BACKGROUND:Patients with immune-mediated disorders such as ankylosing spondylitis, inflammatory bowel disease, psoriasis and rheumatoid arthritis are increasingly treated with tumor necrosis factor ...(TNF) inhibitors. The safety of anti-TNF therapy in patients with a history of cancer requires further evaluation. We conducted a systematic review and a meta-analysis of observational studies including patients with a history of cancer exposed to anti-TNF therapy assessing for a risk of new cancer or cancer recurrence.
MATERIALS AND METHODS:A computerized literature search of MEDLINE, Google scholar, and Cochrane Database of Systematic Reviews was performed through September 1, 2015. Study characteristics, quality, and risk of bias were assessed. Random-effects model meta-analyses were used to estimate the risk of new cancer development or cancer recurrence.
RESULTS:Nine English-language observational studies including patients with a history of cancer and exposed to anti-TNF therapy were idenitifed. The pooled incidence rate ratio of new or recurrent cancer among individuals with a history of cancer exposed to anti-TNF therapy was not significantly different compared with control therapies (incidence rate ratio, 0.90; 95% confidence interval, 0.59-1.37). Subgroup analyses were performed according to disease type, underlying cancer diagnosis, time to initiation of anti-TNF therapy and study quality. Heterogeneity of study populations, heterogeneity of the included cancer subtypes and utilization of observational studies limits the study quality.
CONCLUSIONS:The risk of new cancer or cancer recurrence among patients with a history of cancer and use of anti-TNF therapy is similar to the risk with nonbiological disease modifying therapies. These results support the use of anti-TNF medications in select populations despite prior diagnosis of cancer.
Patients with ulcerative colitis are at increased risk for colorectal cancer, although mechanisms underlying neoplastic transformation are poorly understood. We sought to evaluate the role of ...microRNAs in neoplasia development in this high-risk population.
Tissue from 12 controls, 9 ulcerative colitis patients without neoplasia, and 11 ulcerative colitis patients with neoplasia was analyzed. miRNA array analysis was performed and select miRNAs assayed by real-time PCR on the discovery cohort and a validation cohort. DNA methylation of miR-193a was assessed. Following transfection of miR-193a-3p, proliferation, IL17RD expression, and luciferase activity of the 3'UTR of IL17RD were measured. Tumor growth in xenografts as well as EGFR signaling were assessed in HCT116 cells expressing IL17RD with either a mutant 3' untranslated region (UTR) or wild-type (WT) 3'UTR.
miR-31, miR-34a, miR-106b, and miR-193a-3p were significantly dysregulated in ulcerative colitis-neoplasia and adjacent tissue. Significant down-regulation of miR-193a-3p was also seen in an independent cohort of ulcerative colitis cancers. Changes in methylation of miR-193a or expression of pri-miR-193a were not observed in ulcerative colitis cancer. Transfection of miR-193a-3p resulted in decreased proliferation, and identified IL17RD as a direct target of miR-193a-3p. IL17RD expression was increased in ulcerative colitis cancers, and miR-193a-3p treatment decreased growth and EGFR signaling of HCT116 cells in xenografts expressing both IL17RD with WT 3'UTR compared with cells expressing IL17RD with mutant 3'UTR.
miR-193a-3p is downregulated in ulcerative colitis neoplasia, and its loss promotes carcinogenesis through upregulation of IL17RD. These findings provide novel insight into inflammation-driven colorectal cancer and could suggest new therapeutic targets in this high-risk population.
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Vedolizumab is a gut-selective α4β7 integrin antagonist therapy for ulcerative colitis and Crohn's disease. The GEMINI long-term safety LTS trial is an ongoing open-label study investigating the ...safety of vedolizumab. We present interim exploratory analyses of efficacy in patients with Crohn's disease.
Patients from the C13004, GEMINI 2 and GEMINI 3 studies and vedolizumab-naïve patients could enrol in GEMINI LTS and received vedolizumab every 4 weeks. Data were collected from May 22, 2009 to June 27, 2013. Outcomes of clinical response and remission, defined by the Harvey-Bradshaw Index, and health-related quality of life HRQL were assessed for up to 152 weeks of treatment in the efficacy population.
Among patients with response at week 6 in GEMINI 2 who received vedolizumab continuously, 83% n=100/120 and 89% n=62/70 of patients with available data were in remission after 104 and 152 weeks, respectively. Increased dosing frequency from every 8 weeks GEMINI 2 to every 4 weeks GEMINI LTS improved outcomes in patients who had withdrawn early from GEMINI 2, with 47% n=27/57 experiencing clinical response and 32% n=18/57 in remission at week 52 of GEMINI LTS up from 39% and 4% before the dose increase. Similar improvements were observed regardless of prior tumour necrosis factor TNF antagonist exposure. Long-term benefits of HRQL were also observed.
The clinical benefits of vedolizumab continued with long-term treatment regardless of prior TNF antagonist exposure. Increased dosing frequency might improve outcomes in patients who lose response to conventional 8-weekly dosing.
Background:
Anti‐tumor necrosis factor (TNF) therapy is an important treatment option for management of active Crohn's disease (CD) and is labeled for use after failure of conventional therapy ...(step‐up). However, there is debate on the introduction of anti‐TNF agents earlier in the treatment strategy (top‐down) to potentially improve clinical outcomes. The aim of this study was to determine if a top‐down approach with anti‐TNF therapy is associated with improved outcomes for patients with active CD.
Methods:
Claims data were from adult patients with CD with continuous enrollment in the same health plan for ≥6 months prior to the initial diagnostic claim for CD, ≥12 months after their initial anti‐TNF claim, and with ≥1 anti‐TNF claims after their initial diagnosis for CD.
Results:
Three patient groups were identified: The Step‐Up group used 5‐aminosalicylates and/or corticosteroids prior to anti‐TNF; the immunosuppression (IS)‐to‐TNF inhibitor group used IS prior to anti‐TNF therapy; the Early‐TNF group initiated anti‐TNF therapy within 30 days of the first prescription for CD. Response to anti‐TNF therapy was determined up to 24 months following anti‐TNF initiation by concomitant corticosteroid use, CD surgery, anti‐TNF dose escalation, and anti‐TNF discontinuation/switch. A top‐down approach to anti‐TNF therapy was associated with a lower risk of concomitant corticosteroid use, anti‐TNF dose escalation, discontinuation/switch of anti‐TNF, and CD‐related surgery compared with the step‐up and IS‐to‐TNF therapy approaches.
Conclusions:
These “real‐world” data show that a top‐down approach to anti‐TNF therapy in CD is associated with reductions in loss of response and fewer surgeries than conventional step‐wise management. (Inflamm Bowel Dis 2012;)
Medications are major cost drivers in the treatment of patients with inflammatory bowel disease. Recent analyses suggest that there is no added efficacy in continuing nor harm in stopping ...5-aminosalicylate (ASA) therapy in patients with inflammatory bowel disease escalated to biological therapies or tofacitinib. We assessed the cost-effectiveness of discontinuing 5-ASA therapy in patients with ulcerative colitis on biological therapies or tofacitinib, compared with continuing 5-ASA therapy.
We performed a cost-effectiveness analysis of 5-ASA with biologic therapy and tofacitinib compared with the same treatment without 5-ASA. Our primary outcome was to determine whether biologic/tofacitinib monotherapy was cost-effective compared with biologic/tofacitinib and 5-ASA combination therapy using the incremental cost-effectiveness ratio at a willingness to pay of $50,000/quality-adjusted life year. Owing to the uncertainty surrounding outcome probabilities, probabilistic sensitivity analyses with 10,000 simulations were also performed. We conducted a sensitivity analysis comparing biologic/tofacitinib and 5-ASA therapy compared with biologic/tofacitinib monotherapy, whereby vedolizumab was the first biologic used, followed by infliximab and finally tofacitinib.
Our model shows that biologic/tofacitinib monotherapy dominates (cheaper and more effective) combination therapy of biologics/tofacitinib with 5-ASA. Probabilistic sensitivity analyses simulations resulted in biologic/tofacitinib monotherapy dominating 100% of the scenarios, with mean cost savings of $24,483.01 over 2 years. When vedolizumab was the first-line therapy in the sensitivity analysis, biologic/tofacitinib monotherapy continued to dominate the combination of 5-ASA and biologic/tofacitinib therapy.
This analysis in patients with ulcerative colitis who require treatment with biologics or tofacitinib demonstrates that continuing 5-ASA therapy is not a cost-effective strategy. Discontinuation of 5-ASA therapy in these patients is safe and less expensive and should be recommended.
Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in ...patients with moderately to severely active Crohn’s disease with inadequate response or intolerance to conventional or biologic therapy.
GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn’s Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm.
Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn’s Disease Activity Index from baseline (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 vs placebo: –36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn’s Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups.
At week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. ClinicalTrials.gov, Number: NCT03466411.
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Guselkumab, an anti-interleukin-23, induced clinically meaningful improvements vs placebo at week 12 in patients with moderately to severely active Crohn’s disease with an inadequate response to, or intolerance to, conventional/biologic therapies.
Abstract
The management of IBD has been highly affected in the context of the COVID-19 pandemic, with restriction of hospitalisations and unprecedented redeployment of health care resources. Hospital ...admissions of IBD patients should be limited to reduce the risks of coronavirus transmission. However, delaying hospitalisation of IBD patients with severe or complicated disease may increase the risk of poor outcomes. Delaying surgery in some cases may increase the risk of disease progression, postoperative morbidity, and disease complications. IBD patients who are infected with SARS-CoV-2 may have a higher risk of poor outcomes than the general population, potentially related to concomitant medications, especially corticosteroids. There is no evidence today that IBD patients with COVID-19 have worse outcomes if they receive immunosuppressant medications including thiopurines, biologics, and novel small molecules. This article summarises recommendations by the international membership of IOIBD regarding hospitalisations of IBD patients, either for active or complicated IBD or for severe COVID-19, and for management of IBD patients according to SARS-CoV-2 infectious status.
Abstract
Background
Despite significant differences in surgical outcomes between pediatric and adult patients with ulcerative colitis (UC) undergoing colectomy, counseling on pediatric outcomes has ...largely been guided by data from adults. We compared differences in pouch survival between pediatric and adult patients who underwent total proctocolectomy with ileal pouch–anal anastomosis (IPAA).
Methods
This was a retrospective single-center study of patients with UC treated with IPAA who subsequently underwent pouchoscopy between 1980 and 2019. Data were collected via electronic medical records. We stratified the study population based on age at IPAA. Differences between groups were assessed using t tests and chi-square tests. Kaplan-Meier curves were used to compare survival probabilities. Differences between groups were assessed using a log-rank test.
Results
We identified 53 patients with UC who underwent IPAA before 19 years of age and 329 patients with UC who underwent IPAA at or after 19 years of age. Subjects who underwent IPAA as children were more likely to require anti-tumor nerosis factor (TNF) postcolectomy compared with adults (41.5% vs 25.8%; P < .05). Kaplan-Meier estimates revealed that pediatric patients who underwent IPAA in the last 10 years had a 5-year pouch survival probability that was 28% lower than that of those who underwent surgery in the 1990s or 2000s (72% vs 100%; P < .001). Further, children who underwent IPAA and received anti-TNF therapies precolectomy had the most rapid progression to pouch failure when compared with anti-TNF–naive children and with adults who were either exposed or naive precolectomy (P < .05).
Conclusions
There are lower rates of pouch survival for children with UC who underwent IPAA following the uptake of anti-TNF therapy compared with both historical pediatric control subjects and contemporary adults.
Lay Summary
Ileal pouch–anal anastomosis is the most common surgical approach for patients with ulcerative colitis undergoing total proctocolectomy. Outcomes are informed by heterogeneous adult data cohorts often predating anti-tumor necrosis factor uptake. We find that for children in the modern era pouch loss occurs at higher rates.
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