Wei Sheng Chen

Association of serum interleukin-17 and interleukin-23 levels with disease activity in Chinese patients with ankylosing spondylitis.

Background: Ankylosing spondylitis (AS) is a chronic arthritis with a pathogenesis which is not fully understood. A third subset of IL‐17‐producing T helper cells, called Th17 cells, has been discovered and characterized. We investigated whether IL‐17 and IL‐23, two Th17‐related cytokines, play any roles in the pathogenesis of, and have any correlations with, disease activity and clinical manifestations in AS. Methods: This cross‐sectional study included 49 AS patients and 25 healthy control subjects. The serum IL‐17 and IL‐23 levels were measured using enzyme‐linked immunosorbent assay kits. At the same time, C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Patient Global Score (BAS‐G) levels were measured, and physical examinations were performed on study participants to determine their extent of physical mobility. Results: The serum IL‐17 and IL‐23 levels of the AS patients were significantly higher than those of the healthy controls. In the AS patients, the BASDAI scores had a better correlation with the serum IL‐17 or IL‐23 levels (IL‐17, r = 0.351, p = 0.014; IL‐23, r = 0.398, p = 0.005) than with ESR (r = 0.078, p = 0.600) and CRP (r = 0.012, p = 0.993). IL‐17 or IL‐23 correlate to the BASFI, BAS‐G and parameters related to physical mobility. In the receiver operating characteristic (ROC) analysis, the serum IL‐17 and IL‐23 levels act better in discriminating patients with BASDAI≥4 (AUC value 0.88, p = 0.001) than ESR and CRP (AUC value 0.727, p = 0.008). Conclusion: Serum IL‐17 and IL‐23 levels were significantly higher in AS patients than in healthy controls and the levels correlate to disease activity measured by BASDAI scores, but not parameters of functional ability and spinal mobility. These results suggest the existence of a role of IL‐17 and IL‐23 in the pathogenesis of inflammation in AS.

Differences Between Juvenile-onset Ankylosing Spondylitis and Adult-onset Ankylosing Spondylitis

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease, which involves the spine, peripheral joints and entheses. Juvenile‐onset ankylosing spondylitis (JAS) affects children under the age of 16 years. JAS has been noted to present as clinical courses different from those of adult‐onset ankylosing spondylitis (AAS). Therefore, the purpose of the present study was to compare the possible risk factors, clinical manifestations, laboratory markers, radiological changes, and functional outcome between these 2 patient groups. Methods: AS patients were enrolled from the rheumatologic clinic of a tertiary medical center from January 1 to June 30 in 2006. The demographic data, clinical symptoms/signs, Bath AS indices, HLA‐B27, inflammatory markers, radiological findings, and treatment history were acquired with questionnaires, clinical evaluation, and chart review. The differences between JAS and AAS patients were evaluated and analyzed. Results: A total of 169 patients (142 males, 27 females) were included, comprising 47 JAS and 122 AAS patients. The ages of onset were 12.8 ± 2.7 years and 25.0 ± 7.4 years for JAS and AAS, respectively. They had similar gender distribution, years of delay to diagnosis and disease duration. A substantial proportion of our patients (40.4% of JAS and 34.4% of AAS) had physical trauma in the 1 month before disease onset. Also, 22.7% of JAS patients had intense physical training, while 25.2% of AAS patients did heavy work during the period. The first manifestation of JAS was mainly peripheral enthesopathy or arthritis, but axial symptoms in most AAS. More JAS patients had peripheral enthesopathies and arthritis on any occasion. Although there was a trend of higher score in Bath AS Disease Activity Index (BASDAI), Bath AS Metrology Index (BASMI) and Physicians Global Assessment (PGA) score, JAS patients had a comparable Bath AS Functional Index (BASFI) and Bath AS Patients Global Assessment (BAS‐G) as AAS patients. As to the laboratory and radiological tests, JAS patients had higher levels of C‐reactive protein and erythrocyte sedimentation rate, and more radiographic changes of hip joints. Conclusion: JAS and AAS patients had distinct presentations. JAS presented more peripheral enthesopathies and arthritis at disease onset and at any time of the course. If treated effectively, JAS will not lead to a worse functional outcome than AAS. Therefore, it is mandatory to diagnose and treat JAS as early as possible.

Thrombotic microangiopathy in systemic lupus erythematosus: a cohort study in North Taiwan

OBJECTIVES Thrombotic microangiopathy (TMA) co-existing with SLE is rarely reported. This study aimed to investigate the triggering factors, clinical features and outcomes of SLE patients with TMA in Northern Taiwan. METHODS Twenty-five TMA cases out of 2461 SLE patients admitted to Taipei Veterans General Hospital, between 2000 and 2010, were enrolled. RESULTS When TMA occurred, 16 (64.0%) patients had infection; 22 (88.0%) were in an active disease state with a SLEDAI score >10. Among the infection group, 13 (81.3%) had an increase in the SLEDAI score of ≥ 4. We found that older age (≥ 50 years), low platelets (≤ 20,000/nm(3)), presence of infection, acute renal failure (ARF) or four or more TMA features were independent risk factors for persistent haematological abnormalities (P < 0.05); older age (≥ 50 years) and a high reticulocyte index (>2%) were the risk factors for persistent renal function impairment (P < 0.05). The overall mortality rate was 52.0% (13 out of 25); older age (≥ 40 years), low complement value, presence of infection (P < 0.001), two or more infection sources, ARF and four or more TMA features were the statistically significant factors contributing to a higher mortality rate. Patients receiving plasma exchange seven times or more had a significantly higher rate of improvement in renal function and haematological abnormalities. CONCLUSIONS Our study showed that infection was one of the major triggers for the flare-up of SLE disease activity and occurrence of TMA in SLE. Infection is also a strong risk factor for outcome in SLE patients with TMA. Plasma exchange can be considered as an adjuvant treatment modality.

Clinical features and outcomes of posterior reversible encephalopathy syndrome in patients with systemic lupus erythematosus.

To analyze the clinical features and outcomes of patients with posterior reversible encephalopathy syndrome (PRES), the risk factors of PRES‐related intracranial hemorrhage (ICH), and all‐cause mortality in patients with systemic lupus erythematosus (SLE).

Survival analysis in systemic lupus erythematosus patients on maintenance dialysis: a nationwide population-based study in Taiwan

OBJECTIVES This study aimed to identify the risk factors for mortality and the impact of dialysis modalities on the survival in SLE patients with end-stage renal disease (ESRD). METHODS This retrospective nationwide population-based study using the National Health Insurance Research Database in Taiwan collected data from 1073 SLE ESRD patients starting maintenance dialysis between March 1997 and December 2006. A multivariate Cox regression hazard model was applied to identify factors predicting mortality in cohorts using different dialysis modalities and the impact of dialysis modalities on the survival outcome of these patients of both genders. RESULTS The major threat to SLE patients on maintenance dialysis was infections. For SLE patients undergoing regular haemodialysis (HD), age, male sex, and high or absence of daily steroid dosing were predictive of higher mortality. For those undergoing regular peritoneal dialysis (PD), age and high daily steroid dosing were the predictive factors. After adjusting confounding factors, male patients with HD had a significantly poorer outcome than the counterpart with PD or female patients with HD. There was no survival difference among female SLE patients with different dialysis modalities. CONCLUSION No underlying comorbidities were identified to increase the mortality of patients receiving particular dialysis modalities after correcting for age and steroid factors. There was no impact of different dialysis modalities on survival of female SLE patients. However, male SLE patients seemed susceptible to fatal events complicated by HD, which led to an inferior survival rate.

Leukocyte Mitochondrial DNA Alteration in Systemic Lupus Erythematosus and Its Relevance to the Susceptibility to Lupus Nephritis

The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA were extracted from leukocytes of the peripheral venous blood. The D310 sequence variations and copy number of mtDNA, and mRNA expression levels of mtDNA-encoded genes in leukocytes were determined by quantitative real-time polymerase chain reaction (Q-PCR) and PCR-based direct sequencing, respectively. We found that leukocyte mtDNA in SLE patients exhibited higher frequency of D310 heteroplasmy (69.4% vs. 48.9%, p = 0.022) and more D310 variants (2.2 vs. 1.7, p = 0.014) than those found in controls. Among normal controls and patients with low, medium or high SLE disease activity index (SLEDAI), an ever-increasing frequency of D310 heteroplasmy was observed (p = 0.021). Leukocyte mtDNA copy number tended to be low in patients of high SLEDAI group (p = 0.068), especially in those harboring mtDNA with D310 heteroplasmy (p = 0.020). Moreover, the mtDNA copy number was positively correlated with the mRNA level of mtDNA-encoded ND1 (NADH dehydrogenase subunit 1) (p = 0.041) and ATPase 6 (ATP synthase subunit 6) (p = 0.030) genes. Patients with more D310 variants were more susceptible to lupus nephritis (p = 0.035). Taken together, our findings suggest that decrease in the mtDNA copy number and increase in D310 heteroplasmy of mtDNA are related to the development and progression of SLE, and that the patients harboring more D310 variants of mtDNA are more susceptible to lupus nephritis.

Immunohistological features of hip synovitis in ankylosing spondylitis with advanced hip involvement

Division of Allergy-Immunology-Rheumatology, Veterans General Hospital, and National Yang-Ming University, Buddhist Tzu Chi General Hospital, Taipei Branch, Department of Nursing, National Taipei College of Nursing, Division of Allergy-ImmunologyRheumatology, Wan Fang Hospital, Department of Pathology and Laboratory Medicine, and Department of Orthopaedics, Veterans General Hospital, Taipei, Taiwan

Hemolytic uremic syndrome with ischemic glomerulonephropathy and obliterative vasculopathy in a systemic sclerosis patient treated with cyclosporine-A

Hemolytic uremic syndrome (HUS) is not a commonly reported complication in post-transplantation patients treated with cyclosporine-A (CSA), and is extremely rare in systemic sclerosis (SSc) patients treated with this drug. CSA may contribute to the development of chronic ischemic glomerulonephropathy and vasculopathy, features not easily distinguished from SSc-related nephropathy. Here, we describe a 41-year-old Chinese man with diffuse-type SSc treated with CSA who developed thrombocytopenia, acute renal failure and hemolytic anemia and was diagnosed with HUS. Renal function and thrombocytopenia improved gradually after intensive treatment of plasma exchange (PE) and high-dose steroid therapy. After PE, renal biopsy showed ischemic glomerulonephropathy and obliterative vasculopathy. This case illustrates that PE can improve the hematological disorders and characteristic renal changes of HUS in SSc patients treated with CSA. However, this therapy may not be effective in normalizing serum creatinine level in SSc patients once CSA has triggered the normal kidney to develop glomerulonephropathy and vasculopathy with ischemic and sclerotic changes.

Increased risk of osteoporotic fractures in patients with systemic sclerosis: a nationwide population-based study

Objectives To identify the incidence rate (IR) and risk factors of osteoporotic fractures (OFs) among systemic sclerosis (SSc) patients. Methods A cohort study was conducted using the Taiwan National Health Insurance database. Patients with SSc and respective age- and gender-matched controls without SSc were enrolled. The primary endpoint was the first occurrence of OF. The Cox proportional hazard model was used to investigate the risk factor of OFs in the SSc cohort. Results Among 1712 SSc patients (77.8% female, mean age 50.3 years) with a median follow-up of 5.2 years, 54 patients developed vertebral fractures, 17 patients developed hip fractures, and 7 patients developed radius fractures (IR: 6.99, 2.18 and 0.90 per 1000 person-years, respectively). Compared with the controls, the incidence rate ratios (IRRs) (95% CIs) among SSc patients were 1.78 (1.30 to 2.39, p<0.001) for vertebral fractures and 1.89 (1.05 to 3.22, p=0.026) for hip fractures. The IRRs for overall OFs were 1.74 (1.32 to 2.27, p<0.001) for women and 1.06 (0.33 to 2.66, p=0.856) for men. The SSc patients experienced hip fractures at a younger age (67.2 vs 75.2 years, p=0.005), and had a higher 1-year mortality rate (13% vs 3%, p=0.006) of vertebral fractures than did the controls. Multivariable Cox regression analyses indicated that older age, being female, using daily prednisolone equivalent to >7.5 mg, and bowel dysmotility treated with intravenous metoclopramide are associated with OF. Conclusions SSc patients had a high IR of vertebral and hip fractures, especially those who were female, older, used a high dose of corticosteroid or experienced bowel dysmotility.

Upregulation of BMP-2 expression in peripheral blood mononuclear cells by proinflammatory cytokines and radiographic progression in ankylosing spondylitis

Objectives. To investigate the effect of inflammation on expressions of bone morphogenetic proteins (BMPs) in peripheral blood mononuclear cells (PBMCs) and its association with individual radiographic changes in patients with ankylosing spondylitis (AS). Methods. The changes in BMP-2, -4, and -7 gene expressions in PBMCs were measured after stimulation by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The correlation of increase in gene expression with clinical and radiographic findings in patients with AS were analyzed. Results. Both TNF-α and IL-1β could enhance BMP-2 expression in PBMCs from AS patients. Increases in BMP-2, -4, and -7 expressions in PBMCs positively correlated with total modified Stoke Ankylosing Spondylitis Spinal Score (all p < 0.05). Moreover, increases in BMP-2, -4, and -7 gene expressions after TNF-α and IL-1β stimulation were greater among AS patients with versus without severe sacroiliitis (all p < 0.05). Increases in BMP-2 and -7 expressions were greater in PBMCs from 4 patients with total (cervical, thoracic, and lumbar) spinal ankylosis than in the 8 patients who did not have total spinal ankylosis (all p < 0.05). Conclusions. In AS, inflammation upregulates the expression of BMPs in PBMCs which may lead to the radiographic progression with new bone formation.