[Risk factors for bone mineral density changes in patients with rheumatoid arthritis and fracture risk assessment].

OBJECTIVE: To verify the fracture risk assessment tool (FRAX) to estimate the probability of osteoporotic fracture in patients with rheumatoid arthritis (RA) with or without bone mineral density (BMD), and identify associated risk factors of osteoporosis. METHODS: In the study, 200 patients with rheumatoid arthritis aged more than 40 years in Peking University First Hospital from Dec. 2009 to Dec. 2012 were recruited. Clinical information was obtained from a questionnaire of their case history and medical records. FRAX tool was administered. Their lumber spine and left femoral BMD were determined by dual energy X ray absorptiometry. The gender, age, disease duration, menopause status, body mass index (BMI) and accumulative dose of glucocorticoid were obtained in retrospect. Correlation analysis was conducted between the BMD and clinical information. RESULTS: The study population (female, 77.5%) had a mean age of 59.4 years, in which 10 (13%) patients showed a normal BMD, 67 (87%) were osteopenia or osteoporosis, while 32 patients (16%) had fragile fracture. Compared with the patients with normal BMD, the subjects with low BMD had significantly older age, longer period for corticoids usage, higher day dose and accumulated dose of corticoids.The 10-year fracture risk of sustaining major osteoporotic fractures and hip fracture was higher. No significant difference was observed between the 10-year fracture risks calculated with BMD and without BMD. The values of the different area under the receiver operating characteristic (ROC) curve (AUC) for major and hip fractures calculated in three ways: without BMD, with the femoral neck BMD, and with T-score. The best result was for FRAX tool for hip fracture with the T-score (AUC 0.899). A stepwise multivariate linear regression model was constructed to explore the relationship between the different clinical factors studied and a low BMD. Three statistically significant variables for lumber BMD were pain on visual assessment scale (VAS) (P=0.02), fracture history (P=0.003) and a higher steroid accumulated dose (P=0.008). Three statistically significant variables for left hip BMD were age (P<0.001), fracture history (P=0.05) and lower BMI (P=0.03). CONCLUSION: Low BMD is a common complication in RA patients. Risk factors for major fracture and hip fracture are increased. There is a positive correlation between FRAX calculated with and without BMD or T score. FRAX with the femoral neck T score or BMD presents a discriminatory capacity better than FRAX without BMD, according to the AUC ROC.

Connective tissue disease-associated pulmonary arterial hypertension in Chinese patients.

We sought to investigate the characteristics, survival and risk factors for mortality in Chinese patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (APAH) in modern therapy era. 129 consecutive adult patients who visited one of three referral centres in China with a diagnosis of CTD-APAH confirmed by right heart catheterisation during the previous 5 years were enrolled. The end-point was all-cause death or data censoring. Systemic lupus erythematosus was the most common underlying CTD (49%) and systemic sclerosis just accounted for 6% in this cohort. The overall survival at 1 and 3 years was 92% and 80%, respectively. Pericardial effusion, a shorter 6-min walk distance, lower mixed venous oxygen saturation, higher pulmonary vascular resistance (PVR) and alkaline phosphatase (ALP), and lower total cholesterol levels were all associated with a higher risk of death among the study population. Higher PVR and ALP were independent predictors of mortality. In conclusion, unlike in western patients, systemic lupus erythematosus is the most common underlying disease in Chinese patients with CTD-APAH. The survival of Chinese patients with CTD-APAH in the modern treatment era is similar to that in western countries. Elevated PVR and ALP are independent risk factors for poor outcomes.

[Quantitative ultrasound scans of the calcaneus: a useful tool for screening osteoporosis in patients with connective tissue disease].

OBJECTIVE: To evaluate the ability of calcaneus quantitative ultrasound (QUS) to diagnose osteoporosis in connective tissue disease (CTD) patients. METHODS: In the study, 126 female patients with established CTD underwent dual-energy X-ray absorptiometry (DXA) of the lumber and right hip and QUS of the right heel at the same time. Sensitivity, specificity, as well as positive and negative predictive values were calculated to determine the correlation between cases of osteoporosis detected by the QUS heel scan and by DXA. RESULTS: The mean age of the 126 patients was (43.4 ± 19.8) years (ranging from 30.0 to 80.0 years). Based on their DXA data, 36 (28.6%) patients had normal bone mineral density (BMD, T score ≥ -1.0), 90 (71.4%) patients had abnormal BMD. In abnormal BMD patients, 45 (35.7%) had osteopenia (-2.5 < T score<-1.0), and 42 (33.3%) were osteoporotic (T score ≤ -2.5), while 3 (2.4%) patients had fragile fracture. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were all significantly different between osteopenia and the normal group when scanning with QUS. QUS T score was positively correlated with DXA T score, both at lumber and right hip respectively (r=0.491, 0.648, P<0.01). After correction by age and BMI, QUS T score remained positively correlated with DXA T score by partial correlation analysis (Pearson partial vertebral r=0.430, P=0.006; right hip r=0.593, P<0.001). The area under the ROC curve for diagnosis of lumber and hip osteoporosis were 0.836 (95%CI: 0.695, 0.977) and 0.647 (95%CI: 0.579, 0.957) separately. The sensitivity and specificity for identifying osteoporosis in lumber were 70% and 83.3% respectively when the T score threshold of QUS was defined as -1.5; however, the sensitivity and the specificity for identifying osteoporosis at right hip were 72.7% and 88.9% when T score threshold of QUS was defined as -1.85. The best SI threshold was defined as 76 for identifying osteoporosis, with sensitivity being 0.800 and specificity 0.741. CONCLUSION: Our study confirmed that QUS measurements performed at calcaneus with quantitative ultrasound bone analysis were capable of screening osteoporosis defined by axial BMD using DXA in female CTD patients.

[A multicenter study of coronary artery disease and its risk factors in rheumatoid arthritis in China].

OBJECTIVE: To learn about the prevalence and risk factors of coronary artery disease (CAD) in rheumatoid arthritis (RA). METHODS: Data were obtained from a 12-month retrospective investigation of the patients with RA, randomly selected from Departments of Rheumatology and Immunology in 21 big hospitals in China. The data were collected about their social conditions, clinical conditions, medications associated with RA, such as disease modifying anti-rheumatic drugs (DMARDs), non steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid, biologic agents. A nonparameter test and multivariate logistic regression analysis were performed. RESULTS: In the study, 960 patients were enrolled. The prevalence of CAD was 3.5% in China, which was obviously higher than that of normal people. The prevalence of overweight and obesity, smoking, hypertension, diabetes mellitus, hypercholesterolemia and cerebrovascular disease were 35.1%, 12.3%, 17.0%, 7.7%, 0.4% and 3.0%, respectively. Compared with the control group, the CAD group had higher age [(64.7±9.3) years vs. (52.3±14.0) years,P<0.001], more rheumatoid nodules (14.7% vs. 3.1%,P=0.005), lower rate of hydroxychloroquine (HCQ) use (5.9% vs. 22.6%,P=0.021), higher prevalence rates of lung interstitial disease (17.5% vs. 7.0%,P<0.001), diabetes mellitus and hypertension (29.4% vs. 7.0%,P<0.001; 38.2% vs. 16.2%,P=0.001). There was no obvious correlation of CAD in RA with joint deformity, rheumatoid factor (RF) titer, glucocorticoid use, hypercholesterolemia and body mass index (BMI). Multivariate analysis showed higher age, diabetes mellitus and hypertension were independent predictors of CAD, and the use of HCQ was a protective factor of CAD. CONCLUSION: The prevalence of CAD is 3.5%. Higher age, diabetes mellitus and hypertension are independent predictors of CAD, and the use of HCQ is a protective factor of CAD.

[Survey of tumor necrosis factor inhibitors application in patients with rheumatoid arthritis in China].

OBJECTIVE: To investigate the current status of tumor necrosis factor (TNF) inhibitors application in rheumatoid arthritis (RA) patients in China and to analyze the related factors. METHODS: A retrospective survey was conducted in 21 hospitals from different parts of China. The patients with RA were randomly enrolled. Data of their social backgrounds, clinical conditions, usage and adverse effects of TNF inhibitors were collected. The costs of TNF inhibitors and the indirect costs of the disease were calculated. A multivariate Logistic regression analysis was performed to analyze the factors related to TNF inhibitors application. RESULTS: In the study, 1 095 RA patients from July 2009 to November 2010 were enrolled, of whom 112 had received TNF inhibitors, representing 10.2% of the total patients. The patients who received etanercept and infliximab were 7.4% (86/1 095) of the patients and 2.4% (26/1 095), respectively. There were 0.5% of the patients (5/1 095) who had received both of the TNF inhibitors. The patients who had accepted etanercept and treatment duration for less than 3 months and 3-6 months accounted for 38.5% and 25.0% respectively, while those treated with Infliximab were 38.1%. Their health assessment questionnaire (HAQ) scores were 1.1, 0.5 and 0.1, corresponding to treatment duration of infliximab for less than 3, 3-6 and 6-9 months and those were 1.3, 1.0, 0.3 corresponding to treatment duration of etanercept, respectively. Infliximab costs were RMB 24 525.0, 69 300.0 and 96 800.0 Yuan and etanercept costs were RMB 7 394.8, 9 158.6, 54 910.9 Yuan, respectively. Indirect costs for RA patients who accepted infliximab for less than 3, 3-6 and 6-9 months were RMB 365.6, 0 and 158.9 Yuan and those who accepted etanercept were RMB 2 158.4, 288.5 and 180.1 Yuan, respectively. Allergy and infection were the main side-effects of etanercept and both happened in 3.5% of all the patients. Liver damage happened in 2.3% of all the patients, while allergy and infection happened in 6.5% of all the patients who accepted infliximab. Logistic regression analysis showed that patients with higher education experience increased the odds of entering the TNF inhibitors group (OR: 1.292, 95%CI: 1.132-1.473, P=0.000). CONCLUSION: About one-tenth of RA patients in China have accepted TNF inhibitors. Higher education experience is the key factor for using TNF inhibitors.

[Sulphasalazine in patients with rheumatoid arthritis in China: a cross-sectional study].

OBJECTIVE: To investigate the medication status of rheumatoid arthritis (RA) patients and to analyze the clinical use of sulphasalazine (SSZ) and the adverse effect. METHODS: A total of 1 096 outpatients and inpatients diagnosed with RA were investigated in 21 hospitals all over China from July 2009 to December 2010, including gender, age of onset, clinical manifestations, as well as the clinical characteristics and medication status of 160 RA patients who received SSZ therapy. RESULTS: In the group of 160 patients who received SSZ, the male-to-female ratio was 1:7, The average age at onset was (46.1±15.0) years, while the average course was (9.9±7.8) years. The average dose of sulphasalazine was (1.87±0.52) g/d for a mean duration of (26.3± 14.6) months. Only 17% (27/160) of the patients received SSZ monotherapy. Methotrexate (63.1%), leflunomide (36.2%) and hydroxychloroquine (18.1%) were most commonly used combination drugs. And 36.2% (58/160) of the patients used the two-drug combination of methotrexate plus sulphasalazine .In this group, 41.9% (67/160) once used SSZ but withdrew for adverse events and other reasons, while 17.5% (28/160) withdrew for adverse events, of which the most common were gastrointestinal (8.8%), skin (3.8%) and liver toxicity (3.1%). CONCLUSION: Sulphaszlazine is not a common choice in the RA therapeutics in China, and the average dose of SSZ is lower than the standard dose of 2 to 3 g/d . The adverse events of SSZ are common; however, there are few severe adverse events or threat to life,SSZ is relatively safe in clinical practice.

Clinicopathologic features and outcomes in endocapillary proliferative IgA nephropathy.

OBJECTIVE: Clinical manifestations and histological lesions of IgA nephropathy are variable and correlate with the renal outcome of the patient. The aim of the present study is to clarify the clinicopathological features and the prognosis of patients with IgA nephropathy presenting with dominant diffuse endocapillary proliferative lesions. METHODS: The morphological and clinical features of 126 patients with and without diffuse endocapillary proliferation were compared. 29 out of 126 are IgA nephritis patients with diffuse endocapillary proliferation. The others are patients without diffuse endocapillary proliferation. The prognosis of the patients in the 2 groups was analyzed and the effects of diffuse endocapillary proliferation on renal progression in patients with different renal function were also analyzed. RESULTS: Patients with diffuse endocapillary proliferation show significantly higher proteinuria (p < 0.0001) and crescent percent (p < 0.05). There is no significant difference of renal survival in patients with or without diffuse endocapillary proliferation. Further analysis indicated that patients with diffuse endocapillary proliferation had better renal survival than those without it (log rank, p = 0.0561) if their renal function was normal, whereas renal survival of patients with diffuse endocapillary proliferation was worse than of those without it if their renal function was abnormal (log rank, p = 0.0763). CONCLUSION: IgA nephropathy with diffuse endocapillary proliferation shows a better prognosis in the patients with normal renal function, but it is a relative risk factor for end-stage renal disease in patients with abnormal renal function.

[An open-label, multicentric clinical trial to evaluate the efficacy and impact on bone metabolism of recombinant human tumor necrosis factor-α receptor II IgG Fc fusion protein with methotrexate in active rheumatoid arthritis: 24-week clinical and radiographic results from ReABLE study].

OBJECTIVE: To evaluate the efficacy, radiographic changes and safety of the combination of recombinant human tumor necrosis factor-α receptor II IgG Fc fusion protein (rhTNFR:Fc) and methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: 30 RA patients were treated with rhTNFR:Fc (25 mg subcutaneously twice weekly) and oral MTX (up to 15 mg weekly) in an open-label manner. Clinical response was assessed by American College of Rheumatology (ACR) criteria and Disease Activity Score in 28 joints (DAS28). Radiographs of hands and wrist were assessed by the modified Sharp score. RESULTS: At Week 24, ACR20, ACR50 and ACR70 responses were achieved by 90%, 76.67% and 46.67% respectively. At Week 24, the mean DAS28 was 3.65 ± 1.26 versus 6.41 ± 0.61 at baseline (P < 0.001). And 20% patients achieved remission and 16.67% patients had a low disease activity. At week 24, EULAR good and moderate responses were attained by 36.67% and 60% respectively. Similarly, Health Assessment Questionnaire (HAQ) improved significantly, declining from 1.12 at baseline to 0.36 at week 24 (P < 0.001). No radiographic progression (based on change of total Sharp score) was found in 27 cases. Adverse events were mild. CONCLUSION: rhTNFR:Fc in combination with MTX shows an excellent efficacy of reduced disease activity, improved function and slowed radiographic progression through 24 weeks. A combination therapy for 24 weeks can lead to disease remission and an inhibition of radiographic progression. Further study is warranted.

[Approaches to detect the gene mutations in autosomal recessive Alport's syndrome: analysis of a family].

OBJECTIVE: To explore the gene diagnostic method for autosomal recessive Alport syndrome (AR-AS). METHODS: Genomic DNA was extracted from the peripheral leukocytes of the proband of an AR-AS family. All the exons of COL4A3 and COL4A4 introns were amplified by PCR, and then the PCR products were sequenced by direct sequencing. Meanwhile, the mRNA of the coding region of type IV collagen alpha3 and alpha4 chain was extracted from the PBL and EB virus transfected cell and analyzed by using RT-PCR and sequencing to conform the genomic DNA analysis results. RESULTS: PCR-sequencing analysis identified two novel COL4A3 mutations. One was a 5' donor splice site mutation (c. 3418 + 1 G to A) in exon 39, leading to the deletion of exon 39 in mRNA level by RT-PCR analysis. The other was a deletion mutation of 9 bp at exon 25 (c. 1729-1737 del9). CONCLUSION: Both genomic-DNA-PCR-sequencing and mRNA-RT-PCR-sequencing methods can be carried out to detect the pathogenic mutations. In particular, mRNA-based approach can identify the changes in transcript level, therefore it is better than the genomic DNA-based method.

[Comparative analysis of clinicopathological findings and outcome of Henoch-Schonlein nephritis and IgA nephropathy in adults].

OBJECTIVE: To compare the clinicopathological findings and prognosis of Henoch-Schonlein nephritis (HSPN) and IgA nephropathy (IgAN) in adults. METHODS: We enrolled 31 patients with HSPN and 62 patients with IgAN in the present study. They were followed up for 47+/-23 months and 47+/-20 months respectively, and their clinical manifestations and renal pathological findings were collected. Renal pathological changes were semiquantitatively graded. RESULTS: The clinical manifestations, including hypertension, excretion of serum creatinine and urinary protein, were similar in patients with HSPN and IgAN [38.7% vs 27.4%, (121+/-164) vs (106+/-43) micromol/L, (3.2+/-3.1) vs (2.8+/-2.9) g/d, P>0.05]. Renal pathological investigation showed endothelial proliferation in 40.6% (13/31) of HSPN patients and 19.4% (12/62) of IgAN patients and the difference was significant (P=0.021). In patients with IgAN, the tubulointerstitial chronicity index was higher than that in HSPN (2 vs 1, P=0.009), but there were no statistically significant differences in crescent formation(including segmental glomerular necrosis) and glomerular sclerosis(1 vs 0, 1 vs 1, P>0.05). In patients with HSPN capillary wall staining for IgA was more frequently found than in IgAN (71.0% vs 43.5%, P=0.013). With creatinine level doubling as the end point, the follow-up data indicated that the renal survival was 87.1% in HSPN and 91.9% in IgAN and there was no statistically significant difference between HSPN and IgAN (P=0.481). CONCLUSION: Although significant pathological difference was found between HSPN and IgAN, the renal clinical manifestations and long term outcome were similar between the two diseases in adults.

Magnetic resonance imaging in early rheumatoid arthritis: a multicenter, prospective study.

To identify the magnetic resonance imaging (MRI) features of hands and wrists in early rheumatoid arthritis (RA). A total of 129 early arthritis patients (≤1 year) were enrolled in the study. At presentation, MRI of the hands was performed, with clinical and laboratory analyses. After a 1-year follow-up, clinical diagnosis of early RA or non-RA was confirmed by two rheumatologists. The characteristics of MRI variables at baseline in RA patients not fulfilling ACR 1987 criteria [RA-87(-)] were compared with those fulfilling ACR1987 criteria [RA-87(+)] and non-RA. In the 129 early arthritis patients, 90 were diagnosed with RA in a 1-year follow-up. There were 47.8 % (43/90) of the RA patients not fulfilling ACR 1987 criteria [RA-87(-)]. The scores of synovitis in RA-87(-) patients were similar with those in RA-87(+) [Synovitis score, 14.0 (IQR, 4.0-25.0) vs. 14.0 (IQR, 10.0-25.0), p > 0.05]. Compared with those in non-RA, RA-87(-) patients had higher synovitis scores and occurrence of synovitis in proximal interphalangeal (PIP) joints [synovitis score, 14.0 (IQR, 4.0-25.0) vs. 6.0 (IQR, 2.0-14.5), p = 0.046; occurrence of PIP synovitis: 53.5 vs. 27.3 %, p = 0.02]. There was no significant difference of bone marrow edema, bone erosion, and tenosynovitis between RA-87(-) and non-RA. Synovitis in PIP joints was independent predictor for RA-87(-) [OR, 3.1 (95 %CI 1.2-8.1)]. High synovitis scores and synovitis in PIP joints on MRI were important in early RA, especially those not fulfilling ACR 1987 criteria.

Remission of rheumatoid arthritis and potential determinants: a national multi-center cross-sectional survey.

The aim of this study is to investigate the remission rate of rheumatoid arthritis (RA) in China and identify its potential determinants. A multi-center cross-sectional study was conducted from July 2009 to January 2012. Data were collected by face-to-face interviews of the rheumatology outpatients in 28 tertiary hospitals in China. The remission rates were calculated in 486 RA patients according to different definitions of remission: the Disease Activity Score in 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), and the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definition. Potential determinants of RA remission were assessed by univariate and multivariate analyses. The remission rates of RA from this multi-center cohort were 8.6% (DAS28), 8.4% (SDAI), 8.2% (CDAI), and 6.8% (Boolean), respectively. Favorable factors associated with remission were: low Health Assessment Questionnaire (HAQ) score, absence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP), and treatment of methotrexate (MTX) and hydroxychloroquine (HCQ). Younger age was also predictive for the DAS28 and the Boolean remission. Multivariate analyses revealed a low HAQ score, the absence of anti-CCP, and the treatment with HCQ as independent determinants of remission. The clinical remission rate of RA patients was low in China. A low HAQ score, the absence of anti-CCP, and HCQ were significant independent determinants for RA remission.

[The identification and cloning of human M961 full-length cDNA and its splicing isoform].

OBJECTIVE: To identify and clone the gene encoding human M96 gene and study its expression spectrum in several blood cell lines. METHODS: According to the sequence of human EST which was highly homologous to the mouse M96 gene, primers used for library screening were synthesized, then the human adult testis and fetal brain cDNA library were screened. The gene was analyzed by making use of BLAST and CLUSTAL W, and its expression spectrum was studied by multiple-cell lines Northern blot analysis. The expression change of M961 in cell differentiation was observed by use of K562 cell line induced by hemin. RESULTS: Two cDNA clones encoding human M96 gene were isolated, identified and named as M961, and M962. They were found to be isoforms of each other. Northern, blot showed that M961 gene was expressed highly in CEM, Hel, Dami and K562 cell lines. However, during K562 cell line differentiation, process the expression of M961 elevated only slightly. CONCLUSIONS: M961 gene was expressed highly in pluripotent cell lines with erythrocytic and megakaryocytic potentials.