Systematic Review of Tumor Necrosis Factor Antagonists in Extraintestinal Manifestations in Inflammatory Bowel Disease

Accepted Manuscript Systematic review of tumour necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease Laurent Peyrin-Biroulet, Gert Van Assche, David Gómez-Ulloa, Laura GarcíaÁlvarez, Núria Lara, Chris M. Black, Sumesh Kachroo

PII: DOI: Reference:

S1542-3565(16)30372-X 10.1016/j.cgh.2016.06.025 YJCGH 54816

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 25 June 2016 Please cite this article as: Peyrin-Biroulet L, Van Assche G, Gómez-Ulloa D, García-Álvarez L, Lara N, Black CM, Kachroo S, Systematic review of tumour necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.06.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title - Systematic review of tumour necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease

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Short title – not applicable

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Authors - Laurent Peyrin-Biroulet1, Gert Van Assche2, David Gómez-Ulloa3, Laura García-Álvarez3, Núria Lara3, Chris M Black4, Sumesh Kachroo4

Lorraine University, Gastroenterology Department, Vandoeuvre, France; 2University

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Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium; 3IMS Health, Real-World Evidence Solutions, Barcelona, Spain; 4Merck & Co., Inc., Center for

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Observational and Real-World Evidence (CORE), Kenilworth, NJ, United States

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Grant support – Not applicable.

Abbreviations – ASAS, assessment of the ankylosing spondilytis scale; CD, Crohn’s disease; CTx, c-telopeptide of type-1 collagen; ECCO, European Crohn’s and Colitis Organisation; EIM, extraintestinal manifestations; IBD, inflammatory bowel disease; IBDU, inflammatory bowel disease type unclassified; IS, interventional study; NIS, noninterventional study; OL, open label; P1NP, procollagen type 1 N-terminal propeptide; QoL, quality of life; RCT, randomized controlled trial; TNF, tumour necrosis factor; UC, ulcerative colitis.

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Correspondence - Laurent Peyrin-Biroulet; Inserm U954 and Department of HepatoGastroenterology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France; e-mail

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address: [email protected]; telephone number: +33 3 83 15 36 61; fax number: +33 3 83 15 36 61.

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Disclosures – LPB: lecture fees from Merck, Abbvie, Janssen, Takeda, Ferring, Norgine, Tillots, Vifor, Therakos, Mitsubishi, HAC-pharma; consulting fees from Merck, Abbvie,

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Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, HAC-Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH. GVA: research support from the University of Leuven,

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Abbvie, MSD; speaker's fees from Abbvie, Ferring, MSD, Janssen; consulting fees from the University of Leuven, Abbvie, MSD, Ferring, UCB, Takeda. DGU: consultant for

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Merck. LGA: consultant for Merck. NL: consultant for Merck. CMB: Merck stock holder,

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Merck employee. SK: Merck stock holder, Merck employee.

Writing Assistance – This manuscript was conducted by IMS Health with financial support from Merck & Co.

Author Contributions – LPB contributed to the concept and design of the review, provided expert clinic advice in the field, critically reviewed the protocol, interpreted

ACCEPTED MANUSCRIPT data extracted, and critically reviewed the manuscript. GVA contributed to the concept and design of the review, provided expert clinic advice in the field, critically reviewed the protocol, interpreted data extracted, and critically reviewed the manuscript. DGU drafted the review protocol, conducted the literature search, study selection, data

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extraction and quality assessment of included studies, interpreted data extracted and drafted the manuscript. LGA critically reviewed protocol, contributed to study

selection and data extraction, interpreted data extracted and critically reviewed the

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manuscript. NL critically reviewed the protocol, interpreted data extracted and

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critically reviewed the manuscript. CMB critically reviewed the protocol, interpreted data extracted and critically reviewed the manuscript. SK contributed to the concept and design of the review, critically reviewed the protocol, interpreted data extracted, and critically reviewed the manuscript. All authors read and approved the final

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manuscript.

ACCEPTED MANUSCRIPT Abstract Background and Aims: This systematic review investigated the efficacy and the effectiveness of biologic drugs in extraintestinal manifestations (EIMs) in inflammatory

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bowel disease (IBD). Methods: Literature search was conducted in PubMed, Embase and Cochrane until October 2015. Main inclusion criteria were adults with IBD, use of a biologic drug,

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evolution of EIMs, interventional study (IS) or non-interventional study (NIS).

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Results: Nine IS [two randomized controlled trials (RCTs) (n=797), seven open label (OL) trials (n=1143)] and 13 NIS (n=914) were included. Tumour necrosis factor (TNF) antagonists achieved complete response for pyoderma gangrenosum in 21-25% of patients in IS and in 92-100% patients in NIS, with similar results for other cutaneous

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manifestations such as erythema nodosum or stomatitis. Adalimumab significantly reduced the prevalence of anaemia vs. placebo after 56 weeks in one RCT. In two NIS, anti-TNF therapy improved anaemia in the short-term (67%) and in the long-term

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(34%). Complete response after anti-TNF treatment was reported in IS, including

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arthralgia (reduction in prevalence from 47.1% to 26.8% in the mid-term in one OL trial) and arthritis (reduction in prevalence from 8.7% to 2.1% and from 58% to 12.5% in two OL trials). Anti-TNFs were beneficial for a majority of patients with ocular manifestations. Infliximab was associated with improved outcomes in bone formation and bone mineral density. Conclusions: Anti-TNFs appear to be effective alternatives for certain EIMs associated with IBD including musculoskeletal, cutaneous and ocular manifestations while some

ACCEPTED MANUSCRIPT beneficial effect may be obtained in metabolic bone disease, and on hematologic or vascular EIMs. Keywords: systematic review, extraintestinal manifestations, inflammatory bowel

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disease

ACCEPTED MANUSCRIPT Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory conditions of the gut and comprise the main types of Inflammatory Bowel Disease (IBD). The main signs and symptoms of both UC and CD are observed in the digestive tract. However, manifestations of these disorders are not locally restricted to the intestine and a

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significant portion of IBD patients, ranging between 12% and 35% in UC and between 25% and 70% in CD, show concomitant associated extraintestinal manifestations

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(EIMs).1-4

There is a broad range of EIMs such as musculoskeletal, metabolic bone disease,

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mucocutaneous, ocular, hepatobiliary, vascular or hematologic. The most prevalent EIMs in IBD are arthritis (range 7.2%-28.6% of IBD patients), osteoporosis (11%-14.8%), uveitis (2.1%-5.3%), erythema nodosum (1.7%-5.1%), psoriasis (1.5%-2.5%), ankylosing spondilytis (1.4%-4.1%), sacroilitis (1.9%-4.9%), oral aphthous stomatitis (0.7%-7-4%),

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pyoderma gangrenosum (0.6%-1.8%) and primary sclerosing cholangitis (0.4%-1.8%).1-8 Although the majority of IBD patients usually suffer from one EIM at a time, there are

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reports of as much as 25% of patients experiencing several EIMs at the same time.2 The scientific community is showing growing interest on better understanding the

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incidence and the management of EIMs in IBD in general9-11 due to their strong impact on patient’s quality of life (QoL).12-13 Very recently, consensus recommendations on the management of EIMs in IBD patients have been published by the European Crohn’s and Colitis Organisation (ECCO).14 ECCO recommends considering tumour necrosis factor (TNF) antagonists (i.e. infliximab or adalimumab) as possible alternatives for the management of UC and CD patients presenting with spondyloarthropathy, arthritis, mucocutaneous manifestations like pyoderma gangrenosum or erythema nodosum

ACCEPTED MANUSCRIPT and in patients with scleritis or uveitis, while some potential benefit of anti-TNF treatment in patients with metabolic bone disease or coagulopathy is described.14 Many EIMs (e.g. arthritis, erythema nodosum, pyoderma gangrenosum, iritis, uveitis)

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share a pathogenic TNF-α dependent mechanism with IBD. The introduction of new biologic therapies for the management of IBD, particularly anti-TNF drugs, is perceived as an opportunity to improve the outcomes of EIMs in these patients;15 however, little

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is known about the efficacy and effectiveness of these new therapies in the management of EIMs.

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Several literature reviews have been published in the last few years trying to summarise the evidence available on the use of biologic drugs for the management of EIMs in IBD.16-18 The authors of these studies concluded that anti-TNF therapy should be considered in patients with EIMs due to beneficial effect observed. However, none

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of these reviews has been conducted through a systematic approach. To our knowledge, this is the first systematic review aimed at assessing previously

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published interventional and non-interventional studies that investigate the efficacy

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and the effectiveness, respectively, of biologic drugs in the treatment of EIMs in IBD.

Methods

The scope of the systematic review was defined in a protocol that guided the development of search strategy, study selection, data extraction and reporting. Search Strategy

ACCEPTED MANUSCRIPT Two systematic literature searches to identify relevant citations for interventional and non-interventional studies were conducted in PubMed, Embase and Cochrane databases up until October 2015. The search strategies included common search strings for disease- and drug-related terms and specific search strings for study design-

also searched for any additional relevant citations.

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Study selection

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related terms [Supplementary Tables 1 and 2]. The reference lists of citations were

After duplicate removal, a two-step process was followed to review the citations

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identified during the literature searches: (1) preliminary title and abstract assessment, followed by (2) full text review of relevant studies. Selection criteria were developed in the Participants-Interventions-Comparators-Outcomes-Study design (PICOS) format19

studies).

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and only varied by the type of study design (interventional and non-interventional

The following inclusion criteria were applied for the searches: (1) adult patients

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diagnosed with IBD; (2) use of a biologic drug (i.e. infliximab, adalimumab,

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certolizumab pegol, golimumab, vedolizumab, natalizumab); (3) assessment of the efficacy (for non-interventional studies: assessment of effectiveness) of treatment on EIMs (i.e. musculoskeletal, metabolic bone disease, cutaneous, ocular, hepatobiliary, vascular, hematologic); (4) interventional study or non-interventional study with a minimum of 10 patients receiving the drugs of interest for the management of EIMs; and (5) study published in English language. Conference papers were excluded from the review.

ACCEPTED MANUSCRIPT No limits were applied for dates. A complete overview of inclusion and exclusion criteria used for both searches is available in Supplementary Tables 3 and 4. Data extraction

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Data from eligible studies were abstracted using a specifically developed data extraction form. Variables extracted included general study characteristics such as study objectives, study design, inclusion and exclusion criteria or study duration,

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patients’ demographics and baseline IBD characteristics (including prevalence of EIMs), treatment for IBD and for EIMs and measures of efficacy and effectiveness of

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treatment for EIMs.

The methodological quality of the interventional studies included was assessed using the Centre for Reviews and Dissemination quality assessment criteria for systematic

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reviews (Supplementary Table 5).20 For non-interventional studies, the quality assessment tool developed by the National Institutes of Health 21 was used to assess data quality and evaluate the internal and external validity of the studies

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(Supplementary Table 6).

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The significant heterogeneity of designs, populations and outcomes assessed of the studies included in this systematic review did not allow for data to be meta-analysed. Due to the exploratory nature of this systematic review, and to the significant variability in outcomes measures, grading of evidence identified was not considered.

Results

ACCEPTED MANUSCRIPT Efficacy (interventional studies) A flow diagram depicting the findings of the searches and the selection process is provided in Supplementary Figure 1. A total of 1,403 potentially relevant citations

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were identified through the literature search and four additional citations were identified through manual searches or by reviewing the citations of studies selected.

Removal of duplicates followed by review of titles and abstracts and review of full texts

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yielded nine relevant studies that fulfilled the eligibility criteria and were extracted. The efficacy of biologic drugs in the management of EIMs in IBD patients was

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evaluated in two randomised clinical trials and in seven open label trials. All interventional studies identified in this systematic review were focused on CD patients, with the exception of Brooklyn et al.22 and Kaufmann et al.,23 which also included patients with UC. An overview of the main study characteristics and results reported

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for the selected studies is available in Table 1. Randomised clinical trials

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Our review included two randomised clinical trials.22,24

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Brooklyn et al. assessed the efficacy of infliximab in the treatment of pyoderma gangrenosum in a double blind placebo-controlled randomised clinical trial. The study included 30 patients with pyoderma gangrenosum, of which 13 presented with CD and six with UC. The study comprised of two periods: an initial randomised period of two weeks and a subsequent 4-week open label period in which patients received infliximab. The authors reported significant clinical improvement in pyoderma gangrenosum (as per physician and patient global assessment) in a larger proportion of

ACCEPTED MANUSCRIPT patients receiving infliximab than in those patients receiving placebo at week 2 (46% vs. 6%, p=0.025). During the subsequent open label period, in which all patients received infliximab (n=29), 69% of patients showed clinical improvement of pyoderma

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gangrenosum symptoms.22 A post-hoc analysis of the CHARM trial,24-25 that assessed the efficacy of two different regimes of adalimumab (weekly and every-other-week) vs. placebo in 854 CD patients

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over 56 weeks, showed that the percentage of patients presenting with anaemia at end of follow-up was significantly lower among patients in the adalimumab weekly

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arm (20.7%) or the adalimumab every-other-week arm (25.2%) compared with the placebo arm (31.9%) (p<0.05 for both comparisons).24 Open label trials

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The seven interventional open label trials identified in our search assessed the efficacy of infliximab (n=4)23,26-28 and adalimumab (n=3)29-31 in EIMs. The studies varied considerably in terms of types of EIMs assessed (several vs. specific EIMs), sample size

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and study duration.

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The efficacy of biologic treatment on multiple EIMs was assessed in four studies (two on adalimumab, two on infliximab).23,26,29-30 Favourable results at the end of follow-up period were obtained in all four studies, showing clinical improvement and/or resolution of EIMs symptoms in a substantial number of patients. The CARE study was the largest open label study identified in our search, including 945 CD patients. This was a multicentre Phase IIIb trial that assessed the clinical efficacy of adalimumab in patients with moderate to severe CD. The authors reported a reduction

ACCEPTED MANUSCRIPT in the prevalence of EIMs from baseline to week 20 of treatment. The specific analysis by EIM type showed statistical significance in the difference between baseline and week 20 incidences for the most prevalent EIMs at baseline (Table 1). The global prevalence of EIMs was reduced from 53% (497 of 945 patients) at baseline to 30% at

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week 20. Out of the 497 patients with EIMs at baseline, 79% showed a complete

resolution of signs and symptoms of at least one EIM at week 20, and 51% were free of

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EIMs.29

Similar results were reported in the three remaining smaller single-centre open-label

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studies where treatment efficacy in multiple EIMs was investigated. Barreiro-de-Acosta et al. assessed the efficacy of adalimumab in 42 CD patients with at least 1 EIM over 6months. The most common EIMs at baseline were peripheral arthritis (31 patients) and ankylosing spondilytis (7 patients). Partial response or remission at 6 months for these

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EIMs was reported in 61% and 71% of patients, respectively (Table 1). Overall, complete remission of the EIM at month 6 was achieved in 38.1% of patients and an additional 28.5% of patients achieved a clinical partial response.30 In a short-term

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study conducted in 23 IBD patients with EIMs (22 CD and 1 UC), a single infusion of

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infliximab was associated with clinical improvement at week 2 in 64% of patients with arthralgia and inflammatory back pain, and in 100% of patients with pyoderma gangrenosum. In addition, arthritis, pyoderma gangrenosum and aphthous stomatitis was resolved in 25%, 33% and 100% of patients, respectively (Table 1).23 Rispo et al. assessed the efficacy of infliximab over a 10-week period in 15 CD patients. The authors reported improvement in the assessment of the ankylosing spondilytis scale (ASAS20 and ASAS40) in 80% and 60% of patients with arthritis, respectively, and complete response in 100% of patients showing arthralgia, cutaneous manifestations

ACCEPTED MANUSCRIPT and ocular manifestations. However, in 66% of patients recurrence of EIMs was observed within 8 weeks from the first infusion and a second course of treatment was administered.26

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Three additional open label trials report data on the efficacy of anti-TNF treatment for single EIMs. Two trials assessed the efficacy infliximab in the management of

musculoskeletal disease in CD patients27-28 and one trial evaluated the efficacy of

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adalimumab in metabolic bone disease.31

Herfarth et al. conducted a large 12-week prospective multicentre trial in Germany

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that included 153 CD patients, of which 71 showed signs of arthritis or arthralgia at baseline, and 59 had follow-up information and were included in the analysis. Infliximab use was associated with significant improvement of arthritis or arthralgia in 61% of patients (p<0.001), and with complete resolution in 46% of patients (Table 1).27

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In a long-term cohort study, Generini et al. evaluated the efficacy of infliximab in the treatment of 24 patients with spondyloarthropathies with CD (16 patents with active

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disease; 8 patients with quiescent disease). An additional group of 12 CD patients with active disease but not treated with biologic drugs were considered as a control group.

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Infliximab use resulted in a rapid reduction in the frequency of peripheral arthritis and enthesitis after 6 months of treatment (Table 1).28 Veerappan et al. conducted a 6-month study aimed at exploring the effect of adalimumab on bone metabolism in 20 patients with active CD. The authors reported a significant increase in bone formation markers osteocalcin (OC) and procollagen type 1 N-terminal propeptide (P1NP) compared with baseline, but none of the comparisons remained statistically significant at 6 months. They also reported a non-significant

ACCEPTED MANUSCRIPT decrease in bone resorption marker C-telopeptide of type-1 collagen (CTx) over 6 months (Table 1).31 Effectiveness (non-interventional studies)

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A flow diagram depicting the findings of the searches and the selection process for non-interventional studies is provided in Supplementary Figure 2. Five hundred and

thirty nine relevant citations were identified through the literature search and fifteen

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additional citations were identified through manual searches or by reviewing the

citations of studies selected. Removal of duplicates followed by review of titles and

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abstracts and review of full texts yielded thirteen relevant studies that fulfilled the eligibility criteria and were extracted.

A total of 13 studies were selected for full text review, of which most studies were

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focused on the effectiveness of biologic treatments in the management of metabolic bone disease in CD patients (n=6),32-37 two studies provided evidence on the effectiveness of biologic drugs in the management of anaemia,38-39 two studies on

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pyoderma gangrenosum,40-41 and two studies on altered haemostasis and coagulation.42-43 One additional study provided information on the effectiveness of

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infliximab in the management of skin and/or joint manifestations in IBD patients.44 An overview of main study characteristics is available in Table 2. The effectiveness of infliximab for metabolic bone disease in CD patients has been assessed in six studies. Three cohort studies investigated its long-term effectiveness by evaluating bone mineral density, while other three prospective short-term cohort studies focused on the assessment of surrogate markers for bone formation or resorption.

ACCEPTED MANUSCRIPT Bernstein et al. conducted a cohort study to evaluate the effect of one year maintenance treatment with infliximab on bone mineral density in 46 CD patients.32 Patients receiving bisphosphonates were excluded from the study, while 28% and 30% of patients were on corticosteroids and calcium supplementation, respectively.

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Authors reported statistically significant increases between baseline and year 1 on the bone mineral density of lumbar spine (2.4%), femoral trochanter (2.8%) and femoral neck (2.6%). These gains were not influenced by the presence of osteopenia at

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baseline, corticosteroid therapy or calcium supplementation.

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In a retrospective cohort study, Mauro et al. assessed bone mineral density response to infliximab administered every 4 to 8 weeks by evaluating lumbar bone mass in 15 CD patients, and compared it to a control group of CD patients (n=30) not receiving infliximab. The authors reported reductions in the frequencies of osteopenia and

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osteoporosis from 47% to 33% and from 20% to 7%, respectively, in patients receiving infliximab, between both densitometric evaluations (mean interval 22.6 months). No changes from baseline were observed in the prevalence of osteopenia and

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osteoporosis (from 10% to 10%) in the control group (Table 2). Bisphosphonates were

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used in 20% and 17% of patients in the infliximab group and control group, respectively.33

Pazianas et al. conducted a retrospective cohort study to evaluate the effectiveness of infliximab on bone mineral density in patients with CD and osteopenia or osteoporosis, and assessed the effect of concurrent use of bisphosphonates and corticosteroids. Sixty-one patients were included in the study (23 received infliximab and 36 received bisphosphonates). Among patients not receiving concomitant bisphosphonates, those

ACCEPTED MANUSCRIPT on infliximab did not show statistically significant differences in the lumbar spine Tscore per year compared to those not receiving infliximab. Patients receiving bisphosphonates and infliximab tended to have greater increases in bone mineral density compared to those receiving bisphosphonates only, but the difference did not

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reach statistical significance (p=0.068).34

Three additional short-term prospective cohort studies on CD patients reported

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significant improvements in markers of bone formation like bone alkaline phosphatase (BAP)35-37 and OC36-37 after short term treatment with infliximab, while results for P1NP

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were variable.36-37 The evolution of bone resorption markers was also described in two of these studies. Franchimont et al. reported that 38.2% of patients showed a predefined relevant clinical improvement in CTx.36 In the study of Abreu et al., no differences from baseline to week 4 were observed in N-telopeptide of Type I

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collagen.35

The effectiveness of anti-TNF therapy in the management of anaemia has been

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assessed in two observational studies (a prospective registry and a cross-sectional retrospective study). In a recent prospective single centre registry of IBD patients,

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Koutrobakis et al. assessed the long-term effect of anti-TNF therapy on anaemia in IBD patients. The registry included 430 IBD patients treated with anti-TNF drugs (infliximab, adalimumab or certolizumab pegol), of which 134 presented with anaemia at baseline and had a one year follow-up period. The prevalence of anaemia at year 1 was similar to baseline (36.6% vs. 38.1%, p>0.05). Hematopoietic response (defined as an increase of haemoglobin ≥2g/dL) was observed in 33.6% of patients despite iron replacement therapy was administered to 94% of patients.38

ACCEPTED MANUSCRIPT Bergamaschi et al. conducted a cross-sectional study to assess the prevalence of anaemia in 263 IBD outpatients. Out of these, they selected a cohort of 27 CD patients (18 with anaemia at baseline) who were treated with infliximab and retrospectively assessed their response at 14 weeks of treatment. For patients with anaemia, authors

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reported haematologic response in 67% (Table 2). According to authors,

haematological response was already apparent two weeks after the first infusion of infliximab. None of these patients had received cyclosporine or methotrexate, or

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received blood transfusions, iron supplementation or erythropoiesis-stimulating

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agents.39

Two studies assessed the effectiveness of anti-TNF treatment in pyoderma gangrenosum. In a multicentre retrospective cohort study, Argüelles-Arias et al. assessed the effectiveness of different treatments including infliximab and

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adalimumab, among others in 67 IBD patients (41 CD, 25 UC and 2 Indeterminate IBD) with pyoderma gangrenosum. A definitive cure was achieved in 22 of 24 patients (92%) treated with infliximab and in all patients (n=7) treated with adalimumab, with a time

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to healing ranging between 4 to 8 weeks.40 In a large case series including 13 patients

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with IBD (12 CD and 1 UC) and pyoderma gangrenosum, Regueiro et al. described that infliximab therapy led to a complete resolution of symptoms in all patients treated after a mean of 86 days (range 7 to 210 days) (Table 2).41 The effect of infliximab in haemostasis of patients with IBD has been explored in two recently published studies. Wang et al. conducted a retrospective study on 53 CD patients to assess the influence of infliximab on parameters associated with a hypercoagulation state in patients with CD. Treatment with infliximab was associated

ACCEPTED MANUSCRIPT with significant reductions of platelet counts (p<0.01), mean platelet volume (p<0.05), erythrocyte sedimentation rate (p<0.01) and C-reactive protein levels (p<0.01) at week 14 vs. baseline. A single infliximab infusion was also associated with a significant decrease of the levels of fibrinogen (n=39, p<0.001) and D-dimer (n=25, p=0.018)

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(Table 2).42

In a prospective cohort study, Bollen et al. investigated the effect of infliximab

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induction therapy on the haemostatic profile of patients with IBD. Patients were

classified based on their clinical response to induction treatment with infliximab as

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primary responders (n=78) or primary non-responders (n=13), and analysed separately. Among primary responders, the haemostatic parameters area under the curve (AUC, an integrated measurement reflecting the overall coagulation/fibrinolysis profile) and amplitude (maximal clot absorbance, indicating clot formation) decreased

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significantly at the end of the follow-up period (week 14) compared to baseline. In contrast, differences in the levels of haemostatic parameters between baseline and

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week 14 were not observed for primary non-responders (Table 2).43 Caspersen et al. reported data from a Danish population-based registry of patients

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with IBD and treated with infliximab between 1999 and 2005. The registry included 651 patients, of which 56 (50 CD, 4 UC, 2 IBD type unclassified [IBDU]) presented with concomitant skin and or joint manifestations of IBD. For patients with CD, a clinical response on EIMs was observed in 79.5% of patients, while complete remission was achieved in 43.2% of the patients. All the remaining IBD patients (UC and IBDU) showed a clinical response on EIMs at follow-up.44

ACCEPTED MANUSCRIPT Discussion Despite the increased interest on the potential use of biologic drugs for the management of EIMs in IBD patients, our systematic review indicates that the number

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of studies assessing their efficacy or effectiveness for this indication remains limited, especially in UC. However, evidence available from interventional and non-

interventional studies suggests that the clinical benefit from infliximab or adalimumab

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may not be restricted to the local intestinal effect but expand to ameliorate or cure EIMs of IBD including musculoskeletal, mucocutaneous, and ocular manifestations.

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Evidence also suggests some potential beneficial effect of infliximab and adalimumab therapy on metabolic bone disease, and on hematologic or vascular EIMs. In contrast, no or minimal evidence on the efficacy or effectiveness of other biologic drugs considered in our review (i.e. certolizumab pegol, golimumab, vedolizumab,

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natalizumab) was identified.

In general terms, the studies included in our review showed large heterogeneity in

38,43-44

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designs, including randomised22,24 and open label clinical trials,23,26-31 prospective32,35and retrospective33-34,39-40,42 cohort studies and large case series.41 Variability in

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the number of EIMs assessed was also observed, with some studies assessing the clinical benefit of biologic drugs on several different EIMs23,26,29-30,44 and others evaluating the efficacy or effectiveness on specific EIMs like musculoskeletal,27-28 metabolic bone disease,31-37 mucocutaneous,22,40-41 hematologic alterations, such as anemia38-39 or haemostasis and coagulation alterations.42-43 In addition, outcomes measures used to evaluate efficacy and effectiveness of biologic drugs on EIMs varied from study to study. In some cases, variation in the prevalence of specific EIMs from

ACCEPTED MANUSCRIPT baseline to a certain time point is used,24,28-29,33,38 in other cases clinical improvement or clinical resolution, often considering different definitions for the same EIMs, is reported.22-23,26-27,30,40,41,44 Finally, another set of studies use surrogate measures to assess evolution of EIMs.31-32,34-37,39,42-43 Due to these significant variations, the

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possibility of meta-analysing the data was not considered. A summary of efficacy and effectiveness data extracted from selected studies and classified by EIM is available in

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Supplementary Table 7 for the information and convenience of the reader.

This review did not identify any interventional or non-interventional studies specifically

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assessing the use of biologic drugs for the management of EIMs in UC. In addition, for studies that did not restrict the population to CD patients, the number of UC patients included was either very low22-23,44 or aggregated to CD patients for the reporting of study results.38,40,43 This fact contrasts with a prevalence of EIMs in UC of up to one

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third of patients1 and limits the validity of results available. Future research will be necessary to confirm that the clinical benefit observed replicates in studies including a

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larger number of UC patients.

The results of this systematic review support the recommendations provided in the

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recent ECCO consensus document on the use of anti-TNF drugs for the management of EIMs in IBD patients.14 Both infliximab and adalimumab have proven effective in the management of arthropathy,23,26-30,44 skin manifestations such as pyoderma gangrenosum22-23,26,29-30,40-41,44 or erythema nodosum26,29,44 and, although body of evidence is less robust due to a lower number of patients included, on ocular manifestations like uveitis.26,29-30 For the remaining EIMs for which evidence has been identified (i.e. metabolic bone disease, altered haemostasia and anaemia), some

ACCEPTED MANUSCRIPT beneficial effect of anti-TNF treatment seems apparent from the results reported,24,3139,42-43

although this would need to be confirmed in future studies.

The benefit of anti-TNF therapy on the management of EIMs in IBD seems to be linked

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with a pathogenic TNF-α dependent mechanism, common to IBD and some EIMs (e.g. arthritis, mucocutaneous manifestations such as pyoderma gangrenosum or erythema nodosum, or ocular manifestations including iritis or uveitis).15 Whether new biologic

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drugs such as vedolizumab or ustekinumab with different mechanisms of action would show similar benefit on EIMs compared to anti-TNFs currently remains unclear, and

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data are awaited. Recently published results of a post-hoc analysis of the GEMINI 2 study did not show statistically significant benefit of vedolizumab over placebo for the treatment of EIMs in CD.45 Interestingly, some authors have suggested that IBD patients with EIMs and refractory to anti-TNF treatment may receive vedolizumab as a

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subsequent treatment line, to allow additional mucosal healing, combined with infliximab, to control EIMs.46 While the potential economic impact of this innovative combination regimen may pose a significant hurdle for implementation in clinical

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studies.

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practice, its efficacy and effectiveness would need to be further explored in new

The interpretation of this systematic review should take into consideration some limitations related to the methodology followed. First, we decided to exclude from our review all studies with less than 10 patients, which reduced the number of studies included in our review by three, if we consider studies that reached full text review stage only. Given the low incidence of some of the EIMs in IBD, we cannot discard that some potentially relevant evidence available from case series or small studies was not

ACCEPTED MANUSCRIPT assessed; however, the evidence provided by this type of studies is relatively weak. In addition, non-English language publications were excluded from this review and conference abstracts were also not included. Although we acknowledge that some of these decisions may lead to some extent to publication bias, potential impact for the

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results is expected to be low. There are currently discussions among the scientific community about how and when these limitations should be implemented in

systematic reviews.47-49 Due to the exploratory nature of our review and the expected

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variability in the reporting of outcomes measures for efficacy and effectiveness of

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biologic drugs in EIMs, we did not conduct an assessment of the strength of the body of evidence identified. However, future systematic reviews in the area of EIMs where specific EIMS are targeted would benefit from this approach in order to facilitate the clinicians’ decision-making process.

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In summary, EIM management is critical for IBD patients and an unmet need currently exists. The results of the studies included in our systematic review suggest that infliximab and adalimumab may be effective alternatives for the treatment of certain

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EIMs associated with IBD including musculoskeletal, cutaneous and ocular

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manifestations, while some beneficial effect may be obtained in metabolic bone disease, and on hematologic or vascular EIMs. However, the number of studies that have investigated the use of biologic therapy for the treatment of EIMs is relatively low and the simple sizes are often small to draw any definitive conclusions. This review highlights the need for additional studies that specifically assess the efficacy and effectiveness of biologic drugs in the treatment of EIMs in UC and including a large number of patients.

ACCEPTED MANUSCRIPT Bibliography 1. Zippi M, Corrado C, Pica R, et al. Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients. World J Gastroenterol 2014;20(46):17463-

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7. 2. Vavricka SR, Brun L, Ballabeni P, et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol.

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4. Ott C, Takses A, Obermeier F, et al. Smoking increases the risk of extraintestinal

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ACCEPTED MANUSCRIPT 8. Schoon EJ, van Nunen AB, Wouters RS, et al. Osteopenia and osteoporosis in Crohn's disease: prevalence in a Dutch population-based cohort. Scand J Gastroenterol. Suppl 2000;(232):43-7.

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ACCEPTED MANUSCRIPT 16. Barrie A, Regueiro M. Biologic therapy in the management of extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2007 Nov;13(11):1424-9.

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ACCEPTED MANUSCRIPT 24. Rubin DT, Mulani P, Chao J, et al. Effect of adalimumab on clinical laboratory parameters in patients with Crohn's disease: results from the CHARM trial. Inflamm Bowel Dis 2012;18(5):818-25.

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26. Rispo A, Scarpa R, Di Girolamo E, et al. Infliximab in the treatment of extra-

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intestinal manifestations of Crohn's disease. Scand J Rheumatol 2005;34(5):387-91. 27. Herfarth H, Obermeier F, Andus T, et al. Improvement of arthritis and arthralgia after treatment with infliximab (Remicade) in a German prospective, open-label, multicenter trial in refractory Crohn's disease. Am J Gastroenterol 2002;97(10):2688-

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28. Generini S, Giacomelli R, Fedi R, et al. Infliximab in spondyloarthropathy associated with Crohn's disease: an open study on the efficacy of inducing and maintaining

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29. Löfberg R, Louis EV, Reinisch W, et al. Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn's disease: results from CARE. Inflamm Bowel Dis 2012;18(1):1-9. 30. Barreiro-de-Acosta M, Lorenzo A, Domínguez-Muñoz JE. Efficacy of adalimumab for the treatment of extraintestinal manifestations of Crohn's disease. Rev Esp Enferm Dig 2012;104(9):468-72.

ACCEPTED MANUSCRIPT 31. Veerappan SG, Healy M, Walsh BJ, et al. Adalimumab Therapy Has a Beneficial Effect on Bone Metabolism in Patients with Crohn's Disease. Dig Dis Sci 2015;60(7):2119-29.

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32. Bernstein M, Irwin S, Greenberg GR. Maintenance infliximab treatment is associated with improved bone mineral density in Crohn's disease. Am J Gastroenterol 2005;100(9):2031-5.

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33. Mauro M, Radovic V, Armstrong D. Improvement of lumbar bone mass after

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infliximab therapy in Crohn's disease patients. Can J Gastroenterol 2007;21(10):637-42. 34. Pazianas M, Rhim AD, Weinberg AM, et al. The effect of anti-TNF-alpha therapy on spinal bone mineral density in patients with Crohn's disease. Ann N Y Acad Sci 2006;1068:543-56.

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35. Abreu MT, Geller JL, Vasiliauskas EA,et al. Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease. J Clin

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36. Franchimont N, Putzeys V, Collette J, et al. Rapid improvement of bone metabolism

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37. Ryan BM, Russel MG, Schurgers L, et al. Effect of antitumour necrosis factor-alpha therapy on bone turnover in patients with active Crohn's disease: a prospective study. Aliment Pharmacol Ther. 2004;20(8):851-7.

ACCEPTED MANUSCRIPT 38. Koutroubakis IE, Ramos-Rivers C, Regueiro M, et al. The Influence of Anti-tumor Necrosis Factor Agents on Hemoglobin Levels of Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2015;21(7):1587-93.

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39. Bergamaschi G, Di Sabatino A, Albertini R, et al. Prevalence and pathogenesis of anaemia in inflammatory bowel disease. Influence of anti-tumor necrosis factor-alpha treatment. Haematologica 2010;95(2):199-205.

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40. Argüelles-Arias F, Castro-Laria L, Lobatón T, et al. Characteristics and treatment of pyoderma gangrenosum in inflammatory bowel disease. Dig Dis Sci 2013;58(10):2949-

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41. Regueiro M, Valentine J, Plevy S, et al. Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease. Am J Gastroenterol

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ACCEPTED MANUSCRIPT 45. Rubin D, Feagan B, Dryden G, et al. P-105 The Effect of Vedolizumab on Extraintestinal Manifestations in Patients with Crohn’s Disease in GEMINI 2. Inflamm Bowel Dis. 2016 Mar;22.

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46. Hirten R, Longman RS, Bosworth BP, Steinlauf A, Scherl E. Vedolizumab and Infliximab Combination Therapy in the Treatment of Crohn's Disease. Am J Gastroenterol. 2015 Dec;110(12):1737-8.

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48. Berkman ND, Lohr KN, Ansari M, et al. Grading the Strength of a Body of Evidence When Assessing Health Care Interventions for the Effective Health Care Program of the

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Table 1. Summary of characteristics of interventional studies included Treatment for EIMs

DB RCT (2wk) + OL (4wk)

6 wk (DB RCT: 2wk; OL (4 wk)

RCT period: IFX 5 mg/kg (1 dose) (n=13); PBO (n=17) OL period: 29/30 pts IFX 5 mg/kg (1 dose)

Rubin et 24 al, 2012

Anaemia

CD (n=854); 778 pts randomised after induction

DB RCT (posthoc analysis)

56 wk

Randomised treatment: PBO (n=261); ADA eow (n=260); ADA weekly (n=257)

Lofberg et 29 al, 2012

Several

CD (n=945)

OL multicentre phase IIIb

20 wk

ADA sc 160/80 mg at 0/2 wk, then 40 mg eow

Barreiro-deAcosta et 30 al, 2012

Several

CD (n=42)

OL single centre

6 mo

ADA sc 160/80 mg at 0/2 wk, then 40 mg eow

Kaufman et 23 al, 2005

Several

CD (n=22) UC (n=1)

OL single centre

2 wk

Several

CD (n=30); 15 pts with EIMs at BL CD (n=153); 71 pts with BL arthritis/ arthralgia, 59 pts analysed

OL single centre

Rispo et al, 2005

26

Herfarth et 27 al, 2002

MD

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PG

OL multicentre

Efficacy of EIMs treatment

10 wk

12 wk

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Follow-up

RCT period (w0 to w2): IFX: CI in 6/13 (46%); PBO: CI in 1/17 (6%); p=0.025 OL period (w2 to w6): CI in 20/29 (69%); CR in 6/29 (21%)

Anaemia prevalence BL: PBO 30.4%; ADA eow 29.8%; ADA weekly 25.9% w26: PBO 31.9%; ADA eow 24.4% (p<0.05); ADA weekly 21.1% (p<0.05) w56: PBO 31.9%; ADA eow 25.2% (p<0.05); ADA weekly 20.7% (p<0.05)

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Study design

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Brooklyn et 22 al, 2005

IBD patients included CD (n=13)* UC (n=6)*

IFX 5 mg/kg (1 dose)

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EIM

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Study

IFX 5 mg/kg at 0, 2, 6 wk

FD: IFX 5 mg/kg at 0, 2, 6 wk Non FD: IFX 5 mg/kg (1 dose)

EIM prevalence: BL (n=945) vs. w20 (n=942) (p-value) Arthralgia: 445 (47.1%) vs. 252 (26.8%) (p<0.001); Arthritis: 82 (8.7%) vs. 20 (2.1%) (p<0.001); Oral aphthous ulcers: 49 (5.2%) vs. 20 (2.1%) (p<0.001); Sacroilitis: 34 (3.6%) vs. 18 (1.9%) (p=0.016); EN: 23 (2.4%) vs. 4 (0.4%) (p<0.001); AS: 16 (1.7%) vs. 15 (1.6%) (p=nt); Nephrolithiasis: 8 (0.8%) vs. 8 (0.8%) (p=nt); Iritis: 7 (0.7%) vs. 2 (0.2%) (p=nt); PG: 4 (0.4%) vs. 2 (0.2%) (p=nt); Uveitis: 3 (0.3%) vs. 3 (0.3%) (p=nt); CD-related hepatic disease: 1 (0.1%) vs. 1 (0.1%) (p=nt) Peripheral arthritis: CI or CR in 19/31 (61%); AS: CI or CR 5/7 (71%); Sacroilitis: CI or CR 1/1 (100%); Uveitis: CI or CR in 1/1 (100%); PG: CI or CR in 2/2 (100%) Arthritis: CR in 1/3 (33%); Arthralgia: CI in 7/11 (63.6%); Inflammatory back pain: CI in 7/11 (63.6%); PG: CI in 4/4 (100%) and CR in 1/4 (25%); Aphthous stomatitis: CR in 3/3 (100%) Arthritis: ASAS20 improvement in 8/10 (80%); ASAS40 improvement in 6/10 (60%); Arthralgia: CR in 6/6 (100%); Cutaneous manifestations: CR in 4/4 (100%); Uveitis: CR in 2/2 (100%); Episcleritis: CR in 1/1 (100%) Arthritis or arthralgia: CI in 36/59 (61%) (p<0.001 vs. BL); CR in 27/59 (46%)

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EIM

Generini et 28 al, 2004

MD

IBD patients included CD (n=24) 16 active CD 8 quiescent CD

Study design

Follow-up

Treatment for EIMs

Efficacy of EIMs treatment

OL single centre

18 mo

Active CD (n=16): IFX 5 mg/kg at 0, 2, 6 wk, then IFX 3-5 mg/kg every 5–8 wk

Spondyloarthropathy prevalence Peripheral arthritis: 58% at BL to 12.5% at 6 mo Enthesitis: 67% at BL to 24% at 6 mo

CG: 12 active CD MBD

CD (n=20)

OL single centre

6 mo

Bone formation markers: OC: p=0.015 (1mo vs. BL), p=0.038 (3mo vs. BL), p=NS (6mo vs. BL); P1NP: p=0.008 (1mo vs. BL); p=0.006 (3mo vs. BL), p=NS (6mo vs. BL) Bone resorption marker: CTx: p=NS (6mo vs. BL)

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Veerappan 31 et al, 2015

Quiescent CD (n=8): IFX 3 mg/kg ADA sc 160/80 mg at 0/2 wk, then 40 mg eow

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Study

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ADA: adalimumab; AS: ankylosing spondilytis; ASAS20: 20% improvement in the Assessment of the ankylosing spondilytis scale; ASAS40: 40% improvement in the Assessment of the ankylosing spondilytis scale; BL: baseline; CD: Crohn’s disease; CG: control group; CI: clinical improvement; CR: complete response/resolution; CTx: C-terminal telopeptide of type-1 collagen; DB: double blind; EIM: extraintestinal manifestation; EN: erythema nodosum; eow: every-other-week; FD: fistulising disease; IBD: inflammatory bowel disease; IFX: infliximab; MBD: metabolic bone disease; MD: musculoskeletal disease; mo: month(s); NS: not significant; nt: not tested; OC: osteocalcin; OL: open label; P1NP: procollagen type-1 N-terminal propeptide; PBO: placebo; PG: pyoderma gangrenosum; RCT: randomised controlled trial; UC: ulcerative colitis; wk: week(s); y: year(s)

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* 30 patients were included in the RCT (19 with IBD). Distribution of patients: IFX group (n=13) - IBD: 7/13 (CD: 5/7; UC 2/7); PBO group (n=17) - IBD 12/17 (CD: 8/12; UC 4/12)

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Table 2. Summary of characteristics of non-interventional studies included

Skin and joint EIMs

Bernstein et 32 al, 2005

MBD

Study design

Follow-up

Treatment for EIMs

Baseline prevalence of EIM NR

Retrospective population based cohort

Median: 29.1 mo (range 0.172.1 mo)

IFX

Prospective single centre cohort study

1y

FD (n=17): IFX 5mg/kg (at 0, 2, and 6 wk) + IFX 5 mg/kg every 6–8 wk

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Caspersen et 44 al, 2008

IBD patients included CD (n=619); 50 pts on IFX UC (n=15); 4 pts on IFX IBDU (n=17); 2 pts on IFX CD (n=46)

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EIM

ID (n=29): IFX 5 mg/kg (1 infusion) + IFX 5 mg/kg every 6–8 wk MBD

IFX group: CD (n=15)

Retrospective single centre cohort study

CG: CD (n=30)

Abreu et al, 2006

MBD

35

MBD

CD (n=61)

CD (n=74); 38 pts analysed

Retrospective cohort study

Prospective single centre cohort study

IFX 5 mg/kg every 4-8 wk

Mean: 2.2 y (range 1.0– 4.5)

IFX: 23 pts (bisphosphonates n=11)

4 wk

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Pazianas et 34 al, 2006

Mean lapse between DEXA: IFX: 22.6mo; CG: 20.4mo

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33

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Mauro et al, 2007

Osteoporosis: Lumbar spine 1 (2%); Femoral neck 3 (7%); Femoral trochanter 3 (7%) Osteopenia: Lumbar spine 19 (41%); Femoral neck 18 (39%); Femoral trochanter 21 (46%) Osteopenia (lumbar bone): IFX group: 47%; CG:27% Osteoporosis (lumbar bone): IFX group: 20%; CG: 10% Baseline mean lumbar spine T score: IFX: −1.67 ± 0.96; no IFX: −1.66 ± 0.87

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Study

no IFX: 38 pts (bisphosphonates n=38) IFX 5 mg/kg (1 infusion)

NR

Effectiveness of EIMs treatment Skin and/or joint symptoms CD (n=50): CI in 35/50 (80%); CR in 19/50 (43%) UC (n=4): CI in 4/4 (100%); CR in 1/4 (25%) IBDU (n=2): CI in 2/2 (100%)

BMD change (DPA) (BL to 1y) (n=46): Lumbar spine: 2.4% ± 0.7% (p=0.002); femoral trochanter: 2.8% ± 1.2% (p=0.03); femoral neck: 2.6% ± 0.7% (p=0.001)

IFX group (n=15): Osteopenia: 33% (vs. 47% at BL); osteoporosis 6.6% (vs. 20% at BL) CG (n=30): Osteopenia: 26.6% (vs. 26.6% BL); osteoporosis 10% (vs. 10% BL) Mean yearly change in lumbar spine T score Patients not receiving bisphosphonates: IFX: −4.09± 3.85%; no IFX: −3.25±4.53% (p>0.05) Patients on bisphosphonates: IFX: +4.38 ± 2.94%; no IFX +3.98 ± 2.35% (p=0.068) Bone formation markers: BAP (n=38): Median change (BL to w4): 0.4 ng/mL (range -3.0, 7.4) (p=0.010) Bone resorption markers: NTx (n=36): Median change (BL to w4): 0.0 nmol BCE (range -10.0, 6.0) (p=0.801)

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Koutroubakis 38 et al, 2015

MBD

CD (n=24)

Anaemia

CD (n=324) UC (n=106) 352 pts were analysed (134 pts with anaemia)

Bergamaschi 39 et al, 2010

Argüelles40 Arias et al, 2013 Regueiro et 41 al, 2003 Bollen et al, 2015

43

Anaemia

PG

PG

Altered haemostasia

CD (n=165) UC (n=98) 27 CD pts received IFX CD (n=41) UC (n=25) IBDU (n=1) CD (n=12) UC (n=1) CD (n=59) UC (n=44) 91 IBD pts analysed

Prospective cohort study

8 wk

FD (n=21): IFX 5 mg/kg (at 0, 2, and 6 wk)

Prospective single centre cohort study Prospective, single centre, longitudinal registry

16 wk

LD (n=50): IFX 5 mg/kg (1 infusion) IFX 5mg/kg

Baseline prevalence of EIM NR

RI PT

37

Treatment for EIMs

NR

SC

Ryan et al, 2004

Follow-up

1y

Anti-TNF therapy: IFX; ADA; CZP (n=352)

Anaemia: 38.1% Severe anaemia: 10.0%

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MBD

Study design

126/134 patients with anaemia (94%) received iron replacement therapy

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Franchimont 36 et al, 2004

IBD patients included CD (n=71)

Retrospective cohort study

14 wk

IFX 5 mg/kg at 0, 2, and 6 wk

Anaemia: 18/27 pts (66.6%)

Multicentre retrospective cohort study Multicentre retrospective case series Prospective cohort study

NR

IFX: 24 (35.8%) ADA: 7 (10.4%)

PG: n=67 (100%)

Range 1 day to 4 y

IFX 5 mg/kg (range 1-24 doses)

PG: n=13 (100%)

14 wk

IFX at 0, 2, 6 wk and every 8 wk

NR

EP

EIM

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Study

Effectiveness of EIMs treatment Bone formation markers: BAP: CI* in 29.7%; OC: CI* in 60.8%; P1NP: CI* in 46.5% Bone resorption markers: CTx: CI* in 38.2%

Bone formation markers: Significant increase in BAP (p=0.022) and OC (p=0.008); no changes in P1NP (p=0.5) Anaemia: 36.6% (vs. 38.1% at BL); hematopoietic response**: 45/134 (36.6%) Severe anaemia: 9.9% (vs. 10.0% at BL); hematopoietic response**: 14/35 (40%) Median minimum Hb (BL to y 1) (n=134): 10.8 g/dL (IQR: 9.8–11.6) to 11.6 g/dL (IQR: 10.0–13.1), p=0.0001) Median Hb (BL to y 1) (n=134): (11.4 g/dL IQR: (10.4–12.0) to 11.8 g/dL (IQR: 10.8–13.3), p=0.0009) Hematologic response***: 12/18 pts (66.6%) (10 major response, 2 minor response)

IFX: CR in 22/24 (92%) ADA: CR in 7/7 (100%) Time to healing: range 4–8 wk PG: CR in 13/13 (100%) Mean time to CI: 11 days (range 2-30 days) Mean time to CR: 86.1 days (range 7-210 days) PR (BL vs. w14) (n=78) AUC (29 [20–38] vs. 20 [14–28]) (p<0.001) Amplitude (0.4 [0.3–0.5] vs. 0.3 [0.3–0.4]) (p<0.001) PNR (BL vs. w14) (n=13): No changes

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Study

EIM 42

IBD patients included CD (n=123)

Study design

Follow-up

Treatment for EIMs

Baseline prevalence of EIM NR

Effectiveness of EIMs treatment

Week 14 vs. BL: Platelet counts (n=33) (p<0.01); mean platelet volume (n=32) (p<0.05); ESR (n=28) 53 pts in self(p<0.01); CRP (n=32) (p<0.01) control study Week 2-6 vs. BL: Fibrinogen levels (n=39, 271.39 mg/dL ± 102.16 vs. 348.20 mg/dL ± 83.25, p<0.001); D-dimer levels (n=25, 155.6 mcg/L ± 108.16 vs. 329.52 mcg/L ± 372.35, p=0.018); all other items of the coagulation tests showed no statistically significant differences. ADA: adalimumab; AUC: area under the curve; BAP: Bone alkaline phosphatase; BCE: Bone collagen equivalent; BL: baseline; BMD: bone mineral density; CD: Crohn’s disease; CG: control group; CI: clinical improvement; CR: complete response/resolution; CRP: C-reactive protein; CTx: C-terminal telopeptide of type-1 collagen; CZP: certolizumab pegol; DB: double blind; DEXA: dual-energy x-ray absorptiometry; DPA: dual photon absorptiometry; EIM: extraintestinal manifestation; ESR: erythrocyte sedimentation rate; FD: fistulising disease; Hb: haemoglobin; IBD: inflammatory bowel disease; IBDU: inflammatory bowel disease type unclassified; ID: inflammatory disease; IFX: infliximab; IQR: interquartile range; MBD: metabolic bone disease; mo: month(s); NR: not reported; NTx: Cross-linked N-telopeptide of Type I collagen; OC: osteocalcin; P1NP: procollagen type-1 N-terminal propeptide; PG: pyoderma gangrenosum; PNR: primary non-responder; PR: primary responder; TNF: tumour necrosis factor; UC: ulcerative colitis; wk: week(s); y: year(s) Retrospective study (case– control+ selfcontrol)

14 wk

IFX at 0, 2, 6 and 14 wk

RI PT

Altered haemostasia

M AN U

SC

Wang et al, 2014

AC C

EP

TE D

* A clinically relevant change in bone metabolism (clinical improvement) was defined as a 30% increase or decrease in BAP, OC, P1NP or CTx serum concentration 8 weeks after infliximab treatment; ** Hematopoietic response was defined as an increase of Hb ≥2 g/dL; *** A major hematologic response was defined as the normalization of the Hb level or a Hb increase of 1.0 g/dL or more; a minor hematologic response was represented by a Hb increase of 0.5 to 0.9 g/dL.

ACCEPTED MANUSCRIPT Supplementary Figure 1. PRISMA Flow Diagram – Interventional studies Studies identif ied through database searching (n=1,403)

Additional records identif ied through other sources (n=4)

Duplicates removed (n=80)

17 Records excluded: 14 - No inf ormation on the evolution of EIMs f ollowing intervention of interest 1 - No results reported 1 - Pooled post-hoc analysis of RCTs 1 - Population included did not match population of interest

M AN U

Full texts included (n=9)

RI PT

Full-text articles assessed f or inclusion (n=26)

Records excluded (n=1,301)

SC

Records screened by abstract (n=1,327)

AC C

EP

TE D

RCTs (n=2) Other Interventional studies (n=7)

ACCEPTED MANUSCRIPT Supplementary Figure 2. PRISMA Flow Diagram – Non-interventional studies Studies identif ied through database searching (n=539)

Additional records identif ied through other sources (n=15)

Duplicates removed (n=39)

42 Records excluded: 33 - No inf ormation on the evolution of EIMs f ollowing intervention of interest 3 - <10 patients receiving intervention of interest f or EIM 2 - Ef f ectiveness of interventions of interest not assessed 1 - No ref erence to interventions of interest 1 - No patients in the population of interest receiving the interventions of interest 1 - Review paper 1 - Paper in Chinese

SC

Full-text articles assessed f or inclusion (n=55)

Records excluded (n=460)

RI PT

Records screened by abstract (n=515)

AC C

EP

TE D

M AN U

Full texts included (n=13)

ACCEPTED MANUSCRIPT Supplementary Table 1. Search strategy used for PubMed and Embase (searches conducted on October 13th 2015)

16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Results 77812 65265 91604 108498 85060

RI PT

SC

M AN U

9 10 11 12 13 14 15

TE D

6 7 8

EP

1 2 3 4 5

Search term Disease-related terms ulcerative colitis.mp. Colitis, Ulcerative/ exp Crohn disease/ or exp colon Crohn disease/ or crohn.mp. (crohn$ or crohn$ disease).mp. (inflammatory bowel disease or IBD).mp. (arthropathy or spondilytis or sacroilitis or osteop$ or erythema or pyoderma or skin lesions or episcleritis or uveitis or iritis or conjunctivitis or hepatitis or cholangitis or gallstone or pancreatitis or thromb$ or anaemia or anaemia or iron deficiency).mp. extraintestinal manifestation$.mp. (or/1-5) and (or/6-7) Drug-related terms (infliximab or Remicade).mp. (adalimumab or Humira).mp. (certolizumab or Cimzia).mp. (golimumab or Simponi).mp. (vedolizumab or Entyvio).mp. (natalizumab or Tysabri).mp. or/9-14 Interventional studies-related terms Randomized Controlled Trial/ exp clinical trial/ randomization/ experimental design/ control group/ (clin$ adj3 trial$).mp. randomi?ed controlled trial$.mp. RCT.mp. ((doubl$ or tripl$) adj3 (blind$ or mask$)).mp. placebo$.mp. (random$ adj2 allocat$).mp. or/16-26 Non-interventional studies-related terms Case control study.mp. Longitudinal study/ Retrospective study/ Prospective study/ not Randomized controlled trials/ Cohort analysis/ (Cohort adj (study or studies)).mp. (Case control adj (study or studies)).tw. (follow up adj (study or studies)).tw. (observational adj (study or studies)).tw. (epidemiologic$ adj (study or studies)).tw. (cross sectional adj (study or studies)).tw. register/ or registry/ or/28-39 8 and 15 and 27 8 and 15 and 40

AC C

#

2453159 2908 28575 44654 23645 4542 3502 737 8210 60705 785099 1855429 152327 96250 82033 1983359 1038964 30622 344348 498717 136027 2951112 194442 177141 980098 704362 408384 398963 160323 81104 138093 140759 194229 138525 2824142 1418 504

ACCEPTED MANUSCRIPT 1338 474

EP

TE D

M AN U

SC

RI PT

limit 41 to (human and English language) limit 42 to (human and English language)

AC C

43 44

ACCEPTED MANUSCRIPT Supplementary Table 2. Search strategy used for Cochrane searches (searches conducted on October 13th 2015) Results 1802 826 1569 1997 1263

RI PT

SC

M AN U

9 10 11 12 13 14 15 16

TE D

6 7 8

EP

1 2 3 4 5

Search term Disease-related terms ulcerative colitis.mp. Colitis, Ulcerative/ exp Crohn disease/ or exp colon Crohn disease/ or crohn.mp. (crohn$ or crohn$ disease).mp. (inflammatory bowel disease or IBD).mp. (arthropathy or spondilytis or sacroilitis or osteop$ or erythema or pyoderma or skin lesions or episcleritis or uveitis or iritis or conjunctivitis or hepatitis or cholangitis or gallstone or pancreatitis or thromb$ or anaemia or anaemia or iron deficiency).mp. extraintestinal manifestation$.mp. (or/1-5) and (or/6-7) Drug-related terms (infliximab or Remicade).mp. (adalimumab or Humira).mp. (certolizumab or Cimzia).mp. (golimumab or Simponi).mp. (vedolizumab or Entyvio).mp. (natalizumab or Tysabri).mp. or/9-14 8 and 15

AC C

#

68520 10 463 1187 944 209 247 41 198 2305 65

ACCEPTED MANUSCRIPT Supplementary Table 3. Selection criteria for interventional studies (PICOS format)

Any not listed in the inclusion criteria

English language

AC C

Restrictions

EP

Study design

TE D

M AN U

Outcomes

Studies not including at least one of the interventions of interest listed in the inclusion criteria Any not listed in the inclusion criteria

RI PT

Intervention and Comparators

Exclusion Patients not diagnosed of IBD Patients <18 years of age

SC

Population

Inclusion Adult patients (>18 years of age) diagnosed of UC Adult patients (>18 years of age) diagnosed of CD Adult patients (>18 years of age) diagnosed of IBD (i.e. UC or CD but not specified) Infliximab (Remicade) Adalimumab (Humira) Certolizumab Pegol (Cimzia) Golimumab (Simponi) Vedolizumab (Entyvio) Natalizumab (Tysabri) Placebo or no adjunctive treatment (provided that at least one other arm of the study includes one of the drugs of interest listed above) Incidence/prevalence of EIMs: Musculoskeletal: Arthropathy (including ankylosing spondilytis), sacroilitis, Metabolic bone disease: osteoporosis, osteopenia Cutaneous manifestations: erythema (nodosum), pyoderma (gangrenosum), oral aphthous ulcers, psoriasis, general skin lesions Ocular manifestations: episcleritis, uveitis, iritis, conjunctivitis Hepatobiliary disorders: hepatitis, (primary sclerosing) cholangitis, gallstone, pancreatitis Vascular disease: thrombosis Hematologic disease: anaemia, iron deficiency Improvement/evolution of EIMs listed during follow-up period Clinical trials (Phase 3 and Phase 2/3)

* Reviews identified in the search were checked for additional relevant citations

Editorials Notes Comments Letters Reviews* Conference papers Retrospective studies including pooled post hoc analyses of clinical trials Case reports/observational studies Non-English language studies Abstracts without full papers

ACCEPTED MANUSCRIPT Supplementary Table 4. Selection criteria for non-interventional studies (PICOS format)

English language

AC C

Restrictions

EP

TE D

Study design

RI PT

Outcomes

Studies not including at least one of the interventions of interest listed in the inclusion criteria

Any not listed in the inclusion criteria

SC

Intervention and Comparators

Exclusion Patients not diagnosed of IBD Patients <18 years of age

M AN U

Population

Inclusion Adult patients (>18 years of age) diagnosed of UC Adult patients (>18 years of age) diagnosed of CD Adult patients (>18 years of age) diagnosed of IBD (i.e. UC or CD but not specified) Infliximab (Remicade) Adalimumab (Humira) Certolizumab Pegol (Cimzia) Golimumab (Simponi) Vedolizumab (Entyvio) Natalizumab (Tysabri) Incidence/prevalence of EIMs: Musculoskeletal: Arthropathy (including ankylosing spondilytis), sacroilitis, Metabolic bone disease: osteoporosis, osteopenia Cutaneous manifestations: erythema (nodosum), pyoderma (gangrenosum), oral aphthous ulcers, psoriasis, general skin lesions Ocular manifestations: episcleritis, uveitis, iritis, conjunctivitis Hepatobiliary disorders: hepatitis, (primary sclerosing) cholangitis, gallstone, pancreatitis Vascular disease: thrombosis Hematologic disease: anaemia, iron deficiency Improvement/evolution of EIMs listed during follow-up period (list above) Observational/non-interventional studies with prospective or retrospective design

Editorials Notes Comments Letters Reviews* Conference papers Clinical Trials Case reports/observational studies including less than 10 patients receiving the interventions of interest Non-English language studies Abstracts without full papers

* Reviews identified in the search were checked for additional relevant citations

ACCEPTED MANUSCRIPT

RI PT

Supplementary Table 5. Assessment of risk of bias of interventional studies through the Centre for Reviews and Dissemination quality assessment criteria Brooklyn 2005

Generini 2004

Herfarth 2002

Kaufman 2005

Lofberg 2012

Rispo 2005

Rubin 2012 (Colombel 2007)

Veerappan 2015

1. Was randomisation carried out appropriately?

Open-label, single arm study

Not reported

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Yes, via central interactive voice response system

Open-label, single arm study

2. Was the concealment of treatment allocation adequate?

Open-label, single arm study

Not reported

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Yes, randomized

Open-label, single arm study

3. Were the groups similar at the outset of the study in terms of prognostic factors, for example, severity of disease?

Open-label, single arm study

Yes

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Yes

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Yes

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Open-label, single arm study

Yes, drop-outs were lower in the adalimumab 40 mg weekly group.

Open-label, single arm study

No

No

No

No

No

No

No

No

No

No

No

No details reported if ITT analysis

No

No

6. Is there any evidence to suggest that the authors measured more outcomes than they reported?

No

7. Did the analysis include an intentionto-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data?

No details reported if ITT analysis

No

Yes, all efficacy analyses were conducted according to the intention to treat principle, with the last observation carried forward

Open-label, single arm study

M AN U

Open-label, single arm study

TE D

5. Were there any unexpected imbalances in drop-outs between groups? If so, were they explained or adjusted for?

EP

Open-label, single arm study

Yes, a pharmacist prepared each infusion of IFX or an identical appearing placebo. Neither the patients nor the investigators were aware of the treatment assignment. No, there were no drop-outs during randomization period (week 0 to week 2)

AC C

4. Were the care providers, participants and outcome assessors blind to treatment allocation? If any of these people were not blinded, what might be the likely impact on the risk of bias (for each outcome)?

SC

Barreiro-deAcosta 2012

ACCEPTED MANUSCRIPT

Supplementary Table 6. Assessment of risk of bias of non interventional studies through the National Institutes of Health quality assessment tool Bernstein 2005

Mauro 2007

Pazianas Abreu 2006 2006

Franchimont 2004

Ryan 2004

Koutroubakis 2015

Bergamaschi 2010

ArgüellesArias 2013

Regueiro 2003

Bollen 2015

Wang 2014

1. Was the research question or objective in this paper clearly stated?

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

2. Was the study population clearly specified and defined?

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

3. Was the participation rate of eligible persons at least 50%?

Yes

Yes

CD

CD

CD

Yes

CD

CD

CD

Yes

CD

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NR

Yes

Yes

No

No

No

No

No

No

No

No

No

No

NA

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

No

No

No

No

No

No

No

No

No

No

No

No

Yes

Yes

NA

NA

13. Was loss to follow-up after baseline 20% or less? 14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?

Yes

SC

M AN U Yes

Yes

Yes

Yes

Yes

Yes

CD

Yes

Yes

Yes

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

CD

CD

Yes

Yes

Yes

Yes

Yes

Yes

No

No

Yes

No

No

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NA

NA

Yes

Yes

No

Yes

No

Yes

Yes

Yes

No

Yes

No

No

No

Yes

Yes

No

AC C

11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants?

TE D

10. Was the exposure(s) assessed more than once over time?

Yes

EP

4. Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 5. Was a sample size justification, power description, or variance and effect estimates provided? 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? 8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?

RI PT

Caspersen 2008

CD: cannot determine; NA: not applicable; NR: not reported

ACCEPTED MANUSCRIPT

EIM

n

Follow-up data reported

IFX ADA ADA ADA IFX IFX IFX IFX ADA

CD, UC CD CD CD, UC CD CD CD CD CD

PG Anaemia Several Several Several Several MD MD MBD

19 778 945 42 23 30 59 24 20

6 weeks 56 weeks 20 weeks 6 months 2 weeks 10 weeks 12 weeks 6 months 6 months

CD UC IBDU CD CD CD CD CD CD

Skin and joint Skin and joint Skin and joint MBD MBD MBD MBD MBD MBD

Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA

CD, UC CD CD, UC, IBDU CD, UC, IBDU

Anaemia Anaemia PG PG

Regueiro 2003 Bollen 2015 Wang 2014

IFX IFX IFX

CD, UC CD, UC CD

PG Haemostasis Haemostasis

Comment

Data corresponds to OL period Data corresponds to ADA eow arm (regular regimen) Data is reported for CI or CR in a single category

50 4 2 46 15 61 74 71 24

29.1 months 29.1 months 29.1 months 1 year 22.6 months 2.2 years 4 weeks 8 weeks 16 weeks

TE D

EP

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004

SC

IBD

Data for arthritis based on ASAS20 improvement

M AN U

Treatment

RI PT

Supplementary Table 7. Efficacy and effectiveness data extracted from studies included by extraintestinal manifestation

1 year 14 weeks NR NR range 1 day to 4 13 years 91 14 weeks 53 14 weeks

Results on bone markers provided as p-values only

Results provided as BMD % change

Results provided as mean lumbar spine T-score Results on bone markers provided as median change and p-values only Results of Clinical Improvement provided by marker (BAP, OC, P1NP) Results on bone markers provided as p-values only

352 27 24 7

Results on coagulation tests provided as mean values Results on coagulation tests provided as mean values

ACCEPTED MANUSCRIPT

Arthralgia n IFX ADA ADA ADA IFX IFX IFX IFX ADA

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

%

CR N

n

%

n

445

7

11

64%

EP

TE D

M AN U

6

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

CI n

RI PT

IBD

SC

Treatment

6

100%

Prevalence BL N %

945

47.1%

n

252

Prevalence FU N %

942

26.8%

ACCEPTED MANUSCRIPT

11

64%

RI PT

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

7

n

Inflammatory back pain Prevalence BL % n N %

SC

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

%

CR N

M AN U

CD, UC CD CD CD, UC CD CD CD CD CD

n

CI n

EP

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

IBD

TE D

Treatment

n

Prevalence FU N %

ACCEPTED MANUSCRIPT

Enthesitis Treatment

IBD

n

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

EP

TE D

M AN U

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

CR N

%

n

Prevalence BL N %

n

Prevalence FU N %

RI PT

n

CI n

16

24

67%

6

24

24%

ACCEPTED MANUSCRIPT

Arthritis

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

n

CI n

%

19

31

61%

8

10

80%

CR N

n

M AN U

EP

3

SC

1

%

n

RI PT

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

IBD

TE D

Treatment

Prevalence BL N %

n

Prevalence FU N %

82

945

8.7%

20

942

2.1%

14

24

58%

3

24

12.5%

33%

ACCEPTED MANUSCRIPT

Sacroilitis

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

n

CI n

%

1

1

100%

CR N

n

%

n

RI PT

IFX ADA ADA ADA IFX IFX IFX IFX ADA

M AN U

SC

34

EP

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

IBD

TE D

Treatment

Prevalence BL N %

945

3.6%

n

18

Prevalence FU N %

942

1.9%

ACCEPTED MANUSCRIPT

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

n

CI n

%

5

7

71%

CR N

n

Ankylosing Spondilitis Prevalence BL % n N %

RI PT

IFX ADA ADA ADA IFX IFX IFX IFX ADA

M AN U

SC

16

EP

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

IBD

TE D

Treatment

945

1.7%

n

15

Prevalence FU N %

942

1.6%

ACCEPTED MANUSCRIPT

%

36

59

61%

CR N

n

Arthritis or arthralgia Prevalence BL % n N %

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

27

M AN U

CD, UC CD CD CD, UC CD CD CD CD CD

SC

RI PT

n

CI n

EP

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

IBD

TE D

Treatment

59

46%

n

Prevalence FU N %

ACCEPTED MANUSCRIPT

20

29

69%

6

2 4

2 4

100% 100%

1

RI PT

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

n

Pyoderma Gangrenosum Prevalence BL % n N %

29

22 7 13

n

Prevalence FU N %

21%

4

25%

24 7 13

92% 100% 100%

SC

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

%

CR N

M AN U

CD, UC CD CD CD, UC CD CD CD CD CD

n

CI n

EP

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

IBD

TE D

Treatment

4

945

0.4%

2

942

0.2%

ACCEPTED MANUSCRIPT

Treatment

IBD

IFX ADA ADA ADA IFX IFX IFX IFX ADA

CD, UC CD CD CD, UC CD CD CD CD CD

n

Erythema Nodosum Prevalence BL % n N %

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

EP

TE D

M AN U

SC

23

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

CR N

RI PT

n

CI n

945

2.4%

n

4

Prevalence FU N %

942

0.4%

ACCEPTED MANUSCRIPT

Stomatitis IBD n IFX ADA ADA ADA IFX IFX IFX IFX ADA

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

%

CR N

n

%

n

49

3

EP

TE D

M AN U

SC

3

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

CI n

RI PT

Treatment

100%

Prevalence BL N %

945

5.2%

n

20

Prevalence FU N %

942

2.1%

ACCEPTED MANUSCRIPT

Treatment

IBD

n

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

EP

TE D

M AN U

4

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

Cutaneous manifestations CR Prevalence BL N % n N %

RI PT

n

CI n

4

100%

n

Prevalence FU N %

ACCEPTED MANUSCRIPT

IBD

n

Skin and joint EIMs Prevalence BL % n N %

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

50 4 2

EP

TE D

35 4 2

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

CR N

RI PT

n

CI n

M AN U

Treatment

70% 100% 100%

19 1

50 4

38% 25%

n

Prevalence FU N %

ACCEPTED MANUSCRIPT

Uveitis

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

%

1

1

100%

CR N

n

M AN U

2

EP

%

RI PT

CD, UC CD CD CD, UC CD CD CD CD CD

n

CI n

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

IBD

TE D

Treatment

2

100%

n

3

Prevalence BL N %

945

0.3%

n

3

Prevalence FU N %

942

0.3%

ACCEPTED MANUSCRIPT

Episcleritis Treatment

IBD

n

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

EP

TE D

M AN U

1

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

CR N

%

RI PT

n

CI n

1

100%

n

Prevalence BL N %

n

Prevalence FU N %

ACCEPTED MANUSCRIPT

Iritis Treatment

IBD

n

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

EP

TE D

M AN U

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

CR N

%

RI PT

n

CI n

n

7

Prevalence BL N %

945

0.7%

n

2

Prevalence FU N %

942

0.2%

ACCEPTED MANUSCRIPT

Osteopenia Treatment

IBD

n

%

n

Prevalence BL N %

n

Prevalence FU N %

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

EP

TE D

M AN U

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

CR N

RI PT

n

CI n

7

15

47%

5

15

33%

ACCEPTED MANUSCRIPT

Osteoporosis Treatment

IBD

n

%

n

Prevalence BL N %

n

Prevalence FU N %

CD, UC CD CD CD, UC CD CD CD CD CD

IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX, ADA, CZP IFX IFX ADA IFX IFX IFX

CD UC IBDU CD CD CD CD CD CD CD, UC CD CD, UC, IBDU CD, UC, IBDU CD, UC CD, UC CD

EP

TE D

M AN U

SC

IFX ADA ADA ADA IFX IFX IFX IFX ADA

AC C

Interventional studies Brooklyn 2005 Rubin 2012 Lofberg 2012 Barreiro de Acosta 2012 Kaufmann 2005 Rispo 2005 Herfarth 2002 Generini 2004 Veerappan 2015 Non-interventional studies Caspersen 2008 Caspersen 2008 Caspersen 2008 Bernstein 2005 Mauro 2007 Pazianas 2006 Abreu 2006 Franchimont 2004 Ryan 2004 Koutroubakis 2015 Bergamaschi 2010 Argüelles-Arias 2013 Argüelles-Arias 2013 Regueiro 2003 Bollen 2015 Wang 2014

%

CR N

RI PT

n

CI n

3

15

20%

1

15

6.6%

ACCEPTED MANUSCRIPT

Treatment

IBD

n

CI n

%

CR N

n

%

n

Prevalence BL N %

n

Prevalence FU N %

AC C

EP

TE D

M AN U

SC

RI PT

Interventional studies Brooklyn 2005 IFX CD, UC Rubin 2012 ADA CD 77 260 29.8% 66 260 25.2% Lofberg 2012 ADA CD Barreiro de Acosta 2012 ADA CD, UC Kaufmann 2005 IFX CD Rispo 2005 IFX CD Herfarth 2002 IFX CD Generini 2004 IFX CD Veerappan 2015 ADA CD Non-interventional studies Caspersen 2008 IFX CD Caspersen 2008 IFX UC Caspersen 2008 IFX IBDU Bernstein 2005 IFX CD Mauro 2007 IFX CD Pazianas 2006 IFX CD Abreu 2006 IFX CD Franchimont 2004 IFX CD Ryan 2004 IFX CD Koutroubakis 2015 IFX, ADA, CZP CD, UC 45 134 34% 51 134 38.1% 49 134 36.6% Bergamaschi 2010 IFX CD 12 18 67% Argüelles-Arias 2013 IFX CD, UC, IBDU Argüelles-Arias 2013 ADA CD, UC, IBDU Regueiro 2003 IFX CD, UC Bollen 2015 IFX CD, UC Wang 2014 IFX CD ADA: adalimumab; ASAS20: 20% improvement in the Assessment of the ankylosing spondilytis scale; BAP: Bone alkaline phosphatise; BL: baseline; BMD: bone mineral density; CD: Crohn’s disease; CI: clinical improvement; CR: complete response/resolution; EIM: extraintestinal manifestation; EN: erythema nodosum; FU: follow-up; IBD: inflammatory bowel disease; IBDU: inflammatory bowel disease type unclassified; IFX: infliximab; MBD: metabolic bone disease; MD: musculoskeletal disease; OC: osteocalcin; P1NP: procollagen type-1 N-terminal propeptide; PG: pyoderma gangrenosum; UC: ulcerative colitis