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Low serum trough levels are associated with post-surgical recurrence in Crohn's disease patients undergoing prophylaxis with adalimumab

Digestive and Liver Disease, Volume 46, Issue 11, November 2014, Pages 1043–1046

Abstract

Background

Whether therapeutic drug monitoring of biologic therapy can predict the efficacy of adalimumab to prevent postoperative Crohn's disease recurrence is unknown.

Aim

To investigate whether adalimumab trough levels and anti-adalimumab antibodies correlate with endoscopic and clinical outcomes in a series of patients treated with prophylactic adalimumab monotherapy after resective surgery.

Methods

Post hoc analysis of a randomized, mesalamine-controlled trial. Adalimumab trough levels and antibodies were analysed every 8 weeks for 2 years using an homogeneous mobility shift assay.

Results

At two years, 1/6 patient had clinical recurrence and 1/6 patient had endoscopic and clinical recurrence. At baseline (9.5 vs. 14.4 mcg/mL) and during follow-up [7.5 (4.4–9.8) vs. 13.9 (8.9–23.6) mcg/mL,p < 0.01], median adalimumab trough levels in patients with clinical or endoscopic recurrence were lower than in those who maintained remission. Persistent antibodies-against-adalimumab were detected in the patient with both endoscopic and clinical recurrence.

Conclusion

Measurement of adalimumab trough levels and anti-adalimumab antibodies after surgery could be useful to further reduce postoperative recurrence.

Keywords: Adalimumab, Anti-tumour necrosis factor alpha antibodies, Crohn's disease, Post-surgical recurrence.

1. Introduction

Crohn's disease (CD) is a chronic, disabling and progressive condition. Surgery is not curative and the need for surgery remains high in the biologics era [1] . Endoscopic postoperative CD recurrence is common and is observed in up to 90% in available reports [2] . Clinical and surgical recurrence will occur in half and one third of CD patients after a first intestinal resection [2] . Anti-TNF therapy is the most potent drug class to prevent postoperative CD recurrence[3], [4], [5], [6], and [7].

There is growing evidence that therapeutic drug monitoring of anti-TNFα agents (infliximab and adalimumab) and antibodies against anti-TNFα drugs is associated with better outcomes[8] and [9]. Notably, pharmacokinetics of anti-TNF therapy is associated with clinical remission and mucosal healing rates in both CD and ulcerative colitis[10], [11], and [12].

Whether anti-TNF trough levels and antibodies can predict postoperative CD recurrence rates and could be used in the postoperative to guide decision making has yet to be determined.

The aim of this retrospective study was to report a series of patients who underwent intestinal resection for CD and were treated with ADA as prophylactic therapy to prevent CD recurrence for two years. We studied the correlation between trough levels of ADA and the presence of antibodies against ADA (AAAs) with endoscopic and clinical outcomes.

2. Methods

2.1. Patients

The charts of all ADA-treated CD patients included in our previous randomized, prospective, three-armed, mesalamine-controlled trial with parallel group design, between 2008 and 2010, who had available serial ADA and AAAs levels were screened for inclusion in this post hoc study [6] . During the trial, patients who underwent resection of macroscopically diseased bowel with complete removal of involved intestine and anastomosis between normal ileum and colon were treated, starting medication within 4 weeks after surgery, with ADA therapy at the induction dose of 160/80 mg, then 40 mg eow for two years. The study protocol was approved by the local independent Ethics Committee and performed according to the Declaration of Helsinki.

After surgery, patients were followed up weekly for the first 4 weeks and then every 8 weeks with detailed history taken, physical examination, blood tests, CD Activity Index (CDAI) and Harvey-Bradshaw Index (HBI) evaluation, and every year, until 2 years after surgery, with endoscopy and magnetic resonance imaging (MRI). In patients who agreed, serum samples for the assessment of ADA and AAAs levels were taken just before each ADA injection at consecutive time points (i.e. every 8 weeks).

2.2. Definitions

Endoscopic recurrence was defined by a score ≥i2 based on Rutgeerts's endoscopic recurrence grading scale. Clinical recurrence was defined as a score of 2 or greater on the clinical recurrence grading scale as proposed by Hanauer. We also evaluated clinical recurrence based on CDAI and HBI for all patients at each time point and recurrence was set in case of a score greater than 200 and 7, respectively, while clinical remission was defined by a CDAI score of less than 150 and a HBI less than or equal to 6. Finally, radiological recurrence was defined as a score of 2 or greater on the radiographic recurrence grading scale.

2.3. Adalimumab trough levels and antidrug antibodies

Adalimumab and AAAs levels in the sera were measured by an homogeneous mobility shift assay [Prometheus Laboratories Inc., San Diego, CA, USA], as previously described [13] .

Serum trough ADA levels are expressed as μg/ml with the lower limit of quantification for adalimumab being 0.68 mcg/mL. AAAs are expressed in U/mL. The lowest level of quantification for AAAs is 0.55 U/mL, but levels as low as 0.1 U/mL could be detected and used for statistical analysis. Hence all values below 0.1 U/mL were considered undetectable for AAAs.

2.4. Statistical analysis

All data were statistically assessed using SPSS (v17.0). The statistical analysis included descriptive statistics. Presence of AAAs was used as a dichotomous variable: present or absent. For this analysis the Mann–WhitneyUtest was used. Statistical significance was inferred at thep = 0.05 level.

3. Results

3.1. Characteristics of the six patients at study entry

Six patients (mean age 47, range 34–66) on ADA treatment and with serial blood samples taken for ADA and AAAs measurement were included. The characteristics of these patients are shown in Table 1 . The indication for surgery in these patients was small bowel obstruction (n = 4) and intra-abdominal abscess (n = 2).

Table 1 Demographic and clinical characteristics of Crohn's disease patients on adalimumab maintenance treatment at study entry.

  Patient

P1
Patient

P2
Patient

P3
Patient

P4
Patient

P5
Patient

P6
Demographic and clinical features
Gender Female Male Male Male Male Male
Age, years 34 66 43 54 32 53
Active smoker Yes Yes No No No Yes
Duration of CD, years 12 18 24 5 5 19
Disease behaviour B2 B3 B3 B2 B2 B3
Disease Location at surgery L3 L3 L3 L1 L1 L1
Type of surgery Ileal resection Ileocecal resection Ileocecal resection Ileal resection Ileocecal resection Ileocecal resection
Weight (kg) 60 48 79 86 100 57
BMI, kg/m2 21 17 25 26 33 19
Reason for surgery Stenosis Uncontrolled disease Stenosis Stenosis Uncontrolled disease Stenosis
Prior surgical resection No No No No No No
Prior azathioprine use Yes Yes No No No Yes
Prior anti-TNFα use No No No No No No

CD, Crohn's disease; BMI, body mass index; TNFα, tumour necrosis factor alpha.

3.2. Clinical and endoscopic recurrence

As illustrated in Table 2 , at two years of follow-up, 1 patient (P4) had clinical recurrence (CDAI = 180 and HBI = 7), but endoscopic remission (score i1) and one patient (P5) experienced both endoscopic (score i2) and clinical recurrence (CDAI = 290 and HBI = 12). Four patients (P1, P2, P3 and P6) maintained clinical (mean CDAI = 89.5 and HBI = 3) and endoscopic remission (mean score i0) during the whole follow-up period. Mean C-reactive protein (CRP) values were elevated only in the patient who had both clinical and endoscopic recurrence [0.9 (0.4–1.5) mg/dL], whereas CRP of the patient with only clinical recurrence was normal (0.5 (0.2–0.7) mg/dL) as were the values of the other four patients who kept in remission [0.3 (0.1–0.7) mg/dL]. Radiologic recurrence (score = 2) was observed only in the patient (P5) with both endoscopic and clinical recurrence, whereas the remaining patients had no evidence of disease recurrence at MRI assessment.

Table 2 Estimates of clinical efficacy of Crohn's disease patients on adalimumab maintenance treatment at 1 and 2-year follow-up evaluation and median levels of adalimumab and antibodies against adalimumab measured every 8 weeks during the 2-years follow-up period.

  Patient

P1
Patient

P2
Patient

P3
Patient

P4
Patient

P5
Patient

P6
Estimates of clinical efficacy
At 1 year of follow-up
Endoscopic recurrence No No No No No No
Clinical recurrence No No No No No No
CDAI 115 110 115 125 130 110
HBI 3 3 3 4 4 3
Radiologic recurrence 1 1 1 1 1 1
Abnormal median CRP (>0.8 mg/dL) No No No No No No
 
At 2 year of follow-up
Endoscopic recurrence No No No No Yes No
Clinical recurrence No No No Yes Yes No
CDAI 85 90 78 180 290 105
HBI 3 3 3 7 12 3
Radiologic recurrence 1 1 1 1 2 1
Abnormal median CRP (>0.8 mg/dL) No No No No Yes No
 
Pharmacokinetics of adalimumab
Median ADA levels, mcg/mL 13.0 (9.7–18.6) 13.4 (8.9–17.1) 13.0 (10.7–15.8) 8.3 (6.4–9.8) 6.31 (4.4–9.1) 20.1 (18.5–23.6)
AAAs presence/absence Transient Absent Absent Absent Persistent Absent
AAAs levels at recurrence, U/mL NA NA NA 0.00 0.9 NA
ADA levels at recurrence, mcg/mL NA NA NA 7.2 4.4 NA

CD, Crohn's disease; CDAI, Crohn's disease activity index; HBI, Harvey Bradshaw index; CRP, C reactive protein; ADA, adalimumab; AAA, antibodies against Adalimumab; TNFα, tumour necrosis factor alpha.

3.3. Pharmacokinetics of adalimumab

ADA trough levels at each time point during the follow-up period are illustrated in Fig. 1 . All patients were treated with ADA monotherapy and in those patients with clinical or endoscopic recurrence median ADA trough levels were found to be lower than in those who maintained clinical and endoscopic remission [7.5 (4.4–9.8) mcg/mL vs. 13.9 (8.9–23.6) mcg/mL,p < 0.01]. Interestingly, median ADA trough levels in patients with disease recurrence were lower also at baseline compared to patients who maintained remission (9.5 mcg/mL vs. 14.4 mcg/mL) and progressively decreased over subsequent injections until CD recurrence (P4, from 9.8 mcg/mL to 7.2 mcg/mL and P5, from 9.1 mcg/mL to 4.4 mcg/mL). Moreover, persistent AAAs were determined in the patient with both clinical and endoscopic recurrence (P5), whereas one patient in remission (P1) was found positive for transient AAAs presence throughout the follow-up period. The remaining 4 patients had no evidence of AAAs.

gr1

Fig. 1 Trough levels of adalimumab at each time point (i.e. every 8 weeks) during the entire follow-up period (2 years) in patients who maintained clinical and endoscopic remission (green lines) and those who experienced a clinical or endoscopic recurrence (red lines).

4. Discussion

Anti-TNF therapy is increasingly used in the postoperative setting in CD. However, data on the impact of trough serum levels of anti-TNF and anti-drug antibodies in CD patients after intestinal resection on recurrence risk are lacking.

We found that ADA trough levels in patients without recurrence were higher during the follow-up, whereas in patients who had recurrence they progressively decreased until recurrence. These data confirm previous findings that increased ADA trough levels well correlate with the clinical and endoscopic status of CD patients [10] . However, available studies were retrospective, with blood samples not longitudinally and systematically collected. Furthermore, ADA-treated patients likely had remnant disease in their bowel since they did not undergo resective surgery, a factor that might influence pharmacokinetics of ADA. In contrast, in our study, ADA trough levels as well as AAAs formation could not be influenced by residual disease or systemic inflammation (i.e. alterations in serum albumin levels, TNFα serum and/or tissue concentrations, etc.). Finally, none of our patients took immunosuppressive medications such as azathioprine or methotrexate, which have been recently thought to influence ADA trough levels and AAAs presence [12] .

Interestingly, we observed that the patient who developed both clinical and endoscopic recurrence had persistent AAAs. We also found that AAAs were absent or at least present in transient form in the remaining patients. These data are in agreement with those recently published by several authors highlighting the importance of antibodies against anti-TNFα drugs in reducing drugs trough levels and favouring the occurrence of loss of response in patients undergoing treatment with either IFX or ADA[8], [9], [10], [11], and [12].

It is noteworthy that ADA serum concentrations in our patients who experienced CD recurrence were already low at baseline. This finding could be partly explained by differences in drug clearance between individuals and neutralization of ADA activity by AAAs development [14] . Moreover, low albumin serum levels were found to be predictive of low values of anti-TNFα serum concentration [14] . However, in our study, this could not be analysed as all included patients had normal albumin values. Another possible explanation could be difference in body weight of our patients, as increased BMI is a predictor of loss of response in patients on anti-TNF therapy [14] . Interestingly, both our patients who had recurrence had a BMI higher than 25 kg/m2. These data suggest that low ADA levels at baseline (≤10 mcg/mL) are associated with disease recurrence within 2 years, whereas ADA levels higher than 10 mcg/mL are associated with prolonged remission.

The present observations are limited by the small number of patients included in this post hoc analysis (n = 6), which is at least partly due to the stringent inclusion criteria we applied. The main strengths of our study are the systematic evaluation of clinical, endoscopic and radiologic disease activity in all patients, with a standardized follow-up, and the prospective collection of blood samples at consecutive time points. Furthermore, this is the first investigation aimed to assess the impact of pharmacokinetics of anti-TNF in the postoperative setting.

In conclusion, considering the high costs of biological therapy together with its well-known efficacy at preventing post-surgical recurrence of CD, our preliminary observations suggest that the evaluation of drug trough levels at baseline and during prophylactic treatment after surgery may be useful in order to adopt a tailored use of these drugs and to further decrease CD postoperative recurrence. This may lead to the development of strategies that have a more favourable cost-efficacy ratio in this patient population [15] . Our findings await confirmation in large prospective studies.

Conflict of interest

None declared.

References

  • [1] L. Peyrin-Biroulet, P. Deltenre, S. Ardizzone, et al. Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn's disease: a meta-analysis. American Journal of Gastroenterology. 2009;104:2089-2096
  • [2] A. Buisson, J.B. Chevaux, P.B. Allen, et al. Review article: the natural history of postoperative Crohn's disease recurrence. Alimentary Pharmacology and Therapeutics. 2012;35:625-633
  • [3] M. Regueiro, W. Schraut, L. Baidoo, et al. Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology. 2009;136:441-450
  • [4] D. Sorrentino, A. Paviotti, G. Terrosu, et al. Low-dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn's disease. Clinical Gastroenterology and Hepatology. 2010;8:591-599
  • [5] E. Savarino, P. Dulbecco, G. Bodini, et al. Prevention of postoperative recurrence of Crohn's disease by Adalimumab: a case series. European Journal of Gastroenterology and Hepatology. 2012;24:468-470
  • [6] E. Savarino, G. Bodini, P. Dulbecco, et al. Adalimumab is more effective than azathioprine and mesalamine at preventing postoperative recurrence of Crohn's disease: a randomized controlled trial. American Journal of Gastroenterology. 2013;108:1731-1742
  • [7] M. Regueiro, K.E. Kip, L. Baidoo, et al. Postoperative therapy with infliximab prevents long-term Crohn's disease recurrence. Clinical Gastroenterology and Hepatology. 2014;10.1016/j.cgh.2013.12.035 [Epub ahead of print]
  • [8] S. Ben-Horin, Y. Chowers. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nature Reviews Gastroenterology & Hepatology. 2014;11:243-255
  • [9] K.S. Nanda, A.S. Cheifetz, A.C. Moss. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. American Journal of Gastroenterology. 2013;108:40-47
  • [10] K. Karmiris, G. Paintaud, M. Noman, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Gastroenterology. 2009;137:1628-1640
  • [11] W. Afif, E.V. Loftus, W.A. Faubion, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. American Journal of Gastroenterology. 2010;105:1133-1139
  • [12] S. Ben-Horin, M. Waterman, U. Kopylov, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology. 2013;11:444-447
  • [13] S.-L. Wang, S. Hauenstein, L. Ohrmund, et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay. Journal of Pharmaceutical and Biomedical Analysis. 2013;78–79:39-44
  • [14] M. Allez, K. Karmiris, E. Louis, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. Journal of Crohn's and Colitis. 2010;4:355-366
  • [15] F.S. Velayos, J.G. Kahn, W.J. Sandborn, et al. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab. Clinical Gastroenterology and Hepatology. 2013;11:654-666

Footnotes

a Division of Gastroenterology, Department of Internal Medicine, University of Genoa, Genoa, Italy

b Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France

c Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy

lowast Corresponding author at: Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, 35128 Padua, Italy. Tel.: +39 049 8217749; fax: +39 049 8760820.