Neeti Bhardwaj

Biomarkers for eosinophilic esophagitis: a review

BACKGROUND The complex pathophysiology of eosinophilic esophagitis (EoE) provides several candidate biomarkers that could be used to establish diagnosis, assess response to therapy, and document disease recurrence. OBJECTIVE To review the literature on various biomarkers of EoE, with respect to their correlation to disease activity and response to treatment. DATA SOURCES A literature search was performed using PubMed and OVID with keyword combinations of EoE and various potential biomarkers. STUDY SELECTIONS Between 2006 and 2012, 26 studies that investigated the correlation of various tissue and serum biomarkers with EoE were identified. RESULTS The markers investigated included eotaxins-1,-2, and -3, interleukin-5 (IL-5), interleukin-13 (IL-13), eosinophil-derived neurotoxin, mast cell markers, absolute eosinophil count, and micro-RNAs. Several studies have shown a positive correlation between eotaxin-3, IL-5, and IL-13 messenger RNA (mRNA) expression in esophageal tissue and disease activity. Eotaxin-3 mRNA staining was found to have 89% sensitivity for diagnosing EoE. Staining for mast cells and their products has also shown promise. More recently, a microRNA signature that can potentially distinguish EoE from non-EoE esophagitis has been identified. CONCLUSION The studies are quite heterogeneous with respect to their methodology and the biomarker(s) studied, but most have investigated tissue biomarkers. Eotaxin-3 and IL-13 have emerged as the most promising ones with respect to sensitivity and degree of positive correlation to disease process. Future research on biomarkers for EoE should include longitudinal studies, establishment of normal values, effects of concomitant atopic diseases, age and gender, and validation of methodology of the tests.

Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection

The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN‐γ. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4+ and CD8+ T cells in mediating immunity against L. major by transferring T cells from wild‐type (WT) and STAT1−/− C57BL/6 mice into Rag2−/− C57BL/6 mice. Rag2−/− mice reconstituted with unfractionated STAT1−/− splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL‐4, and developed large lesions full of parasites. In contrast, Rag2−/− mice reconstituted with WT (STAT1+/+) splenocytes mounted a Th1 response and developed self‐resolving lesions. Studies using Rag2−/− recipients that received a combination of purified CD4+ and CD8+ T cells from WT or STAT1−/− mice revealed that STAT1 deficiency in CD4+ T cells, but not in CD8+ T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2−/− recipients of WT Thy1.1+ and STAT1−/− Thy1.2+ T cells showed that STAT1 in CD4+ T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up‐regulation of CXCR3 on CD4+ T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4+ T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4+ T cell STAT1 in preventing systemic dissemination of L. major infection.—Barbi, J., Snider, H. M., Bhardwaj, N., Lezama‐Davila, C. M., Durbin, J. E., Satoskar, A. R. Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection. FASEB J. 23, 3990–3999 (2009). www.fasebj.org

Treatment of hereditary angioedema: a review (CME)

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self‐limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on‐demand therapy, short‐term (preprocedural) prophylaxis, and long‐term prophylaxis. Newer therapies include C1 esterase inhibitor (C1‐INH) and contact system modulators, namely, ecallantide and icatibant. Recombinant C1‐INH, which is available in Europe, is awaiting approval in the United States. C1‐INH concentrate is approved for prophylaxis as well as on‐demand therapy while ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow‐up to monitor therapeutic response and safety.

Effect of topical beclomethasone on inflammatory markers in adults with eosinophilic esophagitis: A pilot study.

Background Topical corticosteroids have proven efficacy in the treatment of eosinophilic esophagitis (EoE) and are considered the cornerstone of therapy. Objective To evaluate the effect of topical beclomethasone dipropionate (BDP) therapy on clinical outcomes, esophageal eosinophilia, and other markers of inflammation in patients with EoE. Methods Nine subjects with a biopsy-proven diagnosis of EoE were enrolled. In a cross-over design, the subjects were randomly assigned to a sequence of BDP and placebo. Treatment periods were 8 weeks, with a 4-week washout period. The subjects had endoscopic biopsies and blood tests at baseline and after each treatment period. They were instructed to maintain a diary of symptoms. Immuno-histochemical studies were performed for interleukins IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor (TGF) beta. Reverse transcription polymerase chain reaction was performed for IL-3, IL-4, IL-5, IL-10, IL-13, IL-17F, IL-25, IL-33, chemokine ligands (CCL)2, CCL5, CCL11, GM-CSF, and TGF-beta levels. The mast cell tryptase (MCT) level was measured in esophageal tissues. Results BDP led to a significantly larger decrease in esophageal eosinophilia compared with placebo, but there was no significant change in peripheral eosinophilia and high-sensitivity C-reactive protein between the two groups. The study was not powered enough for us to report a significant improvement in clinical symptoms. There was a significant decrease in tissue IL-13 and MCT levels from baseline to the end of treatment between the treatment and placebo groups. Mean fold decreases in cytokine expression between the baseline and treatment groups were observed for IL-17F, IL-25, CCL2, and CCL5. Conclusion Treatment with topical BDP was associated with significant decrease in esophageal eosinophilia, MCT and IL-13. BDP is a potential alternative to fluticasone propionate and budesonide for treatment of EoE. Larger studies are needed to validate these findings.