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.

Antibody blockade of Dectin-2 suppresses house dust mite-induced Th2 cytokine production in dendritic cell- and monocyte-depleted peripheral blood mononuclear cell co-cultures from asthma patients.

BACKGROUND: Dectin-2, which is a C-type lectin, interacts with the house dust mite (HDM) Dermatophagoides pteronyssinus allergen. This study aimed to investigate whether Dectin-2 blockade by antagonistic monoclonal antibodies (MoAbs) attenuates HDM-induced allergic responses. METHODS: Two anti-Dectin-2 MoAbs were generated and validated for specific binding to Dectin-2 Fc fusion protein (Dectin-2.Fc) and inhibition of Dectin-2.Fc/HDM interaction. Patients with asthma exhibiting high titers of anti-D. pteronyssinus IgE were enrolled. Peripheral blood mononuclear cells with depleted CD14+ monocytes were obtained from these patients and co-cultured with autologous monocyte-derived conventional dendritic cells in the presence of D. pteronyssinus or its group 2 allergens (Der p 2). Interleukin (IL)-5 and IL-13 levels in the culture supernatants were determined using ELISA in the presence or absence of anti-Dectin-2 MoAbs. RESULTS: Two MoAbs, 6A4G7 and 17A1D10, showed specific binding to recombinant Dectin-2.Fc and inhibited HDM binding to Dectin-2.Fc. Both anti-Dectin-2 MoAbs inhibited IL-5 and IL-13 production in co-cultures with Der p 2 stimulation in a dose-dependent manner. 6A4G7 and 17A1D10 (3 µg/mL) significantly inhibited Der p 2-induced (3 µg/mL) IL-5 production by 69.7 and 86.4% and IL-13 production by 84.0 and 81.4%, respectively. Moreover, this inhibitory effect of the two MoAbs remained significant in the presence of D. pteronyssinus. CONCLUSIONS: Anti-Dectin-2 MoAbs significantly inhibited HDM-induced allergic responses in vitro and therefore have the potential to become therapeutic agents in mite-induced allergic diseases.

Serum decoy receptor 3 is a biomarker for disease severity in nonatopic asthma patients.

BACKGROUND/PURPOSE: Decoy receptor 3 (DcR3), a soluble receptor of the tumor necrosis factor receptor superfamily, is a pleiotropic immunomodulator. The aim of this study was to investigate serum DcR3 levels in atopic and nonatopic asthma patients. METHODS: The serum DcR3 levels of 70 adults with asthma and 20 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA). The asthma patients were divided into atopic and nonatopic subgroups, based on the presence or absence of immunoglobulin E (IgE) specific to allergen. Correlations between serum DcR3 levels and blood total-eosinophil counts, forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), and Asthma Control Test (ACT) scores were analyzed. RESULTS: The mean serum DcR3 level was significantly higher in asthma patients than in healthy controls (266.1 ± 60.6 pg/mL vs. 63.7 ± 21.9 pg/mL, p = 0.003), but there was no significant difference between the mean serum DcR3 level of asthma patients with atopy (37 patients) and patients without atopy (33 patients; 298.7 ± 111.2 pg/mL vs. 230.6 ± 38.5 pg/mL, p = 0.064). However, the serum DcR3 level was positively correlated with the total eosinophil count (r = 0.448, p = 0.012) and inversely correlated with the percentages of predicted FEV1, FEV1/FVC, and ACT score (r = 0.409, p = 0.018; r = -0.399, p = 0.021; and r = -0.505, p = 0.003, respectively) in nonatopic asthma patients, but not in atopic patients. CONCLUSION: High serum DcR3 levels are associated with disease severity in nonatopic asthma patients, which suggests that DcR3 is a potential biomarker that can be used to predict the severity of nonatopic asthma.

The impact of introducing biologics to patients with rheumatoid arthritis in Taiwan: a population-based trend study.

AIM: The biologics used to treat rheumatoid arthritis (RA) patients with a catastrophic illness certificate have been free without co-payment since 2003 in Taiwan. The purpose of this study was to explore the trend of health care expenditures and the cost of biologics for the treatment of RA patients between 1999 and 2009. METHODS: This study used a specially requested nation-wide RA patient claim dataset from National Health Insurance program. We identified all patients by both the primary diagnosis code ICD-9-CM 714.0 and the catastrophic illness certificate for RA. A total of 30 013 patients were recorded in the treated RA cohort from 1999 to 2009.The growth rates before and after introducing biologics were compared and tested. RESULTS: We found that from 1999 to 2009 the adjusted incidence rate for RA stably increased. Drug costs accounted for 53.2-70.3% of the total medical cost during the study period. There was a significant increase in biologics cost, climbing rapidly from 2.8% in 2003 to 60.4% of the total drug cost in 2009. The growth rate of outpatient drug costs was much higher after the introduction of biologics (2003-2009), which was 207.8% versus 42.0% as compared to the earlier period (1999-2002). Biologics such as etanercept, adalimumab and rituximab, were the crucial factors responsible for this increase in drug cost. CONCLUSIONS: The financial impact of adopting new biologics on healthcare costs is a critical issue that needs to be addressed by the National Health Insurance.

The rapid immunosuppression in phytohemagglutinin-activated human T cells is inhibited by the proliferative Ca(2+) influx induced by progesterone and analogs.

Progesterone, an endogenous immunomodulator, suppresses human T-cell activation during pregnancy. A sustained Ca(2 +) influx is an important signal for T-cell proliferation after crosslinking of T-cell receptor/CD3 complexes by anti-CD3 antibodies or phytohemagglutinin (PHA). Progesterone targets cell membrane sites inducing rapid responses including elevated intracellular free calcium concentration ([Ca(2+)]i) and suppressed T-cell PHA-activated proliferation. Interestingly, both PHA and progesterone induce [Ca(2+)]i elevation, but it remains unclear whether the PHA-induced Ca(2+) influx is affected by progesterone leading to T-cell immunosuppression. Primary T-cells were isolated from human peripheral blood and the quench effect on intracellular fura-2 fluorescence of Mn(2+) was used to explore the responses to Ca(2+) influx with cell proliferation being determined by MTT assay. PHA-stimulated Ca(2+) influx was dose-dependently suppressed by progesterone and its agonist R5020, which correlated with PHA-activated T-cell proliferation inhibition. A similar dose-dependent suppression effect on cellular Ca(2+) influx and proliferation occurred with the TRPC channel inhibitor BTP2 and selective TRPC3 channel inhibitor Pyr3. In addition, two progesterone analogs, Org OD 02-0 and 20α-hydroxyprogesterone (20α-OHP), also produced dose-dependent suppression of Ca(2+) influx, but had no effect on proliferation. Finally, inhibition of PHA-activated T-cell proliferation by progesterone is further suppressed by 20α-OHP, but not by Org OD 02-0. Overall, progesterone and R5020 are able to rapidly decrease PHA-stimulated sustained Ca(2+) influx, probably via blockade of TRPC3 channels, which suppresses T-cell proliferation. Taken together, the roles of progesterone and its analogs regarding the rapid response Ca(2+) influx need to be further explored in relation to cytokine secretion and proliferation in activated T-cells.

Localization of the cricothyroid muscle under ultrasound guidance for vagal nerve mapping.

During surgical removal of tumors of the skull base or cerebellopontine angle with brainstem compression, the vagus nerve is at a high risk for injury that can result in permanent or transient swallowing and speech dysfunction. Intramuscular recording of cricothyroid muscle can be used for vagal nerve mapping during intraoperative neurophysiologic monitoring so as to prevent the above complications. However, it is a small muscle that lies beneath the strap muscles over the anterior neck and is not easily accessible by a blind approach. Here, we present a case in which cricothyroid muscle was identified for precise electrode placement under ultrasound guidance during preparation for intraoperative monitoring. We concluded that localization of the cricothyroid muscle by ultrasonography proved to be a feasible and easy technique, and the compound muscle action potential recorded by this approach is clearly recognizable during intraoperative vagal nerve mapping.

Ultrasound-guided refilling of an intrathecal baclofen pump--a case report.

INTRODUCTION: Refilling intrathecal baclofen (ITB) pumps can be difficult because many patients gain excessive weight after implantation due to their reduced expenditure of energy on muscle spasticity. METHODS: We report a case of a 12-year-old girl with spastic quadriplegia who gained 20 lbs after pump implantation. It was necessary to identify the access port of her pump by ultrasonography during drug refilling so as to avoid multiple needle punctures. RESULTS: The access port of the pump was readily visible by ultrasonography and stood out from other parts of the pump. CONCLUSION: Localisation of the access ports of ITB pumps by ultrasonography proved to be a feasible and easy technique for refilling the drug reservoir in patients with excessive weight gain and abundant subcutaneous fat after ITB therapy.

A vacuolar serine protease (Rho m 2) is a major allergen of Rhodotorula mucilaginosa and belongs to a class of highly conserved pan-fungal allergens.

BACKGROUND: Rhodotorula mucilaginosa is one of the most frequently encountered species of yeasts in our environment. We reported here a major allergen of R. mucilaginosa. METHODS: A major R. mucilaginosa allergen (Rho m 2) was characterized by two-dimensional (2D) immunoblotting, protein sequencing, cDNA cloning and IgE cross-reactivity with fungal serine proteases. RESULTS: Fourty-four sera (28%) from 157 bronchial asthmatic patients showed IgE-immunoblot reactivity against R. mucilaginosa extract. Among these 44 sera, 25 (57%) demonstrated IgE binding against a 31-kDa protein of R. mucilaginosa. Protein sequencing results suggest that it is a vacuolar serine protease. The corresponding cDNA clone encoding a mature protein of 312 residues was isolated. It shares 67-68% sequence identity with vacuolar serine protease allergens from three different Penicillium species (Pen ch 18, Pen o 18 and Pen c 18) and designated as Rho m 2 by the Allergen Nomenclature Committee. The native and recombinant Rho m 2 react with IgE antibodies and monoclonal antibody (MoAb) FUM20 against fungal serine proteases. IgE cross-reactivity between nRho m 2 and nPen ch 18 was observed. It was also detectable between rRho m 2 and rPen o 18. CONCLUSION: Our results suggest that R. mucilaginosa may also be a significant causative agent of human respiratory allergic disorders. We identified a vacuolar serine protease as a major allergen of R. mucilaginosa (Rho m 2) and a pan allergen of prevalent airborne fungal species. We detected IgE cross-reactivity among these highly conserved serine protease pan-fungal allergens.

Laryngotracheal involvement as the initial manifestation of relapsing polychondritis.

Relapsing polychondritis (RP) is a rare multisystemic disease characterized by recurrent inflammation of cartilaginous and noncartilaginous tissues. When laryngotracheal or bronchial cartilages are involved, the disease can be life-threatening and needs aggressive treatment. Upper airway complaints are rare as initial presentations of RP. Here, however, we present a case of RP, with initial manifestations of cough and dyspnea that were treated as bronchial asthma for 6 months. Subglottic stenosis was found in April 2003, during a bronchoscopic examination, and emergency tracheostomy was performed. Auricular and nasal chondritis and bilateral scleritis developed 3 months after tracheostomy. High doses of methylprednisolone and immunosuppressive agents were used, and active inflammation in the eyes and ears was controlled, but the patient's upper airway was completely collapsed. This case is reported with the hope of increasing awareness about the potential for early upper airway involvement in RP.

Acute massive pulmonary hemorrhage after craniotomy in a patient with systemic lupus erythematosus.

Acute massive pulmonary hemorrhage (AMPH) is a rare life-threatening complication of systemic lupus erythematosus (SLE). We report a lupus nephritis patient with active disease, in whom AMPH developed after craniotomy for brain injury. Computed tomography scan of the brain revealed a subdural hemorrhage and intracranial hemorrhage with a midline shift, indicating increased intracranial pressure (IICP). Neurogenic pulmonary edema (NPE) was suspected 5 days after operation due to dyspnea and chest radiograph findings of bilateral infiltrations. Seven days after the craniotomy, she had bloody sputum, a sudden drop in blood hemoglobin level (from 12.3 g/dL to 8.8 g/dL), and diffuse alveolar infiltrates in both lung fields. All of these features were characteristic manifestations of AMPH. Complete blood count disclosed mild thrombocytopenia (88,000/mm3). We believe that in an SLE patient, IICP or NPE might be risk factors in the development of AMPH.

The prevalence of IgE antibody reactivity against the alkaline serine protease major allergen of Penicillium chrysogenum increases with the age of asthmatic patients.

BACKGROUND: Penicillium species are prevalent airborne fungi. However, the prevalence of allergic sensitization to Penicillium antigens and the true impact of these ubiquitous fungi on atopic respiratory disorders remain to be determined. OBJECTIVE: The purpose of this study was to analyze the prevalence of immunoglobulin (Ig)E and IgG antibodies against Penicillium chrysogenum (Pen ch 13), the alkaline serine protease major allergen of P. chrysogenum, in asthmatic patients of different age groups. METHODS: Pen ch 13 was purified from a culture medium of P. chrysogenum. The reactivity of IgE and IgG antibodies to Pen ch 13 in the serum samples of 212 asthmatic patients was analyzed by immunoblotting methods. RESULTS: Sixty-nine (33%) of the 212 sera analyzed showed IgE and/or IgG immunoblot reactivity to Pen ch 13. Significant differences in the prevalence of IgE and/or IgG antibody reactivity to Pen ch 13 were found among eight different age groups of 212 asthmatic patients. The frequency of IgE-binding reactivity to Pen ch 13 increased significantly with the age of the patients. It was 7% for the group less than 10 years old and 42% for the group older than 70 years old. In addition, a significant difference between the prevalence of IgE (7%) and IgG (33%) antibodies against Pen ch 13 in the group aged 10 or less was also found. CONCLUSIONS: Our study demonstrates that IgE and IgG antibodies specific for Pen ch 13 were detected in approximately one-third of the 212 asthmatic patients analyzed. Our results suggest that allergic sensitization to Pen ch 13, and possibly to other airborne Penicillium species, is more common in older asthmatic patients.

Effect of selective posterior rhizotomy on transverse myelitis in a patient with systemic lupus erythematosus.

This report describes the case of a 26-yr-old man experiencing transverse myelitis, a rare but serious complication of systemic lupus erythematosus occurring in less than 1% of patients with systemic lupus erythematosus, 4 yr after the onset of systemic lupus erythematosus. Significant neurologic deficits, including spastic paraplegia, dysthetic pain, and impaired bladder control, which made him completely bedridden and dependent in activities of daily living, continued, despite his immediate diagnosis and treatment. The patient received bilateral L1 to S1 selective posterior rhizotomy 1 yr after the onset of transverse myelitis, and 10 mo after selective posterior rhizotomy, he was completely independent in ambulation and self-care, demonstrating that selective posterior rhizotomy can be safely performed and its goals achieved under different medical conditions, as long as thorough preoperative evaluation and every possible precaution have been taken.