Effectiveness and Safety of Tofacitinib for Ulcerative Colitis

Two-year Results of the ICC Registry

Tessa Straatmijer; Fiona D. M. van Schaik; Alexander G. L. Bodelier; Marijn Visschedijk; Annemarie C. de Vries; Cyriel Y. Ponsioen; Marieke Pierik; Ad A. van Bodegraven; Rachel L. West; Nanne K. H. de Boer; Nidhi Srivastava; Tessa E. H. Romkens; Jildou Hoekstra; Bas Oldenburg; Gerard Dijkstra; Janneke C. van der Woude; Mark Löwenberg; Zlatan Mujagic; Vince B. C. Biemans; Andrea E. van der Meulen-de Jong; Marjolijn Duijvestein

Disclosures

Aliment Pharmacol Ther. 2023;57(1):117-126.

Abstract and Introduction

Abstract

Background: Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment.

Aim: The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands.

Methods: Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid-free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤2) at week 104. Secondary outcomes included biochemical remission (C-reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 μg/g), safety, and discontinuation rate.

Results: We included 110 patients of whom 104 (94.5%) were anti-TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty-one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7–34). The main reasons for discontinuation were non-response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib-related adverse events per 100 patient-years during follow-up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient-years.

Conclusion: Tofacitinib was effective in 31.8% of patients after 24 months of treatment.

Introduction

Tofacitinib is the first JAK inhibitor approved for the treatment of moderate to severe ulcerative colitis (UC).^[1] Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, which inhibits JAK1 and JAK3. By preventing phosphorylation and subsequent dimerisation of signal transducer and activator of transcription (STATs) proteins, it impairs intracellular signalling in certain immune cells, resulting in reduced inflammatory cytokine production.^[2]

In the phase 3 OCTAVE trial, a remission rate (defined as a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0) in 34.3% of UC patients after 52 weeks of treatment with tofacitinib was shown.^[1] This drug is administered orally and has a rapid onset of action in most patients.^[3] The effect of tofacitinib cannot be reduced by the development of anti-drug antibodies, a potential advantage compared to biologicals, such as anti-tumour necrosis factor (aTNF) agents.^[4] However, there are safety concerns about tofacitinib, such as interference with lipid metabolism, increased risk of venous thromboembolisms and infections.^[5]

Although in the OCTAVE study it was demonstrated that the therapeutic efficacy of tofacitinib in UC, a study population did not accurately reflect patients who initiate tofacitinib in daily practice. This is partly due to strict in-and exclusion criteria of clinical trials and the pre-specified follow-up period.^[6] Therefore, so-called real-world studies evaluating the effectiveness and safety of tofacitinib are of great importance. Several studies demonstrated the effectiveness of tofacitinib in UC patients, but the follow-up did not exceed 1 year.^[7–13] In the current era of many (new) therapeutic options for UC, personalisation of an individual's treatment is a beckoning perspective. As much as up to one-third of UC patients lose therapeutic response within a year in the case of modern, complex therapies. This necessitates effectiveness and safety data over longer periods, best with standardisation of disease and clinical characterisation of included patients. In this study, we assessed the effectiveness and safety of 24 months of tofacitinib treatment in UC patients.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline characteristics.
		Tofacitinib (n = 110)
Age (years)	Mean (SD)	45 (14)
Female	N (%)	50 (45.5)
Disease duration (years)	Median (IQR)	7 (3–14)
Follow-up (weeks)	Mean (SD)	102 (7)
BMI	Mean (SD)	24.8 (4.2)
Disease activity
SCCAI-score	Median (IQR)	7 (5–10)
CRP (mg/L), n = 103	Median (IQR)	5.9 (2–13)
FC (mg/kg), n = 88	Median (IQR)	1765 (633–2763)
Medical history
Disease location^a
Proctitis	N (%)	8 (7.3)
Left-sided	N (%)	36 (32.7)
Pancolitis	N (%)	64 (58.2)
Unknown	N (%)	2 (1.8)
Prior treatment
Prior thiopurine	N (%)	95 (86.4)
Prior ≥1 anti-TNF	N (%)	104 (94.5)
Prior ≥2 anti-TNF	N (%)	41 (37.2)
Prior vedolizumab	N (%)	67 (60.9)
Prior ustekinumab	N (%)	4 (3.6)
JAK inhibitor
Concomitant treatment
Oral prednisone	N (%)	41 (37.3)
Oral prednisone dose	mg (IQR)	20 (15–30)
Budesonide	N (%)	17 (15.5)
Mesalazine	N (%)	40 (36.4)
Thiopurine	N (%)	3 (2.7)
Methotrexate	N (%)	2 (1.8)

Abbreviations: BMI, body mass index; CRP, C-reactive protein; FC, faecal calprotectin; SCCAI, Simple Clinical Colitis Activity Index.
^aMaximum extend until inclusion.

Table 2. Univariate and multivariate predictors of corticosteroid-free clinical remission at week 104.
	Univariate analyses			Multivariate analyses
	OR	95% CI	p-value	OR	95% CI	p-value
Age at inclusion	1.01	0.96–1.07	0.67
BMI per point	1.13	0.86–1.47	0.39
Sex
Male	Ref
Female	1.27	0.22–7.20	0.79
Disease duration (year)	1.13	0.94–1.37	0.20	1.11	0.91–1.35	0.31
Disease location^a
Proctitis	0.19	0.01–3.72	0.60
Left-sided	2.10	0.01–21.10	0.27
Pancolitis	Ref		0.53
Prior biological treatments
Vedolizumab	2.25	0.36–13.97	0.38
≥2 biologic therapy	3.95	0.42–37.50	0.23
Clinical disease activity^b
SCCAI per point	0.77	0.56–1.06	0.11	1.13	0.94–1.37	0.20
Biochemical disease activity^a
CRP (mg/L)	1.02	0.94–1.11	0.64
Faecal calprotectin (μg/g)	1.00	1.00–1.00	0.79
Concomitant medication^a
Corticosteroids	2.78	0.47–16.35	0.26

^aAt inclusion.

Table 3. Discontinuation within 104 weeks of treatment.
	UC, N = 61 (55.5%)
Treatment duration—weeks, Median (IQR)	13 (7–34)
Reason discontinuation, N (%)
No response	36 (59)
Adverse events	11 (18)
Secondary loss of response	9 (14.8)
Request patient	2 (3.3)
Death after euthanasia (non-IBD related)	1 (1.6)
Long-term biochemical remission	1 (1.6)
No effect on arthralgia	1 (1.6)

Table 4. Tofacitinib-related adverse events.
	Tofacitinib: 109 years
Mild infections	24 (22.0 per 100 patient-years)
Flu-like symptoms	4
Upper respiratory tract	4
Herpes simplex	3
Herpes zoster	3
Covid-19	2
Fever of unknown origin	2
Dental	1
Ear	1
Gynaecologic	1
Lower respiratory tract	1
Skin	1
Urinary tract	1
Moderate infections	15 (13.8 per 100 patient-years)
Urinary tract	6
Herpes zoster	4
CMV	3
Herpes simplex	3
Flu-like symptoms	2
Fever of unknown origin	1
Gastrointestinal	1
Gynaecologic	1
Lower respiratory tract	1
Skin	1
Throat	1
Upper respiratory tract	1
Severe infections	2 (1.8 per 100 patient-years)
Flu-like symptoms	1
Lower respiratory tract	1
Possibly related	37 (33.9 per 100 patient-years)
Skin	10
Headache	6
Gastrointestinal	3
Respiratory	3
Cardiac	2
Musculoskeletal	2
Glaucoma	1
Genital	1
Hepatobiliary	1
Kidney and urinary tract	1
Malaise	1
Mouth	1
Nerve system	1
Oedema	1
Psychiatric	1
Sleep disturbance	1
Vascular	1
Probably related	8 (7.3 per 100 patient-years)
Musculoskeletal	3
Skin	3
Cardiac	1
Headache	1
Serious adverse events	10 (9.2 per 100 patient-years)
Severe headache	2
Dizziness	1
Gastrointestinal	1
Hepatocellular hepatitis	1
Malaise	1
Musculoskeletal	1
Nausea	1
Skin	1
Throat	1

Note: Number of adverse events during treatment of ulcerative colitis patients with tofacitinib. Infections were classified as: mild infections: no antibiotics or antiviral medication; moderate infections: oral antibiotics or antiviral medication; severe infections: hospitalisation or intravenously administrated antibiotic or antiviral medication.

Authors and Disclosures

Tessa Straatmijer^1,2, Fiona D. M. van Schaik³, Alexander G. L. Bodelier⁴, Marijn Visschedijk⁵, Annemarie C. de Vries⁶, Cyriel Y. Ponsioen², Marieke Pierik⁷, Ad A. van Bodegraven⁸, Rachel L. West⁹, Nanne K. H. de Boer¹⁰, Nidhi Srivastava¹¹, Tessa E. H. Romkens¹², Jildou Hoekstra⁴, Bas Oldenburg³, Gerard Dijkstra⁵, Janneke C. van der Woude⁶, Mark Löwenberg², Zlatan Mujagic⁷, Vince B. C. Biemans³, Andrea E. van der Meulen-de Jong¹ and Marjolijn Duijvestein¹³

¹Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
²Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
³University Medical Centre Utrecht, Utrecht, The Netherlands
⁴Amphia Hospital, Breda, The Netherlands
⁵University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
⁶Erasmus Medical Centre, Rotterdam, The Netherlands
⁷Maastricht University Medical Centre, Maastricht, The Netherlands
⁸Department of Gastroenterology and Hepatology, Zuyderland Hospital, Sittard, The Netherlands
⁹Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
¹⁰Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
¹¹Haaglanden Medical Centre, the Hague, The Netherlands
¹²Jeroen Bosch Hospital, S-Hertogenbosch, The Netherlands
¹³Radboud University Medical Centre, Nijmegen, The Netherlands

Correspondence
Marjolijn Duijvestein, Radboud University Medical Centre, Nijmegen, The Netherlands. Email: marjolijn.duijvestein@radboudumc.nl
Andrea E. van der Meulen-de Jong and Marjolijn Duijvestein are shared last authors.

Author Contributions
Tessa Straatmijer: Conceptualization (supporting); data curation (equal); formal analysis (lead); project administration (equal); writing – original draft (lead); writing – review and editing (equal). Fiona D.M. van Schaik: Data curation (equal); writing – review and editing (equal). Alexander Bodelier: Data curation (equal); writing – review and editing (equal). Marijn C. Visschedijk: Data curation (equal); writing – review and editing (equal). Annemarie C. De Vries: Data curation (equal); writing – review and editing (equal). Cyriel Ponsioen: Data curation (equal); methodology (supporting); writing – review and editing (equal). Marie Pierik: Conceptualization (equal); data curation (equal); methodology (equal); writing – review and editing (equal). Ad A van Bodegraven: Data curation (equal); writing – review and editing (equal). Rachel L West: Data curation (equal); writing – review and editing (equal). Nanne de Boer: Data curation (equal); writing – review and editing (equal). Nidhi Srivastava: Data curation (equal); writing – review and editing (equal). Tessa Romkens: Data curation (equal); writing – review and editing (equal). Jildou Hoekstra: Data curation (equal); writing – review and editing (equal). Bas Oldenburg: Data curation (equal); writing – review and editing (equal). Gerard Dijkstra: Data curation (equal); writing – review and editing (equal). C. Janneke van der Woude: Data curation (equal); writing – review and editing (equal). Mark Lowenberg: Data curation (equal); writing – review and editing (equal). Zlatan Mujagic: Data curation (equal); writing – review and editing (equal). Vince Biemans: Data curation (equal); writing – review and editing (equal). Andrea E. van der Meulen-de Jong: Conceptualization (equal); data curation (equal); methodology (equal); supervision (lead); writing – original draft (supporting); writing – review and editing (equal). Marjolijn Duijvenstein: Conceptualization (equal); data curation (equal); methodology (equal); supervision (lead); writing – original draft (supporting); writing – review and editing (equal).

Funding information
Pfizer, Grant/Award Number: 57944353; AbbVie; Teva Pharmaceutical Industries; Ferring pharmaceuticals
N de Boer has served as a speaker for AbbVie, Takeda and MSD. He has served as a consultant and principal investigator for Takeda and/or TEVA Pharma B.V. He has received research grants from Dr. Falk, MLDS and Takeda. All outside the submitted work. A.C. de Vries served as an advisory board member of Jansen, Abbvie, Galapagos and Takeda. ISR grant from Pfizer, Jansen and Takeda. Mark Löwenberg has served as a speaker and/or principal investigator for: Abbvie, Alimentiv, Bristol Myers Squibb, Celgene, Covidien, Dr. Falk, Ferring Pharmaceuticals, Galapagos, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Protagonist therapeutics, Receptos, Takeda, Tillotts, Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Dr Falk, Achmea healthcare, Galapagos and ZonMW. Marijn Visschedijk has served as speaker for Janssen-Cilag. N de Boer has served as a speaker for AbbVie, Takeda and MSD. He has served as a consultant and principal investigator for Takeda and/or TEVA Pharma B.V. He has received research grants from Dr. Falk, MLDS and Takeda. All outside the submitted work. Fiona DM van Schaik served as a consultant for Takeda, Galapagos and Dr Falk. AAvB has received speaker or consultancy or advisory board fees from AbbVie, BMS/Celgene, Ferring, Janssen/J&J, Galapagos, Pfizer, Takeda, and TEVA. Ferring, Janssen, and Takeda supported educational programmes. He participated in Tofacitinib phase 2 and phase 3 registration studies. Research grants were provided by Pfizer, TEVA, Zon-MW and Zuyderland MC. Vince B.C. Biemans: none.
The ICC fellowship is sponsored by AbbVie, Pfizer, Takeda, Celgene, Janssen Pharmaceutica, MLDS Teva Pharmaceutical Industries, Cablon Medical, Ferring pharmaceuticals, Mundipharma, Dr. Falk Pharma, Sandoz and Tramedico.
Independent Investigator Sponsored Research Grant (Pfizer Tracking Number #57944353).

Declaration of personal interests: Fiona D. M. van Schaik: Advisory Boards Takeda, Galapagos; Alexander G. L. Bodelier has participated in advisory boards of Takeda, Janssen Pharmaceutica, Ferring and Mundipharma; Marijn Visschedijk: has served on the advisory board for Janssen-Cilag and a speakers fee from Takeda, outside the submitted work; Annemarie C. de Vries: has participated in advisory board and/or received financial compensation from the following companies: Jansen, Takeda, Abbvie and Tramedico; Cyriel Y. Ponsioen: received grants or contracts from Takeda, Pliant, and Gilead Sciences; consulting fees from Pliant and Shire (Takeda); and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Tillotts Pharma, and Pfizer outside of the submitted work; Marieke Pierik: has served on advisory boards, or as speaker or consultant for Abbvie, Janssen-Cilag, MSD, Takeda, Ferring, Dr Falk, and Sandoz and has received unrestricted grants from, Janssen Cilag, Abbvie and Takeda outside the submitted work; Ad A. van Bodegraven: has served as consultant or speaker for AbbVie, ARENA, Ferring, Janssen, MSD, Pfizer, Takeda, TEVA, Tramedico, VIFOR, and Dutch Ministry of Health (ZonMW). He has received (unrestricted) research grants from Aventis and Ferring, Pfizer, TEVA, and the Dutch Ministry of Health. He performed as (local) principal investigator in studies sponsored by Schering-Plough, Roche, Teva, Janssen, MSD, Pfizer, ARENA and Centocor; Nanne K. H. de Boer: has served as a speaker for AbbVie and MSD and has served as consultant and/or principal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted) research grant from Dr. Falk, TEVA Pharma BV, MLDS and Takeda. All outside the submitted work; Bas Oldenburg: has served as speaker for Galapagos, MSD, Janssen and received unrestricted grants from Takeda, Pfizer, Galapagos, Ferring, Celltrion and Abbvie; Gerard Dijkstra: has received grant support from DSM nutritional products LTD and speaker's fees from Janssen Pharmaceuticals, Abbvie and Takeda, outside of the submitted work; Mark Löwenberg: has served as speaker and/or principal investigator for: Abbvie, Alimentiv, Bristol Myers Squibb, Celgene, Covidien, Dr. Falk, Ferring Pharmaceuticals, Galapagos, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Protagonist therapeutics, Receptos, Takeda, Tillotts, Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Dr Falk, Achmea healthcare, Galapagos and ZonMW; Andrea E. van der Meulen-de Jong: has received a presentation fee from Janssen and served on the advisory board of Takeda and Galapagos, outside of the submitted work.; Marjolijn Duijvestein: reports advisory fees from Echo Pharma and Robarts Clinical Trials, Inc., speaker fees from Janssen, Merck & Co., Inc., Pfizer, Takeda and Tillotts Pharma, and nonfinancial support from Dr. Falk Pharma. All authors approved the last version of the manuscript.