Ming-Han Chen

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.

Hepatitis B Virus Reactivation in Rheumatoid Arthritis Patients Undergoing Biologics Treatment

Background Immunosuppressants can induce hepatitis B virus (HBV) reactivation; however, informative data about the risk of different immunosuppressive regimens, including biologics, on HBV reactivation (HBVr) among patients with rheumatoid arthritis (RA) are incomplete. Methods Among 2334 RA patients who had available hepatitis B surface antigen (HBsAg) data, 123 patients positive for HBsAg who were not receiving anti-HBV prophylaxis were enrolled. These patients were undergoing varied mono or combination immunosuppressive therapy, including 36 who were receiving biological disease-modifying antirheumatic drugs (bDMARDs). Results During 3459 person-months of follow-up, 30 (24.4%) patients developed HBVr. The multivariate Cox proportional hazard models showed that glucocorticoid significantly increased the risk of HBVr. Among all kinds of immunosuppressive treatments, glucocorticoid in combination with bDMARDs and synthetic disease-modifying antirheumatic drugs (sDMARDs) had the highest risk of HBVr (adjusted hazard ratio [HR] = 5.14; 95% confidence interval [CI] = 1.77-14.92; P = .003). Rituximab had the greatest risk for HBVr (adjusted HR = 16.51; 95% CI = 1.82-149.67; P = .01) among the patients who received bDMARDs. Conclusions Glucocorticoid has a detrimental effect on HBVr in RA patients. Antiviral prophylactic strategies should be justified according to the risk of HBVr under different combinations of immunosuppressive therapy in rheumatic patients.

Inverse correlation of programmed death 1 (PD-1) expression in T cells to the spinal radiologic changes in Taiwanese patients with ankylosing spondylitis

Programmed death 1 (PD-1) has been shown to be involved in the negative regulation of the immune response. However, the role of PD-1 in ankylosing spondylitis (AS) has not been studied. Therefore, we analyzed the expression of PD-1 in peripheral blood mononuclear cells (PBMC) from patients with AS. Twenty-three AS patients, 20 rheumatoid arthritis (RA) patients, and 25 normal healthy subjects were recruited. The percentage of the PBMC and PD-1 levels in these subjects were measured by flow cytometry. A higher percentage of CD4+ T cells was noted in AS patients than in healthy controls (37.53 ± 1.65% vs. 31.55 ± 0.92%, P < 0.01), but a similar result was not observed with regard to CD3+ T lymphocytes, CD4 + CD25 high + regulatory T cells, CD19+ B cells, and CD14+ and CD16+ monocytes/macrophages. PD-1 levels in PBMC were not significantly higher in AS patients than in RA patients or age- and gender-matched healthy controls and were also not correlated to the erythrocyte sedimentation rate, C-reactive protein, limitation of back flexion, and chest expansion in patients with AS. Of interest, the percentages of PD-1 + CD3+ T cells and PD-1 + CD4+ T cells were significantly lower in AS patients with higher modified Stokes Ankylosing Spondylitis Spinal Scores (mSASSS ≥30) than in those with lower mSASSS ( < 30; 0.07 ± 0.04% vs. 0.42 ± 0.14%, P < 0.05; 0.06 ± 0.03% vs. 0.40 ± 0.14%, P < 0.05, respectively). These results have suggested that the increased number of T helper cells lacking PD-1 may contribute to the spinal radiologic changes in AS patients.

Lung involvement in primary Sjögren's syndrome: Correlation between high-resolution computed tomography score and mortality.

Background: Lung involvement is one of the major systemic manifestations of primary Sjögrens syndrome (pSS). This study aims to demonstrate the correlation between high‐resolution computed tomography (HRCT), pulmonary function test (PFT) results, and outcome in these patients. Methods: Forty‐four pSS patients were enrolled and their PFT results and HRCT findings/scores were retrospectively investigated. Results: All patients had reduced carbon monoxide‐diffusing capacity (DLCO; <75% of the predicted value); <60% of the predicted value of peak expiratory flow (PEF), of forced vital capacity (FVC), and of forced expiratory volume in the 1st second (FEV1) were noted in 15 (34.1%) patients, 13 (29.5%) patients, and 12 (27.3%) patients, respectively. HRCT scores had a negative correlation with DLCO (r = −0.376, p = 0.012), but not with other PFT results. Twelve patients (27.3%) expired during a mean follow‐up of 3.7 years; 11 (91.7%) patients died of respiratory failure in the lung‐involved patients, of which three were present with pneumonia. The expired patients had lower predicted values of FEV1 (63.1 ± 19.4% vs. 79.0 ± 22.7%, p = 0.017), FVC (58.7 ± 20.4% vs. 77.1 ± 17.5%, p = 0.005), and PEF (54.3 ± 20.5% vs. 72.0 ± 24.8%, p = 0.035), and higher HRCT scores (9.2 ± 5.7 vs. 5.2 ± 3.5, p = 0.033) than those patients who survived. Patients with FEV1, FVC, PEF < 60% of the predicted value, or high HRCT score (13–18) presented shorter median overall survival (p = 0.005, p < 0.001, p = 0.021, p < 0.001, respectively). Multivariate analysis adjusted for PFT results showed that HRCT ≥13 was an independent risk factor for mortality (p = 0.007). Conclusion: The clinical outcome of pSS patients with lung involvement in Taiwan is not very favorable. Although HRCT score was poorly correlated with PFT, high HRCT score was significantly associated with higher mortality.

The Expression of Proinflammatory Cytokines and Intracellular Minerals in Patients with Ankylosing Spondylitis

Objective: Our study aimed to investigate the expression of intracellular proinflammatory cytokines and mineral contents in patients with ankylosing spondylitis (AS). Methods: Serum samples from 40 patients with AS and 19 healthy individuals were collected for this study. Flow cytometry was used to determine the intracellular concentration of interleukin (IL)-1β, interferon (IFN)-γ and tumor necrosis factor (TNF)-α in the CD3–, CD4–, and CD8– bearing T cells. The mass fraction of calcium (Ca(superscript 2+)) and magnesium (Mg(superscript 2+)) in phytohemagglutin (PHA)-stimulated lymphocytes were measured using a spectrofluorometer. Clinical variables, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), age at onset, uveitis and family history were recorded. Results: Intracellular proinflammatory cytokine (IL-1β, TNF-α, & IFN-γ) expression in CD3+ and CD4+ T cells after phorbol myristate acetate (PMA) stimulation was more significantly increased in AS patients than in healthy controls (p＜0.05). Intracellular Ca(superscript 2+) exhibited a significant correlation to the TNF-α level in stimulated CD8+ T cells in AS patients (r=0.439, p＜0.05), but not in healthy controls. Comparison between an increase in cytokine expression and clinical variables showed that the increase in IFN-γ was significantly less prominent in patients with a lower BASFI score (BASFI＜20 vs. ≧20, p＜0.05) and more prominent in patients with uveitis. The IL-1β increase after stimulation was less prominent in patients with a higher age of onset (＞30 years of age, p＜0.05). Conclusion: The increased expression of intracellular proinflammatory cytokines, including IL-1β, TNF-α and IFN-γ after PMA-stimulation was more pronounced in AS patients than in normal individuals. A significant correlation between intracellular TNF-α level and Ca(superscript 2+) was found in AS patients. Whether the elevation of intracellular Ca(superscript 2+) can enhance intracellular TNF-α expression in AS patients requires further study.

Toxicities, safeties and clinical response of dacarbazine-based chemotherapy on neuroendocrine tumors in Taiwan population

Background: Currently, the role of dacarbazine (DTIC) based chemotherapy in neuroendocrine tumors (NETs) in Asia is unclear. Here, we report the outcomes of dacarbazine (DTIC)‐based chemotherapy in Taiwan population. Methods: DTIC alone (250 mg/m2/day), or 5‐fluorouracil (5‐FU, 500 mg/m2/day) and DTIC (200 mg/m2/day) with or without epirubicin (200 mg/m2/day), for 3 days, every 3–4 weeks. Subgroups were analyzed by grading, and by Ki‐67 index. Results: 48 patients were reviewed in this study, including 3 had grade 1 tumors, 23 had grade 2, while 22 were grade 3. In grade 3 NEC patients, the tumor Ki‐67 index of 21–55% were noted in 8 patients, and >55% in 14 patients. Progression‐free survival (PFS) was 5.1 months, and overall survival (OS) was 31.6 months. The PFS (in months) were 12.5 and 1.8 for patients with NETs and neuroendocrine carcinomas (NECs), respectively (p < 0.001). The OS were not reached and 5.9 months for patients with NETs and NECs, respectively (p = 0.001). Patients with NECs were divided into two groups, according to their Ki‐67 index. In patients with a tumor Ki‐67 index of 21–55%, PFS was 4.1 months, and OS was not reached; in those with a tumor Ki‐67 index of >55%, they were 1.5 and 1.8 months, respectively (p < 0.001 and p = 0.013). Conclusion: NETs, and grade 3 NECs, with Ki‐67 indices of 20–55% had good responses to DTIC‐based chemotherapy, with acceptable side effects. Ki‐67 index could predict prognosis for grade 3 NEC patients, and guide further chemotherapy choices.

Relationship between The Level Of Anti-Double Strand DNA Antibody And Lupus Renal Diseases In Patients With Systemic Lupus Erythematosus

Objective: The goal of this study was to investigate the development of acute lupus nephritis or end stage renal disease in patients who had persistently high or variant levels of anti-dsDNA. Methods: Patients who fulfilled the diagnostic criteria for SLE were placed into one of three groups: persistent high levels, variant levels, and persistent normal levels of anti-dsDNA. Clinical renal diseases were based on the present of acute lupus nephritis, and the development of end stage renal disease (ESRD). Results: A total of 257 patients were enrolled in the study. Among them, 86 patients never have an elevation of anti-dsDNA during the follow-up period, 46 patients had variant levels of anti-dsDNA, and 125 patients had persistently high levels of anti-dsDNA. We compared the lupus nephritis flares and ESRD between normal anti-dsDNA group with high anti-dsDNA group or variant anti-dsDNA group, and the results showed significantly statistics different in acute lupus nephritis between the comparisons (p＜ 0.001, p＜0.001 respectively). However, there were no statistics different in ESRD (p=0.539, p=0.061 respectively). Conclusion: Patients who consistently showed a high anti-dsDNA level would have higher rate of acute lupus nephritis. Besides, if their serum elevated level of anti-dsDNA could not back and consistently within normal range, these patients also have less favorable renal outcome. Therefore, more intensive follow up and aggressive medical treatments are needed for these patients.

Association of High Sensitivity C-reactive Protein with Hyperuricemia in Taiwanese Patients with Gout

Objective: To analyze the relationship between high sensitivity C-reactive protein (hsCRP) and hyperuricemia in gout patients in a Taiwan population. Methods: Forty gout patients and 25 normal healthy control subjects were recruited. The serum hsCRP, uric acid, and erythrocyte sedimentation rate (ESR) levels of each participant were measured. The disease duration, visual analogue scale (VAS) pain score and presence or absence of tophi were recorded. The correlations between hsCRP levels and clinical features or laboratory profiles in gout patients were analyzed. Results: The findings demonstrated statistical significance in hsCRP levels in gout patients compared with normal healthy control individuals (p＜0.001). HsCRP correlated with serum ESR (r=0.549, p＜0.001), uric acid (r=0.381, p=0.020) and the VAS pain score (r=0.385, p=0.014), but not with disease duration and presence of tophi. Conclusion: HsCRP was associated with hyperuricemia, high ESR levels and high VAS pain scores in gout patients in Taiwan, suggesting increased hsCRP may be an indicator of uncontrolled hyperuricemia or gouty arthritis.

Chronic graft-versus-host disease mimicking rapid progressive rheumatoid arthritis with atlantoaxial subluxation.

Chronic graft-versus-host disease (cGVHD) may mimic clinical and serological features of various autoimmune diseases. We present a case of a 23-year-old man who developed vitiligo, symmetric polyarthritis, high titre rheumatoid factor, antinuclear antibodies and anti-double stranded DNA antibodies after allogenic peripheral blood stem cell transplantation for severe aplastic anaemia. He was treated with low dose oral steroids, non-steroid anti-inflammatory drugs and azathioprine and clinical improvement of polyarthritis were observed initially. However, atlantoaxial subluxation (C1-C2) and rapid progression of symmetrical joint space narrowing in knees and wrists developed within 1 year. cGVHD mimicking rheumatoid arthritis with unusual presentations was observed in this patient.