Evaluation of apremilast,an oral phosphodiesterase 4 inhibitor,for refractory cutaneous dermatomyositis: A phase 1b clinical trial

Dermatomyositis, an idiopathic inflammatory myopathy, is characterized by cutaneous itchy manifestations, which are frequently refractory and recurrent even after intensive immunosuppressive treatments. To evaluate the effectiveness and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in treating skin-dominant dermatomyositis in which myositis and interstitial lung disease are absent or in remission, we performed this prospective, single-arm, interventional study. A total of five Japanese patients (one male and four females, median [range] age, 64 [37–71] years) with refractory dermatomyositis-associated cutaneous manifestations were recruited and treated with a 12-week course of oral apremilast. Among five enrolled patients, three experienced diarrhea with full-dose apremilast (30 mg twice daily), two of whom withdrew from the study and recovered quickly afterwards. A total of three evaluable female patients (median [range] age, 65 [64–71] years) received apremilast treatment for 12 weeks. A 39.4% reduction from baseline Cutaneous Dermatomyositis Disease Area and Severity Index total activity score, but not the damage score, at week 12 was observed in all three patients. Visual analog scale of itching, and quality of life by Dermatology Life Quality Index were slightly improved in one and two apremilast-treated patients, respectively. As apremilast was effective, with expected and recoverable digestive adverse events (diarrhea), in patients with refractory and recurrent dermatomyositis-associated cutaneous manifestations in this first phase Ib study, it can be suggested as a possible treatment when aggressive immunosuppressive therapies with high-dose systemic corticosteroid and/or immunosuppressive agents for other manifestations, myositis, and interstitial lung disease, are not required.     

Theory-based analysis of anti-inflammatory effect of infliximab on Crohn’s disease and rheumatoid arthritis

In Japan, the recommended dosage regimens of infliximab (IFX) for treatment of rheumatoid arthritis (RA) and Crohn’s disease (CD) are different. However, the differences have not been analyzed theoretically. In a previous study, we constructed a pharmacokinetic–pharmacodynamic model to investigate the effects of IFX for CD and found it useful to establish a rational dosage regimen of IFX for individual patients with CD. In the present study, we investigated whether the theory-based model could be used for cases of RA and also used it to evaluate the validity of the dosage regimen. The results obtained with our model were in good agreement with observed tender joint count (TJC) ratio data, which was considered to show the validity of our analysis. Thus, we concluded that the model could be used for patients with RA. Furthermore, a second administration of IFX given 2 weeks after the first infusion was important to achieve remission in the early stage of RA. We also compared the estimated pharmacodynamic parameters of RA with those of CD. The elimination rate constant of inflammation in RA was greater than that in CD, suggesting that the recovery from inflammation in RA is faster than that in CD, and indicating a reason for the difference in dosage between RA and CD. In conclusion, use of our model in light of the individual quantitative factor of tumor necrosis factor (TNF)-α allows establishment of IFX dosage regimens for individual patients.     

Ribosomal Protein S6 Phosphorylation is Associated with Epithelial Dysplasia and Squamous Cell Carcinoma of the Oral Cavity

Ribosomal protein S6 (RPS6), a downstream effector of the mammalian target of rapamycin pathway (mTOR), is activated in many cancers including oral squamous cell carcinoma (OSCC). However, the role of RPS6 in the progression of potentially malignant disorders (or premalignant lesions) to OSCC is unknown. The purpose of this study was to examine the expression of RPS6 in epithelial dysplasia and OSCC to determine the association of RPS6 in tumor progression. In our study, an immunohistochemical analysis of RPS6 was performed on tissue microarrays containing 30 control samples, 15 epithelial dysplasia cases, and 53 OSCC cases. Correlations between the clinicopathologic features of OSCC and RPS6 expression were analyzed using the Chi-square test. We found RPS6 phosphorylation (p-RPS6) in 15/30 (50 %) control normal oral mucosa samples, 15/15 (100 %) epithelial dysplasia cases, and 47/53 (88.68 %) OSCC cases. The frequency of p-RPS6 in epithelial dysplasia or OSCC showed a statistically significant difference compared to control (P?<?0.001). However, there were no significant correlations between p-RPS6 and the clinicopathologic features of OSCC. Our findings suggest that RPS6 activation is associated with the early events of tumor progression, suggesting p-RPS6 as a potential marker for early detection of oral cancer.     

Neutrophil Phagocytosis of Platelets in the Early Phase of 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced Dermatitis in Mice

Activated platelets form platelet–leukocyte aggregates in the circulation in inflammatory diseases. We investigated whether activated platelets in inflamed skin tissues are phagocytized and removed by neutrophils. To investigate the kinetics of platelets and neutrophils, we immunohistochemically examined the spatiotemporal distribution of them in a murine model of 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced dermatitis by using confocal and structured illumination microscopy. Four hours after elicitation, aggregates of CD41-positive platelets were adhered to CD31-positive endothelial cells within the vessels, and CD62P and PF4, markers of activated platelets, were expressed on platelet aggregates. At 8 hour post-elicitation, fragmented CD41-positive platelets were located both inside and outside vessels. Twenty-four hours after elicitation, the number of Ly-6G-positive neutrophils ingesting fragmented CD41-positive platelets outside vessels was increased, and CD62P and PF4 expression on the phagocytosed platelets was no longer observed. Disc-shaped CD41-positive platelets were not found outside vessels at any time during the experiment. Our data revealed that aggregates of activated platelets inside vessels were ingested and removed by neutrophils in the early stage of TNCB-induced dermatitis, suggesting that the process of removal of activated platelets by neutrophils may play an important role not only in the early phase of skin inflammation but also in other types of acute inflammation.     

Influence of topical steroids on intraocular pressure in patients with atopic dermatitis

Background

Topical corticosteroids (TCS) can induce adverse effects, such as skin atrophy. Although TCS can cause increases in intraocular pressure (IOP), the effects of daily TCS use on IOP have not been fully elucidated. We evaluated the clinical doses of TCS and the change in the IOP during the daily treatment of atopic dermatitis (AD).

Sustained Viral Response Is Rarely Achieved in Patients with High Viral Load of HCV RNA by Excessive Interferon Therapy

Adequate dosing of interferon (IFN) and its cost-effectiveness for sustained virological response were evaluated in relation to viral load and subtype. Prospective analysis of IFN therapy on 326 patients with chronic hepatitis C free from cirrhosis was performed using 9 or 6 million unit (MU) of IFN for six months daily and/or three times a week. Sustained virological response was achieved in 50–94% of patients with 2 × 10⁴ copies/ml (competitive RT-PCR) or <100 × 10³ copies/ml (Amplicor monitor) of HCV RNA by 468–1206 MU of IFN, but response was only 0–25% of the patients with 2 × 10^5.5 copies/ml (competitive RT-PCR) or >200 × 10³ copies/ml (Amplicor monitor), even with 468–1206 MU of IFN. A high sustained rate was demonstrated in patients with 100–200 × 10³ copies/ml of HCV RNA by 901–1206 MU of IFN, in comparison to that with 900 MU of IFN. Multivariate analysis showed that IFN dose had a significant value for the efficacy of IFN therapy in patients presenting 100–200 × 10³ copies/ml of HCV RNA. Cost efficacy analysis indicated that it cost approximately $10,000, $26,000, and $50,000–227,000 for one person-viral eradication in the patients with <100, 100–200, and >200 × 10³ copies/ml, respectively. High-dose IFN is only cost effective in patients with intermediate viral loads, and IFN therapy could be recommended in patients with <200 × 10³ copies/ml of HCV RNA.     

Age-related changes of NGF, BDNF, parvalbumin and neuronal nitric oxide synthase immunoreactivity in the mouse hippocampal CA1 sector

We investigated the age-related alterations in nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), parvalbumin and neuronal nitric oxide synthase (nNOS) immunoreactivity of the mouse hippocampal CA1 sector. NGF and BDNF immunoreactivity was unchanged in the hippocampal CA1 pyramidal neurons from 2 to 50-59 weeks of birth. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector from 40-42 to 50-59 weeks of birth. On the other hand, the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. Our results indicate that NGF and BDNF immunoreactivity was unaltered in the hippocampal CA1 pyramidal neurons during aging processes. In contrast, a significant increase in the NGF and BDNF immunoreactivity was observed in glial cells of the hippocampal CA1 sector during aging processes. The present study also shows that the number of parvalbumin- and nNOS-positive interneurons was unchanged in the hippocampal CA1 sector during aging processes, except for a significant decrease of nNOS-positive interneurons 2 weeks of birth. These results demonstrate that the expression of glial NGF and BDNF may play a key role for helping survival and maintenance of pyramidal neurons and neuronal functions in the hippocampal CA1 sector during aging processes. Furthermore, our findings suggest that parvalbumin- and nNOS-positive interneurons in the hippocampal CA1 sector are resistant to aging processes. Moreover, our findings suggest that nitric oxide synthesized by the nNOS may play some role for neuronal growth during postnatal development.