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JAMA Sep 2023Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, with a prevalence exceeding 400 per 100 000 in North America. Individuals with UC have a... (Review)
Review
IMPORTANCE
Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, with a prevalence exceeding 400 per 100 000 in North America. Individuals with UC have a lower life expectancy and are at increased risk for colectomy and colorectal cancer.
OBSERVATIONS
UC impairs quality of life secondary to inflammation of the colon causing chronic diarrhea and rectal bleeding. Extraintestinal manifestations, such as primary sclerosing cholangitis, occur in approximately 27% of patients with UC. People with UC require monitoring of symptoms and biomarkers of inflammation (eg, fecal calprotectin), and require colonoscopy at 8 years from diagnosis for surveillance of dysplasia. Risk stratification by disease location (eg, Montreal Classification) and disease activity (eg, Mayo Score) can guide management of UC. First-line therapy for induction and maintenance of remission of mild to moderate UC is 5-aminosalicylic acid. Moderate to severe UC may require oral corticosteroids for induction of remission as a bridge to medications that sustain remission (biologic monoclonal antibodies against tumor necrosis factor [eg, infliximab], α4β7 integrins [vedolizumab], and interleukin [IL] 12 and IL-23 [ustekinumab]) and oral small molecules that inhibit janus kinase (eg, tofacitinib) or modulate sphingosine-1-phosphate (ozanimod). Despite advances in medical therapies, the highest response to these treatments ranges from 30% to 60% in clinical trials. Within 5 years of diagnosis, approximately 20% of patients with UC are hospitalized and approximately 7% undergo colectomy. The risk of colorectal cancer after 20 years of disease duration is 4.5%, and people with UC have a 1.7-fold higher risk for colorectal cancer compared with the general population. Life expectancy in people with UC is approximately 80.5 years for females and 76.7 years for males, which is approximately 5 years shorter than people without UC.
CONCLUSIONS AND RELEVANCE
UC affects approximately 400 of every 100 000 people in North America. An effective treatment for mild to moderate UC is 5-aminosalicylic acid, whereas moderate to severe UC can be treated with advanced therapies that target specific inflammation pathways, including monoclonal antibodies to tumor necrosis factor, α4β7 integrins, and IL-12 and IL-23 cytokines, as well as oral small molecule therapies targeting janus kinase or sphingosine-1-phosphate.
Topics: Adult; Female; Humans; Male; Antibodies, Monoclonal; Colitis, Ulcerative; Colorectal Neoplasms; Inflammation; Mesalamine; Quality of Life; Tumor Necrosis Factor-alpha
PubMed: 37698559
DOI: 10.1001/jama.2023.15389 -
The American Journal of Gastroenterology Sep 2023Rapidity of symptom resolution informs treatment choice in patients with moderate-severe ulcerative colitis (UC). We conducted a systematic review and network... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Rapidity of symptom resolution informs treatment choice in patients with moderate-severe ulcerative colitis (UC). We conducted a systematic review and network meta-analysis comparing early symptomatic remission with approved therapies.
METHODS
Through a systematic literature review to December 31, 2022, we identified randomized trials in adult outpatients with moderate-severe UC treated with approved therapies (tumor necrosis factor α antagonists, vedolizumab, ustekinumab, janus kinase inhibitors, or ozanimod), compared with each other or placebo, reporting rates of symptomatic remission (based on partial Mayo score, with resolution of rectal bleeding and near-normalization of stool frequency) at weeks 2, 4, and/or 6. We performed random-effects network meta-analysis using a frequentist approach and estimated relative risk (RR) and 95% confidence interval values.
RESULTS
On network meta-analysis, upadacitinib was more effective than all agents in achieving symptomatic remission at weeks 2 (range of RR, 2.85-6.27), 4 (range of RR, 1.78-2.37), and 6 (range of RR, 1.84-2.79). Tumor necrosis factor α antagonists and filgotinib, but not ustekinumab and vedolizumab, were more effective than ozanimod in achieving symptomatic remission at week 2, but not at weeks 4 and 6. With approximately 10% placebo-treated patients achieving symptomatic remission at 2 weeks, we estimated 68%, 22%, 23.7%, 23.9%, 22.2%, 18.4%, 15.7%, and 10.9% of upadacitinib-, filgotinib-, infliximab-, adalimumab-, golimumab-, ustekinumab-, vedolizumab-, and ozanimod-treated patients would achieve early symptomatic remission, ustekinumab and vedolizumab achieving rapid remission only in biologic-naïve patients.
DISCUSSION
In a systematic review and network meta-analysis, upadacitinib was most effective in achieving early symptomatic remission, whereas ozanimod was relatively slower acting.
Topics: Adult; Humans; Colitis, Ulcerative; Tumor Necrosis Factor-alpha; Network Meta-Analysis; Adalimumab; Ustekinumab; Treatment Outcome
PubMed: 36976548
DOI: 10.14309/ajg.0000000000002263 -
Journal of Clinical Medicine Aug 2023Patients with Crohn's disease can present with a variety of clinical manifestations; treatment strategies should focus on long-term remission and improvement of quality... (Review)
Review
Patients with Crohn's disease can present with a variety of clinical manifestations; treatment strategies should focus on long-term remission and improvement of quality of life. There is no standardized process of diagnosing, predicting prognosis, and treating the disease. This narrative review was based on a literature search using PubMed, Embase, and Science Direct. Data on unmet challenges in patients with Crohn's disease were extracted from identified manuscripts. The aim was to discuss present research on standardized processes in the management of patients with Crohn's disease and to identify the unmet needs in clinical evaluation and treatment approaches. There is no consensus on standardized diagnostic, treatment, and surveillance algorithms, particularly in assessing complications of Crohn's, such as stricturing disease, intestinal cancer risk, and cutaneous manifestations. Complications and treatment failure rates of conventional, interventional, and surgical therapy place emphasis on the need for standardized treatment algorithms, particularly in the case of acute complications of the disease. Research on standardized clinical approaches, reliable biomarkers for disease diagnosis and therapy monitoring, and new treatment agents is necessary to improve therapy and reduce complications in patients with Crohn's disease.
PubMed: 37685662
DOI: 10.3390/jcm12175595 -
International Journal of Gynecological... Dec 2023To evaluate the feasibility of uterine transposition as a method of preserving fertility and ovarian function after pelvic radiation. (Observational Study)
Observational Study
OBJECTIVE
To evaluate the feasibility of uterine transposition as a method of preserving fertility and ovarian function after pelvic radiation.
METHODS
This prospective multicenter observational study included patients with non-gynecologic pelvic cancers who underwent pelvic radiation as part of their cancer treatment between June 2017 and June 2019. For inclusion in the study, patients were required to have normal menstrual cycles and hormone levels (follicle-stimulating hormone, luteinizing hormone, and estrogen) before treatment. Uterine transposition to the upper abdomen was performed prior to irradiation. Clinical examinations and Doppler ultrasonography were used to evaluate the gonadal vasculature post-surgery. The uterus was repositioned into the pelvis 2-4 weeks after radiation therapy or at the time of rectosigmoid resection in patients with rectal cancer who had undergone neoadjuvant treatment. Cancer treatment and follow-up were performed according to standard guidelines.
RESULTS
Eight patients (seven with rectal cancer and one with pelvic liposarcoma) underwent uterine transposition at a median age of 30.5 years (range 19-37). The uterus was successfully preserved in six patients, accompanied by normal menses, hormonal levels, and vaginal intercourse after treatment. One patient with rectal cancer died of carcinomatosis 4 months after uterine transposition. One patient presented with uterine necrosis 4 days after uterine transposition, and the uterus was removed; however, one ovary was preserved. Cervical ischemia was the most common post-surgical complication in three (37.5%) patients. Three patients attempted to conceive, and two (66%) were spontaneously successful and delivered healthy babies at 36 and 38 weeks by cesarean section without complications.
CONCLUSIONS
Uterine transposition is a feasible procedure for preserving gonadal and uterine function in patients requiring pelvic radiotherapy for non-gynecological cancer, with the potential for achieving spontaneous pregnancy and successful delivery.
Topics: Adult; Female; Humans; Pregnancy; Young Adult; Cesarean Section; Fertility; Fertility Preservation; Prospective Studies; Rectal Neoplasms; Uterine Cervical Neoplasms; Uterus
PubMed: 37898483
DOI: 10.1136/ijgc-2023-004723 -
The American Surgeon Apr 2024Idiopathic acute rectal necrosis (IARN) is a rare condition due to a robust rectal blood supply. This report describes an 83-year-old man presenting with septic shock...
Idiopathic acute rectal necrosis (IARN) is a rare condition due to a robust rectal blood supply. This report describes an 83-year-old man presenting with septic shock due to distal sigmoid and complete rectal necrosis with perforation. He underwent emergent exploratory laparotomy, sigmoid and proximal rectum resection, and end sigmoid colostomy creation with delayed distal rectal evaluation. Bedside proctoscopy revealed pale, viable-appearing distal rectal mucosa on postoperative day 3. The patient had a protracted, complicated hospital stay but required no further operative intervention. Subsequent colostomy reversal was done 8 months postoperatively, and the patient did well and has been discharged with normal gastrointestinal function. Our successful conservative operative management of IARN deviates from previously described management in the literature which is emergent abdominoperineal resection. This conservative surgical strategy appears to have contributed to the patient's positive outcomes, highlighting the importance of considering a similar approach for future IARN cases.
PubMed: 38569206
DOI: 10.1177/00031348241241690 -
Trauma Case Reports Oct 2023The rectum is an anatomically protected and well vascularized structure. Injury to the rectum is usually the result of penetrating perineal mechanisms or reported...
The rectum is an anatomically protected and well vascularized structure. Injury to the rectum is usually the result of penetrating perineal mechanisms or reported scalding enemas. Here, we report a case of isolated rectal necrosis following a 72 % total body surface area burn that resulted from a motor vehicle crash. The patient's rectal injury was managed with open resection, left in discontinuity and ultimately expired. In presenting this case, we hope to share an unusual development in a patient with critical illness and guide future care.
PubMed: 37654702
DOI: 10.1016/j.tcr.2023.100886 -
Digestive Diseases and Sciences Oct 2023Crohn's disease perianal fistulae (CD-PAF) occur in 25% of patients and are notoriously challenging to manage. Tumor necrosis factor inhibitors are first line agents.
BACKGROUND
Crohn's disease perianal fistulae (CD-PAF) occur in 25% of patients and are notoriously challenging to manage. Tumor necrosis factor inhibitors are first line agents.
AIMS
The aim of this study was to compare infliximab (IFX) versus adalimumab (ADA) efficacy in CD-PAF healing over time.
METHODS
A retrospective study at two large-tertiary medical centers was performed. Inclusion criteria were actively draining CD-PAF and initial treatment with IFX or ADA following CD-PAF diagnosis. The primary endpoints were perianal fistula response and remission at 6 and 12 months. Secondary endpoints included biologic persistence over time and dose escalation at 6 and 12 months.
RESULTS
Among 151 patients included in the study, 92 received IFX and 59 received ADA as first line agents after CD-PAF diagnosis. At 6 months, the 64.9% of the IFX group and 34.8% of the ADA group demonstrated CD-PAF clinical improvement (p < 0.01). Univariate and multivariate analyses demonstrated significant differences among the IFX and ADA groups for clinical response at 6-months and 12-months (p = 0.002 and p = 0.042, respectively). There were no factors that predicted response, with the exception of concomitant immunomodulator affecting the 6-month clinical response (p = 0.021). Biologic persistence, characterized by Kaplan Meier methods, was significantly longer in the IFX group compared to the ADA group (Log-rank p = 0.01).
CONCLUSION
IFX induction and maintenance is associated with higher rates of response and remission in CD-PAF healing as well as higher treatment persistence compared to ADA. Additionally, our study supports the use of concomitant immunomodulator therapy for CD-PAF healing and remission.
Topics: Humans; Infliximab; Adalimumab; Crohn Disease; Retrospective Studies; Treatment Outcome; Immunologic Factors; Rectal Fistula; Biological Products; Tumor Necrosis Factor-alpha
PubMed: 37540392
DOI: 10.1007/s10620-023-08060-7 -
International Journal of Pharmaceutics:... Dec 2023Infliximab is a monoclonal antibody that plays an important role in the management and treatment of chronic inflammatory bowel diseases (IBD). Due to its macromolecular...
Infliximab is a monoclonal antibody that plays an important role in the management and treatment of chronic inflammatory bowel diseases (IBD). Due to its macromolecular structure, its delivery through the oral route is challenging, limiting its administration to only via the parenteral route. The rectal route offers an alternative way for administering infliximab, allowing it to be localised at the disease site and circumventing its passage across the alimentary canal and thus, maintaining its integrity and bioactivity. Three-dimensional (3D) printing is an advanced production technology that permits the creation of dose-flexible drug products from digital designs. The current study assessed the feasibility of utilising semi-solid extrusion 3D printing for the fabrication of infliximab-loaded suppositories for the local treatment of IBD. Various printing inks composed of Gelucire® (48/16 or 44/14) mixed with coconut oil and/or purified water were investigated. It was shown that following reconstitution in water, the infliximab solution can be directly incorporated into the printing ink of Gelucire® 48/16 and can withstand the extrusion process, resulting in well-defined suppositories. Since water content and temperature are critical for safeguarding infliximab's potency, the effect of changing the composition of the printing inks and printing parameters on infliximab's biologic efficiency was evaluated by measuring its binding capacity (i.e., the amount of infliximab that actively binds to its antigen to exert an effect). Despite drug loading assays showing that infliximab remains intact following printing, it was found that the incorporation of water in isolation results in only ∼65% binding capacity. However, when oil is added to the mixture, infliximab's binding capacity increases up to ∼85%. These promising results demonstrate that 3D printing has the potential to be exploited as a novel platform for fabricating dosage forms containing biopharmaceuticals, avoiding patients' compliance issues observed with injectables and addressing their unmet needs.
PubMed: 37396625
DOI: 10.1016/j.ijpx.2023.100176 -
Mucosal Immunology Dec 2023This study investigated the role of Alpha-tocopherylquinone (TQ) in regulating the intestinal immune system and the underlying mechanisms. In the experimental dextran...
Alpha-tocopherylquinone-mediated activation of the Aryl Hydrocarbon Receptor regulates the production of inflammation-inducing cytokines and ameliorates intestinal inflammation.
This study investigated the role of Alpha-tocopherylquinone (TQ) in regulating the intestinal immune system and the underlying mechanisms. In the experimental dextran sodium sulfate and T cell-mediated colitis models, TQ significantly reduced the mRNA levels of interleukin (IL)-6, IL-1β, IL-17A, IL-23, and tumor necrosis factor (TNF)-α and the abundance of proinflammatory macrophages, T helper (Th)17 cells, and ILC3s in the colons of wild-type mice. TQ also prevented lipopolysaccharide (LPS)-induced activation of NFκB and signal transducer and activator of transcription (Stat)-3 pathways in the human macrophage U937 cells. Pharmacological inhibition or CRISPR-Cas-9-mediated knockout of Aryl hydrocarbon Receptor (AhR) prevented the anti-inflammatory effects of TQ in the LPS-treated U937 cells. Furthermore, TQ reduced the mRNA levels of the LPS-induced pro-inflammatory cytokines in the WT but not Ahr mice splenocytes. TQ also reduced IL-6R protein levels and IL-6-induced Stat-3 activation in Jurkat cells and in vitro differentiation of Th17 cells from wild-type but not Ahr mice naive T cells. Additionally, TQ prevented the pro-inflammatory effects of LPS on macrophages and stimulation of T cells in human PBMCs and significantly reduced the abundance of tumor necrosis factor-α, IL-1β, and IL-6 inflammatory macrophages and Th17 cells in surgically resected Crohn's disease (CD) tissue. Our study shows that TQ is a naturally occurring, non-toxic, and effective immune modulator that activates AhR and suppresses the Stat-3-NFκB signaling.
Topics: Mice; Humans; Animals; Cytokines; Interleukin-6; Receptors, Aryl Hydrocarbon; Lipopolysaccharides; Inflammation; Tumor Necrosis Factor-alpha; RNA, Messenger
PubMed: 37716509
DOI: 10.1016/j.mucimm.2023.09.003