Prevalence of Anti-endothelial Cell Antibodies in Patients with Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases

Objective To investigate the prevalence of anti-endothelial cell antibodies (AECAs) in the sera of connective tissue diseases (CTD) patients with pulmonary arterial hypertension (PAH) and its correlation with clinical manifestations. Methods AECAs in sera of 39 CTD patients with PAH,22 CTD patients without PAH,and 10 healthy donors as controls were detected with Western blotting. The prevalence of different AECAs in different groups was compared and its correlation with clinical manifestations was also investigated. Results The prevalence of AECAs was 82.1% in CTD patients with PAH,72.7% in CTD patients without PAH,and 20.0% in healthy donors. Anti-22 kD AECA was only detected in CTD patients with PAH (15.4%). Anti-75 kD AECA was more frequently detected in CTD patients with PAH than in those without PAH (51.3% vs. 22.7%,P<0.05). In CTD patients with PAH,anti-75 kD AECA was more frequently detected in those with Raynaud’s phenomenon or with positive anti-RNP antibody. Conclusion AECAs could be frequently detected in CTD patients with or without PAH,while anti-22 kD and anti-75 kD AECA might be specific in CTD patients with PAH.

Competition between TRAF2 and TRAF6 Regulates NF-κB Activation in Human B Lymphocytes

Objective To investigate the role of TNF receptor-associated factor 2 (TRAF-2) and TRAF6 in CD40-induced nuclear factor-κB (NF-κB) signaling pathway and whether CD40 signaling requires TRAF2. Methods Human B cell lines were transfected with plasmids expressing wild type TRAF2 or dominant negative TRAF2,TRAF2-shRNA,or TRAF6-shRNA. The activation of NF-κB was detected by Western blot,kinase assay,transfactor enzyme-linked immunosorbent assay (ELISA),and fluorescence resonance energy transfer (FRET). Analysis of the role of TRAF-2 and TRAF-6 in CD40-mediated NF-κB activity was examined following stimulation with recombinant CD154. Results TRAF2 induced activity of IκB-kinases (IKKα,IKKi/ε),phosphorylation of IκBα,as well as nuclear translocation and phosphorylation of p65/RelA. In contrast,TRAF6 strongly induced NF-κB activation and nuclear translocation of p65 as well as p50 and c-Rel. Engagement of CD154-induced nuclear translocation of p65 was inhibited by a TRAF6-shRNA,but conversely was enhanced by a TRAF2-shRNA. Examination of direct interactions between CD40 and TRAFs by FRET documented that both TRAF2 and TRAF6 directly interacted with CD40. However,the two TRAFs competed for CD40 binding. Conclusions These results indicate that TRAF2 can signal in human B cells,but it is not essential for CD40-mediated NF-κB activation. Moreover,TRAF2 can compete with TRAF6 for CD40 binding,and thereby limit the capacity of CD40 engagement to induce NF-κB activation.

Exploring pathogenesis of primary biliary cholangitis by proteomics: A pilot study

AIM To explore the pathogenesis of primary biliary cholangitis(PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics.METHODS Nine antimitochondrial antibody(AMA)-positive PBC patients and nine age-and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells(Hi BECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with Max Quant software(version 1.5.2.8),DAVID platform,and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of PBC.RESULTS In total,1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them,371 were determined to be significantly differentially expressed between AMA-positive and-negative PBC patients(P < 0.05). Fisher's exact test was performed for enrichment analysis of Gene Ontology protein annotations(biological processes,cellular components,and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and-negative PBC patients. As expected,autoantigens related to mitochondria were highly enriched in AMApositive PBC patients. However,lower levels of AMA were also detected in AMA-negative PBC patients. In addition,autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation,recognition of phagocytosis,and complement activation.CONCLUSION AMA-negative PBC individuals may not exist,but rather,those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.

Unique mutation spectrum of progressive pseudorheumatoid dysplasia in the Chinese population:a retrospective genotype-phenotype analysis of 105 patients

Background Progressive pseudorheumatoid dysplasia(PPRD)is a rare genetic disease with autosomal recessive inherit-ance.There was a lack of genotype-phenotype correlation data from the Chinese population.This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype-phenotype analysis of Chinese PPRD patients.Methods Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital.Medi-cal records were collected from the electronic medical record system and patient-held portable health records.Published Chinese PPRD cases were gathered from both international and Chinese local databases.We collected demographic infor-mation,genetic variants,clinical manifestations,and imaging characteristics for further analysis.Results We included 105 Chinese PPRD patients in the current study.Thirty-three variants,including nine novels and five hotspot variants,were identified,with 26/33(79%)variants exclusively seen in the Chinese population.Chinese PPRD patients share a phenotype similar to that in international reports.Joint involvement may progress with age(R2=0.2541).Long bone shortening and severe deformities occur in three patients with biallelic null variants,of which at least one vari-ant is located in exon 2.Among hotspot variants,c.624dupA(p.C209Mfs*21)were associated with later onset and more involved joints.Elbow joints were more likely to be affected in patients carrying c.624dupA(p.C209Mfs*21)and c.866dupA(p.S209Efs*13).Shoulder joints are more likely to be involved in patients with biallelic null variants(P=0.027).Conclusions Chinese PPRD patients share a unique mutation spectrum.Among the five hotspot variants,c.624dupA is associated with later onset of disease,more extensive joint involvement,and a tendency to affect elbow joints.Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities.

Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry IX： Clinical Features and Survival of Childhood-Onset Systemic Lupus Erythematosus in China

Background： Approximately 15-20% cases of systemic lupus erythematosus （SLE） are diagnosed in children. There have been a Few studies reporting the epidemiological data of pediatric-onset SLE （cSLE） in China, neither comparing the differences between cSLE and adult-onset SLE （aSLE）. The aim of this study was to describe the impact of age of onset on clinical features and survival in cSLE patients in China based on the Chinese SLE Treatment and Research group （CSTAR） database. Methods： We made a prospective study of 225 cSLE patients （aged 〈16 years） and 1759 patients aged 16-50 years based on CSTAR registry. We analyzed initial symptoms, clinical presentations, SLE disease activity, damages, and outcomes ofcSLE, as well as compared with aSLE patients. Results： The mean age ofcSLE patients was 12.16 ± 2.92 years, with 187 （83.1%） females. Fever （P 〈 0.001） as well as mucocutaneous （P 〈 0.001 ） and renal （P = 0.006） disorders were found to be significantly more frequent in cSLE patients as initial symptoms, while muscle and joint lesions were significantly less common compared to aSLE subjects （P 〈 0.001 ）. The eSLE patients were found to present more fi＇equently with malar rash （P = 0.001; odds ratio {OR], 0.624; 95% confidence interval [CI ], 0.470 0.829） but less tYequently with arthritis （P 〈 0.001 ; OR, 2.013; 95% CI, 1.512-2.679） and serositis （P = 0.030; OR, 1.629; 95% CI, 1.053 2.520）. There was no significant difl＇erence in SLE disease activity index scores between cSLE and aSLE groups （P = 0.478）. Cox regression indicated that childhood onset was the risk factor for organ damage in lupus patients （hazard ratio 0.335 [0.170 0.658], P = 0.001）. The survival curves between the cSLE and aSLE groups had no significant difference as determined by the log-rank test （0.557, P = 0.455）. Conclusions： cSLE in China has different clinical features and more inflammation than aSLE patients. Damage may be less in children and there is no difl＇erence in 5- year survival between cSLE and aSLE groups.

CBLN2 rs2217560 was Associated with Pulmonary Arteria Hypertension in Systemic Lupus Erythematosus

To the Editor:Pulmonary arterial hypertension (PAH)is a hemodynamic disorder with elevated pressure of pulmonary circulation.Genetic studies in familial PAH (fPAH)and idiopathic PAH (iPAH)have discovered that transforming growth factor-β (TGF-β) superfamily plays an important role,and the identified mutations occur in bone morphogenetic protein type 2 receptor (BMPR2), activin receptor-like kinase type 1 (ALK1),Endoglin,and SMAD9. A genome-wide association study (GWAS)in patients without BMPR2 mutations discovered that one single-nucleotide polymorphism (SNP)rs2217560 had a significant association with i/fPAH,which located 52-kb downstream of the CBLN2 gene.

Treatment satisfaction with rheumatoid arthritis in patients with different disease severity and financial burden:A subgroup analysis of a nationwide survey in China

Background:Despite the recent advances in treatments for rheumatoid arthritis (RA), there are still unmet needs in disease outcomes. This study aimed to analyze the satisfaction with drug therapies for RA according to the levels of disease severity (patientassessed) and proportions of treatment cost to household income.Methods:This was a subgroup study of a cross-sectional study in patients with RA and their physicians. The patients were subdivided into different subgroups based on their self-assessed severity of RA and on the proportions of treatment cost to household income (<10%, 10-30%, 31-50%, and >50%). The Treatment Satisfaction Questionnaire for Medication version II was used to assess patients’ treatment satisfaction.Results:When considering all medications, effectiveness, convenience, and global satisfaction scores were lower in the severe and moderate RA subgroups than those in the mild and extremely mild RA subgroups (all P < 0.001). Effectiveness, side effects, and convenience scores were higher in the <10% subgroup compared to those in the >50% subgroup (all P < 0.05). Global satisfaction score was higher in the <10% subgroup than that in the 31% to 50% subgroup ( F = 13.183, P = 0.004). For biological diseasemodifying anti-rheumatic drugs, effectiveness and convenience scores were lower in the severe RA subgroup than those in the extremely mild RA subgroup (both P < 0.05). Convenience score was higher in the <10% subgroup compared to that in the 31% to 50% and >50% subgroups ( F = 12.646, P = 0.005). Global satisfaction score was higher in the <10% subgroup than that in the 31% to 50% subgroup ( F = 8.794, P = 0.032). Conclusion:Higher disease severity and higher financial burden were associated with lower patient satisfaction.

Chinese registry of rheumatoid arthritis: IV. Correlation and consistency of rheumatoid arthritis disease activity indices in China

Background:Disease activity indices(DAIs)including disease activity score 28(DAS28),simplified disease activity index(SDAI),and clinical disease activity index(CDAI)have been widely used in clinical practice and research studies of rheumatoid arthritis(RA).The objective of our study was to evaluate the correlation and concordance among different DAIs in Chinese patients with RA.Methods:A cross-sectional study,including patients enrolled in the Chinese registry of rheumatoid arthritis from November 2016 to August 2018,was conducted.The correlations were evaluated using Spearman correlation coefficient and concordance with Bland-Altman plots,quadratic weighted kappa,and discordance rates in the crosstab.For other indices,the optimal cutoff points corresponding to SDAI remission were explored through receiver operating characteristic curve analysis.Results:A total of 30,501 patients were included,of whom 80.46%were women.Most individuals were with moderate disease activity or high disease activity.High correlations among DAS28-erythrocyte sedimentation rate(ESR)and DAS28-C-reactive protein(CRP),SDAI and CDAI were observed.Similarly,the weighted kappa value among the indices was high.In Bland-Altman plots,a positive difference between DAS28-ESR and DAS28-CRP was observed,with an absolute difference of>1.2 in 3079(10.09%)patients.In crosstab,approximately 30%of the patients were classified into different groups.Concordance values between SDAI remission and the optimal cutoff points of DAS28-ESR,DAS28-CRP,and CDAI were 3.06,2.37,and 3.20,respectively.Conclusions:Although DAIs had high correlations and weighted kappa values,the discordance between DAIs was significant in Chinese patients with RA.The four DAIs are not interchangeable.

Lupus Myocarditis： A Case-Control Study from China

Background：Myocarditis is an uncommon but serious manifestation of systemic lupus erythematosus （SLE）.This study aimed to investigate clinical characteristics and outcomes of lupus myocarditis （LM） and to determine risk factors of LM in hospitalized Chinese patients with SLE.Methods：We conducted a retrospective case-control study.A total of 25 patients with LM from 2001 to 2012 were enrolled as the study group,and 1 O0 patients with SLE but without LM were randomly pooled as the control group.Univariable analysis was performed using Chi-square tests for categorical variables,and the Student＇s t-test or Mann-Whitney U-test was performed for continuous variables according to the normality.Results：LM presented as the initial manifestation of SLE in 7 patients （28％） and occurred mostly at earlier stages compared to the controls （20.88 ± 35.73 vs.44.08 ± 61.56 months,P =0.008）.Twenty-one patients （84％） experienced episodes of symptomatic heart failure.Echocardiography showed that 23 patients （92％） had decreased left ventricular ejection fraction （＜50％） and all patients had wall motion abnormalities.A high SLE Disease Activity Index was the independent risk factor in the development of LM （odds ratio =1.322,P ＜ 0.001）.With aggressive immunosuppressive therapies,most patients achieved satisfactory outcome.The in-hospital mortality was not significantly higher in the LM group than in the controls （4％ vs.2％,P =0.491）.Conclusions：LM could result in cardiac dysfunction and even sudden death.High SLE disease activity might potentially predict the occurrence of LM at the early stage of SLE.Characteristic echocardiographic findings could confirm the diagnosis of LM.Early aggressive immunosuppressive therapy could improve the cardiac outcome of LM.

Validating the Chinese version of the psoriasis epidemiology screening tool and early arthritis for psoriatic patients questionnaires

To the Editor:Psoriatic arthritis(PsA)is a chronic musculoskeletal disease associated with psoriasis.A high proportion of patients with psoriasis have a missed diagnosis of PsA,which will lead to delay in treatment,worse physical function,and severe radiographic progression.Skin symptoms precede joint symptoms in about 80%of patients with PsA,which places dermatologists in a unique position to identify PsA early.Therefore,a lot of screening questionnaires have been developed for early screening.The Early Arthritis for Psoriatic Patients(EARP)and Psoriasis Epidemiology Screening Tool(PEST)questionnaires are two of the commonly used.[1,2]To date,only the verified Chinese language version of the EARP questionnaire exists.