Expert Opinion on Biological Therapy

ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: https://www.tandfonline.com/loi/iebt20

Choosing the most appropriate biologic therapy

for Crohn’s disease according to concomitant
extra-intestinal manifestations, comorbidities, or
physiologic conditions

Ciro Romano, Sergio Esposito, Roberta Ferrara & Giovanna Cuomo

To cite this article: Ciro Romano, Sergio Esposito, Roberta Ferrara & Giovanna Cuomo (2019):
Choosing the most appropriate biologic therapy for Crohn’s disease according to concomitant extra-
intestinal manifestations, comorbidities, or physiologic conditions, Expert Opinion on Biological
Therapy, DOI: 10.1080/14712598.2020.1689953

To link to this article: https://doi.org/10.1080/14712598.2020.1689953

Accepted author version posted online: 05

Nov 2019.

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Opinion on Biological Therapy

DOI: 10.1080/14712598.2020.1689953

Choosing the most appropriate biologic therapy for Crohn’s disease

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according to concomitant extra-intestinal manifestations,

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comorbidities, or physiologic conditions

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Ciro Romano¹.; Sergio Esposito¹.; Roberta Ferrara¹.; Giovanna Cuomo¹
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¹University of Campania Luigi Vanvitelli, Piazza Miraglia-Division of Internal Medicine, Department

of Medical and Surgical Sciences, Naples, Italy

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ABSTRACT

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Introduction: Approximately half of Crohn’s disease (CD) patients suffer from concomitant extra-intestinal

manifestations (EIMs). Moreover, CD patients may suffer from comorbidities or have physiologic

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characteristics that may influence the outcome of a biologic treatment. Previous guidelines, published when

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only TNF-α antagonists were available as biological agents, addressed only management of CD patients with

the most common EIMs. an

Areas covered: Because of the recent introduction of new biologics for the treatment of Crohn’s disease as
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well as increased awareness about comorbidities potentially able to affect the impact of biological drugs,

here we provide an update on management considering old and new biologics with proven efficacy on both
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Crohn’s disease and associated conditions, in order to ideally profile the patient to the best of the current

knowledge.
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Expert Opinion: While waiting for identification and validation of widely available and reliable biomarkers
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able to predict which biologic may yield the best response in the individual IBD patient (rigorous precision

medicine), the choice of biologic agents in CD patients in order to achieve the best outcome still lies on a
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thorough assessment of patient-related characteristics as well as deep knowledge of the properties and place

in therapy of each biologic drug.

Keywords: Crohn’s disease, biologic therapy, extra-intestinal manifestations, comorbidities, pregnancy,

elderly patients
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ARTICLE HIGHLIGHTS

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• Real-life Crohn’s disease (CD) patients often suffer from concomitant extra-intestinal manifestations
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and comorbidities

• The current availability of biologic drugs with different molecular targets requires comprehensive
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knowledge of their characteristics for optimal management of CD patients with coexisting extra-

intestinal manifestations and comorbidities

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• Tailored treatment suggestions for extra-intestinal manifestations and comorbidities simultaneously

occurring in CD patients are provided based on the available evidence

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• Tailored treatment suggestions are provided for such physiologic conditions as pregnancy and old

age based on the available evidence

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1. INTRODUCTION

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, typically involving the

terminal ileum and colon, although all segments of the gastrointestinal tract can be affected. The course of

the disease is progressive, with a relapsing and remitting inflammatory pattern, often leading to such

complications as strictures, fistulas, or abscesses ultimately requiring surgery [1]. Moreover, CD may be

associated with extra-intestinal manifestations (EIMs) of disease, some of which may even predate intestinal

involvement. Indeed, up to 50% of patients present with cutaneous, articular, or ocular EIMs that can
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precede diagnosis. Among these, erythema nodosum and oligoarticular large joint arthritis are typically

associated with active intestinal disease, while axial spondilarthritis or primary sclerosing cholangitis are

independent of disease activity [2]. Ideally, therapy of CD should warrant sustained remission, so as to stop

the course of the disease, control EIMs, and prevent complications. The introduction of biologic drugs in the

armamentarium of therapies for inflammatory bowel disease (IBD) has improved the outcome of the disease;

however, a substantial proportion of patients may not satisfactorily respond to these therapies thus requiring

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eventually surgery [3]. In some instances, the characteristics and/or associated comorbidities of CD patients

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may have a negative impact on the successful outcome of biologic therapy; in other cases, the choice of a

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specific biologic agent should also take into account the associated EIM, since some biologic drugs work

well on CD but not on associated EIMs. Although guidelines for management of EIMs are already available

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[4], here we provide an update considering the latest evidence and focus on the use of biologic drugs in

specific CD contexts, beyond EIMs, that may favor choice of a biologic agent over another because of a
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predictable better outcome, so as to ideally profile the patient to the best of the current knowledge.
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1.1 BIOLOGIC DRUGS CURRENTLY AUTHORIZED FOR CROHN’S DISEASE TREATMENT

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Six biologic agents have thus far been granted approval for use in CD. They may be classified according to

structural characteristics, mechanism of action, route and frequency of administration. Half of them share the
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same molecular target (i.e., TNF-α). Table 1 summarizes the main characteristics of each biologic agent
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currently available for CD treatment. Natalizumab has primary indication for multiple sclerosis; it is also

available for CD in the USA.

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1.2 SPECIFIC CONDITIONS

Real-life CD patients eligible for biologic therapy may present with concomitant EIMs, comorbidities, or

specific physiologic conditions (Table 2) that may raise more than one question as to which biotherapy may

be more appropriate considering the whole clinical picture. Management suggestions for common conditions

are detailed below.

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2. EXTRA-INTESTINAL MANIFESTATIONS

2.1 Enteropathic spondyloarthritis

Joint involvement is the most common EIM of CD [5,6]. Patients may present with peripheral or

axial involvement, collectively known as enteropathic spondylarthritis. Peripheral joint arthritis

occurs in 10-20% of CD patients, is usually non-erosive and non-deforming, and may present with

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an oligoarticular or polyarticular pattern. Oligoarticular involvement is characterized by asymmetric

arthritis, usually of large joints of lower limbs (i.e., hips, knees, and ankles), whose activity parallels

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that of CD; polyarticular involvement is typically symmetric and also affects small joints, with

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longstanding pain and swelling, independently of CD activity. Thus, control of oligoarticular arthritis

is usually achieved with therapies aimed at controlling CD, while polyarticular arthritis may require
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an independent treatment strategy [7].

Axial involvement, suggested by persistent inflammatory back pain, is underlain by sacroiliitis. Five
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to 20% of CD patients may suffer from axial spondylarthritis. Magnetic resonance imaging is the

diagnostic tool of choice to reveal inflammation of one or both sacroiliac joints, even before sequelae
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of sacroiliitis become apparent on conventional radiology. Like polyarticular peripheral arthritis,

axial involvement runs an independent course from that of CD, thus possibly predating CD and
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needing exclusive treatment. Finally, axial and peripheral joint involvement may coexist in 3-6% of

CD patients [2,7]. The correct recognition of the pattern of articular involvement, along with
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assessment of CD activity, is paramount in order to implement the most appropriate biologic

treatment [8]. Since guidelines for treatment of CD and spondylarthritis are separately available [9-
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11], close collaboration between gastroenterologists and rheumatologists is crucial in order to ensure

optimal management of combined conditions. In general, judicious application of guidelines, based

on recognition of the prevalently active disease and the type of biologic agents suitable for treatment

of both conditions, is usually advised.

Treatment of peripheral arthritis differs depending on the oligoarticular or polyarticular pattern and

coexistence of quiescent or active CD; in general, peripheral arthritis is observed with higher
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frequency in colitis than in ileitis [12]. The same therapeutic considerations apply to axial

involvement. The basic clinical scenarios are as follows (Figure 1):

- In case of peripheral oligoarthritis, since this type of articular involvement is self-limiting and

parallels intestinal disease activity, if biologic treatment is necessary to control CD activity, either

TNF-α inhibitors or ustekinumab at the doses and administration schedules used in gastroenterology

usually suffice for concomitant control of peripheral oligoarthritis (Table 1). Vedolizumab, despite

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being highly specific for a gut-selective integrin [13], may also be considered for this type of

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arthritis, perhaps better after failure of TNF-α inhibitors or ustekinumab on CD activity control,

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since the main goal of biologic therapy in this setting is to dampen intestinal inflammation; in fact,

following control of CD, this type of arthritis usually resolves. Indeed, clinical benefit of

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vedolizumab therapy on inflammatory arthralgia/arthritis has been documented in patients with

synchronous occurrence of intestinal and articular inflammation [14,15].

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- In case of peripheral polyarthritis, biologic therapy differs depending on the activity of underlying

CD. As stated above, this type of arthritis is independent of CD activity; thus, it may occur with or
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without active CD. In case of active CD, both TNF-α inhibitors and ustekinumab may be used,

according to the doses and schedules used in gastroenterology; if CD is quiescent, the same agents
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may be administered, following the doses and the schedules used in rheumatology (Table 1).

Vedolizumab in this context may not be the most appropriate choice, since this agent has been
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observed to be associated with flares of arthritis in several case series [14-17], despite α4β7 integrin
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has also been found on leukocytes infiltrating the synovium [18,19]. However, in some instances,

caution should be exercised in interpreting this cause-effect relationship. In fact, when vedolizumab
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is introduced in therapy following failure of a TNF-α inhibitor to control CD activity, arthritis flares

may be due to loss of the effect of the previous biologic drug on arthritis activity rather than to “true”

vedolizumab-induced arthritis [16].

- In case of axial involvement, which is independent of CD activity, the type of therapy again depends

on the underlying CD activity. Since long-term use of nonsteroidal antinflammatory drugs

(NSAIDs), which have been shown to be useful in controlling axial spondylarthritis [11], are

contraindicated in CD patients, resort to biologic therapy is more immediate. In case of quiescent

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CD, first-line biologics are TNF-α inhibitors, since randomized trials of ustekinumab in patients

with axial spondyloarthritis failed to achieve the key primary and secondary endpoints, despite

preliminary evidence of positive outcomes in this setting [20]. This also means that, following

failure of a first TNF-α inhibitor, a second agent in the same class should be tried. Doses and

administration schedules are per rheumatologic recommendations (Table 1). In case of active CD

and axial disease, TNF-α inhibitors should be administered following the protocols used in

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gastroenterology. For vedolizumab, considerations are the same as for peripheral polyarthritis, that

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is, there is no evidence of clinical benefit on axial disease.

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- In case of overlapping features (i.e., concomitant peripheral and axial involvement), considerations

are the same as in case of isolated axial involvement.

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- If predominant manifestations of spondylarthritis are enthesitis and/or dactylitis, the most effective
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strategy is use of biologic agents [21]. Sound choices are, again, TNF-α inhibitors or ustekinumab,

at doses and schedules depending on the underlying activity of CD. Vedolizumab is not considered
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appropriate for concomitant treatment of enthesitis and/or dactylitis.
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2.2 Erythema nodosum

Up to 15% of patients may suffer from recurrent episodes of erythema nodosum (EN), the most
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common cutaneous EIM of CD. EN is classified as a panniculitis, as it involves the subcutaneous fat,
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and appears to be more frequent in patients with isolated colonic involvement [22]. EN presents with

raised, tender, red or violet, 1- to 5-cm subcutaneous nodules, typically located bilaterally on the
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extensor surface of lower limbs, is self-limiting, and resolves without sequelae. Its course usually

depends on the underlying CD activity. Since control of CD activity is usually propedeutic to

achieving remission of EN episodes, any type of available biologic therapy, if necessary for control

of CD activity, can be chosen by the clinician, as appropriate. Real-life data from the latest European

Crohn’s and Colitis Organisation (ECCO) conference have also indicated efficacy of ustekinumab on

EN in case of failure of prior anti-TNF-α treatment, while vedolizumab therapy appeared to be less

effective [23]. Nevertheless, since EN has been found to be frequently associated with peripheral
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arthritis [22,24], biologic therapy should be implemented primarily considering the biotherapies

effective on joint manifestations (i.e., TNF-α inhibitors or ustekinumab). Other possible associations

are with ocular involvement and pyoderma gangrenosum [22], which should also be taken into

account when deciding the choice of biologic therapy (see next paragraphs for details and figure 2).

Refractory cases usually respond well to TNF-α antagonists [25-27], if not used as first-choice

biologic agents.

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2.3 Pyoderma gangrenosum

As opposed to EN, pyoderma gangrenosum (PG) is a severe, debilitating EIM of IBD, more

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frequently observed in ulcerative colitis than in CD. In the latter case, PG usually follows onset of

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CD in most of the patients [7]. PG is characterized by single or multiple painful erythematous

papules or pustules, evolving in deeply excavated ulcerations with purulent but sterile material,
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characterized by high recurrence rates. The lesions usually localize on shins or the peristomal area,

although any skin district can be affected, particularly at sites of previous trauma (e.g., venipuncture
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or biopsy), suggesting pathergy phenomenon [28]. PG may parallel activity of underlying CD or run

an independent course; its incidence in CD is between 0.1-1.2%. Typical associations are with
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pancolitis, permanent stoma, EN, and ocular involvement [28]. Since the disease course is severely

debilitating, early, aggressive treatment is warranted in order to attempt rapid resolution of lesions.
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For these reasons, biologic therapy may be an early option when considering treatment strategies.

TNF-α antagonists, the only biotherapies available for IBD treatment at the beginning of the
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biologic era, were tried first in the treatment of recalcitrant PG cases, based on a hypothetical shared
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pathomechanism with CD. Indeed, blocking TNF-α resulted in healing of PG in a number of case

reports and small series [25,29-32], making therapies with anti-TNF-α monoclonal antibodies sound

choices for changing the course of the disease. More recently, some authors have documented high

expression of IL-23 in a recalcitrant PG lesion, both at the transcriptional and protein level. This

finding led to a treatment trial with ustekinumab, an inhibitor of both IL-12 and IL-23, which

resulted in complete healing within 14 weeks of treatment [33]. Targeting IL-23 was then confirmed

to be another effective treatment strategy for IBD-associated PG, with clinical benefit also reported
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for peristomal localization [34-36]. Recent real-life data from the latest ECCO conference also

support use of ustekinumab for inducing remission of PG in patients failing therapy with TNF-α

inhibitors [23]. Ustekinumab efficacy is not surprising, given the prior positive experiences with

anti-TNF-α strategies in PG, since IL-23 appears to act upstream of TNF-α, therefore inhibition of

IL-23 may lead to TNF-α downregulation [37]. Conversely, no efficacy data have emerged for

vedolizumab [23].

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Finally, in case of multiple associations, a biologic agent known to be possibly effective on all

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manifestations should be used (Figure 2).

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2.4 Scleritis and uveitis
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Scleritis and uveitis represent the most bothersome ocular EIM of CD. In general, eye

manifestations, including also such mild conditions as conjunctivitis and episcleritis, occur in 2-6%
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of patients and usually are associated with joint involvement [38]. Management of scleritis and

uveitis requires close collaboration with an ophthalmologist, since ocular involvement may lead to
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visual impairment up to loss of vision in untreated patients. Eye manifestations usually follow the

course of CD activity; hence, treatment of the underlying IBD with conventional or biological
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therapies, as appropriate, along with the therapy suggested by the ophthalmologist, may suffice for

control of ocular inflammation [7]. Refractory cases naïve to biologic therapy have been successfully
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treated with TNF-α inhibitors [39-42]. Particularly, adalimumab has been shown to be effective in

patients with different noninfectious forms of uveitis despite continued steroid treatment for at least

2 weeks and to lower the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal

[43,44]. Ustekinumab may be tried as a rescue therapy in case of failure of TNF-α inhibitors [45-47],

while awaiting for efficacy confirmation from ongoing trials investigating the effect of IL-12/IL-23

blockade in sight-threatening uveitis (ClinicalTrials.gov identifiers: NCT02911116, NCT03847272).

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2.5. Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC), a chronic cholestatic disease due to inflammation and

progressive fibrosis of the intrahepatic and extrahepatic bile ducts, is strongly associated with IBD,

since nearly 80% of PSC patients suffer from concomitant IBD [48]. Conversely, less than 10% of

IBD patients have an attendant condition of biliary duct inflammation. Treatment outcomes are

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disappointing since no medical therapies have been shown to prevent progression in PSC [49]. On

the other hand, the role of biologics in PSC remains uncertain. Although TNF-α has been found to

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promote inflammation around bile ducts in PSC through recruitment of T cells [50,51], there is no

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robust evidence that TNF-α inhibitors may be effective. Indeed, although a transient benefit,

evaluated as a decrease in alkaline phosphatase (ALP) levels, was observed for adalimumab as
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opposed to infliximab and vedolizumab in the largest study published so far, the authors concluded

that current biologic therapies do not appear to be effective for treatment of PSC [52]. A transient
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reduction in ALP levels was also seen in 2 out of 3 adalimumab-treated patients in a smaller case

series [53]. In that study, one patient on infliximab had reduced γ-glutamyltransferase levels after 6
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and 12 months of therapy, but liver function tests tended to deteriorate thereafter [53]. With regard to

vedolizumab, the rationale for its use in IBD-associated PSC stems from the observation of gut
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adhesion molecules also in the PSC liver, which could mediate recruitment of gut-derived, α4β7-

expressing effector T cells from the inflamed bowel to the liver [54]. While this rationale has not yet
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translated into clinical benefit [52], there has also been a report of acute cholestasis after
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vedolizumab treatment, progressing to chronic liver injury despite immediate drug withdrawal and

corticosteroid administration [55]. Nevertheless, a recent review suggests that TNF-α antagonists

may benefit subgroups of CD-associated PSC patients by either resolving intestinal inflammation or

by a direct effect on the liver; similarly, vedolizumab may work in subsets of IBD patients with

concomitant PSC [56]. However, biomarkers capable of identifying potential responders are

currently lacking. Thus, while waiting for innovative therapies, able to induce a paradigm shift in the

treatment of PSC, if the clinician’s choice for biologic therapy falls on TNF-α antagonists,
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adalimumab may be a candidate drug among this class of biologics to treat CD patients with

attendant chronic inflammation of bile ducts, on the basis of the available, albeit scarce, evidence.

2.6. Glomerulonephritis

Parenchymal renal involvement in IBD is rare [57,58]. IgA nephropathy is by far the most common

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type of glomerulonephritis reported in IBD patients, followed by membranoproliferative and

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minimal change glomerulonephritis [57,58]. Inclusion of glomerulonephritis among EIMs of CD is

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suggested by the general improvement of renal function following achievement of intestinal

remission [59]. Therefore, in patients with concomitant nephropathy, the primary goal is to treat the

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underlying bowel inflammation to limit renal damage. This concept holds particularly true for

prevention of amyloidosis, which cannot be considered a classic EIM of CD, but rather a
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complication occurring when chronic bowel inflammation is not appropriately abated in a timely

fashion [58,59]. The typical clinical presentation of CD-related amyloidosis (∼70% of patients) is
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renal failure and nephrotic range proteinuria. Once CD patients present with overt amyloidosis and

initiation of biologic therapy is considered, the clinician should opt for TNF-α inhibitors. Indeed,
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infliximab has been shown to decrease serum amyloid A circulating levels and proteinuria as well as

to stabilize renal function and to improve survival in several reports [60-65]. However, it is unclear
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if reversibility of established damage can be achieved. Of importance, due to their high molecular
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weight, TNF-α inhibitors are not affected by glomerular filtration rate; thus, no adjustments in

dosing are needed based on creatinine clearance.

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2.7 Neurologic manifestations

Peripheral neuropathies are the most common neurological manifestations in patients with CD.

These neuropathies are generally independent of intestinal activity and do not respond to IBD-

specific treatment [66,67]. Further complicating matters are reports describing onset of peripheral

neuropathy following therapy with TNF-α antagonists [68-72], which is nonetheless a rare adverse
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event overall [71]. Conversely, a beneficial effect of these biotherapies on peripheral nerve

involvement complicating CD has been much rarely reported [73]. However, since evidence is

anecdotal, there is no reason to exclude a priori TNF-α inhibitors from the possible therapeutic

choices in CD patients with attendant peripheral neuropathy. Clearly, a vigilant eye must be kept on

the outcome of neurological involvement so as to promptly swap to alternatives to TNF-α

antagonists (i.e., ustekinumab or vedolizumab), in case of unexpected worsening.

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With regard to central nervous system (CNS) involvement associated with IBD, demyelinating

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diseases such as multiple sclerosis (MS) and ischemic optic neuropathy are the most common

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entities [67]. TNF-α inhibitors are contraindicated in patients with demyelinating diseases since they

may exacerbate disease or trigger demyelination [74]. Although well-tolerated, ustekinumab did not

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show efficacy in relapsing-remitting MS in a phase II clinical trial [75]. Natalizumab has been the

first monoclonal antibody approved for MS treatment [76]; in countries where natalizumab is also
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indicated for treatment of CD, this monoclonal antibody may be the best choice for combined CD

and MS.
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3. COMORBIDITIES
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3.1. Obesity

Obesity is increasing in prevalence among CD patients and may constitute a further challenge in their
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management [77]. Indeed, obese patients have been shown to experience earlier loss of response during

biological therapy [78,79] and higher rates of postoperative complications as compared to lean subjects
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[80]. With regard to biologic therapy, obesity has been demonstrated to hamper the effects of TNF-α
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inhibitors [78,79]; particularly, studies in obese rheumatoid arthritis patients revealed that infliximab had

the worst performance when compared to other TNF-α antagonists [81], probably due to a lower

distribution volume with respect to other same class biologics [82,83]. However, infliximab treatment in

obese CD patients may be optimized by increasing doses both at the induction phase and during

maintenance according to serum concentrations, suggesting that a personalized treatment strategy may

aid overcoming impaired treatment responses in this setting [84]. Specifically, infliximab trough

concentrations >3.5 μg/ml at week 14 have been associated with sustained response to therapy in CD
 13

[82]; moreover, keeping trough concentrations at ≥5 μg/ml during maintenance therapy are considered

sufficient for infliximab to exert its clinical effects. In practice, loss of response on ideal trough

concentrations should prompt a change in biologic therapy (secondary loss of response), while a trough

concentration below the above threshold combined with an unsatisfactory clinical response should

encourage dose escalation [82].

Ustekinumab efficacy may also be limited by excess body weight [85,86]. However, in studies carried

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out in psoriasis patients, doubling the 45-mg dose in patients weighing > 100 kg was associated with

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improved response rates [87,88]. In CD patients, the i.v. induction dose is calculated based on body

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weight while the maintenance phase includes only the 90-mg dose. Moreover, dosing intervals may be

reduced to 8 weeks based on clinician judgement of efficacy, as opposed to the 12-week dose intervals

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typically used in protocols of psoriasis and psoriatic arthritis treatment. Again, therapeutic drug

monitoring may help decide how to best manage administration of ustekinumab in obese patients.
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Depending on the select outcome (i.e., clinical response at week 8, biological response at week 8, clinical

and biochemical response at week 16, 50% decrease in fecal calprotectin at week 8, etc.) and the time
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point of drug trough level assessment (week 4 or week 8 from start of therapy), a number of serum drug

thresholds ranging from >2 to >15.9 μg/ml have been established as predictors of good response [89].
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Thus, tailoring ustekinumab doses and administration intervals upon clinical judgement and therapeutic

drug monitoring may help achieve treatment goals in obese patients as well. There are no sufficient data
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about the impact of body weight on vedolizumab efficacy in CD; however, a retrospective study in
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biologic-treated ulcerative colitis patients also identified a high body mass index as a limiting factor for

vedolizumab efficacy [90]. If feasible, measuring vedolizumab levels at week 6 may be useful for
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outcome prediction in IBD patients, since approximately >20 μg/ml have been shown to be associated

with improved clinical responses, including mucosal healing rates during maintenance. However, drug

thresholds predictive of good outcome may vary (from >18 to >35.2 μg/ml) depending on the time of

measurement (week 2, week 6, or week 14 from start of therapy) and the desired outcome (clinical

response at week 6, biochemical remission at week 6, clinical response at week 14, mucosal healing

within 52 weeks, sustained remission, etc.) [89]. Thus, measuring serum levels of vedolizumab may help

adjusting the therapeutic dose before concluding for a lack of response [91].
 14

Finally, body weight has also been shown to be the most important factor associated with natalizumab

effective distribution [92]. Indeed, natalizumab efficacy has been demonstrated to be dependent on

saturations of VLA-4 on lymphocytes of more than 70%, and the median saturation of Very Late

Antigen-4 (VLA-4) on lymphocytes declines with increasing body weight [93]. However, since patients

heavier than 75 kg still show lymphocyte VLA-4 saturations greater than 85%, body weight may be an

issue in patients with frank obesity. Nevertheless, since natalizumab is associated with the development

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of progressive multifocal leukoencephalopathy (PML) and no tests are currently available for reliable

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prediction of those at risk of developing PML, increasing natalizumab doses may further predispose

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patients to this potentially fatal complication [94]; therefore, it is not an advisable therapeutic choice in

obese patients due to the anticipated need of using higher than usual doses.

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3.2. Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)
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According to a recent systematic review with meta-analysis including 5620 patients, the overall pooled

prevalence of NAFLD in IBD patients has been calculated to be 27.5%, with even higher rates in elderly
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patients, coexisting metabolic comorbidities, methotrexate use, prior surgery, and longer duration of IBD

[95]. Importantly, NASH poses an increased risk of morbidity and mortality due to possible progression
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to liver cirrhosis. Unfortunately, there is no established medical treatment for NASH, owing to an

incomplete understanding of its pathogenesis. According to several lines of evidence, such

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proinflammatory cytokines as TNF-α and interleukin (IL)-6 may be involved in the pathogenesis of
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NASH by promoting liver inflammation, insulin resistance, and hepatocyte apoptosis [96]. However,

anti-TNF-α therapy has not been evaluated for the treatment of NASH. Notwithstanding, anecdotal
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reports highlight the beneficial effects of TNF-α inhibitors on altered liver histology and biochemistry

due to experimentally-induced or naturally occurring NASH in mouse and human hosts, respectively

[97,98]. Thus, based on the scant evidence available and while waiting for confirmatory results in large

ad hoc studies, patients with active CD and concomitant NAFLD/NASH may be considered for biologic

therapy with TNF-α inhibitors; moreover, in case CD is in control but concomitant peripheral arthritis is

bothersome to the NAFLD/NASH patient, biologic therapy may be started at rheumatologic doses just

for control of this EIM, skipping the trial with conventional antirheumatic drugs (e.g., sulphasalazine or
 15

methotrexate) because of concerns about possible liver toxicity. Finally, since NAFLD/NASH is

commonly observed in overweight/obese patients (Figure 2), dosage and administration schedules of

TNF-α inhibitors should be adjusted taking into account the role of body weight on efficacy (Figure 2),

as previously detailed.

3.3. Diabetes mellitus

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Patients with IBD may have an increased risk of developing type 2 diabetes mellitus [99]. Insulin

resistance is the most important pathophysiologic feature of type 2 diabetes mellitus and prediabetic

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states. Since TNF-α has been shown to contribute to the pathogenesis of insulin resistance during the

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course of chronic inflammatory diseases [100], therapies aimed at neutralizing TNF-α should

theoretically result in amelioration of insulin resistance. Indeed, several pieces of evidence point to a
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beneficial role of TNF-α inhibitors in improving glucose homeostasis, both in experimental models and

human subjects [101-103]. Noteworthy, relapse of diabetes has been observed following discontinuation
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of infliximab [104], further strengthening the role of TNF-α in modulating insulin resistance. Although

available data supports the concept that targeting inflammation improves insulin sensitivity and
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pancreatic β-cell function, thus suggesting preferential use of TNF-α inhibitors for CD patients suffering

from concomitant type 2 diabetes mellitus, it should also be remembered that the positive metabolic
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effects registered in most clinical trials carried out so far have been rather modest [105]. Finally, the

higher prevalence of fatty liver disease in diabetic patients may, again, suggest early implementation of
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biologic therapy in this subset of patients (i.e., CD and type 2 diabetes and fatty liver disease) if

peripheral arthritis also coexists, in order to avoid possible adverse effects of conventional antirheumatic
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drugs used for relief of joint inflammation on the liver (Figure 2).

On a purely theoretical basis, as experimental and clinical data are still insufficient, the combination of

type 1 diabetes mellitus and CD would be best approached by using ustekinumab. In type 1 diabetes

mellitus, proinflammatory pathways are mainly orchestrated by Th1 and Th17 cells, T cell subsets

secreting interferon-γ (IFN-γ) and IL-17, respectively [106]. IL-12 and IL-23 are crucial cytokines for
 16

sustaining Th1 and Th17 cell activity. Ustekinumab, a dual inhibitor of IL-12 and IL-23, has been shown

to be effective in dampening IFN-γ- and IL-17-driven inflammation [106].

In both type 1 and type 2 diabetes mellitus, it is wise to start biologic therapy when glucose homeostasis

is under control, since decompensated diabetes may represent an additional risk for serious infections

during biologic therapy.

t
ip
3.4. Cardiovascular disease

TNF-α inhibitors have long been known to worsen heart failure [107]. Conversely, there are no reports

cr
of exacerbation of heart failure using biologics with a different molecular target. Therefore,

us
ustekinumab, vedolizumab or natalizumab may be used in place of TNF-α inhibitors, as appropriate, in

patients with CD and concomitant heart failure. TNF-α antagonists should only be used if there are no
an
other reasonable options, and then, perhaps, only in compensated heart failure.

Conversely, anti-TNF-α treatment has been shown to reduce cardiovascular risk by preventing
M

progression of subclinical atherosclerosis and arterial stiffness in patients with different types of chronic

inflammatory diseases [108,109]. Indeed, a chronic inflammatory state is deemed to be responsible for
ed

accelerated atherosclerosis in these patients [110]; however, whether this effect is specific to TNF-α

inhibitors or relates to better control of chronic inflammation, regardless of the therapeutic strategy
pt

implemented, is currently unknown. Therefore, early control of chronic inflammation may be beneficial
ce

for reducing cardiovascular risk and this should be borne in mind when deciding whether to scale up

therapy, particularly in case of other concomitant cardiovascular risk factors (i.e., smoking, hypertension,
Ac

dyslipidemia, etc.).

3.5. Psoriasis

Common genetic and inflammatory pathways have been implicated in psoriasis and IBD [111], therefore

it is not surprising that the two conditions are frequently associated [112]. Patients with CD and

comorbid psoriasis may be effectively treated with TNF-α inhibitors or ustekinumab [113-118], whereas

vedolizumab and natalizumab are not considered effective on skin manifestations. It should not be
 17

overlooked that paradoxical psoriasis may occur during treatment with biological agents, particularly

TNF-α inhibitors [119]. Female gender and history of extra-intestinal manifestations have been

suggested to predispose to development of paradoxical psoriatic lesions. Stopping TNF-α inhibitor

therapy and swapping to ustekinumab has been shown to result in complete remission in nearly all cases,

while maintaining or attaining intestinal remission [120].

t
ip
3.6. History of infections

cr
A recent systematic review and meta-analysis including a total of > 5000 IBD patients from different

trials found no increased infection risk in CD patients treated with TNF-α inhibitors, as opposed to

us
ulcerative colitis patients who were shown to be at increased infection risk vs. placebo with the same

biotherapies [121]. Anti-integrin therapy was found to be safe as well. Nevertheless, in patients with a
an
history of frequent serious infections (i.e., requiring hospitalization), ustekinumab or vedolizumab may

be prudentially considered as first choices in accordance with the patient’s characteristics.

M
ed

4. PHYSIOLOGIC CONDITIONS

4.1 Pregnancy and child-bearing age

pt

Although IBD increases the risk of pregnancy complications irrespective of disease activity, adverse
ce

pregnancy outcomes occur more frequently in case of active disease [122]. Thus, CD occurring during

child-bearing age raises concerns about the impact of the disease and its treatment on fertility, maternal
Ac

and fetal health during pregnancy, and breastfeeding safety. Ideally, women should conceive while CD is

quiescent. With regard to biologic therapy, collective evidence from hundreds of pregnancies in chronic

inflammatory diseases have suggested that exposure to TNF-α inhibitors at the time of conception or

during the first trimester is not associated with an increased risk of adverse pregnancy and fetal outcomes

[123]. However, monoclonal antibodies do cross the placenta during the second and third trimester and

have been shown to be functional in the fetus [123]. Nevertheless, data from the TREAT registry,

summarizing a 13-year experience with infliximab given before or during pregnancy, showed that the
 18

clinical condition of infants born to women with gestational infliximab exposure was similar to those

without exposure, even though a lower live birth rate was recorded among infliximab-exposed women

[124]. However, these patients had more severe CD and were more likely to have been exposed to

immunosuppressive drugs [124]. Likewise, the recent European multicenter TEDDY study did not find

an increased short-term and long-term risk of severe infections in children of mothers with IBD, who had

been exposed to TNF-α inhibitors in utero with respect to children never exposed to such drugs [125].

t
Still, among TNF-α inhibitors, is now available a modified monoclonal antibody lacking the Fc

ip
fragment, namely, certolizumab pegol, which has become first choice, where available, for biologic

cr
therapy during pregnancy. In fact, certolizumab pegol is unable to bind the neonatal Fc receptor and thus

does not cross the placental barrier, as opposed to other therapeutic monoclonal antibodies [126,127].

us
Consistently, pregnancy outcomes after exposure to certolizumab pegol do not suggest harmful effects

on fetal/child health, such as teratogenicity or increased risk of fetal death [128,129]; moreover,
an
certolizumab pegol treatment can be continued during breast feeding as no or minimal (but clinically

insignificant) transfer occurs into maternal milk [130]. In a wider perspective, apart from pregnancy, it
M

may be judicious to start treatment of sexually-active CD patients in child-bearing age with certolizumab

pegol, since this approach will not need adjustments even in case of planned or unexpected pregnancies.
ed

Besides, most of the EIMs of CD are amenable to treatment with certolizumab pegol. Certolizumab

pegol, however, is licensed for treatment of CD only in the USA and Switzerland.
pt

The data for ustekinumab in pregnancy are limited to case studies and registry data [131-133].
ce

Experience in the field of rheumatology suggests that ustekinumab does not result in an increased risk of

miscarriage or congenital malformation [134]. However, controlled data are lacking and continuing
Ac

ustekinumab throughout pregnancy is a matter of debate [135]. Likewise, limited data are available about

outcomes of pregnancies exposed to vedolizumab [136-140]. No significant safety concerns have been

thus far identified, although vedolizumab-exposed pregnancies have been found to be associated with

more complications in both mothers and infants [139,140]; however, when excluding from the analysis

patients with active disease, no significant difference was observed with respect to pregnancies exposed

to TNF-α antagonists or to conventional therapy, suggesting that complications may more likely arise

because of active disease in pregnancy rather than as a drug adverse effect [139]. Vedolizumab may
 19

nonetheless be considered during pregnancy only if strictly necessary, with benefits to the mother

outweighing the risks to the mother/unborn child, as complications cannot be completely excluded [140].

Larger prospective studies are awaited to clarify this issue.

4.2. Elderly patients

The widely accepted definition of elderly-onset IBD is disease occurrence at an age of 60 years or older

t
ip
[141]. About 25-35% of the IBD population falls within the age range of elderly people, with about 15%

having true late-onset IBD and about 20% transitioning into older age having been diagnosed with the

cr
disease at a younger age [142,143]. Infections and related serious complications are more common in

us
elderly IBD patients [144], and elderly IBD patients treated with TNF-α inhibitors have an increased risk

of severe infection compared with younger patients [145]. Moreover, the frequent coexistence of heart
an
failure in the elderly population makes TNF-α inhibitors unsuitable for treatment of CD (Figure 2). By

contrast, ustekinumab and vedolizumab appear to have a better safety profile and may thus be
M
prudentially chosen as primary biotherapies [146-148].
ed

5. CONCLUSIONS
pt

Choosing the right drug for the right patient at the right time is one of the biggest unmet needs in current IBD

care. While waiting for further studies to address these issues, a thorough assessment of patient
ce

characteristics is necessary to choose the biologic agent likely to work best in each specific case.
Ac

6. EXPERT OPINION

TNF-α inhibitors have been the mainstay of treatment for IBD since their introduction in the market as first

available biotherapies and still have a prominent role in the treatment of CD. Subsequently, a number of

further biologic agents with a different mechanism of action (i.e., targeting different molecules involved in

inflammation or leukocyte migration) have obtained market authorization and have been shown to be

suitable options for treatment of CD patients. Since real-life patients with CD often suffer from associated
 20

comorbidities or EIMs, which are usually excluded from or unaccounted for in clinical trials, the choice of

biologic therapy in the everyday clinical practice should take into account all possible patient-related

variables capable to affect treatment effectiveness.

In the next future, innovative therapies are likely to receive market authorization for treatment of CD. As the

pathophysiologic mechanisms of CD and associated EIMs and comorbidities are progressively unraveled,

finely tuned targeted therapy may become available capable to control the whole spectrum of disease.

t
Meanwhile, due to the association with PML, the availability of alternative safer biologic agents, and the

ip
introduction of newer drugs, natalizumab is less likely to be used in CD patients failing conventional medical

cr
therapy in the next future. Conversely, the use of other biologic agents is likely to be refined as more clinical

data become available with respect to specific subsets of real-life CD patients.

us
Innovative therapies are now mainly represented by so-called small oral molecules, which act intracellularly

through unique mechanisms of action. Specifically, their mechanism of action involves inhibition of pro-
an
inflammatory cytokine synthesis through intracellular Janus kinase (JAK) signaling inhibition, inhibition of

the TGF-β pathway, or interference with lymphocyte trafficking via sphingosine 1-phosphate (S1P) receptor
M

modulation [149]; in addition, some other small molecules with different molecular targets are in the pipeline

[150]. There is, however, weak evidence of substantial efficacy in CD to date, although some of these
ed

molecules have demonstrated beneficial effects in patients with UC (as in the case of tofacitinib, a

preferential inhibitor of JAK1 and JAK3) [151]. Conversely, the phase 2 study of filgotinib, a selective JAK1
pt

inhibitor, has demonstrated more robust clinical efficacy in moderately to severely active CD [152]. The
ce

phase 3 study, including biologic-naïve and biologic-experienced CD patients with moderately to severely

active disease, is ongoing and is expected to be completed by November 2021 (ClinicalTrials.gov identifier:
Ac

NCT02914561). Clearly, because of the limited experience accumulated thus far, the role of small molecules

in patients with concomitant EIMs and/or comorbidities has yet to be determined. Nevertheless, it is

predictable that EIMs may benefit from novel treatments for CD provided they are demonstrated to be

superior in efficacy than currently available drugs, as most EIMs follow the course of the underlying CD

activity.

Real-life CD patients may suffer from concomitant combinations of EIMs or comorbidities which sometimes

may not be optimally managed with the same biologic drug, e.g, the biologic drug may be effective on CD
 21

and beneficial on the coexisting comorbidity but may not be suitable for the associated EIM(s) or vice versa.

Therefore, the idea of combining biologic therapies with different molecular targets may be entertained.

Indeed, a number of case reports or series have been published reporting on increased efficacy of combined

biologic therapy in IBD with no concomitant increase in adverse events, mainly involving the combination

of a TNF-α inhibitor with vedolizumab or ustekinumab [153-157]. Moreover, one short-term controlled trial

assessing the safety and tolerability of concurrent natalizumab in 79 active CD patients despite infliximab

t
therapy concluded that combined biologic therapy was well tolerated with no increase in adverse events,

ip
while even recording a trend toward improved disease activity [158]. A recent systematic review analyzing

cr
the limited available literature to date on combining biologics across a number of immune-mediated

conditions concluded for a lack of consistent superior efficacy with respect to biologic monotherapy while

us
still raising safety concerns, particularly with regard to serious, life-threatening infections [159]. An open

label prospective study is currently ongoing to investigate the effect of triple combination therapy including
an
vedolizumab, adalimumab, and oral methotrexate on endoscopic remission in patients with newly diagnosed

moderately to severely active CD stratified at higher risk for complications (Clinical Trials.gov
M

identifier: NCT02764762), which should provide more reliable data on the effectiveness and safety of the

combinatorial approach, at least in the short-term. Indeed, long-term safety issues, including cancer
ed

susceptibility, will not be resolved in the next future; thus, a prudent approach may still be the wisest choice,

by selecting a single biotherapy following thorough assessment of patient characteristics in order to

pt

maximize treatment outcomes.

ce

Ideally, to implement a personalized medicine in CD, biomarkers able to predict treatment response to the

biologic drugs currently available would be desirable. Work is still in progress and is at the current time far
Ac

from becoming reality, since sophisticated instrumentations, available only in research centers, are needed

for identification, characterization, and interpretation of candidate biomarkers, which need then to be

validated in clinical studies. Fields of intense investigations include proteomics, molecular imaging, and

genetic analysis, which will hopefully provide clinicians with reliable biomarkers of response prediction to a

given biologic drug or small molecule, in terms of control of both CD activity and associated EIMs [160-

162]. Meanwhile, the choice of biologic agents in CD patients in order to achieve the best outcome still lies

on a thorough assessment of patient-related characteristics as well as deep knowledge of the properties and
 22

place in therapy of each biologic drug. By critically tempering all the currently available evidence on patient

characteristics and biologic agent properties, the clinician may nonetheless opt for the best therapeutic option

for the individual CD patient (Figure 1).

Funding

This paper was not funded

Declaration of Interest

t
ip
The authors have no relevant affiliations or financial involvement with any organization or entity with a

cr
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants

us
or patents received or pending, or royalties. an
Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose
M
ed
pt
ce

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Ac

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FIGURE LEGENDS
 39

Figure 1. Summary of suggested therapeutic choices in Crohn’s disease patients eligible to biologic therapy,

according to concomitant extra-intestinal manifestations (A), comorbidities (B), or physiologic

characteristics (C). DM, diabetes mellitus; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic

steatohepatitis; PSC, primary sclerosing cholangitis. See text for details.

Figure 2. Examples of suggested therapeutic choices when multiple EIMs or comorbidities coexist. NAFLD,

non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. See text for details.

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 40

Table 1. Main characteristics of the biologic agents used for Crohn’s disease treatment

Name Structure Molecular Route of Frequency of Schedule used in Crohn’s Schedul

target administration administration disease
Adalimumab fully human TNF-α s.c. biweekly 160 mg at week 0, 80 mg at 40 mg every
monoclonal week 2 (induction phase)
IgG1 and then 40 mg every 2
antibody weeks
Certolizumab PEGylated TNF-α s.c. biweekly 400 mg at weeks 0, 2 and 4 400 mg
pegol Fab of a (induction phase) and then (induction p
humanized 400 mg every 4 weeks e
monoclonal
antibody

t
Infliximab chimeric TNF-α i.v. every 8 weeks during 5 mg/kg at weeks 0, 2 and 6 3-5 mg/k

ip
human- maintenance (induction phase) and then (induction p
mouse IgG1 treatment (for every 8 weeks

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monoclonal induction, three
antibody infusions at T0, T2,
and T6 weeks)
Natalizumab humanized α4 i.v. every 4 weeks 300 mg every 4 weeks

us
IgG4 integrin
monoclonal
antibody
Ustekinumab fully human IL-12 and i.v. and s.c. every 8-12 weeks 260-520 mg i.v. based on
an 45 or 90 m
monoclonal IL-23 during maintenance body weight respectiv
IgG1 treatment (for (approximatively 6 mg/kg) (induction p
antibody induction, one at week 0, followed by 90
weight-based mg s.c. at week 8 (induction
M
infusional dose at T0) phase) and then 90 mg s.c.
every 8-12 weeks
Vedolizumab humanized α4β7 i.v. every 8 weeks during 300 mg at weeks 0, 2 and 6
IgG1 integrin maintenance (induction phase) and then
ed

monoclonal treatment (for 300 mg every 8 weeks

antibody induction, three
infusions at T0, T2,
and T6 weeks)
pt

Fab, antigen-binding fragment; IL, interleukin; i.v., intravenous; s.c., subcutaneous; TNF, tumor necrosis
factor
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 41

Table 2. Examples of extra-intestinal manifestations and comorbidities possibly coexisting with Crohn’s
disease at the time of consideration of biologic therapy. Included are also physiologic conditions that should
be taken into account before starting any type of biotherapy.

EXTRA-INTESTINAL MANIFESTATIONS COMORBIDITIES PHYSIOLOGIC CONDITIONS

JOINTS METABOLIC CHILD-BEARING AGE and
• peripheral oligoarthritis • obesity PREGNANCY
• peripheral polyarthritis • NAFLD/NASH
• axial spondilarthritis • diabetes mellitus
• mixed peripheral and axial

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spondylarthritis

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cr
SKIN CARDIOVASCULAR OLD AGE
• erythema nodosum • atherosclerosis
• pyoderma gangrenosum • heart failure

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EYE DERMATOLOGIC
• scleritis • psoriasis
• uveitis
LIVER IMMUNOLOGIC
an
• primary sclerosing cholangitis • history of infections
KIDNEY
• glomerulonephritis
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(amyloidosis)
NERVOUS SYSTEM
• peripheral neuropathies
• multiple sclerosis
ed

NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis

pt
ce
Ac
 Fig 1
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42
2
 fig 2
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ed
M
an
us
cr
ip
t
43
3