Efficacy and safety of anti-integrin antibodies in inflammatory bowel disease: systematic review and meta-analysis

Juan Lasa, Astrid Rausch, Ignacio Zubiaurre

Gastroenterology Department. Hospital Británico de Buenos Aires. Ciudad Autónoma de Buenos Aires, Argentina.

Acta Gastroenterol Latinoam 2018;48(2):106-116
Recibido: 15/05/2017 / Aprobado: 25/08/2017 / Publicado en www.actagastro.org el 18/06/2018

Summary

Background. Integrins are heterodimeric proteins that stimulate leukocyte adhesion to endothelial cells. Antibodies against integrins have been used as a therapeutic option in inflammatory bowel disease. Class-effect of these drugs has not been extensively assessed. Aim. To estimate the efficacy and safety of these drugs in inflammatory bowel disease. Ma­terial and methods. MEDLINE, EMBASE, LILACS and The Cochrane libraries were searched from 1966 to April 2017. Randomized, placebo-controlled trials in adults com­paring anti-integrin antibodies versus placebo were eligible. Data was pooled to obtain relative risk of failure to achieve remission in active disease and relative risk of relapse of ac­tivity in quiescent disease, once remission had been achieved. Results. The search yielded 4201 citations, 10 of which were eligible. Anti-integrin antibodies were superior to placebo in inducing remission of both Crohn’s disease and ulcerative colitis [RR of no remission = 0.80 (0.73-0.87) and 0.86 (0.79-0.94), respectively]. They were superior to placebo in preventing relapse of Crohn’s disease [RR of relapse = 0.80 (0.73-0.87)]. One trial assessing anti-integrin antibodies ef­ficacy in preventing relapse of Ulcerative colitis, showed that they were superior to placebo. Conclusion. Anti-integrin antibodies were superior to placebo in inducing and maintaining remission of active Crohn’s disease and Ulcerative Colitis.

Key words. Inflammatory bowel disease, integrins, biologi­cal therapy.

Eficacia y seguridad de los anticuer­pos anti-integrina en la enfermedad inflamatoria intestinal: una revision sistematica y meta-analisis

Resumen

Introducción. Las integrinas son proteínas heterodiméri­cas que estimulan la adhesión leucocitaria al endotelio. Los anticuerpos anti-integrinas se han utilizado como alterna­tiva terapéutica en la enfermedad inflamatoria intestinal. El efecto de clase de estas drogas no fue exhaustivamente evaluado. Objetivo. Estimar la eficacia y la seguridad de este tipo de drogas en la enfermedad inflamatoria intesti­nal. Material y métodos. Las bases de datos de MEDLI­NE, EMBASE, LILACS y Cochrane fueron revisadas desde 1966 hasta abril de 2017. Fueron seleccionados los ensayos aleatorizados y controlados con placebo en adultos compa­rando anticuerpos anti-integrinas versus placebo. Se buscó obtener el riesgo relativo del fallo en inducir la remisión en pacientes con enfermedad activa y el riesgo relativo del fallo en el mantenimiento de la remisión. Resultados. La búsque­da arrojó 4201 citas, de las cuales fueron 10 las utilizadas para el análisis. Los anticuerpos anti-integrina fueron supe­riores al placebo para inducir la remisión en la enfermedad de Crohn y la colitis ulcerosa [RR 0,80 (0,73-0,87) y 0,86 (0,79-0,94), respectivamente]. A su vez, mostraron ser superiores al placebo para el mantenimiento de la remisión en la en­fermedad de Crohn [RR = 0,80 (0,73-0,87)]. Un estudio mostró que estos anticuerpos fueron superiores al placebo para el mantenimiento de la remisión en la colitis ulcerosa. Conclusiones. Los anticuerpos anti-integrinas demostraron ser superiores al placebo para la inducción y el mantenimiento de la remisión en enfermedad de Crohn y colitis ulcerosa.

Palabras claves. Enfermedad inflamatoria intestinal, inte­grinas, terapia biológica.

Abbreviations
CD: Crohn’s disease.
IBD: inflammatory bowel disease.
NNT: number necessary to treat.
PML: progressive multifocal leucoencephalopathy.
RR: relative risk.
UC: ulcerative colitis.

Inflammatory bowel disease (IBD) is a chronic dis­order of the gastrointestinal tract of unknown etiology.¹

There are two well-defined clinical entities of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). These conditions carry a considerable morbidity, with an in­creased risk for hospital admissions, surgical treatment or even colorectal cancer.²

A wide variety of therapeutic options have been pro­posed, both pharmacological and surgical.^{3, 4} The investi­gation of the immunological mechanisms related to IBD has allowed the development of new therapeutic alterna­tives. Among these, antibodies against tumor necrosis fac­tor alpha (TNF-a) have resulted in a significant impact on IBD’s natural history and prognosis.⁵ However, up to 30% of patients may not have and adequate response to these agents and approximately 50% may experience loss of efficacy during the first year of treatment.⁶

As a consequence, different monoclonal antibodies against other immunological mediators have been tested on IBD, such as anti-integrin antibodies. Integrins are heterodimeric proteins that stimulate leukocyte adhesion to endothelial cells.⁷ Thus; they play a key role in chronic inflammatory response. Alpha-4-beta-7 integrin is in­volved in the recruitment of leukocytes in the intestine. Natalizumab, an a4-integrin that acts against a4b1 and a4b7 integrin was first used on CD patients.⁸ Recently, a novel antibody directed against a4b7 integrin, Vedoli­zumab, was introduced, with promising results.⁹

Class-effect of these drugs on IBD has not been ex­tensively assessed. Hence, we thought to perform a sys­tematic review and meta-analysis of current evidence on this subject to assess their global efficacy as therapeutic agents against IBD. What is more, data on their safety is relevant, since Natalizumab8 has a restricted use due to the occurrence of potentially serious adverse events. Therefore, we also aimed to estimate the incidence of these events.

Materials and methods

Search strategy and study selection
A computer-based search of compatible papers from 1966 to April 2015 was performed using the following databases: MEDLINE-PubMed, EMBASE, LILACS and The Cochrane Library. Search strategy consisted of the following MESH terms: biologic therapy OR integrin OR leukocyte adhesion OR monoclonal antibody AND inflam­matory bowel disease OR Crohn’s disease OR ulcerative colitis.

Relevant paper’s bibliographies were revised, as well as bibliographies from previously published meta-analyses. A manual search for potentially relevant abstracts from Digestive Disease Week and United European Gastro­enterology Week from 2009-2016 was also undertaken.

Two authors performed bibliographic search in an independent manner. Potentially relevant abstracts were revised to check its inclusion. Inclusion criteria were: a) trials examining the efficacy of any anti-integrin antibody for IBD treatment; b) randomized, placebo-controlled trials; c) trials performed on adults. There were no lan­guage restrictions. Studies that implied simultaneous ad­ministration of anti-integrin antibodies and anti-TNF-a antibodies were excluded.

Search findings were then compared. If there was dis­agreement on the inclusion of a particular trial, it was discussed and determined by consensus. If there was evi­dence of duplication of data, the main author would be contacted to determine its inclusion.

Methodological evaluation of included studies
Methodological assessment was done using the Evi­dence-Based Gastroenterology Steering Group recommen­dations.¹⁰ A Jaded score of each trial was also calculat­ed. If a significant difference in methodological quality among studies was observed, a sensitivity analysis would be undertaken by excluding those trials with less quality. If relevant data was missing in original manuscripts, au­thors would be contacted.

Outcome measures

The following outcomes were considered for analysis: efficacy of anti-integrin antibodies compared to placebo in terms of failure to achieve remission in active IBD and relapse of disease activity in quiescent IBD. Secondary outcomes included assessing the frequency of adverse events occurring as a result of therapy. Data were extract­ed as intention-to-treat analyses, in which all dropouts are assumed to be treatment failures, wherever trial re­porting allowed this.

Statistical analysis
Meta-analysis was performed using REVMAN soft­ware (Review Manager Version 5.2. Copenhagen: The Nordic Cochrane Collaboration, 2012). Heterogeneity among studies was evaluated by means of chi square and I2 tests. A random-effect model was used to give a more conservative estimate of the effect of individual therapies, allowing for any heterogeneity among studies. Outcome measures were described as relative risk (RR) of failure to achieve remission and RR of relapse of disease activ­ity in CD patients as well as in UC patients. Also, 95% confidence intervals were calculated. Funnel plots were designed to evaluate possible publication bias. Numbers necessary to treat (NNT) were calculated.

Results

Search yielded 4201 bibliographic citations, 29 of which were identified as potentially relevant. Figure 1 describes reasons for exclusion of identified studies. Fi­nally, ten randomized, placebo-controlled trials were in­cluded for analysis, which enrolled 4048 subjects.^11-20

The characteristics of the included trials are described in Tables 1 (trials on induction of remission in CD pa­tients), 2 (trials on relapse prevention in CD patients) and 3 (trials on induction of remission in UC patients). Clinical remission definitions as well as time of evaluation after intervention were similar among included studies.

Methodological evaluation of included trials is de­scribed in Table 4. No trial was excluded due to meth­odological limitations. Funnel plot is detailed in Figure 2, showing an asymmetry that suggests the presence of a potential publication bias.

Figure 1. Flow diagram of assessment of studies identified in the systematic review.

Efficacy of anti-integrin antibodies in inducing remis­sion in CD
Four trials evaluating Natalizumab efficacy^11-14 and three trials evaluating Vedolizumab efficacy^{15, 19, 20} were assessed. These trials enrolled 3408 patients. No signifi­cant heterogeneity was found among trials. Results are shown in Figure 3. Anti-integrin antibodies showed a sig­nificantly lower RR of failure to induce remission com­pared with placebo [RR 0.89 (0.83-0.94)], with a global NNT of 33. When considering trials that evaluated Ve­dolizumab, 1401 patients were analyzed. Vedolizumab also showed a significant lower RR of failure to induce re­mission [RR 0.86 (0.82-0.90)]. It is noteworthy that the trial published by Sands et al included patients with pre­vious TNF antagonist failure. A sensitivity analysis was performed considering only anti-TNF-naïve patients and no significant differences were found on the outcome.

Table 1. Characteristics of randomized controlled trials of anti-integrin antibodies vs. placebo in inducing remission in active CD.

Table 2. Characteristics of randomized controlled trials of anti-integrin antibodies vs. placebo in preventing relapse in quiescent CD.

Table 3. Characteristics of randomized controlled trials of anti-integrin antibodies vs. placebo in inducing remission in active UC.

Table 4. Methodological evaluation of included randomized controlled trials.

Figure 2. Funnel plot of included studies.

Efficacy of anti-integrin antibodies in inducing remis­sion in UC
Two trials evaluating Vedolizumab efficacy on 555 patients^{16, 17} and one phase II trials assessing the efficacy of Etrolizumab¹⁸ were included. The trial published by Feagan et al in 2013 included a cohort of patients en­rolled in an open-label group, which was not consid­ered for analysis. No trials on Natalizumab were found on this particular subject. No significant heterogeneity among trials was found. Results are shown in Figure 4. Vedolizumab showed a significantly lower RR of fail­ure to induce remission versus placebo [RR 0.85 (0.77- 0.94)], with a NNT of 8. Both trials assessed mucosal healing as an endpoint, though they used different scores (modified Baron Score and Mayo Score). When assess­ing Etrolizumab, the study by Vermeire et al showed that compared to placebo, Etrolizumab was significantly more effective in inducing clinical remission at week 10; however, more evidence is needed before drawing a valid conclusion since only a phase I and a phase II trial using Etrolizumab were published so far. Pooled results of Ve­dolizumab and Etrolizumab, as shown in Figure 4, still showed a significant efficacy of anti-integrin antibodies to induce remission. Once again, Vedolizumab showed a significantly lower RR of failure to induce mucosal heal­ing versus placebo [RR 0.84 (0.74-0.94)]. Results are shown in Figure 5.

Figure 3. Forest plot of randomized controlled trials of anti-integrin antibodies versus placebo in inducing remission in ac­tive CD.

Figure 4. Forest plot of randomized controlled trials of anti-integrin antibodies versus placebo in inducing remission in ac­tive UC.

Figure 5. Forest plot of randomized controlled trials of anti-integrin antibodies versus placebo in inducing mucosal healing in active UC.

Efficacy of anti-integrin antibodies in preventing re­lapse in CD
Two trials assessed the efficacy of anti-integrin an­tibodies for relapse prevention in CD: one evaluating Natalizumab¹³ and the other evaluating Vedolizumab.¹⁹ Overall, they comprised 799 patients. No significant het­erogeneity was found. Results are described in Figure 6. A significant difference was detected versus placebo [RR 0.80 (0.73-0.87)]. Global NNT was 11.

Efficacy of anti-integrin antibodies in preventing re­lapse in UC
Only one trial assessed Vedolizumab efficacy in pre­venting relapse in subjects with UC.¹⁷ A significantly higher efficacy for remission maintenance was found in those receiving Vedolizumab every 8 weeks (51/122, 41.8%) and every 4 weeks (56/125, 44.8%) than pla­cebo (20/126, 15.9%) at 52 weeks (p < 0.001 in each case).

Figure 6. Forest plot of randomized controlled trials of anti-integrin antibodies versus placebo in preventing relapse in qui­escent CD.

Adverse events
Tables 5 and 6 show adverse events incidence in pa­tients treated with Natalizumab and Vedolizumab respec­tively versus placebo. Overall, no significant differences were found in terms of serious adverse events or serious infections when comparing Natalizumab versus placebo. Progressive Multifocal Leukoencephalopathy (PML) was not reported in any of the included studies. On the other hand, Vedolizumab showed an increased risk in serious adverse events and serious infections.

Table 5. Adverse events with Natalizumab vs. placebo in inducing remission in active CD.

Table 6. Adverse events with Vedolizumab vs. placebo in inducing remission in active CD and UC.

Discussion

As specified by the results of our meta-analysis, there is a class-effect of anti-integrin antibodies for remission induction in patients with CD and UC. There is less evi­dence supporting their role for remission maintenance; in fact, available evidence failed to show a significant benefit for remission maintenance in patients with CD. According to our knowledge, this systematic review puts on perspective the utility of this kind of drugs suggesting that in the future new medicines that interfere leukocyte adhesion may represent a valid therapeutic alternative.

There is growing evidence regarding anti-TNF anti­bodies efficacy for induction and maintenance of clini­cal remission in CD and UC.²¹ However, a significant proportion of patients may not have a clinical response or lose response over time.²² Thus, there is a need for new therapeutic strategies in this area.

Integrin a4 inhibition has a proven effect on inflam­matory response, not only on intestinal but also on ex­tra-intestinal inflammation.⁸ Natalizumab inhibits a4ß7 and a1b1 integrins and is effective for CD treatment, as shown in previous meta-analysis by Ford et al. As a result of a1b1 inhibition, it has a significant effect on leuko­cyte adhesion in the central nervous system. In fact, it has been used as a therapeutic option for central nervous sys­tem autoimmune conditions, such as multiple sclerosis.²⁴

Nevertheless, during the last few years, increasing re­ports on the development of PML caused by activation of JC virus in patients treated with Natalizumab have been published.²⁵ As a consequence, its use has been restricted, resulting in the lack of further published experiences with this drug and the need for selective inhibition of a4b7 integrin.²⁶ While Ertrolizumab²⁷ and Vedolizumab have been developed, evidence of efficacy is strongest for Ve­dolizumab.

Vedolizumab is an IgG1 human antibody directed against a4b7 integrin that is effective for CD and UC in multicenter trials.^{17, 19, 20} According to our meta-analysis, Vedolizumab seems to have a better performance on UC than CD. More evidence is still required to determine the real magnitude of these differences. What is more, ad­ditional evidence is still required to evaluate the efficacy of this kind of drugs for maintenance of remission. It is worth mentioning that only one trial evaluated mucosal healing as an outcome measure.¹⁷ As a consequence, more evidence is still necessary on the efficacy of these drugs to induce and maintain mucosal healing. According to the trial published by Sands et al, Vedolizumab efficacy was greater when clinical outcomes were assessed at 10 weeks, after finishing induction therapy.²⁰ This is an important point to be considered when conducting future clini­cal trials with anti-integrin antibodies, since remission should then be monitored a few weeks after induction therapy completion.

A rather promising therapeutic agent was also intro­duced in this systematic review: Etrolizumab, a human­ized monoclonal antibody that selectively binds the b7 subunit of the heterodimeric integrins a4b7 and aEb7. There is very little evidence on its clinical efficacy, so caution must be taken when analyzing the results of the phase II clinical trial included in this systematic review.

Included trials with Vedolizumab have not shown any reported cases of PML. However, it is noteworthy that, unlike Natalizumab, Vedolizumab patients had a significant higher risk of serious adverse events and seri­ous infections. This aspect highlights the need for further evidence assessing this aspect.

Finally, little evidence is shown on the efficacy of these drugs in patients who have already experienced TNF an­tagonist failure. Although anti-integrin antibodies would seem like a valid option in this clinical scenario, more evidence is still needed from prospective clinical trials.28

The main strength of this meta-analysis is that, it eval­uates the class-effect of anti-leukocyte adhesion antibod­ies, instead of the individual effect of a single drug. This is relevant because it enforces the potential utility of future anti-leukocyte adhesion antibodies. Despite the rigorous search strategy, funnel plot asymmetry suggests the pres­ence of publication bias that could be a significant limita­tion of this meta-analysis. We think, however, that this asymmetry may be due to the relatively scarce number of published trials. It is important to highlight that the results were expressed as a relative risk of failure to induce and/or maintain remission due to previously published meta-analyses such as the one published by Ford et al that use the same methodology.²³

In conclusion, anti-integrin antibodies have shown a beneficial class effect for induction of clinical remission in patients with CD and UC. There is a need for more evidence on their efficacy for maintaining remission. Their role on IBD treatment still needs to be determined.

Authors’ contributions. JL performed the bibliograph­ic search, undertook statistical analysis, contributed to the writing of the draft. AR performed the bibliographic search, contributed to the writing of the draft. IZ performed the bib­liographic search, contributed to the writing of the draft, and reviewed the final draft.

Acknowledgements. We would like to thank to Dr. Mi­chael Picco for the critical review made on this manuscript.

Conflicts of interest. Astrid Rausch is consultant physi­cian for Takeda Pharmaceuticals. Ignacio Zubiaurre and Astrid Rausch are speakers for Abbvie Pharmaceutical Com­pany. Ignacio Zubiaurre is consultant physician for Ferring Pharmaceuticals. Juan Lasa declares no conflict of interests.

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Correspondencia: Juan Lasa
Libertad 984 (ZIP Code: 1012). Ciudad Autónoma de Buenos Aires,
Argentina. Tel: (5411) 48234642 / Fax: (5411)48127944
Correo electrónico: drjuanslasa@gmail.com

Acta Gastroenterol Latinoam 2018;48(2): 106-116