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/lp/ou_press/proactive-infliximab-monitoring-following-reactive-testing-is-IzlhjZ9McK
- Publisher
- Oxford University Press
- Copyright
- Copyright © 2022 European Crohn's and Colitis Organisation (ECCO) Published by Oxford University Press
- ISSN
- 1873-9946
- eISSN
- 1876-4479
- DOI
- 10.1093/ecco-jcc/jjy039
- pmid
- 29590345
- Publisher site
- See Article on Publisher Site
Abstract
Abstract Background and Aims Reactive testing has emerged as the new standard of care for managing loss of response to infliximab in inflammatory bowel disease [IBD]. Recent data suggest that proactive infliximab monitoring is associated with better therapeutic outcomes in IBD. Nevertheless, there are no data regarding the clinical utility of proactive infliximab monitoring after first reactive testing. We aimed to evaluate long-term outcomes of proactive infliximab monitoring following reactive testing compared with reactive testing alone in patients with IBD. Methods This was a retrospective multicenter cohort study of consecutive IBD patients on infliximab maintenance therapy receiving a first reactive testing between September 2006 and January 2015. Patients were divided into two groups; Group A [proactive infliximab monitoring after reactive testing] and Group B [reactive testing alone]. Patients were followed through December 2015. Time-to-event analysis for treatment failure and IBD-related surgery and hospitalization was performed. Treatment failure was defined as drug discontinuation due to either loss of response or serious adverse event. Results The study population consisted of 102 [n = 70, 69% with CD] patients [Group A, n = 33 and Group B, n = 69] who were followed for (median, interquartile range [IQR]) 2.7 [1.4–3.8] years. Multiple Cox regression analysis identified proactive following reactive TDM as independently associated with less treatment failure (hazard ratio [HR] 0.15; 95% confidence interval [CI] 0.05–0.51; p = 0.002) and fewer IBD-related hospitalizations [HR: 0.18; 95% CI 0.05–0.99; p = 0.007]. Conclusions This study showed that proactive infliximab monitoring following reactive testing was associated with greater drug persistence and fewer IBD-related hospitalizations than reactive testing alone. Crohn’s disease, ulcerative colitis, immunogenicity, anti-TNF therapy 1. Introduction Anti-TNF drugs are effective for the treatment of moderate-to-severe inflammatory bowel disease [IBD]: Crohn’s disease [CD] and ulcerative colitis [UC].1,2 Nevertheless, up to half of patients lose response over time or develop a serious adverse event [SAE], such as a serious infusion reaction [SIR], necessitating drug cessation.3 Therapeutic drug monitoring [TDM], defined as the evaluation of drug concentration and anti-drug antibodies, has rationalized the management of secondary loss of response [SLR] of anti-TNF therapy and is more cost-effective when compared with empiric dose escalation.4–10 Moreover, reactive TDM for optimizing infliximab therapy is associated with better endoscopic outcomes than clinical decision-making alone.11 Recent studies have demonstrated that proactive TDM with drug titration to a target trough concentration is associated with better clinical outcomes when compared with standard of care or reactive TDM.12–14 Nevertheless, there are no data regarding the clinical utility of initiating proactive infliximab monitoring after having performed reactive testing in IBD patients with SLR. Thus, the aim of this study was to evaluate long-term outcomes of proactive infliximab monitoring after first reactive testing compared with reactive testing alone in patients with IBD. The investigated outcomes of interest were treatment failure and IBD-related surgery and hospitalization. 2. Materials and Methods 2.1. Study design and population This was a retrospective multicenter cohort study. Consecutive IBD patients on infliximab maintenance therapy who underwent a first reactive testing in the period between September 2006 and January 2015 were eligible for the study. Exclusion criteria were total colectomy with an ileal pouch–anal anastomosis or permanent ostomy prior to infliximab TDM, no follow-up visit after first reactive TDM, a long [≥4 months] drug holiday during infliximab maintenance therapy and treatment failure within 6 months following first reactive testing. The patients were divided into two groups. Group A consisted of patients undergoing proactive infliximab monitoring with the aim of prospectively titrating infliximab, typically to a target trough concentration of 5–10 mg/mL, after reactive testing had been performed for either presumed loss of response or an infusion reaction, while Group B consisted of patients undergoing reactive testing alone, currently considered as standard of care. Patients were followed through December 2015. Therapeutic decisions were made at each physician’s discretion and were reflective of real-life clinical practice. Demographic and clinical characteristics of and outcomes for the patients were acquired from their electronic medical records. The study was approved by the Institutional Review Boards of the Beth Israel Deaconess Medical Center [BIDMC], Harvard Medical School, Boston, Massachusetts and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 2.2. Definitions Treatment failure was defined as infliximab discontinuation for loss of response or SAE. Inflammatory bowel disease–related surgery was defined as any intestinal or perianal surgical procedure performed for underlying IBD.14 Inflammatory bowel disease–related hospitalization was defined as any hospitalization with IBD as the primary diagnosis, not associated with drug effects or other conditions, as previously described.14 An SIR was defined as any acute or delayed infusion reaction necessitating infliximab discontinuation. The study observation time for IBD-related surgery and hospitalization was set from start of infliximab TDM until treatment failure or the end of follow-up. 2.3. Infliximab trough concentrations and antibodies to infliximab Serum infliximab concentrations and antibodies to infliximab [ATIs] were measured by Prometheus Laboratories [San Diego, CA]. The study period overlapped with the use of two methods of TDM: a drug-sensitive in-house-developed enzyme-linked immunosorbent assay [ELISA] until July 2012, followed by the drug-tolerant homogeneous mobility shift assay [HMSA].15 Infliximab concentrations of <1 and 1.4 µg/mL and ATIs < 3.1 U/mL and 1.7 µg/mL equivalents were considered as undetectable for the HMSA and ELISA, respectively. 2.4. Statistical analysis Descriptive statistics were provided with median and interquartile range [IQR] for continuous variables, and frequency and percentages for categorical variables. Continuous and discrete variables were compared between the two groups using the Mann–Whitney U test and the chi-square or Fisher’s Exact test, as appropriate, respectively. A time-to-event [survival] analysis for treatment failure and IBD-related surgery and hospitalization was performed. Kaplan–Meier estimates were used to draw the cumulative incidence curves compared by log-rank test. Univariable and multivariable Cox proportional hazards regression analyses were also performed to determine the independent effects of variables associated with therapeutic outcomes of interest. Only variables with a p-value of <0.1 from the univariable analysis entered the multivariable analysis, which was based on the Wald backward selection method. The results for the statistically significant variables were expressed as hazard ratios [HRs] with 95% confidence intervals [CI] followed by the corresponding p-value. Results were considered statistically significant when p was <0.05. All statistical analyses were performed using the SPSS 23.0 software [SPSS, Chicago, IL, USA] and GraphPad Prism version 5.03 for Windows [GraphPad Software, San Diego, CA, USA]. 3. Results 3.1. Study population The study population consisted of 102 patients [CD: n = 70, 69%; BIDMC: n = 70] [Figure 1] divided into two groups as previously described: Group A [n = 33] and Group B [n = 69]. The patients were followed for a median of 2.7 [IQR 1.4–3.8] years. Patients’ baseline characteristics were comparable between the two groups [Table 1]. The indication for first reactive TDM was presumed SLR [n = 91, 89%] or infusion reaction (n = 11, acute [n = 5] or delayed [n = 6]). The proactive TDM group had a longer follow-up than the reactive TDM alone group (median 3.7 [IQR: 2.7–4.7] vs 2.2 [IQR: 1.4–3.3] years, p = 0.001). Patients of Group A underwent a median of 3 [range 1–7] proactive infliximab monitoring evaluations after first reactive testing, most of whom [23/33, 70%] had more than one follow-up concentration. The median time between different assessments was 8 [IQR: 6–13] months, and the interval was not the same for all patients, reflective of real-life clinical practice. About half of the patients [16/33, 48%] were exclusively followed with the HMSA, while the others were monitored initially with the ELISA and subsequently with the HMSA. At first proactive infliximab monitoring, the vast majority of patients [31/33, 94%] had a trough infliximab concentration of >5 μg/mL, and upon further dose optimization and repeat proactive TDM, all patients attained a trough infliximab concentration of >5 μg/mL. At last available sample, 21/23 [91%] patients had a trough infliximab concentration trough of >5 μg/mL. Figure 1. Open in new tabDownload slide Flow chart of the study population. IBD: inflammatory bowel disease; TDM: therapeutic drug monitoring; IPAA: ileal pouch–anal anastomosis. Table 1. Baseline characteristics of the study cohort Patient characteristics . Total cohort [N = 102] . Group A [N = 33] . Group B [N = 69] . p-value . Male, [%] 54 [53] 16 [48] 38 [55] 0.672 Age at diagnosis, median [IQR], years 22 [18–31] 22 [18–31] 22 [18–32] 0.758 Age at start of IFX, median [IQR], years 33 [25–43] 37 [31–46] 30 [24–43] 0.072 Disease duration, median [IQR], months 15 [8–40] 13 [5–42] 18 [8–38] 0.411 IBD type, [%] 0.562 CD 70 [69] 24 [73] 46 [67] UC 30 [29] 9 [27] 21 [30] IBDU 2 [2] 0 [0] 2 [3] UC extensiona, [%] 0.694 E1 [proctitis] 0/30 [0] 0/9 [0] 0/21 [0] E2 [left-sided colitis] 14/30 [47] 5/9 [56] 9/21 [43] E3 [pancolitis] 16/30 [53] 4/9 [44] 12/21 [57] CD locationa, [%] 0.787 L1 [ileal] 13/70 [19] 5/24 [21] 8/46 [17] L2 [colonic] 23/70 [33] 6/24 [25] 17/46 [37] L3 [ileocolonic] 33/70 [47] 12/24 [50] 19/46 [41] L4 [upper GI disease] 3/70 [1] 1/24 [4] 2/46 [5] CD behaviora, [%] 0.486 B1 [non-stricturing, non-penetrating] 36/70 [51] 11/24 [46] 25/46 [54] B2 [stricturing] 14/70 [20] 4/24 [16] 10/46 [22] B3 [penetrating] 20/70 [29] 9/24 [38] 11/46 [24] Perianal fistulizing disease, [%] 30/70 [43] 12/24 [50] 18/46 [39] 0.450 Prior ileocolonic resection, [%] 16/70 [23] 7/24 [29] 9/46 [20] 0.383 Smoking ever, [%] 21 [21] 8 [24] 13 [19] 0.603 IFX dosing other than 5 mg/kg q8wb, [%] 46 [45] 14 [42] 32 [46] 0.832 Anti-TNF naïve, [%] 95 [93] 30 [91] 65 [94] 0.679 Concomitant IMMsb, [%] 32 [31] 12 [36] 20 [29] 0.498 Thiopurines 22/32 [69] 8/12 [67] 14/20 [70] Methotrexate 10/32 [31] 4/12 [33] 6/20 [30] Indication for first reactive TDM, [%] 0.496 SLR 91 [89] 31 [94] 60 [87] IR 11 [11] 2 [6] 9 [13] IFX concentrationb, median, [IQR], μg/ml 6.2 [1.5–11] 6.4 [2.4–11.1] 5.4 [1.4–11.1] 0.646 ATIb, [%] 18 [18] 4 [12] 14 [20] 0.410 Type of assayb: HMSA, [%] 48 [47] 12 [36] 36 [52] 0.145 Patient characteristics . Total cohort [N = 102] . Group A [N = 33] . Group B [N = 69] . p-value . Male, [%] 54 [53] 16 [48] 38 [55] 0.672 Age at diagnosis, median [IQR], years 22 [18–31] 22 [18–31] 22 [18–32] 0.758 Age at start of IFX, median [IQR], years 33 [25–43] 37 [31–46] 30 [24–43] 0.072 Disease duration, median [IQR], months 15 [8–40] 13 [5–42] 18 [8–38] 0.411 IBD type, [%] 0.562 CD 70 [69] 24 [73] 46 [67] UC 30 [29] 9 [27] 21 [30] IBDU 2 [2] 0 [0] 2 [3] UC extensiona, [%] 0.694 E1 [proctitis] 0/30 [0] 0/9 [0] 0/21 [0] E2 [left-sided colitis] 14/30 [47] 5/9 [56] 9/21 [43] E3 [pancolitis] 16/30 [53] 4/9 [44] 12/21 [57] CD locationa, [%] 0.787 L1 [ileal] 13/70 [19] 5/24 [21] 8/46 [17] L2 [colonic] 23/70 [33] 6/24 [25] 17/46 [37] L3 [ileocolonic] 33/70 [47] 12/24 [50] 19/46 [41] L4 [upper GI disease] 3/70 [1] 1/24 [4] 2/46 [5] CD behaviora, [%] 0.486 B1 [non-stricturing, non-penetrating] 36/70 [51] 11/24 [46] 25/46 [54] B2 [stricturing] 14/70 [20] 4/24 [16] 10/46 [22] B3 [penetrating] 20/70 [29] 9/24 [38] 11/46 [24] Perianal fistulizing disease, [%] 30/70 [43] 12/24 [50] 18/46 [39] 0.450 Prior ileocolonic resection, [%] 16/70 [23] 7/24 [29] 9/46 [20] 0.383 Smoking ever, [%] 21 [21] 8 [24] 13 [19] 0.603 IFX dosing other than 5 mg/kg q8wb, [%] 46 [45] 14 [42] 32 [46] 0.832 Anti-TNF naïve, [%] 95 [93] 30 [91] 65 [94] 0.679 Concomitant IMMsb, [%] 32 [31] 12 [36] 20 [29] 0.498 Thiopurines 22/32 [69] 8/12 [67] 14/20 [70] Methotrexate 10/32 [31] 4/12 [33] 6/20 [30] Indication for first reactive TDM, [%] 0.496 SLR 91 [89] 31 [94] 60 [87] IR 11 [11] 2 [6] 9 [13] IFX concentrationb, median, [IQR], μg/ml 6.2 [1.5–11] 6.4 [2.4–11.1] 5.4 [1.4–11.1] 0.646 ATIb, [%] 18 [18] 4 [12] 14 [20] 0.410 Type of assayb: HMSA, [%] 48 [47] 12 [36] 36 [52] 0.145 aMontreal classification; bat start of therapeutic drug monitoring. IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; CI: confidence interval; IFX: infliximab; IMM: immunomodulator; TNF: tumor necrosis factor; ATI: antibodies to infliximab; IQR: interquartile range; HMSA: homogeneous mobility shift assay; w: week; IR: infusion reaction; SLR: secondary loss of response; TDM: therapeutic drug monitoring. Open in new tab Table 1. Baseline characteristics of the study cohort Patient characteristics . Total cohort [N = 102] . Group A [N = 33] . Group B [N = 69] . p-value . Male, [%] 54 [53] 16 [48] 38 [55] 0.672 Age at diagnosis, median [IQR], years 22 [18–31] 22 [18–31] 22 [18–32] 0.758 Age at start of IFX, median [IQR], years 33 [25–43] 37 [31–46] 30 [24–43] 0.072 Disease duration, median [IQR], months 15 [8–40] 13 [5–42] 18 [8–38] 0.411 IBD type, [%] 0.562 CD 70 [69] 24 [73] 46 [67] UC 30 [29] 9 [27] 21 [30] IBDU 2 [2] 0 [0] 2 [3] UC extensiona, [%] 0.694 E1 [proctitis] 0/30 [0] 0/9 [0] 0/21 [0] E2 [left-sided colitis] 14/30 [47] 5/9 [56] 9/21 [43] E3 [pancolitis] 16/30 [53] 4/9 [44] 12/21 [57] CD locationa, [%] 0.787 L1 [ileal] 13/70 [19] 5/24 [21] 8/46 [17] L2 [colonic] 23/70 [33] 6/24 [25] 17/46 [37] L3 [ileocolonic] 33/70 [47] 12/24 [50] 19/46 [41] L4 [upper GI disease] 3/70 [1] 1/24 [4] 2/46 [5] CD behaviora, [%] 0.486 B1 [non-stricturing, non-penetrating] 36/70 [51] 11/24 [46] 25/46 [54] B2 [stricturing] 14/70 [20] 4/24 [16] 10/46 [22] B3 [penetrating] 20/70 [29] 9/24 [38] 11/46 [24] Perianal fistulizing disease, [%] 30/70 [43] 12/24 [50] 18/46 [39] 0.450 Prior ileocolonic resection, [%] 16/70 [23] 7/24 [29] 9/46 [20] 0.383 Smoking ever, [%] 21 [21] 8 [24] 13 [19] 0.603 IFX dosing other than 5 mg/kg q8wb, [%] 46 [45] 14 [42] 32 [46] 0.832 Anti-TNF naïve, [%] 95 [93] 30 [91] 65 [94] 0.679 Concomitant IMMsb, [%] 32 [31] 12 [36] 20 [29] 0.498 Thiopurines 22/32 [69] 8/12 [67] 14/20 [70] Methotrexate 10/32 [31] 4/12 [33] 6/20 [30] Indication for first reactive TDM, [%] 0.496 SLR 91 [89] 31 [94] 60 [87] IR 11 [11] 2 [6] 9 [13] IFX concentrationb, median, [IQR], μg/ml 6.2 [1.5–11] 6.4 [2.4–11.1] 5.4 [1.4–11.1] 0.646 ATIb, [%] 18 [18] 4 [12] 14 [20] 0.410 Type of assayb: HMSA, [%] 48 [47] 12 [36] 36 [52] 0.145 Patient characteristics . Total cohort [N = 102] . Group A [N = 33] . Group B [N = 69] . p-value . Male, [%] 54 [53] 16 [48] 38 [55] 0.672 Age at diagnosis, median [IQR], years 22 [18–31] 22 [18–31] 22 [18–32] 0.758 Age at start of IFX, median [IQR], years 33 [25–43] 37 [31–46] 30 [24–43] 0.072 Disease duration, median [IQR], months 15 [8–40] 13 [5–42] 18 [8–38] 0.411 IBD type, [%] 0.562 CD 70 [69] 24 [73] 46 [67] UC 30 [29] 9 [27] 21 [30] IBDU 2 [2] 0 [0] 2 [3] UC extensiona, [%] 0.694 E1 [proctitis] 0/30 [0] 0/9 [0] 0/21 [0] E2 [left-sided colitis] 14/30 [47] 5/9 [56] 9/21 [43] E3 [pancolitis] 16/30 [53] 4/9 [44] 12/21 [57] CD locationa, [%] 0.787 L1 [ileal] 13/70 [19] 5/24 [21] 8/46 [17] L2 [colonic] 23/70 [33] 6/24 [25] 17/46 [37] L3 [ileocolonic] 33/70 [47] 12/24 [50] 19/46 [41] L4 [upper GI disease] 3/70 [1] 1/24 [4] 2/46 [5] CD behaviora, [%] 0.486 B1 [non-stricturing, non-penetrating] 36/70 [51] 11/24 [46] 25/46 [54] B2 [stricturing] 14/70 [20] 4/24 [16] 10/46 [22] B3 [penetrating] 20/70 [29] 9/24 [38] 11/46 [24] Perianal fistulizing disease, [%] 30/70 [43] 12/24 [50] 18/46 [39] 0.450 Prior ileocolonic resection, [%] 16/70 [23] 7/24 [29] 9/46 [20] 0.383 Smoking ever, [%] 21 [21] 8 [24] 13 [19] 0.603 IFX dosing other than 5 mg/kg q8wb, [%] 46 [45] 14 [42] 32 [46] 0.832 Anti-TNF naïve, [%] 95 [93] 30 [91] 65 [94] 0.679 Concomitant IMMsb, [%] 32 [31] 12 [36] 20 [29] 0.498 Thiopurines 22/32 [69] 8/12 [67] 14/20 [70] Methotrexate 10/32 [31] 4/12 [33] 6/20 [30] Indication for first reactive TDM, [%] 0.496 SLR 91 [89] 31 [94] 60 [87] IR 11 [11] 2 [6] 9 [13] IFX concentrationb, median, [IQR], μg/ml 6.2 [1.5–11] 6.4 [2.4–11.1] 5.4 [1.4–11.1] 0.646 ATIb, [%] 18 [18] 4 [12] 14 [20] 0.410 Type of assayb: HMSA, [%] 48 [47] 12 [36] 36 [52] 0.145 aMontreal classification; bat start of therapeutic drug monitoring. IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; CI: confidence interval; IFX: infliximab; IMM: immunomodulator; TNF: tumor necrosis factor; ATI: antibodies to infliximab; IQR: interquartile range; HMSA: homogeneous mobility shift assay; w: week; IR: infusion reaction; SLR: secondary loss of response; TDM: therapeutic drug monitoring. Open in new tab 3.2. Treatment failure Twenty-eight [27%] patients overall had a treatment failure. Three [9%] patients in Group A [proactive infliximab monitoring after reactive testing] had treatment failure, compared with 25 [36%] patients in Group B [reactive testing alone]. Treatment failure was attributed to loss of response [Group A, n = 2 and Group B, n = 19] or SAE (Group A, n = 1 [low-grade colonic dysplasia] and Group B, acute SIR [n = 4]; delayed SIR [n = 2] 3 of whom had detectable ATIs). Kaplan–Meier analysis demonstrated a statistically significantly lower cumulative probability of treatment failure in Group A compared with Group B [p = 0.001, Figure 2], which was true both for CD [Figure 3A] and UC [Figure 3B]. This was also the case for patients with CD and a previous ileocolonic resection [Supplementary Figure 1A] or perianal fistulizing CD [Supplementary Figure 1B]. The first and third year cumulative probability of treatment failure in Group A was 0% and 3.4% (standard error [SE] 0.034) compared with 19.2% [SE 0.048] and 43% [SE 0.072] in Group B, respectively. Multiple Cox regression analysis identified the following variables to be independently associated with treatment failure: preemptive after reactive infliximab monitoring [HR 0.15; 95% CI 0.05–0.51; p = 0.002], type of IBD [UC vs CD] [HR 3.9; 95% CI 1.7–8.9; p = 0.001], male gender [HR 5.3; 95% CI 2.1–13.7; p = 0.001] and infliximab concentration at first reactive TDM [HR 0.89; 95% CI 0.82–0.97; p = 0.006] [Table 2]. Figure 2. Open in new tabDownload slide Kaplan–Meier cumulative probability curves of treatment failure in patients with proactive infliximab monitoring after reactive testing [solid line] or patients with reactive testing alone [dotted line]. IFX: infliximab; TDM: therapeutic drug monitoring. Figure 3. Open in new tabDownload slide Kaplan–Meier cumulative probability curves of treatment failure in patients with proactive infliximab monitoring after reactive testing [solid line] or patients with reactive testing alone [dotted line] stratified by the type of IBD; Crohn’s disease [A] or ulcerative colitis [B]. IFX: infliximab; TDM: therapeutic drug monitoring. Table 2. Variables associated with treatment failure . Univariable analysis . Multivariable analysis . Variables . p . HR . 95% CI . p . HR . 95% CI . Male 0.013 3 1.3–7 0.001 5.3 2.1–13.7 IBD type [UC vs CD] 0.010 2.7 1.3–5.8 0.001 3.9 1.7–8.9 CD locationa 0.281 CD behaviora 0.657 Age at diagnosis 0.461 Age at start of IFX 0.439 Disease duration 0.433 UC extensiona 0.264 Perianal fistulizing disease 0.293 Prior ileocolonic resection 0.549 Concomitant IMMsb 0.094 Anti-TNF naïve 0.685 Smoking ever 0.524 IFX dosing other than 5 mg/kg q8wb 0.422 IFX concentrationb 0.039 0.93 0.87–0.99 0.006 0.89 0.82–0.97 ATIb 0.845 Proactive IFX monitoring following reactive testing 0.001 0.17 0.05–0.55 0.002 0.15 0.05–0.51 Center 0.503 Type of assayb 0.243 . Univariable analysis . Multivariable analysis . Variables . p . HR . 95% CI . p . HR . 95% CI . Male 0.013 3 1.3–7 0.001 5.3 2.1–13.7 IBD type [UC vs CD] 0.010 2.7 1.3–5.8 0.001 3.9 1.7–8.9 CD locationa 0.281 CD behaviora 0.657 Age at diagnosis 0.461 Age at start of IFX 0.439 Disease duration 0.433 UC extensiona 0.264 Perianal fistulizing disease 0.293 Prior ileocolonic resection 0.549 Concomitant IMMsb 0.094 Anti-TNF naïve 0.685 Smoking ever 0.524 IFX dosing other than 5 mg/kg q8wb 0.422 IFX concentrationb 0.039 0.93 0.87–0.99 0.006 0.89 0.82–0.97 ATIb 0.845 Proactive IFX monitoring following reactive testing 0.001 0.17 0.05–0.55 0.002 0.15 0.05–0.51 Center 0.503 Type of assayb 0.243 aMontreal Classification; bat start of therapeutic drug monitoring. IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; HR: hazard ratio; CI: confidence interval; IFX: infliximab; IMM: immunomodulator; TNF: tumor necrosis factor; ATI: antibodies to infliximab; w: week. Open in new tab Table 2. Variables associated with treatment failure . Univariable analysis . Multivariable analysis . Variables . p . HR . 95% CI . p . HR . 95% CI . Male 0.013 3 1.3–7 0.001 5.3 2.1–13.7 IBD type [UC vs CD] 0.010 2.7 1.3–5.8 0.001 3.9 1.7–8.9 CD locationa 0.281 CD behaviora 0.657 Age at diagnosis 0.461 Age at start of IFX 0.439 Disease duration 0.433 UC extensiona 0.264 Perianal fistulizing disease 0.293 Prior ileocolonic resection 0.549 Concomitant IMMsb 0.094 Anti-TNF naïve 0.685 Smoking ever 0.524 IFX dosing other than 5 mg/kg q8wb 0.422 IFX concentrationb 0.039 0.93 0.87–0.99 0.006 0.89 0.82–0.97 ATIb 0.845 Proactive IFX monitoring following reactive testing 0.001 0.17 0.05–0.55 0.002 0.15 0.05–0.51 Center 0.503 Type of assayb 0.243 . Univariable analysis . Multivariable analysis . Variables . p . HR . 95% CI . p . HR . 95% CI . Male 0.013 3 1.3–7 0.001 5.3 2.1–13.7 IBD type [UC vs CD] 0.010 2.7 1.3–5.8 0.001 3.9 1.7–8.9 CD locationa 0.281 CD behaviora 0.657 Age at diagnosis 0.461 Age at start of IFX 0.439 Disease duration 0.433 UC extensiona 0.264 Perianal fistulizing disease 0.293 Prior ileocolonic resection 0.549 Concomitant IMMsb 0.094 Anti-TNF naïve 0.685 Smoking ever 0.524 IFX dosing other than 5 mg/kg q8wb 0.422 IFX concentrationb 0.039 0.93 0.87–0.99 0.006 0.89 0.82–0.97 ATIb 0.845 Proactive IFX monitoring following reactive testing 0.001 0.17 0.05–0.55 0.002 0.15 0.05–0.51 Center 0.503 Type of assayb 0.243 aMontreal Classification; bat start of therapeutic drug monitoring. IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; HR: hazard ratio; CI: confidence interval; IFX: infliximab; IMM: immunomodulator; TNF: tumor necrosis factor; ATI: antibodies to infliximab; w: week. Open in new tab Mucosal healing data was only available for 12 out of 33 patients who underwent proactive dose optimization following initial reactive TDM. Eight out of 12 [67%] patients achieved complete mucosal healing during the study period, defined as a Mayo endoscopic sub-score of ≤1 for UC, absence of any mucosal break [ulceration or erosion] for CD, or a Rutgeerts score of ≤i1 for patients with a previous ileocolonic resection. 3.3. IBD-related surgery Nine [9%] patients underwent an IBD-related surgery. One [3%] patient in Group A had an IBD-related surgery versus 8 [12%] patients in Group B. Kaplan–Meier analysis demonstrated a numerically lower cumulative probability of an IBD-related surgery in Group A that approached statistical significance [p = 0.066, Figure 4A]. The first and third year cumulative probability of IBD-related surgery in Group A was 0% compared with 7.7% [SE 0.033] and 16.4% [SE 0.057] in Group B, respectively. Multiple Cox regression analysis did not identify any variables independently associated with IBD-related surgery [Supplementary Table 1]. Figure 4 Open in new tabDownload slide Kaplan–Meier cumulative probability curves of IBD-related surgery [A] and hospitalization [B] in patients with proactive infliximab monitoring after reactive testing [solid line] or patients with reactive testing alone [dotted line]. IBD: inflammatory bowel disease; IFX: infliximab; TDM: therapeutic drug monitoring. 3.4. IBD-related hospitalization Eighteen [18%] patients overall had an IBD-related hospitalization. Two [6%] patients in Group A had an IBD-related hospitalization, compared with 16 [23%] patients in Group B. The total number and days of IBD-related hospitalizations were also lower in Group A compared with in Group B [3 vs 18, p = 0.042 and 12 vs 74, p = 0.041, respectively]. Kaplan–Meier analysis demonstrated a statistically significantly lower cumulative probability of an IBD-related hospitalization in Group A compared with Group B [p = 0.011, Figure 4B]. The first and third year cumulative probability of IBD-related hospitalization in Group A was 3% [SE 0.03] compared with 10.7% [SE 0.038] and 31.2% [SE 0.070] in Group B, respectively. Multiple Cox regression analysis identified at least one proactive following reactive TDM [HR 0.18; 95% CI 0.05–0.99; p = 0.007] as the only variable independently associated with IBD-related hospitalization [Supplementary Table 2]. 4. Discussion Reactive TDM has emerged as the new standard of care for optimizing anti-TNF therapy in IBD because it can efficiently treat SLR and is more cost-effective when compared with empiric symptoms-based dose escalation.16 However, recent studies suggest that proactive TDM is also associated with more favorable therapeutic outcomes, even compared with reactive TDM.12–14 To our knowledge, this is the first study to demonstrate the clinical utility of proactive infliximab monitoring [dosing to a therapeutic window of >5 μg/ml] following reactive testing in IBD. We demonstrated that this therapeutic strategy of continued optimization was associated with greater drug persistence and fewer IBD-related hospitalizations compared with reactive testing alone, which is currently the standard of care. A single-center, retrospective study by our group was the first to demonstrate the long-term benefit in terms of greater drug persistence of proactive TDM of infliximab with the goal of dosing the drug to a therapeutic window of 5–10 μg/mL compared with blind treatment optimization or reactive TDM.13 The landmark TAXIT [Trough level Adapted infliXImab Treatment] randomized controlled trial showed that there was less need for rescue therapy and were fewer undetectable infliximab trough concentrations in patients undergoing proactive TDM-based optimization of infliximab compared with in clinically dosed patients.12 Additionally, dose escalation in patients with infliximab trough concentrations <3 μg/mL at screening resulted in a higher proportion of CD patients in remission, with a decrease in C-reactive protein when compared with the level pre-optimization.12 Recently, in a large multicenter retrospective cohort study, we demonstrated that proactive TDM improved objective therapeutic outcomes, such as greater drug durability, lower risk of ATIs or SIRs and less need for IBD-related surgery or hospitalization, when compared with reactive TDM.14 The latter, along with the application of a de-escalation therapeutic strategy, in patients with supra-therapeutic drug concentrations guided by proactive TDM can potentially decrease the cost of therapy.12–14 In the TAXIT trial, 27% of patients underwent dose de-escalation without negative impact on remission rates.12 In the same line, in our study 8/33 [24%] patients undergoing proactive TDM following reactive testing de-escalated infliximab therapy during the study period. Additionally, we identified a diagnosis of UC, lower infliximab concentration at start of TDM, and male gender as associated with treatment failure. The first two variables likely characterize patients with a higher inflammatory burden and consequently a higher drug clearance and were also found to be associated with treatment failure when undergoing either proactive or reactive TDM of infliximab in a previous study.14 Regarding the latter variable, pharmacokinetic studies have shown that men may have a higher drug clearance than women,17 and male sex was identified as a risk factor for relapse following discontinuation of infliximab in patients with CD with stable clinical remission.18 The limitations of this study are its retrospective nature and the potential for residual/selection bias. However, confounding factors that could influence the outcomes are likely limited in this study as all patients initially underwent reactive testing, and the two groups were similar regarding the patients’ baseline and clinical characteristics. Moreover, to ensure population homogeneity and diminish potential differences in disease activity and inability to optimize infliximab as potential confounding factors, only patients without early treatment failure who were still on drug for at least 6 months after the first reactive testing were included in the study. An additional limitation of this study could be that two different assays for TDM were used based on the evolution of laboratory technology over time. In conclusion, this study, performed in two large tertiary IBD centers, demonstrates that proactive infliximab monitoring following reactive testing can prevent treatment failure and IBD-related hospitalization and may be a valuable therapeutic option for improving the management of IBD patients treated with anti-TNF therapy who experience a SLR. Though larger prospective studies are certainly warranted, physicians currently performing reactive testing should consider incorporating future proactive monitoring for the same patients. Funding KP: Ruth L. Kirschstein NRSA Institutional Research Training Grant [5T32DK007760-18]. The content of this project is solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Conflict of Interest BPV: receives research support from Takeda and Genentech and has received compensation from Janssen and AbbVie for speaking and advisory boards. ASC: received consultancy fees from AbbVie, Janssen, Takeda, Ferring, Samsung, Miraca, AMAG and Pfizer; MTO: received consultancy fees from Janssen, AbbVie, UCB, Takeda, Pfizer, Merck and Lycera, and received research grant support from UCB; the remaining authors disclose no conflicts of interest. Author Contributions KP: study concept and design, data acquisition, analysis and interpretation, statistical analysis and manuscript writing; RKV, BPV: data acquisition and manuscript critical revision; ASC, MO: study concept and design, data analysis and interpretation and manuscript critical revision. All the authors approved the final draft. Supplementary Data Supplementary data are available at ECCO-JCC online. References 1. Miligkos M , Papamichael K, Vande Casteele N, et al. Efficacy and safety profile of anti-tumor necrosis factor-α versus anti-integrin agents for the treatment of Crohn’s disease: a network meta-analysis of indirect comparisons . Clin Ther 2016 ; 38 : 1342 – 58.e6 . 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Google Scholar Crossref Search ADS PubMed WorldCat Author notes These two authors contributed equally Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
Journal
Journal of Crohn's and Colitis – Oxford University Press
Published: Jun 28, 2018
Keywords: inflammatory bowel disease; treatment failure; treatment outcome; infliximab; surgical procedures, operative