Wen-Nan Huang

Immunogenicity, drug trough levels and therapeutic response in patients with rheumatoid arthritis or ankylosing spondylitis after 24-week golimumab treatment

Golimumab, a fully humanised antitumour necrosis factor (anti-TNF)-α monoclonal antibody, has been proven effective in the treatment of both rheumatoid arthritis (RA)1 and ankylosing spondylitis (AS).2 As with other anti-TNF-α inhibitors, golimumab may elicit antidrug antibodies (ADAb), leading to pharmacokinetic changes.3 ,4 With the limited data regarding the immunogenicity of golimumab,1 ,2 ,5 we aim to evaluate the relations among ADAb, serum drug trough levels, therapeutic response and methotrexate (MTX) dosage in golimumab-treated patients. We initially enrolled 78 biologic-naive patients who started golimumab therapy at a dosage of 50 mg given subcutaneously once a month. Two patients with AS were lost to follow-up due to skin reactions at the 2nd and 3rd month, respectively. Hence, the remaining 76 patients (33 RA and 43 AS) completed the 24-week treatment course, and were eligible for this study. Serum ADAb levels and drug trough levels were determined at week 24 of golimumab therapy by bridging ELISA and capture ELISA (Progenika Biopharma SA, Derio, Spain), respectively, a modified version of the method used in our previous study.6 A positive ADAb result was defined as a titre >30 arbitrary unit/mL in combination with a golimumab level <5.0 μg/mL. Because all of the enrolled patients were …

Procalcitonin May be a Potential Biomarker for Distinguishing Bacterial Infection from Disease Activity in Febrile Patients with Systemic Lupus Erythematosus

Objective: To investigate the utility of procalcitonin (PCT) in febrile patients with systemic lupus erythematosus (SLE). Methods: Serum PCT levels were measured with enzyme-linked fluorescent assay and C-reactive protein (CRP) with nephrometry in 49 febrile patients with SLE. Serum PCT levels were measured in 20 healthy people for normal control. The predictive values of PCT and CRP for detecting bacteria infection were evaluated by receiver operating characteristic (ROC) curves. Results: Enrolled patients included 30 patients without clinical evidence of infection favoring diagnosis of SLE disease flare, and 19 patients with bacterial infection. In febrile patients with SLE, PCT level was significantly higher in bacterial infection group compared with SLE disease flare group (median 7.11 ng/mL vs. 0.06 ng/mL, p＜0.001), especially in patients with sepsis and septic shock. The most appropriate cutoff value of PCT was 0.74 ng/mL and CRP 16.1 mg/dL for predicting bacterial infection in febrile patients with SLE. The sensitivity (89.5%) and specificity (100%) of the PCT level for predicting bacterial infection were superior to those of CRP. Conclusion: Our results suggest that serum PCT level could be used as an additional biomarker for timely differential diagnosis between bacterial infection and disease flare in febrile patients with SLE.

The diagnostic value of anti-cyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis

Objective: To identify the diagnostic value of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) in patients with rheumatoid arthritis (RA). Methods: Serum levels of anti-CCP antibodies were determined by enzyme-linked immunosorbent assay, and levels of RF were determined by nephelometry in 145 patients with RA and 75 patients with non-RA rheumatic diseases. Results: Among the 145 patients with RA, 119 patients (82.1%) tested positive for anti-CCP antibodies, and 116 patients (80.0%) tested positive for RF. The sensitivity, specificity, positive predictive value, and negative predictive value of anti-CCP antibodies for diagnosing RA were 82.1%, 88.0%, 93.0%, and 71.7% respectively. Those for RF were 80.0%, 62.7%, 81.1%, and 61.0% respectively. The presence of either anti-CCP antibodies or RF increased sensitivity to 88.3%, and when they both were present, the specificity increased to 94.7%. The positive rates for anti-CCP antibodies in the RF-positive RA, RFnegative RA, and non-RA patients were 93.1%, 37.9%, and 12.0% respectively. Conclusion: With its high sensitivity and specificity, the anti-CCP antibodies assay is a useful test for diagnosing RA. The use of anti-CCP antibodies and RF in combination further increases the diagnostic value for RA.

The risk of tuberculosis disease in rheumatoid arthritis patients on biologics and targeted therapy: A 15-year real world experience in Taiwan

The objective of this study is to determine the risk of tuberculosis (TB) disease in biologics users among rheumatoid arthritis (RA) patients in Taiwan from 2000 to 2015. This retrospective cohort study enrolled adult RA patients initiated on first biologics at Taichung Veterans General Hospital. TB risks were determined as hazard ratio (HR) with 95% confidence interval (CI) using cox regression. A total of 951 patients were recruited; etanercept (n = 443), adalimumab (n = 332), abatacept (n = 74), golimumab (n = 60), tocilizumab (n = 31) and tofacitinib (n = 11). Twenty-four TB cases were identified; 13 in etanercept and 11 in adalimumab group with the TB incidence rate of 889.3/ 100,000 and 1055.6/ 100,000 patient-years respectively. There was no significant difference in TB risk between adalimumab and etanercept users with an incidence rate ratio of 1.27 (p = 0.556 by Poisson model). Significant 2-year TB risk factors included elderly patient >65 year-old (HR: 2.72, 95% CI: 1.06–6.99, p = 0.037), history of TB (HR: 6.24, 95% CI: 1.77–22.00, p = 0.004) and daily glucocorticoid use ≥5mg (HR:5.01, 95% CI: 1.46–17.21, p = 0.010). Sulfasalazine treatment appeared to be protective (HR: 0.32, 95% CI: 0.11–0.97, p = 0.043). Risk management plan (RMP) for TB before initiation of biologics commenced in 2012. The 2-year TB risks after RMP was compared with that before 2012 (HR:0.67, 95% CI: 0.30–1.49, p = 0.323). Elderly RA patients with a history of previous TB infection and concomitant moderate dose glucocorticoid were at higher risk of TB disease. Concurrent sulfasalazine treatment appeared to be a protective factor against TB disease.

Tocilizumab potentially prevents bone loss in patients with anticitrullinated protein antibody-positive rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with a high risk of osteoporosis and fracture. Interleukin (IL)-6 inhibitors may suppress osteoclast activation. Anticitrullinated protein antibody (ACPA) titers are inversely associated with bone mineral density (BMD). However, the differential effect of ACPA on bone turnover marker (BTM) and BMD changes after IL-6 inhibition remains unclear. This prospective study recruited patients with active RA with inadequate response to methotrexate or biologics. BMD was measured before and after 2-year tocilizumab (TCZ) treatment. Serum osteocalcin, N-terminal propeptide of type I collagen (P1NP), and C-terminal cross-linking telopeptide of type I collagen (CTX) levels were assessed at the baseline and after treatment. We enrolled 76 patients with RA (89.5% women, age: 57.2 ± 13.3 years) receiving TCZ. The 28-joint disease activity score was negatively correlated with BMD and T-scores of the lumbar spine and bilateral femoral neck. ACPA-positive patients had lower lumbar spine and femoral neck T-scores. After 2-year TCZ treatment, CTX levels significantly decreased (0.32 ± 0.21 vs. 0.26 ± 0.17, p = 0.038). Femoral neck BMD increased significantly (0.71 ± 0.22 vs. 0.69 ± 0.55, p = 0.008). Decreased CTX levels and improved BMD were observed only in ACPA-positive patients. After treatment, femoral neck BMD significantly increased only in patients receiving a glucocorticoid dose of ≥5 mg/day. Two-year TCZ treatment reduced bone resorption and increased femoral BMD in ACPA-positive patients. The net effects of glucocorticoids and IL-6 inhibition on BMD imply that strict inflammation control might affect bone metabolism.

Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis – A three-year study in Taiwan

OBJECTIVE To evaluate the long-term safety and effectiveness of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Taiwan. METHOD All refractory RA patients who initiated intravenous TCZ between August 2012 and March 2015 were enrolled. Data on patient characteristics, drug safety and effectiveness were collected. RESULTS A total of 114 RA patients were recruited. Despite the majority of them (93%) had previous biologic failure, 43.75% of the patients were able to reach ACR50 after one year. Serious adverse events commonly found were bacterial pneumonia (4.24/100 patient-years) followed by cellulitis (2.12/100 patient-years). Twenty-three patients had old or latent TB infections, 11 patients had chronic hepatitis B. During the 3 years follow-up, none of them had reactivation of TB, or hepatitis B with concomitant use of isoniazid prophylaxis or pre-emptive antiviral treatment. CONCLUSION In this 3-year real-world study on RA patients of Taiwan, we found a good long-term effectiveness and similar safety profiles for the TCZ treatment. With prophylactic strategy for latent TB and pre-emptive antiviral treatment for HBV carriers, the risk of reactivation of latent TB and HBV may be reassured.

Hypereosinophilic syndrome in a medical center in Taiwan - an analysis of fourteen cases

Objectives: Hypereosinophilic syndromes are disorders with persistent overproduction of eosinophils. The diseases are characterized by damage to multiple organs due to eosinophilic infiltration and mediator release. This study aimed to investigate the clinical manifestation, frequency of organ involvement, treatment and outcome among patients with hypereosinophilic syndrome in a single medical center in Taiwan. Material and Methods: Patients admitted to our hospital due to hypereosinophilic syndrome from December 1986 to July 2007 were enrolled in this study. The initial symptoms, spectrum of organ involvement, total eosinophil count, therapeutic regimen and clinical outcome were retrospectively reviewed and documented. Result: A total of 14 cases were diagnosed with hypereosinophilic syndrome. The average age was 44.1 years old. The male/female ratio was 3.7: 1. The average duration of symptom onset to diagnosis was 14.3 months. The most common initial symptoms were skin rashes (50%), followed by gastrointestinal symptoms (abdominal pain and diarrhea, 36%) and fever (36%). The most frequently involved organ was cutaneous involvement (50%), followed by gastrointestinal involvement (43%) and peripheral vascular involvement (36%). The frequency of cardiovascular involvement was lower (14%) than in western countries. All patients received corticosteroid treatment initially. Most patients required long-term oral prednisolone and immunosuppressive therapy. Conclusion: This study displays clinical characteristics of hypereosinophilic syndrome in Taiwan. Cutaneous and gastrointestinal systems are the most frequently involved organs. A high clinical suspicious index and early biopsy of the involved organ helps in diagnosis of this rare disease.

The clinical application of tumor markers in the screening of malignancies and interstitial lung disease of dermatomyositis/polymyositis patients: A retrospective study

Objective: To examine the clinical utility of tumor markers in dermatomyositis/polymyositis patients in Taiwan. Method: Data were collected retrospectively from the database of Taichung Veterans General Hospital in Taiwan from 1998 to 2014. Patients who fulfilled Bohan and Peter criteria of dermatomyositis/polymyositis were recruited. Serum level of tumor markers including carcinoembryonic antigen, alpha-fetoprotein, carbohydrate antigen 125, carbohydrate antigen 19-9 and carbohydrate antigen 15-3 were measured. The occurrence of malignancies and interstitial lung disease was identified. The association of tumor markers with malignancies and interstitial lung disease was examined using Chi-square test or Fisher’s exact test. Results: Among the enrolled 151 patients, 98 (64.9%) dermatomyositis and 53 (35.1%) polymyositis, a total of 15 malignancies were detected: breast ductal carcinoma (n = 4), bladder transitional cell carcinoma (n = 2), lung adenocarcinoma (n = 2), cervical intraepithelial neoplasia 3 and papillary squamous cell carcinoma (n = 2), colorectal (colon and rectal adenocarcinoma) (n = 2), uterine adenocarcinoma (n = 1), nasopharyngeal carcinoma (n = 1) and hematological malignancy (myelodysplastic with excess blast cells) (n = 1). Among the patients with malignancies, 13 (86.7%) had dermatomyositis, 2 (13.3%) polymyositis and 3 (20%) interstitial lung disease. The mean duration from dermatomyositis/polymyositis diagnosis to the occurrence of malignancies was 6.05 ± 5.69 years. There was no significant association of raised tumor markers with the occurrence of malignancies (p > 0.085), while a significant association was observed between the elevated levels of carbohydrate antigen 15-3 and the presence of interstitial lung disease (p = 0.006). Conclusion: Tumor markers were not useful in malignancy screening or dermatomyositis/polymyositis patients in this tertiary center. The evaluation of the occurrence of malignancy in dermatomyositis/polymyositis patient should include a multidimensional approach. A raised level of carbohydrate antigen 15-3 may be a potential indicator of the presence of interstitial lung disease in dermatomyositis/polymyositis patients.

Clinical Correlation between Anti-Mi-2 Antibodies and Polymyositis/Dermatomyositis in Chinese Patients

Objective: Myositis-specific antibodies are present in idiopathic inflammatory myopathies (IIM), and may have an association with prognosis of polymyositis (PM) and dermatomyositis (DM). To our knowledge, few studies have been conducted on anti-Mi-2 positivity in the Chinese population. The aim of this study was to investigate the prevalence of anti-Mi-2 antibody in PM/DM in the Taiwan Chinese population and explore the clinical characteristics among these patients. Methods: Eighty-nine patients with PM/DM followed up at the rheumatology outpatient clinics of Taichung Veterans General Hospital (TCVGH) were enrolled between Jan. 1st 2001 and Jan. 1st 2013. Anti-Mi-2 IgG antibodies were detected by enzyme fluoroimmunoassay. Demographic data, clinical features, and laboratory findings were analyzed. Results: Anti-Mi-2 antibodies were detected in six (6.7%) of 89 participants with IIM. The female-male ratio was 1:1. All six patients had an initial presentation of malar rash. Five had Gottrons sign, V sign, or periungual erythema. Two patients had heliotrope rash or Shawl sign. Anti-Mi-2 antibody positivity was associated with a higher chance of developing malar rash and V sign, but not with malignancy or interstitial lung disease (ILD). Conclusion: The frequency of anti-Mi-2 antibodies in our PM/DM cohort was comparable with that in previous studies. Anti-Mi-2 positivity was not associated with ILD or malignancy. Long-term follow-up of a large cohort is needed to determine the true prevalence and prognostic value of anti-Mi2 antibodies in patients with PM/DM.

Low Dose Intravenous cyclophosphamide-induced Ovarian Failure in Chinese Patients with Lupus Nephritis

Objective: The efficacy of cyclophosphamide (CYC) in the treatment of lupus nephritis has been well documented. However, few studies regarding its effects on ovarian function in Chinese lupus patients have been reported. Method: One hundred and six lupus nephritis patients treated with CYC, the effects of the starting age of CYC treatment, total doses of CYC administration and routes of administration on ovarian failure were investigated. Results: The mean cumulative dose of CYC was less than 4.5 gm in all patients. By logistic regression, we found that ovarian failure was significantly correlated with starting age of intravenous CYC treatment. None of the patients that started intravenous CYC therapy before the age of 25 had ovarian failure while 15.7% of those starting CYC treatment between the ages of 26 to 44 developed permanent amenorrhea and all patients receiving CYC after the age of 45 developed ovarian failure (p＜0.0001). Patients taking oral CYC had a higher frequency of developing permanent amenorrhea compared with an intravenous route (p=0.024). Conclusion: We conclude that younger patients had a decreased risk of developing CYC-induced ovarian failure. Monthly intravenous administration has less ovarian toxicity than a daily oral regiment.