobulinemia, anemia, leukopenia, and, especially, CD4 (+) lymphocytopenia at the time of pSS diagnosis, thus highlighting the increased risk of lymphoproliferative disease development. Furthermore, this study revealed that HC might help in the early identification of patients with pSS who need to receive more aggressive treatments. However, further large-scale prospective studies are needed to confirm these findings.