Outpatient Ulcerative Colitis Primary Anti-TNF Responders Receiving Adalimumab or Infliximab Maintenance Therapy Have Similar Rates of Secondary Loss of Response.

GOALS: To compare the proportion of secondary loss of response to adalimumab and infliximab during maintenance treatment of ulcerative colitis (UC) after primary response to induction therapy. BACKGROUND: The efficacy of anti-tumor necrosis factor-α (TNF-α) therapy used to maintain response in patients with UC after primary response to induction therapy wanes with time, resulting in secondary loss of response. METHODS: A retrospective cohort study evaluating anti-TNF-naive UC outpatients who were primary responders to adalimumab and infliximab induction therapy and who advanced onto a maintenance regimen with the respective anti-TNF agent from 2003 to 2013 was conducted. The primary outcome was the proportion of patients in each treatment group that had secondary loss of response. The secondary outcome was time to secondary loss of response, analyzed by the Kaplan-Meier method analysis. RESULTS: A total of 102 UC primary anti-TNF responders met inclusion criteria. Thirty-six patients (35.3%) were treated with adalimumab and 66 patients (64.7%) with infliximab. Mean follow-up was 139.0 weeks for adalimumab and 158.8 weeks for infliximab. A total of 21/36 (58.3%) adalimumab-treated patients and 39/66 (59.1%) infliximab-treated patients experienced a secondary loss of response during maintenance therapy. Mean time to secondary loss of response was similar for adalimumab (55.8 wk) and infliximab (59.4 wk) (P=0.82). Sex, extent of colitis, previous or concomitant azathioprine, and concurrent corticosteroids with anti-TNF induction were not associated with increased risk of secondary loss of response. CONCLUSIONS: In this real-life cohort of anti-TNF-naive primary responders with UC, the proportion of secondary loss of response and the time to secondary loss of response are similar for adalimumab and infliximab.

Anti-TNF Therapy Within 2 Years of Crohn's Disease Diagnosis Improves Patient Outcomes: A Retrospective Cohort Study.

BACKGROUND: Although biological agents targeting tumor necrosis factor (TNF) alpha are effective in the management of Crohn's disease (CD), use of anti-TNF agents is often delayed until after failure of other treatment modalities, resulting in potentially long delays between diagnosis and initiation of infliximab or adalimumab. We aim to determine if early treatment with anti-TNF agents reduces the rate of surgical resection and clinical secondary loss of response in CD patients. METHODS: A retrospective cohort study was conducted evaluating CD outpatients who were primary responders to anti-TNF therapy, on a maintenance regimen with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first dose of anti-TNF therapy; early initiation was defined as starting anti-TNF therapy within 2 years of diagnosis. The primary outcome was occurrence of surgical resection or clinical secondary loss of response requiring dose escalation. Kaplan-Meier analysis was used to assess time to the primary outcomes. RESULTS: One hundred ninety CD patients met inclusion criteria (100 infliximab, 90 adalimumab). Median follow-up duration was 154.4 weeks (inter quartile range, 106.4-227.8). Fifty-three patients (27.9%) had early initiation of anti-TNF therapy. Fewer patients in the early initiation group required surgery (5.7% versus 30.7%, P < 0.001) or experienced clinical secondary loss of response (45.3% versus 67.2%, P = 0.006). In Kaplan-Meier analysis, early initiation of anti-TNF therapy prolonged time to surgery (P = 0.001) and secondary loss of response (P = 0.006). CONCLUSIONS: In CD patients, early initiation of infliximab or adalimumab within the first 2 years of diagnosis reduces the rate of surgery and secondary loss of response requiring dose escalation.

Similar Clinical and Surgical Outcomes Achieved with Early Compared to Late Anti-TNF Induction in Mild-to-Moderate Ulcerative Colitis: A Retrospective Cohort Study.

Background. Biologic agents targeting tumor necrosis factor alpha are effective in the management of ulcerative colitis (UC), but their use is often postponed until after failure of other treatment modalities. Objectives. We aim to determine if earlier treatment with infliximab or adalimumab alters clinical and surgical outcomes in UC patients. Methods. A retrospective cohort study was conducted evaluating UC outpatients treated with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first anti-TNF exposure; early initiation was defined as starting treatment within three years of diagnosis. Primary outcomes were colectomy, UC-related hospitalization, and clinical secondary loss of response. Kaplan-Meier analysis was used to assess time to the primary outcomes. Results. 115 patients were included (78 infliximab, 37 adalimumab). Median follow-up was 175.6 weeks (IQR 72.4-228.4 weeks). Fifty-seven (49.6%) patients received early anti-TNF therapy; median time to treatment in this group was 38.1 (23.3-91.0) weeks compared to 414.0 (254.0-561.3) weeks in the late initiator cohort (p < 0.0001). Patients treated with early anti-TNF therapy had more severe endoscopic disease at induction (mean Mayo endoscopy subscore 2.46 (SD ± 0.66) versus 1.86 (±0.67), p < 0.001) and trended towards increased risk of colectomy (17.5% versus 8.6%, p = 0.16) and UC-related hospitalization (43.9% versus 27.6%, p = 0.07). In multivariate regression analysis, early anti-TNF induction was not associated with colectomy (HR 2.02 [95% CI: 0.57-7.20]), hospitalization (HR 1.66 [0.84-3.30]), or secondary loss of response (HR 0.86 [0.52-1.42]). Conclusions. Anti-TNF therapy is initiated earlier in patients with severe UC but earlier treatment does not prevent hospitalization, colectomy, or secondary loss of response.

Inflammatory bowel disease patients are frequently nonadherent to scheduled induction and maintenance infliximab therapy: A Canadian cohort study.

BACKGROUND: Adherence to maintenance medication regimens in inflammatory bowel disease patients has traditionally been poor. Although infliximab has demonstrated efficacy in inducing and maintaining disease remission, adherence to regularly scheduled infliximab infusions is required to maintain therapeutic trough drug levels and prevent the development of anti-infliximab antibodies. OBJECTIVES: To characterize patient adherence to regularly scheduled induction and maintenance infliximab infusions. METHODS: A retrospective cohort study was conducted evaluating adult outpatients with Crohn disease or ulcerative colitis on an induction or maintenance regimen of regularly scheduled infliximab from 2008 to 2010 at the University of Alberta (Edmonton, Alberta). Nonadherence was defined by a discrepancy of >72 h between the scheduled date of infusion and the actual date of administration. Patients were defined as nonadherent if they received <80% of their infliximab infusions per schedule. RESULTS: A total of 215 patients (173 Crohn disease, 42 ulcerative colitis) met the inclusion criteria. Patients received a median of 12.0 infliximab infusions (interquartile range 7.0 to 13.0) during the study period; 412 induction and 1837 maintenance infliximab infusions were administered. Of 140 patients, 109 (77.9%) were adherent to their infliximab induction regimen, while 68 of 215 (31.6%) were adherent to their infliximab maintenance regimen. One hundred ninety-eight of 215 (92.1%) patients received at least one delayed maintenance infliximab infusion and 20 (10.1%) received maintenance infusions, on average, >1 week late. CONCLUSIONS: While three-quarters of patients are adherent to infliximab induction therapy, fewer than one-third remained adherent to their scheduled maintenance infliximab regimen.

Knowledge of Fecal Calprotectin and Infliximab Trough Levels Alters Clinical Decision-making for IBD Outpatients on Maintenance Infliximab Therapy.

BACKGROUND: Infliximab is an effective therapy for inflammatory bowel disease (IBD). However, more than 50% of patients lose response. Empiric dose intensification is not effective for all patients because not all patients have objective disease activity or subtherapeutic drug level. The aim was to determine how an objective marker of disease activity or therapeutic drug monitoring affects clinical decisions regarding maintenance infliximab therapy in outpatients with IBD. METHODS: Consecutive patients with IBD on maintenance infliximab therapy were invited to participate by providing preinfusion stool and blood samples. Fecal calprotectin (FCP) and infliximab trough levels (ITLs) were measured by enzyme linked immunosorbent assay. Three decisions were compared: (1) actual clinical decision, (2) algorithmic FCP or ITL decisions, and (3) expert panel decision based on (a) clinical data, (b) clinical data plus FCP, and (c) clinical data plus FCP plus ITL. In secondary analysis, Receiver-operating curves were used to assess the ability of FCP and ITL in predicting clinical disease activity or remission. RESULTS: A total of 36 sets of blood and stool were available for analysis; median FCP 191.5 µg/g, median ITLs 7.3 µg/mL. The actual clinical decision differed from the hypothetical decision in 47.2% (FCP algorithm); 69.4% (ITL algorithm); 25.0% (expert panel clinical decision); 44.4% (expert panel clinical plus FCP); 58.3% (expert panel clinical plus FCP plus ITL) cases. FCP predicted clinical relapse (area under the curve [AUC] = 0.417; 95% confidence interval [CI], 0.197-0.641) and subtherapeutic ITL (AUC = 0.774; 95% CI, 0.536-1.000). ITL predicted clinical remission (AUC = 0.498; 95% CI, 0.254-0.742) and objective remission (AUC = 0.773; 95% CI, 0.622-0.924). CONCLUSIONS: Using FCP and ITLs in addition to clinical data results in an increased number of decisions to optimize management in outpatients with IBD on stable maintenance infliximab therapy.

Crohn's disease outpatients treated with adalimumab have an earlier secondary loss of response and requirement for dose escalation compared to infliximab: a real life cohort study.

BACKGROUND: The efficacy of anti-tumor necrosis factor alpha agents in maintaining remission in Crohn's disease may wane over time, leading to secondary loss of response that can often be overcome with dose escalation. Comparison of secondary loss of response of adalimumab and infliximab during long-term treatment of CD in a real-life IBD clinic has not been previously evaluated. METHODS: A retrospective cohort study was conducted evaluating outpatients with CD on a maintenance regimen with adalimumab or infliximab from 200 to 2013 and who experienced a secondary loss of response. All infliximab-treated patients were anti-TNF naïve. Adalimumab-treated patients were stratified by prior anti-TNF exposure. Kaplan-Meier analysis was conducted to compare time to loss of response. RESULTS: 218 CD patients met inclusion criteria (117 infliximab, 101 adalimumab). Median follow-up duration was 170.0weeks for infliximab and 122.0weeks for adalimumab (p=0.61). The proportion of patients with secondary loss of response was similar for infliximab-treated - 51.3% (60/117) compared to adalimumab patients naïve to anti-TNF therapy - 60.5% (23/38) (p=0.32), and adalimumab patients with prior anti-TNF exposure - 65.1% (41/63) (p=0.08). Median time to secondary loss of response was longer for infliximab patients (99.3wk, IQR 55.7-168.5) compared to both adalimumab patients naïve to anti-TNF therapy (58.9wk, IQR 29.0-85.7) (p=0.03), and adalimumab patients with prior anti-TNF exposure (52.7wk, IQR 20.1-85.0) (p<0.001). CONCLUSIONS: Over 50% of CD patients treated with infliximab and adalimumab develop secondary loss of response. Time to loss of response was shorter in patients treated with adalimumab compared to those treated with infliximab. Prior anti-TNF exposure further accelerated time to loss of response.