Introduction

Intravenous infliximab and vedolizumab are used as maintenance therapy for moderate to severe ulcerative colitis and Crohn’s disease. During maintenance therapy these drugs are administrated usually at every 6 to 8 weeks. In Finland, subcutaneous vedolizumab became available 2020 and subcutaneus infliximab 2021, making it possible to switch from infusions to injections. According to previous studies, subcutaneous administration of these drugs is equally effective as intravenous in treatment of inflammatory bowel disease (IBD). It has also been calculated that in most European countries switching from infusions to injections reduces costs.

Aims & Methods

At Hyvinkää hospital, a development project was performed 1.1.-31.12.2022 to switch all IBD patients on intravenous infliximab or vedolizumab therapy to injections. The median intravenous dose of infliximab was 500 mg (300-1000 mg) at a median interval of 8 weeks (6-10 weeks) and the standard dose of intravenous vedolizumab was 300 mg every 8 weeks. Standard doses on infliximab 120 mg and vedolizumab 108 mg every second week were used for subcutaneous therapy. Infliximab and vedolizumab trough levels were measured both during infusions and injections to ensure that the concentrations remained within therapeutic levels. We also wanted to calculate the average yearly drug costs per patient during infusions and injections and the impact on the day hospital burden.

Results

75 patients (mean age 43 years, range 19-76, 44 male, 31 female) switched from infliximab and 21 patients (mean age 52 years, range 21-77, 16 male, 5 female) from vedolizumab infusions to injections. The infliximab concentration was 8,1 ± 4,5 µg/ml during infusions and 14,8 ± 6,6 µg/ml during injections (n = 41), P < 0.001. The vedolizumab concentration was 15,2 ± 7,2 mg/m during infusions and 28,3 ± 14,3 mg/ml during injections (n = 15), P < 0.005. Four patients in the infliximab and two patients in the vedolizumab group interrupted therapy because of relapse or remission. Eleven patients in the infliximab and one in the vedolizumab group were inductions and their trough levels for infusions are not available. Follow-up is still going on and results for all drug concentrations are not yet available. The average yearly cost of infusions and injections per patient were 17556,20 € and 7481,76 € for infliximab (n = 75) and 22777,61 € and 13101,01 € for vedolizumab (n = 21), respectively. The reduction of day hospital visits was 517 in total (on average 6,9 visits per patient). 23 patients (mean age 49 years, range 17-81, 14 male, 9 female, 20 on infliximab and 3 on vedolizumab) wished to continue infusions.

Conclusion

The trough levels of infliximab and vedolizumab are significantly higher during injections than during infusions. Subcutaneous administration reduces costs compared to intravenous administration and considerably reduces the burden of day hospital visits. Further studies are needed to assess separate trough levels for subcutaneous administration of infliximab and vedolizumab and to make recommendations for optimal dosing of these drugs.

Introduction

Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α₄β₇ integrin antibody for treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The GEMINI Long-Term Safety (LTS) study demonstrated the durable efficacy and safety of vedolizumab for inflammatory bowel disease (IBD) treatment. Patients experiencing clinical benefit from vedolizumab in GEMINI LTS (NCT00790933) or VERSIFY (NCT02425111) studies could continue treatment in the vedolizumab extended access programme (XAP).

Aims & Methods

​​​​​​The XAP study was a phase 3b/4, prospective, open-label, multinational, interventional study (NCT02743806)^1,2 conducted from Aug 2016 to Jan 2023 to investigate long-term treatment persistence and safety of vedolizumab 300mg IV every 4 weeks (Q4W) or every 8 weeks (Q8W) in adults with UC or CD.

Results

The study enrolled 331 patients (UC=142; CD=189) including 20 rolling over from VERSIFY and 311 patients from GEMINI LTS. Patients treated with vedolizumab in the XAP study had either dose frequency reduction Q4W to Q8W or were maintained on their current Q8W or Q4W dosing; 297 patients started the XAP study on Q8W dosing, of which 295 received at least one dose of vedolizumab in XAP. At XAP study baseline, mean (SD) disease duration was 13.9 (6.8) and 13.2 (6.8) yrs for patients with UC and CD, respectively; most patients were in clinical remission (Table 1). In total, 283/295 patients (95.9%) were persistent on Q8W dosing for ≥6 months without relapse (UC: 129/132 [97.7%] and CD: 154/163 [94.5%]). Median (range) duration of vedolizumab treatment in the XAP study was UC: 3.8 (0–6) and CD: 4.2 (0–6) yrs. Only 27 patients (9.2%) were re-escalated from Q8W to Q4W dosing during the study (UC: 11/132 [8.3%] and CD: 16/163 [9.8%]); median (range) duration from last dose in the qualifying study to dose escalation in XAP was 1.5 (0.6–3.0) and 1.2 (0.2–5.2) yrs for UC and CD groups, respectively; the corresponding duration from last dose in the qualifying study to relapse was 1.4 (0.4–4.0) and 1.2 (0.06–5.4) yrs. Adverse events (AEs) after enrolment into XAP occurred in 61.3% of patients with UC and 62.4% with CD (treatment-related in 2.1% UC and 4.2% CD) but only 4.2% UC and 1.6% CD had AEs leading to study discontinuation (treatment-related: 0.7% UC, 0.5% CD); 13.4% UC and 16.4% CD had serious AEs (treatment-related: 0.7% UC, 0.5% CD). Severe infections occurred in 2 patients with UC (1.4% including 1 patient with COVID-19) and in 1 patient with CD (0.6%), none were considered treatment-related. There was 1 death from COPD reported during the study.

Table 1. Baseline Patient Characteristics
Parameter	UC Vedolizumab N=142 from GEMINI LTS				CD Vedolizumab N=169 from GEMINI LTS, N=20 from VERSIFY
	Dose frequency reduction to Q8W (N=121)	Dose frequency escalation to Q4W (N=10)	Q4W Maintenance (N=8)	Total (N=142)a	Dose frequency reduction to Q8W (N=128)	Dose frequency escalation to Q4W (N=14)	Q4W Maintenance (N=26)	VERSIFY Q8W Maintenance (N=20)	Total (N=189)b
Age, mean (SD), years	47.0 (11.6)	46.2 (10.7)	55.1 (13.6)	47.7 (11.8)	42.6 (11.8)	37.7 (5.7)	44.6 (13.8)	38.4 (14.6)	42.1 (12.1)
Clinical remission, n (%)	118 (97.5)	8 (80.0)	5 (62.5)	133 (93.7)	118 (92.2)	13 (92.9)	19 (73.1)	15 (75.0)	166 (87.8)
Partial Mayo score, mean (SD)	0.4 (0.9)	0.9 (1.3)	1.3 (1.8)	0.5 (1.0)	NA	NA	NA	NA	NA
Harvey Bradshaw Index score, mean (SD)	NA	NA	NA	NA	1.3 (2.1)	1.8 (1.6)	3.3 (2.8)	-	1.7 (2.3)
Prior anti-TNFα therapy, n (%)	22 (18.2)	4 (40.0)	2 (25.0)	28 (19.7)	41 (32.0)	8 (57.1)	13 (50.0)	11 (55.0)	73 (38.6)
Concomitant medications, n (%) CS CS + IMM IMM	5 (4.1) 2 (1.7) 24 (19.8)	1 (10.0) 0 1 (10.0)	0 0 3 (37.5)	6 (4.2) 2 (1.4) 29 (20.4)	6 (4.7) 2 (1.6) 28 (21.9)	1 (7.1) 0 5 (35.7)	1 (3.8) 0 4 (15.4)	4 (20.0) 0 8 (40.0)	12 (6.3) 2 (1.1) 45 (23.8)
aIncludes 3 patients who had multiple dose changes; bIncludes 1 patient from GEMINI LTS who had multiple dose changes.

Conclusion

This long-term, prospective study reported high patient persistence on vedolizumab Q8W after the reduction of dosing frequency, together with low rates of dose frequency escalation to Q4W and relapse. Safety results were consistent with the known safety profile of vedolizumab; no new safety signal was identified.

References

1. Vermeire S, et al. J Crohns Colitis 2020;14(8):1066-73.
2. Danese S, et al. Aliment Pharmacol Ther 2021;53(2):265-72.

Disclosure

Silvio Danese: Lecture fees: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim; Consultancy: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim. Grazyna Rydzewska: Lecture fees: AbbVie, Ferring, Johnson & Johnson, Takeda, Pfizer Inc, Celltrion, Sandoz, Boehringer Ingelheim; Alfa Sigma, ProMed, Biocodex, Sanprobi; Consultancy: AbbVie, Ferring, Johnson & Johnson, Takeda, Pfizer Inc, Celltrion, Sandoz, Sobi, ProMed. Stephen Jones: consultant to Takeda. Shashi Adsul and Dirk Lindner: employees of Takeda and hold Takeda stock/stock options; medical writing support was provided by Excel Medical Affairs and funded by Takeda. Séverine Vermeire: Grants: AbbVie, Galapagos, Johnson & Johnson, Pfizer, Takeda; consulting/and or speaker fees: AbbVie, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki, Dr Falk, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots, Zealand.

Introduction

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The safety of tofacitinib was evaluated in the Overall Cohort, which consisted of 6 studies: 4 randomised, placebo-controlled Phase (P)2/3 studies (NCT00787202; NCT01465763; NCT01458951; NCT01458574), an open-label, long‑term extension study (NCT01470612) and a randomised P3b/4 study (NCT03281304). We report final safety analyses from the tofacitinib UC clinical programme of ≤9.2 years of tofacitinib exposure (cut off date: 18 April 2022).

Aims & Methods

This analysis included 1157 patients (pts) receiving tofacitinib 5 or 10 mg twice daily (BID; predominant dose [PD]) in the Overall Cohort and a previously reported 52-week Maintenance Cohort.^1,2 Proportions and incidence rates (IRs; unique pts with events/100 pt-years of exposure) were evaluated for deaths and adverse events of special interest (AESI): serious infections; herpes zoster (HZ); opportunistic infections (OIs); malignancies (excluding non‑melanoma skin cancer [NMSC]); NMSC; major adverse cardiovascular events (MACE); deep vein thrombosis (DVT); pulmonary embolism (PE); and gastrointestinal (GI) perforations.

Results

In the Overall Cohort, 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID; 938 (81.1%) received a PD of 10 mg BID; 552 (47.7%) pts had received tofacitinib for ≥2 years. Median treatment duration was 1.7 years (mean 2.8; range 0.0–9.2). IRs (95% CI) for all tofacitinib in the Overall Cohort (Table): deaths 0.24 (0.10, 0.48); serious infections 1.80 (1.37, 2.32); HZ (non-serious and serious) 3.24 (2.63, 3.94); serious HZ 0.24 (0.10, 0.48); OIs 0.96 (0.65, 1.36); malignancies (excluding NMSC) 0.88 (0.59, 1.26); NMSC 0.71 (0.45, 1.07); MACE 0.27 (0.12, 0.52); DVT 0.06 (0.01, 0.22); PE 0.18 (0.07, 0.40); and GI perforations 0.09 (0.02, 0.27).

Table. Baseline demographics and disease characteristics, and IRs (unique pts with events/100 PY of exposure) for AESI in the tofacitinib UC clinical programme, by cohort
	Maintenance Cohort1,2 (52 weeks)				Overall Cohort (≤9.2 years)
	Placebo (N=198; 100.4 PY)	Tofacitinib 5 mg BID (N=198; 146.2 PY)	Tofacitinib 10 mg BID (N=196; 154.3 PY)	Tofacitinib all (N=394; 300.5 PY)	PD tofacitinib 5 mg BID (N=219; 902.3 PY)	PD tofacitinib 10 mg BID (N=938; 2299.7 PY)	Tofacitinib all (N=1157; 3202.0 PY)
Baseline demographics and clinical characteristics Age (yrs), mean (SD)a TMS, mean (SD)b,c Disease duration (yrs), mean (SD)b Prior TNFi failure, n (%)d CS use at baseline, n (%)b AEs Pts with AEs, n (%) Pts with serious AEs, n (%) Deaths, n (%), IR [95% CI]e	43.4 (14.0) 3.3 (1.8) 8.8 (7.5) 89 (44.9) 100 (50.5) 149 (75.3) 13 (6.6) 0 (0.0), 0.00 [0.00, 3.57]	41.9 (13.7) 3.3 (1.8) 8.3 (7.2) 83 (41.9) 101 (51.0) 143 (72.2) 10 (5.1) 0 (0.0), 0.00 [0.00, 2.48]	43.0 (14.4) 3.4 (1.8) 8.7 (7.0) 92 (46.9) 86 (43.9) 156 (79.6) 11 (5.6) 0 (0.0), 0.00 [0.00, 2.35]	42.5 (14.0) 3.4 (1.8) 8.5 (7.1) 175 (44.4) 187 (47.5) 299 (75.9) 21 (5.3) 0 (0.0), 0.00 [0.00, 1.21]	44.0 (14.4) 7.9 (2.4) 8.3 (6.6) 93 (42.5) 89 (40.6) 205 (93.6) 46 (21.0) 0 (0.0), 0.00 [0.00, 0.40]	40.6 (13.7) 8.8 (1.8) 8.2 (7.1) 490 (54.1) 434 (46.3) 789 (84.1) 208 (22.2) 8 (0.9), 0.34 [0.14, 0.66]	41.3 (13.9) 8.6 (2.0) 8.2 (7.0) 583 (51.9) 523 (45.2) 994 (85.9) 254 (22.0) 8 (0.7),f 0.24 [0.10, 0.48]
Infections, n (%), IR [95% CI]g SIsh All HZ (non-serious and serious) Serious HZ OIsd,j,k HZ OIsj	2 (1.0), 1.94 [0.23, 7.00] 1 (0.5), 0.97 [0.02, 5.42] 0 (0.0), 0.00 [0.00, 3.57] 1 (0.5), 0.97 [0.02, 5.42] 1 (0.5), 0.97 [0.02, 5.42]	2 (1.0), 1.35 [0.16, 4.87] 3 (1.5),i 2.05 [0.42, 6.00] 0 (0.0), 0.00 [0.00, 2.48] 2 (1.0), 1.36 [0.16, 4.92] 2 (1.0), 1.36 [0.16, 4.92]	1 (0.5), 0.64 [0.02, 3.54] 10 (5.1),i 6.64 [3.19, 12.22] 0 (0.0), 0.00 [0.00, 2.35] 4 (2.0), 2.60 [0.71, 6.65] 4 (2.0), 2.60 [0.71, 6.65]	3 (0.8), 0.98 [0.20, 2.87] 13 (3.3),i 4.38 [2.33, 7.50] 0 (0.0), 0.00 [0.00, 1.21] 6 (1.5), 1.99 [0.73, 4.34] 6 (1.5), 1.99 [0.73, 4.34]	10 (4.6), 1.08 [0.52, 1.99] 23 (10.5), 2.71 [1.72, 4.06] 1 (0.5), 0.11 [0.00, 0.60] 8 (3.7), 0.89 [0.39, 1.76] 7 (3.2), 0.78 [0.31, 1.61]	49 (5.2), 2.07 [1.53, 2.74] 76 (8.1), 3.44 [2.71, 4.31] 7 (0.7), 0.29 [0.12, 0.61] 23 (2.5), 0.99 [0.63, 1.48] 19 (2.1), 0.81 [0.49, 1.27]	59 (5.1), 1.80 [1.37, 2.32] 99 (8.6), 3.24 [2.63, 3.94] 8 (0.7), 0.24 [0.10, 0.48] 31 (2.8), 0.96 [0.65, 1.36] 26 (2.3), 0.80 [0.53, 1.18]
Malignancies, n (%), IR [95% CI]d,e,j Malignancies (excl. NMSC) NMSC	1 (0.5),l 0.97 [0.02, 5.39] 1 (0.5), 0.97 [0.02, 5.40]	0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.48]	0 (0.0), 0.00 [0.00, 2.35] 3 (1.5), 1.91 [0.39, 5.59]	0 (0.0), 0.00 [0.00, 1.21] 3 (0.8), 0.98 [0.20, 2.87]	5 (2.3), 0.54 [0.18, 1.26] 6 (2.7), 0.66 [0.24, 1.43]	24 (2.7), 1.01 [0.65, 1.51] 17 (1.9), 0.73 [0.43, 1.17]	29 (2.6),m 0.88 [0.59, 1.26] 23 (2.0), 0.71 [0.45, 1.07]
MACE, n (%), IR [95% CI]d,e,j	0 (0.0), 0.00 [0.00, 3.57]	1 (0.5),n 0.68 [0.02, 3.77]	1 (0.5),o 0.64 [0.02, 3.54]	2 (0.5), 0.66 [0.08, 2.37]	4 (1.8), 0.44 [0.12, 1.12]	5 (0.6), 0.21 [0.07, 0.49]	9 (0.8),p 0.27 [0.12, 0.52]
VTE, n (%), IR [95% CI]g,j DVT PE	1 (0.5), 0.97 [0.02, 5.39] 1 (0.5), 0.98 [0.02, 5.44]	0 (0.0), 0.00 [0.00, 2.48] 0 (0.0), 0.00 [0.00, 2.48]	0 (0.0), 0.00 [0.00, 2.35] 0 (0.0), 0.00 [0.00, 2.35]	0 (0.0), 0.00 [0.00, 1.21] 0 (0.0), 0.00 [0.00, 1.21]	0 (0.0), 0.00 [0.00, 0.40] 0 (0.0), 0.00 [0.00, 0.40]	2 (0.2), 0.08 [0.01, 0.30] 6 (0.6), 0.25 [0.09, 0.55]	2 (0.2),q 0.06 [0.01, 0.22] 6 (0.5),r 0.18 [0.07, 0.40]
GI perforations, n (%), IR [95% CI]d,g,j,s	1 (0.5), 0.97 [0.02, 5.39]	0 (0.0), 0.00 [0.00, 2.48]	0 (0.0), 0.00 [0.00, 2.35]	0 (0.0), 0.00 [0.00, 1.21]	1 (0.5), 0.11 [0.00, 0.60]	2 (0.2), 0.08 [0.01, 0.30]	3 (0.3), 0.09 [0.02, 0.27]
The Maintenance Cohort has been reported previously1,2 and includes pts receiving placebo, tofacitinib 5 mg BID or tofacitinib 10 mg BID in the 52-week maintenance study (OCTAVE Sustain; NCT01458574); the Overall Cohort includes final data from the open-label, long‑term extension study (OCTAVE Open; NCT01470612) and P3b/4 data as of 18 April 2022; in the Overall Cohort, PD tofacitinib 5 mg BID was defined as an average total daily dose of tofacitinib <15 mg and PD tofacitinib 10 mg BID was defined as an average total daily dose of tofacitinib ≥15 mg aData are from screening of P3 induction studies (OCTAVE Induction 1&2; NCT01465763 and NCT01458951, respectively) for the Maintenance Cohort, and from Day 1 (start of active treatment in the tofacitinib UC clinical programme) for the Overall Cohort; bData are from baseline of the P3 maintenance study (OCTAVE Sustain) for the Maintenance Cohort, and from Day 1 (start of active treatment in the tofacitinib UC clinical programme) for the Overall Cohort; cFor the Overall Cohort, N=936 and N=1155 for the PD tofacitinib 10 mg BID and tofacitinib all groups, respectively; dData are from baseline of OCTAVE Induction 1&2; for the Overall Cohort, N=905 and N=1124 for the PD tofacitinib 10 mg BID and tofacitinib all groups, respectively (excludes P2; NCT00787202); eFor the Maintenance Cohort, and generally for the Overall Cohort, events that occurred >28 days after the last dose of study drug were excluded; for the Overall Cohort, deaths, malignancies and MACE outside the 28‑day risk period were included; fDeaths (number of events): aortic dissection (1), cardiac arrest (1), PE (1), hepatic angiosarcoma (1), acute myeloid leukaemia (1), malignant melanoma (1), metastatic adenocarcinoma (1), COVID-19 pneumonia/respiratory failure (1); gEvents that occurred >28 days after the last dose of study drug were excluded; hDefined as any infection AE that required hospitalisation or parenteral antimicrobials, or met other criteria that required the infection to be classified as a serious AE; iIRs of HZ in the Maintenance Cohort were numerically higher with tofacitinib 5 mg BID vs placebo and all tofacitinib vs placebo, and statistically higher with tofacitinib 10 mg BID vs placebo; jAdjudicated events; kExcludes tuberculosis and HZ with two adjacent dermatomes; lInvasive ductal breast carcinoma; mMalignancy (number of events): acute myeloid leukaemia (1), breast cancer (3), Bowen’s disease (1), cervical dysplasia (2), cholangiocarcinoma (2), colorectal cancer (5), diffuse large B-cell lymphoma (2), Epstein-Barr virus associated lymphoma (1), essential thrombocythaemia (1), hepatic angiosarcoma (1), leiomyosarcoma (1), lung cancer (2), malignant melanoma (2), oesophageal adenocarcinoma (1), penile dysplasia (1), renal cell carcinoma (1), vulvar cancer (1), prostate cancer (1); nMyocardial infarction; oHaemorrhagic stroke; pMACE (number of events): acute coronary syndrome (1), acute myocardial infarction (1), aortic dissection (1), cardiac arrest (1), cerebellar haemorrhage (1), cerebrovascular accident (2), haemorrhagic stroke (1), myocardial infarction (1); qPt with DVT was diagnosed following a long-haul flight and management of an infected leg wound sustained in a recent motorbike accident; the second DVT event was assessed as related to the study drug by the investigator; rPts with PE had the following notable medical history: one with prior DVT and PE, one with phlebothrombosis and stroke, one was receiving oral contraceptives for dysfunctional uterine bleeding and one had cholangiocarcinoma and metastases to the peritoneum, and PE was the cause of death. Two pts had a medical history with no prior risk factors for PE; sGI perforation excludes Preferred Terms of pilonidal cyst, perirectal abscess, rectal abscess, anal abscess, perineal abscess and any Preferred Terms containing the term fistula AE, adverse event; AESI, AEs of special interest; BID, twice daily; CI, confidence interval; CS, corticosteroid; DVT, deep vein thrombosis; GI, gastrointestinal; HZ, herpes zoster; IR, incidence rate (unique pts with events/100 PY of exposure); MACE, major adverse cardiovascular events; N, number of pts treated in the treatment group; n, number of unique pts with a particular AE; NMSC, non‑melanoma skin cancer; OI, opportunistic infection; P, Phase; PD, predominant dose; PE, pulmonary embolism; PY, pt-years; pt, patient; SD, standard deviation; SI, serious infection; TMS, total Mayo score; TNFi, tumour necrosis factor inhibitor; UC, ulcerative colitis; VTE, venous thromboembolic events; yrs, years

Conclusion

IRs for AESI remained stable over an extended period of time (≤9.2 years) with the inclusion of the P3b/4 final data and were consistent with prior Overall Cohort analyses (≤7.8 years).^1,2 The safety profile of tofacitinib in the UC clinical programme was consistent with that observed in other indications.^3,4

References

1. Sandborn WJ et al. Clin Gastroenterol Hepatol 2019;17:1541–50.
2. Sandborn WJ et al. J Crohns Colitis 2023;17:338–51.
3. Cohen SB et al. RMD Open 2020;6:e001395.
4. Burmester GR et al. Drug Saf 2020;43:379–92.

Disclosure

Julian Panés has received grants and/or research support from AbbVie and Pfizer Inc, is a member of the speakers’ bureau for Abbott, Ferring, Janssen, Pfizer Inc and Takeda, has been an advisory board member for AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer Inc, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance and Wasserman, and has developed educational presentations for AbbVie, Janssen, Pfizer Inc, Roche and Takeda. Geert R. D’Haens has received speaker fees from AbbVie, Boehringer Ingelheim, Celltrion, Johnson & Johnson, Pfizer Inc, Takeda and Tillotts, and has been an advisory board member for AbbVie, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cosmo, Eli Lilly, Galapagos, GlaxoSmithKline, Johnson & Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus, Tillotts and Ventyx. Bruce E. Sands has acted as a consultant for, or received speaker fees from, AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, GlaxoSmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kallyope, Merck, MiroBio, Morphic, MRM Health, OSE Immunotherapeutics, Pfizer Inc, Progenity, Prometheus, Protagonist, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance, TLL Pharmaceutical, USWM Enterprises, Ventyx and Viela Bio, and is a shareholder of Ventyx. Siew C. Ng has received grants and/or research support from AbbVie, Ferring, Janssen and Olympus, has received speaker fees from AbbVie, Ferring, Janssen, Menarini, Pfizer Inc, Takeda and Tillotts, has been an advisory board member for AbbVie, Ferring, Janssen and Pfizer Inc, holds a Directorship with Microbiota I Center, and is the scientific co-founder and a shareholder of GenieBiome Limited. Nervin Lawendy is an employee and shareholder of Pfizer Inc. Nicole Kulisek is an employee and shareholder of Pfizer Inc. Xiang Guo is an employee and shareholder of Pfizer Inc. Joseph Wu is an employee and shareholder of Pfizer Inc. Ivana Vranic is an employee and shareholder of Pfizer Inc. Remo Panaccione has received grants and/or research support from AbbVie, Janssen, Pfizer Inc, and Takeda, and has acted as a consultant for and/or received speaker fees from Abbott, AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos, Eisai, Elan, Eli Lily, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer Inc, Progenity, Prometheus, Protagonist, Roche, Sandoz, Satisfai Health, Shire, Sublimity, Takeda, Theravance, Trellus, Viatris and Ventyx. Séverine Vermeire has received grants from AbbVie, Galapagos, MSD, Pfizer Inc, and Takeda, has acted as a consultant for AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CVasThera, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead Sciences, Hospira, IMIdomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer Inc, ProDigest, Progenity, Prometheus, Robarts, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts and Zealand, and has received speaker fees from AbbVie, Dr Falk Pharma, Ferring, Hospira, MSD, Takeda and Tillotts.

Introduction

The feasibility of anti-TNF discontinuation in inflammatory bowel disease (IBD) must be proven in clinical trials including patients in clinical, endoscopic, and radiologic remission at the time of anti-TNF withdrawal, to give recommendations for clinical practice.

Aims & Methods

Aims: Primary: to compare the rates of clinical remission at 1 year in patients who discontinue anti-TNF treatment vs. those who maintain it. Secondary objectives: to know the effect of anti-TNF withdrawal on relapse-free time, mucosal healing and safety; and to identify predictive factors for relapse.
Methods: Prospective, quadruple-blind, multicentre, randomised, controlled trial. Patients with ulcerative colitis (UC) or Crohn’s disease (CD) in clinical remission for > 6 months were randomised to maintain anti-TNF treatment [maintenance arm (MA)] or to withdraw it [withdrawal arm (WA)]. Patients who were on infliximab (IFX) received IFX 5 mg/kg or an intravenous placebo every 8 weeks, while patients on adalimumab (ADA) received subcutaneous ADA 40 mg or placebo every other week. Patients were followed-up until month 12 or up to the time of clinical relapse, whichever came first. Inclusion and exclusion criteria were as follows: patients should have been in clinical remission for ≥6 months at a non-intensified dose of anti-TNF (where an intensified dose is defined as ≥10 mg/kg/8 weeks or 5 mg/kg/≤4 weeks for IFX, and 40 mg/week for ADA); patients should have been receiving concomitant immunosuppressants; for patients with CD, the indication for anti-TNF treatment must have been for luminal involvement only (not perianal); the baseline colonoscopy performed within 3 months of inclusion should have not shown significant lesions; for patients with ileal or ileocolic CD, the magnetic resonance enterography performed within 3 months of inclusion should have not shown significant lesions; patients with prior intestinal resection were excluded. Results were analysed by intention-to-treat (ITT) and by per-protocol (PP). Local investigators were blinded to faecal calprotectin (FC) and IFX and ADA trough levels. On-site monitoring was performed to assess data quality.

Results

159 patients were screened, from whom 140 were randomised and comprised the ITT cohort: 70 allocated to the MA and 70 to the WA. Fifteen patients dropped out before the end of follow-up (12 months or relapse), leaving 63 patients in the MA and 62 patients in the WA for the PP analysis. The characteristics of patients in the MA and WA were similar. The proportion of patients who maintained clinical remission [59/70 (84%), 95% confidence interval (CI)=74-92% in the MA vs. 53/70 (76%), 95%CI=64-85% in the WA] and those with significant endoscopic lesions at the end of follow-up (8% in the MA vs. 19% in the WA, p>0.05) were similar between groups. Only the proportion of patients with FC >250 mg/g was higher in the WA at the end of follow-up (12% in the MA vs. 33% in the WA, p<0.01). The proportion of patients with sustained clinical remission during follow-up was no different between groups. In the multivariate analysis, FC >250 mg/g at baseline, but not anti-TNF withdrawal, was the only variable associated with lower likelihood of sustained clinical remission (HR=0.2, CI95%=0.07 - 0.7). The same percentage of patients in both groups had at least one adverse event (69%). The proportion of patients with serious adverse events was also similar between groups (4% in MA vs. 7% in WA).

Conclusion

Anti-TNF withdrawal in selected IBD patients in clinical, endoscopic, and radiologic remission could be feasible without an increase in the risk of clinical relapse.

Introduction

Diet has been suggested to impact the clinical course of Crohn’s disease (CD). However, the importance of food processing level is uncertain.

Aims & Methods

We aimed to evaluate whether ultra-processed foods (UPFs) are associated with increased risk of relapse amongst patients with CD.
​In this prospective cohort study, adult CD patients in clinical remission (Harvey Bradshaw index, HBI<5) were followed every three months, for one year or until clinical relapse (HBI>4). Dietary intake was assessed using a food frequency questionnaire (FFQ) and using a dedicated validated processed food questionnaire (PFQ) to evaluate UPFs consumption. Multivariable Cox proportional hazards were used to estimate the adjusted Hazard Ratio of disease relapse according to high or low UPFs consumption.

Results

A total of 111 CD patients in clinical remission with a mean age of 37.9±14.0 years entered the final analysis. Over a median follow-up duration of 12 months [interquartile range, 8-12], 24 patients (21.6%) experienced a clinical relapse. A higher intake of UPFs was found to be associated with an increased risk of relapse occurrence (HR = 3.86, 95% CI 1.30-11.47). Clinical relapse was associated with high FC levels at the relapse visit compared to baseline (193.0 μg/g [114.0-807.0], 79.0 μg/g [17.0-274.5], respectively, P=0.002, n=16 for paired analysis). Among different UPF subgroups, ultra-processed breads, pastries and starches, as well as processed oils and spreads showed the strongest positive associations with CD relapse (HR = 3.27, 95% CI 1.26-8.45; HR = 2.76, 95% CI 1.02-7.45, respectively).

Table 1. Multivariable analysis^ƚ of the association between ultra-processed food consumption and disease relapse in patients with Crohn’s disease

Ultra-processed food consumption	Low intake	High intake	HR (95% CI)	P-value
Entire cohort (N=111)
N cases/N total	7/57	17/54	3.86 (1.30-11.47)	0.015
No elimination diet sub-sample (N=103)*
N cases/N total	6/51	17/52	4.38 (1.41-13.63)	0.011

The cut-off for low and high ultra-processed food consumption was determined by the median number: 3.6 servings/day.
^ƚ Cox model with time-dependent covariates. HRs are adjusted for: sex, age (years), smoking status, energy intake (kcal/day), saturated fat (% of total kcal) and monounsaturated fatty acids (% of total kcal).
*Patients during elimination diet treatment were excluded from the analysis (N=8).
Abbreviations: CI: confidence interval; HR: hazard ratio; CD: Crohn’s disease.

Conclusion

Higher consumption of UPFs was associated with an increased risk of relapse in patients with CD in remission. This study, along with future prospective research, can contribute to establish nutritional guidelines aimed at reducing UPFs consumption for patients in clinical remission.