Efficacy and Safety of Infliximab and Adalimumab in CD
Efficacy and Safety of Infliximab and Adalimumab in CD
During the study period, 93 patients with CD fulfilling the inclusion criteria were treated with anti-TNFs. Forty-four patients were treated with infliximab and 49 patients with adalimumab. Table 1 details reasons for choosing each anti-TNF treatment at enrolment.
Demographic and clinical characteristics of patients treated with anti-TNFs are summarised in Table 1. As shown, most of clinical characteristics (including age, gender, previous surgery, smoking habits, concomitant medications) were comparable between patients treated with infliximab vs. adalimumab. Differently, the two study populations differed in terms of CD duration (P = 0.02) and in the infliximab group, a higher percentage of patients were treated for perianal disease and a lower percentage of patients for refractory CD (P = 0.006) (Table 1). At enrolment, 7/44 patients (16%) in the infliximab group and 9/49 patients (18%) in the adalimumab group were on dual immunosuppression with thiopurine, initiated by >6 months, while no patients were on concomitant methotrexate treatment. Furthermore, in the infliximab group, 30/44 patients (75%) were on steroids (prednisolone 1 mg/kg tapered 5 mg/week in 14 patients or budesonide 9 mg). Accordingly, in the adalimumab group, 36/49 patients (73%) received steroids (prednisolone 1 mg/kg tapered 5 mg/week in 15 patients or budesonide 9 mg in 21 patients). In the infliximab group, 13 patients (30%) had a previous exposure to anti-TNFs (10 with infliximab, 3 adalimumab) (Table 1). In these patients, anti-TNFs were discontinued due to clinical remission (n = 11), no response (n = 1) or loss of response (n = 1). In the adalimumab group, 17 patients (35%) had previous exposure to infliximab (Table 1). Reasons for infliximab discontinuation was clinical remission (n = 13), infusion reaction (n = 2) or no response (n = 2). The flow chart in Figure 1 summarises the outcome of patients treated with either infliximab or adalimumab. During the study period, none of the patients had doses of infliximab or adalimumab increased or dosing intervals reduced.
(Enlarge Image)
Figure 1.
The flow chart summarises the outcome of the 93 CD patients treated with either infliximab or adalimumab.
Indication for infliximab included active CD in 15 (34%) patients, refractory CD in 13 (30%) patients and perianal disease in 16 (36%) patients ( Table 1 ).
Induction Treatment Among the 44 patients treated with infliximab, only 34 (77.3%) completed the induction treatment (Figure 1). Reasons for drop out before the end of the induction included no response requiring urgent surgery after week 2 in 2 (4.5%) patients and severe adverse events (SAE) in 8 (18.2%) patients. When considering the outcome of both the 34 patients completing the induction regimen and the 2 patients requiring surgery due to no response (n = 36), at week 6, 25 (70%) were in remission, 2 (5%) showed clinical improvement and 9 (25%) were no responders. In particular, two of these nine patients showing no response required urgent surgery due to refractory CD.
In the per-protocol analysis, when considering the clinical outcome at the end of the induction treatment in the 34 patients completing the induction regimen, the CDAI value significantly reduced when comparing week 0 vs. both week 2 and week 6 (P < 0.0001 for both) (Figure 2). Among the 23 patients on steroids at enrolment, 10 (43%) were able to wean off steroids within week 6. Among the 14 patients showing active perianal disease at baseline and completing the induction regimen in the per-protocol analysis, none showed fistula closure at week 6. All these 14 patients had seton drainage from enrolment to week 6.
(Enlarge Image)
Figure 2.
Histograms show the CDAI and IBDQ values before and after infliximab treatment, expressed as median with interquartile range. Panel upper right.CDAI value in the 34 patients completing the induction regimen. The CDAI value significantly reduced when comparing week 0 vs. both week 2 and week 6 (***P < 0.001 for both). Panel upper left.IBDQ value in a subgroup of 16 compliant patients completing the induction regimen. The IBDQ value significantly increased when comparing week 0 vs. week 6 (***P < 0.001). Panel lower right.CDAI value in the 23 patients completing both the induction and the maintenance treatment. The CDAI value significantly reduced when comparing week 6 vs. week 0 (*P < 0.04), week 12 vs. week 0 (**P < 0.01), week 30 and week 54 vs. week 0 (***P < 0.001), week 6 vs. week 30 (**P < 0.01), week 6 vs. week 54 (**P < 0.01), week 30 and week 54 vs. week 12 (*P < 0.04). Panel lower left.IBDQ value in a subgroup of 10 compliant patients completing both the induction and the maintenance treatment. The IBDQ did not significantly increase when comparing week 0 vs. week 6 and week 0 vs. week 54.
The IBDQ was performed in 16 compliant patients, showing a significant improvement at week 0 vs. week 6 (P < 0.001) (Figure 2).
Maintenance Treatment Among the 44 patients enrolled, 33 received maintenance treatment. As shown in Figure 1, 10 (30%) patients dropped out before week 6, while in one patient remission was maintained by using azathioprine with no infliximab. The maintenance treatment at week 54 was completed by 23 of these 33 (60%) patients, as 10 patients dropped out. Reasons for drop out included clinical worsening or loss of response (n = 5), SAE (n = 5). Three of the five patients with loss of response required surgical resection due to refractory CD at weeks 8, 10 and 30 respectively. None of these three patients showed early post-operative complications.
When considering the clinical outcome of all patients starting the maintenance treatment (n = 33), including not only the 23 patients completing the 54 weeks treatment, but also the 5 patients dropped out due loss of efficacy, the analysis included 28 patients. Among these 28 patients, 20 (74%) patients were in clinical remission, 1 (3%) patient showed clinical improvement, 4 (13%) patients clinical worsening and 3 (10%) patients loss of response.
As shown in Figure 2, in the per-protocol analysis when considering the clinical outcome in these 23 patients, the CDAI value significantly reduced at each visit during the maintenance treatment vs. baseline (week 6 vs. week 0 P < 0.04; week 12 vs. week 0 P < 0.01; week 30 and week 54 vs. week 0 P < 0.001 for both), as also at different observations within the 54 weeks follow-up. Among the 23 patients completing the maintenance treatment, 20 were on steroids at enrolment and 16 patients (80%) were able to wean off steroids within week 54.
The IBDQ was performed in a small subgroup of compliant patients (n = 10) before treatment, at week6 and at week 54. A slight improvement at week 0 vs. both week 6 and week 54 was observed, not reaching statistical significance due to the small number of patients (Figure 2). At baseline, active perianal fistulae were observed in 13 out of the 23 patients completing the maintenance treatment. At week 54, fistula closure was achieved in 11 out of these 13 patients (84%).
Among the 49 patients treated with adalimumab, indications for treatment included active CD in 17 (35%), refractory CD in 26 (53%) and active perianal disease in 6 (12%) patients ( Table 1 ).
Induction Treatment As shown in Figure 1, all the 49 patients enrolled completed the induction treatment as no SAE were observed during the 4 weeks treatment.
When considering the outcome of all the 49 patients, at week 4, 32 (66%) were in clinical remission, 7 (14%) showed clinical improvement and 10 (20%) patients were no responders. The CDAI value significantly reduced when comparing week 0 vs. both week 2 and week 4 (P < 0.0001 for both) (Figure 3). Among the 36 patients on steroid treatment at enrolment, 13 (36%) were able to wean off steroids within week 4. Among the 8 patients showing active perianal fistula at week 0, all patients had seton drainage up to the end of the induction regimen, and therefore no patients showed fistula closure at week 4.
(Enlarge Image)
Figure 3.
Histograms show the CDAI and IBDQ values before and after adalimumab treatment expressed as median with interquartile range. Panel upper right.CDAI value in 49 patients completing the induction treatment, showing that the CDAI significantly reduced when comparing week 0 vs. week 2 and week 4 (***P < 0.001 for both). Panel upper left.IBDQ value in a subgroup of patients (n = 34) during the induction treatment with Adalimumab. The IBDQ value significantly increased when comparing week 0 vs. week 4 (**P < 0.01). Panel lower right.CDAI value in 33 patients completing the induction and maintenance treatment. The CDAI significantly reduced when comparing week 0 vs. week 4, week 8, week 30 and week 54 (***P < 0.001 for all). Panel lower left.IBDQ value in a subgroup of patients (n = 10) completing the induction and maintenance treatment. The IBDQ significantly increased when comparing week 0 vs. week 4, week 8, week 30 and week 54 (*P < 0.04).
The IBDQ performed in 34 patients before and after treatment showed a significant improvement at week 0 vs. week 4 (P < 0.01) (Figure 3).
Maintenance treatment Maintenance treatment was completed by 33 out of 49 patients (67%), completing the induction regimen, as 16 patients dropped out before the scheduled 54 weeks treatment (Figure 1). Reasons for drop out included: clinical worsening or loss of response (n = 8), delayed hypersensitivity reactions (DHR) (n = 1), Herpes Zoster viral infection (n = 1), dysplasia of the uterine cervix (n = 1) or other causes (n = 5, including: lost to follow-up, ectopic pregnancy, remission while on combined azathioprine treatment, low compliance or pregnancy, on the basis of patient's decision after detailed information regarding the possibility to continue treatment).
Among the 8 patients with loss of response, 4 required elective surgery at week 6, 8, 20 and 28, respectively. None of these patients showed early post-operative complications.
The clinical outcome was first considered in the 41 patients including both the 33 patients completing the 54 week maintenance treatment and the 8 patients who dropped out due to loss of response. At week 54, 30 of these 41 patients (73%) were in clinical remission, 1 (2%) showed clinical improvement, 7 (17%) have clinical worsening and 3 (8%) showed loss of response.
In the per-protocol analysis, when considering the clinical outcome in the 33 patients completing the maintenance treatment, the CDAI value significantly reduced when comparing week 0 vs. each scheduled visit and during the maintenance treatment (week 54, week 30, week 12, week 4 vs. week 0 P < 0.001 for all) (Figure 3). Among the 24 patients on steroids at baseline, 17 (71%) were able to wean off steroids within week 54.
The IBDQ, performed in 10 compliant patients, showed a significant improvement at week 0 vs. each scheduled visit (P < 0.002) (Figure 3, panel d).
At week 54, fistula closure was observed in five of the six patients showing active perianal disease at baseline.
Univariate Analysis To assess whether clinical characteristics of patients at baseline may have influenced the likelihood of success of treatments, univariate analysis including patients with no steroid-free remission at week 0 was performed. This analysis therefore included the 80 patients with no steroid-free remission at week 0 (35 treated with infliximab and 45 with adalimumab). None of the following factors was predictive of steroid-free remission in univariate analysis (log-rank test): different anti-TNFs (infliximab or adalimumab) (P = 0.4), age (continuous variable, years) (P = 0.1), CD location (ileum, ileum-colon, colon) (P = 0.056), CD duration (continuous variable, years) (P = 0.5), previous appendectomy (yes, no) (P = 0.3), previous CD-related surgery (yes, no) (P = 0.06), perianal disease (active draining fistula or not) (P = 0.7), previous exposure to anti-TNFs (infliximab, adalimumab or naive patient) (P = 0.7), indication for anti-TNFs (active, refractory or perianal CD) (P = 0.7). Only two clinical characteristics were predictors of steroid-free remission. In particular, smoking was a negative predictor of steroids free remission when compared with no smoking [HR 0.49 (95% CI 0.26–0.92); log-rank test P = 0.02]. An additional parameter was CD behaviour, as B1 (non stricturing non penetrating) was predictive of steroid-free remission when compared with CD behaviour B3 (penetrating) and B2 (structuring) [HR 2.72 (95% CI 0.94–7.8); log-rank test P = 0.01].
The Kaplan–Meier survival analysis showed the risk of steroid-free remission in patients treated with infliximab vs. adalimumab for 54 weeks and subsequently followed up for 6 months (week 76) (Figure 4). As shown, log-rank test analysis detected no significant differences between the two groups (P = 0.4). The same analysis performed for patients treated with anti-TNFs for 54 weeks and subsequently followed up for 6 months (week 76), showed significant differences according to CD behaviour (log-rank test P = 0.01) (Figure 5) and smoking habits (log-rank test P = 0.02) (Figure 6).
(Enlarge Image)
Figure 4.
The Kaplan–Meier survival analysis shows the cumulative steroid-free remission probability in patients treated with infliximab vs. adalimumab for 54 weeks and subsequently followed up for additional 6 months (week 76). As shown, log-rank test analysis detected no significant differences between the two treatment groups (P = 0.4).
(Enlarge Image)
Figure 5.
The Kaplan–Meier survival analysis shows the cumulative steroid-free remission probability in patients with different CD behaviour treated with anti-TNFs for 54 weeks, and subsequently followed up for additional 6 months (week 76). As shown, log-rank test analysis detected significant differences between groups (P = 0.01).
(Enlarge Image)
Figure 6.
The Kaplan–Meier survival analysis shows the cumulative steroid-free remission probability in patients with different smoking habits treated with anti-TNFs for 54 weeks and subsequently followed up for additional 6 months (week 76). As shown, log-rank test analysis detected significant differences between smokers and non smokers (P = 0.02).
Multivariate Analysis Among the tested variables, only age, smoking habits, CD site, CD behaviour and previous CD-related surgery resulted in candidate variables. The variable comparing the two anti-TNFs (infliximab or adalimumab) was included in the final model, as they represent a key issue of the study. Absence of interaction and multicollinearity between variables was checked. In the final model, only no smokers and non stricturing non penetrating CD behaviour showed a significant association with an increased steroid-free remission risk [no smokers vs. smokers HR 2.94 (95% CI 1.52–5.70), P = 0.00142; non stricturing non penetrating vs. fistulising and penetrating CD behaviour HR 3.11 (95% CI 1.06–9.13); P = 0.038]. The use of adalimumab vs. infliximab was not significantly associated with the risk of steroid-free remission. Surgery for CD was associated with both the pattern (P = 0.0071) and the site (P = 0.0092), which were in turn associated (P = 0.0026).
In the infliximab group, SAE occurred in 13/44 patients (29.5%). During the induction regimen, DHR were observed in three patients and infusion reactions in five patients (subsiding after i.v. steroids and anti-histaminic drugs). All these eight patients had a previous exposure to infliximab (mean 7 years; range 6–9). During maintenance with infliximab, DHR occurred in four patients with no previous infliximab exposure, while infusion reaction was observed in one patient previously treated with adalimumab. In the adalimumab group, only 1 of 49 patients (2%) had a SAE, showing a DHR during the maintenance treatment. This patient was treated with infliximab in the previous 12 months. One additional AE was observed in one patient developing Herpes Zoster infection during the maintenance treatment, requiring drug discontinuation.
Results
During the study period, 93 patients with CD fulfilling the inclusion criteria were treated with anti-TNFs. Forty-four patients were treated with infliximab and 49 patients with adalimumab. Table 1 details reasons for choosing each anti-TNF treatment at enrolment.
Demographic and clinical characteristics of patients treated with anti-TNFs are summarised in Table 1. As shown, most of clinical characteristics (including age, gender, previous surgery, smoking habits, concomitant medications) were comparable between patients treated with infliximab vs. adalimumab. Differently, the two study populations differed in terms of CD duration (P = 0.02) and in the infliximab group, a higher percentage of patients were treated for perianal disease and a lower percentage of patients for refractory CD (P = 0.006) (Table 1). At enrolment, 7/44 patients (16%) in the infliximab group and 9/49 patients (18%) in the adalimumab group were on dual immunosuppression with thiopurine, initiated by >6 months, while no patients were on concomitant methotrexate treatment. Furthermore, in the infliximab group, 30/44 patients (75%) were on steroids (prednisolone 1 mg/kg tapered 5 mg/week in 14 patients or budesonide 9 mg). Accordingly, in the adalimumab group, 36/49 patients (73%) received steroids (prednisolone 1 mg/kg tapered 5 mg/week in 15 patients or budesonide 9 mg in 21 patients). In the infliximab group, 13 patients (30%) had a previous exposure to anti-TNFs (10 with infliximab, 3 adalimumab) (Table 1). In these patients, anti-TNFs were discontinued due to clinical remission (n = 11), no response (n = 1) or loss of response (n = 1). In the adalimumab group, 17 patients (35%) had previous exposure to infliximab (Table 1). Reasons for infliximab discontinuation was clinical remission (n = 13), infusion reaction (n = 2) or no response (n = 2). The flow chart in Figure 1 summarises the outcome of patients treated with either infliximab or adalimumab. During the study period, none of the patients had doses of infliximab or adalimumab increased or dosing intervals reduced.
(Enlarge Image)
Figure 1.
The flow chart summarises the outcome of the 93 CD patients treated with either infliximab or adalimumab.
Infliximab Group
Indication for infliximab included active CD in 15 (34%) patients, refractory CD in 13 (30%) patients and perianal disease in 16 (36%) patients ( Table 1 ).
Induction Treatment Among the 44 patients treated with infliximab, only 34 (77.3%) completed the induction treatment (Figure 1). Reasons for drop out before the end of the induction included no response requiring urgent surgery after week 2 in 2 (4.5%) patients and severe adverse events (SAE) in 8 (18.2%) patients. When considering the outcome of both the 34 patients completing the induction regimen and the 2 patients requiring surgery due to no response (n = 36), at week 6, 25 (70%) were in remission, 2 (5%) showed clinical improvement and 9 (25%) were no responders. In particular, two of these nine patients showing no response required urgent surgery due to refractory CD.
In the per-protocol analysis, when considering the clinical outcome at the end of the induction treatment in the 34 patients completing the induction regimen, the CDAI value significantly reduced when comparing week 0 vs. both week 2 and week 6 (P < 0.0001 for both) (Figure 2). Among the 23 patients on steroids at enrolment, 10 (43%) were able to wean off steroids within week 6. Among the 14 patients showing active perianal disease at baseline and completing the induction regimen in the per-protocol analysis, none showed fistula closure at week 6. All these 14 patients had seton drainage from enrolment to week 6.
(Enlarge Image)
Figure 2.
Histograms show the CDAI and IBDQ values before and after infliximab treatment, expressed as median with interquartile range. Panel upper right.CDAI value in the 34 patients completing the induction regimen. The CDAI value significantly reduced when comparing week 0 vs. both week 2 and week 6 (***P < 0.001 for both). Panel upper left.IBDQ value in a subgroup of 16 compliant patients completing the induction regimen. The IBDQ value significantly increased when comparing week 0 vs. week 6 (***P < 0.001). Panel lower right.CDAI value in the 23 patients completing both the induction and the maintenance treatment. The CDAI value significantly reduced when comparing week 6 vs. week 0 (*P < 0.04), week 12 vs. week 0 (**P < 0.01), week 30 and week 54 vs. week 0 (***P < 0.001), week 6 vs. week 30 (**P < 0.01), week 6 vs. week 54 (**P < 0.01), week 30 and week 54 vs. week 12 (*P < 0.04). Panel lower left.IBDQ value in a subgroup of 10 compliant patients completing both the induction and the maintenance treatment. The IBDQ did not significantly increase when comparing week 0 vs. week 6 and week 0 vs. week 54.
The IBDQ was performed in 16 compliant patients, showing a significant improvement at week 0 vs. week 6 (P < 0.001) (Figure 2).
Maintenance Treatment Among the 44 patients enrolled, 33 received maintenance treatment. As shown in Figure 1, 10 (30%) patients dropped out before week 6, while in one patient remission was maintained by using azathioprine with no infliximab. The maintenance treatment at week 54 was completed by 23 of these 33 (60%) patients, as 10 patients dropped out. Reasons for drop out included clinical worsening or loss of response (n = 5), SAE (n = 5). Three of the five patients with loss of response required surgical resection due to refractory CD at weeks 8, 10 and 30 respectively. None of these three patients showed early post-operative complications.
When considering the clinical outcome of all patients starting the maintenance treatment (n = 33), including not only the 23 patients completing the 54 weeks treatment, but also the 5 patients dropped out due loss of efficacy, the analysis included 28 patients. Among these 28 patients, 20 (74%) patients were in clinical remission, 1 (3%) patient showed clinical improvement, 4 (13%) patients clinical worsening and 3 (10%) patients loss of response.
As shown in Figure 2, in the per-protocol analysis when considering the clinical outcome in these 23 patients, the CDAI value significantly reduced at each visit during the maintenance treatment vs. baseline (week 6 vs. week 0 P < 0.04; week 12 vs. week 0 P < 0.01; week 30 and week 54 vs. week 0 P < 0.001 for both), as also at different observations within the 54 weeks follow-up. Among the 23 patients completing the maintenance treatment, 20 were on steroids at enrolment and 16 patients (80%) were able to wean off steroids within week 54.
The IBDQ was performed in a small subgroup of compliant patients (n = 10) before treatment, at week6 and at week 54. A slight improvement at week 0 vs. both week 6 and week 54 was observed, not reaching statistical significance due to the small number of patients (Figure 2). At baseline, active perianal fistulae were observed in 13 out of the 23 patients completing the maintenance treatment. At week 54, fistula closure was achieved in 11 out of these 13 patients (84%).
Adalimumab Group
Among the 49 patients treated with adalimumab, indications for treatment included active CD in 17 (35%), refractory CD in 26 (53%) and active perianal disease in 6 (12%) patients ( Table 1 ).
Induction Treatment As shown in Figure 1, all the 49 patients enrolled completed the induction treatment as no SAE were observed during the 4 weeks treatment.
When considering the outcome of all the 49 patients, at week 4, 32 (66%) were in clinical remission, 7 (14%) showed clinical improvement and 10 (20%) patients were no responders. The CDAI value significantly reduced when comparing week 0 vs. both week 2 and week 4 (P < 0.0001 for both) (Figure 3). Among the 36 patients on steroid treatment at enrolment, 13 (36%) were able to wean off steroids within week 4. Among the 8 patients showing active perianal fistula at week 0, all patients had seton drainage up to the end of the induction regimen, and therefore no patients showed fistula closure at week 4.
(Enlarge Image)
Figure 3.
Histograms show the CDAI and IBDQ values before and after adalimumab treatment expressed as median with interquartile range. Panel upper right.CDAI value in 49 patients completing the induction treatment, showing that the CDAI significantly reduced when comparing week 0 vs. week 2 and week 4 (***P < 0.001 for both). Panel upper left.IBDQ value in a subgroup of patients (n = 34) during the induction treatment with Adalimumab. The IBDQ value significantly increased when comparing week 0 vs. week 4 (**P < 0.01). Panel lower right.CDAI value in 33 patients completing the induction and maintenance treatment. The CDAI significantly reduced when comparing week 0 vs. week 4, week 8, week 30 and week 54 (***P < 0.001 for all). Panel lower left.IBDQ value in a subgroup of patients (n = 10) completing the induction and maintenance treatment. The IBDQ significantly increased when comparing week 0 vs. week 4, week 8, week 30 and week 54 (*P < 0.04).
The IBDQ performed in 34 patients before and after treatment showed a significant improvement at week 0 vs. week 4 (P < 0.01) (Figure 3).
Maintenance treatment Maintenance treatment was completed by 33 out of 49 patients (67%), completing the induction regimen, as 16 patients dropped out before the scheduled 54 weeks treatment (Figure 1). Reasons for drop out included: clinical worsening or loss of response (n = 8), delayed hypersensitivity reactions (DHR) (n = 1), Herpes Zoster viral infection (n = 1), dysplasia of the uterine cervix (n = 1) or other causes (n = 5, including: lost to follow-up, ectopic pregnancy, remission while on combined azathioprine treatment, low compliance or pregnancy, on the basis of patient's decision after detailed information regarding the possibility to continue treatment).
Among the 8 patients with loss of response, 4 required elective surgery at week 6, 8, 20 and 28, respectively. None of these patients showed early post-operative complications.
The clinical outcome was first considered in the 41 patients including both the 33 patients completing the 54 week maintenance treatment and the 8 patients who dropped out due to loss of response. At week 54, 30 of these 41 patients (73%) were in clinical remission, 1 (2%) showed clinical improvement, 7 (17%) have clinical worsening and 3 (8%) showed loss of response.
In the per-protocol analysis, when considering the clinical outcome in the 33 patients completing the maintenance treatment, the CDAI value significantly reduced when comparing week 0 vs. each scheduled visit and during the maintenance treatment (week 54, week 30, week 12, week 4 vs. week 0 P < 0.001 for all) (Figure 3). Among the 24 patients on steroids at baseline, 17 (71%) were able to wean off steroids within week 54.
The IBDQ, performed in 10 compliant patients, showed a significant improvement at week 0 vs. each scheduled visit (P < 0.002) (Figure 3, panel d).
At week 54, fistula closure was observed in five of the six patients showing active perianal disease at baseline.
Predictors of Steroid-free Remission and Comparison Between Anti-TNFs
Univariate Analysis To assess whether clinical characteristics of patients at baseline may have influenced the likelihood of success of treatments, univariate analysis including patients with no steroid-free remission at week 0 was performed. This analysis therefore included the 80 patients with no steroid-free remission at week 0 (35 treated with infliximab and 45 with adalimumab). None of the following factors was predictive of steroid-free remission in univariate analysis (log-rank test): different anti-TNFs (infliximab or adalimumab) (P = 0.4), age (continuous variable, years) (P = 0.1), CD location (ileum, ileum-colon, colon) (P = 0.056), CD duration (continuous variable, years) (P = 0.5), previous appendectomy (yes, no) (P = 0.3), previous CD-related surgery (yes, no) (P = 0.06), perianal disease (active draining fistula or not) (P = 0.7), previous exposure to anti-TNFs (infliximab, adalimumab or naive patient) (P = 0.7), indication for anti-TNFs (active, refractory or perianal CD) (P = 0.7). Only two clinical characteristics were predictors of steroid-free remission. In particular, smoking was a negative predictor of steroids free remission when compared with no smoking [HR 0.49 (95% CI 0.26–0.92); log-rank test P = 0.02]. An additional parameter was CD behaviour, as B1 (non stricturing non penetrating) was predictive of steroid-free remission when compared with CD behaviour B3 (penetrating) and B2 (structuring) [HR 2.72 (95% CI 0.94–7.8); log-rank test P = 0.01].
The Kaplan–Meier survival analysis showed the risk of steroid-free remission in patients treated with infliximab vs. adalimumab for 54 weeks and subsequently followed up for 6 months (week 76) (Figure 4). As shown, log-rank test analysis detected no significant differences between the two groups (P = 0.4). The same analysis performed for patients treated with anti-TNFs for 54 weeks and subsequently followed up for 6 months (week 76), showed significant differences according to CD behaviour (log-rank test P = 0.01) (Figure 5) and smoking habits (log-rank test P = 0.02) (Figure 6).
(Enlarge Image)
Figure 4.
The Kaplan–Meier survival analysis shows the cumulative steroid-free remission probability in patients treated with infliximab vs. adalimumab for 54 weeks and subsequently followed up for additional 6 months (week 76). As shown, log-rank test analysis detected no significant differences between the two treatment groups (P = 0.4).
(Enlarge Image)
Figure 5.
The Kaplan–Meier survival analysis shows the cumulative steroid-free remission probability in patients with different CD behaviour treated with anti-TNFs for 54 weeks, and subsequently followed up for additional 6 months (week 76). As shown, log-rank test analysis detected significant differences between groups (P = 0.01).
(Enlarge Image)
Figure 6.
The Kaplan–Meier survival analysis shows the cumulative steroid-free remission probability in patients with different smoking habits treated with anti-TNFs for 54 weeks and subsequently followed up for additional 6 months (week 76). As shown, log-rank test analysis detected significant differences between smokers and non smokers (P = 0.02).
Multivariate Analysis Among the tested variables, only age, smoking habits, CD site, CD behaviour and previous CD-related surgery resulted in candidate variables. The variable comparing the two anti-TNFs (infliximab or adalimumab) was included in the final model, as they represent a key issue of the study. Absence of interaction and multicollinearity between variables was checked. In the final model, only no smokers and non stricturing non penetrating CD behaviour showed a significant association with an increased steroid-free remission risk [no smokers vs. smokers HR 2.94 (95% CI 1.52–5.70), P = 0.00142; non stricturing non penetrating vs. fistulising and penetrating CD behaviour HR 3.11 (95% CI 1.06–9.13); P = 0.038]. The use of adalimumab vs. infliximab was not significantly associated with the risk of steroid-free remission. Surgery for CD was associated with both the pattern (P = 0.0071) and the site (P = 0.0092), which were in turn associated (P = 0.0026).
Safety Profile of Anti-TNFs
In the infliximab group, SAE occurred in 13/44 patients (29.5%). During the induction regimen, DHR were observed in three patients and infusion reactions in five patients (subsiding after i.v. steroids and anti-histaminic drugs). All these eight patients had a previous exposure to infliximab (mean 7 years; range 6–9). During maintenance with infliximab, DHR occurred in four patients with no previous infliximab exposure, while infusion reaction was observed in one patient previously treated with adalimumab. In the adalimumab group, only 1 of 49 patients (2%) had a SAE, showing a DHR during the maintenance treatment. This patient was treated with infliximab in the previous 12 months. One additional AE was observed in one patient developing Herpes Zoster infection during the maintenance treatment, requiring drug discontinuation.
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