Recent advances in inflammatory bowel disease (IBD) therapeutics include novel medical, surgical, and endoscopic treatments. Among these, stem cell therapy is still in its infancy, although multiple ...studies suggest that the immunomodulatory effect of stem cell therapy may reduce inflammation and tissue injury in patients with IBD. This review discusses the novel avenue of stem cell therapy and its potential role in the management of ulcerative colitis and Crohn's disease. We conducted a comprehensive literature search to identify studies examining the role of stem cell therapy (without conditioning and immunomodulatory regimens) in IBD. Taken together, these studies suggest a promising role for stem cell therapy in IBD although the substantial challenges, such as cost and inadequate/incomplete characterization of effect, limit their current use in clinical practice.
Background & Aims: The aim of this study was to determine the 1-year outcome after the first course of corticosteroids in an inception cohort of patients with inflammatory bowel disease.Methods: All ...patients in Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 173) or ulcerative colitis (n = 185) from 1970 to 1993 who were treated with systemic corticosteroids were identified (4 denied research authorization).Immediate outcome (30 days) and 1-year outcome after the first course of corticosteroids were determined.Results: Seventy-four (43%) patients with Crohn's disease and 63 (34%) with ulcerative colitis were treated with corticosteroids.Immediate outcomes for Crohn's disease were complete remission in 43 (58%), partial remission in 19 (26%), and no response in 12 (16%).Immediate outcomes for ulcerative colitis were complete remission in 34 (54%), partial remission in 19 (30%), and no response in 10 (16%).One-year outcomes for Crohn's disease were prolonged response in 24 (32%), corticosteroid dependence in 21 (28%), operation in 28 (38%), and lost to follow-up in 1 (1%).One-year outcomes for ulcerative colitis were prolonged response in 31 (49%), corticosteroid dependence in 14 (22%), and operation in 18 (29%).Conclusions: Most patients with Crohn's disease and ulcerative colitis initially respond to corticosteroids.At 1 year, 32% of patients with Crohn's disease and 48% with ulcerative colitis are corticosteroid free without operation.
GASTROENTEROLOGY 2001;121:255-260
Background & Aims The IMAgINE 1 study ( NCT00409682 ) evaluated the safety and efficacy of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients ...with moderate to severe Crohn's disease (CD). Methods We studied 192 patients with Pediatric Crohn's Disease Activity Index (PCDAI) scores >30 for whom conventional treatment was unsuccessful. Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight ≥40 kg or <40 kg). At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as decrease in PCDAI ≥15 points from baseline; 155/188 82.4%) and prior exposure to infliximab (82/188 43.6%). Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for body weight ≥40 kg or <40 kg; n = 93) or low doses (20 mg or 10 mg for body weight ≥40 kg or <40 kg; n = 95) every other week for 48 weeks. Clinical remission (PCDAI ≤10) at week 26 (the primary end point) was compared between groups using the Cochran–Mantel–Haenszel test, adjusting for strata, with nonresponder imputation. Adverse events were monitored to evaluate safety. Results A total of 152 of 188 patients (80.9%) completed all 26 weeks of the study. At week 26, 63 patients (33.5%) were in clinical remission, with no significant difference between high- and low-dose groups (36/93 38.7% vs 27/95 28.4%; P = .075). No new safety signals were detected. Conclusions Adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to that of adult patients with CD. More children who received high compared with low dose were in remission at week 26, but the difference between dose groups was not statistically significant.
Inflammatory bowel disease (IBD) is an immune-mediated disease and involves a complex interplay of host genetics and environmental influences. Recent advances in the field, including data from ...genome-wide association studies and microbiome analysis, have started to unravel the complex interaction between host genetics and environmental influences in the pathogenesis of IBD. A drawback of current clinical trials is inadequate or lack of immune phenotyping of patients. However, recent advances in high-throughput technologies provide an opportunity to monitor the dynamic and complex immune system, which may to lead to a more personalized treatment approach in IBD.
In Crohn's disease (CD), clinical symptoms correspond poorly to inflammatory disease activity. Biomarkers reflective of mucosal and bowel wall inflammation would be useful to monitor disease ...activity. The EMBARK study evaluated disease activity in patients with ulcerative colitis (UC) and CD, and used endoscopy with or without cross-sectional imaging for biomarker discovery.
UC (n=107) and CD (n=157) patients were characterized and underwent ileocolonoscopy (ICO). A subset of CD patients (n=66) also underwent computed tomography enterography (CTE). ICO and CTE were scored by a gastroenterologist and radiologist who incorporated findings of inflammation into a single score (ICO-CTE) for patients that underwent both procedures. Serum and fecal biomarkers were evaluated for association with the Mayo Clinic endoscopy score in UC patients and with ICO alone or ICO-CTE in CD patients. Individual biomarkers with a moderate degree of correlation (P≤0.3) were evaluated using multivariate analysis with model selection using a stepwise procedure.
In UC, ordinal logistic regression using Mayo Clinic endoscopy subscore selected the combination of fecal calprotectin and serum matrix metalloproteinase 9 (MMP9; pseudo R(2)=0.353). In CD, we found that use of the ICO-CTE increased specificity of known biomarkers. Using ICO-CTE as the dependent variable for biomarker discovery, the selected biomarkers were the combination of fecal calprotectin, serum MMP9, and serum IL-22 (r=0.699).
Incorporation of both ICO and CTE into a single measure increased biomarker performance in CD. Combinations of fecal calprotectin and serum MMP9 for UC, and combinations of fecal calprotectin, serum MMP9, and serum interleukin-22 in CD, demonstrated the strongest association with imaging/endoscopy-defined inflammation.
Regulatory T cells (Tregs) are crucial for preserving tolerance in the body, rendering Treg immunotherapy a promising treatment option for both organ transplants and autoimmune diseases. Presently, ...organ transplant recipients must undergo lifelong immunosuppression to prevent allograft rejection, while autoimmune disorders lack definitive cures. In the last years, there has been notable advancement in comprehending the biology of both antigen-specific and polyclonal Tregs. Clinical trials involving Tregs have demonstrated their safety and effectiveness. To maximize the efficacy of Treg immunotherapy, it is essential for these cells to migrate to specific target tissues, maintain stability within local organs, bolster their suppressive capabilities, and ensure their intended function's longevity. In pursuit of these goals, the utilization of biomaterials emerges as an attractive supportive strategy for Treg immunotherapy in addressing these challenges. As a result, the prospect of employing biomaterial-enhanced Treg immunotherapy holds tremendous promise as a treatment option for organ transplant recipients and individuals grappling with autoimmune diseases in the near future. This paper introduces strategies based on biomaterial-assisted Treg immunotherapy to enhance transplant medicine and autoimmune treatments.
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•Biomaterial-enhanced Treg therapy has the potential to transform organ transplantation and autoimmune disease treatments by enhancing Treg efficacy.•Interventions utilizing biomaterials can improve Treg migration, stability, and suppressive abilities in target tissues, maximizing therapeutic impact.•The safety and efficacy demonstrated by biomaterial-based Treg therapy lay the groundwork for future treatments in this field.•Biomaterial properties are crucial in guiding the design of platforms that support Treg function, thereby enhancing treatment precision.•Biomaterials provide diverse options for modulating immune responses, expanding the potential applications of Treg therapy.
Abstract
Background
This study sought to re-estimate the cumulative incidence of perianal or rectovaginal fistulas and the associated proctectomy rate in the prebiologic era vs the biologic era using ...a population-based cohort of Crohn's disease (CD) patients.
Methods
The medical records of 414 residents of Olmsted County, Minnesota, who were diagnosed with CD between 1970 and 2010 were reviewed. The cumulative incidence of perianal or rectovaginal fistulas from time of CD diagnosis and the cumulative rate of proctectomy from date of first perianal or rectovaginal fistula diagnosis were estimated using the Kaplan-Meier method.
Results
Eighty-five patients (20.5%) diagnosed with CD between 1970 and 2010 had at least 1 perianal or rectovaginal fistula episode between January 1, 1970, and June 30, 2016. The cumulative incidence of perianal or rectovaginal fistulas was 18% after 10 years, 23% after 20 years, and 24% after 30-40 years from CD diagnosis. The cumulative incidence of perianal or rectovaginal fistulas was significantly lower in patients diagnosed in 1998 or after than in patients diagnosed before 1998 (P = 0.03, log-rank). Among 85 patients developing perianal or rectovaginal fistulas, 16 patients (18.8%) underwent proctectomy for the treatment of perianal or rectovaginal fistulas during follow-up.
Conclusions
In a population-based inception cohort of CD, one-fifth of patients were diagnosed with at least 1 perianal or rectovaginal fistula. The cumulative probability of perianal or rectovaginal fistulizing disease has decreased over time.
Video Abstract
10.1093/ibd/izy329_video1
izy329.video1
5850901975001
Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of ...these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis.
Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn’s disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell–induced murine colitis models.
Mitochondria–endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria–endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn’s disease intestinal Tregs. Adoptively transferred Il21r–/– Tregs efficiently rescued murine colitis in contrast to wild-type Tregs.
IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell–driven chronic intestinal inflammation.
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Interleukin 21 induces metabolic alterations and acquisition of an inflammatory-like phenotype by perturbing mitochondria–endoplasmic reticulum crosstalk, thereby diminishing the capacity of Tregs in suppressing inflammatory bowel disease.
Human anti-chimeric antibodies (HACAs) and subtherapeutic infliximab concentrations are associated with decreased duration of response. We evaluated the clinical utility of measuring HACA and ...infliximab concentrations.
The medical records of patients with inflammatory bowel disease (IBD) who had HACA and infliximab concentrations measured were reviewed to determine whether the result affected clinical management.
One hundred fifty-five patients had HACA and infliximab concentrations measured. The main indications for testing were loss of response to infliximab (49%), partial response after initiation of infliximab (22%), and possible autoimmune/delayed hypersensitivity reaction (10%). HACAs were identified in 35 patients (23%) and therapeutic infliximab concentrations in 51 patients (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In HACA-positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92% of patients, whereas dose escalation had a response of 17%. In patients with subtherapeutic infliximab concentrations, dose escalation was associated with complete or partial clinical response in 86% of patients whereas changing to another anti-TNF agent had a response of 33%. Patients with clinical symptoms and therapeutic infliximab concentrations were continued at the same dose 76% of the time and had no evidence of active inflammation by endoscopic/radiographic assessment 62% of the time.
Measurement of HACA and infliximab concentration impacts management and is clinically useful. Increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent.
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