Comparative Efficacy of Subcutaneous Compared to Intravenous Biologics for Inflammatory Bowel Disease: Systematic Review and Meta-Analysis
, Rana Ismail 1, Hissa Al-Kuwari 1, Khalifa H. Al-Ansari 1, Mohammed A. Al-Matwi 1, Noor A. Aweer 1, Wejdan N. Al-Marri 1, Yousif Al-Kubaisi 1, Muneera Al-Mohannadi 2, Shahd Hamran 1, Habib H. Farooqui 1,* and Tawanda Chivese 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis article is interesting to readers. Figures depicted (table 1, Fig 2, Fig 3, Fig 4 and Fig 5) wrong author's names.. Please ammend this. Williams to sandborn, Stefan to Schreiber, Bruce to Sands, Silvio to Danese. On the other parts there is no questin or miswritings.
Comments on the Quality of English Languageno more
Author Response
Reviewer #1:
This article is interesting to readers. Figures depicted (table 1, Fig 2, Fig 3, Fig 4 and Fig 5) wrong author's names.. Please ammend this. Williams to sandborn, Stefan to Schreiber, Bruce to Sands, Silvio to Danese. On the other parts there is no questin or miswritings.
Response 1:
We thank the reviewer for this observation – we have corrected the author’s names in Table 1, Figure 2, Figure 3, Figure 4, Figure 5, and supplementary material.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis review and meta-analysis article was performed to determine whether subcutaneous administration of biologics provided a better outcome than IV in IBD patients trial. The research was novel and attracted wide readers in the field.
14 research had been concluded for the analysis which is adequate for a proper conclusion.
Pros and cons were discussed in the later section of the study.
The presentation of results and discussion were clear to readers. The conclusion was also clear in ratifying the findings of the article.
Author Response
Reviewer #2:
Comment 1: This review and meta-analysis article was performed to determine whether subcutaneous administration of biologics provided a better outcome than IV in IBD patients trial. The research was novel and attracted wide readers in the field.
14 research had been concluded for the analysis which is adequate for a proper conclusion.
Pros and cons were discussed in the later section of the study.
The presentation of results and discussion were clear to readers. The conclusion was also clear in ratifying the findings of the article.
Response 1:
We thank the reviewer for this comment.
Reviewer 3 Report
Comments and Suggestions for AuthorsMy comments are as follows:
1. The introduction is too long and needs to be shortened.
2. It is mentioned in the introduction that remission is not maintained in patients. Back this statement up by adding pertinent data from already well-established literature about response rates and remission rates etc.
3. Provide more detailed eligibility criteria for study selection. Were only studies including adult IBD patients included?
4. It is unclear if all studies reported pertinent outcomes and for each pertinent variable what was the minimum number of studies required for meta-analyzing variables.
5. While this meta-analysis reports the efficacy and safety of sub-q vs iv therapy for IBD. The authors have done a good job of stratifying pooled results based on ibd subtype. However, this paints a totally incomplete interpretation of results. While subclassifying by IBD subtype is good, there are many variables at play that are not considered in the context. With 14 RCTs qualifying for this meta the following needs to be addressed:
A. Stratify subclasses according to the mechanism of action, while all are biological therapies, the class effect needs to be taken in to consideration.
B. Stratifying based on disease behavior and phenotype, smoking, gender, BMI, prior biologic exposure, treatment-naive status, age at diagnosis, prior surgical status are well-established factors driving treatment response.
Author Response
Reviewer #3:
Comment 1: The introduction is too long and needs to be shortened.
Response 1: We thank the reviewer for their comments. We have shortened the introduction to make it more concise and clearer.
Comment 2: It is mentioned in the introduction that remission is not maintained in patients. Back this statement up by adding pertinent data from already well-established literature about response rates and remission rates etc.
Response 2: We thank the reviewer for their comments. We added references 9 and 10 to back up our statement on the maintenance of remission in the introduction.
- Parigi TL, D'Amico F, Abreu MT, Dignass A, Dotan I, Magro F, Griffiths AM, Jairath V, Iacucci M, Mantzaris GJ, O'Morain C, Reinisch W, Sachar DB, Turner D, Yamamoto T, Rubin DT, Peyrin-Biroulet L, Ghosh S, Danese S. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023 Sep;8(9):853-859. doi: 10.1016/S2468-1253(23)00154-1. Epub 2023 Jul 6. PMID: 37423233.
- Zhang B, Gulati A, Alipour O, Shao L. Relapse From Deep Remission After Therapeutic De-escalation in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. 2020 Oct 5;14(10):1413-1423. doi: 10.1093/ecco-jcc/jjaa087. PMID: 32335670; PMCID: PMC7533897.
Comment 3: Provide more detailed eligibility criteria for study selection. Were only studies including adult IBD patients included?
Response 3: We thank the reviewer for their comments. We added the following paragraph in the eligibility criteria:
“Studies were eligible for inclusion if they were RCTs evaluating the efficacy and safety of subcutaneous compared to intravenous biologic therapies in adult or pediatric participants with IBD. We excluded observational studies, trials where the comparator was placebo, as well as those in which both the induction and maintenance phases used the same route of administration without a direct comparison between subcutaneous and intravenous biologic therapies. This approach was adopted to ensure that only studies providing a direct, head-to-head comparison between subcutaneous and intravenous administration were included”
Comment 4: It is unclear if all studies reported pertinent outcomes and for each pertinent variable what was the minimum number of studies required for meta-analyzing variables.
Response 4: Thank you for the comment we have now added this information in the flowchart Figure 1 and the results.
“Seven RCTs(24, 26-29, 47, 49) compared subcutaneous to intravenous biologics for the induction of remission”
“Seven RCTs(23-26, 48, 50, 51) measured the maintenance of remission with one study that had both cohorts of IBD”
“A total of 13 trials reported adverse events(23-29, 45-48, 50, 51) “
Comment 5: While this meta-analysis reports the efficacy and safety of sub-q vs iv therapy for IBD. The authors have done a good job of stratifying pooled results based on ibd subtype. However, this paints a totally incomplete interpretation of results. While subclassifying by IBD subtype is good, there are many variables at play that are not considered in the context. With 14 RCTs qualifying for this meta the following needs to be addressed:
5.1 Stratify subclasses according to the mechanism of action, while all are biological therapies, the class effect needs to be taken into consideration.
Response 5.1: We carried out the subgroup analysis based on the mechanism of action and presented the results in Supplementary Table 3 and added the following paragraphs in section 3.4 of the induction:
“When the data were analyzed according to the drug mechanism of action, subcutaneous biologics showed a trend towards being superior to intravenous biologics for TNF-alpha inhibitors (OR 1.27, 95%CI (0.85-1.89), I2=0.0%, p=0.620, n=2 studies), while subcutaneous showed a trend towards being inferior to intravenous biologics for interleukin 12/23 inhibitors (OR 0.77, 95%CI (0.53-1.12), I2=0.0%, p=0.972, n=4 studies) and for the combination of integrin and TNF-alpha inhibitors (OR 0.23, 95%CI (0.15-1.35), I2=0.0%, p < 0.00, n=1 studies) (Supplementary Table 3).”
We added the following paragraph in section 3.5 of the maintenance:
“When the data were analyzed according to the drug mechanism of action, subcutaneous biologics showed a trend towards being superior to intravenous biologics for TNF-alpha inhibitors (OR 1.95, 95%CI (1.03-3.66), I2=0.0%, p=0.587, n=2 studies), interleukin inhibitors (OR 1.71, 95%CI (0.92-3.19), I2=0.0%, p=0.559, n=2 studies) and anti-integrin antibody (OR 1.16, 95%CI (0.60-2.24), I2=0.0%, p < 0.00, n=1 studies). While subcutaneous showed a trend towards being inferior to intravenous biologics for the combination of TNF-alpha inhibitor and anti-integrin antibody (OR 0.69, 95%CI (0.53-0.90), I2=0.0%, p=0.419, n=2 studies) (Supplementary Table 3)”
5.2: Stratifying based on disease behavior and phenotype, smoking, gender, BMI, prior biologic exposure, treatment-naive status, age at diagnosis, prior surgical status are well-established factors driving treatment response.
Response 5.2: The trials did not provide results stratified by disease behavior and phenotype, smoking, gender, BMI, prior biologic exposure, treatment-naive status, age at diagnosis, prior surgical status. We have included this as one of the limitations of the current review in the discussion as follows:
“Finally, due to a lack of data from the included studies, we were unable to perform subgroup analyses based on well-established factors that are associated with treatment response. These factors include disease behavior and phenotype, smoking, gender, BMI, prior biologic exposure, treatment-naive status, age at diagnosis, prior surgical status. Future RCTs should consider reporting stratified analyses on these factors to better understand variations in treatment response”
Reviewer 4 Report
Comments and Suggestions for AuthorsCongratulations to the authors on this comprehensive meta-analysis of the effectiveness of different methods of switching (subcutaneous vs intravenous) biological therapy in IBD (Crohn disease and ulcerative colitis). The study applied an appropriate methodology. The results are presented clearly, with a suitable discussion and clear conclusions. The appropriate supplementary material is provided. The references are appropriate and up-to-date. The authors stated the limitations of this study.
The age of the patients was not discussed in the paper, and I believe it should be mentioned due to the specific nature of IBD in different age categories (pediatric age vs adults).
I believe the paper can be accepted after minor revisions.
Author Response
Reviewer #4:
Comment 1: Congratulations to the authors on this comprehensive meta-analysis of the effectiveness of different methods of switching (subcutaneous vs intravenous) biological therapy in IBD (Crohn disease and ulcerative colitis). The study applied an appropriate methodology. The results are presented clearly, with a suitable discussion and clear conclusions. The appropriate supplementary material is provided. The references are appropriate and up-to-date. The authors stated the limitations of this study. The age of the patients was not discussed in the paper, and I believe it should be mentioned due to the specific nature of IBD in different age categories (pediatric age vs adults).
Response 1: We thank the reviewer for their comment. All the included studies except two [1, 2] had adult participants. We added the following statement in the characteristics of the included studies:
“All trials included adult participants aged 18 to 85 with moderate-to-severe IBD, except for two trials on Risankizumab[1, 2] which included participants with ages ranging from 16 to 80”
We have also added the below statement in the limitations section of the discussion.
“Another limitation is that most of the studies focused on adult participants and therefore there remains an evidence gap on the comparative efficacy of the two routes of administration of biologics in treating pediatric IBD”
Reviewer 5 Report
Comments and Suggestions for AuthorsIn this manuscript, Nouran Alwisi et al. summarized the efficacy and safety of subcutaneous versus intravenous biologics for IBD. The results showed that subcutaneous administration has lower efficacy in the induction of remission but demonstrates better efficiency and safety in CD compared to UC. Overall, the research is valuable and interesting, with conclusions that offer better insights into drug delivery methods.
In this manuscript, Table 1 presents information about the participant groups, including the phases of remission and mechanisms of action, which vary across groups. During the analysis, how did the authors account for these factors' potential impact on the results? The authors should discuss how these differences may have influenced the outcomes.
In the Data Extraction section, could the authors provide specific numbers and descriptions related to age and gender? Additionally, please include more details regarding the data extraction process.
Regarding the figure legend, please ensure that the font and line spacing remain consistent throughout.
Comments on the Quality of English LanguageMinor editing of English language required
Author Response
Reviewer #5:
In this manuscript, Nouran Alwisi et al. summarized the efficacy and safety of subcutaneous versus intravenous biologics for IBD. The results showed that subcutaneous administration has lower efficacy in the induction of remission but demonstrates better efficiency and safety in CD compared to UC. Overall, the research is valuable and interesting, with conclusions that offer better insights into drug delivery methods.
In this manuscript, Table 1 presents information about the participant groups, including the phases of remission and mechanisms of action, which vary across groups.
Comment 1: During the analysis, how did the authors account for these factors' potential impact on the results? The authors should discuss how these differences may have influenced the outcomes.
Response 1: We thank the reviewer for their comment. This issue has been raised by reviewer 3 and we carried out subgroup analysis by the type of IBD, phase of remission, and the mechanism of action of the biologics (results in the main text and supplementary materials). A limitation of the study is the lack of striatum efficacy estimates for some of the characteristics and this limitation is noted in the discussion (see response to reviewer 3).
Comment 2: In the Data Extraction section, could the authors provide specific numbers and descriptions related to age and gender?
Response 2: Thank you, we have added specific numbers for the gender and mean age and standard deviation for age in Table 1, additionally, we added the following statement in the characteristics of included studies to address the age of participants:
“All trials included adult participants aged 18 to 85 years with moderate-to-severe IBD, except for two trials on Risankizumab[1, 2] which included participants with ages ranging from 16 to 80 years”
Comment 3: Additionally, please include more details regarding the data extraction process.Regarding the figure legend, please ensure that the font and line spacing remain consistent throughout.
Response 3: We added the following statement to provide more details regarding the data extraction:
“Data was extracted from included studies on Microsoft Excel. Eight authors (NA, RI, HA, K-HA, M-AA, N-AA, W-NA, YA) independently extracted data on the study characteristics including study design, date, location, number of participants, and selected demographic characteristics (e.g., age, gender, race, comorbidities, type, and severity of IBD)”
Thank you and we have adjusted the font and line spacing for the figure legends.
