Ustekinumab Drug Levels and Outcomes in Inflammatory Bowel Disease.

BACKGROUND: Data regarding the utility of therapeutic drug monitoring with ustekinumab (UST) are sparse. Our aim was to determine the correlation of UST levels with outcomes in a cohort of patients with inflammatory bowel disease (IBD). METHODS: This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. The primary outcomes were the correlation of UST level with clinical remission (per physician global assessment), endoscopic healing [the absence of ulcers/erosions in Crohn's disease (CD) and Mayo endoscopic score ≤1 for ulcerative colitis (UC)], and normal serum C-reactive protein (CRP) (≤5 mg/L). Secondary outcomes included defining optimal UST trough levels associated with favorable outcomes. RESULTS: A total of 71 patients (74.6% with CD; 57.7% female) were included. The median age was 39.5 years [interquartile range (IQR): 26 to 52] and 12.6% were on combination therapy with immunomodulators. Median UST trough levels were significantly higher in patients who achieved endoscopic healing at 5.4 µg/mL versus 3.5 µg/mL (P=0.035) and normal CRP at 5.5 µg/mL versus. 3.1 µg/mL (P=0.002). A cutoff UST level of 4.8 µg/mL yielded the highest area under the curve (AUC) of 0.73 (95% CI: 0.61-0.80) to predict a normal CRP followed by a cutoff of 3.5 µg/mL which yielded an AUC of 0.66 (95% CI: 0.52-0.81) to predict endoscopic healing. CONCLUSIONS: UST trough levels were significantly higher in patients who achieved a normal CRP and endoscopic healing. A cutoff UST level of 4.8 µg/mL reliably predicted CRP normalization.

Rates, Predictors, and Outcomes of Ustekinumab Dose Escalation in Inflammatory Bowel Disease.

OBJECTIVE: Ustekinumab (UST) is effective for the induction and maintenance of remission in inflammatory bowel disease (IBD). However, a significant proportion of patients will require UST dose escalation. We sought to determine the rates, predictors, and outcomes of UST dose escalation in patients with IBD. PATIENTS AND METHODS: This was a multicenter, retrospective study of all patients with IBD who received UST from January 1, 2014 to March 1, 2022. Primary outcomes were the rates and predictors of UST dose escalation. Secondary outcomes included steroid-free clinical remission, endoscopic healing, and normalization of serum c-reactive protein in patients who underwent UST dose escalation. RESULTS: A total of 198 patients were included (58% females and 76.7% with Crohn's disease). UST dose was escalated by 55.5% (n = 110). Mean baseline albumin was lower in the UST dose escalation group at 3.86 ± 0.47 versus 4.03 ± 0.45 g/dL (P = 0.044). The mean hemoglobin was lower in the UST dose escalation group at 12.1 ± 1.83 versus 12.7 ± 1.42 (P = 0.049). On multivariate analysis, male sex alone was associated with the need for dose escalation (odds ratio: 4.08, 95% CI: 1.20 - 13.90; P = 0.025). In the UST dose escalation group, 66.1% achieved steroid-free clinical remission, 55.8% had normalization of c-reactive protein, and 35.8% achieved endoscopic healing. CONCLUSIONS: UST dose escalation was needed in more than half of patients with IBD in this real-world cohort. UST dose escalation resulted in clinical remission in more than half of the cohort and endoscopic healing in one-third of patients.

Ocular, Auricular, and Oral Manifestations of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is primarily a disease of the gastrointestinal tract, though it can often affect other organ systems. These extraintestinal manifestations occur in a quarter to one-third of patients with Crohn's disease and ulcerative colitis. While musculoskeletal and dermatologic manifestations are the most common, it is also important to be cognizant of head, eye, ear, nose, and throat (HEENT) manifestations and educate IBD patients about them. Here we review the ocular manifestations in conjunction with the lesser-known but increasingly recognized ENT manifestations. Considering the lack of randomized controlled trials in treating HEENT manifestations of IBD, this review is primarily based on case reports, case series, and expert opinion with a particular focus on the newer literature supporting use of anti-TNF agents.

Clinical Decision Making in Inflammatory Bowel Disease Mimics: Practice Management from Inflammatory Bowel Disease LIVE.

Background: Since 2009, inflammatory bowel disease (IBD) specialists have utilized "IBD LIVE," a weekly live video conference with a global audience, to discuss the multidisciplinary management of their most challenging cases. While most cases presented were confirmed IBD, a substantial number were diseases that mimic IBD. We have categorized all IBD LIVE cases and identified "IBD-mimics" with consequent clinical management implications. Methods: Cases have been recorded/archived since May 2018; we reviewed all 371 cases from May 2018-February 2023. IBD-mimics were analyzed/categorized according to their diagnostic and therapeutic workup. Results: Confirmed IBD cases made up 82.5% (306/371; 193 Crohn's disease, 107 ulcerative colitis, and 6 IBD-unclassified). Sixty-five (17.5%) cases were found to be mimics, most commonly medication-induced (n = 8) or vasculitis (n = 7). The evaluations that ultimately resulted in correct diagnosis included additional endoscopic biopsies (n = 13, 21%), surgical exploration/pathology (n = 10, 16.5%), biopsies from outside the GI tract (n = 10, 16.5%), genetic/laboratory testing (n = 8, 13%), extensive review of patient history (n = 8, 13%), imaging (n = 5, 8%), balloon enteroscopy (n = 5, 8%), and capsule endoscopy (n = 2, 3%). Twenty-five patients (25/65, 38%) were treated with biologics for presumed IBD, 5 of whom subsequently experienced adverse events requiring discontinuation of the biologic. Many patients were prescribed steroids, azathioprine, mercaptopurine, or methotrexate, and 3 were trialed on tofacitinib. Conclusions: The diverse presentation of IBD and IBD-mimics necessitates periodic consideration of the differential diagnosis, and reassessment of treatment in presumed IBD patients without appropriate clinical response. The substantial differences and often conflicting treatment approaches to IBD versus IBD-mimics directly impact the quality and cost of patient care.

Extraintestinal Manifestations of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is primarily a disease of the digestive tract system, though it may affect other organ systems outside of the intestines. Extraintestinal manifestations (EIMs) can occur in up to one third of patients with Crohn's disease or ulcerative colitis. The most common EIMs involve dermatologic and musculoskeletal manifestations. EIMs may either parallel intestinal inflammation or be completely independent of disease activity. Physicians should be aware of EIMs and think systematically when evaluating patients with IBD, as nearly every organ can be involved, and a multidisciplinary treatment approach should be undertaken to improve outcomes and quality of life.

Whipple's Disease Mimicking Common Digestive Disorders.

Whipple's disease is a rare infectious disease caused by the bacterium Tropheryma whipplei. The prevalence of Whipple's disease is 3/1,000,000 in Western populations. It most often causes a malabsorption disorder with weight loss and diarrhea as common presenting symptoms. In one-third of patients, however, there are no gastrointestinal symptoms at presentation; patients instead report a wide variety of non-specific extraintestinal complaints, potentially involving every organ system. We report a case of a 37-year-old man who presented with a 3-month history of non-bloody diarrhea and 15-pound weight loss. He was ultimately diagnosed with biopsy-confirmed Whipple's disease. Despite its rarity, Whipple's disease remains an important clinical entity and should be included on the differential diagnosis for selected patients presenting with an array of non-specific symptoms.

Overuse of Tuberculosis Surveillance Testing in Patients With Inflammatory Bowel Disease Compared to Non-IBD Patients on Biologic Therapy.

Background: Biologic treatment for moderate to severe inflammatory bowel disease (IBD) places patients at risk for infectious complications. Tuberculosis (TB) infection and reactivation can lead to serious morbidity and mortality for immunosuppressed patients. As a result, guidelines recommend screening for TB before starting biologic treatment, but a paucity of data remains on the utility of surveillance testing. Methods: We performed a retrospective chart review at a single academic center evaluating both IBD and non-IBD patients on biologic therapy. The primary outcome was to determine the number of subsequent surveillance tests performed after initial screening for latent TB in both patient groups. Results: A total of 188 patients (147 IBD and 41 non-IBD patients) on biologic therapy were included. Screening for TB before biologic treatment was performed in 56% of non-IBD patients versus 83% for patients with IBD (P = 0.0003). Of the total cohort, 65% had at least 2 follow-up surveillance tests for TB. Three or more surveillance tests were performed in 40% of patients with IBD versus only 13% for non-IBD patients (P = 0.0132). A total of 7 patients (4%) had an abnormal surveillance test. No patients were confirmed to have a diagnosis of TB or underwent treatment. Conclusions: Patients on biologic therapy unnecessarily undergo surveillance testing for TB. Patients with IBD on biologic therapy are screened annually for TB at a higher rate compared to non-IBD patients. Standardization of care among patients on biologic therapy is necessary to avoid excessive testing in areas with a low incidence of TB.

Etiology and Management of Lack or Loss of Response to Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease.

The management of patients with moderate to severe inflammatory bowel disease was transformed with the arrival of anti-tumor necrosis factor (TNF) therapy. Nevertheless, a considerable number of patients do not respond to anti-TNF induction therapy (primary nonresponse) or lose response to treatment over time after initially experiencing clinical improvement (secondary loss of response). Studies suggest that these outcomes are often due to inadequate drug concentrations. Therapeutic drug monitoring (TDM) is a practical tool that can be used to better define the etiologies of and help manage primary nonresponse or secondary loss of response. Proactive TDM, or drug titration to a target trough concentration, can improve the efficacy of anti-TNF treatment and lead to favorable clinical outcomes. However, in patients with adequate anti-TNF drug concentrations and active disease, alternate pathways of inflammation (not driven by TNFa agents) are at play, and therapies with another mechanism of action should be employed.

A Successful Steroid-Sparing Approach in Cronkhite-Canada Syndrome.

Cronkhite-Canada Syndrome (CCS) is a rare, sporadic polyposis condition. The literature on CCS consists mostly of case reports. Although disease presentation has been well-described, there is no consensus on the management of CCS. We present a severe case of CCS that demonstrated clinical and endoscopic response to corticosteroids. This response was maintained with azathioprine. This case provides additional experience on a therapeutic strategy to induce and maintain a durable corticosteroid-free remission.

Increased Risks for Suicide, Self-Harm, Substance Use, and Psychiatric Disorders in Adults With Inflammatory Bowel Disease: A Nationwide Study in the United States From 2007 to 2017.

In an analysis of over 260 million emergency department visits across the United States from 2007 to 2017, inflammatory bowel disease conferred >10-fold risk for suicide deaths, self-harm, substance use, and psychiatric disorders, though the overall self-harm rates were low (<1% of all-cause inflammatory bowel disease emergency department visits; total 56 suicide deaths).

Human herpesvirus-8 positive iatrogenic Kaposi's sarcoma in the setting of refractory ulcerative colitis.

Although Kaposi sarcoma (KS) has been more traditionally considered an AIDS-defining illness, it may also be seen in individuals on immunosuppresive therapy. We report a case of a patient who presented to the hospital in the setting of increasingly refractory ulcerative colitis. Computed tomography scan of the abdomen was consistent with sigmoid diverticulititis and blood cultures were positive for Klebsiella. After a course of antibiotics with resolution of infection, a colonoscopy was performed to evaluate his diverticulitis and incidentally revealed a new rectal tumor. Immunohistochemistry showed the tumor was consistent with KS, with cells staining strongly positive for human herpesvirus-8. This case not only illustrates a rare case of KS found in an HIV-negative individual, but it also highlights the importance of considering an alternative diagnosis in a patient refractory to medical treatment. We discuss the management and care of an ulcerative colitis patient diagnosed with KS on immunosuppressive therapy.

Continued evidence for safety of endoscopic retrograde cholangiopancreatography during pregnancy.

AIM: To report the safety of continued use of endoscopic retrograde cholangiopancreatography (ERCP) during pregnancy at various maternal ages. METHODS: A retrospective chart review of pregnant patients who underwent ERCP at a tertiary academic center was undertaken between 2002 and 2012. Pertinent past medical history and initial presenting laboratory data were collected. Review of the procedure note for each ERCP performed provided documentation of lead shielding, type of sedation, fluoroscopy time, and post-procedure complications. Patients' clinical courses were reviewed until the time of delivery and pregnancy complications with fetal outcomes were examined. Data was stratified based upon the mother's age at the time of ERCP: 18-21, 22-29, and ≥ 30 years of age. RESULTS: Twenty pregnant patients who underwent ERCP between 2002 and 2012 were identified. The mean age at the time of ERCP was 26.4 years (18-38 years) and the average trimester was the second. The indications for ERCP were choledocholithiasis in 17 patients, gallstone pancreatitis in 2 patients, and cholangitis in 1 patient. The mean fluoroscopy time of ERCP was 3.8 min (0.3-23.6 min). Sphincterotomy was performed in 18 patients with therapeutic intent and not as a prophylactic measure to prevent recurrences. Clinical documentation of use of protective shielding was found in only 8 notes (40%). Post procedure complications were limited to two cases of post-ERCP pancreatitis (10%). Elective cholecystectomy was performed shortly after ERCP in 11 of the pregnant patients. Birth records were available for 16 patients, of which 15 had full-term pregnancies. Cesarean sections were performed in 5 (31%) patients. Term birth weight was greater than 2500 g in all cases except one in which the mother had a known hypercoagulable state. CONCLUSION: ERCP during pregnancy is both safe and efficacious regardless of maternal age or trimester.

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice.

TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10-/-Tlr4-/- mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10-/- and Il10-/-Tlr9-/- mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in which transfer of naive Il10-/-Tlr4-/- CD4+ T cells into Rag1-/- recipients sufficient for both IL-10 and TLR4 induced more aggressive colitis than the transfer of naive Il10-/- CD4+ T cells. Mechanistically, LPS stimulation of TLR4-bearing CD4+ T cells inhibited ERK1/2 activation upon subsequent TCR stimulation via the induction of MAPK phosphatase 3 (MKP-3). Our data therefore reveal a tonic inhibitory role for TLR4 signaling on subsequent TCR-dependent CD4+ T cell responses.