Clinical Long-Term Outcomes of Patient-Reported Outcomes in the Prospective Real-World Tofacitinib Response in Ulcerative Colitis Registry.

INTRODUCTION: We previously reported the results of tofacitinib induction therapy in the prospective multisite US real-world Tofacitinib Response in Ulcerative Colitis registry. We now assessed patient-reported outcomes (PROs) and predictors of success during tofacitinib maintenance therapy. METHODS: Tofacitinib Response in Ulcerative Colitis included 103 patients with refractory ulcerative colitis (UC); 67% had failed ≥ 2 biologics. Patients reported the Simple Clinical Colitis Activity Index (SCCAI), Patient-Reported Outcome Measurement Information System measures for anxiety, depression, social satisfaction, and adverse events between weeks 8 and 52 using a web-based system. Paired t test and P for trend were used to compare changes in PRO measures over time. Bivariate analyses and logistic regression models were used to determine factors associated with response (SCCAI <5) or remission (SCCAI <2) at week 52. RESULTS: Of 103 patients, 82.5% entered the maintenance phase and 43.7% remained on tofacitinib at week 52. Tofacitinib de-escalation to 5 mg BID occurred in 15% of patients. At week 52, 42.7% and 31.1% of all patients reported an SCCAI <5 and SCCAI ≤2, respectively. Normalization of bowel frequency, rectal bleeding, and urgency occurred in 79%, 61%, and 48% of patients remaining on maintenance therapy. Social satisfaction improved significantly ( P < 0.001), while anxiety and depression scores only numerically improved. No consistent predictors for tofacitinib long-term treatment efficacy were identified, and safety findings were consistent with the known safety profile of tofacitinib. DISCUSSION: Tofacitinib is an effective maintenance therapy in patients with refractory UC. Dose reductions infrequently occurred during maintenance. Unmet needs in UC maintenance include improvement of urgency and psychosocial factors (NCT03772145).

Tofacitinib Response in Ulcerative Colitis (TOUR): Early Response After Initiation of Tofacitinib Therapy in a Real-world Setting.

BACKGROUND: Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Using a novel electronic reporting tool, we aimed to prospectively describe the onset of tofacitinib efficacy during induction therapy in a real-world study. METHODS: Patient-reported outcome data (PROs) including the simple clinical colitis activity index (SCCAI), PRO Measurement Identification Systems (PROMIS) measures, and adverse events were collected daily for the first 14 days and at day 28 and 56. Paired t tests and P for trend were utilized to compare changes in SCCAI over time. Bivariate analyses and logistic regression models were performed to describe response (SCCAI <5) and remission (SCCAI ≤2) by clinical factors. RESULTS: Of all included patients (n = 96), 67% had failed ≥2 biologics, and 61.5% were on concomitant steroids. Starting at day 3, PROs showed significant and persistent decline of the mean SCCAI (-1.1, P < 000.1) including significantly lower SCCAI subscores for stool frequency (-0.3; P < .003), bleeding (-0.3; P < .0002) and urgency (-0.2; P < .001). Steroid-free remission at day 14, 28, and 56 was achieved in 25%, 30.2%, and 29.2% of patients, respectively. Neither prior biologics nor endoscopic severity were independently predictive of response or remission in multivariate models. Numeric improvements in all PROMIS measures (anxiety, depression, social satisfaction) were seen through day 56. Rates of discontinuation due to adverse events were low. CONCLUSIONS: In this prospective real-world study, tofacitinib resulted in a rapid and persistent improvement in UC disease activity PROs. The safety findings were consistent with the established safety profile of tofacitinib.

Complementary and Alternative Medicine in Crohn's Disease.

Complementary and alternative medicine (CAM) is a growing entity within inflammatory bowel disease (IBD). CAM includes mind-based therapies, body-based therapies, supplements, vitamins, and probiotics. Limitations currently exist for health care providers as it pertains to IBD and CAM that stem from knowledge gaps, conflicting reports, limited oversight, and a lack of well-organized clinical data. Even without well-described data, patients are turning to these forms of therapy at increasing rates. It is imperative that the ongoing review of CAM therapies is performed, and future trials are performed to better understand efficacy as well as adverse effects related to these therapies.

Impact of Obesity on the Management and Clinical Course of Patients with Inflammatory Bowel Disease.

BACKGROUND: Obesity has been linked with a proinflammatory state and the development of inflammatory diseases. Data on the clinical course and treatment of obese patients with inflammatory bowel disease (IBD) are limited. We used an institutional IBD registry to investigate the impact of obesity on IBD severity and treatment. METHODS: This was a retrospective analysis of prospectively collected data for 3 years (2009-2011). Patients with IBD were categorized by body mass index (BMI). IBD-related quality of life, biochemical markers of inflammation, comorbidities, health care utilization, and treatment were characterized. Obesity was defined as a BMI ≥30 (type I: 30-34.9, type II: 35-39.9, and type III ≥40). RESULTS: Among 1494 patients with IBD, 71.9% were above their ideal BMI and 31.5% were obese. Obesity was more common in ulcerative colitis compared with patients with Crohn's disease (P = 0.04). Obese class II and class III patients were predominantly female. Obesity in IBD was associated with female gender (P < 0.0001), diabetes mellitus (P < 0.001), hypertension (P < 0.001), hyperlipidemia (P < 0.001), poor quality of life (P < 0.0001), and increased rates of C-reactive protein elevation (P = 0.008). In logistic regression analysis, quality of life and C-reactive protein elevation were not independently correlated with obesity. There was no association between increasing BMI and annual prednisone use, emergency department visits, hospitalization, and surgery. Obesity was associated with lower milligrams per kilogram doses of purine analogs and biologics. CONCLUSIONS: Obesity in IBD is not associated with increased health care utilization and IBD-related surgeries. Optimal regimens for drug dosing in obese patients with IBD have yet to be defined.

Jejunal feeding in patients with pancreatitis.

Patients with severe acute pancreatitis complicated by organ failure and/or pancreatic necrosis or fluid collections should have placement of a double-lumen nasogastric-jejunal tube to be used for both gastric decompression and jejunal feeding. These patients are at risk for gastric outlet obstruction, which may be treated so that complications such as aspiration and reflux are avoided. Furthermore, early enteral feeding can prevent ileus, suppress further organ failure, and ultimately restore gut function if continued in an uninterrupted manner. Ultimately, this patient population will benefit from pancreatic rest and jejunal feeding specifically when compared with patients using nasogastric feeding tubes.

Infliximab for Crohn's disease: the first 500 patients followed up through 2009.

BACKGROUND: The aim of this study was to assess the long-term usage patterns and safety of infliximab in patients with Crohn's disease in clinical practice. METHODS: The medical records of 492 unselected patients treated with infliximab at Mayo Clinic were reviewed and abstracted for demographic features, usage patterns, and adverse events. RESULTS: The patients received a median of seven infusions and had a median follow-up of 6.3 years. Twenty-eight patients (6 %) were lost to follow-up, 63 patients (13 %) had no clinical benefit, and 401 patients (80 %) had partial or complete response. Of the responding patients, 114 (28 %) received induction treatment only, 167 (42 %) received initial episodic treatment (62 switched to scheduled maintenance treatment of whom 32 [42 %] were still on infliximab at last follow-up), and 120 (30 %) received scheduled maintenance treatment (56 patients [32 %] still on infliximab at last follow-up). Three patients (0.6 %) developed septic shock and six patients (1.5 %) developed septicemia. One patient (0.2 %) developed Mycobacterium avium complex. Histoplasmosis occurred in three patients (0.6 %). The cumulative 10-year probability for developing cancer after infliximab was 9 %. Among the 31 patients developing malignancies (6 %), 15 (3 %) had solid tumors, 11 (2 %) had melanoma and non-melanoma skin cancers, three (0.6 %) had lymphomas (0.6 %), and two (0.4 %) had leukemia. Overall 10-year survival after the final course of infliximab was 94 %. Among the 28 deaths (6 %), nine occurred within 12 weeks of an infliximab infusion-two of these deaths were due to infections. CONCLUSIONS: Long-term follow-up of patients with Crohn's disease who were treated with infliximab initially between 1998 and 2002 showed persistence of therapy (due to clinical benefit) and an acceptable safety profile, despite the fact that less than one-third initially received three-dose induction followed by scheduled maintenance therapy. Infections and malignancy occurred at rates similar to those previously reported.

Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts.

OBJECTIVE: Because ouabain activates several pathways that are critical to cardioprotective mechanisms such as ischemic preconditioning, we tested if this digitalis compound could protect the heart against ischemia-reperfusion injury through activation of the Na+,K+-ATPase/c-Src receptor complex. METHODS AND RESULTS: In Langendorff-perfused rat hearts, a short (4 min) administration of ouabain 10 muM followed by an 8-minute washout before 30 min of global ischemia and reperfusion improved cardiac function, decreased lactate dehydrogenase release and reduced infarct size by 40%. Western blot analysis revealed that ouabain activated the cardioprotective phospholipase Cgamma1/protein kinase Cepsilon (PLC-gamma1/PKCepsilon) pathway. Pre-treatment of the hearts with the Src kinase family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2) blocked not only ouabain-induced activation of PLC-gamma1/PKCepsilon pathway, but also cardiac protection. This protection was also blocked by a PKCepsilon translocation inhibitor peptide (PKCepsilon TIP). CONCLUSION: Short exposure to a low concentration of ouabain protects the heart against ischemia/reperfusion injury. This effect of ouabain on the heart is most likely due to the activation of the Na+,K+-ATPase/c-Src receptor complex and subsequent stimulation of key mediators of preconditioning, namely PLC-gamma1 and PKCepsilon.

Rapamycin preserves renal function compared with cyclosporine A after ischemia/reperfusion injury.

OBJECTIVES: To determine the effect of cyclosporine and rapamycin administration on renal function after ischemia/reperfusion injury (I/R). Cyclosporine A has known nephrotoxic effects. Thus, cyclosporine therapy subsequent to I/R injury may further exacerbate graft dysfunction. Rapamycin is a newer agent that suppresses the immune system by a different mechanism. METHODS: Male Wistar rats (250 g) were anesthetized, and the suprarenal aorta was clamped for 40 minutes. The right kidney was removed. After recovery, the rats were divided into four groups: group 1, controls, no ischemia and no treatment (n = 10); group 2, ischemia with no treatment (n = 8); group 3, ischemia plus rapamycin (0.17 mg/kg/day gavage, n = 8); and group 4, ischemia plus cyclosporine A (30 mg/kg/day intraperitoneally, n = 9). The glomerular filtration rate was measured 5 to 7 days after I/R injury using urinary iohexol clearance. Data are expressed as the mean +/- SEM, and intergroup comparisons were made using one-way analysis of variance. RESULTS: The mean GFR value for the controls (no ischemia, no treatment) was 1.23 +/- 0.08 mL/min; for group 2 (ischemia, no treatment), it was 1.05 +/- 0.10 mL/min; for group 3 (ischemia plus rapamycin) 1.06 +/- 0.14 mL/min; and for group 4 (ischemia plus cyclosporine A) 0.44 +/- 0.06 mL/min (P <0.05 versus the other three groups). The mean arterial pressure was significantly lower in the ischemic rats treated with cyclosporine A (P <0.05 versus the other three groups). CONCLUSIONS: After I/R injury, rapamycin may preserve renal function compared with cyclosporine treatment, because it does not have a direct vasoconstrictor effect on the renal microcirculation.