Efficacy of IL-23 inhibitors and IL-12/23 inhibitors in the induction treatment of Crohn's disease: a meta-analysis based on randomized controlled trials

doi:10.21203/rs.3.rs-3211474/v1

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Efficacy of IL-23 inhibitors and IL-12/23 inhibitors in the induction treatment of Crohn's disease: a meta-analysis based on randomized controlled trials

https://doi.org/10.21203/rs.3.rs-3211474/v1

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Background

A growing number of randomized controlled trials (RCTs) have demonstrated interleukin (IL)-23 and IL-12/23 inhibitors effectiveness in treating Crohn's disease (CD). This study evaluated the efficacy of IL-23 and IL-12/23 inhibitors in the induction phase for the treatment of CD.

Methods

We searched the following databases from inception until December, 2022: Medline, Embase, Web of Science and the Cochrane Library. The primary outcome was the proportion of CD patients who achieved clinical remission at the end of the induction therapy period. Secondary outcomes included clinical response, endoscopic remission, endoscopic response and normalized C-reactive protein (CRP).

Results

After screening, 7 RCTs were included in our study. The meta-analysis showed that, in the induction period, more patients treated with IL-23 inhibitors and IL-12/23 inhibitors achieved clinical remission than patients with placebo therapy (RR = 2.11; 95%CI: 1.83–2.44; RR = 1.94; 95%CI: 1.64–2.29; respectively). The IL-23 inhibitor group and the IL-12/23 inhibitor group showed higher clinical response rates than the placebo group (RR = 1.92; 95%CI: 1.74-2,11; RR = 1.83; 95%CI: 1.61–2.09; respectively). In addition, IL-23 inhibitor group had higher endoscopic remission rate and endoscopic response rate than placebo group, the corresponding pooled RR were 3.40 (95%CI: 2.57–4.50) and 2.65 (95%CI: 2.65–3.12), respectively.

Conclusions

IL-23 and IL-12/23 inhibitors were efficiency methods in the induction treatment of CD.

Crohn's disease

IL-12/23 inhibitors

IL-23 inhibitors

meta-analysis

biologics

RCT

Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) characterized by granulomatous, chronically recurrent gastrointestinal inflammation that tends to occur in the terminal ileum and colon. [1, 2] Over time, nearly half of patients develop complications (strictures, perianal disease, fistula or abscess), often resulting in surgical interventions.[3, 4]

CD occurs more frequently in developed countries in North America and Western Europe.[5] Since the 21st century, the incidence of CD has gradually increased globally, especially in some emerging industrialized countries in Asia, South America, and Africa. [6] Currently, the goal of treating CD is to induce remission in the short term and maintain it in the long term. Pharmacological treatments include corticosteroids, thiopurine, methotrexate, and biological therapies. The introduction of biologics has brought considerable efficacy to the management of CD, along with a better safety profile than corticosteroids and immunosuppressants / immunosuppressive agents [2, 7]. However, some inhibitors, such as tumor necrosis factor (TNF) inhibitors, still have drawbacks in the treatment of CD, primarily non-response, loss of secondary reaction, potential serious adverse events (SAEs), and treatment-related costs.[8–10]

The IL23 pathway has been implicated in the pathogenesis of several immune-mediated chronic inflammatory diseases including psoriasis and CD. [11, 12] Besides, biologics like IL-23 inhibitors and IL-12/23 inhibitors have been shown to be effective in the treatment of patients with CD in randomized controlled trials (RCTs), both in the induction period and maintenance period. With the continuous emergence of the IL-23 inhibitors, there has not been a comprehensive analysis of the research in this area. In the present study, the efficacy of IL-23 and IL-12/23 inhibitors in the induction phase for the treatment of CD was further evaluated through a meta-analysis based on published randomized controlled trials.

Search strategy

This study was carried out according to the latest Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) 2020 guidelines.[13] A comprehensive systematic search of the literatures was conducted from inception until December, 2022, using Medline, Embase, Web of Science and the Cochrane Library. Any potential RCTs relevant to the efficacy of IL-23 inhibitors or IL-12/23 inhibitors in the treatment of CD would be adopted. The search algorithms were as the follows: ((Interleukin-23) OR (Interleukin 23) OR (IL-23) OR (IL 23) OR (Interleukin-12) OR (Interleukin 12) OR (IL-12) OR (IL 12)) AND ((Crohn's Enteritis) OR (Crohn Disease) OR (Regional Enteritis) OR (Crohn's Disease) OR (Crohns Disease) OR (Inflammatory Bowel Disease 1) OR (Enteritis, Granulomatous) OR (Granulomatous Enteritis) OR (Colitis, Granulomatous) OR (Granulomatous Colitis)). The literature search was conducted independently by two experienced researchers in systematic reviews.

Study Selection

The study selection was based on the PICOS (participants, intervention, comparison, outcomes and study design) principle. Studies met the following criteria were considered eligible: (a) participants: patients aged 18 years or older who were suffering from CD; (b) intervention: IL-23 inhibitors or IL-12/23 inhibitors (alone or combined with other therapies) in the induction period; (c) comparison: placebo and/or other non-biological treatments; (d) outcomes: improvement/normalization of symptoms (Crohn’s Disease Activity Index [CDAI]) and/or biochemical markers and/or endoscopic findings; (e) study design: phase II/III RCTs.

The exclusion criteria were as follows: (a) studies limited to maintenance therapy; (b) the data was unavailable or missing; (c) articles not published in English; (d) studies including pediatric patients. For updated duplicated articles, the latest published or the studies with largest sample sizes were included in the study.

Data Extraction

Two investigators independently completed the extraction according to the pre-specified formats, and discrepancies were ironed out through discussion. The following study characteristics were extracted: author, year of publication, country, trial phase, participants’ characteristics (e.g., age, gender, disease duration, biological therapy experience, etc.), number of patients, treatment regimen, follow-up duration and reported outcomes.

The primary outcome of the induction therapy was achievement of clinical remission (defined by a CDAI < 150). Secondary endpoints included achievement of clinical response (defined by a reduction in the CDAI ≥ 100 points compared to baseline), endoscopic remission, endoscopic response and normalization of C-reactive protein (CRP).

Quality Assessment

The Cochrane Collaboration’s tool [14]was used to assess the

risk of bias inherent in the included RCTs. The inherent risk of bias included random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other biases. Each aspect was scored as “low risk,” “high risk,” or “unclear risk,” with the low overall risk indicating that the study was less prone to bias.

Statistical analysis

RevMan version 5.4 software was used in the statistical analysis. For dichotomous variables, the effect size was calculated using relative risk (RR) and corresponding 95% confidence interval (CI). The heterogeneity between studies was evaluated using the I² statistic: a value of 0% indicates no observed heterogeneity, and a larger value denotes increased heterogeneity.[15] Considering the / Given the complexity of patient baseline characteristics and the use of different biological inhibitors, a random-effects model was used to analyze the results of the included studies. In order to increase the credibility of the results, publication bias (Egger’s weighted regression test[16]) and sensitivity analyses were performed since more than 10 studies were included. Moreover, a two-sided P-value < 0.05 for all statistical outcomes described above was considered statistically significant.

Study selection

Based on our literature search, a total of 944 studies were identified. After excluding duplicates, 524 studies remained, 15 of which were considered potentially relevant and were read in full text. Among the 15 studies, 1 was excluded because the study protocol did not meet the inclusion criteria, 4 were excluded because no interested outcomes was reported and 3 were excluded because the dates were unavailable. Finally, 7 studies containing 3,990 patients were included in the meta-analysis. The flowchart for the search procedure is displayed in Fig. 1.

Study Characteristics and Quality Assessment

The characteristics of the selected RCTs are showed in Table 1. Of these 7 studies, 5 RCTs evaluated the induction of IL-23 inhibitors (Including Risankizumab, Guselkumab, Mirikizumab and Brazikumab.) [17–21], and 3 RCTs evaluated the induction of IL-12/23 inhibitors (Ustekinumab only) [18, 22, 23]. Notably, one of the studies evaluated both IL-23 inhibitors and IL-12/23 inhibitors. All intervention groups were treated with a single IL-23 inhibitor or IL-12/23 inhibitor, while control groups were placebo-controlled only. Clinical remission and clinical response were reported in all studies. In addition, among the research of IL-23 induced therapy, 3 studies reported endoscopic remission rates, and 4 studies reported endoscopic response rates. The IL-23 inhibitors were assessed at week 12, while IL-12/23 inhibitors were at week 8.

Table 1

Baseline characteristics of included studies in the meta-analysis.
Author, year	Trial phase	Number of patients		Therapeutic regimen	Induction duration	Primary outcome definition
Author, year	Trial phase	Treatment	Control	Therapeutic regimen	Induction duration	Primary outcome definition
Feagan, Brian G. 2017	2	82	39	Risankizumab, 200 mg/600 mg at 0, 4, and 8 week	12 week	Clinical remission: CDAI < 150
Sands, B. E. 2017	2	59	60	Brazikumab, 700 mg at 0 and 4 week	12 week	Clinical remission: CDAI decrease of 100 points from baseline or clinical remission [CDAI < 150]
D'Haens, Geert 2022	3	675	175	Risankizumab, 600 mg/1200 mg at 0, 4, and 8 week	12 week	Clinical remission: CDAI < 150 and average daily liquid or very soft stool frequency ≤ 2.8, plus average daily abdominal pain score ≤ 1, and both not worse than baseline; Endoscopic response: A greater than 50% decrease in SES-CD from baseline
D'Haens, Geert 2022	3	382	187	Risankizumab, 600 mg/1200 mg at 0, 4, and 8 week	12 week
Sands, B. E. 2022	2	127	64	Mirikizumab, 200 mg/600 mg/1000 mg at 0, 4, and 8 week	12 week	Endoscopic response: 50% reduction from baseline in SES-CD score
Sandborn, W. J. 2022	2	185	61	Guselkumab, 200 mg/600 mg/1200 mg at 0, 4, and 8 week	12 week	The change from baseline in CDAI score: Undefined
Sandborn, W. J. 2012	2	394	132	Ustekinumab, 1/3/6 mg/kg at 0 week	8 week	Clinical response: ≤100-point decrease from the baseline CDAI
Feagan, B. G. 2016	3	494	247	Ustekinumab, 130 mg; 6mg/kg at 0 week	8 week	Clinical response: Decrease from baseline in CDAI of at least 100 points or a total CDAI score less than 150
Feagan, B. G. 2016	3	419	210	Ustekinumab, 130 mg; 6 mg/kg at 0 week	12 week
Sandborn, W. J. 2022	2	63	61	Ustekinumab, 6 mg/kg at 0 week	12 week	The change from baseline in CDAI score: Undefined
mg, milligram; Kg, kilogram; CDAI, Crohn’s Disease Activity Index; SES-CD, Simplified Endoscopic activity Score for Crohn's Disease.

The mean age of patients ranged from 35–40 years old. The mean duration of CD history in patients across studies ranged from 8.8 to 13 years. Most patients had been treated with TNF inhibitors. For more information, please refer to the Supplementary Table 1.

SFig.1 and SFig.2 show the results of the quality assessment. In the meta-analysis, the 7 studies were appraised for quality using the Cochrane Collaboration’s tool and all were judged to be of low overall risk and high quality.

Analysis of IL-23 or IL-12/23 inhibitors for the CD patients

For the primary outcome, patients receiving IL-23 inhibitors showed a higher clinical remission rate than patients with placebo therapy (RR = 2.11; 95%CI: 1.83–2.44; P < 0.001; I² = 9%; Fig. 2a), and patients receiving IL-12/23 inhibitors also had a higher clinical remission rate than the placebo group (RR = 1.94; 95%CI: 1.64–2.29; P < 0.001; Fig. 2b). In terms of the second endpoints, both the IL-23 inhibitor group and the IL-12/23 inhibitor group showed significantly higher clinical response rates compared to the placebo group (RR = 1.92; 95%CI: 1.74-2,11; RR = 1.83; 95%CI: 1.61–2.09; respectively, Fig. 3). In addition, the IL-23 inhibitor group had a higher endoscopic remission rate and endoscopic response rate than placebo group, with a corresponding pooled RR of 3.40 (95%CI: 2.57–4.50; P < 0.001; Fig. 4) and 2.65 (95%CI: 2.65–3.12; P < 0.001; Fig. 5), respectively. Moreover, a higher proportion of patients in the IL-23 inhibitor group and IL-12/23 inhibitor group achieved CRP normalization compared to the placebo group (RR = 5.76; 95%CI: 4.10–8.11; RR = 2.38; 95%CI: 1.86–3.04; respectively, Fig. 6).

In this study, we analyzed the efficacy of IL-23 inhibitors and IL-12/23 inhibitors in the induction phase for the treatment of CD. To our knowledge, this is the first systematic review and meta-analysis evaluating the effectiveness of IL-23 inhibitors in the induction phase of CD treatment. Although there have been previous meta-analyses on IL-12/23 inhibitors, [24], this review was updated based on high-quality RCTs. Overall, our analysis validates the good performance of IL-23 inhibitors and IL-12/23 inhibitors in the induction phase of treating CD in patients with or without TNF experience. Comparing with placebo, more patients in the IL-23 and IL-12/23 inhibitor groups achieved clinical remission, clinical response and CRP normalization. Additionally, more patients treated with IL-23 inhibitors achieved endoscopic remission and endoscopic response compared to those who received placebo intervention.

IL-23 plays an important role in a variety of inflammation-mediated autoimmune diseases such as psoriasis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, and IBD.[25–28] Biologics targeting IL-23p19 and IL-12/23p40 subunits have been confirmed to be effective in the treatment of psoriasis and psoriatic arthritis.[29–31]IL-23 is a member of the IL-12 cytokine family and consists of the IL-23p19 subunit and the IL-12/23p40 subunit, which is shared with IL-12.[32] Ustekinumab specifically blocks the IL-12/23 subunit p40 in CD patients whereas risankizumab, brazikumab, guselkumab and mirikizumab selectively block the unique subunit p19. Ultimately, they all lead to the blockade of the IL-23 signaling pathway and suppress the inflammatory response. [12]

In previous studies, results from animal experiments and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of IBD. A significant and selective increase of IL-23-responsive innate lymphoid cells (ILCs) were found in the inflamed intestine in CD patients but not in ulcerative colitis (UC) patients, where ILCs may promote intestinal inflammation through cytokine production and lymphocyte recruitment.[33, 34] In addition, there are T-helper-cell-17 cells, γδT cell subsets, and natural killer T cells that respond to IL-23, and an increase in these cells also promotes the intestinal inflammatory response in CD patients.[35–37] In conclusion, various lines of evidence has suggested that IL-23 is an effector cytokine in the innate gut immune system, which may be a more specific target for the treatment of CD. Additionally, preclinical studies have shown no benefit of selective blocking of IL-12 in IBD[38], and other studies in animal models have demonstrated that blocking IL-23 is more important than IL-12 in suppressing intestinal inflammation. [39, 40] Research by Laurence Chapuy et al. found that IL-12 and mucosal CD14 monocytes-like cells induce IL-8 in colonic memory CD4 T cells in UC patients, but not in CD patients. This may be relevant to the pathogenesis of UC and CD.[41]

The natural history of CD is characterized by periods of remission and relapse, and the probability of gastrointestinal complications increases when intestinal inflammation has not been well controlled. [3] The risk of developing stenosis or penetrating disease within 5 years of diagnosis of CD was 33.7%. The cumulative incidence of perianal or rectovaginal fistula within 10 years of diagnosis is 18%.[42, 43] Two RCTs reported improved fistula closure rates with TNF inhibitor treatment compared to placebo. However, due to the high recurrence rate and side effects, the long-term effect of TNF inhibitors was less favorable.[44–46] There is therefore a need to find better treatments for CD and its complications.

In this study, the efficacy of IL-12/23 and IL-23 inhibitors in the induction phase of CD was confirmed in terms of clinical manifestations, endoscopic response and inflammatory markers. Clinical symptoms of CD correlate poorly with the degree of mucosal inflammation, and it is common to find significant mucosal inflammation during complete clinical remission.[47] Endoscopic healing is considered to be a better indicator of the severity of inflammation of the intestinal mucosa. Therefore, scholars consider symptom relief (clinical response, clinical remission) to be a short-term and intermediate treatment goal, while treatment aimed at endoscopic healing is more reflective of long-term outcomes and may reduce the risk of bowel injury. [48, 49] Fecal calprotectin and CRP were the two most widely used biomarkers in IBD, Fecal calprotectin has high sensitivity and low specificity in identifying mucosal inflammation, whereas CRP has the opposite profile. Therefore, a normal CRP after initiating treatment should be considered as a minimal obligatory short- to medium-term target.[48]

Treatment of CD includes induction therapy during an acute phase of the attack and long-term maintenance therapy. Therapeutic agents during the induction phase include higher doses of corticosteroids and biological therapies. However, with corticosteroids, adverse effects (especially metabolic bone diseases, infectious complications and growth disorders[50]) and complications associated with long-term use limit their use during the maintenance phase. In the maintenance phase, treatment options include immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) and biological therapies (TNF-α, IL-12/23, IL23 and integrin α4β7).

At present, the "step-up" strategy (the introduction of biological therapies when multiple traditional therapeutic agents have failed) is still widely used in clinical practice. [7, 51]However, recent studies have shown that early biological therapy (mainly anti-TNF therapy) may improve the prognosis of patients and prevent progression to irreversible bowel damage.[2, 52–54] Berg, D. R. et al. showed that the benefits of early biologics for CD were to control inflammation and avoid progression to irreversible stricture and penetrating disease. In contrast, patients with UC have predominantly mucosal rather than transmural inflammation and complications such as strictures are rare.[7] The British Society of Gastroenterology consensus guidelines indicated that, patients with jejunum or extensive small bowel disease have a poor prognosis, and they may consider early use of biological therapies. It also recommended that ustekinumab could be used in the induction and maintenance period of CD, both in anti-TNF naïve and in patients who have failed anti-TNF treatment.[55] This is despite growing evidence that IL-23 inhibitors are effective and safe for the treatment of CD. However, the use of IL-23 inhibitors was not explicitly recommended in recently published guidelines.[2, 52, 55] For the treatment of advanced severe CD, a head-to-head RCT showed that laparoscopic ileocecal resection is more medically effective and more cost-effective in treating end-stage ileitis in CD compared with biological therapies.[56, 57]

There are some limitations to present study. Firstly, IL-12/23 inhibitors other than ustekinumab were not included as data could not be extracted. Secondly, because the study focused on evaluating the efficacy of IL-23 and IL-12/23 inhibitors in the induction phase for the treatment of CD, the efficacy of long-term maintenance therapy is unknown. At last / Finally, due to differences among the designs of studies of the included RCTs, the efficacy between IL-23 and IL-12/23 inhibitors in induction period were not directly compared.

In this systematic review and meta-analysis, IL-12/23 inhibitors and IL-23 inhibitors were shown to be effective in the induction phase in the treatment of patients with CD, as evidenced by three aspects: clinical symptoms, endoscopic symptoms, and inflammatory markers. The IL-23 and IL-12/23 Inhibitors have the potential to be a promising therapeutic option for CD patients who have had insufficient responses to conventional and TNF therapies.

RCTs, randomized controlled trials; CD, Crohn's disease; CRP, C-reactive protein; IL, interleukin; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; SAEs, serious adverse events; PRISMA, Preferred Reporting Items for Systematic review and Meta-Analysis; CDAI, Crohn’s Disease Activity Index; RR, relative risk; CI, confidence interval; ILCs, innate lymphoid cells; UC, ulcerative colitis.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets supporting this article’s conclusions are included within the article and its additional files.

Competing interests

The authors declare that they have no conflict of interest.

Funding

No funding was obtained for this study.

Authors’ contributions

All authors had read and approved the manuscript. Wenying Guo, Haojie Shentu and Suyong Sha writing manuscript; Dongying Wang, Xi Chen, Zhengwei Huang and Nan Dong performing procedures and data analysis; Haijia Lai, Meiling Chen, Jianying Xu and Jianing Huang contribution to writing the manuscript; Ziwei Zhong contribution to drafting conception and design.

Acknowledgments

None.

Permission to reuse and Copyright

All data copyright belongs to the author.

Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L: Crohn's disease. Lancet 2017, 389:1741-1755.
Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, Adamina M, Armuzzi A, Bachmann O, Bager P, et al: ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis 2020, 14:4-22.
Peyrin-Biroulet L, Loftus EV, Jr., Colombel JF, Sandborn WJ: The natural history of adult Crohn's disease in population-based cohorts. Am J Gastroenterol 2010, 105:289-297.
Meima-van Praag EM, Buskens CJ, Hompes R, Bemelman WA: Surgical management of Crohn's disease: a state of the art review. Int J Colorectal Dis 2021, 36:1133-1145.
Feuerstein JD, Cheifetz AS: Crohn Disease: Epidemiology, Diagnosis, and Management. Mayo Clin Proc 2017, 92:1088-1103.
Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, Panaccione R, Ghosh S, Wu JCY, Chan FKL, et al: Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017, 390:2769-2778.
Berg DR, Colombel JF, Ungaro R: The Role of Early Biologic Therapy in Inflammatory Bowel Disease. Inflamm Bowel Dis 2019, 25:1896-1905.
Ben-Horin S, Chowers Y: Review article: loss of response to anti-TNF treatments in Crohn's disease. Aliment Pharmacol Ther 2011, 33:987-995.
Roda G, Jharap B, Neeraj N, Colombel JF: Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol 2016, 7:e135.
Ben-Horin S, Novack L, Mao R, Guo J, Zhao Y, Sergienko R, Zhang J, Kobayashi T, Hibi T, Chowers Y, et al: Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials. Gastroenterology 2022, 162:482-494.
Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, Robinson N, Buonocore S, Tlaskalova-Hogenova H, Cua DJ, Powrie F: Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 2006, 25:309-318.
Schmitt H, Neurath MF, Atreya R: Role of the IL23/IL17 Pathway in Crohn's Disease. Front Immunol 2021, 12:622934.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021, 372:n71.
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JAC: The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical Research ed) 2011, 343:d5928.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ (Clinical Research ed) 2003, 327:557-560.
Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315:629-634.
D'Haens G, Panaccione R, Baert F, Bossuyt P, Colombel J-F, Danese S, Dubinsky M, Feagan BG, Hisamatsu T, Lim A, et al: Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. The Lancet 2022, 399:2015-2030.
Sandborn WJ, D'Haens GR, Reinisch W, Panes J, Chan D, Gonzalez S, Weisel K, Germinaro M, Frustaci ME, Yang Z, et al: Guselkumab for the Treatment of Crohn's Disease: Induction Results From the Phase 2 GALAXI-1 Study. Gastroenterology 2022, 162:1650-1664 e1658.
Sands BE, Peyrin-Biroulet L, Kierkus J, Higgins PDR, Fischer M, Jairath V, Hirai F, D'Haens G, Belin RM, Miller D, et al: Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn's Disease. Gastroenterology 2022, 162:495-508.
Sands BE, Chen J, Feagan BG, Penney M, Rees WA, Danese S, Higgins PDR, Newbold P, Faggioni R, Patra K, et al: Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn's Disease: A Phase 2a Study. Gastroenterology 2017, 153:77-86 e76.
Feagan BG, Sandborn WJ, D'Haens G, Panés J, Kaser A, Ferrante M, Louis E, Franchimont D, Dewit O, Seidler U, et al: Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study. The Lancet 2017, 389:1699-1709.
Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, Blank MA, Johanns J, Gao LL, Miao Y, et al: Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med 2016, 375:1946-1960.
Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, et al: Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med 2012, 367:1519-1528.
Honap S, Meade S, Ibraheim H, Irving PM, Jones MP, Samaan MA: Effectiveness and Safety of Ustekinumab in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Dig Dis Sci 2022, 67:1018-1035.
Lubberts E: The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol 2015, 11:415-429.
Vecellio M, Hake VX, Davidson C, Carena MC, Wordsworth BP, Selmi C: The IL-17/IL-23 Axis and Its Genetic Contribution to Psoriatic Arthritis. Frontiers In Immunology 2020, 11:596086.
Bunte K, Beikler T: Th17 Cells and the IL-23/IL-17 Axis in the Pathogenesis of Periodontitis and Immune-Mediated Inflammatory Diseases. Int J Mol Sci 2019, 20.
Gaffen SL, Jain R, Garg AV, Cua DJ: The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 2014, 14:585-600.
Huang X, Shentu H, He Y, Lai H, Xu C, Chen M, Zhu H: Efficacy and safety of IL-23 inhibitors in the treatment of psoriatic arthritis: a meta-analysis based on randomized controlled trials. Immunol Res 2023.
Yang K, Oak ASW, Elewski BE: Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review. Am J Clin Dermatol 2021, 22:173-192.
van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, Werth VP, Gordon RM, Zhou B, Hsu B, et al: Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 2018, 392:1330-1339.
Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, et al: Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000, 13:715-725.
Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, et al: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006, 314:1461-1463.
Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ, Travis SP, Powrie F: IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med 2011, 208:1127-1133.
Doisne JM, Becourt C, Amniai L, Duarte N, Le Luduec JB, Eberl G, Benlagha K: Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor (gamma)t+ and respond preferentially under inflammatory conditions. J Immunol 2009, 183:2142-2149.
McVay LD, Li B, Biancaniello R, Creighton MA, Bachwich D, Lichtenstein G, Rombeau JL, Carding SR: Changes in human mucosal gamma delta T cell repertoire and function associated with the disease process in inflammatory bowel disease. Mol Med 1997, 3:183-203.
Nanno M, Kanari Y, Naito T, Inoue N, Hisamatsu T, Chinen H, Sugimoto K, Shimomura Y, Yamagishi H, Shiohara T, et al: Exacerbating role of gammadelta T cells in chronic colitis of T-cell receptor alpha mutant mice. Gastroenterology 2008, 134:481-490.
Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, et al: Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421:744-748.
Yen D, Cheung J Fau - Scheerens H, Scheerens H Fau - Poulet F, Poulet F Fau - McClanahan T, McClanahan T Fau - McKenzie B, McKenzie B Fau - Kleinschek MA, Kleinschek Ma Fau - Owyang A, Owyang A Fau - Mattson J, Mattson J Fau - Blumenschein W, Blumenschein W Fau - Murphy E, et al: IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.
Iwakura Y, Ishigame H: The IL-23/IL-17 axis in inflammation.
Chapuy L, Bsat M, Rubio M, Sarkizova S, Therrien A, Bouin M, Orlicka K, Weber A, Soucy G, Villani AC, Sarfati M: IL-12 and Mucosal CD14+ Monocyte-Like Cells Induce IL-8 in Colonic Memory CD4+ T Cells of Patients With Ulcerative Colitis but not Crohn's Disease. J Crohns Colitis 2020, 14:79-95.
Thia KT, Sandborn WJ, Harmsen WS, Zinsmeister AR, Loftus EV, Jr.: Risk factors associated with progression to intestinal complications of Crohn's disease in a population-based cohort. Gastroenterology 2010, 139:1147-1155.
Park SH, Aniwan S, Scott Harmsen W, Tremaine WJ, Lightner AL, Faubion WA, Loftus EV: Update on the Natural Course of Fistulizing Perianal Crohn's Disease in a Population-Based Cohort. Inflamm Bowel Dis 2019, 25:1054-1060.
Lichtiger S, Binion DG, Wolf DC, Present DH, Bensimon AG, Wu E, Yu AP, Cardoso AT, Chao J, Mulani PM, et al: The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy. Aliment Pharmacol Ther 2010, 32:1228-1239.
Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, et al: Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999, 340:1398-1405.
Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, et al: Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004, 350:876-885.
Laterza L, Piscaglia AC, Minordi LM, Scoleri I, Larosa L, Poscia A, Ingravalle F, Amato A, Alfieri S, Armuzzi A, et al: Multiparametric Evaluation Predicts Different Mid-Term Outcomes in Crohn's Disease. Dig Dis 2018, 36:184-193.
Turner D, Ricciuto A, Lewis A, D’Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, et al: STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021, 160:1570-1583.
Mumolo MG, Bertani L, Ceccarelli L, Laino G, Di Fluri G, Albano E, Tapete G, Costa F: From bench to bedside: Fecal calprotectin in inflammatory bowel diseases clinical setting. World J Gastroenterol 2018, 24:3681-3694.
Irving PM, Gearry RB, Sparrow MP, Gibson PR: Review article: appropriate use of corticosteroids in Crohn's disease. Aliment Pharmacol Ther 2007, 26:313-329.
Yadav A, Foromera J, Feuerstein I, Falchuk KR, Feuerstein JD: Variations in Health Insurance Policies Regarding Biologic Therapy Use in Inflammatory Bowel Disease. Inflamm Bowel Dis 2017, 23:853-857.
Lichtenstein GR, Loftus EV, Jr., Isaacs KL, Regueiro MD, Gerson LB, Sands BE: Correction: ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol 2018, 113:1101.
Sriranganathan D, Segal JP, Garg M: Biologics recommendations in the ECCO guidelines on therapeutics in Crohn's disease: medical treatment. Frontline Gastroenterol 2022, 13:168-170.
Schreiber S, Reinisch W, Colombel JF, Sandborn WJ, Hommes DW, Robinson AM, Huang B, Lomax KG, Pollack PF: Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease. J Crohns Colitis 2013, 7:213-221.
Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee B, Lomer MCE, Parkes GC, Selinger C, et al: British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019, 68:s1-s106.
Ponsioen CY, de Groof EJ, Eshuis EJ, Gardenbroek TJ, Bossuyt PMM, Hart A, Warusavitarne J, Buskens CJ, van Bodegraven AA, Brink MA, et al: Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial. Lancet Gastroenterol Hepatol 2017, 2:785-792.
Stevens TW, Haasnoot ML, D'Haens GR, Buskens CJ, de Groof EJ, Eshuis EJ, Gardenbroek TJ, Mol B, Stokkers PCF, Bemelman WA, et al: Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: retrospective long-term follow-up of the LIR!C trial. The Lancet Gastroenterology & Hepatology 2020, 5:900-907.

No competing interests reported.

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Efficacy of IL-23 inhibitors and IL-12/23 inhibitors in the induction treatment of Crohn's disease: a meta-analysis based on randomized controlled trials

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Abstract

Background

Methods

Results

Conclusions

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Introduction

Methods

Search strategy

Study Selection

Data Extraction

Quality Assessment

Statistical analysis

Results

Study selection

Study Characteristics and Quality Assessment

Analysis of IL-23 or IL-12/23 inhibitors for the CD patients

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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