Efficacy and Safety of Opinercept Tumor Necrosis Factor Inhibitor Therapy for Drug-Refractory Rheumatoid Arthritis: A Randomized Clinical Trial.

OBJECTIVES: This study aims to evaluate the efficacy and safety profile of opinercept for rheumatoid arthritis (RA) patients undergoing disease- modifying anti-rheumatic drugs (DMARDs) therapy. PATIENTS AND METHODS: A total of 98 patients with active RA (17 males, 81 females; mean age 58.6±12.2 years; range, 24.3 to 85.3 years) were randomized into opinercept plus DMARDs (OD group) or placebo plus DMARDs (PD group), in a 24-week treatment period. Primary outcome was American College of Rheumatology score (ACR20) at week 24. Other exploratory endpoints included ACR50, ACR70 and disease activity score-28 (DAS28) at week 12 and 24, tender/swollen joint counts, pain, Health Assessment Questionnaire-Disability Index, erythrocyte sedimentation rate, and C-reactive protein level. Incidence of adverse events (AEs), vital signs and physical findings, and laboratory test results were also evaluated. RESULTS: Patients in OD group showed significantly higher achievement percentage of ACR20 at week 24 than the PD group (76.6% vs. 30.3%, p<0.001). The evaluation of DAS28 was significantly improved in OD patients compared to PD patients at weeks 12 and 24. Most of the occurred AEs were mild or moderate and considered unrelated to study treatments. CONCLUSION: Opinercept concurrent with DMARDs was superior to DMARDs alone in slowing RA progression and ameliorating symptoms, with well- tolerated and acceptable safety profile.

Alterations of oxygen consumption and extracellular acidification rates by glutamine in PBMCs of SLE patients.

We evaluated plasma glutamine levels and basal mitochondrial oxygen consumption rate (mOCRB) and basal extracellular acidification rate (ECARB) of peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients and healthy controls (HCs). Lower plasma glutamine levels correlated with higher SLE disease activity indexes (p=0.025). Incubated in DMEM containing 100mg/dL glucose, SLE-PBMCs displayed lower mOCRB (p=0.018) but similar ECARB (p=0.467) to those of HC-PBMCs, and their mOCRB got elevated (p<0.001) without altering ECARB (p=0.239) by supplementation with 2 or 4mM glutamine. We conclude that impaired mitochondrial respiration of SLE-PBMCs could be improved by glutamine under euglycemic condition.

Oxidative DNA and mitochondrial DNA change in patients with SLE.

We evaluated plasma IL-10, IFN-alpha, IL-23, IFN-gamma, IP-10, MCP-1, 8-OHdG, leukocyte mtDNA, serum anti-dsDNA antibodies and disease activity index (SLEDAI) in SLE patients. 93 patients (35 nephritis, 4 under dialysis, 5 under rituximab) and 50 healthy controls were recruited. Compared with healthy controls, SLE patients had higher IL-10, IFN-alpha, IL-23, IFN-gamma, IP-10 and MCP-1 (p<0.05). High IFN-alpha (p=0.031) and IP-10 (p=0.026) correlated with high SLEDAI; high IFN-alpha (p<0.001), IL-23 (p=0.023) and IP-10 (p<0.001) correlated with high anti-dsDNA. High IL-10 (p=0.014), IL-23 (p<0.001), IFN-gamma (p<0.001) and MCP-1 (p=0.002) correlated with high 8-OHdG and high IL-23 (p<0.001), INF-gamma (p<0.001), IP-10 (p=0.023) and MCP-1 (p=0.002) correlated with low leukocyte mtDNA. mtDNA 4977 deletion correlated with high mtDNA (p=0.011) and low IL-10 (p=0.009). MCP-1 (p=0.043) decreased after rituximab therapy. 54 SLE patients without nephritis, 35 with nephritis but without dialysis, and 4 with nephritis under dialysis exhibited stepwise increases in IL-23 (p=0.009) and MCP-1 (p=0.015). These data suggest that oxidative DNA and mtDNA alterations and coordinate changes in cytokines/chemokines are implicated in progression of SLE and rituximab in amelioration of SLE.

The pathogenesis of systemic lupus erythematosus - From the viewpoint of oxidative stress and mitochondrial dysfunction.

SLE is characterized by an increased production of detrimental autoantigens, exaggerated effects of pro-inflammatory cytokines, dysregulated functioning of immunocompetent cells including lymphocytes and leukocytes, and devastating tissue and organ damage. All of these derangements can be potentiated or attenuated by the abnormal energy expenditure and overproduction of reactive oxygen species (ROS). Mitochondrial heteroplasmy or dysfunction has been recognized to play a role in these abnormalities. Abnormal redox reaction, decreased functioning of biogenesis-related enzymes, increased NETosis, harmful cytokine effects, and aberrant lymphocyte behavior have been shown to be associated with the pathological state of mitochondria. There is accumulating data which support the importance of abnormal oxygen metabolism and mitochondrial disorders in the immunopathogenesis of SLE. Further laboratory as well as clinical data are required to expand our understanding of SLE pathogenesis.

The role of hOGG1 C1245G polymorphism in the susceptibility to lupus nephritis and modulation of the plasma 8-OHdG in patients with systemic lupus erythematosus.

We investigated whether the C1245G polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1) gene confers the susceptibility to systemic lupus erythematosus (SLE) occurrence of lupus nephritis and affects the plasma level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in patients with SLE. A total of 45 healthy controls and 85 SLE patients were recruited. The C1245G polymorphism of the hOGG1 gene was determined by direct sequencing. The frequency of occurrence of the hOGG1 1245 GG genotype in SLE patients was 31.8% (27/85), which is lower than that of healthy controls of 53.3% (24/45). Thirty-three (33/85, 38.8%) SLE patients developed lupus nephritis. Significantly, SLE patients harboring the hOGG1 1245 GG genotype had a higher incidence to develop lupus nephritis than did those harboring the hOGG1 1245 CC or CG genotype (15/27, 55.6% vs.18/58, 31.0%, p=0.031). Divided into subgroups, SLE patients harboring the hOGG1 1245 GG genotype had the highest plasma levels of 8-OHdG among patients with all genotypes, with regard to the coexistence of lupus nephritis (p=0.020, ANOVA), including those with nephritis harboring the hOGG1 1245 CC or CG genotypes (p=0.037), those without nephritis harboring the hOGG1 1245 GG genotype (p=0.050), and those without nephritis harboring the hOGG1 1245 CC or CG genotype (p=0.054). We conclude that the C1245G polymorphism of hOGG1 may be one of the factors that confer the susceptibility to lupus nephritis and modulate the plasma level of 8-OHdG in patients with SLE.

Cross-domain probabilistic inference in a clinical decision support system: examples for dermatology and rheumatology.

INTRODUCTION: Maintaining a large diagnostic knowledge base (KB) is a demanding task for any person or organization. Future clinical decision support system (CDSS) may rely on multiple, smaller and more focused KBs developed and maintained at different locations that work together seamlessly. A cross-domain inference tool has great clinical import and utility. METHODS: We developed a modified multi-membership Bayes formulation to facilitate the cross-domain probabilistic inferencing among KBs with overlapping diseases. Two KBs developed for evaluation were non-infectious generalized blistering diseases (GBD) and autoimmune diseases (AID). After the KBs were finalized, they were evaluated separately for validity. RESULT: Ten cases from medical journal case reports were used to evaluate this "cross-domain" inference across the two KBs. The resultant non-error rate (NER) was 90%, and the average of probabilities assigned to the correct diagnosis (AVP) was 64.8% for cross-domain consultations. CONCLUSION: A novel formulation is now available to deal with problems occurring in a clinical diagnostic decision support system with multi-domain KBs. The utilization of this formulation will help in the development of more integrated KBs with greater focused knowledge domains.

Better short-term clinical response to etanercept in Chinese than Caucasian patients with active ankylosing spondylitis.

Tumor necrosis factor-alpha (TNF-α) inhibitors including etanercept have been demonstrated to be very effective in severe ankylosing spondylitis (AS) in Caucasian patients. However, clinical efficacy of etanercept to treat active AS in Chinese patients has not been reported. In this study, a prospective, open-label trial of etanercept (25 mg BIW), involving 46 AS patients from 16 medical centers of Taiwan, was conducted. Questionnaire was utilized to record demographic data and clinical parameters, including Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Bath AS Global Index (BASGI), Assessment in Ankylosing Spondylitis (ASAS) 20, 50, and 70, and others, before and at different time intervals after etanercept treatment. Laboratory tests including blood chemistry, hematology, urine analysis, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were done at baseline and at weeks 4, 8, and 12. In this 12-week study, etanercept demonstrated rapid and significant improvement in the ASAS20 response criteria (91.3%), at as early as 2 weeks of therapy (71.3%). Partial remission of AS was achieved in 49.3% of patients after 12 weeks of treatment. Disease activity (BASDAI) and function (BASFI) were also significantly improved after 12 weeks etanercept treatment (p < 0.0001 and p < 0.0001, respectively). In addition, significant increase of chest expansion (2.77 ± 1.69 cm versus 3.56 ± 1.82 cm, p = 0.0004) and lumbar flexion (2.11 ± 2.76 cm versus 2.58 ± 3.42 cm, p = 0.0075) and significant reduction of occiput-to-wall distance (6.59 ± 7.14 cm versus 5.32 ± 6.65 cm, p = 0.0006) were also demonstrated. Both ESR and CRP declined significantly after patients were treated with etanercept. There were no severe adverse effects during the treatment period. Etanercept is generally safe, well tolerated, and effective in Chinese patients with severe AS. Clinical efficacy, including partial remission and BASDAI, is even better in Chinese than in Caucasian patients. Further study is required to assess long-term efficacy and safety in Chinese patients with AS.

Etoricoxib improves pain, function and quality of life: results of a real-world effectiveness trial.

OBJECTIVE: To evaluate the effectiveness and tolerability of etoricoxib in patients with osteoarthritis (OA) with suboptimal response to existing pain regimens. METHODS: A multicenter, prospective, open-label, single-arm study. OA patients (n = 500) taking nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics who had inadequate response as determined by their physicians (>or= 40 mm on a 0-100 mm pain scale) were switched directly to etoricoxib 60 mg once daily for 4 weeks without prior medication washout. The primary endpoint was the percentage of patients with >or= 30% improvement in Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain walking on a flat surface after 4 weeks of treatment. Other endpoints included WOMAC Pain, Stiffness, and Physical Function subscales, Brief Pain Inventory (BPI), investigator's global assessment of response to therapy (IGART), the Treatment Satisfaction Questionnaire for Medication (TSQM) and Short Form 36 (SF36). Safety and tolerability were assessed by collecting adverse events. RESULTS: After switching to etoricoxib, 52% (95% confidence interval: 47%, 57%) of patients reported a clinically meaningful reduction (>or= 30%) for WOMAC pain walking on a flat surface. Disability in daily activities and pain interference were significantly improved (P < 0.0001). IGART scores improved after the switch to etoricoxib (P < 0.05). Results from TSQM demonstrated that patient perceptions of effectiveness, convenience and overall satisfaction increased. Etoricoxib was generally well tolerated in most patients. The most commonly reported adverse event was edema (4.2%). CONCLUSIONS: In OA patients experiencing inadequate relief from a wide variety of analgesics, pain, function, quality of life, and treatment satisfaction significantly improved when switched to etoricoxib.

Juvenile idiopathic arthritis presenting with prolonged fever.

BACKGROUND/PURPOSE: Systemic-onset juvenile idiopathic arthritis (s-JIA) is a systemic disease often accompanied by a fever. We examined 16 patients with s-JIA and reported the clinical manifestations, laboratory data, treatments and outcomes. METHODS: From 1984 to 2007, 16 children (aged 1-16 years), who were diagnosed as having s-JIA, were admitted to the Mackay Memorial Hospital in Taiwan. We retrospectively reviewed their medical charts. RESULTS: There were nine boys and seven girls, with mean age of onset of 7.4±5.5 years. Fever (100%), typical rash (63%), and arthritis (75%) were the three most common symptoms. Lymphadenopathy (50%), hepatosplenomegaly (63%), pleural pulmonary manifestations (13%) and myalgia (25%) were also noted. One patient had Epstein-Barr virus-associated hemophagocytic syndrome complications. Neutrophilic leukocytosis was a common feature. Other laboratory data showed elevated C-reactive protein levels (25.1±50.3 mg/dL), and erythrocyte sedimentation rates (69±28 mm/hr) and abnormal liver enzymes. Marked hyperferritinemia (> 2,000 ng/mL) was noted in 57% (4/7) of the patients. The mean time from onset of symptoms to diagnosis was 9.2 weeks. Non-steroidal anti-inflammatory drugs, steroids, disease-modifying anti-rheumatic drugs and anti-tumor necrosis factor agents were used for treatment. Due to prolonged fever, 2.0±1.6 (maximum=5) different kinds of antibiotics were used before a diagnosis was made. Most cases had satisfactory therapeutic outcomes except one boy, who had permanent joint contracture. CONCLUSION: The clinical manifestations of s-JIA in Taiwan were often accompanied by a prolonged fever. This results in clinicians often suspecting bacterial infections and prescribing several kinds of antibiotics. In the case of prolonged fever, s-JIA should always be placed on the list of differential diagnoses.

Necrolytic acral erythema without hepatitis C infection.

Necrolytic acral erythema is a newly described entity characterized by sharply demarcated scaly plaques on the dorsum of the hands and feet. More than 30 patients have been reported since 1996, all of whom had anti-hepatitis C virus antibody. A 32-year-old Taiwanese woman had been diagnosed with and treated for systemic lupus erythematosus with lupus nephritis about 10 years earlier. Soon thereafter, she noted several well-demarcated keratotic plaques with erythematous borders on her feet, with sparing of the soles. Histopathology showed diffuse parakeratosis with a neutrophil infiltrate, hypogranulosis, pale upper keratinocytes, scattered and grouped dyskeratotic cells, psoriasiform hyperplasia and a mild lymphocytic infiltrate in the upper dermis. The diagnosis was made after three biopsies. The lesions regularly worsened just before and during menstruation, but patch and intradermal tests for progesterone and estrogen were negative. There was no evidence of either hepatitis B or hepatitis C infection. The lesions did not respond to treatment with zinc. The rash regressed spontaneously when corticosteroids were stopped and recurred when they were restarted, finally resolving completely after she was treated with high-dose pulse steroids for her lupus.

Mechanical bowel strangulation mimicking mesenteric vasculitis in a systemic lupus erythematosus patient.

A case of systemic lupus erythematosus with jaundice and vague abdominal pain which did not respond to steroid pulse therapy is presented. Noninvasive examinations and imaging studies showed ileus. Two weeks later, an emergency laparotomy was performed because of severe refractory abdominal pain and hemodynamic decompensation. An ischemic part of the terminal ileum was resected. It was pathologically determined to be ischemic bowel disease because of mechanical strangulation resulting from adhesion band, but without evidence of vasculitis, atherosclerotic change, or thrombosis. After intensive postoperative care, the patient gradually recovered. This unusual case shows that nonlupus-related mechanical strangulation should be considered in the differential diagnosis of acute abdomen in lupus patients, particularly in those who have received steroid therapy or have a history of previous abdominal operation.

Influence of HLA-DRB1 genes and the shared epitope on genetic susceptibility to rheumatoid arthritis in Taiwanese.

OBJECTIVE: To investigate the association of predisposing and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in a Taiwanese population. METHODS: A total of 273 patients with RA and 480 healthy controls, all of Taiwanese origin, were genotyped for HLA-DRB1 alleles by polymerase chain reaction and sequence-based typing assays. The associations between RA and HLA-DRB1 alleles and genotypes were investigated by chi-squared test. RESULTS: The DRB1*0405 and *1001 phenotypes showed the most significant associations with RA (OR 4.04, 95% CI 2.84-5.77, pc = 3.2 10(-14); OR 5.25, 95% CI 2.10-13.06, pc = 3.0 10(-3), respectively). Individuals carrying single or double doses of the shared epitope (SE/non-SE or SE/SE) had higher risks of RA. The compound heterozygote of DRB1*0405/*1001 showed the largest increase in RA risk (OR 15.8, 95% CI 2.48-100.7, pc = 0.004). Single or double doses of SE alleles were significantly associated with a higher bone erosion rate. Rheumatoid factor positivity and bone erosion were more frequent in patients with at least one copy of DRB1*0405. CONCLUSION: Our results show that SE-encoding HLA-DRB1*0405 and *1001 are associated with RA in a Taiwanese population; this is the first time DRB1*1001 has been described in persons of Asian ethnicity. Heterozygotes of DRB1*0405 and *1001 predicted the strongest susceptibility to RA, suggesting that this genotype enhances susceptibility to RA in Taiwanese.

Outcome of pregnancy in patients with systemic lupus erythematosus.

OBJECTIVE: To study the maternal and fetal outcomes in women with systemic lupus erythematosus (SLE). MATERIALS AND METHODS: Over a period of 10 years, 24 pregnancies in 17 females with SLE in a single center were enrolled. Fetal and maternal outcomes were studied retrospectively. RESULTS: The mean patient age was 27.7 years. Twenty-one of the 24 pregnancies occurred in the period of disease remission at the time of conception. Proteinuria presented in 12 pregnancies; however, no patient developed acute renal failure or deterioration of renal function. There were three cases of preeclampsia in this study. Two patients had their disease flare up and delivered stillborns. One woman with secondary antiphospholipid syndrome (APS) had a fetal loss. There was no maternal mortality. The mean gestation age was 34.3 weeks (range, 17-41 weeks), and the mean birth weight was 2,179 g. The mean APGAR scores were 8 and 9 at 1 and 5 minutes, respectively. One baby with congenital atrioventricular block was born to a mother with positive anti-SSA antibody. There were five cases (20.8%) of intrauterine growth retardation and 10 preterm deliveries (41.6%) in this study. CONCLUSION: Pregnancy is relatively safe in women with SLE in remission but should be considered as a high-risk pregnancy. APS is associated with poor pregnancy outcome. The patient needs to cooperate with obstetricians and physicians for optimal disease control and detailed monitoring throughout the gestation.

Improvement of insulin resistance by Acanthopanax senticosus root in fructose-rich chow-fed rats.

1. In an attempt to develop new substances for handling insulin resistance, an aqueous extract of the root of Acanthopanax senticosus (Araliaceae) was used to screen the effect on insulin resistance induced by fructose-rich chow in rats. 2. Insulin action on glucose disposal rate was measured using the glucose-insulin index, the product from areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test. In addition to the modification of feeding behaviour and a marked decrease in bodyweight, oral administration (three times daily for 3 days) of the aqueous extract of A. senticosus root to rats that had received fructose-rich chow for 4 weeks reversed the elevated value of the glucose--insulin index, indicating that this herb has the ability to improve insulin sensitivity. 3. Time for the loss of the plasma glucose-lowering response to tolbutamide (10.0 mg/kg, i.p.) in fructose-rich chow-fed rats was markedly delayed by repeated treatment with the aqueous extract of A. senticosus root compared with the vehicle (saline) -treated group. Thus, an improving effect of A. senticosus root on insulin resistance can be considered. 4. An increase in insulin sensitivity following the administration of this herb was further identified using the plasma glucose-lowering action of exogenous insulin in streptozotocin (STZ)-diabetic rats. Oral administration of the aqueous extract of A. senticosus root at a dose of 150.0 mg/kg three times daily to STZ-diabetic rats increased the responses to exogenous insulin 10 days later. 5. The results obtained suggest that oral administration of the aqueous extract from A. senticosus root has the ability to improve insulin sensitivity and delay the development of insulin resistance in rats and, thus, may be used as an adjuvant therapy for patients with insulin resistance.