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Scandinavian Journal of Gastroenterology
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/igas20
Prospective observational study on Stelara
(ustekinumab) assessing effectiveness in Crohn’s
disease (PROSE): a 16-week follow-up
Anders Forss, Mark Clements, Pär Myrelid, Hans Strid, Charlotte Söderman,
Agnieszka Wagner, David Andersson, Fredrik Hjelm, The PROSE SWIBREG
study group, Ola Olén, Jonas F. Ludvigsson & Jonas Halfvarson
To cite this article: Anders Forss, Mark Clements, Pär Myrelid, Hans Strid, Charlotte Söderman, Agnieszka Wagner, David Andersson, Fredrik Hjelm, The PROSE SWIBREG study group, Ola Olén, Jonas F. Ludvigsson & Jonas Halfvarson (2021): Prospective observational study on Stelara (ustekinumab) assessing effectiveness in Crohn’s disease (PROSE): a 16-week follow-up, Scandinavian Journal of Gastroenterology, DOI: 10.1080/00365521.2021.1906946
To link to this article: https://doi.org/10.1080/00365521.2021.1906946
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published online: 01 Apr 2021.
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ORIGINAL ARTICLE
Prospective observational study on Stelara (ustekinumab) assessing
effectiveness in Crohn
’s disease (PROSE): a 16-week follow-up
Anders Forssa , Mark Clementsa, P€ar Myrelidb,c , Hans Stridd, Charlotte S€odermane, Agnieszka Wagnerf, David Anderssong, Fredrik Hjelmh, The PROSE SWIBREG study group, Ola Oleni,j, Jonas F. Ludvigssona,k,l,mand Jonas Halfvarsonn
a
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden;bDepartment of Surgery, Link€oping University Hospital, Link€oping, Sweden;cDepartment of Clinical and Experimental Medicine, Link€oping University, Link€oping, Sweden;
d
Department of Internal Medicine, S€odra €Alvsborg Hospital, Borås, Sweden;eMedical Department, Capio St G€oran Hospital, Stockholm, Sweden;fDepartment of Internal Medicine, Blekinge Hospital, Karlskrona, Sweden;gDepartment of Internal Medicine, Danderyd University Hospital, Stockholm, Sweden;hJanssen Cilag AB, Stockholm, Sweden;iDepartment of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden;jSachs’ Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden;
k
Department of Paediatrics, €Orebro University Hospital, €Orebro, Sweden;lDivision of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK;mDepartment of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA;nDepartment of Gastroenterology, Faculty of Medicine and Health, €Orebro University, €Orebro, Sweden
ABSTRACT
Background: Prospectively and systematically collected real-world data on the effectiveness of usteki-numab (anti-interleukin-12/23) for treating Crohn’s disease (CD) are still limited.
Aim: To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD. Methods: Prospective multicentre study of adult CD patients initiating ustekinumab according to rec-ommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (3-point-decrease of Harvey–Bradshaw index (HBI)) and remission (HBI 4 points) at week 16. Secondary outcomes included C-reactive protein (CRP) and haemoglobin (Hb) at baseline compared to week 16.
Results: Of 114 included patients, 107 (94%) had failed 1 and 58 (51%) 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) show-ing a clinical response). The median CRP concentration (N ¼ 65) decreased from 6 to 4 mg/l (p ¼ .006). No significant changes in Hb were observed. No incident malignancies or infections, requiring anti-biotic treatment, were reported.
Conclusions: In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option.
Abbreviations: CD: Crohn’s disease; HBI: Harvey–Bradshaw Index; IBD: Inflammatory bowel disease; ICD: International classification of disease; SWIBREG: Swedish Inflammatory Bowel Disease Registry; aTNF: Anti-tumour necrosis factor
ARTICLE HISTORY Received 12 January 2021 Revised 15 March 2021 Accepted 17 March 2021 KEYWORDS Crohn’s disease; inflammatory bowel disease; ustekinumab; real-world data; clinical practice
Introduction
Crohn’s disease (CD) is a chronic relapsing inflammatory condi-tion of the gastrointestinal tract [1]. The disease is becoming increasingly common worldwide, with more than 20,000 affected individuals in Sweden only [2]. Diagnosis is often at a young age, and the disease course is associated with loss of work productivity, increased morbidity and mortality [2–5]. To minimise disease progression, treatment algorithms of CD aim to induce and maintain remission [6]. Historically,
immunomodulators were often used as first-line treatment [7,8]. When this option failed, anti-tumour necrosis factor (aTNF) agents and surgery remained as alternative treatment options. However, the observation that around 30% of aTNF treated patients are primary non-responders and approximately 40% of responders experience secondary failure with loss of response or intolerance [9–13] has triggered a search for new treatment options. Additional biological agents with novel mechanisms of actions have recently been introduced and among these usteki-numab represents an increasingly used option.
CONTACT Anders Forss anders.forss@ki.se Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm 17177, SE, Sweden
These authors have contributed equally to this work.
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. https://doi.org/10.1080/00365521.2021.1906946
Ustekinumab was approved by the European Medicines Agency and by the Food and Drug Administration in the United States in 2016. It is indicated for the treatment of adult patients with moderately to severely active CD who have had an inadequate response with, lost response to or were intolerant to either conventional therapy or aTNF or had medical contraindications to such therapies. The efficacy of ustekinumab to induce and maintain disease remission in patients with moderate to severe CD has been demonstrated in two randomised clinical induction trials (UNITI-1 and UNITI-2) [14], and a maintenance trial (IM-UNITI) [15]. Even though the pivotal trials included both patients with previ-ous aTNF failure and aTNF naïve patients [16–19], they do not accurately reflect real-world clinical practice. In real-world clinical settings, patients with CD are more heterogeneous. Furthermore, many patients seen in clinical practice would not be eligible for inclusion in a clinical trial [18]. To date, there are several observational studies presenting real-world data on the clinical effectiveness of ustekinumab [19–28]. In several of these studies, ustekinumab was administered sub-cutaneously and/or with various dosing patterns [23–26,29,30], since they were based on compassionate use before the drug was approved for the treatment of CD. Previous studies are also limited by retrospective designs and, to our knowledge, only one study is entirely based on prospectively collected data [22]. Whether the results from these studies can be applied to ustekinumab-treated patients in general remains unknown since data from nation-wide real-world cohorts, with a balanced representation of regional hospitals and university hospitals, are lacking.
The aim of this study was to examine the short-term clin-ical effectiveness of ustekinumab in CD. We did so through a nation-wide observational study, where real-world data were prospectively and systematically collected. We assessed out-comes 16 weeks after initiation of treatment.
Methods
Study design and endpoints
This was a Swedish nation-wide multicentre prospective non-interventional observational study of patients initiated on ustekinumab according to the standard practice of care between 23 January 2017 and 22 November 2018. Treating physicians independently initiated ustekinumab treatment and assessed clinical and biochemical response during fol-low-up according to national treatment guidelines [27].
Study participants
We included patients with a confirmed international classifica-tion of disease (ICD) diagnosis of CD (ICD-10: K50 all sub-classi-fications) with active CD, as defined by the treating physician, based on clinical activity, inflammatory markers, endoscopic findings or response to concomitant medication (including cor-ticosteroids). Included patients were (i) naïve to, (ii) had an inadequate response to, (iii) lost response to, (iv) were intoler-ant to either conventional therapy or aTNF or (v) had medical
contraindications to such therapies. All patients began treat-ment with ustekinumab on or after their 18th birthday.
Patients with previous exposure to ustekinumab or con-current participation in other clinical studies were excluded. For the included patients from 20 Swedish hospitals, baseline and clinical follow-up data were reported through a standar-dised study-specific electronic case report form (eCRF) dir-ectly linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG) [28]. SWIBREG is a nation-wide registry for IBD founded in 2005, covering around 80% of the Swedish IBD population (n ¼ 52,003 patients, August 2020) [31]. The registry contains extensive quality data on CD phenotype, treatment (including biologics), surgery and qual-ity of life. To be included in the study, a patient had to be initiated on ustekinumab within the last 2 weeks before inclusion or started treatment <12 months ago if detailed information on the treatment was documented in SWIBREG within 2 weeks of treatment initiation.
The primary objective was to determine the short-time clin-ical effectiveness of ustekinumab as the proportion of patients with clinical response and remission assessed as a change in Harvey–Bradshaw index (HBI) [32] comparing scores at base-line, i.e. at the initiation of ustekinumab treatment, and at week 16. Clinical response was defined as a reduction of HBI score 3 points. Clinical remission was defined as HBI score 4 points. Secondary objectives included the impact of usteki-numab on inflammatory biomarkers, C-reactive protein (CRP), haemoglobin (Hb) and faecal (f)-calprotectin, comparing levels at baseline and at week 16.
Ustekinumab
All induction doses of ustekinumab were administered intra-venously according to the EU summary of product Characteristics recommendation of 6 mg/kg in steps of 130 mg. A 90 mg subcutaneous injection was administered 8 weeks after the intravenous dose and the next 90 mg sub-cutaneous dose either 8 or 12 weeks after first subcutane-ous injection.
Data collection
Baseline data, including demographics and clinical character-istics such as year of diagnosis, age at diagnosis, history of previous CD related bowel surgery, relevant comorbidities and extraintestinal manifestations, disease location and behaviour according to the Montreal Classification [33] and clinically relevant medication for CD (including biologics and reasons for discontinuation) were collected from SWIBREG. Data on clinical and biochemical disease activity were recorded at baseline (±2 weeks) and follow-up visit at week 16 (±2 weeks). We also documented if and why patients dis-continued ustekinumab treatment during follow-up. During the scheduled visits, we recorded adverse events of special interest for ustekinumab, such as malignancy and infections. Any such adverse events were promptly reported by the investigating physician directly to Janssen Cilag AB according
to the obligations of pharmacovigilance of drug manufac-turers and to the Swedish Medical Products Agency.
Statistical analysis
We reported descriptive findings as median and interquartile range (IQR) for continuous variables, biochemical and clinical outcomes and as proportions for categorical variables. Calculations of clinical response and remission rates at week 16 were restricted to patients with data on HBI recorded at baseline (±2 weeks). Comparisons of clinical disease activity and inflammatory markers between baseline and week 16 were restricted to patients who had data recorded at both time points. Changes in median HBI, CRP, Hb and f-calprotec-tin were analysed by the Wilcoxon matched-pairs signed-rank test. All statistical tests were two-tailed, and tests withp<.05 were considered statistically significant. Data management and statistical analyses were performed using Microsoft Excel (MS Office 2016), SAS version 9 (SAS Inc., Cary, NC) and STATA software version 14.2 (StataCorp, College Station, TX, USA).
Ethical considerations
All patients included in PROSE signed an informed consent authorising access to and the use of clinical data collected in this study. This project was approved by the Regional Ethical Review Board in Link€oping, Sweden (2017-290-31).
Results
Patient characteristics
We included 114 patients representing 20 different hospitals (Appendix 1) with a geographical coverage of almost all of Sweden (Figure 1). Patient characteristics at baseline are pre-sented in Table 1. Patients were predominately male (n ¼ 60, 53%), nearly all (n ¼ 107, 94%) had previously failed at least one biological drug and approximately one third (n ¼ 37, 32%) had a history of previous CD-related bowel surgery. At base-line, 47 (41%) patients had concomitant treatment with immu-nomodulators and/or corticosteroids, and 69 (72%) patients had an HBI5 with a median HBI of 6 (IQR 4–11) (Table 1).
Dosing and treatment persistence
The 16-week drug retention rate was 105/114 (92%) (Figure 1). Reasons for termination of ustekinumab before week 16 were lack of response (n ¼ 6), pregnancy (n ¼ 1) and lost to follow-up (n ¼ 2). Of 114 patients receiving an intravenous induction dose, 110 received at least one 90 mg subcutane-ous dose of ustekinumab 8 weeks after the induction dose.
Clinical effectiveness
Clinical remission and response
We calculated clinical response and remission based on HBI at week 16 compared to baseline. Data on HBI were available for 96 patients at baseline, and 89 (93%) of these patients
remained on ustekinumab treatment after 16 weeks. At week 16, 23/96 (24%) patients had a clinical response (HBI decrease 3), 25/96 (26%) were in clinical remission (HBI 4), and 38/96 (40%) achieved either clinical response or remission. However, data on HBI at week 16 were missing for 25 patients with ongoing ustekinumab treatment.
Of patients with HBI 5 at baseline (n ¼ 50), response at week 16 was achieved in 23 (46%), remission in 13 (26%) and 26 (52%) achieved either clinical response or remission (Table 2). Overall, the median HBI was 6 (IQR 4–11) at base-line and 5 (IQR 4–7) at week 16. Among patients with data on HBI at both time points, the median HBI decreased by 1 (IQR3 to 1, p ¼ .003) from baseline to week 16 (Table 3).
Biochemical effectiveness
In total, 65 patients had data on CRP at baseline and week 16, and 18 patients had the corresponding information on f-calprotectin (Table 3). The median CRP concentration decreased from 6 mg/l at baseline to 4 mg/l at week 16 (p ¼ .006). The median f-calprotectin level decreased from 266 to 189mg/g (p ¼ .02). No significant changes in Hb were observed.
Adverse events
No incident malignancies or infections requiring antibiotic treatment were recorded during follow-up.
Patients with IV induction ustekinumab Confirmed CD diagnosis
N=114
Discontinued ustekinumab or lost to follow-up before week 8
n=4 (4%)
Continued treatment with ustekinumab at week 16 n=105 (92%)
Discontinued ustekinumab after week 8 n=5 (4%)
Figure 1. Flowchart of ustekinumab treatment in the PROSE study population. A total of 114 patients with confirmed Crohn’s disease (CD) diagnosis received intravenous ustekinumab induction treatment at week 0. A total of 110 (96%) patients received a subcutaneous injection at week 8. Treatment retention at week 16 was 105 (92%) patients. Of these, four (4%) patients discontinued or were lost to follow-up (lack of response,n ¼ 1; pregnancy, n ¼ 1; lost to follow-up,n ¼ 2) before week 8 and 5 (4%) patients (lack of response, n ¼ 5) between week 8 and 16.
Discussion
In this nation-wide Swedish prospective observational multi-centre study, we report patient characteristics, clinical and inflammatory markers of response and remission rates in a cohort of patients with CD initiated on ustekinumab
according to clinical practice. We included a total of 114 patients. Of these, 105 were still on treatment with ustekinu-mab at week 16. Data were collected and reported by treat-ing physicians through an eCRF linked to the Swedish IBD registry SWIBREG. The results represent the real-world clinical
Table 1. Baseline patient characteristics and phenotype according to the Montreal classification.
Characteristics N
Median age– years (IQR) 40 (31–54) 114
Sex, female (%) 54 (47) 114 BMI– mean (SD) 25.4 (5.7) 110 Smoking status– n (%) 114 Current 12 (11) Previous 40 (35) Never 62 (54) Age at diagnosis– n (%) 114 16 years (A1) 17 (15) 17–40 years (A2) 75 (66) <40 years (A3) 22 (19) Location– n (%) 114 Ileum (L1) 24 (21) Colon (L2) 35 (31) Ileocolonic (L3) 55 (48) Behaviour– n (%) 114 Inflammatory (B1) 51 (45) Structuring (B2) 50 (44) Penetrating (B3) 13 (11) Perianal involvement (B1p–B3p) 18 (16)
Prior surgical resection– n (%) 37 (32) 114
Prior biological treatment– n (%) 112
1 107 (94)
2 58 (51)
3 24 (21)
Reason for termination of last biological agent– n (%) 107
Lack of or loss of response 83 (78)
Intolerance 21 (20) Other reason 3 (3) Concomitant medications– n (%) 114 Corticosteroids 21 (18) Immunomodulators 26 (23) Endoscopic ulcersa– n (%) 14 (70) 20
HBI median (IQR)/mean (SD) 6 (4–11)/7.8 (5.1) 96
Clinical disease activityn (%)
Remission (HBI< 5) 27 (28)
Mild (HBI 5–7) 31 (32)
Moderate (HBI 8–16) 31 (32)
Severe (HBI 17) 7 (7)
Median f-calprotectin– mg/g (IQR) 292 (163–1143) 37
250 mg/g – n (%) 21 (57)
Median CRP– mg/l (IQR)/mean (SD) 7 (4–15)/15 (20) 98
3 mg/l – n (%) 91 (93)
Median Hb– g/l (IQR)/mean (SD) 135 (125–146)/135 (16) 99
CRP: C-reactive protein; f-calprotectin: faecal calprotectin; Hb: haemoglobin; HBI: Harvey–Bradshaw index; IQR: interquartile range; SD: standard deviation.
aPresence aphthous lesions (defined as ulcers with a surface diameter<5 mm) or ulcers (surface diameter >5 mm).
Table 2. Harvey–Bradshaw index, clinical remission, response and inflammatory marker levels at baseline and at week 16. Parameter Baselinea N ¼ 114 Week 16 b N ¼ 105 Baseline c N ¼ 105 Week 16 c N ¼ 105 Mild-severe clinical activity (HBI5) n/N (%) 69/96 (72) 51/80 (64) 50/70 (71) 45/70 (64) Clinical remission (HBI4) n/N (%) 27/96 (28) 29/80 (36) 20/70 (29) 25/70 (36)
Clinical remittersd n/N (%) – – – 13/50 (26)
Maintained clinical remissione n/N (%) – – – 12/20 (60)
Clinical respondersf n/N (%) – – – 23/50 (46)
Clinical response or remission n/N (%) – – – 38/70 (54)
Clinical responders or remittersg n/N (%) – – – 26/50 (52)
Elevated f-Calprotectin or CRPh n/N (%) 95/102 (93) 69/80 (86) 67/71 (94) 61/71 (86)
HBI: Harvey–Bradshaw index;aincludes patients with recorded HBI scores or inflammatory markers recorded within ±2 weeks of base-line; bIncludes patients with recorded HBI scores or inflammatory markers recorded within ±2 weeks of week16;cincludes patients
with recorded. HBI scores or inflammatory markers both at baseline ±2 weeks and at week 16 ± 2 weeks;dHBI5 at baseline and remission at week 16;eRemission at baseline and week 16;fHBI5 at baseline and response at week 16;gHBI5 at baseline and
response or remission at week 16;hFaecal (f)-calprotectin250 mg/g or C-reactive protein (CRP) 3 mg/l. 4 A. FORSS ET AL.
practice of ustekinumab treatment in patients with active CD.
We observed clinical remission at week 16 in 26% (n ¼ 25/ 96) patients, and response was achieved in 24% (n ¼ 23/96) and clinical benefit, defined as response or remission at week 16, in 40% (n ¼ 38/96). These results were supported by a statistically significant decrease in median HBI, CRP and f-calprotectin at week 16 compared to baseline but no sig-nificant change in levels of Hb (Table 3).
These findings can be compared with those of the regis-tration trials UNITI-1 and 2 where response rates of 34 and 56% were reported at 6 weeks [14]. However, randomised controlled trials (RCTs) provide data only on well-defined and selected groups of patients treated under strict protocols. In this study, patients were included independently by physi-cians and treated according to clinical practice. In such a real-world clinical setting, patient populations are more het-erogeneous, and treatment patterns vary depending on patient characteristics and clinical decisions by treating physicians. Furthermore, in UNITI-1 and 2 patients without previous treatment with aTNF and primary or secondary non-response to such treatment were included. In the main-tenance study IM-UNITI, 44% of patients had previous aTNF treatment [15]. In our study, 94% (n ¼ 107/114) had failed at least one biological drug (aTNF or vedolizumab). Some 78% (n ¼ 83/107) of those terminated last biological treatment due to lack of response. This is similar to recent real-world observational studies [19–22] and confirms the short-term effectiveness of ustekinumab even when used outside the context of tertiary referral centres, i.e. in a variety of care contexts, including both regional and university hospitals.
One-quarter of the patients in this study recorded a clin-ical response, and a similar proportion was in clinclin-ical remis-sion at week 16. A total of nine patients discontinued or were lost to follow-up. Of these, six terminated ustekinumab treatment due to lack of response. Previous observational real-world single and multicentre studies with comparable patient cohorts and follow-up times have shown short-term response rates between 16 and 84% [19–26,29,34,35]. However, the dosing regimens have varied, not always reflecting the current EU Summary of Product Characteristics for ustekinumab with intravenous induction followed by sub-cutaneous injections. This may play an important role in the largely varying rates in previous studies along with the use of different assessment scores for response and remission, such as Crohn’s Disease (CD) Activity Index and HBI. When
restricting the comparison to real-world studies adhering to the summary of product characteristics, and using the same definitions for response and remission as in our study, short-term (12–16 weeks follow-up) response rates of 16–52% and remission rates of 31–58% have been observed [19–22]. In our study, we show comparable response and remission rates of 24 and 26%, respectively.
Our study has several strengths, such as the nation-wide prospective observational design, which enabled us to cap-ture the real-world clinical effectiveness of ustekinumab. A nation-wide inclusion of patients from 20 Swedish regional and university hospitals based on the individual physician’s independent decision to initiate the patient on ustekinumab according to clinical practice reflects a real-world setting. To our knowledge, no previous prospective studies of ustekinu-mab have included IBD patients representing both different hospital types and different clinical settings. The quality of the collected data was strengthened by the standardisation of data collection through an eCRF. Furthermore, in contrast to some previous studies where heterogeneous dosing pro-tocols have been applied [23,25,26,30], induction and main-tenance dosing adhered to the label and national guidelines in our study. In this study, all patients received one intraven-ous induction dose followed by subcutaneintraven-ous doses.
Among the limitations of this study are the inherent limi-tations of multicentre observational studies, including a lack of compulsory assessment of HBI, inflammatory markers and endoscopic activity. To determine the clinical remission and response rate at week 16, we applied an intention-to-treat methodology and included all patients with data on HBI at baseline, including those who had discontinued treatment (n ¼ 7) before week 16. The number of patients with reported HBI score within the set time-frame was lower than expected, rendering lower statistical power than planned. However, the calculated clinical response and remission were both statistically significant and supported by a reduction in the concentration of CRP. Data on f-calprotectin were avail-able for only 16% of the patients at both time points, mak-ing it difficult to assess the overall inflammatory response based solely on f-calprotectin. The low proportion of patients with data on f-calprotectin levels at both baseline and week 16 may in part be explained by the tight time-windows for recording this information. The lack of f-calprotectin assay standardisation further complicates the interpretation of this inflammatory marker. Therefore, the results of f-calprotectin should be interpreted with caution. The nine patients who
Table 3. Clinical and laboratory parameters at baseline and at week 16 among ustekinumab treated patients with Crohn’s disease. Parameter Baseline median (IQR) Week 16 median (IQR) Baselinea median (IQR) Week 16a median (IQR)
Change week 16 vs. baselinea
median (IQR) p Value
HBI 6 (4–11) (n ¼ 96) 5 (4–7) (n ¼ 80) 6 (4–10) (n ¼ 70) 5.5 (4–8) (n ¼ 70) 1 (3–1)(n ¼ 70) p¼.003 CRP mg/l 7 (4–15) (n ¼ 98) 5 (4–7) (n ¼ 75) 6 (4–14) (n ¼ 65) 4 (4–6) (n ¼ 65) 1 (9–0)(n ¼ 65) p¼.006 f-calprotectinmg/g 292 (163–1143) (n ¼ 37) 204 (134–367) (n ¼ 46) 266 (142–1001) (n ¼ 18) 189 (150–325) (n ¼ 18) 65 (754–19)(n ¼ 18) p ¼.02 Hb g/l 135 (125–146) (n ¼ 99) 138 (128–149) (n ¼ 75) 136 (125–146) (n ¼ 66) 138 (128–149) (n ¼ 66) 0 (4–7) (n ¼ 66) p¼.3
HBI: Harvey–Bradshaw index; CRP: C-reactive protein; f-calprotectin: faecal calprotectin; Hb: haemoglobin; n: number of patients with available data within ±2 weeks of baseline and week 16 visit to physician;aincludes patients with recorded data at baseline ±2 weeks and at week 16 ± 2 weeks; calculated as
discontinued or were lost-to follow-up before week 16 did not differ significantly at baseline from those included in the week 16-analyses (data not shown).
In conclusion, ustekinumab achieved both clinical remis-sion and response, as well as biochemical response in patients with active CD who were almost exclusively aTNF refractory. Ustekinumab proved safe in this real-world setting of CD patients. Our results give further support to previous studies showing evidence for ustekinumab as a valuable, effi-cient and safe treatment of CD.
Acknowledgements
Ida Gustavsson, Kristin Klarstr€om-Engstr€om and Mariam Lashkariani.
Disclosure statement
P Myrelid served as speaker and/or advisory board member for AbbVie, Ferring, Janssen, Pfizer, Takeda, Baxter and Tillotts Pharma.
H Strid served as speaker and/or advisory board member for AbbVie, Ferring, Janssen, Pfizer, Takeda, Gilead and Tillotts Pharma.
D Andersson served as speaker and/or advisory board member for AbbVie, Janssen and Takeda. O.
F Hjelm is an employee of Janssen Cilag AB.
Olen has been PI on projects at Karolinska Institutet, partly financed by investigator-initiated grants from Janssen and Ferring, and Karolinska Institutet has received fees for lectures and participation on advisory boards from Janssen, Ferring, Takeda, and Pfizer.
O Olen also reports a grant from Pfizer in the context of a national safety monitoring programme.
J Halfvarson served as speaker and/or advisory board member for AbbVie, Celgene, Celltrion, Dr. Falk Pharma and the Falk Foundation, Ferring, Hospira, Janssen, MEDA, Medivir, MSD, Olink Proteomics, Pfizer, Prometheus Laboratories, Sandoz/Novartis, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and received grant support from Janssen, MSD, and Takeda. No potential conflict of interest was reported by the author(s).
Author contributions
Study concept and design: JFL, JH, FH. Acquisition of data: AF, JFL, JH, HS, CS, AW, DA. Statistical analyses: AF, MC. First draft of the manuscript: AF, JFL, JH. Critical revision of the manuscript for important intellectual content: JH, JFL, AF, OO, PM, HS, CS, AW, DA, FH. Funding: FH. Study supervision: JFL.
Funding
This work was supported by Janssen Cilag AB, Sweden.
ORCID
Anders Forss http://orcid.org/0000-0002-1906-4982 P€ar Myrelid http://orcid.org/0000-0001-7518-9213
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Appendix 1
List of Swedish hospitals including patients in the PROSE study
Blekinge Hospital, Karlskrona
Danderyd University Hospital, Stockholm Kalmar County Hospital, Kalmar Karolinska University Hospital, Stockholm Link€oping University Hospital, Link€oping N€AL Hospital Trollh€attan, Trollh€attan Ryhov County Hospital, J€onk€oping Sahlgrenska University Hospital, G€oteborg Skaraborgs Hospital Lidk€oping, Lidk€oping Skåne University Hospital, Lund Skåne University Hospital, Malm€o Stockholm Gastro Center, Stockholm Capio St G€oran Hospital, Stockholm Sunderby Hospital, Luleå
Sundsvall Regional Hospital, Sundsvall S€odra €Alvsborg Hospital, Borås University Hospital of Umeå, Umeå Uppsala University Hospital, Uppsala V€asterås Central Hospital, V€asterås €Orebro University Hospital, €Orebro
