Introduction
Data are needed to clarify the positioning of biological therapies and small molecules for early resolution of moderately to severely active luminal Crohn’s disease (CD). We aimed to compare early response for advanced CD therapies in a systematic review with network meta-analysis.
Aims & Methods
We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and Sep 10, 2022. The co-primary outcomes were the induction of clinical response, defined as ≥70-point reduction in Crohn’s Disease Activity Index (CDAI-70 response) from baseline, and clinical remission, defined as CDAI ≤150 at week 2. Network meta-analysis was conducted under the Bayesian framework (PROSPERO ID: CRD42022368509).
Results
Of 16,242 and 19,281 studies from databases and congress proceedings, respectively, a total of 61 studies, comprising 17,436 patients, were included in this study. Infliximab 5 mg/kg combined with azathioprine or monotherapy ranked highest for induction of clinical response at week 2 and was significantly superior to adalimumab 160/80 mg, adalimumab 80/40 mg, certolizumab 400 mg, risankizumab 1200 mg, and risankizumab 600 mg. Accordingly, infliximab 5 mg/kg ranked highest for induction of clinical remission at week 2. Findings were consistent throughout week 6 in the overall population and bio-naïve patients. Upadacitinib 45 mg QD ranked highest at week 2 but was not significantly superior to biologics for the induction of CDAI-100 response; of note, no data on CDAI-100 response for infliximab 5 mg/kg were found. Comparison of agents for bio-exposed patients was first possible at week 4; herein, adalimumab 160/80 mg and ustekinumab 6 mg/kg ranked highest for induction of both clinical response and clinical remission in the absence of data on infliximab 5 mg/kg. Finally, Vedolizumab 300 mg, guselkumab 200/600/1200 mg, mirikizumab 200/600/1000 mg, and filgotinib 200 mg reached significant differences from placebo at weeks 4, 8, 8, and 10, respectively, in either CDAI scores or 2-item patient-reported outcome (PRO-2) scores.
Table 1: League plot for the comparison of biologics and small molecule drugs for the induction of a CDAI-70 response at week 2 in patients with moderately to severely active luminal Crohn’s disease. The values in each cell represent the relative treatment effect (relative risk and 95% credible intervals) of the column-defining treatment compared to the row-defining treatment. A double asterisk indicates statistical significance.
| Infliximab 5 mg/kg + azathioprine
| Infliximab 5 mg/kg
| Adalimumab 80/40 mg
| Adalimumab 160/80 mg
| Certolizumab 400 mg
| Risankizumab 1200 mg
| Risankizumab 600 mg
| Upadacitinib 24 mg BID
| Placebo
|
Infliximab 5 mg/kg + azathioprine
|
| 0.88 (0.74-1.05)
| **0.41 (014-0.94)**
| **0.34 (0.12-0.75)**
| **0.31 (0.11-0.68)**
| **0.29 (0.10-0.64)**
| **0.29 (0.10-0.64)**
| **0.25 (0.08-0.70)**
| **0.22 (0.08-0.47)** |
Infliximab 5 mg/kg
| 1.13 (0.95-1.36)
|
| 0.46 (0.16-1.04)
| **0.39 (0.14-0.83)**
| **0.35 (0.13-0.76)**
| **0.33 (0.12-0.71)**
| **0.33 (0.12-0.70)**
| **0.28 (0.09-0.78)**
| **0.25 (0.09-0.52)**
|
Adalimumab 80/40 mg
| **2.47 (1.07-7.10)**
| 2.17 (0.96-6.13)
|
| 0.84 (0.62-1.13)
| 0.75 (0.50-1.13)
| 0.71 (0.48-1.05)
| 0.71 (0.48-1.05)
| 0.62 (0.30-1.31)
| **0.54 (0.39-0.75)**
|
Adalimumab 160/80 mg
| **2.93 (1.33-8.24)**
| **2.59 (1.20-7.12)**
| 1.20 (0.88-1.61)
|
| 0.90 (0.65-1.24)
| 0.85 (0.62-1.16)
| 0.84 (0.62-1.15)
| 0.74 (0.37-1.50)
| **0.65 (0.51-0.81)**
|
Certolizumab 400 mg
| **3.26 (1.47-9.19)**
| **2.88 (1.32-7.96)**
| 1.33 (0.88-1.99)
| 1.11 (0.80-1.54)
|
| 0.94 (0.69-1.30)
| 0.94 (0.68-1.29)
| 0.82 (0.41-1.68)
| **0.72 (0.57-0.91)**
|
Risankizumab 1200 mg
| **3.46 (1.57-9.66)**
| **3.05 (1.41-8.36)**
| 1.41 (0.95-2.08)
| 1.18 (0.87-1.60)
| 1.06 (0.77-1.46)
|
| 0.99 (0.84-1.18)
| 0.87 (0.44-1.77)
| **0.76 (0.61-0.94)**
|
Risankizumab 600 mg
| **3.48 (1.57-9.70)**
| **3.07 (1.42-8.41)**
| 1.42 (0.96-2.09)
| 1.18 (0.87-1.61)
| 1.06 (0.77-1.47)
| 1.01 (0.85-1.19)
|
| 0.88 (0.44-1.78)
| **0.77 (0.62-0.94)**
|
Upadacitinib 24 mg BID
| 4.02 (1.44-13.32)**
| **3.54 (1.28-11.56)**
| 1.62 (0.76-3.36)
| 1.35 (0.66-2.70)
| 1.22 (0.60-2.43)
| 1.15 (0.57-2.28)
| 1.14 (0.56-2.28)
|
| 0.87 (0.45-1.68)
|
Placebo
| **4.54 (2.12-12.40)**
| **4.01 (1.92-10.72)**
| **1.85 (1.33-2.57)**
| **1.55 (1-24-1.94)**
| **1.39 (1.10-1.77)**
| **1.31 (1.06-1.63)**
| **1.31 (1.06-1.62)**
| 1.14 (0.60-2.24)
|
|
Conclusion
We found infliximab 5 mg/kg, combined with azathioprine or alone, to be consistently superior to all other agents and associated with the most rapid onset of effect, particularly among bio-naïve patients. This network meta-analysis has implications for rational individualized therapeutic decision-making in patients with CD.
Disclosure
M.A., J.G., and O.H.N.: None
C.S.: reports research grants from Takeda, paid speaker by MSD, Tillotts.
A.P.: reports research grants and personal fees from Janssen, Takeda, and MSD, personal fees from Bristol Myers Squibb. National coordinator of studies from AbbVie, Boehringer Ingelheim, and Bristol Myers Squibb. None of these pertain to the research submitted here.
J.B.: reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants, and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, personal fees from Galapagos, outside the submitted work.
J.B.S.: has received research grants from Takeda, Janssen and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim. None of these pertain to the research submitted here.