Introduction
The EXIT trial showed there is no difference between inflammatory bowel disease (IBD) patients who were in remission and withdrew anti-TNF therapy, and those who maintained anti-TNF therapy with respect to the percentage of sustained remission at 12 months. However, data of the long-term outcomes are crucial.
Aims & Methods
Aims: To compare long-term risk of relapse in IBD patients in remission who withdrew anti-TNF therapy versus those who maintained anti-TNF therapy, to analyse the response to anti-TNF resumption in those patients who relapsed after anti-TNF withdrawal, and to evaluate the overall success of the anti-TNF resumption strategy.
Methods: This study is an extension of the follow-up from the EXIT trial. Patients included in EXIT trial were IBD patients who have achieved clinical remission for ⩾6 months at standard anti-TNF dosage, with absence of significant endoscopic/radiological lesions, no previous IBD-related surgery, and ongoing immunomodulatory treatment. Patients were randomised either to maintain or to withdraw the anti-TNF therapy1. The long-term outcomes of patients in sustained clinical remission who have completed the follow-up of EXIT trial per-protocol were analysed at the end of the EXIT trial. After that, patients were managed at the discretion of their physicians. Patients who were randomised in EXIT trial to continue with the anti-TNF comprised the maintenance arm (MA). For these patients, follow-up continued until either the anti-TNF resumption, or until the initiation of another biologic treatment or until the small molecule therapy (due to relapse or electively) or until the last visit (if no relapse occurred). Patients who were randomised in EXIT trial to withdraw the anti-TNF comprised the withdrawal arm (WA). For these patients, follow-up ended either at the time of relapse, at the withdrawal of anti-TNF treatment (electively, due to relapse, or adverse events), or at the last visit. The success of the anti-TNF resumption strategy was defined as the achievement and maintenance of clinical remission after restarting the anti-TNF therapy due to relapse, without experiencing adverse events or major complications (such as the need for surgery for IBD or the appearance of new perianal fistulas) that led to treatment withdrawal.
Results
125 patients were included, 63 in MA and 62 in WA. Median follow-up was 12 and 26 months in MA and in WA, respectively (p<0.05). The main characteristics of the study population are detailed in table 1. In MA, the cumulative incidence of relapse was 8% at 12 months, 47% at 24 months, and 65% at 36 months, whereas in the WA was 16% at 12 months, 39% at 24 months and 43% at 36 months of follow-up, (p=0.3). The incidence rate of relapse was 22% (95% CI 14-31) and 19% (95% CI 13-26) per patient-year of follow-up in MA and WA, respectively. In the multivariate analysis, having a fecal calprotectin at baseline of the EXIT trial >250 μg/g was the only variable associated with a higher risk of relapse (HR=3.94, 95% CI=1.92-8.06; p<0.0001). Of the 29 patients of WA who relapsed, 26 patients (90%) resumed the same anti-TNF and 69% of them achieved clinical remission. At the end the of follow-up, 16 out of 26 patients (62%) who restarted anti-TNF maintained remission, while 10 out of 26 patients (38%) discontinued anti-TNF: 4 due to non-response, 2 due to loss of response, and 4 due to adverse events. The proportion of adverse events was similar in the MA and the WA, 69% and 68%, respectively (p>0.05).
Conclusion
In the long-term analysis of the outcomes of patients included in EXIT trial, the withdrawal of anti-TNF therapy in patients with IBD in remission was not associated with higher risk of relapse. Resumption of anti-TNF after relapse recapture remission in the majority of patients. The anti-TNF withdrawal approach was safe.
Table 1. Characteristics of the study population at baseline.
Variables
| Maintenance arm
N=63
| Withdrawal arm N=62
| P
|
-Mean age at inclusion, years (range)
-Mean age at diagnosis, years (range)
-Median time under current anti-TNF (years), IQR
-Median time in remission with current anti-TNF at standard dose (months), IQR
-Median disease duration at inclusion (months), IQR
| 41 (18-65)
31 (10-58)
2.8 (1.8-4.9)
23.2 (13-41)
77.2 (39-163)
| 42 (20-68)
32 (12-65)
2.6 (1.2-5.7)
21.9 (9.2-37.4)
100.8 (36.5-188)
| 0.5
0.9
0.7
0.9
0.4 |
Male gender, n (%)
Current smoker, n (%)
| 36 (57)
10 (16)
| 42 (68)
10 (16%)
| 0.2
0.9 |
Crohn’s disease, n (%)
-L1, n (%)
-L2, n (%)
-L3, n (%)
-L4, n (%)
-B1, n (%)
-B2, n (%)
-B3, n (%)
-Perianal, n (%)
| 29 (46)
9 (31)
9 (31)
11 (38)
1 (3)
20 (69)
7 (24)
2 (7)
2 (6)
| 25 (40)
7 (28)
6 (24)
12 (48)
1 (3)
23 (92)
2 (8)
0 (0)
2 (6)
| 0.5
0.7
0.3
0.09
1 |
Ulcerative colitis, n (%)
-Extensive, n (%)
-Left-sided, n (%)
-Proctitis, n (%)
| 39 (56)
25 (73)
8 (24)
1 (3)
| 39 (56)
20 (54)
16 (43)
1 (3)
| 1
|
Extraintestinal manifestations
| 13 (21)
| 8 (13)
| 0.2 |
Type of anti-TNF, n (%)
-Adalimumab, n (%)
-Infliximab, n (%)
|
9 (14)
54 (86)
|
9 (15)
53 (85)
| 0.9 |
Indication for the anti-TNF, n (%)
-Refractoriness to immunomodulators, n (%)
-Steroid-dependency, n (%)
-Steroid-refractoriness, n (%)
-Top-down strategy, n (%)
-Others, n (%)
|
18 (29)
22 (35)
13 (21)
1 (2)
9 (14)
|
20 (32)
19 (31)
12 (19)
4 (7)
7 (11)
| 0.7 |
Prior intensification of current anti-TNF, n (%)
Median C-reactive protein, IQR
Faecal calprotectin >250 mg/g, n (%)
| 11 (18)
0.1 (0.1-0.3)
4 (7)
| 9 (15)
0.1 (0.1-0.4)
8 (15)
| 0.7
0.1
0.35 |
IQR, interquartile range; TNF, tumour necrosis factor |
References
1. Chaparro M., Donday MG., Barreiro-de Acosta M., Domènech E., Esteve M., García-Sánchez V., et al. Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial. Therap Adv Gastroenterol 2019;12. Doi: 10.1177/1756284819874202.
Disclosure
Manuel Barreiro-de Acosta has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, GALAPAGOS, Pfizer, Sandoz, Biogen, Fresenius, Lilly, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma.
María José Casanova, has received education funding from Pfizer, Takeda, Janssen, MSD, Dr. Falk, Shire, Ferring, Galápagos and Abbvie.
María Chaparro has served as speaker, consultant or research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly.
Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine and Vifor Pharma.
Ana Gutiérrez-Casbas has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts, Pharma, Chiesi and Otsuka Pharmaceutical.
Marisa Iborra reports grants and personal fees from MSD, Janssen, Abbvie, Takeda, Kern and Chiesi, during the conduct of the study.
Eduardo Leo has received grants or honoraria for scientific activities, presentations or as a scientific advisor for MSD, Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma, Shire Pharmaceuticals, Ferring, Dr. Falk Pharma, Adacyte and Otsuka Pharmaceutical
Montserrat Rivero has served as a speaker or advisory member from TaKeda, Janssen, Galapagos, Ferring and Pfizer.
Iago Rodríguez-Lago has received financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Celltrion, Chiesi, Danone, Ferring, Faes Farma, Janssen, Galapagos, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma. IRL-L is supported by a research grant from Gobierno Vasco-Eusko Jaurlaritza [Grant No 2020111061] and by a research grant from Biobizkaia Bizkaia HRI [Grant No BCB/I/LIB/22/008].
Cristina Rubín de Célix has received education funding from Ferring, Tillotts Pharma, AbbVie, Norgine, MSD, Pfizer, Takeda and Janssen.
Manuel Van Domselaar has received educational funding from Janssen. Kern Pharma. and Takeda.
Rest of authors have nothing to declare.