Introduction
Data are needed to inform therapeutic positioning of advanced therapies, including biological drugs, small molecule agents, and stem cells for fistulizing Crohn’s disease (CD).
Aims & Methods
We aimed to assess the comparative efficacy of these advanced therapies in patients with fistulizing CD. We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and March 21st, 2023. The co-primary outcomes were induction of fistula remission, defined as closure of all draining fistulas at week 6-14 and week 44-54. Network meta-analysis was conducted under the Bayesian framework.
Results
We identified a total of 1,275 citations, of which 21 randomized clinical trials comprising 1,452 patients were eligible and included in the analysis. Based on the probability of achieving fistula remission within the induction period (week 6-14), infliximab 5 mg/kg monotherapy or in combination with ciprofloxacin ranked highest but was not statistically superior to other advanced therapies. Further, upadacitinib 45 mg once daily, infliximab 10 mg/kg, and ustekinumab 6 mg/kg were similarly superior to placebo, while adipose-derived stem cells Cx401, bone marrow-derived mesenchymal stem cells, vedolizumab 300 mg, and adalimumab 80/40 mg were not superior to placebo. Based on the probability of inducing long-term fistula remission during the maintenance period (week 44-56), upadacitinib 30 mg or 15 mg ranked highest although not superior to placebo; of note, both doses of upadacitinib did achieve statistical significance in terms of superiority to placebo for fistula remission at week 52 in the original trial. In contrast, adalimumab 80/40 mg, infliximab 5 mg/kg and adipose-derived stem cells Cx601 were superior to placebo but no differences between the active interventions were demonstrated.
Table 1: League plot for the comparison of advanced therapies in patients with fistulizing Crohn’s disease for maintenance of fistula remission at weeks 44-56. 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.
| Upadacitinib 30 mg
| Upadacitinib 15 mg
| Adalimumab 80/40 mg
| Vedolizumab 300 mg
| Infliximab 5 mg/kg
| Ustekinumab 6 mg/kg
| ASCs Cx601
| Adalimumab 160/80 mg
| Placebo
|
Upadacitinib 30 mg
|
| 0.85 (0.27-3.11)
| 0.33 (0.01-2.89)
| 0.31 (0.01-3.51)
| 0.25 (0.01-1.98)
| 0.23 (0.01-2.07)
| 0.20 (0.01-1.51)
| 0.18 (0.01-1.88)
| 0.14 (0.00-1.02)
|
Upadacitinib 15 mg
| 1.18 (0.32-3.75)
|
| 0.38 (0.01-3.01)
| 0.36 (0.01-3.75)
| 0.30 (0.01-2.05)
| 0.28 (0.01-2.16)
| 0.24 (0.01-1.57)
| 0.21 (0.01-1.98)
| 0.17 (0.01-1.06)
|
Adalimumab 80/40 mg
| 3.06 (0.35-97.11)
| 2.60 (0.33-82.27)
|
| 0.93 (0.24-4.63)
| 0.78 (0.29-1.85)
| 0.71 (0.24-2.23)
| 0.62 (0.25-1.34)
| 0.55 (0.14-2.25)
| **0.43 (0.18-0.88)**
|
Vedolizumab 300 mg
| 3.28 (0.28-113.23)
| 2.80 (0.27-95.01)
| 1.08 (0.22-4.20)
|
| 0.84 (0.18-2.68)
| 0.77 (0.16-3.04)
| 0.67 (0.15-1.98)
| 0.59 (0.10-2.94)
| 0.47 (0.11-1.32)
|
Infliximab 5 mg/kg
| 3.96 (0.51-124.21)
| 3.36 (0.49-103.92)
| 1.29 (0.54-3.44)
| 1.19 (0.37-5.44)
|
| 0.91 (0.40-2.55)
| 0.80 (0.45-1.40)
| 0.71 (0.22-2.60)
| **0.55 (0.34-0.89)**
|
Ustekinumab 6 mg/kg
| 4.28 (0.48-135.38)
| 3.63 (0.46-114.35)
| 1.40 (0.45-4.18)
| 1.30 (0.33-6.34)
| 1.10 (0.39-2.49)
|
| 0.88 (0.33-1.79)
| 0.77 (0.33-1.77)
| 0.61 (0.24-1.16)
|
ASCs Cx601
| 4.95 (0.66-152.08)
| 4.20 (0.64-127.86)
| 1.61 (0.74-4.02)
| 1.49 (0.50-6.54)
| 1.25 (0.71-2.24)
| 1.14 (0.56-3.00)
|
| 0.89 (0.29-3.10)
| **0.70 (0.51-0.93)**
|
Adalimumab 160/80 mg
| 5.63 (0.53-192.41)
| 4.79 (0.51-159.41)
| 1.82 (0.45-7.16)
| 1.69 (0.34-9.95)
| 1.40 (0.38-4.59)
| 1.29 (0.56-2.99)
| 1.12 (0.32-3.44)
|
| 0.78 (0.23-2.28)
|
Placebo
| 7.12 (0.98-217.65)
| 6.02 (0.95-182.46)
| **2.32 (1.14-5.55)**
| 2.15 (0.76-9.19)
| **1.80 (1.13-2.97)**
| 1.63 (0.86-4.14)
| **1.44 (1.08-1.96)**
| 1.29 (0.44-4.32)
|
|
Conclusion
We found no apparent differences in efficacy between currently available advanced therapies for fistulizing CD. The study supports the role of infliximab 5 mg/kg, upadacitinib 45 mg, ustekinumab 6 mg/kg, and adipose-derived stem cells in the clinical management of fistulizing CD. The current study informs the positioning of advanced therapies; however, clinical decisions need to be individualized.
Disclosure
M.A.: None
D.N.R.: None
F.B.: Personal fees from Tillotts Pharma, outside the submitted work.
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 Tillotts 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.
