Abstract
Background and Aims
This GEMINI 1 post hoc analysis evaluated vedolizumab efficacy for inducing deep remission in patients with ulcerative colitis and correlation between vedolizumab trough ...concentrations and deep remission rates.
Methods
Week 6 vedolizumab responders were re-randomized to placebo or vedolizumab every 8 or 4 weeks. Deep remission at Week 52 was measured using four different definitions from most to least stringent: 1 Mayo Clinic endoscopic score = 0, rectal bleeding score = 0 and decrease or no change from baseline in stool frequency score; 2 endoscopic score ≤1, rectal bleeding score = 0 and stool frequency score = 0; 3 endoscopic score ≤1, rectal bleeding score = 0, decrease or no change from baseline stool frequency score, and total score endoscopic score + rectal bleeding score + stool frequency score ≤1; and 4 endoscopic score ≤1, rectal bleeding score = 0 and stool frequency score ≤1. Steady-state trough vedolizumab serum concentrations were evaluated.
Results
At Week 6, 373 vedolizumab responders were re-randomized to maintenance placebo n = 126 or vedolizumab every 8 n = 122 or 4 n = 125 weeks. Significantly more vedolizumab patients achieved deep remission at Week 52 for the most (placebo 8.7%, every 8 weeks 27.0% p = 0.0001, every 4 weeks 28.0% p < 0.0001) and least (placebo 15.9%, every 8 weeks 43.4% p < 0.0001, every 4 weeks 43.2% p < 0.0001) stringent definitions. Patients with higher vedolizumab trough concentration quartiles had higher deep remission rates all definitions compared with those with the lowest quartile or who received placebo.
Conclusion
Vedolizumab was associated with significantly higher deep remission rates than placebo at Week 52, regardless of deep remission definition NCT00783718.
Background:
Inadequate response to infliximab IFX therapy in Crohn’s disease CD may necessitate dose intensification. We evaluated safety and efficacy of high-dose IFX HD IFX greater than 10mg/kg ...every 8 weeks in CD and characterized predictors of response to HD IFX intensification.
Methods:
Electronic medical records were queried for CD patients between 2010 and 2012 who received HD IFX and were reviewed for history, medications, laboratory data, efficacy, and safety.
Results:
In all, 86 patients received HD IFX for CD at doses between 10 and 22.5mg/kg every 4 to 7 weeks. In early HD IFX therapy week 1–16, 25.8% and 59.1% experienced full and partial response, respectively. In later HD IFX therapy week 38–100, 27.9% and 34.4% experienced full and partial response, respectively. Median serum IFX levels increased from 1.7 to 7.3µ/mL p = 0.017, and median C-reactive protein CRP values decreased from 20.5 at baseline to 4.7mg/L after 16 weeks p < 0.001. Baseline CRP values were significantly elevated in the group that responded at 1–16 weeks compared with nonresponders 22.0 vs 3.5mg/L, p < 0.01. HD IFX therapy was discontinued in 26% and 7.3% of patients for inadequate response and adverse events, respectively. Eleven cases of infection required hospitalization for a serious infection rate of 7.41 events per 100 patient-years.
Conclusions:
HD IFX therapy may benefit CD patients who have failed standard doses of IFX. HD IFX therapy may be associated with more serious adverse events compared with standard dosing. Baseline CRP value may predict clinical response to HD IFX.
In nonresponders to golimumab induction for ulcerative colitis, we assessed clinical response rates and golimumab serum concentrations when the 100-mg dose was used early in the course of ...maintenance.
This post-hoc analysis of golimumab maintenance dosing in the PURSUIT-M study examined clinical outcomes and golimumab concentrations in early Week 6 responders and nonresponders to induction, including subgroups based on body weight.
In nonresponders to golimumab induction assessed at Week 6, the 100-mg maintenance dose starting at Week 6 resulted in a meaningful proportion 28.1% of patients achieving a partial Mayo response at Week 14. After 1 year of maintenance, clinical outcome response, remission, mucosal healing, corticosteroid-free state rates in these "late" Week 14 responders were similar to those in early Week 6 responders. Golimumab concentrations in early nonresponders were approximately half those of early responders, suggesting that early nonresponders had more rapid golimumab clearance. Examined by body weight, the early nonresponders weighing <80 kg and receiving 100 mg had golimumab concentrations similar to the early responders weighing <80 kg or ≥80 kg and receiving 50 mg or 100 mg, respectively.
Early use of the 100-mg maintenance dose leads to positive clinical outcomes in a meaningful proportion of patients who did not respond to golimumab at Week 6. Early nonresponders <80 kg who received the 100-mg maintenance dose achieved adequate golimumab concentrations and a clinically meaningful proportion of these patients had a late clinical response.PURSUIT-M protocol number C0524T18; ClinicalTrials.gov, NCT00488631; EudraCT, 2006-003399-37.
Crohn's disease is a destructive, inflammatory condition. The recent IMPACT survey showed that it has a major impact on quality of life including fatigue, relationships and employment. Although ...patients are generally satisfied with healthcare services, improvements are needed in the timeliness of diagnosis and in communication between patients and healthcare professionals. Evidence is lacking about what constitutes quality of care and value to patients. Moving forward, value should become the primary goal of healthcare delivery, which is likely to require new treatment goals. Indeed, goals are already evolving beyond symptom control towards deep remission, which encompasses clinical remission together with mucosal healing. The ultimate goals are to prevent bowel damage, reduce long-term disability and maintain normal quality of life. A new treat-to-target approach, with increased monitoring and tighter control of symptoms and inflammation, will be needed. This approach will be enabled by use of biomarkers and new indices such as the Lémann score, which assesses the extent and severity of bowel damage at a specific time-point and over time, and a new disability index for patients with inflammatory bowel disease. These principles have been adopted for managing rheumatoid arthritis where there is now a focus on treat-to-target to achieve early remission. Lessons from rheumatoid arthritis can be translated to Crohn's disease.
Background & Aims:
An open study reported that patients with Crohn’s disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is ...discontinued. To confirm this observation, we performed a multicenter, double-blind, noninferiority withdrawal study.
Methods:
Patients who were in clinical remission on azathioprine for ≥42 months were randomized to continue azathioprine or to receive an equivalent placebo for 18 months. The primary end point was clinical relapse at 18 months.
Results:
Forty patients were randomly assigned to receive azathioprine and 43 to receive placebo. Characteristics of patients at entry were similar in the 2 study groups. At 18 months, 3 patients had a relapse in the azathioprine group, and 9 had a relapse in the placebo group. Kaplan-Meier estimates of the relapse rate at 18 months were 8% ± 4% and 21% ± 6%, respectively. The hypothesis that placebo was inferior to azathioprine was not rejected (
P = .195). Among the baseline variables, C-reactive protein level >20 mg/L, time without steroids <50 months, and hemoglobin level <12 g/dL were found to be predictive of relapse in the multivariate analysis.
Conclusions:
This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn’s disease who have been in remission on azathioprine for ≥3.5 years. Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.
Crohn's disease (CD) and ulcerative colitis (UC), the 2 main clinical phenotypes of inflammatory bowel disease (IBD), are diseases that result from a dysregulated immune response to gut microbiota in ...genetically susceptible hosts. This aberrant immune response may intrinsically predispose IBD patients to infectious complications. Moreover, immunosuppressive medications used to treat IBD including corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-tumor necrosis factor (anti-TNF) agents and other biologics, further increase patients' susceptibility to opportunistic infections. Herpes zoster (HZ), also known as shingles, is an opportunistic viral reactivation often observed in IBD patients with several case reports demonstrating complicated or disseminated disease in those on immunosuppression. While HZ vaccination is recommended in all immunocompetent adults aged ≥60 years, as a live virus vaccine, it is currently contraindicated in IBD patients on anti-TNF therapy and in other significantly immunocompromised patient groups. While caution is still warranted in these circumstances, recent clinical data has emerged which has prompted us to review and examine the universal approach to HZ vaccination in the immunosuppressed IBD population. In the following narrative review, we will discuss and provide an overview of the clinical manifestations, incidence, management and prevention of HZ in the IBD patient.
We evaluated the effects of adalimumab maintenance therapy on health-related quality of life (HRQOL) in patients with moderate to severe Crohn's disease.
In a Phase III, randomized, double-blind ...clinical trial (CHARM) of moderate to severe Crohn's disease patients, HRQOL outcomes were compared between the adalimumab maintenance treatment groups (every other week and weekly injection) and the adalimumab induction-only group. The Zung Self-Rating Depression Scale, functional assessment of chronic illness therapy (FACIT)-Fatigue, visual analog pain scales, Inflammatory Bowel Disease questionnaire (IBDQ), and Medical Outcomes Study 36-item Short Form Health Survey (SF-36) were analyzed for 499 randomized responders (a decrease of > or =70 points from baseline in the Crohn's Disease Activity Index CDAI) at baseline and weeks 4, 12, 26, and 56.
CHARM patients' HRQOL was substantially impaired at baseline. Following a 4-week adalimumab induction therapy, patients experienced statistically significant improvements in all HRQOL measures (P < 0.0001). Compared with patients who were assigned to placebo after induction therapy, patients who continued adalimumab at 40 mg every other week maintenance therapy reported less depression (P < 0.01), fewer fatigue symptoms (P < 0.001), greater improvements in the IBDQ (P < 0.05), greater SF-36 physical component summary scores (P < 0.05), and less abdominal pain (P < 0.05) from weeks 12 to 56. They also had greater SF-36 mental component summary scores at week 56 (P < 0.05). Patients who continued adalimumab at 40-mg weekly maintenance therapy reported less depression and fewer fatigue symptoms at week 56, greater improvement in IBDQ, and less abdominal pain from weeks 12 to 56 (all P < 0.05 vs. placebo).
Adalimumab maintenance therapy provided sustained improvements in HRQOL for patients with moderate to severe Crohn's disease through week 56.
Discontinuation of anti–tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be ...influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing.
This was a multicenter, prospective study in adult patients with Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3–4) versus complete (Mayo 0/SES-CD 0–2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use.
Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6–2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate aHR, 3.28; 95% confidence interval CI, 1.43–7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01–0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months.
The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.
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