Samir A. Shah

Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

BackgroundThe inflammatory bowel diseases (IBD) Crohns disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status.ResultsFirmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohns disease was notable for increases in virulence and secretion pathways.ConclusionsThis inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.

Clinical experience with infliximab therapy in 100 patients with Crohn's Disease

OBJECTIVE:The aim of this study was to assess our clinical experience with infliximab, a monoclonal antitumor necrosis factor antibody, following its approval for treatment of refractory Crohns disease (CD).METHODS:We followed 100 consecutive patients with CD (53 women and 47 men; mean age, 41 yr) who received a total of 233 infliximab (5 mg/kg) infusions. Adverse events were noted and clinical response assessed every 2 wk for 6 months after each infusion using the Harvey Bradshaw Index (HBI) for active disease, the Perianal Disease Activity Index (PDAI) for fistulous disease, and steroid withdrawal rates for steroid-sparing efficacy.RESULTS:Indications for therapy were active disease (n = 57), perianal fistulous disease (n = 33), and steroid dependency (n = 10). Significant infusion reactions occurred in 16 patients (6.9% of infusions) including anaphylactic shock in one patient. Fourteen patients experienced infectious adverse events, 13 of whom were on concurrent steroids. Sixty percent of patients with active disease experienced ≥50% HBI reduction at 2 wk; mean duration of response, 8.2 wk. Three of 26 first-time nonresponders with active disease (12%) responded to a second infusion. Sixty-nine percent of patients with fistulous disease experienced >50% reduction in their PDAI at 2 wk; mean duration of response, 10.9 wk. Four of 10 steroid-dependent patients (40%) discontinued steroid therapy, one of whom recommenced steroid therapy at 24 wk.CONCLUSIONS:Our clinical response rates mirror the efficacy reported in the controlled trials for active and fistulous disease. Steroid-sparing efficacy was seen in 40% of steroid-dependent patients. Concurrent steroids did not reduce the risk of significant infusion reactions (6.9%), but did increase the risk of infections.

Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis.

BACKGROUND & AIMS Membrane lymphotoxin (LT) alpha/beta, a member of the tumor necrosis factor (TNF) family of immune regulatory molecules, is involved both in the development of secondary lymphoid tissues and the maintenance of organized lymphoid tissues in the adult. Defects observed in the mucosal immune system in animals with a genetically disrupted LTalpha/beta pathway coupled with the expression of LTalpha/beta in activated T cells motivated an examination of the importance of this pathway in experimental colitis. METHODS Soluble LTbeta receptor (LTbetaR) immunoglobulin fusion protein was used to inhibit the LTalpha/beta/light axis in two independent rodent models of colitis: CD45RBhi CD4(+)-reconstituted SCID mice and bone marrow-transplanted tg26 mice (BM --> tg26). RESULTS Treatment with LTbetaR immunoglobulin attenuated the development of both the clinical and histological manifestations of the disease in these two murine models of colitis. Given the success of TNF inhibitors in the treatment of human Crohns disease, the effects of LTbetaR immunoglobulin have been compared with antibody to TNF in the BM --> tg26 model, and both treatments were equally efficacious. CONCLUSIONS The LT pathway plays a role in the development of colitis as important as that of the TNF system and, therefore, represents a potential novel intervention point for the treatment of inflammatory bowel disease.

Ocular manifestations of inflammatory bowel disease

Extraintestinal manifestations of inflammatory bowel disease (IBD) occur in one third of patients. Ocular complications are infrequent, occurring in less than 10% of cases, but can be associated with significant morbidity, including blindness. Ocular complaints are often nonspecific; clinical relevance may not be appreciated by patient or physician and, thus, be misdiagnosed. Evaluation of the eye should be a routine component in the care of patients with IBD. Clinicians must be aware of the spectrum of ocular symptoms and know that these complaints may precede a diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD). We review ocular pathology in IBD to alert clinicians to the diverse, at times confusing, spectrum of eye disorders associated with these diseases. Clinical manifestations include blurred vision, teary, burning or itchy eyes, ocular pain, photophobia, conjunctival or scleral hyperemia, loss of visual acuity, and possible blindness. Many patients are unaware that IBD has a risk of eye complications and, therefore, patient education is vital.

Risk of early surgery for Crohn's disease: implications for early treatment strategies.

OBJECTIVES:In this study we aimed to define the rate of early surgery for Crohns disease and to identify risk factors associated with early surgery as a basis for subsequent studies of early intervention in Crohns disease.METHODS:We assembled a retrospective cohort of patients with Crohns disease diagnosed between 1991 and 1997 and followed for at least 3 yr, who were identified in 16 community and referral-based practices in New England. Chart review was performed for each patient. Details of baseline demographic and disease features were recorded. Surgical history including date of surgery, indication, and procedure were also noted. Risk factors for early surgery (defined as major surgery for Crohns disease within 3 yr of diagnosis, exclusive of major surgery at time of diagnosis) were identified by univariate analysis. Multiple logistic regression was used to identify independent risk factors.RESULTS:Of 345 eligible patients, 69 (20.1%) required surgery within 3 yr of diagnosis, excluding the 14 patients (4.1%) who had major surgery at the time of diagnosis. Overall, the interval between diagnosis and surgery was short; one half of all patients who required surgery underwent operation within 6 months of diagnosis. Risk factors identified by univariate analysis as significantly associated with early surgery included the following: smoking; disease of small bowel without colonic involvement; nausea and vomiting or abdominal pain on presentation; neutrophil count; and steroid use in the first 6 months. Disease localized to the colon only, blood in the stool, use of 5-aminosalicylate, and lymphocyte count were inversely associated with risk of early surgery. Logistic regression confirmed independent associations with smoking as a positive risk factor and involvement of colon without small bowel as a negative risk factor for early surgery.CONCLUSIONS:The rate of surgery is high in the first 3 yr after diagnosis of Crohns disease, particularly in the first 6 months. These results suggest that improved risk stratification and potent therapies with rapid onset of action are needed to modify the natural history of Crohns disease.

Gemcitabine, paclitaxel and radiation for locally advanced pancreatic cancer: a phase I trial

PURPOSE To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of gemcitabine, paclitaxel, and concurrent radiation for pancreatic cancer. METHODS AND MATERIALS Twenty patients with locally unresectable pancreatic cancer were studied. The initial dose level was gemcitabine 75 mg/m(2) and paclitaxel 40 mg/m(2) weekly for 6 weeks. Concurrent radiation to 50.4 Gy was delivered in 1.8 Gy fractions. The radiation fields included the primary tumor, plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. RESULTS Dose-limiting toxicities of diarrhea, dehydration, nausea, and anorexia occurred in 3 of 3 patients at the second dose level of gemcitabine, 150 mg/m(2)/week. An intermediate dose level of gemcitabine, 110 mg/m(2)/week, was added, but gastrointestinal toxicity and pulmonary pneumonitis were encountered. The MTD therefore was gemcitabine 75 mg/m(2)/week with paclitaxel 40 mg/m(2)/week and concurrent radiation. Two of 11 patients treated at the MTD had Grade 3/4 toxicity. Four of 10 assessable patients treated at the MTD responded (40%), including one pathologic complete response. CONCLUSION The maximum tolerated dosage of gemcitabine is 75 mg/m(2)/week with paclitaxel 40 mg/m(2)/week and conventional 50.4 Gy radiation fields. A Phase II Radiation Therapy Oncology Group study is under way.

Fatigue is highly associated with poor health‐related quality of life, disability and depression in newly‐diagnosed patients with inflammatory bowel disease, independent of disease activity

Fatigue is common in Crohns disease (CD) and ulcerative colitis (UC). Data on fatigue in newly diagnosed patients are unavailable.

Smoking and immunomodulators do not influence the response or duration of response to infliximab in Crohn's disease

Objective:Clinical predictors for infliximab response are still unknown. Identifying predictors of response to infliximab in Crohns disease may improve our selection of patients. Methods:Two hundred patients with luminal (61%) or fistulous (39%) Crohns disease and at least 6 months of follow-up following a total of 416 infliximab infusions were evaluated. Clinical response and duration of response were the primary endpoints. Results:Patients with fistulous disease had a higher response rate (83% versus 70%, P = 0.044) and a significantly longer duration of response compared with patients with luminal disease (17.4 versus 10.1 wks, P = 0.017). For luminal disease, nonsmokers and smokers had similar response rates (74% versus 64%, P = 0.5) and similar durations of response (9.4 wks versus 8.4 wks P = 0.6) while patients taking concurrent immunomodulators had similar response rates compared with those not taking immunomodulators (74% versus 71%, P = 0.9) and similar durations of response (10.4 wks versus 10.6 wks, P = 0.9). For fistulous disease, response rates (89% versus 83%P = 0.9) and duration of response (16.9 wks versus 10.1 wks, P = 0.10) were similar between nonsmokers and smokers and concurrent immunomodulators had no effect on response (89% versus 86%, P = 0.9) or duration of response (19.8 wks versus 15.4 wks, P = 0.46). Multivariable analysis confirmed that neither smoking, corticosteroids, immunomodulator therapy, gender, age, age of disease onset, disease duration, nor luminal disease location significantly influenced response or duration of response. Conclusions:Patients with fistulous disease had a higher response rate and a significantly longer duration of response compared with patients with luminal disease. However, among patients with luminal or fistulous disease, neither smoking nor immunomodulators had any effect on response or duration of response.

Autoimmune (Hashimoto's) thyroiditis associated with Crohn's disease.

We report the occurrence of autoimmune (Hashimotos) thyroiditis in three patients with Crohns disease. Previously, thyroid disease has been described only in association with ulcerative colitis. We review the pertinent literature on thyroid disease in inflammatory bowel disease (IBD) and suggest that this association supports the hypothesis that autoimmunity is involved in the pathogenesis of IBD. Early diagnosis and treatment of thyroid dysfunction in patients with IBD is desirable because thyroid dysfunction worsens the symptoms and course of IBD.

Development of colonic adenocarcinomas in a mouse model of ulcerative colitis

Summary: Mice deficient in both interleukin‐2 and &bgr;2‐microglobulin expression (&bgr;2mnull × IL‐2null mice) develop an inflammatory disease of the colon resembling ulcerative colitis. To examine long‐term complications of disease in these mice, a group of 34 &bgr;2mnull × IL‐2null mice was monitored for 6‐12 months. Development of clinical disease was assessed by wasting, general appearance, and diarrhea. Further analysis included histologic examination of the distal colon for colitis, staining of CD4+ T cells for surface activation markers, and cytoplasmic staining of CD4+ T cells for IFN‐&ggr; and TNF‐&agr;. These older &bgr;2mnull × IL‐2null mice had activated CD4+ T cells as assessed by surface markers on flow cytometry. Cytoplasmic staining revealed IFN‐&ggr; production, but not TNF‐&agr; production by CD4+ T cells. The majority of these older &bgr;2mnull × IL‐2null mice continued to have colitis on histology. However, they lived much longer and had less wasting in comparison to IL‐2null mice. At necropsy, 11 (32%) of 34 of the &bgr;2mnull × IL‐2null mice had tumors in the proximal half of the colon. Histologic examination confirmed these tumors to be adenocarcinomas. These mice may be useful as a model for studying carcinogenesis in chronic colitis.