Sjögren's syndrome combined with cold agglutinin disease: A case report / 北京大学学报(医学版)

Sjögren's syndrome(SS)is a chronic autoimmune disease that affects exocrine glands, especially salivary and lacrimal glands. The main clinical manifestations are dry mouth and dry eyes, but also multi-organ and multi-system can be involved. Cold agglutinin disease(CAD)is an autoimmune disease characterized by red blood cell agglutination in the blood vessels of extremities caused by cold agglutinin at low temperature, resulting in skin microcirculation disturbance, or hemolytic anemia. Cold agglutinin disease is divided into two categories, primary cold agglutinin disease and secondary cold agglutinin disease. Primary cold agglutinin disease is characterized with cold agglutinin titer of 1 ∶4 000 or more and positive Coomb's test. However, the Coomb's test is not necessarily positive and the cold agglutinin titer is between 1 ∶32 and 1 ∶4 000 in secondary cold agglutinin disease. Here, we reported an elderly patient admitted to hospital due to fever. He was diagnosed with respiratory infection, but he showed incompletely response to the anti-infection treatment. Further laboratory tests showed the patient with positive ANA and anti-SSA antibodies. Additionally, the patient complained that he had dry mouth and dry eyes for 1 year. Schirmer test and salivate gland imaging finally confirmed the diagnosis Sjogren's syndrome. During the hospital stay, the blood clots were found in the anticoagulant tubes. Hemolytic anemia was considered as the patient had anemia with elevated reticulocytes and indirect bilirubin. In addition, further examination showed positive cold agglutination test with a titer of 1 ∶1 024, and cold agglutinin disease was an important type of cold-resistant autoimmune hemolytic anemia. Furthermore, the patient developed cyanosis after ice incubating at the tip of the nose. Hence, the patient was diagnosed as CAD and he was successfully treated with glucocorticoids instead of anti-infection treatments. Hence, the patient was diagnosed with SS combined with secondary CAD. SS combined CAD are rarely reported, and they are both autoimmune diseases. The abnormal function of B lymphocytes and the production of autoantibodies might be the common pathogenesis of them. Cold agglutinin disease can lead to severe hemolytic anemia, even life-threatening. In clinical practice, timely recognizing and dealing with CAD might promote the prognosis of the patient.

Consistency analysis and clinical guiding significance of cytomegalovirus nucleic acid and antibody detections in patients with different clinical characteristics / 北京大学学报(医学版)

OBJECTIVE@#To investigate the consistency of cytomegalovirus deoxyribo nucleic acid (CMV-DNA) and immunoglobulin M (IgM) antibody detections in patients with different clinical characteristics and their guiding value for clinical practice.@*METHODS@#From December 2014 to November 2019, a total of 507 patients who were detected with both CMV-IgM and CMV-DNA were collected in Peking University International Hospital. Their general information, such as gender, age and clinical data, including the patient's diagnosis, medication, and outcome were also collected. The groups were stratified according to whether CMV-DNA was negative or positive, CMV-IgM was negative or positive, age, gender, and whether they received immunosuppressive therapy or not. The Pearson Chi-square test or Fisher's exact test was used for comparison of the rates between the groups. P < 0.05 means the difference is statisti-cally significant.@*RESULTS@#Of the 507 patients submitted for examination, 55 (10.85%) were positive for CMV-DNA, 74 (14.60%) were positive for CMV-IgM, and 20 (3.94%) were positive for both CMV-DNA and CMV-IgM. Of the 55 patients with CMV-DNA positive, 37 were male, accounting for 67.27%. In addition, 25 patients were older than 60 years, accounting for 45.45% and 33 patients received immunosuppressive therapy, accounting for 60%. The rates were higher than that of CMV-DNA negative group, 47.35% (P=0.005), 68.14% (P=0.043), 46.02% (P=0.050), respectively. Of the patients with both CMV-DNA and IgM positive, 45% received immunosuppressive threapy, which was lower than that of CMV-DNA positive but IgM negative patients (68.57%, P=0.086), and also lower than CMV-DNA negative but IgM positive patients (68.52%, P=0.064). In the patients with both CMV-DNA and IgM positive, 91.67% showed remission after receiving ganciclovir, whereas in the patients with CMV-DNA positive but IgM negative, the rate was only 60% (P=0.067).@*CONCLUSION@#CMV-IgM antibody detection is affected by age, gender, and immune status. It is not recommended to use CMV-IgM alone to determine CMV infection in patients with immunosuppressive status and those older than 60 years. CMV-DNA and CMV-IgM combined detection may help to predict patients' immune status and outcomes of antiviral therapy.

Association of Semaphorin 3A with thrombocytopenia in systemic lupus erythematosus / 北京大学学报(医学版)

OBJECTIVE@#To measure the level of serum Semaphorin 3A (Sema3A) and to analyze the relationship between serum Sema3A and systemic lupus erythematosus (SLE) with thrombocytopenia.@*METHODS@#The concentration of serum Sema3A was detected by enzyme-linked immuno sorbent assay (ELISA) in 170 SLE patients, 50 Sjögren's syndrome (SS) patients, 19 hypersplenism (HS) patients and 150 healthy controls (HC). Based on the presence of thrombocytopenia and whether the thrombocytopenia was in remission, the SLE patients were divided into three groups: SLE with thrombocytopenia (41 cases), SLE with thrombocytopenia remission (28 cases), and SLE without thrombocytopenia (101 cases). According to whether there was thrombocytopenia, the SS patients were divided into SS with thrombocytopenia (18 cases) and SS without thrombocytopenia (32 cases). The 28 SLE patients who underwent bone marrow aspiration biopsy were divided into two groups from the aspect of whether the bone marrow hyperplasia was normal (19 cases) or low (9 cases), as well as from the aspect of whether the maturity disturbance of megakaryocyte was positive (8 cases) or negative (20 cases). The serum Sema3A levels in SLE, SS, HS with HC were compared, meanwhile, the correlation between serum Sema3A level and platelet (PLT) in the patients with different diseases analyzed.@*RESULTS@#(1) Serum Sema3A levels in SLE were significantly lower than in HC [(3.84±2.76) μg/L vs. (6.96±2.62) μg/L, P < 0.001], serum Sema3A levels in SS were also obviously lower than in HC [(4.35±3.57) μg/L vs. (6.96±2.62) μg/L, P < 0.001], and in HS it was lower than HC at a certain extant [(5.67±2.26) μg/L vs. (6.96±2.62) μg/L, P=0.041]. (2) Serum Sema3A levels in SLE were slightly lower than in SS, but there was no significant difference [(3.84±2.76) μg/L vs. (4.35±3.57) μg/L, P=0.282]. However, when compared with HS, serum Sema3A levels in SLE were significantly lower [(3.84±2.76) μg/L vs. (5.67±2.26) μg/L, P=0.006]. (3) Serum Sema3A concentration in SLE with thrombocytopenia was significantly lower than in SLE with thrombocytopenia remission [(1.28±1.06) μg/L vs. (3.83±2.65) μg/L, P < 0.001], and in SLE patients without thrombocytopenia [(1.28±1.06) μg/L vs. (4.87±2.60) μg/L, P < 0.001]. There was no significant difference between SLE with thrombocytopenia remission and SLE without thrombocytopenia [(3.83±2.65) μg/L vs. (4.87±2.600 μg/L, P=0.123]. Serum Sema3A concentration in SLE with thrombocytopenia was slightly lower than in SS with thrombocytopenia, but there was no significant difference [(1.28±1.06) μg/L vs. (1.68±1.11) μg/L, P=0.189]. (4) Strong positive correlations were found between serum Sema3A and PLT in SLE (r=0.600, P < 0.001). Positive correlations were also found between serum Sema3A and PLT in SS (r=0.573, P < 0.001). However, there was no such correlation showed in HS patients (P=0.393). (5) There was no significant difference of serum Sema3A concentration in SLE whether the bone marrow hyperplasia was normal or low. And the same situation appeared in the patients whether the maturity disturbance of megakaryocyte was positive or negative (P>0.05).@*CONCLUSION@#Serum Sema3A was significantly reduced in SLE patients, and it was highly correlated with the blood damage. Similar conclusions could be drawn in patients with SS. The serum level of Sema3A was generally decreasing in desmosis which merged thrombocytopenia, and was obviously positive correlated with platelet counts.

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.

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.

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.

Dermatomyositis combined with IgA vasculitis: A case report / 北京大学学报(医学版)

Dermatomyositis (DM) is an autoimmune disease characterized by muscle involvement of the proximal extremities and specific skin involvement, like Gottron sign and heliotrope rash. HenochSchonlein purpura (IgA vasculitis) nephritis is characterized by hematuria and/or proteinuria clinically, with histologic evidence of IgA nephropathy, and also can be clinically characterized by non-thrombocytopenic purpura, presenting with petechiae and ecchymosis on the skin and mucous membranes, often involving multiple organs and systems, accompanied by abdominal pain, joint swelling and pain, and renal lesions. We reported here a patient with symmetric muscle weakness in her proximal limbs and typical Gottron sign, whose laboratory examination showed elevated creatine kinase (CK) level and myogenic damage electromyographically, which were concomitant with dermatomyositis. We applied prednisone combined with cyclophosphamide, and the patient's muscle strength, interstitial lung disease and all improved gradually. The patient gradually developed severe hepatic damage [significantly increased glutamic-pyruvic transaminase (ALT), glutamic oxalacetic transaminase (AST) and bilirubin], high fever (body temperature fluctuated between 38.0-39.2 °C), thrombocytopenia (limb distal purplish rash, some slightly protruded from the skin surface, some fused into a piece, which did not fade with pressure) and intractable diarrhea (waterlike stool, antidiarrheal drug treatment was not good), with new onset of the skin lesions on multiple areas of her body, as well as abrupt occurrence of massive proteinuria, which resulted in huge challenges in the following diagnosis and treatment. After extensive differential diagnosis from various directions, including pathological biopsies, it finally came out to be dermatomyositis combined with IgA vasculitis, which had been rarely reported. Both cellmediated immunity to muscle antigens and immune-complex disease might participate in the pathogenesis. There was evidence that they were immune complex diseases. Several immune mechanisms played an important role in the pathogenesis of both DM and IgA vasculitis. We conducted a substantial literature review of the above diseases. The purpose of our study is to strengthen the clinical understanding of such complicated diseases, and to highlight the importance of pathological biopsy in the diagnosis (renal biopsy pathology gave us a definite diagnosis). And what is more important is that seizing the opportunity to initiate treatment can control the disease and improve the prognosis.

Elevated Levels of Soluble ST2 were Associated with Rheumatoid Arthritis Disease Activity and Ameliorated Inflammation in Synovial Fibroblasts / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Much evidence has demonstrated that interleukin (IL)-33 plays an important role in rheumatoid arthritis (RA). However, there have been limited studies about soluble ST2, a receptor for IL-33, in RA. The aims of this study were to detect the levels of ST2 in the serum and synovial fluid of RA patients and to reveal the association of these levels with disease activity and the function of ST2 in RA.</p><p><b>METHODS</b>A total of 56 RA patients and 38 age-matched healthy controls were enrolled in this study. Synovial fluid samples were collected from another 30 RA patients and 20 osteoarthritis patients. Serum and synovial fluid levels of ST2 were measured by ELISA. In addition, the levels of ST2 in the serum of RA patients before and after therapy were detected. The function of ST2 in RA was revealed by the results of an in vitro cell assay, where recombinant ST2 proteins were used to treat peripheral blood mononuclear cells (PBMCs) and RA synovial fibroblasts (RASFs).</p><p><b>RESULTS</b>Serum-soluble ST2 levels were significantly higher in RA patients (127.14 ± 61.43 pg/ml) than those in healthy controls (78.37 ± 41.93 pg/ml, P < 0.01). Synovial fluid-soluble ST2 levels (41.90 ± 33.58 pg/ml) were much higher in RA patients than those in osteoarthritis patients (19.71 ± 16.72 pg/ml, P < 0.05). RA patients who received effective therapy for 6 months showed decreased serum-soluble ST2 levels (113.01 ± 53.90 pg/ml) compared to baseline (139.59 ± 68.36 pg/ml) (P = 0.01). RA patients with high disease activity had higher serum-soluble ST2 levels (162.02 ± 56.78 pg/ml) than those with low disease activity (94.67 ± 40.27 pg/ml, P = 0.001). Soluble ST2 did not affect IL-1β, IL-6, IL-8, or tumor necrosis factor-α (TNF-α) expression in PBMCs from RA patients. However, soluble ST2 ameliorated the expressions of IL-33 and IL-1β but not that of IL-6, IL-8, or TNF-α in resting RASFs. Interestingly, in the RASFs stimulated by TNF-α plus IL-1β, soluble ST2 showed extensive suppressive effects on the expression of IL-6, IL-8, and TNF-α.</p><p><b>CONCLUSION</b>Elevated levels of ST2 in the serum and synovial fluid were associated with disease activity and ameliorated IL-33 expression and IL-33-induced inflammation in RASFs, suggesting that soluble ST2 might be a potential therapeutic candidate for RA.</p>

Increased serum soluble-endoglin level and its clinical significance in antiphospholipid syndrome / 北京大学学报(医学版)

OBJECTIVE@#To detect the serum levels of soluble endothelial glycoprotein endoglin (s-Eng) in patients with antiphospholipid syndrome (APS) and to evaluate the correlation between s-Eng levels and clinical features and laboratory parameters.@*METHODS@#The levels of serum s-Eng were measured by enzyme linked immunosorbent assay (ELISA) in 139 patients with APS, 44 patients with SLE but no APS, 37 patients with primary Sjögren's syndrome (pSS), 23 patients with Bechet's disease (BD), 22 patients with systemic sclerosis (SSc) and 22 persistent anticardiolipin antibody (aCL) positive individuals without SLE or APS (simply aCL positive group) and 87 health controls (HC) without any auto-immune diseases. These APS patients included 64 primary APS patients and 75 APS patients secondary to SLE.The correlation between the clinical data, laboratory parameters, and serum s-Eng levels were analyzed.Independent samples t test, paired t test, Chi-square Test, Mann-Whitney U test, Pearson's χ2 test were used for statistical analyses.@*RESULTS@#(1) The serum levels of s-Eng were significantly higher in the patients with APS whether primary or secondary to SLE than in the health controls and simply aCL positive group and the patients with other autoimmune diseases, including SLE, pSS, BD and SSc (P<0.001). There was no significant difference in the serum s-Eng levels between simply aCL positive group and health controls [(5.17±2.00) mg/L vs. (5.04±1.11) mg/L, P>0.05]. (2) The best cut-off value for the diagnosis of APS was no less than 8.37 mg/L as mean ± 3SD value, with the sensitivity at 0.772 and the specificity at 0.928. The Youden index was 0.700. These results indicated good validity of s-Eng as a diagnostic marker for APS. (3) The proportions of artery thrombosis and pathological pregnancy were higher in the group of s-Eng-positive APS patients than that in s-Eng-negative group (46/81 vs. 19/58, 29/65 vs. 10/44, respectively, all P<0.05). The levels of PLT were lower in the group of s-Eng-positive APS patients (72.00×109/L vs. 119.00×109/L, P<0.001). (4) The proportions of the presence (93.83% vs. 37.93%, P<0.001) and titer (61.70 U/mL vs. 15.45 U/mL, P<0.001) of aCL were both higher in the group of s-Eng-positive APS patients than in s-Eng-negative group. The proportions of the presence (61.73% vs. 43.10%, P<0.05) and titer (33.48 U/mL vs.17.40 U/mL, P<0.05) of anti-β2-glycoprotein I antibody were both higher in the group of s-Eng-positive APS patients than in s-Eng-negative group too.@*CONCLUSION@#s-Eng serum levels were significantly increased in the patients with APS, and it may play a role as acomplementary serological marker for the diagnosis and risk prediction of APS.