Han-Ming Lai

Association of tri-nucleotide (CAG and GGC) repeat polymorphism of androgen receptor gene in Taiwanese women with refractory or remission rheumatoid arthritis

We investigated the relationship between CAG and GGC repeat polymorphism of the androgen receptor (AR) gene and rheumatoid arthritis (RA) in female patients with different disease subtypes. This case-control study enrolled 215 women in three groups: RA patients refractory to standardized therapy (n = 51); RA patients at complete remission phase (n = 60); and healthy controls (n = 104). CAG and GGC repeat lengths were determined by automated fluorescence-based DNA fragment-sizing method. Demographic data, allele lengths, allele distribution, and zygosity status of CAG/GGC repeats were assessed for the three groups. Refractory RA patients tend to have a significantly younger onset age of RA and more elevated erythrocyte sedimentation rates than do remission RA patients. Mean and median values of CAG and GGC repeat lengths are similar in both RA and control patients. However, RA patients harboring any long CAG alleles with more than 23 repeats had an increased risk of a refractory course, whereas differences in risk were not observed between these patients and RA subtypes harboring any long GGC alleles with more than 16 repeats. In addition, the homozygous frequency of CAG but not GGC alleles was lower in refractory RA than in remission RA patients or in controls (p = 0.042). Neither CAG nor GGC repeat lengths had a significant relationship with rheumatoid factor reactivity. Our observations indicate that short CAG repeats of the AR gene with higher transactivation activity may have protective effects against refractory course of RA development and that homozygous frequency of CAG alleles may be involved in the disease remission subtype. In contrast, lack of association of GGC polymorphism and RA was also observed. Together, these data imply that CAG but not GGC alleles in the AR polymorphism may play an important role in modulating the disease pattern of RA among Taiwanese women.

The Diagnostic Value of Anti-CCP and Rheumatoid Factor for Patients with Refractory Rheumatoid Arthritis (RA) and RA in Remission

To compare the diagnostic value of antibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) for patients with refractory rheumatoid arthritis (RA) and RA in remission. Methods. A total of one hundred and forty three participants were enrolled: fifty one patients with RA refractory to standard methotrexate therapy, group I (Gr I, refractory RA); forty three RA patients in complete remission status for at least 3 months, group II (Gr II, RA in remission); and forty nine community-based healthy controls, group III (Gr III). Levels of anti-CCP and RF were measured for all of the subjects. The sensitivity and specificity of both tests were determined via these subjects. The receiver operating characteristic (ROC) analysis was used to display the pairs of sensitivity and specificity for different cut off points of anti-CCP and RF. False negative rate and the complementary diagnostic effect of both assays were also calculated and compared. Results. The sensitivity of anti-CCP and RF for Gr I were 84% and 78%, and 74% and 67% for Gr II, respectively. The specificity of anti-CCP and RF was 98% and 92% respectively. The ROC analysis disclosed that anti-CCP, compared to RF, provided the best combination of sensitivity and specificity for detecting either groups of RA. In addition, anti-CCP provided better complementary diagnostic effect for our RA patients when the results of opposite tests were negative (33% vs 11% in Gr I, and 29% vs 9% in Gr II) (p＜0.001). Conclusion. The detection of anti-CCP in the diagnosis of patients with refractory RA and RA in remission showed higher sensitivity and specificity than RF assay.

Inpatients with Allopurinol Hypersensitivity Syndrome: Experiences at a Medical Center in Southern Taiwan

Allopurinol is considered an effective and safe uric-acid lowering drug but occasional severe allopurinol hypersensitivity syndrome (AHS) may develop. Reviewing the records of 22 inpatients with AHS at our hospital, impaired renal function and old age seem to play an important role in the development of AHS. Three cases developed AHS with elevation of total 1gE level only 5-10 minutes after taking 100mg of allopurinol. This finding seems to imply that type I hypersensitivity could play a part in the development of AHS. One patient experienced 5 episodes of AHS due to the ignorance of AHS history at other hospitals or drug stores, which could be avoided by giving these patients Medic-Alert bracelets, noting the history of AHS. Twelve cases (54.5%) received allopurinol because of asymptomatic hyperuricemia, which is a common practice in Southern Taiwan but not an established indication for starting allopurinol. The chances of developing AHS could be lowered if the clinicians follow the proper indications for the use of allopurinol. We suggest that allopurinol should be prescribed in cases that exhibit proper indications. And the dosage for patients with impaired renal function and/or older age should be adjusted.

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.

Clinical Efficacy of Mycophenolic Acid in the Treatment of Lupus Nephritis

Objective: To demonstrate the efficacy and safety of mycophenolic acid (MPA) as an induction therapy for lupus nephritis (LN) due to the availability of limited data in Taiwan. Materials and Methods: This retrospective study included subjects who were treated with MPA for LN at the rheumatology outpatient clinic in Chang Gung Memorial Hospital-Kaohsiung and Linkou Medical Centers between January 2005 and July 2007. Subjects were categorized into 2 groups according to the dose of MPA. We measured complete blood count (CBC), levels of serum creatinine (Scr), albumin, complement (C3 and C4), anti-double-stranded DNA (anti-dsDNA) antibody titer, and daily urinary protein at the baseline, 12 weeks, and 24 weeks after MPA therapy, and therapeutic response and adverse effects were analyzed. Results: A total of 37 subjects were enrolled: 26 in group Ⅰ (Gr Ⅰ) and Ⅱ in group Ⅱ (Gr Ⅱ). At both 12 and 24 weeks, 1 subject from each group achieved a complete response (CR). One-third of the subjects in Gr Ⅰ achieved partial response (PR) at 12 weeks and 43% achieved it at 24 weeks, while 67% and 75% of subjects in Gr Ⅱ achieved CR at 12 and 24 weeks, respectively. Except for a significant improvement in percent changes in the Scr levels in Gr Ⅱ, the changes in the daily urinary protein, serum albumin, complement, and anti-dsDNA levels of both the groups were not statistically significant but showed a similar trend of improvement. Only one serious adverse event occurred in each group. Conclusions: Compared to treatment with mycophenolate mofetil (MMF) at 1 g/day or MPA at 720 mg/day, treatment with either MMF at 2 g/day or MPA at 1440 mg/day had a better therapeutic effect on LN. In general, the regimen followed in our investigation was safe.

TNF-alpha-308A Allele is Associated with the Presence of Tophi: A Preliminary Study

Objective: To investigate the relationship between the presence of tophi and the TNF-alpha (TNFα) promoter-308G/A polymorphism in gouty patients. Methods: Thirty-seven gouty patients with any visible or palpable tophi on the four limbs joints were recruited as study subjects, and 40 gouty patients without visible or palpable tophi were recruited as controls. We collected and analyzed the clinical characteristics and laboratory data of patients in both groups. The TNFα-308G/A polymorphism was analyzed by PCR-RFLP methods. Results: There was no statistically significant difference in personal history, family history of gout or baseline laboratory data between patients with tophi and those without. There were statistically significant differences in favor of developing tophi in the heterozygote TNFα-308G/A (p=0.017, odds ratio 6.11, 95% C.I. 1.22-30.49). The frequency of the TNFα-308A allele was significantly higher in patients with tophi than in patients without (p=0.02, odds ratio 5.4, 95% C.I. 1.13-25.88). The-308 allele carriage of the G allele was 100% in both the tophi and non-tophi groups. In patients with tophi and without tophi, the-308 allele carriage of the A allele was 12.2% and 2.5%, respectively (p=0.035, odds ratio 4.87, 95% C.I. 0.99-24.00). Conclusion: To our knowledge, this is the first study to find that the TNFα-308A allele is associated with the presence of tophi in gouty patients. Further study of other polymorphisms in the TNF promoter is indicated to understand more about the tophi.

Recurrent Attack of Gouty Arthritis in Patients Hospitalized Due to Non-Gout Diseases: Case-Control Study

Recurrent attacks of gouty arthritis at Chang Gung Memorial Hospital (CGMH), Kaohsiung, was the most common reason for consultation by a rheumatologist. The purpose of this study was to survey the clinical manifestations and predisposing factors of acute flares for gouty patients hospitalized due to non-gout diseases. Methods. This study reviewed the clinical features and predisposing factors of 216 hospitalized patients (186 males and 30 females) with known previous diagnoses of gout who were admitted to CGMH, Kaohsiung, during a 15-month period between Jan 2003 and Mar 2004. All subjects were categorized into two groups. Group 1 comprised patients who developed a recurrent attack of gouty arthritis during hospitalization. Group 2 (control) consisted of subjects with a gout history and without a flare-up during admission. Each group 1 patient was age- (±5 years) and sex-matched with 2 control subjects. Results. Patient mean age was 59.1±14.7 years and the male-to-female ratio was 6.2:1 in group 1. The leading cause of recurrent attack in group 1 compared with group 2 was lack of antigout medication (adjusted odds ratio 4.6, 95% confidence intervals 2.34–9.06). During recurrent attacks 69.4% of patients developed monoarthritis, 48.5% had hyperuricemia, and 32.3% developed fever. Ankles were the joints affected most during recurrent attacks. Conclusion. Lack of antigout medication was a significant factor in the development of acute attacks of gouty arthritis in hospitalized patients admitted due to non-gout diseases. Education of patients and physicians to continue antigout therapy is strongly recommended to prevent recurrent attacks of gouty arthritis in hospitalized patients.