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INTRODUCTION: The use of proton-pump inhibitors (PPI) is linked with infrequent but serious adverse events, including acute kidney injury, chronic kidney disease (CKD) and progression of CKD. Data on renal safety in routine use of PPI are more relevant to clinical practice. We studied whether such use of PPI is associated with renal dysfunction. METHODS: Patients taking PPI for at least six weeks had serum creatinine tested pre (n = 200) and post (n = 180) recruitment. These patients were then advised to follow-up: those taking PPI for at least 90 days in the next six months (n = 77) and at least another 90 days in the following six months (n = 50), had serum creatinine tested at such follow-up. Renal dysfunction was defined as any increase in serum creatinine level above baseline. RESULTS: The 200 patients recruited had mean age 39.6 (SD 9.2) years. Ninety-eight (49%) patients had a history of previous PPI use (median six months; interquartile range [IQR] 3-24). Only 20 (11.1%) patients at six weeks, 11 (14.3%) at six months and six (12%) at one year had increase in creatinine level; a majority of them had less than 0.3 mg/dL increase. Ten of these 20 (six weeks), five of 11 (six months) and five of six (one year) had other risk factors for renal dysfunction. No patient developed CKD during the study period. CONCLUSIONS: Mild and non-progressive increase in serum creatinine occurred in 10% to 15% of patients on routine PPI use. A majority of them had other risk factors. Small sample size and short follow-up duration are a few limitations of this study.
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The global burden of inflammatory bowel diseases (IBD) is estimated at 4.9 million and the global prevalence exceeds 0.3%. Multiple newer therapeutic agents have broadened the options for the therapy of IBD in the last three decades. Thiopurines, however, have retained their place as maintenance therapy in IBD, especially in resource-constrained setting. But thiopurines have narrow therapeutic range, often needing discontinuation due to side effects or lack of efficacy. Biologic agents revolutionized the treatment of IBD, but the efficacy is lost in 50% of patient after one year. These outcomes are often due to inadequate drug concentrations that may lead to the development of antibodies as well as pharmacodynamic failure. Therapeutic drug monitoring (TDM) was proposed to reduce loss of response and to optimize the therapy in patients on thiopurine and biologic therapy. TDM is based on exposure-response relationship, suggesting a positive correlation between elevated serum anti-TNF concentrations and favorable therapeutic outcomes. TDM has multiple facets. This article discusses the benefits, evidence and limitations of TDM. The practical use of TDM in clinical practice is highlighted. Newer developments in the field and their relevance in practice are discussed.
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Enfermedades Inflamatorias del Intestino , Inhibidores del Factor de Necrosis Tumoral , Humanos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Monitoreo de Drogas , Anticuerpos , Purinas/uso terapéutico , Enfermedades Inflamatorias del Intestino/epidemiologíaRESUMEN
Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.
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Colitis Ulcerosa , Colitis , Herpes Zóster , Pirimidinas , Adulto , Femenino , Humanos , Anciano , Colitis Ulcerosa/tratamiento farmacológico , Consenso , Piperidinas/efectos adversos , Herpes Zóster/inducido químicamente , Herpes Zóster/tratamiento farmacológicoRESUMEN
Background and Aim: Low-fermentable oligo-, di-, and monosaccharides and polyol (FODMAP) diets have been recommended for individuals with food intolerance and irritable bowel syndrome (IBS). Individual food intolerances may, however, not correspond to the FODMAP content alone. Methods: We conducted a survey on self-reported intolerance to articles of food commonly identified as high FODMAP in 400 healthy Indian subjects (median age 40 years; 69% men) and 204 consecutive consenting patients with IBS (median age 36 years; 58% men). Results: One-hundred seventy-nine (44.8%) healthy subjects and 147 (72.1%) patients with IBS reported some food intolerance (P < 0.00001); the latter reported intolerance to all items (except nuts) more frequently than healthy subjects. The prevalence, however, varied from 2.5 to 32%. Milk intolerance was reported equally commonly by healthy subjects and patients (23% vs 29.9%). Twenty-three (11.3%) patients and no healthy subjects reported wheat sensitivity. The IBS diarrhea subgroup reported intolerance to milk, pulses, capsicum, cauliflower, leafy vegetables, and dry fruits more frequently than the constipation subgroup. Conclusion: From among a list of high-FODMAP items, individuals' intolerance varied widely, suggesting that individuals should be the final judge in deciding their elimination diets rather than devise them based on the FODMAP content alone. As in the West, food intolerance was reported more commonly by patients with IBS, especially those with diarrhea, than by healthy individuals. Also noteworthy is the low prevalence of milk intolerance in a subcontinent labeled as high in lactose intolerance. Unlike in the West, wheat intolerance was not reported by any healthy individual.
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INTRODUCTION: Thiopurine toxicity is related to genetic polymorphism. Thiopurine methyltransferase (TPMT) variants do not explain thiopurine toxicity in more than half of patients. Asians, despite the low prevalence of TPMT variants, are more susceptible to thiopurine toxicity. Since 2014, studies from many Asian countries have shown a strong association between nucleoside diphosphate-linked moiety X-type motif (NUDT) 15 polymorphism and thiopurine-induced myelotoxicity. AREAS COVERED: An English language literature search was performed for TPMT and NUDT15 genetic variants in inflammatory bowel disease and other diseases. This article discusses the merits of preemptive NUDT15 and TPMT testing in Asian and non-Asian IBD populations. EXPERT OPINION: The NUDT polymorphism occurs in up to 27% of the Asian and Hispanic population. Hematological toxicity occurs in up to one-third of patients with this genetic variant. Given this, preemptive testing for NUDT15 variant is worthwhile and is probably more cost-effective than TPMT testing in these groups. Prevalence of NUDT15 variants is low in non-Finnish European population, but NUDT15 variants have been linked to myelotoxicity along with TPMT genetic variants. NUDT15 preemptive testing should be considered in the migrant Asian population in Europe and North America and in Caucasian populations who develop myelotoxicity.
The treatment of patients with inflammatory bowel diseases (ulcerative colitis andCrohn's disease) is based on the severity of the disease. They may need drugs called 'thiopurines' if the disease is not controlled by initial therapy. These drugs have side effects which are related to genetic variations. These side effects can be potentially prevented by testing for these genetic variants prior to starting these drugs. These tests include thiopurine methyltransferase (TPMT) genotype testing and nucleoside diphosphate-linked moiety X-typemotif (NUDT) 15 genotype testing. By doing these tests before starting the drugs, the dose can be modified to prevent side effects on the bone marrow and other tissues.
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Pueblo Asiatico , Enfermedades Inflamatorias del Intestino , Humanos , Pueblo Asiatico/genética , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Polimorfismo Genético , Asia/epidemiología , Europa (Continente) , Metiltransferasas/genéticaRESUMEN
BACKGROUND AND AIMS: Pediatric and elderly inflammatory bowel disease (IBD) are less explored, often in retrospective studies. The pediatric group has a more extensive and aggressive disease phenotype requiring aggressive treatments, whereas the elderly group may have less aggressive diseases. METHODS: We prospectively compared disease characteristics of a single center cohort of IBD patients (pediatric age ≤ 16 years; adults 17 to 59 years; and elderly ≥ 60 years) seen between September 2018 and November 2019 with at least six months of follow-up. RESULTS: Total 266 IBD patients (137 males) included 47 pediatric, 175 adults and 44 elderly patients. Among ulcerative colitis (UC) patients, pancolitis was more common in the pediatric group (p = 0.018), while the elderly group had more indolent behaviors and infrequent extraintestinal manifestations (p = 0.005). Among patients with Crohn's disease (CD), the pediatric group had more often colonic diseases (p = 0.02) and the elderly, ileal diseases (p = 0.04). The disease behavior was similar in the three age groups. Perianal disease was least common in elderly CD patients (p = 0.03). There was no treatment difference among different age groups in UC. In CD, pediatric patients needed biologics more frequently (p = 0.005), while elderly CD patients less frequently required steroids, biologics, immunosuppressants and surgery (p < 0.05). CONCLUSIONS: We noted differences compared to western literature such as colonic location in pediatric CD and ileal location in elderly CD. Perianal disease was less frequent in the elderly CD group. There was no difference in treatment in the three age groups in UC, while there were no inter-age-group disease behavioral differences for UC and CD.
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Productos Biológicos , Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Masculino , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Enfermedades Inflamatorias del Intestino/epidemiología , Colitis Ulcerosa/epidemiología , FenotipoRESUMEN
Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non-response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to maintain the efficacy of biologic agents. Reactive TDM can rationalize the management of primary non-response and secondary loss of response and has shown to be more cost-effective compared with empiric dose escalation. Proactive TDM is shown to increase clinical remission and the durability of the response to a biologic agent. However, the efficacy of proactive and reactive TDM has been questioned in recent studies and meta-analyses. Hence, we need a different approach to TDM, which addresses inflammatory burden, the individual patient, and disease factors. Bayesian approaches, which use population pharmacokinetic models, enable clinicians to make better use of TDM for dose adjustment. With rapid improvement in computer technology, these Bayesian model-based software packages are now available for clinical use. Bayesian dashboard systems allow clinicians to apply model-based dosing to understand an individual's pharmacokinetics and achieve a target serum drug concentration. The model is updated using previously measured drug concentrations and relevant patient factors, such as body weight, C-reactive protein, and serum albumin concentration, to maintain effective drug concentrations in the serum. Initial studies have found utility for the Bayesian approach in induction and maintenance, in adult and pediatric patients, in clinical trials, and in real-life situations for patients with IBD treated with infliximab. This needs confirmation in larger studies. This article reviews the Bayesian approach to therapeutic drug monitoring in IBD.
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Fármacos Gastrointestinales , Enfermedades Inflamatorias del Intestino , Adulto , Humanos , Niño , Infliximab , Teorema de Bayes , Monitoreo de Drogas , Enfermedades Inflamatorias del Intestino/tratamiento farmacológicoRESUMEN
BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) represents the most common hepatobiliary extraintestinal manifestation of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). Limited data exist on PSC in patients with IBD from India. We aimed to assess the prevalence and disease spectrum of PSC in Indian patients with IBD. METHODS: Database of IBD patients at 5 tertiary care IBD centers in India were analyzed retrospectively. Data were extracted and the prevalence of PSC-IBD was calculated. RESULTS: Forty-eight patients out of 12,216 patients with IBD (9,231 UC, 2,939 CD, and 46 IBD unclassified) were identified to have PSC, resulting in a prevalence of 0.39%. The UC to CD ratio was 7:1. Male sex and pancolitis (UC) or colonic CD were more commonly associated with PSC-IBD. The diagnosis of IBD preceded the diagnosis of PSC in most of the patients. Majority of the patients were symptomatic for liver disease at diagnosis. Eight patients (16.66%) developed cirrhosis, 5 patients (10.41%), all UC, developed malignancies (3 colorectal cancer [6.25%] and 2 cholangiocarcinoma [4.16%]), and 3 patients died (2 decompensated liver disease [4.16%] and 1 cholangiocarcinoma [2.08%]) on follow-up. None of the patients mandated surgical therapy for IBD. CONCLUSIONS: Concomitant PSC in patients with IBD is uncommon in India and is associated with lower rates of development of malignancies.
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Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease of unknown etiology, involving complex interactions between the gut microbiome and host immune response. The microbial dysbiosis is well documented in IBD and significantly influences the host metabolic pathways. Thus, a metabolomic fingerprint resulting from the influence of gut dysbiosis in IBD could aid in assessing the disease activity. PubMed, Medline, Science Direct, and Web of Science were searched for studies exploring the association between microbiome and metabolome in IBD patients in the last 5 years. Additionally, references of cited original articles and reviews were further assessed for relevant work. We provide a literature overview of the recent metabolomic studies performed on patients with IBD. The findings report alterations in the metabolite levels of these patients. We also discuss the gut dysbiosis observed in IBD and its influence on host metabolic pathways such as lipids, amino acids, short-chain fatty acids, and others. IBD, being a chronic idiopathic disease, requires routine monitoring. The available non-invasive markers have their limitations. The metabolite changes account for both dysbiosis and its influence on the host's immune response and metabolism. A metabolome approach would thus facilitate the identification of surrogate metabolite markers reflecting the disease activity.
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Colitis Ulcerosa , Enfermedad de Crohn , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Humanos , Disbiosis , Heces/química , Metaboloma , Microbioma Gastrointestinal/fisiología , Biomarcadores/análisisRESUMEN
BACKGROUND: Increasing antibiotic-resistant Helicobacter pylori (H. pylori) strains complicate efforts to eradicate infection. In regions with high dual resistance to both clarithromycin and metronidazole, bismuth quadruple therapy is recommended. But, with lack of easy availability of bismuth, the (non-bismuth) concomitant and sequential regimens are used commonly as first-line therapy. Recent reports indicate suboptimal results with sequential therapy in such regions. We aimed to compare the efficacy of concomitant therapy vs. sequential therapy in the eradication of H. pylori in a region with high antibiotic resistance rates, and to compare adherence rates and adverse events with the regimens. METHODS: One hundred and twenty-four consecutive H. pylori-infected patients (diagnosed using rapid urease test or urea breath test) were randomized to receive sequential or concomitant therapy for 10 days each. Four weeks after treatment completion, urea breath test was done to confirm eradication of the infection. Cure rates were compared between the two regimens and note was made of adherence rates and adverse events. RESULTS: Concomitant therapy showed a statistically non-significant higher cure rate compared to sequential therapy in intention-to-treat (87.1% vs. 81.4%%, p = 0.46) and per-protocol (94.7% vs. 83.9%, p = 0.07) analyses. Both the regimens were well tolerated and showed similar adherence rates (p = 1.00) and incidence of adverse events (p = 0.44). CONCLUSION: In a region with high dual resistance, both concomitant and sequential therapy for H. pylori infection achieved eradication rates >80%, but concomitant therapy showed a statistically non-significant higher cure rate, with similar adherence and adverse event profiles.
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Infecciones por Helicobacter , Helicobacter pylori , Humanos , Amoxicilina , Quimioterapia Combinada , Antibacterianos , Infecciones por Helicobacter/tratamiento farmacológico , Metronidazol , Claritromicina , Farmacorresistencia Microbiana , Urea/uso terapéutico , Resultado del Tratamiento , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
BACKGROUND AND AIM: Inflammatory bowel disease (IBD) is emerging in the newly industrialized countries of South Asia, South-East Asia, and the Middle East, yet epidemiological data are scarce. METHODS: We performed a cross-sectional study of IBD demographics, disease phenotype, and treatment across 38 centers in 15 countries of South Asia, South-East Asia, and Middle East. Intergroup comparisons included gross national income (GNI) per capita. RESULTS: Among 10 400 patients, ulcerative colitis (UC) was twice as common as Crohn's disease (CD), with a male predominance (UC 6678, CD 3495, IBD unclassified 227, and 58% male). Peak age of onset was in the third decade, with a low proportion of elderly-onset IBD (5% age > 60). Familial IBD was rare (5%). The extent of UC was predominantly distal (proctitis/left sided 67%), with most being treated with mesalamine (94%), steroids (54%), or immunomodulators (31%). Ileocolic CD (43%) was the commonest, with low rates of perianal disease (8%) and only 6% smokers. Diagnostic delay for CD was common (median 12 months; interquartile range 5-30). Treatment of CD included mesalamine, steroids, and immunomodulators (61%, 51%, and 56%, respectively), but a fifth received empirical antitubercular therapy. Treatment with biologics was uncommon (4% UC and 13% CD), which increased in countries with higher GNI per capita. Surgery rates were 0.1 (UC) and 2 (CD) per 100 patients per year. CONCLUSIONS: The IBD-ENC cohort provides insight into IBD in South-East Asia and the Middle East, but is not yet population based. UC is twice as common as CD, familial disease is uncommon, and rates of surgery are low. Biologic use correlates with per capita GNI.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Anciano , Asia Sudoriental , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/terapia , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/epidemiología , Estudios Transversales , Diagnóstico Tardío , Asia Oriental , Femenino , Humanos , Factores Inmunológicos , Incidencia , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/terapia , Masculino , Mesalamina , FenotipoRESUMEN
Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.
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BACKGROUND/AIMS: Most patients with irritable bowel syndrome (IBS) report food-related aggravation of symptoms. Wheat/gluten is one of the most commonly incriminated. We studied the prevalence of self-reported wheat sensitivity in patients with IBS and in a healthy population from a region in India consuming mixed-cereal diets, correlated it with serological and human leukocyte antigen (HLA) markers of celiac disease, and evaluated the response to a wheat-free diet. METHODS: We surveyed 204 patients with IBS and 400 healthy persons for self-reported wheat sensitivity. Testing for IgA anti-tissue transglutaminase and HLA DQ2 or DQ8 was done in individuals who reported wheat sensitivity. Consenting persons with wheat sensitivity were put on wheat-free diet and monitored for symptom change. RESULTS: Twenty-three of 204 patients with IBS (11.3%) and none of the healthy subjects self-reported wheat sensitivity. Of 23 patients, 14 (60.9%) were positive for HLA DQ2 or DQ8 and none for anti-tissue transglutaminase antibody. After 6 weeks on wheat-free diet, all 19 participating patients reported clinical improvement; fewer patients had bloating, diarrhea, constipation, and easy fatigue. CONCLUSIONS: Eleven percent of patients with IBS self-reported wheat sensitivity. None of them had positive celiac serology; 60.9% were positive for HLA DQ2 and DQ8, suggesting a possible genetic basis. All of them improved symptomatically on a wheat-free diet.
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BACKGROUND: Unlike perianal fistula, long-term outcomes of nonperianal fistulae (NPF) in Crohn's disease (CD) are not clear. We aimed to compare the outcomes of medical and surgical therapies in patients with NPF. METHODS: We retrospectively analyzed the records of patients of CD with NPF who were prospectively followed from January 2005 to December 2018. RESULTS: Of the 53 patients with NPF [mean age at presentation:29 ± 14 years; 54.7% male; median duration of follow-up: 47 months (interquartile range [IQR]:26-76 months)], enteroenteric fistula (37.8%) was the most common presentation. Of 22 patients treated with anti-tumor necrosis factor (TNF) therapy, complete response was achieved in 40.9% (n = 9). Overall probability of maintaining response was similar between the anti-TNF and surgical groups (95.2% vs 82.4%; 71% vs 76%; and 63% vs 69%% [P = 0.8] at 1, 2, and 3 years, respectively), with only 13.6% of patients treated with biologicals requiring surgery over 56 months. Twenty-one patients required upfront surgery (small bowel or ileocolonic resection with/without diversion; 28.5% emergent), with 47.6% postoperative recurrence over 36 months, of which nine patients required biologicals (77.7% response to anti-TNF therapy). Long-term outcome was comparable between medically and surgically treated patients; 6.4% developed tuberculosis on anti-TNF therapy. Two patients (3.7%) developed malignancy (one - enteroenteric, one - colovesical). CONCLUSION: Anti-TNF therapy appears to be as effective as surgery in this retrospective analysis of patients with NPFCD, and it may be indicated in the absence of abscess and other complications. These patients are at higher risk of fistula-associated malignancy, which requires a lower threshold for suspicion, especially over the long term in the presence of nonresponse to medical therapy.
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INTRODUCTION: The relationship between the incidence of intestinal tuberculosis (TB) and Crohn's disease (CD) is interesting, especially considering the striking similarity between the two conditions. Some studies from Asian populations suggested that the incidence of intestinal TB decreases when there is an increase in CD. AIM: To compare the incidence trend between intestinal TB and CD over 15 years. METHODS: Medical records of patients seen in the Division of Gastroenterology over 15 years (2005-2019) were reviewed. CD was diagnosed according to the Copenhagen criteria. Intestinal TB was diagnosed in the appropriate clinical situation if any one or more of the following was present: (1) positive TB MGIT culture; (2) positive Gene Xpert for TB; (3) suggestive histologic findings, with positive tissue acid-fast bacillus (AFB) on smear or with sustained response to anti-TB therapy. The incidence time trend of patients with CD and intestinal TB diagnosis was then studied year-wise. RESULTS: 632 medical case records were accessed; 60 patients were excluded due to inadequate data or not fulfilling diagnostic criteria. The 572 patients included 224 with intestinal TB (median age 37 years, IQR 22; 125 [56%] females) and 348 with CD (median age 40 years, IQR 25; 159 [46%] females [p < 0.02 as compared to TB]). Thus, more patients with CD were seen during the study period, but there was no correlation between the incidence of the two conditions (r = 0.318; p = 0.25). CONCLUSION: In Indian patients in a single private-sector center, there was no inverse correlation between the incidence of intestinal TB and CD over 15 years.