Low dose infliximab for prevention of postoperative recurrence of crohn's disease: Long term follow-up and impact of infliximab trough levels and antibodies to infliximab

Objective In patients with postoperative recurrence of Crohn's disease endoscopic and clinical remission can be maintained for up to 1 year with low infliximab doses (3 mg/Kg). However, in theory low-dose infliximab treated patients could develop subtherapeutic trough levels, infiximab antibodies, and might loose response to therapy. To verify this hypothesis infliximab pharmacokinetics and clinical/endoscopic response were checked in a group of patients treated in the long term with low infliximab doses. Design Infliximab antibodies, infliximab levels, highly-sensitive CRP and fecal calprotectin were measured during the 8-week interval in 5 consecutive patients in clinical (Crohn's Disease Activity Index < 150) and endoscopic (Rutgeerts scores 0-1) remission after one year of therapy with infliximab 3 mg/Kg. For comparison with reported standards, infliximab pharmacokinetics and inflammatory parameters were also tested in 6 Crohn's disease patients who did not undergo surgery and who were in clinical remission while on infliximab 5 mg/ Kg. Patients on low infliximab dose also underwent colonoscopy after 18 additional months of therapy. Results Highly sensitive CRP and fecal calprotectin increased in all patients during the 8-week interval. Infliximab trough levels were lower in patients treated with the low dose compared to controls (mean\ub1SE: 2.0\ub10.3 vs 4.75\ub10.83 \uceg/mL respectively p<0.05). Infliximab antibodies were present in two of the subjects treated with low infliximab dose and in none of the controls. However, in low dose-treated patients after 18 additional months of therapy endoscopy continued to show mucosal remission and none of them developed clinical recurrence or side effects. Conclusions Patients treated with low infliximab doses had lower trough levels compared to patients treated with 5 mg/Kg and some developed antibodies to infliximab. However, low infliximab doses sustained clinical and endoscopic remission for a total of 30 months of treatment

Infliximab concentration (A), Highly Sensitive [HS]–CRP (B) and Fecal Calprotectin (C) during infliximab therapy.

<p>Empty long dash lines: control patients (treated with infliximab 5 mg/Kg); Filled lines: study subjects (treated with infliximab 3 mg/Kg). Square dot lines indicate the upper limit of the normal range for HS-CRP and Fecal Calprotectin. Values are reported as mean and standard error (vertical bars). The asterisk denotes a significant difference (p < 0.05) between controls and study subjects at a given time point during the 8-week therapeutic interval.</p

Study Design.

<p>Patients subjected to prophylactic infliximab [IFX] 5 mg/Kg after surgery and in full remission after 3 years of therapy showed endoscopic recurrence in 83% of cases when the medication was stopped. Those with recurrence (n = 10) re-started IFX in a dose optimization study in which we showed that 3 mg/Kg were sufficient to re-induce and maintain endoscopic remission for 1 year in all patients (ref.2). Five of these ten patients participated in the current study. Antibodies To Infliximab [ATI] and Infliximab Trough Levels [ITL] were measured and compared to those of CD patients who did not undergo surgery in remission on a standard 5 mg/Kg IFX dose. After an additional 18 months the patients treated with 3 mg/Kg IFX underwent colonoscopy.</p

Low-dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn's disease

BACKGROUND & AIMS: Infliximab might prevent postsurgical recurrence of Crohn\u2019s disease. However, it is unclear whether long-term therapy is necessary and whether alternative strategies could be applied to minimize potential side effects and reduce the costs of treatment. METHODS: We performed a prospective cohort study in 12 consecutive patients, treated immediately after surgery with maintenance infliximab (5 mg/kg), who did not have clinical or endoscopic evidence of disease recurrence after 24 months; they were followed up for an additional year. Infliximab treatment was then discontinued; patients with disease recurrence, based on endoscopy (Rutgeerts score, 2), were given lower doses of infliximab (starting with 1 mg/kg) to re-establish mucosal integrity. Surrogate markers of disease activity (fecal calprotectin [FC], C-reactive protein, and erythrocyte sedimentation rate) were assessed after each infliximab dose. RESULTS: None of the patients had clinical or endoscopic recurrence of Crohn\u2019s disease 3 years after surgery. However, discontinuation of infliximab caused endoscopic recurrence after 4 months in 10 of 12 patients (83%). All 10 patients then were treated again with infliximab, which, at a dose of 3 mg/kg every 8 weeks, restored and maintained mucosal integrity for 1 year. Among the surrogate markers, FC levels correlated with endoscopic scores (Wald test, P .0001). CONCLUSIONS: Long-term maintenance therapy with infliximab is required to maintain mucosal integrity in patients after surgery for Crohn\u2019s disease. However, a dose of 3 mg/kg (a 40% reduction from the standard dose) was sufficient to avoid disease recurrence, determined by endoscopy, in all patients at 1 year. FC levels correlate with mucosal status at different infliximab doses

Early diagnosis and treatment of postoperative endoscopic recurrence of Crohn's disease: partial benefit by infiximab - A pilot study

Goals: Primary outcome of this study was to clarify whether infliximab, given after diagnosis of post operative endoscopic recurrence of Crohn\u2019s diseases, can heal mucosal lesions (score &lt;2) at 54 weeks. The secondary outcomes were improvement in the endoscopic score and clinical recurrence at 54 weeks. Background: Current data indicate that infliximab - given immediately after surgery \u2013 may be very effective in preventing postsurgical recurrence of Crohn\u2019s disease. However, it is unknown whether a similar benefit would result from early diagnosis and treatment, rather then prevention, of endoscopic recurrence. Study: In this prospective open label multicenter pilot study 43 patients with ileocolonic Crohn\u2019s disease subjected to curative surgery underwent colonoscopy 6 months after surgery. Patients with endoscopic recurrence (Rutgeerts score 65 2) were treated with either mesalamine 800 mg tid or infliximab 5 mg/Kg bw on a maintenance basis. Colonoscopy was performed after 54 weeks of therapy. Results: A total of 24/43 patients were diagnosed with endoscopic recurrence at 6 months. Thirteen were treated with infliximab and eleven with mesalamine. None of the 11 mesalamine treated patients had mucosal healing at 54 weeks. Two had clinical recurrence at 8 and 9 months. Fifty-four percent of patients treated with infliximab had mucosal healing at 54 weeks (p=0.01) while 69% had an improvement in the endoscopic score. None had clinical recurrence. Conclusions: Treatment of postsurgical endoscopic lesions by infliximab appears superior to mesalamine. However a sizeable proportion of patients did not fully benefit from this strategy