The use of infliximab in the prevention of postsurgical recurrence in polysurgery Crohn's disease patients: a pilot open-labeled prospective study

Purpose

Crohn's disease (CD) commonly recurs after surgery, and a number of patients need repeated surgery, especially smokers and those with repeated surgeries or penetrating disease. Whether infliximab prevents postsurgical recurrence in high-risk CD remains unknown. In the present pilot open-labeled study, we investigated the safety and efficacy of scheduled infliximab, which was started early after surgery, in maintaining remission of CD patients who have undergone multiple surgeries due to penetrating disease.

Methods

Eleven patients (nine male, two female; age range, 26–48?years) who had undergone repeated surgeries (median, 4; range, 2–5) for penetrating disease were enrolled. Two to 4?weeks after surgery, the patients were started on intravenous infliximab (5?mg/kg) at an 8-week interval. The primary end points were the proportion of patients in clinical remission at the end of the study, the rate of endoscopic/radiologic remission at 24?months, and the rate of adverse effects.

Results

One patient dropped out due to non-compliance, and ten patients were eligible for analysis. Clinical remission was maintained in six of ten patients (60.0%) at the end of the study. At 24?months, four out of ten patients were in endoscopic or radiological remission (40.0%). Two patients experienced adverse effects (18.2%), one of whom elected to withdraw from the study.

Conclusion

The findings of no major safety concern and possible clinical benefit in our study suggest that further investigation of infliximab as a treatment for prevention of postsurgical recurrence in high-risk CD is warranted.     

Autofluorescence imaging and the quantitative intensity of fluorescence for evaluating the dysplastic grade of colonic neoplasms

Background and aims

Autofluorescence imaging (AFI) is a novel technology which can capture fluorescence emitted from intestinal tissues. While AFI is useful for detecting colorectal neoplasms, it is unclear whether AFI can facilitate the diagnosis by differentiating the extent of dysplasia of colorectal neoplasms. This study investigated the efficacy of AFI in discriminating high-grade from low-grade adenoma.

Materials and methods

Sixty-seven patients who underwent colonoscopy with AFI were enrolled in this study. The AFI images obtained from 158 lesions in these patients were visually classified into four categories, namely, green (G), green with magenta spots (GM), magenta with green spots (MG), and magenta (M), according to their color intensities, immediately after the examination. The AFI images of the lesions were quantified using an image-analytical software program (F index). Either the F index or the visual assessment was prospectively compared with the dysplastic grade.

Results

The F index of the high-grade adenomas was significantly lower than that of the low-grade adenomas, hyperplasia, and normal mucosa (p?Conclusions AFI, particularly the F index, is considered to be a useful procedure for estimating the dysplastic grade of colonic adenomas.     

M-CSF attenuates severity of chronic GVHD after unrelated BMT

To study the effects of M-CSF administration on long-term outcomes of unrelated BMT, we retrospectively analyzed data from patients transplanted through the Japan Marrow Donor Program. We obtained data from 54 patients who received M-CSF just after BMT and 500 patients who did not receive M-CSF or G-CSF acted as controls. There were no significant differences between the two cohorts with respect to OS, acute GVHD or relapse. Although the incidence of chronic GVHD was comparable between the two groups, extensive chronic GVHD was observed significantly less often in the M-CSF cohort than in the control group. Multivariate analysis identified M-CSF as a significant factor for attenuating extensive chronic GVHD (relative risk: 0.73; 95% confidence interval: 0.55-0.94; P=0.012). We also found the same results in matched-pair analysis. Our observation suggests the potential for clinical use of M-CSF to dampen severe chronic GVHD.     

Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon α (PEG-IFNα) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNα-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNλ). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈ 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈ 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. CONCLUSION: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNα/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.     

Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis

There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis (PBC). Although the vast majority of patients with this disease have anti-mitochondrial antibodies, there is no correlation of anti-mitochondrial antibody titer and/or presence with disease severity. Furthermore, in murine models of PBC, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we focused on a detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, primary sclerosing cholangitis, autoimmune hepatitis, chronic hepatitis C, and graft-versus-host disease, including CD3, CD4, CD8, CD20, CD38, and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle-like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in PBC but not controls; the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with PBC who manifest this unique coronal arrangement were those with significantly higher titers of anti-mitochondrial antibodies. CONCLUSION: These data collectively suggest a role for plasma cells in the specific destruction of intrahepatic bile ducts in PBC and confirm the increasing interest in plasma cells and autoimmunity.     

Circadian clock signals in the adrenal cortex

Circadian secretion of steroid hormones by the adrenal cortex is required to maintain whole body homeostasis and to adequately respond to or anticipate environmental changes. The richly vascularized zona glomerulosa (ZG) cells in the pericapsular region regulate osmotic balance of body fluid by secreting mineralocorticoids responding to circulating bioactive substances, and more medially located zona fasciculata (ZF) cells regulate energy supply and consumption by secreting glucocorticoids under neuronal and hormonal regulation. The circadian clock regulates both steroidogenic pathways: the clock within the ZG regulates mineralocorticoid production via controlling rate-limiting synthetic enzymes, and the ZF secretes glucocorticoid hormones into the systemic circulation under the control of central clock in the suprachiasmatic nucleus. A functional biological clock at the systemic and cellular levels is therefore necessary for steroid synthesis and secretion.