Persistence of Second and Third-Line Biologics in Inflammatory Bowel Disease: A Multi-Centre Cohort Study

Background: Despite proven efficacy of biologics in inflammatory bowel disease (IBD), many exhibit primary non-response or secondary loss of response and switch to subsequent biologic(s). Here, we identified early predictors of second- and/or third-line biologic persistence in IBD, in a real-world cohort of patients. Methods: A retrospective multicentre cohort study was conducted on patients receiving second- and/or third-line biologics for IBD from 2005–2021. Cox regression was applied to identify factors predictive of longer cumulative biologic persistence prior to treatment failure. Results: Of 179 patients who received ≥2 biologics, 159 (88.8%) received an anti-tumour necrosis factor (anti-TNF) first-line. There was a significantly increased likelihood of longer treatment persistence in recipients who received an anti-TNF first, versus those that received a non-anti-TNF agent first (p < 0.01). A diagnosis of CD (OR 7.1, 95% CI [2.3–21.7], p < 0.01), and endoscopic remission achieved on the first biologic (OR 10.4 [1.3–79.9], p = 0.03) were positive predictors of longer biologic persistence, whilst advancing age at IBD diagnosis (OR 0.97 [0.94–0.99], p = 0.04) and primary non-response to initial biologic (OR 0.3 [0.1–0.7], p < 0.01) were inversely associated with biologic persistence. Conclusions: These real-world data demonstrate multiple, simple to identify factors that offer the potential for early objectively assessed response to first-line biologic to predict future biologic persistence

Persistence of Second and Third-Line Biologics in Inflammatory Bowel Disease: A Multi-Centre Cohort Study

Background: Despite proven efficacy of biologics in inflammatory bowel disease (IBD), many exhibit primary non-response or secondary loss of response and switch to subsequent biologic(s). Here, we identified early predictors of second- and/or third-line biologic persistence in IBD, in a real-world cohort of patients. Methods: A retrospective multicentre cohort study was conducted on patients receiving second- and/or third-line biologics for IBD from 2005–2021. Cox regression was applied to identify factors predictive of longer cumulative biologic persistence prior to treatment failure. Results: Of 179 patients who received ≥2 biologics, 159 (88.8%) received an anti-tumour necrosis factor (anti-TNF) first-line. There was a significantly increased likelihood of longer treatment persistence in recipients who received an anti-TNF first, versus those that received a non-anti-TNF agent first (p p p = 0.03) were positive predictors of longer biologic persistence, whilst advancing age at IBD diagnosis (OR 0.97 [0.94–0.99], p = 0.04) and primary non-response to initial biologic (OR 0.3 [0.1–0.7], p < 0.01) were inversely associated with biologic persistence. Conclusions: These real-world data demonstrate multiple, simple to identify factors that offer the potential for early objectively assessed response to first-line biologic to predict future biologic persistence

Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α

IntroductionWe evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab.MethodsBaseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein&lt;3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD&lt;3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models.Results and discussionIn 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance&gt;0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p&lt;0.001, and OR=1.9, 95%CI: 1.4-2.8; p&lt;0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p&lt;0.01) higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p&lt;0.01) and lower clinical and biochemical remission (p&lt;0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p&lt;0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p&lt;0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p&lt;0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD

DataSheet_1_Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.docx

IntroductionWe evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab.MethodsBaseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive proteinResults and discussionIn 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.01) higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD.</p

Endoscopic Postoperative Recurrence In Crohn's Disease After Curative Ileocecal Resection With Early Prophylaxis By Anti-Tnf, Vedolizumab Or Ustekinumab: A Real-World Multicenter European Study

Background: Endoscopic-post-operative-recurrence [ePOR] in Crohn's disease [CD] after ileocecal resection [ICR] is a major concern. We aimed to evaluate the effectiveness of early prophylaxis with biologics and to compare anti-tumour necrosis factor [anti-TNF] therapy to vedolizumab [VDZ] and ustekinumab [UST] in a real-world setting.Methods: A retrospective multicentre study of CD-adults after curative ICR on early prophylaxis was undertaken. ePOR was defined as a Rutgeerts score [RS] &gt;= i2 or colonic-segmental-SES-CD &gt;= 6. Multivariable logistic regression was used to evaluate risk factors, and inverse probability treatment weighting [IPTW] was applied to compare the effectiveness between agents.Results: The study included 297 patients (53.9% males, age at diagnosis 24 years [19-32], age at ICR 34 years 126-431, 18.5% smokers, 276% biologic-naive, 65.7% anti-TNF experienced, 28.6% two or more biologics and 17.2% previous surgery). Overall, 224, 39 and 34 patients received anti-TNF, VDZ or UST, respectively. Patients treated with VDZ and UST were more biologic experienced with higher rates of previous surgery. ePOR rates within 1 year were 41.8%. ePOR rates by treatment groups were: anti-TNF 40.2%, VDZ 33% and UST 61.8%. Risk factors for ePOR at 1 year were: past-infliximab (adjusted odds ratio [adj.OR] = 1.73 [95% confidence interval, CI: 1.01-2.97]), past-adalimumab [adj.OR = 2.32 [95% CI: 1.35-4.01] and surgical aspects. After IPTW, the risk of ePOR within 1 year of VDZ vs anti-TNF or UST vs anti-TNF was comparable (OR = 0.55 [95% CI: 0.25-1.19], OR = 1.86 [95% CI: 0.79-4.381), respectively.Conclusion. Prevention of ePOR within 1 year after surgery was successful in -60% of patients. Patients treated with VDZ or UST consisted of a more refractory group. After controlling for confounders, no differences in ePOR risk were seen between anti-TNF prophylaxis and other groups