Studies on newly recognized chronic sialadenitis / 北京大学学报(医学版)

Some kinds of chronic sialadenitis were recognized during the recent years. They have specific pathogenesis, clinical and histopathologic appearances, and require specific treatment. IgG4-related sialadenitis (IgG4-RS) is one of the immune-mediated diseases, characterized by tumefactive lesions. The incidence of IgG4-RS obviously increased during the past 30 years. The study on the potential relationship between occupational exposure to chemical substances and the incidence of IgG4-RS showed that subjects with occupational exposure to agents known to cause IgG4-RD had an increased risk for IgG4-RS. Surgical excision of involved SMG could not control the disease progression, which is not recommended for treatment of IgG4-RS. The combination of glucocorticoid and steroid-sparing agents is effective for treating IgG4-RS, and restores salivary gland function. Radioiodine induced sialadenitis (RAIS) is one of the common complications of postoperative adjuvant treatment of differentiated thyroid cancer by 131I. The incidence of the disease is related to radiation dosage. Clinically, the patients suffered from swelling and tenderness in the buccal or submandibular regions, especially during the mealtime. Imaging appearances are similar to those of chronic obstructive sialadenitis. Conservative managements, such as gland massage, sialagogues, are the mainstream methods in the treatment of RAIS. Sialendoscopy is feasible for RAIS, but not as effective as conventional obstructive sialadenitis (COS). Therefore the prevention of RAIS is crucial. Eosinophilic sialodochitis (ES) is a new type of chronic inflammatory disease of the salivary gland related to allergy. It has characteristics of swelling of multiple major salivary glands, strip-like gelatinous plugs discharged from the duct orifice of the gland, elevated level of serum IgE and eosinophils in peripheral blood, infiltration of eosinophils and IgE positive plasma cells in the tissues, allergic history, increased expression of allergy-related cytokines, such as IL-4, IL-5, IL-13, and eotaxin, which suggest allergic reactions as a potential pathogenesis of the disease. The clinical, laboratory, histological, and immunohistochemical characteristics of ES are significantly different from conventional obstructive sialadenitis (COS). Therefore, it is suitable to separate ES from COS. Conservative managements, such as self-maintenance therapy and anti- allergic modality are the choices of treatment for ES. Based on the results of our comprehensive studies a new classification of chronic sialadenitis is suggested.

Glucose-6-phosphate isomerase is associated with disease activity and declines in response to infliximab treatment in rheumatoid arthritis / 中华医学杂志(英文版)

BACKGROUND@#Rheumatoid arthritis (RA), a systemic autoimmune disease characterized by synovial inflammation, can cause cartilage and bone damage as well as disability. The aim of this study was to explore whether serum glucose-6-phosphate isomerase (GPI) is correlated with disease activity and the value of GPI in the evaluation of infliximab treatment in patients with RA.@*METHODS@#Sixty-two patients with RA who had an inadequate response to methotrexate (MTX) were enrolled in Peking University People's Hospital from July 1, 2016 to July 31, 2018. Infliximab (3 mg/kg, intravenous at weeks 0, 2, and 6 and then every 8 weeks) was administered to patients with stable background MTX therapy. Serum samples were obtained at baseline and week 18. Serum GPI levels were determined using enzyme-linked immunosorbent assay. The associations between serum GPI levels and clinical features were analyzed.@*RESULTS@#Serum GPI was positively correlated with Disease Activity Score in 28 joints (DAS28), swollen joint count, tender joint count and C-reactive protein level (P < 0.001, P < 0.001, P < 0.001, and P = 0.033, respectively). The change of DAS28 in GPI-positive patients was greater than that in GPI-negative patients (P < 0.001). Compared with those for patients receiving MTX monotherapy at baseline, the GPI levels were significantly declined when MTX was combined with infliximab (P < 0.001).@*CONCLUSION@#Serum GPI is related to disease activity and clinical response to infliximab treatment.

Effect of sustained intensive therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis: a 5-year real-world consecutive study / 中华医学杂志(英文版)

BACKGROUND@#Intensive therapy with disease modifying anti-rheumatic drugs (DMARDs) has been reported to improve the outcomes of rheumatoid arthritis (RA). However, real-world study on the effect of intensive therapy on RA sustained remission is still lacking. This study aimed to investigate the outcome of sustained intensive DMARD therapy (SUIT) for RA in a real-world 5-year consecutive cohort.@*METHODS@#Based on a consecutive cohort of 610 out-patients with RA, remission of RA was assessed in 541 patients from 2012 to 2017, by dividing into SUIT, non-SUIT, and intermittent SUIT (Int-SUIT) groups. Changes in the disease activity scores were evaluated by 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), 28-joint disease activity score based on C-reactive protein (DAS28-CRP), and clinical deep remission criteria (CliDR). Cumulative remission rates between different groups were compared using Kaplan-Meier curves and predictive factors of sustained remission were identified by univariate and multivariate logistic regression analysis.@*RESULTS@#The remission rates of the SUIT group decreased from 12.0% (65/541) to 5.6% (20/359) based on DAS28-ESR, from 14.0% (76/541) to 7.2% (26/359) based on DAS28-CRP, and from 8.5% (46/541) to 3.1% (11/359) based on CliDR, respectively, with a gradually decreasing trend during the 5 years. The SUIT regimen led to a significantly higher cumulative remission rate than non-SUIT regimen based on DAS28-ESR (39.7% vs. 19.5%, P = 0.001), DAS28-CRP (42.0% vs. 19.6%, P = 0.001), and CliDR (24.5% vs. 8.7%, P = 0.001). The cumulative remission rates of patients treated with SUIT regimen were significantly higher than those treated with Int-SUIT regimen based on DAS28-ESR (39.7% vs. 25.7%, P = 0.043) and CliDR (24.5% vs. 14.2%, P = 0.047), but there was no significant difference between the two groups based on DAS28-CRP (42.0% vs. 27.4%, P = 0.066). Multivariate logistic regression analysis showed that the use of SUIT regimen was an independent favorable predictor according to different remission definitions (for DAS28-ESR: odds ratio [OR], 2.215, 95% confidence interval [CI]: 1.271-3.861, P = 0.005; for DAS28-CRP: OR, 1.520, 95% CI: 1.345-1.783, P = 0.002; for CliDR: OR, 1.525, 95% CI: 1.314-1.875, P = 0.013).@*CONCLUSION@#Sustained intensive treatment of RA is an optimal strategy in daily practice and will lead to an increased remission rate.

Comparison of clinical and immunological features between clinically amyopathic dermatomyositis and typical dermatomyositis / 北京大学学报(医学版)

OBJECTIVE@#To study the differences between clinically amyopathic dermatomyositis (CADM) and typical dermatomyositis (DM) on clinical and immunological features.@*METHODS@#By collecting clinical data of 106 CADM patients and 158 DM patients from January 2010 to June 2019 in the department of Rheumatology and Immunology, Peking University People's Hospital, the clinical characteristics and immunological features in the two groups were compared, and the distribution characters and the clinical meanings of myositis autoantibodies were discussed in the two groups respectively. Myositis autoantibodies were measured by immunoblotting according to the manufacturers' instructions.@*RESULTS@#In the aspects of clinical manifestations, CADM presented more with onset of interstial lung diseases (ILD) compared with DM (20.7% vs. 7.6%, P=0.002), and CADM-ILD was more likely to be acute ILD (58.3% vs. 26%, P < 0.001), and there were no differences between CADM and DM in cutaneous manifestations, accompanied with connective tissue disease (CTD) and malignancy. In CADM, the positive rate of rheumatoid factors and antinuclear antibodies was lower in DM. The most common myositis specific autoantibodies (MSAs) in CADM were anti-MDA5 (36%), anti-PL-7 (11.2%) and anti-TIF-1γ (10.1%). The most common MSAs in DM were anti-Jo-1 (19.2%), anti-TIF-1γ (11.5%) and anti-MDA5 (11.5%). Anti-MDA5 was correlated with acute ILD and skin ulceration both in CADM and DM; in CADM, skin ulceration was not associated with the titer of anti-MDA5; while in DM, skin ulceration was associated with high titer of anti-MDA5. In DM, anti-TIF-1γ was correlated with heliotrope eruption, V/shawl neck sign, perionychia erythma and malignancy, and higher rate of malignancy was seen in all titers of the anti-TIF-1γ positive patients. In CADM, anti-TIF1-γ showed no correlation with clinical manifestations. The most common myositis associated autoantibody was anti-Ro-52 both in CADM and DM. In CADM, anti-Ro-52 was associated with Raynaud's phenomenon and chronic ILD, while in DM, anti-Ro-52 was associated with mechanic's hands, noninfectious fever and accompanied CTD.@*CONCLUSION@#Compared with DM, ILD is more likely to be acute in CADM. It is different between CADM and DM about the distribution of myositis autoantibodies and the clinical significance of the same myositis antibody, and the clinical significance of some myositis antibodies is related to titers.

Role of erythroblast-like Ter cells in the pathogenesis of collagen-induced arthritis / 北京大学学报(医学版)

OBJECTIVE@#To explore the role of Ter cells in the development of the collagen-induced arthritis (CIA), we detected their quantity changes in the spleen of different stages of CIA mice and analyzed the correlation between Ter cells and the joint scores, and we also analyzed the correlation between Ter cells and the frequencies of T and B cell subsets, so as to further understand the pathogenesis of rheumatoid arthritis.@*METHODS@#The six to eight weeks DBA/1 mice were used to prepare CIA model. After the second immunization, we began to evaluate the joint score. According to the time of CIA onset and the joint score, the CIA mice were divided into three stages: early, peak and late stages. According to the final joint score, the CIA mice at the peak stage were subdivided into the high score group (score>8) and the low score group (score≤8). The frequencies of Ter cells in the spleen of the naïve mice and the CIA mice at various stages and the frequencies of T and B cell subsets in the spleen of the CIA mice at the peak stage were detected by flow cytometry, then we carried on the correlation analysis.@*RESULTS@#The frequencies of Ter cells in the spleen of the CIA mice was significantly higher than those of the naïve mice (8.522%±2.645% vs. 1.937%±0.725%, P<0.01), the frequencies of Ter cells in the spleen of the high score group mice was significantly lower than those of the low score group (6.217%±0.841% vs. 10.827%±0.917%, P<0.01). The frequencies of Th1 cells in the spleen of the high score group mice was significantly higher than those of the low score group mice (1.337%±0.110% vs. 0.727%±0.223%, P<0.05). The frequencies of Th17 cells in the spleen of the high score group mice was higher than those of the low score group mice (0.750%±0.171% vs. 0.477%±0.051%, P=0.099). The frequencies of germinal center B cells in the spleen of the high score group mice was significantly higher than those of the low score group mice (1.243%±0.057% vs. 1.097%±0.015%, P<0.05). Correlation analysis results showed that the frequencies of Ter cells in the spleen of the CIA mice at the peak stage was strongly negatively correlated with the frequencies of CD4+ T, Th1, Th17, and germinal center B cells, and was strongly positively correlated with the frequencies of B10 cells, indicating that these cells might have a protective effect in CIA. Studies on dynamic changes showed that the frequencies of Ter cells in the spleen of the CIA mice at the late stage was significantly lower than those at the peak stage (0.917%±0.588% vs. 8.522%±2.645%, P<0.001), suggesting the protective effect of these cells in arthritis.@*CONCLUSION@#Ter cells were significantly increased in the spleen of the CIA mice at peak stage, and were negatively correlated with joint scores and pathogenic immune cells, and positively correlated with protective immune cells. Ter cells were significantly decreased in the spleen of the CIA mice at the late stage. What we mentioned above suggests that Ter cells might be involved in the progression of rheumatoid arthritis as an immunomodulatory cell,but further in vivo and in vitro experiments are needed to verify its specific effects and mechanism.

Family history of rheumatic diseases in patients with rheumatoid arthritis: a large scale cross-sectional study / 北京大学学报(医学版)

OBJECTIVE@#To determine the associations between the family history of rheumatic diseases and clinical features in patients with rheumatoid arthritis (RA).@*METHODS@#In total, eight hundred and ninety patients with RA were enrolled. The demographic and clinical data were collected, including gender, age, height, body weight, age of disease onset, history of smoking and drinking, family history of rheumatic diseases, clinical and laboratory features, pain and global visual analogue scale (VAS), and multi-dimensional health assessment questionnaire (MDHAQ). Finally, 803 patients were completed the dataset and were included in the study.@*RESULTS@#In this cohort, the male/female ratio was 1:3.5, and the age of onset was (45.09±14.50) years. A total of 123 (15.32%) patients were accompanied with family history of rheumatic diseases, including RA, spondyloarthritis, Sjögren's syndrome, systemic lupus erythematosus and systemic sclerosis. The percentages of first degree, second degree and both first and second degree relatives were 91 (73.98%), 22 (17.89%), and 10 (8.13%) respectively. The most common disease was RA (70.73%), followed by other rheumatic diseases (21.95%), and RA combined with other rheumatic diseases (7.32%). The clinical and laboratory characteristics were compared between the patients with and without family history. The onset-age of the subjects was significantly different between those with and without family history of rheumatic diseases (39.97 ±13.68 vs. 46.01±14.46; P<0.01), which meant that the onset-age in patients with family history was 6.04 years earlier than that in patients without family history. The patients with family history had higher positive rate of rheumatoid factor (RF) compared with those without family history (78.48% vs. 66.67%, P<0.05). By adjusting with gender, body mass index (BMI), smoking and alcohol drinking, anti-cyclic citrullinated peptide (CCP) antibody and RF level, the age at disease onset in the patients with family history was 4.54 years earlier than that in the patients without family history (β=-4.54; 95%CI:-8.70, -0.38; P<0.05). Further hierarchical regression analysis showed that, the age at onset of the RA patients with family history was 10.02 years earlier than that without family history among the smoking patients (β= -10.02; 95%CI:-17.60, -2.43; P=0.01), while the age at onset of the RA patients with family history was 3.27 years earlier than that without family history among the never smoking patients (β=-3.27; 95%CI:-8.37, 1.82; P=0.21).@*CONCLUSION@#The family history of rheumatic diseases is a risk factor for early onset of RA, and may interact with smoking.

Clinicopathological characteristics and diagnosis of IgG4related sialadenitis / 北京大学学报(医学版)

Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated disease and one of immunoglobulin G4-related diseases (IgG4-RD). Our multidisciplinary research group investigated the clinicopathological characteristics and diagnosis of IgG4-RS during the past 10 years. Clinically, it showed multiple bilateral enlargement of major salivary glands (including sublingual and accessory parotid glands) and lacrimal glands. The comorbid diseases of head and neck region including rhinosinusitis, allergic rhinitis, and lymphadenopathy were commonly seen, which could occur more early than enlargement of major salivary glands. Internal organ involvements, such as autoimmune pancreatitis, sclerosing cholangitis, and interstitial pneumonia could also be seen. Thirty-five (38.5%) patients had the symptom of xerostomia. Saliva flow at rest was lower than normal. Secretory function was reduced more severely in the submandibular glands than in the parotid glands. Serum levels of IgG4 were elevated in almost all the cases and the majority of the patients had increased IgE levels. CT, ultrasonography, and sialography showed their imaging characteristics. Histologically it showed marked lymphoplasmacytic inflammation, large irregular lymphoid follicles with expanded germinal centers, prominent cellular interlobular fibrosis, eosinophil infiltration, and obliterative phlebitis. Their immunohistological examination showed marked IgG-positive and IgG4-positive plasma cell infiltration and high IgG4/IgG ratio. The disease could be divided into three stages according to severity of glandular fibrosis. The serum IgG4 level was higher and the saliva secretion lower as glandular fibrosis increased. IgG4-RS should be differentiated from other diseases with enlargement of major salivary gland and lacrimal gland, such as primary Sjögren syndrome, chronic obstructive submandibular sialadenitis, and eosinophilic hyperplastic lymphogranuloma.

Clinical deep remission and related factors in a large cohort of patients with rheumatoid arthritis / 中华医学杂志(英文版)

BACKGROUND@#Clinical remission is the treatment target in rheumatoid arthritis (RA). This study aimed to investigate clinical remission and related factors in a large cohort of patients with RA.@*METHODS@#This study composed of 342 patients with RA. Data were collected by face-to-face interview of 1049 patients with RA who visited the Department of Rheumatology of three teaching hospitals from September 2015 to May 2016. The patients with RA were clinically assessed by rheumatologists and a four-page questionnaire was completed on site. Subsequently, patients fulfilled remission criteria were further analyzed. The practicability of different definitions of remission of RA was rated by a panel of rheumatologists. Sustained intensive disease modifying anti-rheumatic drug (DMARD) treatment was defined as a combination treatment with two or more DMARDs for at least 6 months.@*RESULTS@#In this cohort of 342 patients with RA, the proportions of patients achieving remission were 38.0%, 29.5%, 24.9%, 21.1%, 19.0%, 18.1%, and 17.0%, based on criteria of disease activity score in 28 joints (DAS28) using CRP (DAS28-CRP), DAS28 using ESR (DAS28-ESR), routine assessment of patient index data 3 (RAPID-3), Boolean, simplified disease activity index (SDAI), clinical disease activity index, and the newly described clinical deep remission (CliDR), respectively. Boolean and CliDR are the best in practicability scored by rheumatologists (7.5 and 8.0, respectively). Compared with the non-sustained intensive group, sustained intensive treatment with DMARDs yielded higher remission rates of 25.6%, 23.8%, and 21.3% in patients with RA based on Boolean (χ = 3.937, P = 0.047), SDAI (χ = 4.666, P = 0.031), and CliDR criteria (χ = 4.297, P = 0.038). The most commonly prescribed conventional synthesized DMARDs (csDMARDs) in patients with RA was leflunomide, followed by methotrexate, and hydroxychloroquine. Compared with the non-remission group, patients achieving remission had a longer median duration of DMARDs (45.0 [22.8-72.3] months, Z = -2.295, P = 0.022).@*CONCLUSIONS@#The findings in this study indicated that clinical deep remission is achievable in patients with RA. Sustained intensive DMARD treatment is needed to achieve a better outcome in RA.

Anti-cyclic citrullinated peptide antibody predicts the development of rheumatoid arthritis in patients with undifferentiated arthritis / 中华医学杂志(英文版)

BACKGROUND@#Clinical outcomes of undifferentiated arthritis (UA) are diverse, and only 40% of patients with UA develop rheumatoid arthritis (RA) after 3 years. Discovering predictive markers at disease onset for further intervention is critical. Therefore, our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development.@*METHODS@#We performed a prospective, multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals. Clinical and serological parameters were obtained at recruitment. Follow-up was undertaken in all patients every 12 weeks for 2 years. Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression.@*RESULTS@#A total of 234 patients were recruited in this study, and 17 (7.3%) patients failed to follow up during the study. Among the 217 patients who completed the study, 83 (38.2%) patients went into remission. UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9% vs. 16.8%, χ = 8.228, P = 0.008), anti-cyclic citrullinated peptide (CCP) antibody-positivity (66.7% vs. 10.7%, χ = 43.897, P < 0.001), and double-positivity rate of RF and anti-CCP antibody (38.1% vs. 4.1%, χ = 32.131, P < 0.001) than those who did not. Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017, 95% confidence interval: 5.803-55.938; P < 0.001).@*CONCLUSION@#As an independent predictor of RA, anti-CCP antibody should be tested at disease onset in all patients with UA.

Clinical deep remission and related factors in a large cohort of patients with rheumatoid arthritis / 中华医学杂志(英文版)

Background:@#Clinical remission is the treatment target in rheumatoid arthritis (RA). This study aimed to investigate clinical remission and related factors in a large cohort of patients with RA.@*Methods:@#This study composed of 342 patients with RA. Data were collected by face-to-face interview of 1049 patients with RA who visited the Department of Rheumatology of three teaching hospitals from September 2015 to May 2016. The patients with RA were clinically assessed by rheumatologists and a four-page questionnaire was completed on site. Subsequently, patients fulfilled remission criteria were further analyzed. The practicability of different definitions of remission of RA was rated by a panel of rheumatologists. Sustained intensive disease modifying anti-rheumatic drug (DMARD) treatment was defined as a combination treatment with two or more DMARDs for at least 6 months.@*Results:@#In this cohort of 342 patients with RA, the proportions of patients achieving remission were 38.0%, 29.5%, 24.9%, 21.1%, 19.0%, 18.1%, and 17.0%, based on criteria of disease activity score in 28 joints (DAS28) using CRP (DAS28-CRP), DAS28 using ESR (DAS28-ESR), routine assessment of patient index data 3 (RAPID-3), Boolean, simplified disease activity index (SDAI), clinical disease activity index, and the newly described clinical deep remission (CliDR), respectively. Boolean and CliDR are the best in practicability scored by rheumatologists (7.5 and 8.0, respectively). Compared with the non-sustained intensive group, sustained intensive treatment with DMARDs yielded higher remission rates of 25.6%, 23.8%, and 21.3% in patients with RA based on Boolean (χ2=3.937, P=0.047), SDAI (χ2=4.666, P=0.031), and CliDR criteria (χ2=4.297, P=0.038). The most commonly prescribed conventional synthesized DMARDs (csDMARDs) in patients with RA was leflunomide, followed by methotrexate, and hydroxychloroquine. Compared with the non-remission group, patients achieving remission had a longer median duration of DMARDs (45.0 [22.8–72.3] months, Z=-2.295, P=0.022).@*Conclusions:@#The findings in this study indicated that clinical deep remission is achievable in patients with RA. Sustained intensive DMARD treatment is needed to achieve a better outcome in RA.

Analysis of the clinical features and misdiagnosis reasons of 17 patients misdiagnosed with IgG4-related disease / 北京大学学报(医学版)

OBJECTIVE@#To summarize the clinical characteristics of patients misdiagnosed with IgG4-related disease, to analyze the reasons of misdiagnosis and to improve the clinical recognition of the disease.@*METHODS@#The general data, clinical manifestations, laboratory examination results and pathological features of 17 patients with IgG4-related diseases misdiagnosed outside the hospital were retrospectively analyzed.@*RESULTS@#Among the 17 patients, there were 9 males and 8 females with a median age of 45 years, and the median time from onset to diagnosis was 12 months. Most patients' initial admission department was not rheumatology or immunology department. Six of the 17 patients were eventually diagnosed with lymphoproliferative disease, 4 with autoimmune disease, and 2 with infectious disease, Rosai Doffman disease, desmofibromatosis, highly differentiated mucoepidermoid carcinoma of the bottom of the mouth, hypereosinophilic syndrome, asthma and allergic rhinitis in 1 case each. The typical sites of IgG4-related disease were involved in 14 patients, including 6 cases of parotid gland, 2 cases of submandibular gland, 3 cases of pancreas and 2 cases of retroperitoneal lesions. Serum IgG4 was elevated in 10 patients, serum IgG4/IgG value was higher than 10% in 7 patients, serum IgE was increased in 7 patients, complement was decreased in 4 patients, and eosinophilic granulocytes were increased in 3 patients. Pathological biopsy was performed in 15 patients, and infiltration of lymphocyte was observed in 10 patients, IgG4+ plasma cells were present in 5 patients, the ratio of IgG4+ plasma cells to IgG+ plasma cells was less than 40% in 4 patients and greater than 40% in 1 patient. However, none of the 15 patients had the storiform pattern of fibrosis and obliterative phlebitis.@*CONCLUSION@#A variety of diseases can perform as IgG4-related disease witih typical sites involved, elevated serum IgG4, even can be characterized by pathological IgG4+ plasma cells infiltration. Physicians should pay attention to the differential diagnosis and comprehensively evaluate the patient's clinical manifestations, and laboratory results. Timely and even repeated pathological biopsy is also needed for definite diagnosis.

Clinical characteristics and treatment outcomes of macrophage activation syndrome in adults: A case series of 67 patients / 北京大学学报(医学版)

OBJECTIVE@#To described the clinical and laboratory features and outcome of 67 macrophage activation syndrome (MAS).@*METHODS@#A total of 67 MAS patients from three centers from January 2007 to December 2017 were enrolled. Clinical and laboratory features, and response to therapy were analyzed. Predictive factors for remission and survival were explored.@*RESULTS@#We identified a mean age of (36.1±16.3) years at diagnosis of MAS and a median connective tissue disease (CTD) duration of 8 months prior to MAS development. Among 67 MAS patients identified, underlying diseases included adult-onset Still's disease (AOSD) in 56.7% and systemic lupus erythematosus (SLE) in 30.0%. Fever and splenomegaly were found in 100.0% and 82.1% of the patients, respectively. Ferritinemia and elevation of serum soluble interleukin-2 receptor was seen in 100.0% and 93.2% of the patients. Serum levels of alanine aminotransferase, D-dimer, ferritin and C reactive protein were significantly higher in MAS associated with the AOSD patients than in MAS associated with the SLE patients. A significant decrease of erythrocyte sedimentation rate was found in MAS associated with AOSD, as compared with MAS associated with SLE. The most commonly used therapy was corticosteroids, which were initially administered in 100.0% of the patients. Intravenous immunoglobulin (IVIG) was administered in 91.0%, cyclosporine A in 64.2%, and etoposide in 46.3% of the patients, respectively. The induction therapy yielded a complete remission (CR) at the end of week 8 in 47.8% of the MAS patients. The overall mortality rate at the end of week 16 was 22.4%. The median serum levels of gamma-glutamyltransferase, alkaline phosphatase, total bilirubin and direct bilirubin were significantly lower in the patients who achieved complete remission at the end of week 8 than in those who did not, and splenomegaly was significantly less frequent (71.9% vs.91.4%, P=0.037). Both the mean age at diagnosis of MAS and the mean age at diagnosis of underlying CTD of the deceased patients were elder than those of the survived population (P=0.014 and P=0.017, respectively). The platelet count was significantly less in the deceased population as compared with the living population (P=0.018). No addition of cyclosporine A (P=0.004) was identified as risk factors associated with death in Logistic regression analysis.@*CONCLUSION@#MAS secondary to connective tissue disease is most common with AOSD and SLE. In terms of laboratory findings, there were considerable differences between the patients with underlying SLE and those with AOSD. Advanced age and low platelet counts are significant predictive factors for death, while treatment with cyclosporine may reduce the risk.

A multi-center cross-sectional survey of medicine application in patients with osteoarthritis in China / 北京大学学报(医学版)

OBJECTIVE@#To investigate the clinical characteristics, the medicine application and to evaluate the disease activity in patients with osteoarthritis (OA) in China.@*METHODS@#This was a cross-sectional study. Totally 1 066 cases of OA from 40 hospitals in China from April to October 2017 were retrospectively enrolled. Demographic characteristics, clinical data, medicine application, and joint function were evaluated. All the data were analyzed by SPSS software 19.0. t test, Mann-Whitney U test and chi-square test were used for statistical analysis.@*RESULTS@#In the 1 066 cases, the male-to-female ratio was 1:3.6 and the average age was (61.9±11.0) years, with an age range from 36 to 94 years. The incidence of knee OA, hip OA, and hand OA were respectively 81.9% (873/1 066), 14.1% (150/1 066), and 36.3% (387/1 066). In the study, 242 (22.7%) cases had two kinds of joint areas involved and three joint areas were involved in 51 cases (4.8%), and 56.6% (603/1 066) of the patients used more than one kind of non-steroid anti-inflammatory drugs (NSAIDs) while 61.2% (652/1 066) used disease modifying osteoarthritis drugs (DMOADs), including glucosamine (37.5%, 400/1 066), chondroitin sulfate (2.0%, 21/1 066), diacetate (5.9%, 63/1 066), and the combination of these drugs (15.8%, 168/1 066). 8.6% (92/1 066) patients only took analgesics to relieve the pain, not using any kind of NSAIDs or DMOADs. And 232 patients (21.7%) had intra-articular injections, including 9.2% (98/1 066) sodium hyaluronate, 4.5%(48/1 066) glucocorticoid, and 8.1% (86/1 066) combination of the two drugs. The proportion of the patients taking topical drugs accounted for 26.5% (283/1 066) and physical therapy accounted for 15.8% (168/1 066). Compared with those who suffered from knee OA, the patients who suffered from hip OA had more severe disease assessment. Moreover, there were significant differences in pain (Z=-7.625, P<0.001), morning stiffness (Z=-6.229, P<0.001), and joint function (Z=-6.777, P<0.001) between the two groups of the patients who suffered from knee or hip OA with The Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. Furthermore, patients with hip OA took more analgesics (χ2=24.838, P<0.001).@*CONCLUSION@#Oral NSAIDs and DMOADs are wildly used in patients with OA in China. However, the treatment of some patients still need to be improved. Patients with hip OA are more seriously ill and require aggressive treatment.

A cross-sectional study of the clinical features and physician visit patterns at onset of immunoglobulin G4 related disease / 北京大学学报(医学版)

OBJECTIVE@#To comprehend clinical features and patient's physician visit patterns at onset of immunoglobulin G4 related disease (IgG4RD).@*METHODS@#In the study, 100 patients with IgG4RD who received treatments in the Department of Rheumatology and Immunology of Peking University People's Hospital from Apr. 1st, 2017 to Apr. 1st, 2018 were investigated, including gender, age, height, body weight, age of onset, physician visit history, primary history and how did the disease affected their life, etc. RESULTS: In this 100 IgG4RD cohort (57 males and 43 females), the male/female ratio was 1:0.75, the mean age of onset was (51.51±12.9) years, and the median duration was 49 months (ranging from 4 to 231 months). The onset age of males was significantly older than that of females (P<0.01). The manifestations showed that up to 69% patients had submaxillay glands lesion, 59% patients had lacrimal glands lesion, 28% patients had pancreas involvement and 28% patients had parotid glands involvement. The females had more lacrimal glands involvement (P<0.05). 62% patients were complicated with anaphylactic disease. The primary physician visit departments concentrated upon general surgery department (19/100), oral and maxillofacial surgery department (17/100), rheumatology and immunology department (16/100), ophthalmology department (15/100) and gastroenterology department (10/100). The departments where the confirmed diagnose was made concentrated upon rheumatology department (67/100),oral and maxillofacial surgery department (16/100) and gastroenterology department (7/100). The mean diagnosis duration after 2010 was (16.96±2.163) months, significantly shorter than that before 2010, which was (113.3±11.01) months. Before the definite diagnose was made, 43% patients underwent surgeries and 12% patients had more than one time surgeries. The patients whose first-visit department was a surgery department were more likely to undergo surgeries (P<0.01). 18% patients (18/100) stated that the disease had affected their work.@*CONCLUSION@#In this cohort of the IgG4RD patients, female is common and has earlier onset age than male. The major manifestations of IgG4RD are salivary glands, lacrimal glands and pancreas involvement. The common chief complains are salivary glands and lacrimal glands enlargement. Accompanied by anaphylactic disease is a marked manifestation of this disease. Delayed diagnoses are not rare, though this situation has been improved since 2010, and more attention still should be paid to the disease.

Study of bone mineral density and serum bone turnover markers in newly diagnosed systemic lupus erythematosus patients / 北京大学学报(医学版)

OBJECTIVE@#To investigate the changes of bone mineral density (BMD) and serum bone turnover factor in newly diagnosed systemic lupus erythematous (SLE) patients.@*METHODS@#Eighty newly diagnosed SLE patients and 80 age and gender matched healthy controls were enrolled. None of the SLE patients had ever received glucocorticoid, immunosuppressive agents or vitamin D. BMD was measured at radius,lumbar spine and hip by dual X ray absorptiometry (DXA). Bone turnover markers including serum levels of tartrate-resistant acid phosphatase 5b (TRAP5b),bone alkaline phosphatase (BAP) and 25-hydroxy vitamin D3 (25-OH-VD3) were measured by enzyme-linked immunosorbent assay (ELISA). Logistic regression was employed to analyze the risk factors associated with decreased BMD.@*RESULTS@#Mean age of the SLE patients was (32.8±12.4) years, and 85% were female, none of whom were post-menopausal. BMD was significantly reduced in all the measured sites, compared with the healthy controls. Sixteen (20%) of the patients were osteopenic in at least one site measured locations. The serum levels of 25-OH-VD3 were markedly reduced in the newly diagnosed SLE patients than those of the normal controls [(46.1+12.3) nmol/L vs. (25.4+11.2) nmol/L, P<0.001)]. The serum levels of 25-OH-VD3 in the SLE patients with nephritis were much lower than those without nephritis (P=0.04). A significant negative correlation was demonstrated between the serum concentration of 25-OH-VD3 and the disease activity scores as measured by SLE disease activity index (SLEDAI) (r=-0.3,P=0.001). The serum TRAP5b concentration was positively correlated with SLEDAI (r=0.435,P=0.003). Age (P=0.058) and SLEDAI (P=0.085) were probably associated with decreased BMD in Logistic regression analysis.@*CONCLUSION@#The study showed reduced BMD in untreated SLE patients. The role of chronic inflammation was of probable importance in bone metabolism.

Increased receptor activator of nuclear factor kappa B ligand expressed on B10 cells in rheumatoid arthritis / 北京大学学报(医学版)

OBJECTIVE@#To detect receptor activator of nuclear factor kappa B ligand (RANKL) expressed on B10 cells in rheumatoid arthritis (RA) and to evaluate the correlation between RANKL-producing B10 cells in RA and clinical features and laboratory parameters, trying to reveal the possible role of B10 cells in the pathogenesis of RA and the potential mechanism of impaired immunosuppressive capacities.@*METHODS@#25 RA patients and 20 healthy volunteers were enrolled. These RA patients did not received treatment with glucocorticoids, disease-modifying anti-rheumatic drug and biologics during the recent half of a year. The levels of RANKL-producing B10 cells were measured by flow cytometry (FCM) and polymerase chain reaction (PCR). The correlation between the frequencies of RANKL-producing B10 cells in RA and clinical data, laboratory parameters were analyzed. The role of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) in inducing RANKL expression in B10 cells was evaluated by in vitro stimulation assay. Independent samples t test, Pearson and Spearman correlation were used for statistical analysis.@*RESULTS@#B10 cells were capable of producing RANKL at a low level in health controls. The frequencies of RANKL-producing B10 cells were markedly higher in RA patients than in health controls (3.65%±1.59% vs. 2.25%±0.68%, P<0.01). The frequencies of these cells correlated positively with RA tender joint counts, swollen joint counts and disease activity score in 28 joints (DAS28) (r=0.479, P=0.035; r=0.519, P=0.008; r=0.526, P=0.019). However, no correlation was found between these cells and RA patient age, disease duration, or the levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA). After in vitro stimulation by TNF-α, but not IL-1β, B10 cells isolated from healthy donors demonstrated fundamentally upregulated expression of RANKL.@*CONCLUSION@#Our studies showed the frequencies of RANKL-producing B10 cells were markedly higher in RA patients, and their frequencies were positively correlated with RA tender joint counts, swollen joint counts and DAS28. These findings suggested that B10 cells might be involved in RA bone destruction.

Gene Polymorphism Is not Associated with Rheumatoid Arthritis Susceptibility in the Northern Chinese Han Population: A Case-Control Study / 中华医学杂志(英文版)

BACKGROUND@#Interleukin (IL)-37, also called IL1F7, is a natural inhibitor of inflammatory and immune responses. It is involved in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the role of IL1F7 gene polymorphism in RA susceptibility in a large cohort of patients.@*METHODS@#Five selected single-nucleotide polymorphisms in IL1F7 genes (rs2723186, rs3811046, rs4241122, rs4364030, and rs4392270) were genotyped by TaqMan Allelic Discrimination in Northern Chinese Han population. The allele and the genotype were compared between patients with RA and healthy controls. Association analyses were performed on the entire data set and on different RA subsets based on the status of the anti-cyclic citrullinated peptide antibody and the rheumatoid factor by logistic regression, adjusting for age and gender.@*RESULTS@#Trend associations were detected between rs2723186, rs4241122, rs4392270, and RA in Stage I (160 patients with RA; 252 healthy controls). Further validation in Stage II comprised 730 unrelated patients with RA (mean age: 54.9 ± 12.6 years; 81.6% females) and 778 unrelated healthy individuals (mean age: 53.5 ± 15.7 years; 79.5% females). No significant differences in the distributions of alleles and genotypes were observed between the case and control groups in both the entire set and the different RA subsets. Disease activity and age of RA onset were also not associated with genotype distributions.@*CONCLUSION@#IL1F7 gene polymorphism does not significantly influence RA susceptibility in the Northern Chinese Han population.

Efficacy and Safety of Tofacitinib in Chinese Patients with Rheumatoid Arthritis / 中华医学杂志(英文版)

Background@#Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies.@*Methods@#ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout.@*Results@#ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population.@*Conclusions@#Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population.@*Clinical Trial Identifier@#NCT00856544 and NCT00413699.

Gene Polymorphism Is not Associated with Rheumatoid Arthritis Susceptibility in the Northern Chinese Han Population: A Case-Control Study / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Interleukin (IL)-37, also called IL1F7, is a natural inhibitor of inflammatory and immune responses. It is involved in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the role of IL1F7 gene polymorphism in RA susceptibility in a large cohort of patients.</p><p><b>METHODS</b>Five selected single-nucleotide polymorphisms in IL1F7 genes (rs2723186, rs3811046, rs4241122, rs4364030, and rs4392270) were genotyped by TaqMan Allelic Discrimination in Northern Chinese Han population. The allele and the genotype were compared between patients with RA and healthy controls. Association analyses were performed on the entire data set and on different RA subsets based on the status of the anti-cyclic citrullinated peptide antibody and the rheumatoid factor by logistic regression, adjusting for age and gender.</p><p><b>RESULTS</b>Trend associations were detected between rs2723186, rs4241122, rs4392270, and RA in Stage I (160 patients with RA; 252 healthy controls). Further validation in Stage II comprised 730 unrelated patients with RA (mean age: 54.9 ± 12.6 years; 81.6% females) and 778 unrelated healthy individuals (mean age: 53.5 ± 15.7 years; 79.5% females). No significant differences in the distributions of alleles and genotypes were observed between the case and control groups in both the entire set and the different RA subsets. Disease activity and age of RA onset were also not associated with genotype distributions.</p><p><b>CONCLUSION</b>IL1F7 gene polymorphism does not significantly influence RA susceptibility in the Northern Chinese Han population.</p>

Clinical Relevance of Autoantibodies against Interleukin-2 in Patients with Systemic Lupus Erythematosus / 中华医学杂志(英文版)

<p><b>Background</b>Increased serum autoantibodies against interleukin-2 (anti-IL-2 autoantibodies) were reported in patients with systemic lupus erythematosus (SLE) and in patients receiving IL-2 therapy. This study aimed to explore the clinical relevance of serum anti-IL-2 autoantibodies and the interactions between low-dose IL-2 therapy and serum anti-IL-2 autoantibodies.</p><p><b>Methods</b>Serum samples were collected from 152 SLE patients and 100 age- and gender-matched healthy controls (HCs). Among them, 75 SLE patients were followed up for 10 weeks, and all of them were treated with corticosteroids, antimalarials, and/or immunosuppressants. Forty-six out of the 75 SLE patients received low-dose IL-2 therapy additionally. Clinical and laboratory parameters were collected at baseline and week 10. Serum anti-IL-2 autoantibodies were determined by enzyme-linked immunosorbent assay.</p><p><b>Results</b>Compared with HCs, median levels and positive rates of serum anti-IL-2 autoantibodies were higher in SLE patients (32.58 [23.63, 45.23] arbitrary unit [AU] vs. 37.54 [27.88, 60.74] AU, P = 0.006, and 5.0% vs. 18.4%, P = 0.002, respectively). Compared to those without the corresponding disorders, serum anti-IL-2 autoantibody was increased in patients with alopecia (49.79 [36.06, 64.95] AU vs. 35.06 [25.40, 58.46] AU, P = 0.033), but it was decreased in those with lupus nephritis (31.71 [22.60, 43.25] AU vs. 44.15 [31.43, 68.52] AU, P = 0.001). Moreover, serum anti-IL-2 autoantibody was positively correlated with serum IgA (r = 0.229, P = 0.005), total IgG (r = 0.327, P < 0.001), and total IgM (r = 0.164, P = 0.050). Treatment with exogenous IL-2 was not significantly associated with serum anti-IL-2 autoantibody. In addition, no significant difference was found in serum anti-IL-2 autoantibody between responders and nonresponders to low-dose IL-2 therapy.</p><p><b>Conclusions</b>Serum anti-IL-2 autoantibody was increased and associated with disease severity in SLE. Exogenous low-dose IL-2 did not significantly induce anti-IL-2 autoantibody production.</p>