Long-term safety and effectiveness of adalimumab in 462 patients with intestinal Behçet's disease: results from a large real-world observational study

BACKGROUND/AIMS: The safety and effectiveness of adalimumab was demonstrated in a phase 3 trial in Japanese patients with intestinal Behçet's disease. The aim of this study was to evaluate the long-term safety and effectiveness of adalimumab in Japanese patients with intestinal Behçet's disease. METHODS: This prospective, all-case, post-marketing study was conducted at 254 centers in Japanese patients with intestinal Behçet's disease receiving adalimumab. The primary endpoint was incidence of adverse drug reactions. Effectiveness endpoints included global improvement rating and change in C-reactive protein levels. RESULTS: Of the 473 registered patients, 462 and 383 included in the safety and effectiveness populations were administered adalimumab for a mean of 515.3 and 579.5 days, respectively. Overall, 395 patients (85.5%) received adalimumab at the recommended dose. Adverse drug reactions and serious adverse drug reactions were reported in 120 (25.97%) and 51 (11.04%) patients, respectively. The incidence of adverse drug reactions was significantly higher in patients with comorbidities (P< 0.0001), patients taking concomitant oral corticosteroids (P< 0.0001), and those not self-administering adalimumab (P= 0.0257). At study end, global improvement rating was "effective" (n = 156, 40.7%) or "markedly effective" (n = 168, 43.9%) in 324 patients (overall effective, 84.6%). Mean C-reactive protein levels (mg/dL) decreased from 1.96 at baseline (n = 324) to 0.58 at week 24 (n = 208) and 0.25 at week 156 (n = 37). CONCLUSIONS: This large real-world study confirmed the long-term safety and effectiveness of adalimumab in patients with intestinal Behçet's disease. No new safety concerns were identified. (Clinical trial registration number: NCT01960790).

Long-term safety and effectiveness of adalimumab in Japanese patients with Crohn's disease: 3-year results from a real-world study.

BACKGROUND/AIMS: Crohn's disease is a chronic disorder; therefore, it is essential to investigate long-term safety and efficacy of treatments. This study assessed the safety and effectiveness of adalimumab for up to 3 years in Japanese patients with Crohn's disease in real-world settings. METHODS: This was a multicenter, single-cohort, observational study of patients with Crohn's disease. Safety assessments included incidence of adverse drug reactions. Effectiveness assessments included clinical remission, mucosal healing, and Work Productivity and Activity Impairment (WPAI). RESULTS: The safety and effectiveness analysis populations comprised 389 and 310 patients, respectively. Mean (standard deviation) exposure to adalimumab in the safety analysis population was 793.4 (402.8) days, with a 58.1% retention rate. A total of 105 patients (27.0%) and 43 patients (11.1%) experienced adverse drug reactions and serious adverse drug reactions, respectively, with no patient reporting tuberculosis or hepatitis B. Infections and serious infections were reported in 37 patients (9.5%) and 17 patients (4.4%), respectively. Malignancy was reported as an adverse drug reaction in 2 patients (0.5%). Remission rate increased from 37.8% (98/259) at baseline to 73.9% (167/226) at week 4 and remained > 70% over 3 years. Proportion of patients without mucosal ulcerations increased from 2.7% (2/73) at baseline to 42.3% (11/26) between years > 2 to ≤ 3. WPAI improvement started at 4 weeks, with the overall work impairment score improving from 42.7 (n = 102) at baseline to 26.9 (n = 84) at 4 weeks. CONCLUSIONS: Results from this study confirm the long-term safety and effectiveness of adalimumab treatment in Japanese patients with Crohn's disease in the real-world setting.

Safety and effectiveness of adalimumab in the treatment of ulcerative colitis: results from a large-scale, prospective, multicenter, observational study.

BACKGROUND/AIMS: Adalimumab has been shown to induce and maintain clinical remission in patients with moderate to severe ulcerative colitis (UC). However, no large-scale population-based studies have been performed in Japan. This study was conducted to evaluate the safety and effectiveness of adalimumab in clinical practice in Japanese patients with UC. METHODS: In this 52-week, prospective, multicenter, single-cohort, noninterventional, observational, postmarketing surveillance study, patients with moderate to severe UC received an initial subcutaneous injection of adalimumab 160 mg, followed by 80 mg at 2 weeks, and then 40 mg every other week. Safety assessments were the incidence of adverse drug reactions (ADRs) and serious ADRs. Effectiveness assessments were clinical remission, corticosteroid-free remission, mucosal healing, and change in C-reactive protein (CRP) levels from baseline. RESULTS: Of 1,593 registered patients, 1,523 (male, 57.6%; mean age, 41.8 years) and 1,241 patients were included in the safety and effectiveness populations, respectively. ADRs were reported in 18.1% and serious ADRs in 4.9% of patients. Clinical remission was achieved in 49.7% of patients at week 4, increasing to 74.4% at week 52. Corticosteroid-free remission rates increased over time, from 10.4% at week 4 to 53.1% at week 52. More than 60% of patients demonstrated mucosal healing at weeks 24 and 52. Mean CRP levels (mg/dL) decreased from 1.2 at baseline to 0.6 at week 4 and 0.3 at week 52. CONCLUSIONS: This large real-world study confirmed the safety and effectiveness of adalimumab in patients with UC in Japan. No new safety concerns were identified.

HPLC Retention time prediction for metabolome analysi.

Liquid Chromatography Time-of-Flight Mass Spectrometry (LC-TOF-MS) is widely used for profiling metabolite compounds. LC-TOF-MS is a chemical analysis technique that combines the physical separation capabilities of high-pressure liquid chromatography (HPLC) with the mass analysis capabilities of Time-of-Flight Mass Spectrometry (TOF-MS) which utilizes the difference in the flight time of ions due to difference in the mass-to-charge ratio. Since metabolite compounds have various chemical characteristics, their precise identification is a crucial problem of metabolomics research. Contemporaneously analyzed reference standards are commonly required for mass spectral matching and retention time matching, but there are far fewer reference standards than there are compounds in the organism. We therefore developed a retention time prediction method for HPLC to improve the accuracy of identification of metabolite compounds. This method uses a combination of Support Vector Regression and Multiple Linear Regression adaptively to the measured retention time. We achieved a strong correlation (correlation coefficient = 0.974) between measured and predicted retention times for our experimental data. We also demonstrated a successful identification of an E. coli metabolite compound that cannot be identified by precise mass alone.

Cathepsin G, a neutrophil protease, induces compact cell-cell adhesion in MCF-7 human breast cancer cells.

Cathepsin G is a serine protease secreted by activated neutrophils that play a role in the inflammatory response. Because neutrophils are known to be invading leukocytes in various tumors, their products may influence the characteristics of tumor cells such as the growth state, motility, and the adhesiveness between cells or the extracellular matrix. Here, we demonstrate that cathepsin G induces cell-cell adhesion of MCF-7 human breast cancer cells resulting from the contact inhibition of cell movement on fibronectin but not on type IV collagen. Cathepsin G subsequently induced cell condensation, a very compact cell colony, resulting due to the increased strength of E-cadherin-mediated cell-cell adhesion. Cathepsin G action is protease activity-dependent and was inhibited by the presence of serine protease inhibitors. Cathepsin G promotes E-cadherin/catenin complex formation and Rap1 activation in MCF-7 cells, which reportedly regulates E-cadherin-based cell-cell junctions. Cathepsin G also promotes E-cadherin/protein kinase D1 (PKD1) complex formation, and Go6976, the selective PKD1 inhibitor, suppressed the cathepsin G-induced cell condensation. Our findings provide the first evidence that cathepsin G regulates E-cadherin function, suggesting that cathepsin G has a novel modulatory role against tumor cell-cell adhesion.

Potential relationships between transaminase abnormality and valproic acid clearance or serum carnitine concentrations in Japanese epileptic patients.

This study tested the hypothesis that the determinants of mild liver injury are prerequisites for more severe idiosyncratic hepatotoxicity. This study verified whether the possible risk factors for rare idiosyncratic valproic acid (VPA)-induced hepatotoxicity, VPA clearance and/or serum carnitine concentrations are common to those for a mild elevation in transaminases in VPA-treated patients. VPA clearance was calculated in 172 Japanese patients with epilepsy, using a non-linear mixed-effects regression program. Carnitine concentrations were determined in a subset of 60 patients. The relationships between VPA clearance, carnitine concentration and levels of transaminases and ammonia were evaluated by Pearson's correlation coefficients. The final model of VPA apparent clearance (CL/F) was as follows: CL/F (L h(-1) = 0.012 x (BW/40)(0.34) x dose(0.55) x 0.90(gender) x 1.32(PHT) x 1.11(CBZ) x 1.12(PB), where BW = total body weight (kg); gender = 1 if female, 0 if male; PHT/CBZ/PB = 1 if phenytoin, carbamazepine, or phenobarbital, respectively, is coadministrated, otherwise 0. Either a higher VPA clearance or acyl/free carnitine ratio and a lower total and/or free carnitine concentration, but not VPA concentration, were associated with the mild elevation in transaminases or ammonia. These results support the initial hypothesis, while also helping to clarify the mechanism of severe idiosyncratic hepatotoxicity with VPA.

[Persistent neutrophilia occurring after pneumonia: a differential diagnosis of neutrophilia based on the WHO classification].

We experienced a 85-year-old female patient with granulocytosis, which occurred after the bacterial pneumonia. The white blood cell counts remained high between 30,000/microl and 120,000/microl for around one year. As the serum G-CSF level was within the normal range and there were no tumors on CT scan images, the existence of G-CSF-producing solid tumors was unlikely. Bone marrow examination revealed hypercellularity without excess of blasts and hiatus leukemia, accompanied by mild dysplasia in myeloid cells and megakaryocytes. No chromosomal abnormalities in bone marrow samples were seen with G-banding and multi-color FISH methods. Major/minor BCR-ABL fusion genes were negative by RT-PCR. As previously reported by several investigators, we often experience difficulties in distinguishing atypical CML from CNL and CMML. In this report, we discussed how to diagnose the cause of granulocytosis based on a literature review.