Second Anti-TNF in IBD When Previous Treatment Has Failed
Second Anti-TNF in IBD When Previous Treatment Has Failed
The literature search revealed 797 references in Pubmed and 1067 in Embase; however, some references were excluded, among other reasons, for duplication and non-availability of data on the effectiveness of the second anti-TNF. Finally, only 46 studies met the inclusion criteria and were included. Of these, 37 focused on CD (Tables S1 and S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38), 8 on UC, and 1 on pouchitis (Table S3 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38). Studies were classified by type of IBD in order to pool data and perform the statistical meta-analysis; therefore, the pouchitis study was excluded from the meta-analysis. Of the CD studies, 32 evaluated switching from IFX to ADA, 4 switching from IFX to CZP, and 1 switching from ADA to IFX. All UC studies evaluated switching from IFX to ADA. As all studies but one used IFX as first-line anti-TNF treatment, switching from ADA to IFX was discussed separately. Methodological information of each study included has been summarised in Table S4 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38.
Remission and Response After Primary Failure. All studies evaluating remission and/or response after primary failure included in the analysis switched from IFX to ADA. Overall remission after primary failure was 30% (175 patients included) (Figure 1). Short-term remission (18%) was lower than that obtained in the medium (30%) and long term (28%) (Figure 2). No analysis was affected by the induction and maintenance doses of ADA; neither these factors nor the follow-up interval could account for the heterogeneity of the analyses (I = 24–68%).
(Enlarge Image)
Figure 1.
Remission rates with adalimumab or certolizumab after failure of infliximab in patients with Crohn's disease. Values are shown for primary failure, secondary failure and intolerance to infliximab.
(Enlarge Image)
Figure 2.
Remission rates with adalimumab or certolizumab after failure of infliximab in patients with Crohn's disease, depending on the cause of withdrawal of Infliximab therapy and the length of follow-up with the second anti-TNF drug (adalimumab or certolizumab). Follow-up intervals: short term (4–8 weeks), medium term (9–40 weeks) and long term (41–52 weeks).
The overall response rate after primary failure was 53% (57 patients included) (Figure S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). The short-, medium- and long-term response rates were, respectively, 35%, 67% and 42% (Figure S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12).
Remission and Response After Secondary Failure. Eleven studies reported remission when the anti-TNF was switched owing to secondary failure. One study reported switching from IFX to CZP; the remaining studies reported switching to ADA. Pooled remission was 45% (367 patients) (Figure 1). This result was not altered when the CZP study was excluded. A sub-analysis was performed to estimate the influence of the ADA induction dose: at doses of 160/80, a pooled remission of 51% (95% CI = 32–70%; I = 89%; 249 patients) was achieved; with a dose of 80/40, a remission rate of 44% (95% CI = 30–58%; I = 0%; 47 patients) was obtained.
The analysis by follow-up interval showed higher remission rates with longer follow-ups, ranging from 41% and 38% in the short and medium term to 60% in the long term (Figure 2).
Response rates were reported in 11 studies, with an overall response of 62% (593 patients) (Figure S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). Response rates for switching from IFX to ADA (70%; 95% CI = 49–91%; I = 91%; 172 patients) were higher than those obtained after switching to CZP (41%; 95% CI = 7–76%; I = 98%; 421 patients). The heterogeneity observed in the switch IFX to ADA was related with the study published by Cozijnsen et al., which was the only one reporting the efficacy of this strategy in paediatric patients, with an ADA dosage adjusted by weight; if this study was excluded, the response increased to 82% (95% CI = 75–88%; I = 0%; 138 patients). The 160/80 ADA dose obtained higher response rates (81% 95% CI = 72–90%; I = 0%; 73 patients) than the 80/40 dose (66%; 95% CI = 44–87%; I = 19%; 23 patients). None of the variables could explain the high heterogeneity found after switching from IFX to CZP.
Pooled response rates were higher in the short-term evaluations (66%) than in the medium term (42%) (Figure S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). All the scores were over 90% for the I statistic. Long-term response could not be pooled owing to lack of data.
Remission and Response After Intolerance. Ten studies switching from IFX to ADA reported remission after intolerance to IFX. The overall pooled remission was 61% (225 patients) (Figure 1). Heterogeneity could not be explained by the dosing schedule. A tendency towards higher remission rates was found at longer terms for measurement, with values of 50% in the short and 60% in the medium term; a long-term value (83% remission) was only reported in one study (Figure 2).
Response could be pooled in nine studies: only one evaluating switching from IFX to CZP. Overall response was 72% (313 patients) (Figure S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). Exclusion of the CZP study did not significantly alter the pooled response. Variability due to ADA dosage could not be pooled for this sub-analysis. The short-term response was 70%, and the medium-term response was 77% (Figure S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). Only one study reported on long-term response (one patient, who responded to treatment).
Remission and Response by Location/Behaviour of CD. Evaluating luminal disease patients, remission rates were 34% (3 IFX/ADA studies; 34 patients) after primary failure; 41% (3 IFX/ADA studies and 1 IFX/CZP; 90 patients) after secondary failure; and 78% (5 IFX/ADA studies; 29 patients) after intolerance (Figure 3). Sub-analyses by follow-up could not be performed, but the studies included in the secondary failure or intolerance reported remission in the short term (4–8 weeks). For secondary failure, if the study using CZP was excluded, heterogeneity disappeared and remission rates reached 48%.
(Enlarge Image)
Figure 3.
Remission rates with adalimumab or certolizumab after failure of infliximab in patients with luminal Crohn's disease. Values are shown for primary failure, secondary failure and intolerance to infliximab.
The corresponding figures for fistulising disease were poorer: remission after primary failure was 36% (95% CI = 27–46%; I = 0%; 2 IFX/ADA studies; 102 patients). No studies evaluating remission after intolerance were identified for fistulising disease, and only one reported remission after secondary failure [40% (75 patients)].
Response rates were only reported in studies on luminal disease. Switching after primary failure achieved a response rate of 45% (2 IFX/ADA studies; 10 patients). This rate increased to 71% after secondary failure (4 IFX/ADA y 2 IFX/CZP; 381 patients) and 78% after intolerance (5 IFX/ADA and 1 IFX/CZP; 242 patients) (Figure S3 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12).
Response rates in luminal disease varied depending on the type of switch: 84% with ADA after secondary failure (95% CI = 75–94%; I = 0%; 57 patients) and 55% with CZP (95% CI = 36–75%; I = 86%; 324 patients). However, studies on ADA evaluated response in the short term, whereas studies on CZP evaluated medium-term response. After intolerance, the switch was to CZP in only one study (63% response in 118 patients). If this study is excluded, response to ADA after intolerance to IFX reaches 88% (95% CI = 78–97%; I = 0%; 44 patients). All these studies reported short-term measurements except that of Goldfeld et al., who evaluated response at week 52; however, as the study included just one patient, its exclusion did not affect the pooled response.
Remission and Response in CD After Switching From ADA to IFX. Chaparro et al. performed the only study evaluating the remission and response rates of switching from ADA to IFX in a historic cohort of 15 CD patients (both luminal and fistulising disease). None of the seven patients with primary failure of ADA achieved remission or partial response to IFX at week 4. After secondary failure, all patients (five) responded to treatment, and one of them achieved remission. After intolerance, again all patients (three) responded, and two of them obtained remission. Eleven patients had luminal disease; IFX led to remission in three patients, and five patients responded to treatment. Of the four patients with fistulising disease, three responded to treatment and one reached remission.
Eight studies were identified. Treatment was switched to ADA after discontinuation of IFX in all of them. No sub-analyses could be performed, as follow-up times were not consistent and most authors did not subdivide results regarding the reason for switching. Consequently, the heterogeneity in study design prevented us from pooling efficacy estimates through a formal meta-analysis. Data shown on Table S3 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38.
Forty-two of 46 studies reported the AE rates with the second anti-TNF therapy. Of those, in 15 studies it was not possible to separately extract the AEs that occurred with the second-line anti-TNF therapy (as AEs were provided jointly with those of patients naïve to biological therapy), so they were excluded from this analysis (Table S5 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38). In CD, the incidence of AEs ranged from 0% to 81%, being the intensity of them relatively low, when it was specified. SAEs were reported in 0–21% of patients that received a second anti-TNF, being gastrointestinal disorders and infections the most frequent. Seven deaths were reported, mostly considered as not related or probably not related with anti-TNF therapy, with the exception of 2 of them. Also, two cases of demyelinating disease were reported. Withdrawal of anti-TNF treatment due to AEs was reported in up to 20% of patients. In UC patients, AE rates ranged from 20% to 39%, with SAEs ranging from 0% to 7%, and discontinuation of therapy related to AEs ranging from 0% to 48%.
Publication bias was assessed in analyses including at least 10 studies. None of the funnel plots showed evidence of publication bias.
Results
The literature search revealed 797 references in Pubmed and 1067 in Embase; however, some references were excluded, among other reasons, for duplication and non-availability of data on the effectiveness of the second anti-TNF. Finally, only 46 studies met the inclusion criteria and were included. Of these, 37 focused on CD (Tables S1 and S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38), 8 on UC, and 1 on pouchitis (Table S3 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38). Studies were classified by type of IBD in order to pool data and perform the statistical meta-analysis; therefore, the pouchitis study was excluded from the meta-analysis. Of the CD studies, 32 evaluated switching from IFX to ADA, 4 switching from IFX to CZP, and 1 switching from ADA to IFX. All UC studies evaluated switching from IFX to ADA. As all studies but one used IFX as first-line anti-TNF treatment, switching from ADA to IFX was discussed separately. Methodological information of each study included has been summarised in Table S4 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38.
Remission and Response in CD
Remission and Response After Primary Failure. All studies evaluating remission and/or response after primary failure included in the analysis switched from IFX to ADA. Overall remission after primary failure was 30% (175 patients included) (Figure 1). Short-term remission (18%) was lower than that obtained in the medium (30%) and long term (28%) (Figure 2). No analysis was affected by the induction and maintenance doses of ADA; neither these factors nor the follow-up interval could account for the heterogeneity of the analyses (I = 24–68%).
(Enlarge Image)
Figure 1.
Remission rates with adalimumab or certolizumab after failure of infliximab in patients with Crohn's disease. Values are shown for primary failure, secondary failure and intolerance to infliximab.
(Enlarge Image)
Figure 2.
Remission rates with adalimumab or certolizumab after failure of infliximab in patients with Crohn's disease, depending on the cause of withdrawal of Infliximab therapy and the length of follow-up with the second anti-TNF drug (adalimumab or certolizumab). Follow-up intervals: short term (4–8 weeks), medium term (9–40 weeks) and long term (41–52 weeks).
The overall response rate after primary failure was 53% (57 patients included) (Figure S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). The short-, medium- and long-term response rates were, respectively, 35%, 67% and 42% (Figure S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12).
Remission and Response After Secondary Failure. Eleven studies reported remission when the anti-TNF was switched owing to secondary failure. One study reported switching from IFX to CZP; the remaining studies reported switching to ADA. Pooled remission was 45% (367 patients) (Figure 1). This result was not altered when the CZP study was excluded. A sub-analysis was performed to estimate the influence of the ADA induction dose: at doses of 160/80, a pooled remission of 51% (95% CI = 32–70%; I = 89%; 249 patients) was achieved; with a dose of 80/40, a remission rate of 44% (95% CI = 30–58%; I = 0%; 47 patients) was obtained.
The analysis by follow-up interval showed higher remission rates with longer follow-ups, ranging from 41% and 38% in the short and medium term to 60% in the long term (Figure 2).
Response rates were reported in 11 studies, with an overall response of 62% (593 patients) (Figure S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). Response rates for switching from IFX to ADA (70%; 95% CI = 49–91%; I = 91%; 172 patients) were higher than those obtained after switching to CZP (41%; 95% CI = 7–76%; I = 98%; 421 patients). The heterogeneity observed in the switch IFX to ADA was related with the study published by Cozijnsen et al., which was the only one reporting the efficacy of this strategy in paediatric patients, with an ADA dosage adjusted by weight; if this study was excluded, the response increased to 82% (95% CI = 75–88%; I = 0%; 138 patients). The 160/80 ADA dose obtained higher response rates (81% 95% CI = 72–90%; I = 0%; 73 patients) than the 80/40 dose (66%; 95% CI = 44–87%; I = 19%; 23 patients). None of the variables could explain the high heterogeneity found after switching from IFX to CZP.
Pooled response rates were higher in the short-term evaluations (66%) than in the medium term (42%) (Figure S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). All the scores were over 90% for the I statistic. Long-term response could not be pooled owing to lack of data.
Remission and Response After Intolerance. Ten studies switching from IFX to ADA reported remission after intolerance to IFX. The overall pooled remission was 61% (225 patients) (Figure 1). Heterogeneity could not be explained by the dosing schedule. A tendency towards higher remission rates was found at longer terms for measurement, with values of 50% in the short and 60% in the medium term; a long-term value (83% remission) was only reported in one study (Figure 2).
Response could be pooled in nine studies: only one evaluating switching from IFX to CZP. Overall response was 72% (313 patients) (Figure S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). Exclusion of the CZP study did not significantly alter the pooled response. Variability due to ADA dosage could not be pooled for this sub-analysis. The short-term response was 70%, and the medium-term response was 77% (Figure S2 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12). Only one study reported on long-term response (one patient, who responded to treatment).
Remission and Response by Location/Behaviour of CD. Evaluating luminal disease patients, remission rates were 34% (3 IFX/ADA studies; 34 patients) after primary failure; 41% (3 IFX/ADA studies and 1 IFX/CZP; 90 patients) after secondary failure; and 78% (5 IFX/ADA studies; 29 patients) after intolerance (Figure 3). Sub-analyses by follow-up could not be performed, but the studies included in the secondary failure or intolerance reported remission in the short term (4–8 weeks). For secondary failure, if the study using CZP was excluded, heterogeneity disappeared and remission rates reached 48%.
(Enlarge Image)
Figure 3.
Remission rates with adalimumab or certolizumab after failure of infliximab in patients with luminal Crohn's disease. Values are shown for primary failure, secondary failure and intolerance to infliximab.
The corresponding figures for fistulising disease were poorer: remission after primary failure was 36% (95% CI = 27–46%; I = 0%; 2 IFX/ADA studies; 102 patients). No studies evaluating remission after intolerance were identified for fistulising disease, and only one reported remission after secondary failure [40% (75 patients)].
Response rates were only reported in studies on luminal disease. Switching after primary failure achieved a response rate of 45% (2 IFX/ADA studies; 10 patients). This rate increased to 71% after secondary failure (4 IFX/ADA y 2 IFX/CZP; 381 patients) and 78% after intolerance (5 IFX/ADA and 1 IFX/CZP; 242 patients) (Figure S3 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0001-FigS1-S3.docx?v=1&s=109f04ea18c8540812a841c89c3a11545551fb12).
Response rates in luminal disease varied depending on the type of switch: 84% with ADA after secondary failure (95% CI = 75–94%; I = 0%; 57 patients) and 55% with CZP (95% CI = 36–75%; I = 86%; 324 patients). However, studies on ADA evaluated response in the short term, whereas studies on CZP evaluated medium-term response. After intolerance, the switch was to CZP in only one study (63% response in 118 patients). If this study is excluded, response to ADA after intolerance to IFX reaches 88% (95% CI = 78–97%; I = 0%; 44 patients). All these studies reported short-term measurements except that of Goldfeld et al., who evaluated response at week 52; however, as the study included just one patient, its exclusion did not affect the pooled response.
Remission and Response in CD After Switching From ADA to IFX. Chaparro et al. performed the only study evaluating the remission and response rates of switching from ADA to IFX in a historic cohort of 15 CD patients (both luminal and fistulising disease). None of the seven patients with primary failure of ADA achieved remission or partial response to IFX at week 4. After secondary failure, all patients (five) responded to treatment, and one of them achieved remission. After intolerance, again all patients (three) responded, and two of them obtained remission. Eleven patients had luminal disease; IFX led to remission in three patients, and five patients responded to treatment. Of the four patients with fistulising disease, three responded to treatment and one reached remission.
Remission and Response in UC
Eight studies were identified. Treatment was switched to ADA after discontinuation of IFX in all of them. No sub-analyses could be performed, as follow-up times were not consistent and most authors did not subdivide results regarding the reason for switching. Consequently, the heterogeneity in study design prevented us from pooling efficacy estimates through a formal meta-analysis. Data shown on Table S3 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38.
Severe and Serious Adverse Events Related to the Administration of a Second Anti-TNF
Forty-two of 46 studies reported the AE rates with the second anti-TNF therapy. Of those, in 15 studies it was not possible to separately extract the AEs that occurred with the second-line anti-TNF therapy (as AEs were provided jointly with those of patients naïve to biological therapy), so they were excluded from this analysis (Table S5 http://onlinelibrary.wiley.com/store/10.1111/apt.13083/asset/supinfo/apt13083-sup-0002-TableS1-S5.docx?v=1&s=fb5d8d9a31153ec2cdea24400d4a8d11ee96ad38). In CD, the incidence of AEs ranged from 0% to 81%, being the intensity of them relatively low, when it was specified. SAEs were reported in 0–21% of patients that received a second anti-TNF, being gastrointestinal disorders and infections the most frequent. Seven deaths were reported, mostly considered as not related or probably not related with anti-TNF therapy, with the exception of 2 of them. Also, two cases of demyelinating disease were reported. Withdrawal of anti-TNF treatment due to AEs was reported in up to 20% of patients. In UC patients, AE rates ranged from 20% to 39%, with SAEs ranging from 0% to 7%, and discontinuation of therapy related to AEs ranging from 0% to 48%.
Reporting/Publication Bias
Publication bias was assessed in analyses including at least 10 studies. None of the funnel plots showed evidence of publication bias.
