Alimentary Pharmacology and Therapeutics
Prior response to infliximab and early serum drug concentrations predict effects of adalimumab in ulcerative colitis F. Baert*, N. Vande Casteele†, S. Tops†, M. Noman*, G. Van Assche*, P. Rutgeerts*, A. Gils†, S. Vermeire* & M. Ferrante*
*Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium. † Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium.
Correspondence to: Dr F. Baert, Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, Leuven B-3000, Belgium. E-mail: fi[email protected]
Publication data Submitted 29 April 2014 First decision 2 June 2014 Resubmitted 5 July 2014 Resubmitted 1 September 2014 Resubmitted 4 September 2014 Accepted 5 September 2014 EV Pub Online 2 October 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Data for adalimumab in ulcerative colitis after prior use of infliximab are scarce. Aims To study adalimumab response rates and predictors of response in ulcerative colitis, including drug concentrations. Methods In this single centre cohort study 73 UC patients, previously exposed to infliximab, were assessed for response to adalimumab at weeks 12 and 52. Serum samples prior to week 12 were available and included in multivariate analysis to predict response. Results Overall clinical response at week 12 and 52 were 75% and 52%, respectively. Adalimumab was continued without need for dose escalation throughout year 1 in 16 patients, 22 needed dose escalation and 35 discontinued treatment within 1 year. Prior response to infliximab and early serum concentrations correlated with response. Receiver operator characteristic curve analysis yielded optimal adalimumab concentrations of 4.58 lg/mL for week 12 and 7.0 lg/mL for week 52. Independent predictors for response at week 12 were primary response to infliximab [odds ratio (OR) 8.33; 95% confidence interval (CI) 1.8–33.3; P = 0.006] and an adalimumab concentration ≥4.58 lg/mL at week 4 (OR 4.85; 95% CI 1.3–18.6; P = 0.009). Positive predictors for week 52 response were primary response to infliximab (OR 5.2; 95% CI 1.14–23.8; P = 0.034) and adalimumab concentration at week 4 of ≥7 lg/mL (OR 3.56; 95% CI 1.17–10.79; P = 0.025). Conclusion Prior response to infliximab and high early adalimumab serum concentrations predict week 12 and year 1 responses to adalimumab in ulcerative colitis. Aliment Pharmacol Ther 2014; 40: 1324–1332
1324
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12968
Second line anti-TNF treatment with adalimumab in UC INTRODUCTION Adalimumab (Humira; Abbvie, Chicago, IL, USA) is approved for the treatment of moderate to severe ulcerative colitis after failure of aminosalicylates plus corticosteroids and/or immunomodulators.1–4 In the registration studies for adalimumab in ulcerative colitis prior anti-TNF treatment was restricted; in ULTRA 1, prior anti-TNF treatment was an exclusion criterion5 and in ULTRA 2, 40% of patients had been exposed to infliximab prior to start of adalimumab, but primary nonresponders to infliximab were excluded.6 Open label real life studies have shown good responses to adalimumab in UC. However typically, these cohorts were very small and most patients were anti-TNF na€ıve. One Italian open label study on 88 patients reported clinical remission rates of 28% and 43% at week 12 and year 1, respectively. No significant differences were observed between infliximab na€ıve and infliximab exposed UC patients.7 Pharmacokinetic studies revealed that anti-TNF agents in the treatment of inflammatory bowel diseases all show high inter-subject variability in serum drug concentrations. Data on serum adalimumab concentrations in ulcerative colitis is scarce. It has been suggested that the required dose of both infliximab and adalimumab should be higher as compared to Crohn’s disease (CD). Alternatively an individualised approach, as opposed to the current standard induction and maintenance dosing regimens, may be indicated to achieve maximum benefit.8 Anti-TNF serum concentrations correlate with clinical
response and remission and with mucosal healing, as recently reviewed elsewhere.9 Furthermore, early serum anti-TNF concentrations have shown to predict longterm outcome of infliximab in CD and UC patients and for adalimumab in CD.10–13 We hypothesised that prior response to infliximab and serum adalimumab drug concentrations early after induction could provide information regarding the response on adalimumab and hence predict response.
METHODS Study design Retrospective single centre cohort study of a consecutive series of ulcerative colitis patients treated with adalimumab at the University Hospitals Leuven Belgium. Study population and treatment modalities From July 2005 through December 2012, a total of 99 patients with an established diagnosis of ulcerative colitis were started on adalimumab in our center. Eleven patients were excluded because of lack of an early (i.e. prior to week 12) serum sample available for therapeutic drug monitoring purposes. Five more patients were excluded from the cohort (three patients were not treated with infliximab prior to adalimumab, one patient was lost to follow-up prior to year 1, and one patient was later reclassified as having Crohn’s disease). (Figure 1) Most patients had an initial response to infliximab and
UC patients treated with adalimumab and >1 year follow-up N = 99 Excluded (n = 21): No serum samples available prior to or At week 12 after start of adalimumab
Patients with early serum available N = 78 Excluded (n = 5): Reclassified as Crohn’s disease (n = 1) Lost to follow-up (n = 1) Anti-TNF naïve (i.e. No prior IFX) (n = 3)
Patients eligible for this study
Figure 1 | Flowchart of the patients. Aliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
N = 73
1325
F. Baert et al. subsequently became intolerant (due to an acute and/or delayed hypersensitivity reactions) or lost response (i.e. increase in symptoms of diarrhoea with appearance of blood or mucus). Eleven patients did not response to an induction regimen of infliximab. (Table 1) A colonoscopy was performed confirming active disease before the start of adalimumab. Induction treatment with adalimumab included 160 mg at week 0 followed by 80 mg at week 2 and thereafter maintenance therapy with adalimumab 40 mg every other week. The adalimumab dosing interval was decreased to once weekly in-patients, who presented with diarrhoea with blood and/or mucus and/or an increase in C-reactive protein (CRP) concenTable 1 | Baseline characteristics at start of adalimumab (n = 73) Female/male ratio: F 31/M 42 Median (IQR) weight at first ADA 68 (58–80) kg Median (IQR) BMI at first ADA 23 (20–27) kg/m² Median (IQR) age at diagnosis of ulcerative colitis: (years) 28.1 (22–36) Median (IQR) age at initiation of adalimumab therapy: (years) 37 (30–49) Median (IQR) disease duration before adalimumab: (months) 84 (45–165) Median (IQR) interval between IFX and adalimumab: (months) 3 (1–14) Endoscopic Mayo subscore: Mayo 1: n = 1 Mayo 2: n = 29 Mayo 3: n = 27 Unknown: n = 15 Extent of colitis (%) L1 (proctitis): 1.5% L2 (left sided colitis): 43.5% L3 (pancolitis): 55 (%) Concomitant medication at baseline: (%) 5-ASA: N = 46 (63%) Corticosteroids: N = 17 (23%) Prior admission for IV corticosteroids and or ciclosporin: N = 21 (29%) Azathioprine/Mercaptopurine: N = 15 (20%) Laboratory values at baseline (median + range) Haemoglobin (g/dL) 13.20 (8.3–15.5) Platelet count 325 9 103 (168–988) CRP (mg/L) 6.4 (0.3–87) [CRP elevated (i.e. >5 mg/L) 50%] Albumin (g/L): 42.75 (29–52) Details regarding prior infliximab treatment Median Age (IQR) (range) at first IFX: 34.1 years (28–46) (15–70) Duration of IFX treatment: (months): 10.4 (1–115) Median number of IFX infusions: 10.4 (2–50) Dose optimisation of IFX: Yes N = 41 No N = 28 Unknown N=4 Reason for discontinuation IFX (%) No response to infliximab N = 11 (15%) Loss of response to infliximab N = 42 (57.5%) Infusion reaction (acute or delayed) N = 18 (24.6%) Other: N = 2 adverse event; pregnancy 1326
tration and confirmed by flexible sigmoidoscopy. The treating physicians were not aware of serum concentrations and antibodies to adalimumab (ATA) concentrations. No dose escalations were performed prior to week 4 after start of the treatment.
Data collection Clinical information on treatment modalities was retrieved from the electronic charts of the patients. In addition to demographical data the following data were collected: extent of colitis according to the Montreal classification, disease duration, details of prior infliximab use, adalimumab start and discontinuation data, concomitant use of immunomodulators (IMM) at start of adalimumab need for dose escalation and reason for discontinuation of adalimumab. All patients were followed until discontinuation of adalimumab or for a minimum of 1 year after the start of adalimumab treatment. Endpoints The co-primary endpoints were response at week 12 and response at week 52. Response at week 12 was defined as a marked clinical improvement with reduction in symptoms as measured in the clinical Mayo subscore at week 12 (i.e. partial response) or a complete absence of blood and diarrhoea (i.e. complete response). In patients not responding this was confirmed by flexible sigmoidoscopy showing an endoscopic Mayo score of 2 or 3. Response at week 52 was defined as continued treatment with adalimumab and no use of corticosteroids. Sustained clinical remission throughout year 1 was defined as the continuation of adalimumab therapy during 1 year follow-up without need for dose optimisation to weekly injection. Secondary endpoints were discontinuation of adalimumab, clinical relapse free survival and adverse events. Serum samples Serum samples from predefined time points were available through systematic bio-banking, which started in 1997 as part of the VLECC (Flemish Study for Genetics Research on IBD) research program (Medical Ethical approval numbers: B322201213950/S53684). All patients in our centre undergo routine 10 mL serum sample collection during their out-patient visit. Patients come to the clinic the day of (and before) their weekly or biweekly injection. These samples are divided into 500 lL aliquots and stored at 20 °C. A total of 461 prospectively collected serum samples were available. A total of 144 samples during or early after induction Aliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
Second line anti-TNF treatment with adalimumab in UC [week 2 (n = 40), week 4 (n = 48), week 8 (n = 18) and week 12 (n = 38)] were used for analysis in this study. All 73 patients had at least one sample available prior to week 12 after induction. When a sample was missing at a certain time point in time (e.g. week 4) the previous sample (e.g. week 2) was used to for the analysis, according to the last observation carried forward (LOCF) principle.
Laboratory methods In addition to routine blood tests all serum samples were analysed for adalimumab serum concentrations and antibodies to adalimumab (ATA) using an in house developed ELISA.14 Serum adalimumab concentrations are expressed as micrograms per millilitre. The lowest level of quantitation (LLOQ) for adalimumab was 0.3 lg/mL. To exclude residual infliximab in the adalimumab concentration assay, infliximab and adalimumab concentrations were determined in all w0 samples. In addition, we determined infliximab trough concentration and antibodies to infliximab from the end of the infliximab treatment period if serum samples were available. Serum infliximab trough concentrations are expressed as micrograms per litre and the LLOQ of the assay was 0.3 lg/mL. Antibodies to infliximab are measured using bridging ELISA and expressed in micrograms per litre equivalents towards polyclonal standard with an LLOQ of 1 lg/mL equivalents. The upper limit of detection is 20 lg/mL equivalents. 15 For statistical analysis, 25 lg/ mL was used for antibodies to infliximab reported as >20 lg/mL equivalents. Statistical analysis All data were analysed using IBM SPSS Statistics version 22.0 (IBM, Costa Mesa, CA, USA). The statistical analysis compiled descriptive statistics including percentage for discrete variables, mean and median and range and interquartile range for continuous variables. Kaplan–Meier survival analysis was used to describe time to discontinuation of adalimumab, and time to clinical relapse. To determine the optimal cut-off of early adalimumab drug concentrations for response a receiver operator characteristic (ROC) curve analysis was performed. With these cut-off values, a Cox regression analysis was performed. Univariate analyses and multivariate logistic regression analysis were performed to look for factors predicting early and late response. Results from the univariate and multivariate analysis were expressed as odds ratio (OR) with 95% confidence intervals (95% CI) with the correAliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
sponding P value. A multivariate Cox regression was performed for discontinuation of adalimumab and clinical relapse free survival (using Log Rank and Breslow test). (Since the length of follow-up varied significantly between patients, the most appropriate test was the Breslow test where time points are weighted by the number of cases at risk at either time point.) Breslow P < 0.10 was used for a variable to enter multivariate analysis. Finally, correlation coefficient and corresponding P values were calculated between serum concentrations of adalimumab at different time points and weight, body mass index (BMI). Statistical significance was inferred at the P = 0.05 level.
RESULTS Patients The baseline demographics and disease characteristics at the start of adalimumab of the 73 patients included in this study are shown in Table 1. Seventeen patients (23%) were on corticosteroids and 15 (20%) on concomitant azathioprine at the start of adalimumab. Twenty one patients (29%) had a history of a prior admission for intravenous corticosteroids and or ciclosporin. The median (interquartile range, IQR) C-reactive protein concentration (CRP) was 6.4 (IQR 2.5–14.7) mg/L. The median follow-up on adalimumab treatment in this study was 20.3 months (IQR 6.8–44.8). Efficacy At week 12, 75% (55/73) of patients had a least a partial response. A complete response was observed in 30% (22/ 73) of patients. At year one, 52% (38/73) of patients still showed response and continued adalimumab treatment. Sustained steroid-free clinical remission (without need for dose escalation in the first year) was observed in 22% (16/73). The median time to adalimumab dose escalation was 2.7 (IQR 1–6.3) months. Thirty five patients (48%) discontinued adalimumab within the first year. The reasons for discontinuation of adalimumab treatment included primary nonresponse in 16, loss of response in 16, adverse events in two (furonculosis, pityriasis rosea) and pregnancy in one patient. Clinical predictors of response The reason for discontinuation of infliximab was a clear clinical predictor for response to adalimumab. Among the primary nonresponders to infliximab, short-term response to adalimumab was observed in 36% (4/11) of 1327
F. Baert et al. infliximab patients as compared to 58% (36/62) of patients having discontinued infliximab for other reasons (P = 0.045). The Kaplan–Meier survival curve for patients with continuation of adalimumab at year one shows a clear difference for patients with primary nonresponse to infliximab as compared to patients started on adalimumab due to prior loss of response or infusion reactions to infliximab (P = 0.001) (Figure 2). The following parameters were not found to be predictors of short-term (w12) or long-term (year one) response at univariate analysis: weight, BMI, sex, CRP, IMM use, disease extension (left sided colitis vs. pancolitis), age at first adalimumab or disease duration at first adalimumab.
1.0 LogRank P = 0.001 Breslow P = 0.002
ADA continuation
0.8 0.6 0.4 0.2
No IFX PNR (n = 62) IFX PNR (n = 11)
0.0 0
12 24 Follow-up (months) 39 26 3 2
N at risk: 62 11
36 20 1
Figure 2 | Kaplan–Meier survival curve showing that patients with primary nonresponse to infliximab (IFX PNR) are more likely to discontinue adalimumab early compared to those with initial response to infliximab (no IFX PNR).
patients as compared to 83% (51/62) of patients that discontinued infliximab for other reasons than primary nonresponse (P = 0.003). Similarly year one response was observed in 27% (3/11) of primary nonresponder to
Pharmacokinetic predictors of response: Median + IQR adalimumab concentrations at the different time points were as follows: week 2: 6.85 (IQR 4.58– 9.25) lg/mL (n = 40); week 4: 6.95 (IQR 3.18–9.64) lg/ mL (n = 48); week 2 or 4 (LOCF): 6.58 (IQR 3.46–9.37) lg/mL (n = 66); week 8: 6.56 (IQR 2.97–9.25) lg/mL (n = 18); week 12: 6.09 (IQR 3.47–8.86) lg/mL (n = 38); Week 8 or 12 (LOCF): 5.93 (IQR 3.06–8.91) lg/mL (n = 51). Early serum adalimumab concentrations at week 4 correlated best with week 12 and week 52 response. A
(a) 1.0
(b) 1.0
0.8
0.8 7.00 µg/mL
Sens 80% PPV 85%
0.6
Spec 56% NPV 47%
Sensitivity
Sensitivity
4.58 µg/mL
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Sens 80% PPV 43%
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Spec 69% NPV 92%
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Figure 3 | (a) Receiver operation curve (ROC) showing an optimal serum adalimumab concentration at week 4 (or week 2 if unavailable) for response at week 12 of 4.58 lg/mL. (b) Receiver operation curve (ROC) showing an optimal week 4 (or week 2 if unavailable) adalimumab serum concentration for sustained clinical response throughout year 1 (without dose optimisation) of 7.0 lg/mL. 1328
Aliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
Second line anti-TNF treatment with adalimumab in UC 1.0 LogRank P = 0.119 ADA continuation
0.8
Breslow
P = 0.050
0.6 0.4 0.2
ADA SL week 4 ≥7 µg/mL (n = 28) ADA SL week 4 7.0 lg/mL.
ROC curve analysis was performed to determine the optimal serum adalimumab concentrations for response. For (any) week 12 response a cut-off of 4.58 lg/mL of week 4 serum adalimumab concentration was chosen to discriminate responders vs. nonresponders (Figure 3a). For sustained clinical remission throughout year 1 (without need for dose escalation) an optimal cut-off of 7 lg/ mL at week 4 was determined (Figure 3b). Adalimumab serum concentrations at week 4 of ≥4.58 lg/mL predicted short-term response (week 12) in 85% (40/47) of patients, as compared to 53% (10/19) of patients for concentrations of
Prior response to infliximab and early serum drug concentrations predict effects of adalimumab in ulcerative colitis F. Baert*, N. Vande Casteele†, S. Tops†, M. Noman*, G. Van Assche*, P. Rutgeerts*, A. Gils†, S. Vermeire* & M. Ferrante*
*Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium. † Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium.
Correspondence to: Dr F. Baert, Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, Leuven B-3000, Belgium. E-mail: fi[email protected]
Publication data Submitted 29 April 2014 First decision 2 June 2014 Resubmitted 5 July 2014 Resubmitted 1 September 2014 Resubmitted 4 September 2014 Accepted 5 September 2014 EV Pub Online 2 October 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Data for adalimumab in ulcerative colitis after prior use of infliximab are scarce. Aims To study adalimumab response rates and predictors of response in ulcerative colitis, including drug concentrations. Methods In this single centre cohort study 73 UC patients, previously exposed to infliximab, were assessed for response to adalimumab at weeks 12 and 52. Serum samples prior to week 12 were available and included in multivariate analysis to predict response. Results Overall clinical response at week 12 and 52 were 75% and 52%, respectively. Adalimumab was continued without need for dose escalation throughout year 1 in 16 patients, 22 needed dose escalation and 35 discontinued treatment within 1 year. Prior response to infliximab and early serum concentrations correlated with response. Receiver operator characteristic curve analysis yielded optimal adalimumab concentrations of 4.58 lg/mL for week 12 and 7.0 lg/mL for week 52. Independent predictors for response at week 12 were primary response to infliximab [odds ratio (OR) 8.33; 95% confidence interval (CI) 1.8–33.3; P = 0.006] and an adalimumab concentration ≥4.58 lg/mL at week 4 (OR 4.85; 95% CI 1.3–18.6; P = 0.009). Positive predictors for week 52 response were primary response to infliximab (OR 5.2; 95% CI 1.14–23.8; P = 0.034) and adalimumab concentration at week 4 of ≥7 lg/mL (OR 3.56; 95% CI 1.17–10.79; P = 0.025). Conclusion Prior response to infliximab and high early adalimumab serum concentrations predict week 12 and year 1 responses to adalimumab in ulcerative colitis. Aliment Pharmacol Ther 2014; 40: 1324–1332
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ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12968
Second line anti-TNF treatment with adalimumab in UC INTRODUCTION Adalimumab (Humira; Abbvie, Chicago, IL, USA) is approved for the treatment of moderate to severe ulcerative colitis after failure of aminosalicylates plus corticosteroids and/or immunomodulators.1–4 In the registration studies for adalimumab in ulcerative colitis prior anti-TNF treatment was restricted; in ULTRA 1, prior anti-TNF treatment was an exclusion criterion5 and in ULTRA 2, 40% of patients had been exposed to infliximab prior to start of adalimumab, but primary nonresponders to infliximab were excluded.6 Open label real life studies have shown good responses to adalimumab in UC. However typically, these cohorts were very small and most patients were anti-TNF na€ıve. One Italian open label study on 88 patients reported clinical remission rates of 28% and 43% at week 12 and year 1, respectively. No significant differences were observed between infliximab na€ıve and infliximab exposed UC patients.7 Pharmacokinetic studies revealed that anti-TNF agents in the treatment of inflammatory bowel diseases all show high inter-subject variability in serum drug concentrations. Data on serum adalimumab concentrations in ulcerative colitis is scarce. It has been suggested that the required dose of both infliximab and adalimumab should be higher as compared to Crohn’s disease (CD). Alternatively an individualised approach, as opposed to the current standard induction and maintenance dosing regimens, may be indicated to achieve maximum benefit.8 Anti-TNF serum concentrations correlate with clinical
response and remission and with mucosal healing, as recently reviewed elsewhere.9 Furthermore, early serum anti-TNF concentrations have shown to predict longterm outcome of infliximab in CD and UC patients and for adalimumab in CD.10–13 We hypothesised that prior response to infliximab and serum adalimumab drug concentrations early after induction could provide information regarding the response on adalimumab and hence predict response.
METHODS Study design Retrospective single centre cohort study of a consecutive series of ulcerative colitis patients treated with adalimumab at the University Hospitals Leuven Belgium. Study population and treatment modalities From July 2005 through December 2012, a total of 99 patients with an established diagnosis of ulcerative colitis were started on adalimumab in our center. Eleven patients were excluded because of lack of an early (i.e. prior to week 12) serum sample available for therapeutic drug monitoring purposes. Five more patients were excluded from the cohort (three patients were not treated with infliximab prior to adalimumab, one patient was lost to follow-up prior to year 1, and one patient was later reclassified as having Crohn’s disease). (Figure 1) Most patients had an initial response to infliximab and
UC patients treated with adalimumab and >1 year follow-up N = 99 Excluded (n = 21): No serum samples available prior to or At week 12 after start of adalimumab
Patients with early serum available N = 78 Excluded (n = 5): Reclassified as Crohn’s disease (n = 1) Lost to follow-up (n = 1) Anti-TNF naïve (i.e. No prior IFX) (n = 3)
Patients eligible for this study
Figure 1 | Flowchart of the patients. Aliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
N = 73
1325
F. Baert et al. subsequently became intolerant (due to an acute and/or delayed hypersensitivity reactions) or lost response (i.e. increase in symptoms of diarrhoea with appearance of blood or mucus). Eleven patients did not response to an induction regimen of infliximab. (Table 1) A colonoscopy was performed confirming active disease before the start of adalimumab. Induction treatment with adalimumab included 160 mg at week 0 followed by 80 mg at week 2 and thereafter maintenance therapy with adalimumab 40 mg every other week. The adalimumab dosing interval was decreased to once weekly in-patients, who presented with diarrhoea with blood and/or mucus and/or an increase in C-reactive protein (CRP) concenTable 1 | Baseline characteristics at start of adalimumab (n = 73) Female/male ratio: F 31/M 42 Median (IQR) weight at first ADA 68 (58–80) kg Median (IQR) BMI at first ADA 23 (20–27) kg/m² Median (IQR) age at diagnosis of ulcerative colitis: (years) 28.1 (22–36) Median (IQR) age at initiation of adalimumab therapy: (years) 37 (30–49) Median (IQR) disease duration before adalimumab: (months) 84 (45–165) Median (IQR) interval between IFX and adalimumab: (months) 3 (1–14) Endoscopic Mayo subscore: Mayo 1: n = 1 Mayo 2: n = 29 Mayo 3: n = 27 Unknown: n = 15 Extent of colitis (%) L1 (proctitis): 1.5% L2 (left sided colitis): 43.5% L3 (pancolitis): 55 (%) Concomitant medication at baseline: (%) 5-ASA: N = 46 (63%) Corticosteroids: N = 17 (23%) Prior admission for IV corticosteroids and or ciclosporin: N = 21 (29%) Azathioprine/Mercaptopurine: N = 15 (20%) Laboratory values at baseline (median + range) Haemoglobin (g/dL) 13.20 (8.3–15.5) Platelet count 325 9 103 (168–988) CRP (mg/L) 6.4 (0.3–87) [CRP elevated (i.e. >5 mg/L) 50%] Albumin (g/L): 42.75 (29–52) Details regarding prior infliximab treatment Median Age (IQR) (range) at first IFX: 34.1 years (28–46) (15–70) Duration of IFX treatment: (months): 10.4 (1–115) Median number of IFX infusions: 10.4 (2–50) Dose optimisation of IFX: Yes N = 41 No N = 28 Unknown N=4 Reason for discontinuation IFX (%) No response to infliximab N = 11 (15%) Loss of response to infliximab N = 42 (57.5%) Infusion reaction (acute or delayed) N = 18 (24.6%) Other: N = 2 adverse event; pregnancy 1326
tration and confirmed by flexible sigmoidoscopy. The treating physicians were not aware of serum concentrations and antibodies to adalimumab (ATA) concentrations. No dose escalations were performed prior to week 4 after start of the treatment.
Data collection Clinical information on treatment modalities was retrieved from the electronic charts of the patients. In addition to demographical data the following data were collected: extent of colitis according to the Montreal classification, disease duration, details of prior infliximab use, adalimumab start and discontinuation data, concomitant use of immunomodulators (IMM) at start of adalimumab need for dose escalation and reason for discontinuation of adalimumab. All patients were followed until discontinuation of adalimumab or for a minimum of 1 year after the start of adalimumab treatment. Endpoints The co-primary endpoints were response at week 12 and response at week 52. Response at week 12 was defined as a marked clinical improvement with reduction in symptoms as measured in the clinical Mayo subscore at week 12 (i.e. partial response) or a complete absence of blood and diarrhoea (i.e. complete response). In patients not responding this was confirmed by flexible sigmoidoscopy showing an endoscopic Mayo score of 2 or 3. Response at week 52 was defined as continued treatment with adalimumab and no use of corticosteroids. Sustained clinical remission throughout year 1 was defined as the continuation of adalimumab therapy during 1 year follow-up without need for dose optimisation to weekly injection. Secondary endpoints were discontinuation of adalimumab, clinical relapse free survival and adverse events. Serum samples Serum samples from predefined time points were available through systematic bio-banking, which started in 1997 as part of the VLECC (Flemish Study for Genetics Research on IBD) research program (Medical Ethical approval numbers: B322201213950/S53684). All patients in our centre undergo routine 10 mL serum sample collection during their out-patient visit. Patients come to the clinic the day of (and before) their weekly or biweekly injection. These samples are divided into 500 lL aliquots and stored at 20 °C. A total of 461 prospectively collected serum samples were available. A total of 144 samples during or early after induction Aliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
Second line anti-TNF treatment with adalimumab in UC [week 2 (n = 40), week 4 (n = 48), week 8 (n = 18) and week 12 (n = 38)] were used for analysis in this study. All 73 patients had at least one sample available prior to week 12 after induction. When a sample was missing at a certain time point in time (e.g. week 4) the previous sample (e.g. week 2) was used to for the analysis, according to the last observation carried forward (LOCF) principle.
Laboratory methods In addition to routine blood tests all serum samples were analysed for adalimumab serum concentrations and antibodies to adalimumab (ATA) using an in house developed ELISA.14 Serum adalimumab concentrations are expressed as micrograms per millilitre. The lowest level of quantitation (LLOQ) for adalimumab was 0.3 lg/mL. To exclude residual infliximab in the adalimumab concentration assay, infliximab and adalimumab concentrations were determined in all w0 samples. In addition, we determined infliximab trough concentration and antibodies to infliximab from the end of the infliximab treatment period if serum samples were available. Serum infliximab trough concentrations are expressed as micrograms per litre and the LLOQ of the assay was 0.3 lg/mL. Antibodies to infliximab are measured using bridging ELISA and expressed in micrograms per litre equivalents towards polyclonal standard with an LLOQ of 1 lg/mL equivalents. The upper limit of detection is 20 lg/mL equivalents. 15 For statistical analysis, 25 lg/ mL was used for antibodies to infliximab reported as >20 lg/mL equivalents. Statistical analysis All data were analysed using IBM SPSS Statistics version 22.0 (IBM, Costa Mesa, CA, USA). The statistical analysis compiled descriptive statistics including percentage for discrete variables, mean and median and range and interquartile range for continuous variables. Kaplan–Meier survival analysis was used to describe time to discontinuation of adalimumab, and time to clinical relapse. To determine the optimal cut-off of early adalimumab drug concentrations for response a receiver operator characteristic (ROC) curve analysis was performed. With these cut-off values, a Cox regression analysis was performed. Univariate analyses and multivariate logistic regression analysis were performed to look for factors predicting early and late response. Results from the univariate and multivariate analysis were expressed as odds ratio (OR) with 95% confidence intervals (95% CI) with the correAliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
sponding P value. A multivariate Cox regression was performed for discontinuation of adalimumab and clinical relapse free survival (using Log Rank and Breslow test). (Since the length of follow-up varied significantly between patients, the most appropriate test was the Breslow test where time points are weighted by the number of cases at risk at either time point.) Breslow P < 0.10 was used for a variable to enter multivariate analysis. Finally, correlation coefficient and corresponding P values were calculated between serum concentrations of adalimumab at different time points and weight, body mass index (BMI). Statistical significance was inferred at the P = 0.05 level.
RESULTS Patients The baseline demographics and disease characteristics at the start of adalimumab of the 73 patients included in this study are shown in Table 1. Seventeen patients (23%) were on corticosteroids and 15 (20%) on concomitant azathioprine at the start of adalimumab. Twenty one patients (29%) had a history of a prior admission for intravenous corticosteroids and or ciclosporin. The median (interquartile range, IQR) C-reactive protein concentration (CRP) was 6.4 (IQR 2.5–14.7) mg/L. The median follow-up on adalimumab treatment in this study was 20.3 months (IQR 6.8–44.8). Efficacy At week 12, 75% (55/73) of patients had a least a partial response. A complete response was observed in 30% (22/ 73) of patients. At year one, 52% (38/73) of patients still showed response and continued adalimumab treatment. Sustained steroid-free clinical remission (without need for dose escalation in the first year) was observed in 22% (16/73). The median time to adalimumab dose escalation was 2.7 (IQR 1–6.3) months. Thirty five patients (48%) discontinued adalimumab within the first year. The reasons for discontinuation of adalimumab treatment included primary nonresponse in 16, loss of response in 16, adverse events in two (furonculosis, pityriasis rosea) and pregnancy in one patient. Clinical predictors of response The reason for discontinuation of infliximab was a clear clinical predictor for response to adalimumab. Among the primary nonresponders to infliximab, short-term response to adalimumab was observed in 36% (4/11) of 1327
F. Baert et al. infliximab patients as compared to 58% (36/62) of patients having discontinued infliximab for other reasons (P = 0.045). The Kaplan–Meier survival curve for patients with continuation of adalimumab at year one shows a clear difference for patients with primary nonresponse to infliximab as compared to patients started on adalimumab due to prior loss of response or infusion reactions to infliximab (P = 0.001) (Figure 2). The following parameters were not found to be predictors of short-term (w12) or long-term (year one) response at univariate analysis: weight, BMI, sex, CRP, IMM use, disease extension (left sided colitis vs. pancolitis), age at first adalimumab or disease duration at first adalimumab.
1.0 LogRank P = 0.001 Breslow P = 0.002
ADA continuation
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No IFX PNR (n = 62) IFX PNR (n = 11)
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Figure 2 | Kaplan–Meier survival curve showing that patients with primary nonresponse to infliximab (IFX PNR) are more likely to discontinue adalimumab early compared to those with initial response to infliximab (no IFX PNR).
patients as compared to 83% (51/62) of patients that discontinued infliximab for other reasons than primary nonresponse (P = 0.003). Similarly year one response was observed in 27% (3/11) of primary nonresponder to
Pharmacokinetic predictors of response: Median + IQR adalimumab concentrations at the different time points were as follows: week 2: 6.85 (IQR 4.58– 9.25) lg/mL (n = 40); week 4: 6.95 (IQR 3.18–9.64) lg/ mL (n = 48); week 2 or 4 (LOCF): 6.58 (IQR 3.46–9.37) lg/mL (n = 66); week 8: 6.56 (IQR 2.97–9.25) lg/mL (n = 18); week 12: 6.09 (IQR 3.47–8.86) lg/mL (n = 38); Week 8 or 12 (LOCF): 5.93 (IQR 3.06–8.91) lg/mL (n = 51). Early serum adalimumab concentrations at week 4 correlated best with week 12 and week 52 response. A
(a) 1.0
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0.8 7.00 µg/mL
Sens 80% PPV 85%
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Spec 69% NPV 92%
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Figure 3 | (a) Receiver operation curve (ROC) showing an optimal serum adalimumab concentration at week 4 (or week 2 if unavailable) for response at week 12 of 4.58 lg/mL. (b) Receiver operation curve (ROC) showing an optimal week 4 (or week 2 if unavailable) adalimumab serum concentration for sustained clinical response throughout year 1 (without dose optimisation) of 7.0 lg/mL. 1328
Aliment Pharmacol Ther 2014; 40: 1324-1332 ª 2014 John Wiley & Sons Ltd
Second line anti-TNF treatment with adalimumab in UC 1.0 LogRank P = 0.119 ADA continuation
0.8
Breslow
P = 0.050
0.6 0.4 0.2
ADA SL week 4 ≥7 µg/mL (n = 28) ADA SL week 4 7.0 lg/mL.
ROC curve analysis was performed to determine the optimal serum adalimumab concentrations for response. For (any) week 12 response a cut-off of 4.58 lg/mL of week 4 serum adalimumab concentration was chosen to discriminate responders vs. nonresponders (Figure 3a). For sustained clinical remission throughout year 1 (without need for dose escalation) an optimal cut-off of 7 lg/ mL at week 4 was determined (Figure 3b). Adalimumab serum concentrations at week 4 of ≥4.58 lg/mL predicted short-term response (week 12) in 85% (40/47) of patients, as compared to 53% (10/19) of patients for concentrations of
