Relationship of Sleep Health and Endoscopic Disease Activity in Inflammatory Bowel Disease: Endoscopic Disease Activity and Sleep.

Among adults with inflammatory bowel disease (IBD), self-reported sleep disturbances are associated with active symptoms, but the association between sleep measures and endoscopic disease activity is unknown. This study aimed to (1) compare sleep-wake behaviors among IBD patients based on endoscopic and clinical disease activity and (2) describe associations between actigraphy, self-reported sleep measures, and symptoms of fatigue, anxiety, and depression. Participants wore a wrist actigraph for 10 consecutive days and completed self-reported sleep questionnaires (Pittsburgh Sleep Quality Index [PSQI] and Patient-Reported Outcome Measures System [PROMIS] Sleep Disturbance and Sleep Interference questionnaires). Clinical and endoscopic disease activity were assessed. Based on actigraphic recordings ( n = 26), average total nighttime sleep was 437 minutes and sleep efficiency was 84%. Objective sleep measures did not differ based on endoscopic or clinical disease activity. Individuals with active clinical disease had higher PROMIS Sleep Disturbance (57.3 vs. 49.7, d = 1.28) and PROMIS Sleep-Related Impairment (58.1 vs. 52.8, d = 0.51) compared with those with inactive clinical disease. Self-reported sleep was significantly associated with anxiety, depression, and fatigue. Further research is needed to better characterize the relationship between sleep and endoscopic disease activity, and determine underlying mechanisms related to poor sleep in the IBD population.

Tofacitinib Appears Well Tolerated and Effective for the Treatment of Patients with Refractory Crohn's Disease.

BACKGROUND: Active Crohn's disease increases the risk of strictures, fistulas, and abscesses. Less than 30% of patients with Crohn's disease achieve endoscopic remission on any therapy. Tofacitinib may be a therapeutic option for patients with refractory Crohn's disease. AIMS: We aimed to evaluate the safety and effectiveness of off-label tofacitinib for refractory Crohn's disease. METHODS: We retrospectively assessed adverse events and clinical/endoscopic response after therapy. RESULTS: Forty-four patients were included in the safety analysis and 35 were included in the clinical and/or endoscopic assessments. The mean age was 41.8 years and the mean disease duration was 17.4 years. All patients had prior biologic exposure. Adverse events were reported in 52.3% of patients; 13.6% had ≥ 1 serious adverse event after a median 54.6 weeks of treatment. Seventy percent achieved clinical response after a mean 29.4 (SD 15.1) weeks, and 33.3% achieved clinical remission after a mean 33.4 (SD 17.6) weeks of therapy. Endoscopic improvement occurred in 25.0%, endoscopic remission in 12.5%, and endoscopic healing in 4.2% of patients after a mean 52.0 (SD 15.0) weeks of therapy. The mean Simple Endoscopic Score in Crohn's disease significantly improved from 23.1 ± 3.7 to 18.0 ± 13.7 after treatment (P = .02). CONCLUSIONS: In the short term, tofacitinib appears well tolerated. The most common adverse event was minor infection. One serious infection and one colorectal cancer occurred. While half of patients reported adverse events, this likely reflects the severe refractory disease in this population and no new safety events were observed. Tofacitinib achieved clinical and endoscopic improvement in some patients with refractory Crohn's disease. Further research is needed to understand the long-term safety and efficacy of tofacitinib in Crohn's disease.

Relationship Between Endoscopic and Clinical Disease Activity With Fatigue in Inflammatory Bowel Disease.

Fatigue is a prevalent symptom among individuals with inflammatory bowel disease. Yet, few studies have examined the relationship between fatigue and endoscopic disease activity. A retrospective chart review was conducted to determine the prevalence of fatigue based on endoscopic inflammation and clinical disease activity and describe the factors associated with fatigue among adults with inflammatory bowel disease. One hundred sixty patients were included. The majority had Crohn disease (72.5%), with an average age of 40.5 years. Sixty-one percent reported fatigue. Both endoscopic (p = .03) and clinical disease activities (p = .001) were significantly associated with fatigue. Among participants reporting fatigue, 52% had inactive disease and 48% had active disease based on endoscopy whereas 63% reported clinically active disease and 37% reported clinically inactive disease. In the multivariate regression model, clinical disease activity (odds ratio [OR] = 8.5; 95% CI [3.9, 18.6]) and anxiety (OR = 2.8; 95% CI [1.0, 7.6]) were significantly associated with fatigue. The prevalence of fatigue is high among individuals with active and inactive disease. Clinical disease activity and anxiety, but not endoscopic disease activity, were associated with fatigue.

Safety and Efficacy of Tofacitinib in Combination With Biologic Therapy for Refractory Crohn's Disease.

BACKGROUND: The majority of patients with Crohn's disease (CD) will not achieve endoscopic remission on current therapy. Addition of tofacitinib to biologics may improve remission rates. METHODS: We retrospectively assessed safety and clinical and endoscopic effectiveness of off-label tofacitinib and biologics for CD. RESULTS: We identified 19 patients treated with tofacitinib and a biologic for refractory CD between 2017 and 2019. Tofacitinib was added for luminal disease on colonoscopy (n = 13), luminal disease on capsule (n = 3), and pyoderma gangrenosum (n = 3). The mean age was 41.2 years (28-62), mean disease was duration 16.9 years (6-36), and prior exposure to biologics was a median of 4 (1-6). Mean treatment duration was 9.6 months (SD, 3.3). Adverse events (AEs) were reported in 36.8% of patients, most commonly minor infection or CD flare, and no patients had a serious AE; 80.0% (n = 8) achieved clinical response, and 60.0% (n = 6) achieved clinical remission based on Harvey-Bradshaw Index. Endoscopic improvement occurred in 54.5% (n = 6), endoscopic remission in 18.2% (n = 2), and endoscopic healing in 18.2% (n = 2) of patients. Mean Simple Endoscopic Score in CD significantly improved from 13.6 ±â€…5.2 to 6.5 ±â€…4.0 after treatment (P < .01). CONCLUSIONS: In patients treated with tofacitinib in combination with a biologic, no new safety signals were observed. Combination tofacitinib and a biologic was effective in achieving clinical and endoscopic improvement in some patients with severe, refractory CD, although a larger sample size is needed to further assess the efficacy and long-term safety of this treatment strategy.

Pustular Rash in Crohn's Patient on Ustekinumab Raises Concern for Drug-Induced Paradoxical Psoriasis.

We report the case of a 51-year-old male with Crohn's disease (CD) who developed a reproducible pustular rash after ustekinumab (UST) administration. The patient first presented with a pustular rash on his hands, body, extremities, and scalp starting 5 weeks after his initial weight-based UST induction. The rash resolved spontaneously, then recurred 4 weeks after his first subcutaneous maintenance dose of UST 90 mg. Biopsy of the affected area demonstrated subcorneal pustular dermatosis (SPD). UST was discontinued and the rash resolved. Unfortunately, the patient experienced clinical recurrence of CD, and given prior failure of multiple CD medications, UST was restarted with premedication. Two weeks after UST re-induction, the rash recurred, though less severe. Given improvement in CD symptoms, UST was continued and the rash managed with topical corticosteroids. This is the first case of drug-induced SPD associated with UST. One case report has previously described de novo pustular psoriasis associated with UST in a patient with CD and enteropathic arthritis. Notably, SPD and pustular psoriasis can be histologically indistinguishable. The development of a paradoxical psoriasiform rash is thought to be one of the few dose and duration dependent side effects of TNF-antagonist therapy but has not previously been established as a side effect of UST. This case demonstrates a new potential side effect of UST.

Developmental changes in propagation patterns and transmitter dependence of waves of spontaneous activity in the mouse cerebral cortex.

Waves of spontaneous electrical activity propagate across many regions of the central nervous system during specific stages of early development. The patterns of wave propagation are critical in the activation of many activity-dependent developmental programs. It is not known how the mechanisms that initiate and propagate spontaneous waves operate during periods in which major changes in neuronal structure and function are taking place. We have recently reported that spontaneous waves of activity propagate across the neonatal mouse cerebral cortex and that these waves are initiated at pacemaker sites in the septal nucleus and ventral cortex. Here we show that spontaneous waves occur between embryonic day 18 (E18) and postnatal day 12 (P12), and that during that period they undergo major changes in transmitter dependence and propagation patterns. At early stages, spontaneous waves are largely GABA dependent and are mostly confined to the septum and ventral cortex. As development proceeds, wave initiation depends increasingly on AMPA-type glutamate receptors, and an ever increasing fraction of waves propagate into the dorsal cortex. The initiation sites and restricted propagation of waves at early stages are highly correlated with the position of GABAergic neurons in the cortex. The later switch to a glutamate-based mechanism allows propagation of waves into the dorsal cortex, and appears to be a compensatory mechanism that ensures continued wave generation even as GABA transmission becomes inhibitory.

Bimodal septal and cortical triggering and complex propagation patterns of spontaneous waves of activity in the developing mouse cerebral cortex.

Spontaneous waves of activity that propagate across large structures during specific developmental stages play central roles in CNS development. To understand the genesis and functions of these waves, it is critical to understand the spatial and temporal patterns of their propagation. We recently reported that spontaneous waves in the neonatal cerebral cortex originate from a ventrolateral pacemaker region. We have now analyzed a large number of spontaneous waves using calcium imaging over the entire area of coronal slices from E18-P1 mouse brains. In all waves, the first cortical region active is this ventrolateral pacemaker. In half of the waves, however, the cortical pacemaker activity is itself triggered by preceding activity in the septal nuclei. Most waves are restricted to the septum and/or ventral cortex, with only some invading the dorsal cortex or the contralateral hemisphere. Waves fail to propagate at very stereotyped locations at the boundary between ventral and dorsal cortex and at the dorsal midline. Waves that cross these boundaries pause at these same locations. Waves at these stages are blocked by both picrotoxin and CNQX, indicating that both GABA(A) and AMPA receptors are involved in spontaneous activity.