Background: Clinicians often utilize off-label dose escalation of ustekinumab (UST) in Crohn’s disease (CD) patients with disease refractory to standard dosing. Previous studies report mixed results with dose escalation of UST. Methods: A retrospective observational study of 143 adult patients with CD receiving UST over a 33-month time period was conducted. Patients receiving UST at standard dosage for a minimum of 16 weeks were included in the analysis. Primary outcomes collected were clinical response [Physician Global Assessment Score (PGA) by >1] and remission (PGA = 0). Changes in clinical parameters were calculated for dose-escalated patients beginning with the time of dose switch (~42 weeks) and compared with a group of patients who were classified as “failing” standard dosing at 42 weeks who were not dose escalated. Results: Dose escalation improved PGA by 0.47 ± 0.19 compared with patients remaining on every 8 weeks dosing (Q8 week), who worsened by 0.23 ± 0.23 ( p < 0.05). Dose escalation decreased CRP 0.33 ± 0.19 mg/L and increased serum albumin 0.23 ± 0.06 g/dL ( p < 0.05). Surprisingly, disease duration and prior CD surgeries inversely correlated with the need for dose escalation. Conclusion: Our results support UST Q4 week dose escalation for selected CD patients who fail to achieve remission on standard Q8 week dosing. Dose escalation improves clinical outcomes, prevents worsening disease severity, and positively impacts CRP and albumin levels. Together these data indicate that clinicians should attempt Q4 week UST dosing in refractory CD patients before switching to an alternative class of biologic therapy.

Patient: Male, 44Final Diagnosis: Cerebral toxoplasmosis after HSCTSymptoms: Hemiparesis • muscle weaknessMedication: —Clinical Procedure: —Specialty: HematologyObjective:Unusual clinical courseBackground:Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation.Case Report:We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis.Conclusions:Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.

INTRODUCTION: Microscopic colitis (MC) is a chronic inflammatory disease of the colon that is responsible for up to 10-15% of chronic watery diarrhea (Cotter TG, Binder M, Loftus EV, et al. Gut 2018). While this disease is often self-limiting, some patients suffer from severe disease that can be refractory to standard medical therapies, such as Imodium and budesonide. These patients are often referred to tertiary care facilities for initiation of anti-tumor necrosis factor agents (anti-TNFs) as they have shown some benefit in refractory disease. However, a significant side effect profile does accompany these agents which can make their use less desirable. Vedolizumab, a monoclonal human antibody to α4β7-integrin that blocks lymphocyte trafficking to the gut, has an excellent safety profile (Battat R, Ma C, et al. Drug Safety 2019) and is an appealing option for patients with severe refractory MC. CASE DESCRIPTION/METHODS: Three patients presenting to the University of Kentucky with severe microscopic colitis refractory to maximum budesonide and Imodium therapy were treated with vedolizumab. Vedolizumab was given at standard induction dosing (300 mg IV at week 0, 2 and 6, and then every 8 weeks). Clinical remission was defined as <3 stools a day following induction of vedolizumab with ability to wean budesonide. DISCUSSION: All three patients had remission of their MC as evidenced by cessation of diarrhea and ability to wean budesonide and Imodium after induction vedolizumab, including one patient who had suffered from microscopic colitis for over 20 years. This case series supports the small number of case reports that have surfaced in publications over the past 18 months, the largest of which consisted of 11 patients. While the definitive mechanism of microscopic colitis remains unknown, one of the proposed mechanisms details activation of CD8 T suppressor cells in the IEC and NF-ƙβ pathway activation leading to tissue damage in epithelial cells and barrier dysfunction (Gentile N, Yen E. Gut Liver 2018). The efficacy of vedolizumab in inducing MC remission supports this proposed mechanism, given its mechanism of action to bind α4β7-integrin and prevent T-cell adhesion. Larger scale clinical trials are needed to support routine clinical use of vedolizumab in refractory microscopic colitis, but this drug presents a promising, low-side effect profile treatment option for MC suffers.

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Background Ustekinumab, a monoclonal antibody of interleukin-12 and interleukin-23, was approved for the treatment of moderate to severe Crohn’s disease (CD) in 2016. Ustekinumab is approved in CD for a weight-based IV induction dose followed by every 8 weeks of subcutaneous dosing. Response rates by 6 weeks range from 34% (anti-TNF failures) to 56% in bio-naïve patients. The remainder includes patients who partially-respond (PR) or do not respond (NR). Response by week 16 is 55% (anti-TNF failures) and 73% in bio-naïve patients suggestive of a ‘delayed response’ in some. Experience with anti-TNF drugs demonstrates that a subset of patients respond to dose escalation, which prompts the notion of a potential delayed response phenomenon with Ustekinumab. Aim Determine the efficacy of dose escalation from standard Q8 dosing to Q4 dosing of Ustekinumab in CD patients, who had PR or NR to standard Q8 dosing. Methods A Retrospective observation study of 143 adult patients with CD, on Ustekinumab standard Q8 dosing over a 2 year and 9-month period was conducted. Data was extracted pertaining to demographics, disease, and treatment-related variables (biomarkers, steroid use, interval surgery, ER visits). Patients were further subcategorized as responders, partial responders(PR), and non-responders(NR), based on changes in fecal calprotectin, albumin, CRP, and Physician Global Assessment Disease Severity (1=mild, 2=moderate, 3=severe). Q8 non-responders (NR) and partial responders (PR) were dose-escalated to Q4, and outcome variables were collected. Biomarkers, steroid utilization, interval surgery, and ER visits, and PGA were compared in Q8 partial responder(PR) and non-responders (NR) from the date of starting Ustekinmuab on Q8 dosing to the date of escalation to Q4 dosing, versus the date of escalation Q4 dosing to the end of patient follow up. Results 30% (n=8) of patients were Q8NR, and 70% (n=19) were Q8PR). In the PR group, biomarkers decreased by up to 21% when these patients were switched to Q4 dosing. 100% of patients saw clinical improvement or remained at mild disease on Q4 dosing. In the NR group, biomarkers decreased by up to 91%. 100% of patients saw clinical improvement or remained at mild disease while on Q4 dosing. In both groups, 50% of patients taking steroids on Q8 dosing were no longer taking steroids or were at a reduced dose at the end of Q4 dosing follow-up. 40% of patients on immunomodulators on Q8 dosing were no longer taking immunomodulators at the end of Q4 dosing follow-up. Conclusions