Mengtao Li

Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjogren's syndrome among 1,726 registry participants.

OBJECTIVE To examine associations between labial salivary gland (LSG) histopathology and other phenotypic features of Sjögrens syndrome (SS). METHODS The database of the Sjögrens International Collaborative Clinical Alliance (SICCA), a registry of patients with symptoms of possible SS as well as those with obvious disease, was used for the present study. LSG biopsy specimens from SICCA participants were subjected to protocol-directed histopathologic assessments. Among the 1,726 LSG specimens exhibiting any pattern of sialadenitis, we compared biopsy diagnoses against concurrent salivary, ocular, and serologic features. RESULTS LSG specimens included 61% with focal lymphocytic sialadenitis (FLS; 69% of which had focus scores of ≥1 per 4 mm²) and 37% with nonspecific or sclerosing chronic sialadenitis (NS/SCS). Focus scores of ≥1 were strongly associated with serum anti-SSA/SSB positivity, rheumatoid factor, and the ocular component of SS, but not with symptoms of dry mouth or dry eyes. Those with positive anti-SSA/SSB were 9 times (95% confidence interval [95% CI] 7.4-11.9) more likely to have a focus score of ≥1 than were those without anti-SSA/SSB, and those with an unstimulated whole salivary flow rate of <0.1 ml/minute were 2 times (95% CI 1.7-2.8) more likely to have a focus score of ≥1 than were those with a higher flow rate, after controlling for other phenotypic features of SS. CONCLUSION Distinguishing FLS from NS/SCS is essential in assessing LSG biopsies, before determining focus score. A diagnosis of FLS with a focus score of ≥1 per 4 mm², as compared to FLS with a focus score of <1 or NS/SCS, is strongly associated with the ocular and serologic components of SS and reflects SS autoimmunity.

Primary Sjögren’s Syndrome as a systemic disease: a study of participants enrolled in an international Sjögren’s Syndrome registry

To study the prevalence of extraglandular manifestations in primary Sjögrens syndrome (SS) among participants enrolled in the Sjögrens International Collaborative Clinical Alliance (SICCA) Registry.

CD4 + CD25 + CD127 low/− T Cells: A More Specific Treg Population in Human Peripheral Blood

The quantitative identification and enrichment of viable regulatory T cells (Treg) requires reliable surface markers that are selectively expressed on Treg. Foxp3 is the accepted marker of nTreg, but it cannot be used to isolate cells for functional studies. In this study, we compared four staining profiles of Treg, including CD4+CD25high T cells, CD4+CD39+ T cells, CD4+CD73+ T cells, and CD4+CD25+CD127low/− T cells. We found that CD4+CD25+CD127low/− T cells expressed the highest level of Foxp3 and had the strongest correlation with CD4+CD25+Foxp3+ T cells, the accepted identifying characteristics for “real” nTreg cells. Moreover, functional data showed that CD4+CD25+CD127low/− T cells could effectively suppress the proliferation of CD4+CD25− T cells, suggesting that compared with the other three populations, CD4+CD25+CD127low/− T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood. Finally, we showed that CD4+CD25+CD127low/− can be used to quantitate Treg cells in individuals with systemic lupus erythematosus supporting the use of CD4+CD25+CD127low/− to identify human Treg cells.

Clinical characteristics of immunoglobulin G4–related disease: a prospective study of 118 Chinese patients

OBJECTIVE To characterize the clinical features of IgG4-related disease (IgG4-RD) in China. METHODS A prospective cohort study of IgG4-RD was carried out in Peking Union Medical College Hospital between 2011 and 2013. Patients with newly diagnosed IgG4-RD were enrolled. RESULTS A total of 118 patients with IgG4-RD were enrolled, including 82 males and 36 females, aged 53.1 (s.d. 13.6) years. The most common symptom at onset was lacrimal gland swelling (38/32.2%). A range of organs were involved: 77 patients (65.3%) had lymphadenopathy, 76 (64.4%) had sialadenitis, 60 (50.8%) had dacryoadenitis, 45 (38.1%) had autoimmune pancreatitis, 32 (27.1%) had pulmonary involvement, 31 (26.3%) had periaortitis/retroperitoneal fibrosis, 29 (35.4% of male patients) had prostatitis and 29 (24.6%) had renal involvement. In addition, there were 21 (17.8%) cases of sclerosing cholangitis, 15 (12.7%) of sinusitis and 10 (8.5%) of inflammatory pseudotumour. Uncommon manifestations included mediastinal fibrosis, skin involvement, sclerosing thyroiditis, hypophysitis, orchitis and colitis. Multiple organ involvement was observed in 93 patients, whereas only 4.2% had only a single organ involved. A history of allergy was reported in 73 (61.9%) patients. The serum IgG4 level was elevated in 97.5% and was correlated with the number of organs involved. Most patients were treated with glucocorticoids alone or in combination with immunosuppressive drugs, and the majority usually improved within 3 months. CONCLUSION IgG4-RD is a systemic inflammatory and sclerosing disease. Parotid and lacrimal involvement (formerly called Mikuliczs disease), lymphadenopathy and pancreatitis are the most common manifestations. Patients with IgG4-RD showed favourable responses to treatment with glucocorticoids and immunosuppressive agents.

Incidence of malignancy in primary Sjögren’s syndrome in a Chinese cohort

OBJECTIVES To evaluate the incidence of malignancies in a cohort of Chinese patients with primary Sjögrens syndrome (pSS) and to identify the risk factors of malignancy in pSS patients. METHODS A retrospective analysis was carried out in 1320 pSS patients who were recruited in Peking Union Medical College Hospital from 1990 to 2005 and were followed up for an average of 4.4 years. Among them, 29 patients developed malignancies. Standardized incidence ratios (SIRs) were calculated along with 95% CIs. Clinical characteristics were compared between patients with and without malignancies, as well as patients with haematological and non-haematological tumours. RESULTS Of the pSS patients, 2.2% developed malignancies during follow-up. Total SIR and SIR for lymphoma were 3.25 and 48.1, respectively. Different types of malignancy were observed including eight lymphomas, two myeloid myelomas and 19 solid tumours, which consisted of invasive thymoma, breast cancer, lung cancer, gastrointestinal adenocarcinoma, hepatoma, squamous cell carcinoma of tongue, uterine cervix cancer, renal carcinoma, thyroid carcinoma and mucoepidermoid carcinoma of parotid gland. Risk factor analysis showed that lymphadenopathy, enlargement of parotid glands, monoclonal immunoglobulin and absence of hypergammaglobulinaemia were correlated with malignancies. CONCLUSIONS The current study confirms the increased incidence of lymphoma in Chinese patients with pSS, with the majority of B-cell non-Hodgkins lymphoma. Associations between pSS and other malignant tumours such as myeloid myeloma, mouth cancer, breast cancer and thymoma need to be further observed.

Novel risk loci for rheumatoid arthritis in han chinese and congruence with risk variants in europeans

To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans.

Chinese SLE Treatment and Research group (CSTAR) registry: I. Major clinical characteristics of Chinese patients with systemic lupus erythematosus

The Chinese systemic lupus erythematosus (SLE) treatment and research group (CSTAR) provides major clinical characteristics of SLE in China and establishes a platform to provide resources for future basic and clinical studies. CSTAR originated as a multicentre, consecutive, and prospective design. The data were collected online from 104 rheumatology centers, which covered 30 provinces in China. The registered patients were required to meet four or more of the American College of Rheumatology (ACR) criteria for the classification of SLE. All CSTAR centers use the same protocol-directed methods to provide uniform evaluations, which included demographic data, clinical features, laboratory examinations, and disease activity evaluations. The patient samples, including DNA samples and sera, were also collected for further quality controls and additional studies. Preliminary analysis from 2104 baseline evaluations was available for this analysis. Of 1914 female and 190 male patients (F:M = 10.1), the mean age at onset was 29.2 y with confirmed diagnosis one year later at the age of 30.3 y. Eighty four (4.2%) of 2002 patients had a family history of rheumatic diseases, including 34 (1.7%) cases with SLE. In addition, one hundred and seven (5.2%) abnormal pregnancies were recorded among 2026 experiences. The characteristics of the CSTAR cohort were compared to similarly sized cohorts from other studies. We found that 56.1% of patients presented with concurrent hematological disorders compared to only 18.2% of European patients. Moreover, 47.4% of patients presented with nephropathy compared to 27.9% of European patients. Conversely, neurological manifestations were only seen in 4.8% of Chinese SLE patients compared to 19.4% of European patients, 12.1% of U.S. patients, 22.8% of Malaysian patients and 26.4% of Latin Americans. Pulmonary arterial hypertension and interstitial lung diseases were complications identified in 3.8% and 4.2% of Chinese lupus patients, respectively. The CSTAR registry has provided epidemiological data and phenotypes of Chinese patients with SLE, and has demonstrated several differences between ethnicities. Clinical data and biologic samples would be valuable resources for future translational studies with national and international collaboration.

Low-dose rituximab therapy for refractory thrombocytopenia in patients with systemic lupus erythematosus—a prospective pilot study

OBJECTIVES To evaluate the safety and efficacy of low-dose rituximab therapy for refractory thrombocytopenia in patients with SLE. METHODS Ten adult SLE patients with severe refractory thrombocytopenia (mean platelet count 10.4 × 10(9)/l) were enrolled in this prospective pilot study. All patients had failed traditional high-dose CSs and immunosuppressants including methylprednisolone pulse therapy. Patients were scheduled to receive i.v. rituximab at a dose of 100 mg once weekly for 4 weeks. Previous dose of CSs were gradually tapered, and immunosuppressants were withdrawn. Patients were followed at Weeks 4, 12, 24 and 36. RESULTS All patients completed four courses of low-dose rituximab infusion. At Week 4, two (20%) patients achieved complete responses (CRs, platelet count >100 × 10(9)/l). The CR rate increased to 60% (six patients) at Week 12, was maintained at Week 24 and began to drop at Week 36 (four patients, 40%). Overall response (OR, platelet count >50 × 10(9)/l) was achieved in 5/10, 6/10, 7/10 and 5/10 patients at Weeks 4, 12, 24 and 36, respectively. Peripheral CD19(+) B cells were depleted (<5 × 10(6)/l) in all patients at Week 4, and gradually increased at Weeks 24 and 36. Serum C3, IgG, IgA and IgM levels did not change significantly (P < 0.05). Infusion reaction was observed in two patients. One patient developed pulmonary thrombosis at Week 14 and active tuberculosis at Week 25. CONCLUSIONS Low-dose rituximab therapy is effective in treating severe thrombocytopenia in SLE patients who do not respond to vigorous glucocorticoid plus immunosuppressants, and in most cases is safe.

Elevated Levels of CD4+CD25+FoxP3+ T Cells in Systemic Sclerosis Patients Contribute to the Secretion of IL-17 and Immunosuppression Dysfunction

Objective Immune imbalance between regulatory T (Treg) and Th17 cells is a characteristic of systemic sclerosis (SSc). The functional heterogeneity among Treg can be elucidated by separating Treg into different subsets based on the expression of FoxP3 and CD45RA. The aim of this study was to investigate the role of Treg subsets in the immune imbalance in naïve SSc. Methods Peripheral blood mononuclear cells (PBMCs) of 31 SSc patients and 33 healthy controls were analyzed for the expression of CD4, CD25, CD45RA, CTLA-4, FoxP3, and IL-17 using flow cytometry. Treg immunesuppression capacity was measured in co-culture experiments. The expression of FoxP3, CTLA-4, IL-17A, and RORC mRNA was measured by real-time PCR. Results The frequency of CD4+CD25+FoxP3+ Treg cells was significantly elevated in patients with SSc (3.62±1.14 vs 1.97±0.75, p<0.001) with diminished immunosuppression capacity. In SSc, the proportion of FoxP3highCD45RA− activated Treg cells (aTreg) was decreased, the proportion of FoxP3lowCD45RA− T cells was increased, and the proportion of FoxP3lowCD45RA+ resting Treg cells (rTreg) was decreased. The immune suppression capacity of aTreg and rTreg was diminished, while FoxP3lowCD45RA− T cells exhibited a lack of suppression capacity. The immune dysfunction of aTreg was accompanied by the abnormal expression of CTLA-4. Th17 cell numbers were elevated in SSc, FoxP3lowCD45RA− T cells produced IL-17, confirming their Th17 potential, which was consistent with the elevated levels of FoxP3+IL-17+ cells in SSc. Conclusion A decrease in aTreg levels, along with functional deficiency, and an increase in the proportion of FoxP3lowCD45RA− T cells, was the reason for the increase in dysfunctional Treg in SSc patients, potentially causing the immune imbalance between Treg and Th17 cells.

Long-Term Survival and Death Causes of Systemic Lupus Erythematosus in China: A Systemic Review of Observational Studies

AbstractSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with an increased risk of death compared to general population. Although previous studies showed improvement in survival of SLE, the long-term prognosis has not been elaborated in China.This study aims to integrate the observational studies estimating current long-term survival of Chinese SLE patients and analyze the death-cause situation of SLE in China.The study is a systemic review of English and non-English articles using MEDLINE, EMBASE, CNKI, WANFANG, and SINOMED databases. Additional studies were found by consultation with clinical experts, browse of references in selected papers, and search of related textbooks. Our major search terms were SLE, follow-up, prognosis, survival, mortality, and China.We included cohort studies for survival analysis, and both cohort studies and case series for death-cause analysis in China.The extraction of the articles were done by 2 authors independently using predesigned charts, including characteristics of study, clinical data, analyzing data, and study quality indicators.All pooled analyses were conducted both for random-effects model and fixed-effects model. Funnel plots and Egger regression tests were applied to check potential publication bias. Heterogeneity was tested by sensitivity analysis. We identified 5 studies for survival analysis comprising 4469 Chinese patients with SLE (380 observed deaths). Thirty-six studies were suitable for death-cause analysis with 2179 observed deaths (derived from more than 20,000 Chinese patients with SLE). The overall pooled survival rates for SLE in China were 94% for 5-year survival rate and 89% for 10-year survival rate after disease onset from the year 1995 to 2013, which were similar with previous publications in Asia-Pacific area. The proportions of different causes of death showed infection (33.2%), renal involvement (18.7%), lupus encephalopathy (13.8%), and cardiovascular disease (11.5%) as the top 4 causes.The overall survival rates for Chinese patients with SLE resembled previous publications in Asia-Pacific area. But the death causes of SLE in China were of some differences indicating relatively higher proportion of infection and lupus encephalopathy and lower cardiovascular disease. Ethnicity and more aggressive treatment might have contributed to the difference in death composition.