The Association of Hypocomplementemia With Disease Activity in Patients With Primary Sjogren's Syndrome

doi:10.21203/rs.3.rs-177190/v1

Download PDF

Research Article

The Association of Hypocomplementemia With Disease Activity in Patients With Primary Sjogren's Syndrome

https://doi.org/10.21203/rs.3.rs-177190/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

We assessed the prevalence of hypocomplementemia (HC), possible risk factors, and its prognosis in patients with primary Sjögren’s syndrome (pSS). The data of 84 patients with HC admitted in Hebei General Hospital were retrospectively analyzed and compared to data of patients with normocomplementemic (NC). Logistic regression analysis was used to detect risk factors. The presence of hyper-immunoglobulin G (IgG) and anti-Ro52 was significantly higher in patients with HC. The patients with pSS with HC had higher hematologic, renal, and nervous system involvement and The European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index score (p < 0.05) and received more immunosuppressant treatments than those with NC (p < 0.05). Multivariate logistic analysis indicated that renal involvement (odds ratio [OR] = 4.09), nervous system involvement (OR = 3.82), leukopenia (OR = 2.57), and hyper-IgG (OR = 3.34) were independent risk factors for pSS with HC. Thus, HC was not an uncommon manifestation of pSS and was associated with leukocytopenia, renal and nervous system involvement, and severe disease activity. HC occurred in younger and short-term patients with pSS. Those with pSS-HC had an increased possibility to develop systemic lupus erythematosus. Such patients have distinctive clinical manifestations and worse prognosis that require extensive treatments.

Rheumatology

hypocomplementemia

disease activity

primary Sjogren's syndrome

patients

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune rheumatic disease characterized by lymphocytic infiltration of exocrine glands, which could lead to heterogeneous and various clinical presentations from sicca symptoms to systemic disease¹. Approximately one-third of patients with pSS present extra-glandular manifestations, and some of these symptoms (e.g., interstitial lung disease, central nervous system [CNS] disease, and renal tubular acidosis) are associated with increased mortality. Abnormal immune response of T and B cells^2–4, recognition of self-antigens (Ro/SSA, La/SSB, and others), and subsequent activation are crucial for the cascade of events leading to the pSS pathology development⁵.

To date, there is increased evidence on distinct clinical phenotypes corresponding to unique autoantibodies. Various antibodies (e.g., anti-SSA, anti-SSB, anti-centromere antibodies [ACA]) have been reported to be classically correlated with parotid enlargement, Raynaud’s disease, arthritis, vasculitis, renal tubular acidosis, peripheral neuropathy, and cytopenias^6–9. Similarly, several serologic abnormalities, such as B-cell proliferation, present special clinical features; for instance, hypergammaglobulinemia is often accompanied by extraglandular manifestations, especially with cutaneous vasculitis and pulmonary, articular, and renal involvements^10–13. To date, few studies have addressed the clinical manifestations of hypocomplementemia (HC) or prognostic factors. This condition is not frequently observed but reported as a prognostic marker for lymphoma development in patients with pSS^14,15.

Here, we described the clinical features and outcomes of patients with pSS with HC as the presenting feature. Our aim was to shed light on the frequency of HC in a cohort of patients with pSS and to evaluate which clinical and serological features are significantly associated with HC.

Prevalence of HC in patients with pSS

The study cohort consisted of 333 patients (310 women and 23 men). The HC rate was 25.23% (84/333). Among the 84 patients with pSS with HC, 78 (92.86%) were women and 6 (7.14%) were men. Those with HC were younger than those without (49.86 ± 15.49 vs. 55.30 ± 12.38 years; p = 0.004).

Laboratory characteristics

As shown in Table 1, the patients with pSS with HC had striking significant differences between the two groups concerning the white blood cell (WBC) count (p < 0.001), in particular the neutrophil and lymphocyte counts (p = 0.003 and p = 0.005, respectively). The serum C-reactive protein (CRP) level was lower in patients with pSS-HC than in those with normal complement levels (p < 0.001), although the serum CRP level was approximately in a normal range. Additionally, the serum rheumatoid factor (RF) level (21.90 [10.6–158] vs. 16.55 [10.60–55.93]) was higher in the HC than in the normocomplementemic (NC) group, but the difference was not statistically significant (p = 0.44). Moreover, higher serum immunoglobulin G (IgG) levels were observed in the HC than in the NC group (p < 0.001). Further, higher serum IgG levels (53.57% vs. 30.04%, p < 0.001) and presence of anti-Ro52 positivity (71.43% vs. 56.22%, p = 0.01) were observed in patients with HC. Whereas, the positive rates of detecting antinuclear antibodies, ACA, anti-Ro/SSA, anti-La/SSB, and anti-RNP antibodies were not significantly different between the two groups. Besides, no significant difference in histologic evaluation of minor salivary gland, as a focus score ≥ 1, was observed between the two groups.

Table 1

Demographic and serological descriptors of patients with pSS with HC and NC
	HC group (n = 84)	NC group (n = 249)	p-value
	HC group (n = 84)	NC group (n = 249)	p-value
Demographic features
Sex (Women/Men)	13:1	13.65:1	0.92
Age at onset, years	49.86±15.49	55.30±12.38	0.004
Disease duration, months	24 [6–84]	60 [12–120]	0.004
Laboratory findings
White blood cell count (×10⁹/L)	4.52 [3.46–5.55]	5.12 [4.06–6.56]	0.001
Neutrophil counts (×10⁹/L)	2.71 [2.02–3.60]	3.11 [2.23–4.41]	0.003
Lymphocyte counts (×10⁹/L)	1.35 [0.98–1.72]	1.57 [1.18–1.90]	0.005
Hemoglobin (×g/L)	118.5 [107–127]	122 [111–134]	0.007
Platelet counts (×10⁹/L)	199 [159.25–260]	228 [182–274]	0.006
ESR (mm/1 h)	15.5 [7–43]	19 [10–35]	0.27
CRP (mg/L)	1.27 [0.59–3.30]	3.3 [1.68–5.33]	<0.001
RF (IU/L)	21.90 [10.6–158]	16.55 [10.60–55.93]	0.44
IgG (g/L)	18.13 [13.16–25.50]	14.90 [12.20–18.13]	<0.001
IgA (g/L)	2.75 [1.80–3.90]	2.73 [2.02–3.55]	0.34
IgM (g/L)	1.12 [0.78–1.59]	1.18 [0.83–1.62]	0.48
Elevated ESR (n, %)	36/80, 45.00	115/241, 47.72	0.67
Elevated CRP (n, %)	8/76,10.53	55/238, 23.11	0.02
Hyper-IgG (n, %)	45/84, 53.57	73/243, 30.04	<0.001
RF (+) (n, %) *	40/78, 51.28	110/233, 47.21	0.45
ANA (+) (n, %) **	66, 78.57	197, 79.12	0.92
Anti-RNP (+) (n, %)	12, 14.29	27, 10.84	0.40
Anti-Ro52 (+) (n, %)	60, 71.43	140, 56.22	0.01
Anti-Ro/SSA (+) (n, %)	54, 64.29	133, 53.41	0.08
Anti-La/SSB (+) (n, %)	26, 30.95	53, 21.29	0.07
ACA (+) (n, %)	11, 13.10	34, 13.65	0.90
Pathological MSG with focus score ≥1 (n, %)	78/80, 97.50	231/243, 95.06	0.53
pSS, primary Sjögren’s syndrome; RF, rheumatoid factor; ANA, antinuclear antibodies; MSG, minor salivary gland; ACA, anti-centromere antibodies; ESR, erythrocyte sedimentation rate; IgM, immunoglobulin M; IgA, immunoglobulin A; IgG, immunoglobulin G; CRP, C-reactive protein; NC, normocomplementemic urticarial vasculitis; HC, hypocomplementemia positive RF > 20 IU/mL; *positive for ANA titers ≥ 1:320.

Clinical manifestations

In our study, the patients with pSS with HC more commonly exhibited hematological involvement (68.23% vs. 51.20%; p = 0.01), thrombocytopenia (11.76% vs. 4.03%; p = 0.01), and leukopenia (34.11% vs. 14.11%; p < 0.001) at pSS diagnosis (Table 2). Compared to patients with pSS-NC, the patients in the HC group presented higher renal (11.76% vs. 4.83%, p = 0.03) and nervous system involvement (18.82% vs. 10.08%, p = 0.03). There were no significant differences in the classic symptoms of sicca syndrome, such as xerostomia, xerophthalmia, and salivary gland enlargement (p = 0.66, p = 0.99, and p = 0.58, respectively). Meanwhile, although the difference was not statistically significant, the incidence of mucocutaneous involvement was higher (p = 0.19), whereas the frequencies of arthritis, pulmonary involvement, and lymphatic system involvement were lower (p = 0.11, p = 0.34, and p = 0.33, respectively) in patients with pSS with HC than in those with NC.

Table 2

Comparisons of disease activity measures between patients with pSS with low (HC) and normal (NC) complement levels
Variables (n/%)	HC group (n = 84)	NC group (n = 249)	p-value
Xerostomia	72, 85.88	218, 87.50	0.66
Xerophthalmia	62, 74.11	184, 73.79	0.99
Salivary gland enlargement	11, 14.11	27, 10.48	0.58
Hematological involvement	57, 68.23	128,51.20	0.01
Thrombocytopenia	10, 11.76	10, 4.03	0.01
Leukopenia	28, 34.11	36, 14.11	< 0.001
Lymphopenia	31, 36.47	57, 22.98	0.10
Arthritis	31, 36.47	115, 46.37	0.11
Pulmonary involvement	15, 17.64	56, 22.58	0.34
Renal involvement	10, 11.76	12, 4.83	0.03
Digestive involvement	6, 7.05	11, 4.43	0.39
Nervous system involvement	16, 18.82	25, 10.08	0.03
Mucocutaneous involvement	26, 30.58	59, 23.79	0.19
Raynaud’s phenomenon	10, 11.76	28, 11.29	0.91
Lymphatic system involvement	6, 7.05	27, 10.88	0.33
ESSDAI	10.5 [6–15.5]	7 [3–12]	0.003
ESSDAI, European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index; NC, normocomplementemic urticarial vasculitis; HC, hypocomplementemia; pSS, primary Sjögren’s syndrome

Risk factors for HC in patients with pSS

Multivariate analysis confirmed that renal involvement (odds ratio [OR] = 4.09, 95% confidence interval [CI] 1.54–10.89, p = 0.005), nervous system involvement (OR = 3.82, 95% CI 1.76–8.27, p = 0.001), leukopenia (OR = 2.57, 95% CI 1.30–5.09, p = 0.007), and hyper-IgG (OR = 3.34, 95% CI 1.73–6.44, p < 0.001) were independent predictors of HC in patients with pSS (Table 3).

Table 3

Multivariate analysis of features predicting hypocomplementemia in patients with pSS
	p-value	OR	95% CI
Renal involvement	0.005	4.09	1.54–10.89
Nervous system involvement	0.001	3.82	1.76–8.27
Leukopenia	0.007	2.57	1.30–5.09
ACA positive	0.07	2.22	0.93–5.30
ANA positive	0.01	0.36	0.16–0.78
Hyper-IgG	< 0.001	3.34	1.73–6.44
CI, confidence interval; OR, odds ratio; pSS; primary Sjögren’s syndrome; ANA, antinuclear antibodies;
ACA, anti-centromere antibodies; IgG, immunoglobulin G

Therapeutic regimens and follow-up examinations

In the pSS-HC group, 25 (29.76%) patients received oral prednisolone, while 89 (33.33%) received immunosuppressants, including cyclophosphamide (n = 1), cyclosporin A (n = 5), mycophenolate mofetil (n = 4), iguratimod (n = 3), leflunomide (n = 15), and hydroxychloroquine (n = 61). Moreover, 75 (89.29%) patients received prednisolone, immunosuppressants, or a combination of the aforementioned drugs. Compared with the patients with pSS-NC, those with pSS-HC required cyclosporin A (p = 0.03) and mycophenolate mofetil (p = 0.04) treatment. Over a median follow-up period of 31.68 (range, 21–49) months, four patients developed systemic lupus erythematosus (SLE), and no patients died.

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 findings^23,24. 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 activities^28,29. 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 pSS^21,30.

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 occurrence^32,33. HC was thought to be associated with lymphoma development and worse prognosis in patients with pSS^14,16,34,35. 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.

Patients

In total, the data of 333 patients with pSS who were admitted to Hebei General Hospital from January 2016 to March 2019 were retrospectively reviewed. All patients fulfilled the American-European Consensus Group 2002 revised classification criteria for pSS³⁶. According to the presence of HC, our patients were divided into the study and control groups. The study was approved by the Research Ethics Committee of the Hebei General Hospital (NO.2016070), all patients provided written informed consent for all subjects.

Procedures

General data and laboratory and clinical information at onset of patients with pSS were retrospectively reviewed, including the first presentation and systemic involvements. Clinical data, such as age at diagnosis, disease duration, oral and ocular dryness, and constitutional symptoms, as well as data on joint, pulmonary, kidney, vasculitis, skin, nervous, gastrointestinal tract, and endocrine involvement were collected. The levels of complements (C3 and C4), erythrocyte sedimentation rate, CRP, immunoglobulins (IgG, IgM, and IgA), RF, anti-SSA, and anti-SSB were retrieved from the case records. The laboratory tests were performed at the regular hospital laboratory. The disease activity was determined according to the 2010 ESSDAI^37,38. All of the tests were performed at the clinical laboratory and all methods were performed in accordance with the relevant guidelines and regulations.

Statistical analysis

All data were analyzed using a standard statistical package (SPSS for Windows, version 25.0; IBM Corp., Armonk, NY, USA). Data are presented as means ± standard deviations, medians and interquartile ranges, or percentage frequencies, as appropriate. Group comparisons were conducted by Student’s t-test, Mann–Whitney’s U-test, or Fisher’s exact test, as appropriate. The potential risk factors for HC were assessed by multiple logistic regression analysis, and the results are expressed as ORs and 95% CIs. The level of significance was set at p < 0.05.

Data availability

The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

This work was funded by the grant from the National Nature Science Foundation of China (No. 81801630) and the National Nature Science Foundation of Hebei Province (No. H2018307047).

Author contributions

Conception and design: LW, ZF, ZW; acquisition of data: XZ, NX, YL, GS; analysis and interpretation of data: LY, NX, LM, SY; statistical analysis: LY, LW; drafting the article or revising it critically for important intellectual content: all authors; final approval of the version published: all authors;

Competing interests

All authors declare that they have no conflict of interest.

Goules, A. V. & Tzioufas, A. G. Primary Sjӧgren's syndrome: Clinical phenotypes, outcome and the development of biomarkers. Autoimmun Rev 15, 695-703, doi:10.1016/j.autrev.2016.03.004 (2016).
Lin, W. et al. B cell subsets and dysfunction of regulatory B cells in IgG4-related diseases and primary Sjögren's syndrome: the similarities and differences. Arthritis research & therapy 16, R118, doi:10.1186/ar4571 (2014).
Hamza, N., Bos, N. A. & Kallenberg, C. G. B-cell populations and sub-populations in Sjögren's syndrome. Presse medicale (Paris, France : 1983) 41, e475-483, doi:10.1016/j.lpm.2012.05.021 (2012).
Ibrahem, H. M. B cell dysregulation in primary Sjögren's syndrome: A review. The Japanese dental science review 55, 139-144, doi:10.1016/j.jdsr.2019.09.006 (2019).
Nocturne, G. & Mariette, X. B cells in the pathogenesis of primary Sjögren syndrome. Nature reviews. Rheumatology 14, 133-145, doi:10.1038/nrrheum.2018.1 (2018).
Ramos-Casals, M. et al. Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine 87, 210-219, doi:10.1097/MD.0b013e318181e6af (2008).
Scofield, R. H., Fayyaz, A., Kurien, B. T. & Koelsch, K. A. Prognostic value of Sjögren's syndrome autoantibodies. Journal of laboratory and precision medicine 3, doi:10.21037/jlpm.2018.08.05 (2018).
Mavragani, C. P., Tzioufas, A. G. & Moutsopoulos, H. M. Sjögren's syndrome: autoantibodies to cellular antigens. Clinical and molecular aspects. International archives of allergy and immunology 123, 46-57, doi:10.1159/000024423 (2000).
Baer, A. N., Medrano, L., McAdams-DeMarco, M. & Gniadek, T. J. Association of Anticentromere Antibodies With More Severe Exocrine Glandular Dysfunction in Sjögren's Syndrome: Analysis of the Sjögren's International Collaborative Clinical Alliance Cohort. Arthritis care & research 68, 1554-1559, doi:10.1002/acr.22859 (2016).
Ter Borg, E. J. & Kelder, J. C. Is extra-glandular organ damage in primary Sjögren's syndrome related to the presence of systemic auto-antibodies and/or hypergammaglobulinemia? A long-term cohort study with 110 patients from the Netherlands. Int J Rheum Dis 20, 875-881, doi:10.1111/1756-185x.13070 (2017).
Tsukamoto, M., Suzuki, K. & Takeuchi, T. Ten-year observation of patients with primary Sjögren's syndrome: Initial presenting characteristics and the associated outcomes. Int J Rheum Dis 22, 929-933, doi:10.1111/1756-185x.13464 (2019).
Baimpa, E., Dahabreh, I. J., Voulgarelis, M. & Moutsopoulos, H. M. Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects. Medicine 88, 284-293, doi:10.1097/MD.0b013e3181b76ab5 (2009).
Fauchais, A. L. et al. Articular manifestations in primary Sjögren's syndrome: clinical significance and prognosis of 188 patients. Rheumatology (Oxford, England) 49, 1164-1172, doi:10.1093/rheumatology/keq047 (2010).
Solans-Laqué, R. et al. Risk, predictors, and clinical characteristics of lymphoma development in primary Sjögren's syndrome. Seminars in arthritis and rheumatism 41, 415-423, doi:10.1016/j.semarthrit.2011.04.006 (2011).
Papageorgiou, A., Voulgarelis, M. & Tzioufas, A. G. Clinical picture, outcome and predictive factors of lymphoma in Sjӧgren syndrome. Autoimmun Rev 14, 641-649, doi:10.1016/j.autrev.2015.03.004 (2015).
Baldini, C. et al. Primary Sjogren's syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology (Oxford, England) 53, 839-844, doi:10.1093/rheumatology/ket427 (2014).
Jordán-González, P., Gago-Piñero, R., Varela-Rosario, N., Pérez-Ríos, N. & Vilá, L. M. Characterization of a subset of patients with primary Sjögren's syndrome initially presenting with C3 or C4 hypocomplementemia. European journal of rheumatology 7, 112-117, doi:10.5152/eurjrheum.2020.19132 (2020).
Lin, D. F. et al. Clinical and prognostic characteristics of 573 cases of primary Sjogren's syndrome. Chin Med J (Engl) 123, 3252-3257 (2010).
Zadura, A. F., Theander, E., Blom, A. M. & Trouw, L. A. Complement inhibitor C4b-binding protein in primary Sjögren's syndrome and its association with other disease markers. Scandinavian journal of immunology 69, 374-380, doi:10.1111/j.1365-3083.2009.02229.x (2009).
Sudzius, G. et al. Could the complement component C4 or its fragment C4d be a marker of the more severe conditions in patients with primary Sjögren's syndrome? Rheumatol Int 34, 235-241, doi:10.1007/s00296-013-2885-y (2014).
Evans, R. D., Laing, C. M., Ciurtin, C. & Walsh, S. B. Tubulointerstitial nephritis in primary Sjögren syndrome: clinical manifestations and response to treatment. BMC musculoskeletal disorders 17, 2, doi:10.1186/s12891-015-0858-x (2016).
Xia, W. et al. Clinical significance of C4d deposition in renal tissues from patients with primary Sjögren's syndrome-a preliminary study. BMC nephrology 20, 189, doi:10.1186/s12882-019-1341-y (2019).
Luo, J., Huo, Y. W., Wang, J. W. & Guo, H. High-Risk Indicators of Renal Involvement in Primary Sjogren's Syndrome: A Clinical Study of 1002 Cases. Journal of immunology research 2019, 3952392, doi:10.1155/2019/3952392 (2019).
Luo, J. et al. Clinical features and potential relevant factors of renal involvement in primary Sjogren's syndrome. Int J Rheum Dis 22, 182-190, doi:10.1111/1756-185X.13429 (2019).
Zhao, Y. et al. Primary Sjögren syndrome in Han Chinese: clinical and immunological characteristics of 483 patients. Medicine 94, e667, doi:10.1097/md.0000000000000667 (2015).
Yang, H. X. et al. Renal involvement in primary Sjögren's syndrome: A retrospective study of 103 biopsy-proven cases from a single center in China. International journal of rheumatic diseases 21, 223-229, doi:10.1111/1756-185x.13182 (2018).
Ye, W. et al. Clinical features and risk factors of neurological involvement in Sjögren's syndrome. BMC neuroscience 19, 26, doi:10.1186/s12868-018-0427-y (2018).
Carpanini, S. M., Torvell, M. & Morgan, B. P. Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System. Frontiers in immunology 10, 362, doi:10.3389/fimmu.2019.00362 (2019).
Brennan, F. H., Anderson, A. J., Taylor, S. M., Woodruff, T. M. & Ruitenberg, M. J. Complement activation in the injured central nervous system: another dual-edged sword? Journal of neuroinflammation 9, 137, doi:10.1186/1742-2094-9-137 (2012).
Mallah, K. et al. Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here? Frontiers in immunology 11, 2021, doi:10.3389/fimmu.2020.02021 (2020).
Yang, Y., Li, Z., Wang, L. & Zhang, F. The clinical and laboratory characteristics of Sjögren's syndrome that progresses to systemic lupus erythematosus: a retrospective case-control study. Int J Rheum Dis 16, 173-177, doi:10.1111/1756-185x.12088 (2013).
Carroll, M. C. The complement system in B cell regulation. Molecular immunology 41, 141-146, doi:10.1016/j.molimm.2004.03.017 (2004).
Roozendaal, R. & Carroll, M. C. Complement receptors CD21 and CD35 in humoral immunity. Immunological reviews 219, 157-166, doi:10.1111/j.1600-065X.2007.00556.x (2007).
Nishishinya, M. B. et al. Identification of lymphoma predictors in patients with primary Sjogren's syndrome: a systematic literature review and meta-analysis. Rheumatol Int 35, 17-26, doi:10.1007/s00296-014-3051-x (2015).
Theander, E., Manthorpe, R. & Jacobsson, L. T. Mortality and causes of death in primary Sjögren's syndrome: a prospective cohort study. Arthritis and rheumatism 50, 1262-1269, doi:10.1002/art.20176 (2004).
Vitali, C. et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Annals of the rheumatic diseases 61, 554-558, doi:10.1136/ard.61.6.554 (2002).
Seror, R. et al. Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Annals of the rheumatic diseases 74, 859-866, doi:10.1136/annrheumdis-2013-204615 (2015).
Seror, R. et al. EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome. Annals of the rheumatic diseases 69, 1103-1109, doi:10.1136/ard.2009.110619 (2010).

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

The Association of Hypocomplementemia With Disease Activity in Patients With Primary Sjogren's Syndrome

Status:

Version 1

Abstract

Introduction

Results

Prevalence of HC in patients with pSS

Laboratory characteristics

Clinical manifestations

Risk factors for HC in patients with pSS

Therapeutic regimens and follow-up examinations

Discussion

Methods

Patients

Procedures

Statistical analysis

Declarations

References

Additional Declarations

Status:

Version 1