Wen-Chan Chiu

Cumulative immunosuppressant exposure is associated with diversified cancer risk among 14 832 patients with systemic lupus erythematosus: a nested case–control study

Objectives. Immunosuppressive therapy is necessary to alter the natural course of SLE. However, immunosuppressant‐related cancer risk is a major concern. The aim of this study was to determine whether immunosuppressant use is associated with cancer risk in SLE. Methods. We designed a retrospective nested case‐control study within an SLE population based on the National Health Insurance Research Database in Taiwan. We screened 14 842 patients with SLE from 2001 to 2013 and compared patients with SLE complicated by later cancer with patients with SLE but without cancer. The cumulative dose of immunosuppressants was calculated from the SLE diagnosis date to the occurrence of cancer. The immunosuppressants of interest were AZA, CYC, MTX, HCQ and systemic glucocorticoids. Adjusted odds ratios (ORs) for cancer were calculated in conditional Cox regression models after propensity score matching. Results. The top five types of cancers were breast (16.9%), haematological (11.7%), colorectal (11.0%), lung (10.6%) and hepatobiliary (10.4%) cancers. After matching, this study included 330 cancer patients and 1320 matched cancer‐free patients. The adjusted analyses showed an association of a higher cumulative CYC dose (OR = 1.09, 95% CI: 1.04, 1.13) and lower HCQ dose (OR = 0.93, 95% CI: 0.90, 0.97) with cancer risk in comparison with the controls. Conclusion. Diverse cancer risks are associated with different immunosuppressants in patients with SLE. CYC increases the risk of cancer, and HCQ decreases this risk in SLE patients, both in a dose‐dependent manner.

EBV-encoded small RNA1 and nonresolving inflammation in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by perpetuated inflammation in multiple joints. To date, there is no cure for RA, and the causal factor for non‐resolving inflammation in RA remains unclear. In this study, we initially observed expression of Epstein–Barr virus‐encoded small RNA1 (EBER1) in the synovial tissue of all five patients who showed nonresolving RA inflammation. By contrast, EBER1 was detected in the synovial tissue of only one out of seven patients with advanced osteoarthritis (OA; p < 0.01, Fishers exact test). To confirm this finding, we conducted a second study on synovial tissue samples taken from 23 patients with nonresolving RA inflammation and 13 patients with OA. All synovial samples from patients with nonresolving inflammation of RA showed positive expression of EBER1 (23/23, 100%), whereas none of the synovial samples from patients with OA showed expression of EBER1 (0/13, 0%; p < 0.001, by Fishers exact test). In vitro, transfection of RA synovial fibroblasts with EBER1 induced the production of interleukin‐6. Taken together, these data strongly suggest that nonresolving RA inflammation is strongly related to the presence of EBER1, which might be, at least partially, responsible for synovial fibroblast interleukin‐6 production.

Ultrasound is more reliable than inflammatory parameters to evaluate disease activity in patients with RA receiving tocilizumab therapy

The target of treatment for rheumatoid arthritis (RA) is to keep low disease activity or remission. Tocilizumab can fully inhibit interleukin-6 and C reactive protein (CRP) production. The goal of the study is to search whether tocilizumab treatment compared with adalimumab treatment had the similar effect on sonography and inflammatory parameters in patients with RA. We compared ultrasound scores and inflammatory parameters between patients with RA receiving tocilizumab therapy and those receiving adalimumab therapy. Power Doppler (PD) ultrasound and grayscale synovial hypertrophy on bilateral radiocarpal joints were performed. Inflammatory mediators and ultrasound scores were compared by independent t-test between the adalimumab and tocilizumab groups. 65 patients with RA (32 tocilizumab and 33 adalimumab) were included. Between the two groups, there were no significant differences in age, gender, rheumatoid factors and anticyclic citrullinated peptide antibody. Following biological therapy, the ultrasound score was 2.33 in the tocilizumab group and 2.08 in the adalimumab group (p=0.570), while the erythrocyte sedimentation rate, CRP and Disease Activity Score in 28 joints (DAS28) were lower in the tocilizumab group. So ultrasound scores between the two groups were not significantly different, but the laboratory parameters and DAS28 were lower in the tocilizumab group than in the adalimumab group. Hence, to assess disease activity cannot be based only on clinical evaluations, so we suggest PD ultrasound to be used for all patients on tocilizumab therapy and reflect the true disease activity in these patients.

Lower In-Hospital Mortality with Plasma Exchange than Plasmapheresis in a Subgroup Analysis of 374 Lupus Patients

Background Apheresis treatment includes plasmapheresis (PP) and plasma exchange (PE), and these terms are commonly used interchangeably. Nevertheless, the two procedures are carried out differently. The aims of this study were to investigate the mortality rate of patients who underwent therapeutic apheresis and compare the mortality rate between PP and PE. Methods We conducted a medical chart review retrospective study. All identified subjects (n = 436) were over 20 years old with at least one ICD-9-CM intervention code plasmapheresis or plasma exchange and at least one diagnosis code with rheumatic disease. All of them were hospitalized to Chang Gung Memorial Hospital between 1st of January, 2000, and 31st of December, 2014. Results 436 nonoverlapping patients had never received PE and/or PP before 1 Jan, 2000. Among all the patients, 350 received PE, 63 received PP, and 23 received both therapies. Female patients accounted for 85.09% of patients. The overall mortality rate was 4.65% in the PE subgroup, 4.76% with combination therapy, and 13.46% in the PP subgroup. There were 374 patients diagnosed as SLE, which is the majority of overall patients who received PE and/or PE. In multivariate analysis, PE was the sole independent factor predictor of survival in SLE subgroup patients (p = 0.02, exp(B) = 0.314, 95% CI 0.12–0.81). Conclusions We showed that both PP and PE were used in treating a variety of autoimmune disorders. Plasmapheresis was preferentially carried out in patients with peripheral neuropathy. In 374 lupus patients treated with either PE or PP, PE is superior to PP in reducing in-hospital mortality.

Generalized estimating equation model to compare drug effects on synovitis of the dominant wrist in severe rheumatoid arthritis between tocilizumab versus adalimumab versus abatacept using high‐resolution ultrasound

The use of biological agents has revolutionized the treatment of rheumatoid arthritis (RA). However, details of serial synovial changes in imaging evaluation are unclear. Using power Doppler (PD) ultrasound, this study aimed to evaluate the comparative efficacy of biologicals for patients with refractory RA, with the hope that these findings could aid in clinical decision making.

The Association among Antioxidant Enzymes, Autoantibodies, and Disease Severity Score in Systemic Lupus Erythematosus: Comparison of Neuropsychiatric and Nonneuropsychiatric Groups

Background. Antioxidative capacity plays an important role in the severity of systemic lupus erythematosus (SLE), which is characterized by autoantibodies. This study aimed to determine the relationship among autoantibody titers, antioxidative stress reserve, and severity of SLE. Methods. The autoantibody titers, clinical markers, antioxidant enzyme levels, and disease activity index (SLEDAI-2k) of 32 SLE patients and 16 healthy controls were compared. We also compared both the neuropsychiatric (NPSLE) and nonneuropsychiatric (non-NPSLE) groups. Results. Superoxide dismutase in red blood cells was significantly lower in the SLE than in the control group. CRP levels are significant higher in SLE patients than in control group (P = 0.034). Among the autoantibodies, anti-U1RNP (P = 0.008), a-Sm (P = 0.027), and anti-ribosomal p (P = 0.028) significantly negatively correlated with glutathione levels. There has no significant correlation between SLE disease activity indexes (SLEDAI) and levels of C3, C4, and antioxidant enzymes. Conclusions. Erythrocyte superoxide dismutase is significantly lower in both NPSLE and non-NPSLE groups. SLE patients have both higher CRP and autoantibodies level and decreased superoxide dismutase level than the healthy control group.

Clinical and Abdominal Computerized Tomography Characteristics of Patients with Image-Defined Lupus Mesenteric Vasculitis

Objective: Lupus mesenteric vasculitis (LMV) is a rare but challenging diagnostic issue related to patients with systemic lupus erythematosus (SLE). Early recognition by means of clinical signs, laboratory parameters and abdominal computerized tomography (CT) can help in differential diagnosis. The aim of this study was to describe the clinical characteristics, images features and discover possible risk factors of patients with LMV.Methods: Seventeen patients with history of SLE at Kaohsiung Chang Gung Memorial Hospital from 2004 to 2012 were identified according to clinical symptoms and fulfilling at least three of the following signs on abdominal CT scan: bowel wall thickening, bowel distention, target sign, comb sign, and fat attenuation. We recorded the clinical symptoms, laboratory data, and compared with 22 control lupus patients who experienced abdominal pain but LMV was excluded after abdominal CT survey.Results: The most frequent clinical symptoms of the 17 patients were abdominal pain, nausea/vomiting, and diarrhea. The abdominal CT findings were mainly bowel wall thickening, bowel distention and the comb sign. There were no significant differences between baseline and LMV onset in the hemogram, C-reactive protein, complement, and anti-double stranded DNA antibody. Patients with positive anti-β2 glycoprotein I antibody had a greater tendency to develop LMV than the control group (OR = 6.33, 95% CI = 1.06-37.78, p=0.04).Conclusions: We identified the frequent clinical symptoms and abdominal CT features present in patients with LMV. Of all the laboratory parameters and serologic markers, anti-β2 glycoprotein I antibody was found to be a risk factor that is associated with LMV.

Outcome of Lupus nephritis-A 5-year Analysis

Objective: To investigate the long-term outcome of class IV lupus nephritis (LN) and to analyze its prognostic factors. Materials and Methods: We performed a retrospective chart review study of 157 patients with LN between January 1986 and June 2004 in Chang Gung Memorial Hospital at Kaohsiung. All of these LN patients fulfilled the systemic lupus erythematosus classification criteria of the American College of Rheumatology and had histopathological findings of LN. Only those pathology-proved subjects with class IV by 2003 ISN/RPS classification were recruited. We reviewed the charts and collected the demographic data, serological parameters, and treatment courses of subjects recruited. The end point of renal outcome were doubling of serum creatinine (I) and end stage renal disease (ESRD)/death (II) within 60 months after renal biopsy Results: A total of 75 subjects were recruited, including 13 male and 62 female. Mean age was 25.9±9.7 year. Five years after renal biopsy, 16 subjects (21.3%) developed outcome I and 15 subjects (20.0%) developed outcome II. Those who did not develop outcome I had higher mean (14.5±2.1) activity index (AI) than that (13.1±2.5) of those did (HR=0.55, CI=0.35-0.87, p=0.01). For those who did not develop outcome II, the mean AI was also higher than those who did (14.4±2.2 vs.13.5±2.3, HR=0.67, CI=0.44-1.00, p=0.05). Conclusions: The 5-year renal survival of current series, in terms of ESRD/death, was 80% and this was not as favorable as those reported in the other investigations. High activity index at biopsy is a predictor of favorable prognosis of long-term renal outcomes in case that aggressive treatment had been given.

Is Antiphospholipid Antibody Related to Outcome of Lupus Nephritis?-A 2-year Analysis

Objective: To investigate the impact of antiphospholipid antibodies (aPLA) on renal outcome in lupus nephritis (LN). Materials and Methods: A retrospective chart review study of patients with biopsy-proven LN was conducted between 1986 and 2007 at Chang Gung Memorial Hospital in Kaohsiung. All of the patients fulfilled the systemic lupus erythematosus classification criteria of the American College of Rheumatology and had histopathological findings compatible with LN. Only those patients whose aPLA, including anti-cardiolipin antibody, anti-β2GPI antibody, Venereal Disease Research Laboratory test, and lupus anticoagulant had been checked were recruited. We reviewed the charts and collected the demographics, clinical characteristics, serological parameters, and treatment courses of the patients recruited. The renal outcome end point was either end-stage renal disease or doubling of serum creatinine within 24 months Results: A total of 66 subjects were recruited, including 55 females and 11 males. The mean age was 30.5±11.1 years. aPLA was present in 18 patients (27.3%) (group I), and 48 patients (72.7%) (group II) had negative test results. The seropositive ratios of anti-dsDNA and anti-RNP in group I were significantly higher (p=0.023 and 0.026) than in group II, respectively. There was no statistical difference in other parameters between the groups. The subjects in group I had a more favorable (p=0.038) renal outcome after 2 years of follow-up. Conclusions: Contradictory to previous studies, the presence of aPLA in patients with LN is probably associated with a better renal outcome.

Myelitis in Patients with Systemic Lupus Erythematosus

Objective: Myelitis is a rare but severe neurologic presentation of patients with systemic lupus erythematosus (SLE). Few large-scale retrospective cohort studies have been conducted, especially in Taiwan; therefore, we designed a retrospective study to investigate the disease parameters, treatment, and prognosis of myelitis in southern Taiwan. Methods: We reviewed medical records of patients with SLE who were evaluated at the Chang Gung Memorial Hospital-Kaohsiung Medical Center between January 1998 and January 2009. A total of 10 patients with myelopathy were included in the study. Neurologic variables and serologic features of SLE were assessed. Magnetic resonance images (MRI) of the spine and cerebrospinal fluid profiles were collected. We also analyzed the treatment and outcome of myelitis. Results: The cohort of 10 patients included 8 females (80%) and 2 males (20%). Three patients (30%) were initially admitted under the tentative impression of urinary tract infection (UTI). In 8 patients diagnosed with myelitis using MRI, 7 patients (88%) had increased T2 MRI signal intensity over the cervical and upper thoracic spinal area. Treatment regimens included conventional high-dose glucocorticoid, pulse methylprednisolone, cyclophosphamide, and plasma exchange. Six patients (60%) had a poor outcome. Additional cyclophosphamide was used in 5 patients and 3 of them (60%) had a good outcome. Conclusion: SLE patients, who contracted myelitis, presented with possible urinary difficulty and were admitted under the tentative impression of UTI. Besides, the most frequent site of lupus myelitis is the cervical to upper thoracic spinal area. Treatment with high-dose glucocorticoid and cyclophosphamide may be related to a better outcome compared to those without using cyclophosphamide.