Thiopurine therapy in inflammatory bowel disease in the pandemic era: Safe or unsafe?

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. Crohn's disease (CD) and Ulcerative colitis (UC) are the two major types affecting millions across the globe. Various immunomodulatory drugs consisting of small molecules (thiopurines, methotrexate and tofacitinib) and biologics are used to treat IBD. Thiopurines (TP) are widely used in the treatment of IBD and it plays an important role both alone and in combination with anti-TNF agents as IBD maintenance therapy. Although the advent of biologics therapy has significantly advanced the management of IBD, TP remains the mainstay of treatment in resource-limited and low economic settings. However, the recently commenced pandemic has raised uncertainty over the safety of the use of immunosuppressant drugs such as TP among healthcare care providers and patients, as there is a scarcity of data on whether IBD patients are at higher risk of COVID-19 infection or more prone to its severe outcomes. AIM: This review aims to encapsulate evidence on the risk of COVID-19 infection and its severe prognosis in IBD patients on TP. Additionally, it also evaluates the role of TP in inhibiting the viral protease, a potential drug target, essential for the replication and pathogenesis of the virus. CONCLUSION: Emerging evidence suggests that TP therapy is safe during the current pandemic and does not carry an elevated risk when used as monotherapy or in combination with other IBD drugs. In-vitro studies demonstrate that TP is a potential therapeutic for present and future betacoronavirus pandemics.

Liquid chromatographic methods in the determination of inosine monophosphate dehydrogenase enzyme activity: a review.

Inosine monophosphate dehydrogenase (IMPDH) is a crucial enzyme involved in the de novo synthesis of purine nucleotides. IMPDH activity is used to evaluate the pharmacodynamics/pharmacokinetics of immunosuppressant drugs such as mycophenolic acid and thiopurines. These drugs are often used to prevent organ transplant rejection and as steroid-sparing agents in autoinflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. Numerous analytical techniques have been employed to evaluate IMPDH activity in biological matrices. However, hyphenated LC techniques were most widely used in the literature. This review focuses on hyphenated LC methods used to measure IMPDH activity and provides detailed insight into the sample preparation techniques, chromatographic conditions, enzymatic assay conditions, detectors and normalization factors employed in those methods.

Diagnostic utility of alarm features in predicting malignancy in patients with dyspeptic symptoms.

BACKGROUND: Clinical features are of modest benefit in determining the etiology of dyspepsia. Dyspeptic patients with alarm features are suspected to have malignancy; but the proportions of patients and true cutoff values of various quantitative parameters in predicting malignancy are explored to a lesser extent. METHODS: This is a prospective observational study of consecutive patients undergoing esophagogastroduodenoscopy (EGD) for dyspeptic symptoms. Patients' alarm features and clinical details were recorded in a predesigned questionnaire. The diagnostic accuracy of alarm features in predicting malignancy was studied. RESULTS: Nine hundred patients, 678 (75.3%) males, with a mean (standard deviation [SD]) age of 44.6 (13.54) years were enrolled. Commonest indication for EGD was epigastric pain in 614 (68.2%) patients. Dyspepsia was functional in 311 (34.6%) patients. EGD revealed benign lesions in 340 (37.8%) and malignancy in 50 (5.5%) patients. Among the malignant lesions, gastric malignancy was present in 28 (56%) and esophageal malignancy in 20 (40%) patients. Alarm features were present in 206 (22.9%), out of which malignant lesions were seen in 46 (22.3%) patients. Altogether, the alarm features had a sensitivity of 92% and specificity of 81.2% for predicting malignancy. The sensitivity and specificity for weight loss were 76% and 90.8%, while that of abdominal mass were 10% and 99.9% respectively. Based on receiver operating characteristic curve, the optimal age for screening of malignancy was 46.5 years in this population. CONCLUSIONS: Patients of age group 40 to 49 years with dyspeptic alarm symptoms (predominant weight loss) need prompt endoscopy to screen for malignancy. The alarm features are inexpensive screening tools, found to be useful in India, and should be utilized in countries with similar healthcare conditions and disease epidemiology.

Apoptosis in peripheral blood lymphocytes in intestinal tuberculosis and Crohn's disease: Implications to diagnostic differentiation.

AIM: Intestinal tuberculosis (ITb) and Crohn's disease (CD) mimic each other often leading to misdiagnosis. We evaluated the difference between ITb and CD using the extent of apoptosis in peripheral blood lymphocytes. METHODS: CD4+ cells as a percentage of the lymphocytes and viable, dead, total apoptotic, early apoptotic, and late apoptotic CD4+ cells were assessed in the peripheral blood by flow cytometry in healthy controls and patients with confirmed active ITb and CD prior to initiating therapy. Early apoptotic and total apoptotic cells were further expressed as a proportion of the percentage of CD4+ cells. RESULTS: The percentages of CD4+ cells (6.5 [3.0, 8.7] vs. 13.40 [10.15, 13.40]; p < 0.001), total apoptotic cells (0.13 [0.0, 0.22] vs. 0.08 [0.0, 0.21]; p = 0.045), early apoptotic (1.24 [0.55, 2.54] vs. 0.71 [0.40, 1.30]; p = 0.037), and the proportion of the latter two parameters (17.18 [5.61, 57.33] vs. 4.84 [2.71, 9.83]; p-value 0.039) and (17.18 [7.4, 67.50] vs. 5.51 [3.10, 11.03]; p-value 0.036) were significantly different between patients with ITb and CD. The best sensitivity, specificity, and positive and negative predictive values for the diagnosis of ITb were seen with the CD4+ cell percentage (82.6%, 82.4%, 86.4%, 77.8%, respectively) and the proportion of early apoptotic cells (73.9%, 70.6%, 77.3%, 66.7%, respectively). CONCLUSION: CD4+ cells as a percentage of peripheral blood lymphocytes and the proportion of early apoptotic CD4+ cells show promise to diagnostic differentiation between ITb and CD.

Indian consensus on gastroesophageal reflux disease in adults: A position statement of the Indian Society of Gastroenterology.

The Indian Society of Gastroenterology developed this evidence-based practice guideline for management of gastroesophageal reflux disease (GERD) in adults. A modified Delphi process was used to develop this consensus containing 58 statements, which were generated by electronic voting iteration as well as face-to-face meeting and review of the supporting literature primarily from India. These statements include 10 on epidemiology, 8 on clinical presentation, 10 on investigations, 23 on treatment (including medical, endoscopic, and surgical modalities), and 7 on complications of GERD. When the proportion of those who voted either to accept completely or with minor reservation was 80% or higher, the statement was regarded as accepted. The prevalence of GERD in India ranges from 7.6% to 30%, being < 10% in most population studies, and higher in cohort studies. The dietary factors associated with GERD include use of spices and non-vegetarian food. Helicobacter pylori is thought to have a negative relation with GERD; H. pylori negative patients have higher grade of symptoms of GERD and esophagitis. Less than 10% of GERD patients in India have erosive esophagitis. In patients with occasional or mild symptoms, antacids and histamine H2 receptor blockers (H2RAs) may be used, and proton pump inhibitors (PPI) should be used in patients with frequent or severe symptoms. Prokinetics have limited proven role in management of GERD.

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia.

BACKGROUND: Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma. METHODS: Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma. RESULTS: Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects. CONCLUSIONS: Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.

Copy number variations are progressively associated with the pathogenesis of colorectal cancer in ulcerative colitis.

AIM: To evaluate the association of known copy number variations (CNVs) in ulcerative colitis (UC) progressing to colorectal cancer. METHODS: Microsatellite instability analysis using the National Cancer Institute's panel of markers, and CNV association studies using Agilent 2 × 105 k arrays were done in tissue samples from four patient groups with UC: those at low risk (LR) or high risk of developing colorectal cancer, those with premalignant dysplastic lesions, and those with colitis-associated colorectal cancer (CAC). DNA from tissue samples of these groups were independently hybridized on arrays and analyzed. The data obtained were further subjected to downstream bioinformatics enrichment analysis to examine the correlation with CAC progression. RESULTS: Microarray analysis highlighted a progressive increase in the total number of CNVs [LR (n = 178) vs CAC (n = 958), 5.3-fold], gains and losses [LR (n = 37 and 141) vs CAC (n = 495 and 463), 13.4- and 3.3-fold, respectively], size [LR (964.2 kb) vs CAC (10540 kb), 10.9-fold] and the number of genes in such regions [LR (n = 119) vs CAC (n = 455), 3.8-fold]. Chromosome-wise analysis of CNVs also showed an increase in the number of CNVs across each chromosome. There were 38 genes common to all four groups in the study; 13 of these were common to cancer genes from the Genetic Disease Association dataset. The gene set enrichment analysis and ontology analysis highlighted many cancer-associated genes. All the samples in the different groups were microsatellite stable. CONCLUSION: Increasing numbers of CNVs are associated with the progression of UC to CAC, and warrant further detailed exploration.

Spontaneous ascitic fluid infection in liver cirrhosis: bacteriological profile and response to antibiotic therapy.

BACKGROUND: Spontaneous ascitic fluid infection (SAI) is common in cirrhotic patients leading to significant morbidity and mortality. Third-generation cephalosporins are currently recommended as first-line therapy. We conducted a prospective study to determine bacterial etiology, susceptibility patterns, and clinical epidemiology including 1-month mortality of SAIs among patients with cirrhosis. METHODS: Records of 600 patients with suspected SAI over a 4-year period were analyzed. Empirical cefotaxime/ceftriaxone was initiated in patients who had a neutrophil count >250/mm(3). Treatment failure was defined by absence of clinical improvement and/or significant decrease in neutrophil count of ascites (<25 % of base line value) by 72 h of therapy. RESULTS: Seventy patients (11.6 %) had SAI, including 40 (57.1 %) culture-negative neutrocytic ascites (CNNA), 25 (35.8 %) spontaneous bacterial peritonitis (SBP), and five (7 %) monomicrobial non-neutrocytic bacterascites (MNB). Gram-negative bacilli (Klebsiella and E. coli) were the commonest organisms. The overall response rate to ceftriaxone was 62.8 % (44/70). Among culture-positive patients (SBP and MNB), sensitivity rates to ceftriaxone was 50 %, while it was 53.3 % for quinolones, 70 % for piperacillin-tazobactam, and 93.3 % for cefoperazone-sulbactam combination. Thirty-day mortality was lower for CNNA compared to SBP (20 % vs. 40 %, p < 0.001) and for patients with response compared to no response to first antibiotic (11.3 % vs. 53.8 %, p < 0.001). CONCLUSION: The response of SAI to third-generation cephalosporins was low at our center. Cefoperazone-sulbactam could be a better alternative choice.

Differentiation of Crohn's disease from intestinal tuberculosis in India in 2010.

Differentiating intestinal tuberculosis from Crohn's disease (CD) is an important clinical challenge of considerable therapeutic significance. The problem is of greatest magnitude in countries where tuberculosis continues to be highly prevalent, and where the incidence of CD is increasing. The final clinical diagnosis is based on a combination of the clinical history with endoscopic studies, culture and polymerase chain reaction for Mycobacterium tuberculosis, biopsy pathology, radiological investigations and response to therapy. In a subset of patients, surgery is required and intraoperative findings with pathological study of the resected bowel provide a definitive diagnosis. Awareness of the parameters useful in distinguishing these two disorders in each of the different diagnostic modalities is crucial to accurate decision making. Newer techniques, such as capsule endoscopy, small bowel enteroscopy and immunological assays for Mycobacterium tuberculosis, have a role to play in the differentiation of intestinal tuberculosis and CD. This review presents currently available evidence regarding the usefulness and limitations of all these different modalities available for the evaluation of these two disorders.

Acute buried bumper syndrome: an endoscopic peg tube salvage approach.

Acute buried bumper syndrome is an uncommon complication of percutaneous endoscopic gastrostomy (PEG) tube placement. If not recognized and treated appropriately, it can lead to serious complications including death. We report a case of an acute buried bumper syndrome, successfully managed with PEG tube repositioning through the original tract, without the need of replacement.