1 s2.0 S0140673623009662 Main

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Ulcerative colitis
Catherine Le Berre, Sailish Honap, Laurent Peyrin-Biroulet
Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. In 2023, the Lancet 2023; 402: 571–84
prevalence of ulcerative colitis was estimated to be 5 million cases around the world, and the incidence is increasing Institut des Maladies de
worldwide. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental l’Appareil Digestif, Hépato-
Gastro-Entérologie et
exposures; gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated.
Assistance Nutritionnelle,
Patients usually present with bloody diarrhoea, and the diagnosis is based on a combination of clinical, biological, Inserm CIC 1413, Inserm UMR
endoscopic, and histological findings. The aim of medical management is, first, to induce a rapid clinical response 1235, Nantes Université, CHU
and normalise biomarkers and, second, to maintain clinical remission and reach endoscopic normalisation to prevent Nantes, Nantes, France
(C Le Berre MD); Department of
long-term disability. Treatments for inducing remission include 5-aminosalicylic acid drugs and corticosteroids.
Gastroenterology, St George’s
Maintenance treatments include 5-aminosalicylic acid drugs, thiopurines, biologics (eg, anti-cytokines and anti- University Hospitals NHS
integrins), and small molecules (Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators). Foundation Trust, London, UK
Although the therapeutic options are expanding, 10–20% of patients still require proctocolectomy for medically (S Honap MBChB); School of
Immunology and Microbial
refractory disease. The keys to breaking through this therapeutic ceiling might be the combination of therapeutics
Sciences, King’s College
with precision and personalised medicine. London, London UK (S Honap);
Department of
Introduction countries also continues to increase.4–6 Figure 1 shows Gastroenterology, INFINY
Institute, FHU-CURE, INSERM
Ulcerative colitis is an inflammatory bowel disease and the incidence and prevalence of ulcerative colitis NGERE, Nancy University
can highly affect a patient’s life, leading to long-term worldwide. Hospital, Vandœuvre-lès-
burdensome complications. Patients with ulcerative Ulcerative colitis has similar prevalence in men and Nancy, France
colitis might have proximal disease extension (until women, although some studies suggest it is slightly (Prof L Peyrin-Biroulet MD PhD);
Division of Gastroenterology
developing pancolitis) or develop structural and more common in men.4,7 The peak age of onset is and Hepatology, McGill
functional changes, leading to impaired quality of life between the second and fourth decades of life, although University Health Centre,
and disability. The therapeutic options have expanded incident cases in people over 60 years of age are Montreal, QC, Canada
substantially over the past decade with biologics (eg, anti- increasing and account for up to 20% of new diagnoses.7,8 (Prof L Peyrin-Biroulet)
tumour necrosis factor (TNF), vedolizumab, and This finding highlights the challenge facing health-care Correspondence to:
Prof Laurent Peyrin-Biroulet,
ustekinumab) and small molecules (eg, Janus kinase professionals when considering treatment options in an Department of Gastroenterology
inhibitors and sphingosine-1-receptor modulators). The ageing population with comorbidities. INFINY Institute, FHU-CURE,
rapid advent of new therapies has allowed more stringent INSERM NGERE, Nancy
therapeutic goals to be considered, including clinical and Risk factors University Hospital, F-54500
Vandœuvre-lès-Nancy, France
endoscopic remission. Ongoing studies will find out There are several genetic and environmental risk factors peyrinbiroulet@gmail.com
whether histological healing could be the ultimate for developing ulcerative colitis (appendix p 2). Genome-
See Online for appendix
therapeutic goal. Once a treatment has been introduced, wide association studies have identified more than
strictly monitoring patients, and performing rapid 250 inflammatory bowel disease risk alleles that are
treatment escalation if the therapeutic goals have not implicated in pathways related to intestinal barrier
been reached, is recommended. Despite these advances, function and T-cell immunity.9–13 However, these risk
remission rates do not surpass 20–30% in induction alleles only explain 8·2% of disease variance and the
clinical trials and 30–60% of patients in a real-life setting. precise effect of these risk variants in ulcerative colitis is
Consequently, some patients still require surgery unknown.10 The inability to predict disease onset or
for medically refractory disease. Although total clinical subphenotype hinders routine clinical
proctocolectomy would potentially cure the inflammation
of the colon, post-operative complications are frequent,
especially pouchitis and faecal incontinence. Here, we Search strategy and selection criteria
review practical and up-to-date evidence on ulcerative We searched for relevant manuscripts in PubMed, MEDLINE,
colitis, which has had increased costs of care in the past Embase, and Cochrane Central from database inception until
decade.1 March 1, 2023. The search combined the MeSH terms
“ulcerative colitis” and “inflammatory bowel disease” with
Epidemiology “epidemiology”, “pathophysiology”, “diagnosis”, “genetics”,
Ulcerative colitis has become a global health challenge “diagnosis”, “endoscopy”, “therapy”, “surveillance”,
over the past two decades, with evolving epidemiological “monitoring”, and “complications”. Bibliographies of included
trends. Although most population-based observational articles were searched to identify additional studies. Relevant
studies show that incidence rates are either stable or articles and abstracts were critically reviewed. Priority was
declining in high-income countries, they are increasing given to manuscripts published in the past 5 years,
sharply in low-income and middle-income countries.2,3 randomised placebo-controlled trials, and meta-analyses.
However, the incidence in several high-income
www.thelancet.com Vol 402 August 12, 2023 571

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Ulcerative colitis incidence per

100 000 person-years, 1990–2016
Unknown
0·00–1·85
1·86–3·09
3·10–4·97
4·98–7·71
>7·71
Western Europe Southern Asia
Figure 1: Worldwide
incidence (A) and
B
prevalence (B) of ulcerative
colitis 1990–2016
The highest incidence rates for
ulcerative colitis (per
100 000 person-years) have
been found in
Northern Europe
(Faroe Islands=57·9),
North America (Canada=23·1),
and Australasia
Ulcerative colitis prevalence
(Australia=17·4). The highest per 100 000 people, 1990–2016
prevalence rates (per
100 000 people) were Unknown
2·42–21·00
observed in Northern Europe
21·10–44·30
(Norway=505) and 44·40–100·90
North America (USA=286). In 101·00–198·00
Asia, the prevalence is >198·00
projected to increase up to
four-fold by 2035, which in
part is explained by a societal Western Europe Southern Asia
shift to be more similar to
high-income countries. The
increasing compounding
prevalence, burdening health-
care systems globally, is driven
by a discordance between the
rates of incidence and
mortality; ulcerative colitis is a
lifelong and incurable
condition with a
comparatively low death rate.
Reproduced from Ng and
colleagues,2 by permission of
Elsevier.
572 www.thelancet.com Vol 402 August 12, 2023

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applicability.9,10 Studies investigating low-frequency The atypical effector T-helper (Th) cell response and
alleles and rarer variations in patients with well T-regulatory cell imbalance results in the dysregulated
phenotyped inflammatory bowel disease are ongoing.11,12 production of several key cytokines and has shaped the
Multiple environmental and dietary factors affect the therapeutic focus for ulcerative colitis towards anti-
risk of developing ulcerative colitis and although the cytokine drugs. These cytokines include TNF, interferon
precise mechanisms are unclear, many are implicated in gamma (Th1), IL-5, IL-6, IL-13 (Th2), IL-17, IL-21, and
the rising global incidence.14 The strength of these IL-22 (Th17), and have been implicated in various ways in
epidemiological associations is variable, and the the pathophysiology of ulcerative colitis.28 Although the
mechanistic reasons are poorly understood. If causal function of IL-22 in intestinal barrier homoeostasis is
relationships do exist, then lifestyle and dietary controversial (as it has been shown to promote both
modifications could feature in future disease prevention barrier repair and return to homoeostasis, as well as
strategies.15 Further high-quality prospective interven promote inflammation), enrichment of IL-22 regulated
tional studies are needed, particularly including younger transcripts in colonic biopsies of patients with ulcerative
patients and those with new onset ulcerative colitis, to colitis was shown to correlate with resistance to therapy
assess the efficacy of lifestyle modification (eg, physical targeting anti-p40 (common to both IL-12 and IL-23).29
activity) in the primary prevention of inflammatory bowel IL-23, which regulates IL-22, is the selective target of a
disease. range of drugs in clinical development, in which the
implication of its pathogenesis in ulcerative colitis and
Pathophysiology other immune-mediated diseases is clear.30
The pathogenesis of ulcerative colitis is complex and is The humoral immune response is less known. A
incompletely understood. The prevailing view is that 2022 study examined the molecular and phenotypic
ulcerative colitis occurs after environmental exposures in characteristics of intestinal and circulating B cells, which
people with a genetic predisposition. Epithelial barrier showed substantial perturbations, including reduced
defects, dysregulated immune responses, and dysbiosis diversity and maturation.31
are integral in this interplay of initiating and perpetuating
inflammation. Dysbiosis
The gastrointestinal microbial flora is also implicated in
Defective gut epithelial barrier ulcerative colitis.32 Surgical specimens examining the
The initial stages of pathogenesis are underpinned by a microbiome associated with the gut wall show depleted
disruption of the gut barrier and a loss of mucosal commensal bacteria from the Bacteroidetes and
homoeostasis.16 Colonic mucus, the principal component Firmicutes phyla in ulcerative colitis.33 Similarly, a lower
of which is mucin-2, is secreted by goblet cells to provide abundance of the butyrate producing species
a protective layer; however, these goblet cells are depleted Roseburia hominis and Faecalibacterium prausnitzii from
in colitis.17,18 Further compromise to barrier function the Firmicutes phylum were seen in other studies.34,35
integrity occurs from cellular apoptosis and the Butyrate is an important energy source for colonocytes
upregulation of claudins, which are pore forming with antimicrobial and anti-inflammatory activity.36
components of apical tight junctions that control Restoration of a healthy microbiome with faecal
paracellular permeability.19,20 Breaching these innate microbiota transplantation is beneficial and has shown
defence mechanisms increases permeability to pathogen moderate success in the treatment of ulcerative colitis;
invasion. However, whether these findings are causative however, remission rates are in line with existing
or associative is unclear.21,22 therapeutic strategies.37 A detailed mechanistic
understanding is necessary for informed applications of
Dysregulated immune responses this therapeutic approach.
An aberrant innate and adaptive immune response
against microbial antigens in people with ulcerative Clinical presentation and differential diagnosis
colitis is well recognised. Neutrophilic accumulation and Ulcerative colitis is a lifelong inflammatory bowel
deployment of chromatin-based extracellular traps at the disease, usually characterised by a relapsing and
site of colonic mucosal injury is increased in ulcerative remitting course (appendix pp 3–4). Ulcerative colitis
colitis and perpetuates inflammation by enhancing TNF commonly presents with rectal bleeding in more than
and interleukin-1β (IL-1β) production.23,24 Dendritic cells 90% of patients.38 Associated symptoms generally reflect
are antigen presenting cells that, alongside macrophages, the severity of mucosal disease and can differ according
mediate immune tolerance to external stimuli and direct to disease extent. Increased stool frequency and
T-cell differentiation to shape the adaptive response. In decreased stool consistency are frequent, notably when
the inflamed colon, there is a shift to a proinflammatory the disease extends beyond the rectum. However, this
cytokine producing and less tolerogenic dendritic cell criterion is not necessary for diagnosis, particularly in
subset that has a reduced capacity to generate regulatory patients with proctitis who can present with constipation
T cells.25–27 in 5–10% of cases.39 Patients might also report rectal

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urgency, tenesmus, faecal incontinence, mucus associated with a higher use of steroids,
discharge, nocturnal defecations, and cramp-like immunosuppressants, and biologics, and a higher
abdominal pain, often localised to the left lower quadrant, likelihood of colectomy.53 The presence of perinuclear
particularly before, and relieved by, a bowel movement. anti-neutrophil cytoplasmic antibodies is the most
Extra-intestinal manifestations can occur in 20–35% of specific serum biomarker but has a low sensitivity, thus
patients and can precede intestinal symptoms in up to its use for diagnosis or therapeutic management is not
25% of patients. Among these extra-intestinal recommended.54,55 Conversely, faecal calprotectin, a stool
manifestations, peripheral arthritis is most common; biomarker that correlates with the number of neutrophils
primary sclerosing cholangitis and pyoderma infiltrating the intestinal mucosa, is much more sensitive
gangrenosum are more common in ulcerative colitis than than serum biomarkers but has low specificity, which
in Crohn’s disease.40 The risk of venous thromboembolism limits its application for diagnosis because it cannot
is increased by two to four times,41 and is greater when the distinguish inflammatory bowel disease from the
patient is admitted with a severe flare-up or is being aforementioned differential diagnoses.52
treated with corticosteroids.42 Although simple perianal Endoscopy with biopsies is the most sensitive and
disease can occasionally occur in ulcerative colitis,43,44 specific tool to establish a diagnosis of ulcerative colitis.
recurrent or complex perianal fistulae should always raise Colonoscopy with intubation of the terminal ileum
the suspicion of Crohn’s disease. is recommended for all patients with suspected
Approximately 15% of patients initially present with acute inflammatory bowel disease. Ulcerative colitis
severe ulcerative colitis, defined as at least six episodes of characteristically affects the rectum and the colon to a
bloody diarrhoea per day (including night time), and any variable extent in a continuous and circumferential
signs of systemic toxic effects (ie, pulse >90 beats per min, manner, with clear demarcation of inflammation, thus
temperature >37·8°C, haemoglobin <105 g/L, erythrocyte classified by the extent of colonic involvement
sedimentation rate >30 mm/h, or C-reactive protein [CRP] (ie, proctitis, left-sided colitis, and extensive colitis).56
>30 mg/L).45,46 Apart from these cases, the onset of ulcerative However, a rectal sparing variant, which is more common
colitis is usually insidious. Symptoms are often present for in patients with primary sclerosing cholangitis,57 and a
weeks before medical advice is sought, and digestive peri-appendiceal patchy inflammation variant have been
symptoms for more than 4–6 weeks allow differentiation of reported.58 Up to 20% of patients, mainly those with
ulcerative colitis from most cases of infectious diarrhoea.47 extensive colitis, can have continuous extension of
Bacterial colitis needs to be investigated and includes macroscopic or histological inflammation from the
infection from Campylobacter spp, Salmonella spp, caecum into the terminal ileum called backwash ileitis,59
Shigella spp, Yersinia spp, and, more rarely, enterotoxigenic which might cast doubt on a Crohn’s disease diagnosis.
Escherichia coli. Stool cultures and Clostridioides difficile In patients with a definite diagnosis of ulcerative colitis,
toxin testing should be used to systematically rule out ileocecal valve gaping and terminal ileum dilatation
infection at diagnosis and also at every disease flare-up to on magnetic resonance enterography suggest the
rule out concomitant infectious exacerbation, which development of backwash ileitis, whereas increased
substantially increases the risk of colectomy, postoperative bowel wall thickness is more suggestive of Crohn’s
complications, and death.48 Similarly, cytomegalovirus disease.60 Oesophagogastroduodenoscopy should be
infection or reactivation should be investigated in patients done in patients with symptoms of upper tract
with ulcerative colitis presenting with worsening of their involvement to rule out Crohn’s disease.
gastrointestinal symptoms due to the association with poor Classic endoscopic features of mild ulcerative colitis
outcomes.49,50 A history of anal receptive sexual practices are erythema, vascular congestion, and partial loss of the
should also be elicited at diagnosis, particularly in visible vascular pattern. Moderately active colitis is
proctitis; if there is any doubt, Neisseria gonorrhoeae, characterised by a complete loss of vascular pattern,
Chlamydia trachomatis, herpes simplex, and syphilis should blood adherent to the surface of the mucosa, erosions,
be investigated for. Mpox (formerly known as monkeypox) and mucosal friability. Severe colitis is defined by
might also be a cause of infectious proctitis and should be spontaneous bleeding and ulceration. Ulcers in ulcerative
investigated when appropriate. Multiple non-infectious colitis are always embedded in inflamed mucosa,
diseases can also lead to similar symptoms (appendix p 5).51 contrary to Crohn’s disease, in which the surrounding
mucosa can appear uninflamed.
Diagnostic investigations A minimum of two biopsies should be obtained from
Diagnosis of ulcerative colitis is based on a combination at least six different areas (eg, terminal ileum, ascending,
of clinical, inflammatory, endoscopic, and histological transverse, descending, sigmoid colon, and rectum),
parameters, but there is no gold standard. Biochemically, including macroscopically normal areas. Samples should
anaemia and iron deficiency are frequent. CRP can be be fixed immediately by immersion in buffered formalin
elevated but has a low sensitivity, especially in mild-to- before transport. The histological diagnosis is based on a
moderate disease.52 Hypoalbuminaemia can serve as a combination of widespread crypt architectural distortion,
prognostic marker at the time of diagnosis and has been mucosal atrophy, and a diffuse transmucosal

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inflammatory infiltrate with increased lymphocytes and used histopathological scoring systems and are similar for
plasma cells in the lamina propria (basal plasmacytosis), stratifying patients into histological remission and
with active inflammation causing cryptitis and crypt activity.71 Due to the higher applicability of the Nancy and
abscesses.61 All the histological features are not present at the Robarts indices, their systematic use is encouraged to
an early stage, especially crypt distortion, which is assess histological remission and response,72 even though
observed in only 20% of patients within 2 weeks of the a simplified Geboes score has been developed.73 In future,
first symptoms. Basal plasmacytosis is the earliest artificial intelligence should help to characterise
diagnostic feature with the highest predictive value for endoscopic and histological inflammation.
the diagnosis of ulcerative colitis, allowing distinction
from infectious colitis, in which crypt architecture is Medical management
preserved.62 The selection of therapies is guided by disease severity
and extent. Several guidelines are available to guide
Disease activity assessment decision making in patients with ulcerative colitis.74–77
The more commonly used clinical activity indices include
the Mayo score,63 the Lichtiger score, which is mostly Mild-to-moderate disease
used for acute severe ulcerative colitis,64 and the Simple The recommended first-line therapy for both induction
Clinical Colitis Activity Index.65 The more frequently used and maintenance of remission in mild-to-moderate
endoscopic activity scores can be used both in clinical ulcerative colitis (figure 2) is based on mesalazine
research and practice, and include the endoscopy compounds that can be administered as suppositories,
subscore of the Mayo score,63 ranging from 0–3 and enemas, foams, or oral formulations (tablets or granules).
widely used for clinical trial recruitment due to its ease of The systemic exposure to mesalazine is similar for all
use, and the Ulcerative Colitis Endoscopic Index of oral formulations and pro-drugs,85 and there is no
Severity (UCEIS),66 which assesses the vascular pattern difference in efficacy or safety among the different
and the presence of bleeding and ulceration, each with formulations.86,87
3 or 4 levels of severity. The UCEIS has been validated Patients with mildly or moderately active proctitis
with an independent cohort of investigators.67 The final should receive rectal mesalazine therapy as it is superior
UCEIS score is the sum of all three descriptors in the to oral formulations for drug delivery in the distal
worst affected area of the colon, ranging from 0–8.67 colon,88,89 preferably with suppositories that better target
Histological activity is also important to define, as the rectum, but foam or enemas can also be used.90
histological remission is being increasingly acknowledged Patients who place a high value on convenience of oral
as a therapeutic endpoint in patients with ulcerative medication administration could reasonably be given
colitis. The Geboes score,68 the Nancy index,69 and the oral mesalazine.75 Combination therapy with topical and
Robarts histopathology index70 are the most commonly oral mesalazine can protect against proximal extension
Proctitis Mild-to-moderate active ulcerative colitis Left-sided or

extensive colitis
Mesalazine suppository* Mesalazine suppository Oral mesalazine ≥2 g per Oral

Induction
No response No response
1 g per day† with oral mesalazine† day†‡ with mesalazine corticosteroids||
or topical steroids enema or foam 1 g per day¶†
Remission§ Remission§
Maintenance
Mesalazine suppository* Oral mesalazine ≥2 g per day†**

≥3 g per week with oral Relapse with topical mesalazine
mesalazine if necessary 2–3 g per week if necessary
Mild-to-moderate but refractory active ulcerative colitis might require

step-up to moderate-to-severe ulcerative colitis algorithm
Figure 2: Suggested treatment approach algorithm for mild-to-moderate ulcerative colitis

The algorithm is based on European Crohn’s and Colitis Organisation and American Gastroenterological Association guidelines.74,75 *Suppositories are more
appropriate in proctitis as they better target the rectum and are better tolerated, but mesalazine foam or enemas can also be used. †Once-daily dosing is as effective
and safe as divided doses.78–81 ‡Despite a higher rate of intolerance, people with prominent arthritic symptoms can reasonably choose sulfasalazine 2–4 g per day, if
alternatives are cost-prohibitive,75 this should be balanced by the risk of sulfasalazine-related adverse events (eg, sensitivity in case of glucose-6-phosphate
dehydrogenase deficiency, pneumonitis, and hepatitis). §Remission is defined as resolution of symptoms and a Mayo endoscopic subscore of 0 at 3–6 months.
¶No statistical differences were found between foam and liquid enemas regarding induction of remission or endoscopic healing. ||Initially at a dose of 40–60 mg
prednisone daily, or the equivalent oral steroid, for 1–2 weeks, then tapered by 10 mg every week until reaching 20 mg, then by 5 mg every week until completed,
resulting in a maximal course of 2–3 months. Given their minimal systemic activity, multimatrix budesonide (9 mg/day) and prolonged-release beclomethasone
dipropionate (5 mg/day) can be considered.82–84 **Rectal mesalazine is an alternative in left-sided ulcerative colitis.

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of mucosal inflammation in patients with isolated topical steroids alone,101 combining both topical mesalazine
proctitis.91 However, topical mesalazine monotherapy for (2 g/day) and beclomethasone dipropionate (3 mg/day) in
maintaining remission is as effective as topical and oral patients with proctitis or left-sided ulcerative colitis who do
combination therapy.92 not reach remission with mesalazine therapy alone can
Patients with mildly or moderately active left-sided or result in better clinical, endoscopic, and histological
extensive ulcerative colitis should receive oral mesalazine improvements than either agent alone.102 Oral
combined with a mesalazine enema because this is more corticosteroids are required to induce remission in patients
effective than oral mesalazine alone93 or topical mesalazine with mild-to-moderate ulcerative colitis who do not
alone.94 The optimal duration of combination therapy is respond to mesalazine therapy.74 If remission is reached
unclear, but should be ideally sustained for 4 weeks.95 For with corticosteroids, mesalazine can be considered for
maintenance therapy, patients who reach remission with maintenance in patients with mild disease that has been
combined oral and topical mesalazine should continue oral newly diagnosed or who are naive to mesalazine. However,
mesalazine.74,77 Rectal mesalazine alone is an alternative in patients with poor prognostic factors (eg, young age of
left-sided ulcerative colitis.96 A combination of mesalazine disease onset, extensive colitis, and deep ulcerations), who
given daily by oral route and intermittently by topical route require two or more courses of steroids in a year, or cannot
can be used for patients at a high risk of relapse or who taper off steroids should be treated as patients with
relapsed on oral mesalazine alone.97,98 Another option is the moderate-to-severe disease.103
use of formulations that provide high concentrations of
mesalazine in the distal colon, such as newer mesalazine Moderate-to-severe disease
granule formulations99 and multimatrix mesalazine100 that Patients with moderate-to-severe ulcerative colitis
could be superior to conventional ileal release mesalazine (figure 3) can be defined as those with more than
in patients with distal ulcerative colitis. four to six bowel movements per day, moderate-to-severe
Patients who do not respond to mesalazine therapy rectal bleeding, constitutional symptoms, and high
should be given corticosteroids, regardless of disease inflammatory burden, based upon the Mayo Clinic score
extent. Although topical mesalazine is more effective than and Truelove and Witt’s criteria.63,104 Oral systemic
Moderate-to-severe active ulcerative colitis
Corticosteroid resistance
Oral corticosteroids* Intravenous steroids
Induction
Remission†
Corticosteroid dependence
Corticosteroid
resistance
Thiopurines, anti-TNF (eg, infliximab, adalimumab, or golimumab)‡, Anti-TNF (eg, infliximab, adalimumab, or golimumab)‡, vedolizumab,
vedolizumab, ustekinumab,mirikizumab, janus kinase inhibitor (eg, tofacitinib, ustekinumab, mirikizumab, janus kinase inhibitor (tofacitinib,
filgotinib, or upadacitinib), or ozanimod filgotinib, or upadacitinib), or ozanimod
Consider patient preference (eg, subcutaneous or intravenous), national reimbursement, and insurance policies
Adequate primary response Primary non-response Secondary loss of response
If non-anti-TNF therapy If anti-TNF therapy used as first line

used as first line then therapeutic drug monitoring
Maintenance
Low or no antidrug Elevated antidrug Low or no antidrug

antibodies antibodies antibodies
Adequate anti-TNF level Low anti-TNF level Low anti-TNF level
Optimise anti-TNF by
Maintenance Change to another Switch to another anti-TNF increasing dose or reducing
with the same treatment drug class or add thiopurine dosing interval
Figure 3: Suggested treatment approach algorithm for moderate-to-severe ulcerative colitis

The algorithm is based on American Gastroenterological Association and European Crohn’s and Colitis Organisation guidelines.74,76 TNF=tumour necrosis factor.
*Initially at a dose of 40–60 mg prednisone daily, or the equivalent oral steroid, for 1–2 weeks, then tapered by 10 mg every week until reaching 20 mg, then by 5 mg
every week until completed, resulting in a maximal course of 2–3 months. †Remission is defined as resolution of symptoms and a Mayo endoscopic subscore of 0 at
3–6 months. ‡Preferably combined with thiopurines, at least for infliximab.

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corticosteroids are the first-line induction treatment in administered once daily. Filgotinib was approved in 2021;123
these patients, on the basis of two hallmark studies from although some concerns were initially raised concerning
the 1960s that showed their superiority over sulfasalazine decreased fertility in males on the basis of animal studies,
in moderate-to-severe extensive colitis.105,106 clinical data from the MANTA study were not suggestive of
Maintenance therapy in patients with moderate-to- filgotinib-related effects on testicular function in men with
severe disease relies on the use of immunosuppressants inflammatory bowel disease.124 Upadacitinib was approved
(thiopurines), biologics (eg, anti-TNF, anti-integrins, in 2022.125 Due to safety signals regarding the potential risk
anti-IL-12, and anti-IL-23), and small molecules (eg, Janus of major adverse cardiovascular events and cancers using
kinase inhibitors and sphingosine-1-receptor modulators). Janus kinase inhibitors,126 the European Medicines
Thiopurines (azathioprine or mercaptopurine) can be Agency’s pharmacovigilance risk assessment committee
used in patients with steroid-dependent moderate-to- (PRAC) recommends that Janus kinase inhibitors should
severe disease to maintain remission.74,76 Methotrexate is be used only if no suitable treatment alternatives are
not recommended for maintenance of remission in available in patients aged 65 years or older, those who are at
ulcerative colitis on the basis of several studies showing its increased risk of major cardiovascular problems, those who
lack of efficacy over placebo.107–109 smoke or have done so for a long time in the past, and
Regarding anti-TNF agents, infliximab (two initial those with an increased risk of cancer. PRAC also
intravenous infusions followed by intravenous or recommends using Janus kinase inhibitors with caution in
subcutaneous maintenance), adalimumab, and golimumab patients with risk factors for venous thromboembolism
(subcutaneous) have been shown to induce and maintain (other than those listed above) by reducing the dose.127
remission in moderate-to-severe ulcerative colitis.110–115 Finally, ozanimod, the first oral sphingosine-1-
Among anti-integrins, which work by blocking leukocyte phosphate-receptor modulator that prevents lymphocyte
integrins thus inhibiting their adhesion and subsequent mobilisation to inflammatory sites, was approved
migration from circulation into the gut, vedolizumab in 2021.128 Ozanimod is administered once a day with a
blocks the gut-homing α4β7 integrin, was approved 7-day period of dose escalation to minimise the risk of
in 2013,116 and can now be considered before adalimumab bradycardia that has been reported within the first few
for patients with ulcerative colitis on the basis of the face-to- hours after administration.
face VARSITY trial, which showed superiority to The use of a combination of targeted therapies, either
adalimumab.117 A subcutaneous formulation is now dual biological therapy or a small molecule combined
available for maintenance treatment.118 Ustekinumab is an with a biological therapy, can also be effective in patients
anti-cytokine that blocks the p40 sub-unit of IL-12 and IL-23 with refractory inflammatory bowel disease who might
and was approved for patients with moderate-to-severe have other overlapping immune-mediated inflammatory
active ulcerative colitis in 2019, with an initial intravenous diseases, without any major adverse events. However, the
infusion followed by subcutaneous maintenance.119 In evidence is uncertain due to the observational nature of
2023, mirikizumab, a p19-directed antibody against IL-23, the studies.129,130 This concept of combining therapies is
was approved in Europe for the treatment of patients with also emerging in a top-down approach as the VEGA
ulcerative colitis, with three induction intravenous proof-of-concept study showed that combination
infusions followed by subcutaneous maintenance.120 induction treatment with guselkumab and golimumab
Combination therapy of infliximab with thiopurine is induced clinical response, clinical remission, and
recommended on the basis of the UC-SUCCESS trial,121 endoscopic improvement at week 12 more effectively
but data comparing combination therapy of other TNF than either monotherapy alone.131
antagonists, vedolizumab, or ustekinumab with
immunosuppressants versus biological monotherapy are Acute severe ulcerative colitis
lacking. On the basis of the pharmacokinetic improve Patients with acute severe ulcerative colitis should be
ment of biological therapy when adding an immuno hospitalised for intensive treatment due to a high
suppressant, US guidelines recommend combination morbidity and mortality of approximately 1%, and higher
therapy with all biologics, particularly in patients with in those with comorbidities or older than 60 years.132
unfavourable pharmacokinetics (eg, more severe disease, Patients should be initially treated with an intravenous
increased inflammatory burden, low albumin, and high methylprednisolone dose equivalent of 40–60 mg per day,
BMI), but monotherapy is possible.76 or hydrocortisone 100 mg three to four times daily. All
Oral tofacitinib was the first oral small molecule to be patients should receive an adequate volume of intravenous
approved in 2018; it is administered twice a day and is fluids, and low molecular weight heparin for
effective regardless of any previous treatment with anti- thromboprophylaxis; electrolyte abnormalities and
TNF therapy.122 Tofacitinib inhibits all Janus kinases that anaemia should be corrected. The response to intravenous
activate signal transducers and activators of transcription, corticosteroids should be assessed by the third day. In
inducing signalling for multiple immune-relevant non-responders, ciclosporin or infliximab can be
cytokines. Two other Janus kinase inhibitors have been attempted and are equally effective.133,134 Colectomy is
approved, both of which preferentially inhibit JAK1 and are recommended if there is no improvement after 4–7 days.

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Surgery ileostomy, and finally stoma closure. A modified two

Despite scientific progress enabling a range of advanced stage procedure, which has a similar initial step but is
therapies to be used in clinical practice, failure rates of followed by pouch construction and ileostomy takedown
drugs are high and more than one patient in ten in one visit, is increasingly favoured given fewer
ultimately requires surgery.46,135 Indications for complication rates and shorter length of stay in
emergency surgery include toxic megacolon, colonic hospital.138–140 IPAA should be done in high-volume
perforation, and uncontrolled bleeding. Electively, centres as low institutional case load has been shown to
patients undergo surgery for medically refractory be an independent predictor of pouch failure.141
disease, medication intolerance, endoscopically Proctocolectomy with end ileostomy or proctocolectomy
irresectable dysplasia, or colorectal cancer.136 Colectomy with IPAA are both reasonable surgical options with
rates after emergency admission are unchanged; up to similar health-related quality-of-life outcomes, which
25% of all patients are hospitalised for acute severe should be discussed to allow patients to make an
colitis, with 20% requiring a colectomy in the first informed decision.142
admission, increasing to 40% at second admission. Complications after colectomy occur in approximately
Annual colectomy rates have fallen, which is probably a third of patients.143 Infection and ileus are the most
due to the wider availability of therapy options and common short-term complications, and pouchitis and
improved treatment strategies.135 faecal incontinence the most frequent in the long term.143
Restorative proctocolectomy and ileal pouch anal Pouch complications are common and despite numerous
anastomosis (IPAA) is the surgical intervention of choice surgical modifications to improve outcomes over the
to avoid a permanent stoma.137 A staged surgical approach past 40 years, approximately 10% of patients with a
is often used to minimise the risk of anastomotic leaks, pouch require excision or permanent diversion at
pelvic sepsis, and subsequent pouch dysfunction.138 The 10 years.144 Pouchitis, a partially understood inflammatory
conventional three stage approach, used in severe disease condition of the ileal pouch reservoir, causes increased
and malnutrition to allow recovery, involves a subtotal stool frequency, urgency, and incontinence, rectal
colectomy and end ileostomy, followed by a completion bleeding, and pelvic pain. Acute pouchitis occurs in 4%
proctectomy and IPAA formation with a temporary loop of people with chronic pouchitis, affecting 20–30% of all
patients.145,146 Patients with primary sclerosing cholangitis
Timepoint* or those receiving anti-TNF therapy before colectomy
Clinical (necessary but insufficient treatment targets)
are at increased risk.145 The mainstay of treatment is with
Clinical response
systemic antibiotics, topical or oral corticosteroids and,
Decreased PRO2 (ie, rectal bleeding and stool frequency) by ≥50% Immediate
in some cases, biological therapy.136 Patients with pouch
Decreased total Mayo score by ≥3 and ≥30% plus 1-point decrease in rectal Immediate
dysfunction should be investigated to exclude other
bleeding or rectal bleeding score 0–1 pouch complications, such as enteric infection, peri-
Clinical remission pouch sepsis, fistulae, de-novo Crohn’s disease, and
PRO2 (ie, rectal bleeding 0 and stool frequency 0) or partial Mayo score <3 Short term to intermediate mechanical problems relating to pouch construction.
with no subscore >1
Total Mayo score ≤2 with no subscore >1 Short term to intermediate Disease monitoring
Biomarkers (necessary but insufficient treatment targets) Historically, symptomatic relief was the primary
Biomarker remission therapeutic target in patients with ulcerative colitis, but
C-reactive protein < upper limit of normal Short term to intermediate treatment goals have evolved in the past decade because of
Faecal calprotectin <125 µg/g Intermediate discrepancies between patient-reported outcomes and
Endoscopic assessment (necessary treatment target) endoscopic appearance. In 2015, the STRIDE consensus
Endoscopic response put both clinical and endoscopic remission as the main
Decreased Mayo endoscopic score by ≥1 or decreased UCEIS by ≥2 Intermediate objectives of medical management in ulcerative colitis.147
Endoscopic healing Since then, the advent of new therapies has allowed
Mayo endoscopic score 0 or UCEIS ≤1 Long term physicians to consider more stringent therapeutic targets.
Histological and transmural assessment (not formal targets, possible adjuncts) 5 years later, the STRIDE-II consensus updated the
Histological healing, possible adjunct but no formal definition Long term original STRIDE statements for incorporating new
Quality of life and disability
treatment targets (table). First, STRIDE-II confirmed the
Normalisation of health-related quality of life Long term
STRIDE-I long-term targets of clinical remission and
Absence of disability Long term
endoscopic healing.148 Endoscopic assessment could be
done with rectosigmoidoscopy, given its high degree of
PRO=Patient-reported outcomes. UCEIS=Ulcerative Colitis Endoscopic Index of Severity. *Time to endpoint will vary
based on specific therapy and its mechanism of action.
correlation with colonoscopy in the assessment of
ulcerative colitis activity.149 Normalisation of biomarkers
Table: Endpoint and measuring tool recommendations for treating to target in ulcerative colitis by the (CRP and faecal calprotectin) was determined as a short-
International Organization for the Study of Inflammatory Bowel Diseases in the Selecting Therapeutic
term target.148 Faecal calprotectin accurately predicts
Targets in IBD II (STRIDE-II) consensus148
endoscopic and histological activity in clinically quiescent

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ulcerative colitis, even though the thresholds vary across required to support its clinical utility and to better define
studies according to the test used and the definition of thresholds.
endoscopic and histological remission.150–152 Quantitative The American College of Gastroenterology published a
tests should be preferred for measuring faecal calprotectin clinical guideline in 2017 on preventive care in
and, if possible, should always be done with the same inflammatory bowel disease.156 Patients receiving
method, and factors influencing faecal calprotectin immunosuppressants or biologics should have their
concentrations should be taken into account when vaccination status reviewed regularly and should have
interpreting the results.153 In STRIDE-II, experts proposed integrated screening programmes (panel 1). In the long
a cutoff of less than 125 µg/g to define endoscopic term, surveillance colonoscopy programmes have been
remission in ulcerative colitis. developed given the increased risk of colorectal cancer by
Intestinal ultrasonography is also a useful tool to 2·4-fold in patients with ulcerative colitis (panel 2).157
monitor therapeutic response as early as week 2,154 even When possible, surveillance colonoscopy should be done
though it has not been implemented yet in the STRIDE-II during remission, otherwise discriminating between
guidelines in the absence of a validated score and cutoff dysplasia and inflammation on biopsies is difficult.
to define ultrasonographic response. In flare-ups, Virtual electronic chromoendoscopy or high-definition
therapeutic drug monitoring can be used to explore the white light endoscopy can supersede dye-based
pharmacokinetics of thiopurines and biologics to guide chromoendoscopy.158 Because of the use of these
treatment adjustment.155 6-tioguanine nucleotide levels of techniques, targeted sampling biopsies of any suspicious
230–450 pmol/8 × 10⁸ red blood cells should be targeted, lesions are sufficient and random biopsies are no longer
at least when used as monotherapy. Suggested target recommended, except in patients at high risk of dysplasia
infliximab (≥5 µg/mL) and adalimumab (≥7·5 µg/mL)
trough concentrations are well established and used in Panel 2: Timeline of endoscopic surveillance according to
routine practice in patients with active ulcerative colitis risk factors after screening colonoscopy according to
on maintenance therapy,155 because antibodies against European Crohn’s and Colitis Organisation guidelines74
anti-TNF have been associated with lower drug levels and
loss of response or primary non-response to therapy. First screening colonoscopy 8 years after the onset of
Therapeutic drug monitoring with agents not directed symptoms for all patients (and reassessment of endoscopic
towards TNF has been less explored; further studies are and histological disease extent), except patients with primary
sclerosing cholangitis, for whom the screening should begin
Panel 1: Recommendations for vaccinations and screening at the time of diagnosis and continue annually
programmes in people with ulcerative colitis receiving • When the disease is only in the rectum without
immunosuppressants, biologics, or small molecules endoscopic or microscopic proximal inflammation,
patients should follow standard screening guidelines (no
Vaccinations increased risk of colorectal cancer compared with the
Contra-indicated general population)
• Live vaccines • When the disease affects the colon before the rectum, the
Recommended timeline of endoscopic surveillance depends on the
• Regular vaccination schedule following risk levels
• Human papillomavirus vaccine
Lower risk (surveillance every 5 years)
• Influenza vaccine
• Extensive colitis with minimal endoscopic or
• Pneumococcal vaccine
histological inflammation
• Herpes zoster vaccine with recombinant zoster vaccine
• Colitis affecting <50% of the colon
in immunocompromised adults aged 19 years and older,
if available Intermediate risk (surveillance every 2–3 years)
• COVID-19 vaccine, probably with additional vaccine • Extensive colitis with mild-to-moderate endoscopic or
boosters due to reduced serological response when using histological inflammation
these treatments • Colorectal cancer in a first-degree relative >50 years of age
• Hepatitis B vaccine if the patient is not immunised
Higher risk (surveillance every year)
Screening programmes • Extensive colitis with severe endoscopic or histological
• Dermatological visit every 1–2 years depending on skin inflammation
type (increased risk of non-melanoma skin cancer with • Colorectal cancer in a first-degree relative ≤50 years of age
thiopurines and of melanoma with biologics) • History of primary sclerosing cholangitis (including post-
• Annual cervical cancer screening liver transplantation)
• Screening for osteoporosis at the time of diagnosis and • Stricture in the past 5 years
periodically after diagnosis in case of conventional risk • Dysplasia in the past 5 years in a patient who declines
factors for abnormal bone mineral density surgery

Seminar
and neoplasia with a history of dysplasia or primary Most of the available comparative effectiveness data come
sclerosing cholangitis, in whom biopsies every 10 cm from network meta-analyses, but more head-to-head
starting from the caecum should be done. trials are being developed.
Finally, in 2022, the International Organization for the Another key for improving the therapeutic response
Study of Inflammatory Bowel Diseases published expert might be the combination of existing therapeutics as
guidance on lifestyle, behaviour, and environmental shown in the VEGA study.131 Combination therapies
modification for the management of inflammatory bowel should select therapeutic agents with different
disease, including avoiding cigarette smoking, screening mechanisms of action and molecular targets but with
for symptoms of depression or anxiety, encouraging careful consideration of safety data—eg, use of a biologic
regular physical activity, and maintaining a healthy BMI.159 with excellent safety data combined with a small molecule
with a rapid mode of action.
Future directions Finally, once treatment is introduced, the ultimate
Despite the increasing number of available therapeutic therapeutic target is still to be determined. In the
agents and the adoption of stricter endpoints, there are STRIDE-II consensus, histological healing is not
many unmet needs in the management of ulcerative considered a therapeutic goal alone, but is considered an
colitis.160 At diagnosis, the challenge relies on the ability to adjunct measure to gauge remission depth. The ongoing
identify patients at high risk of disease progression and VERDICT trial (NCT04259138) should provide results for
who will benefit most from early intensive therapy, while this issue by comparing treatment algorithms on the
sparing those who are at low risk of complications of their basis of corticosteroid-free symptomatic remission alone,
disease and might be overtreated with a top-down strategy. endoscopic and symptomatic remission, and histological,
Indeed, treatment algorithms are currently based on endoscopic, and symptomatic remission. Moreover,
cross-sectional snapshots of disease activity. Yet, a patient’s whether early treatment according to a treat-to-target
disease course and risk of complications are important framework affects the natural course of ulcerative colitis,
features that should guide therapeutic management. This leading to the need for prospective disease-modification
concept is named disease severity and incorporates trials that assess the long-term outcomes, including the
longitudinal and historical factors that capture the overall effect on a patient’s life, disease complications, risk of
burden of disease. neoplastic lesions, and mortality, is still unclear.
An index to define overall disease severity has been Contributors
proposed by the International Organization for the Study All authors contributed to writing, reviewing, and editing of the
of Inflammatory Bowel Diseases,161 but risk stratification manuscript. All authors had final responsibility for the decision to
submit for publication.
based on clinical features alone is insufficient. More
objective biomarkers are needed to develop precision Declaration of interests
CLB has served as a consultant for AbbVie, Janssen, and Gilead; has
medicine in people with inflammatory bowel disease. received payment for lectures from AbbVie, Amgen, Celltrion, Ferring,
Several companies have developed prognostic tools to Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, and Takeda;
predict disease outcomes in people with Crohn’s disease reports grant support from AbbVie and Takeda; and has received meeting
and ulcerative colitis, mostly combining clinical, support fees from AbbVie, Ferring, Fresenius Kabi, Galapagos, Janssen,
Lilly, Pfizer, Sandoz, and Takeda. SH has served as a speaker, consultant,
serologic, genetic, and inflammation markers. Hopefully, or advisory board member for Pfizer, Janssen, AbbVie, and Takeda, and
such tools will soon be widely available to stratify patients has received meeting support fees from Dr Falk Pharma, Pharmacosmos,
with inflammatory bowel disease according to their Pfizer, AbbVie, Ferring, and Janssen. LP-B has served as a consultant for
disease severity. Of note, multiomic studies incorporating AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied
Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT
clinical parameters, biopsies, and blood biomarkers are Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos,
aimed at identifying future markers of diagnosis and Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image
prognosis in ulcerative colitis. Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac,
When introducing therapy, a personalised approach is Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE
Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer,
urgently needed; the identification of biomarkers could Prometheus, Protagonist, Roche, Samsung, Sandoz, Takeda, Theravance,
predict the response to therapy or severe adverse events Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, and Abivax; has
with certain medications and allow the most appropriate received payment for lectures from Galapagos, AbbVie, Janssen,
Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Sandoz, Biogen,
first-line therapy to be selected for each patient. In
MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, Medac, Sanofi, and
parallel, despite the advent of more therapeutic agents, Adacyte; reports grant support from Takeda, Fresenius Kabi, and
remission rates for ulcerative colitis are far from optimal, Celltrion; and has received meeting support fees from Galapagos,
as they do not surpass 20–30% in induction clinical trials. AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer,
Gossamer Bio, Sandoz, MSD, Amgen, Lilly, Gilead, Thermo Fisher,
In a real-life setting, the peak of the population response
Medac, and CONNECT Biopharm.
curves is around 30–60%, depending on the population
and definition. There is a need to improve this therapeutic References
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Ulcerative colitis incidence per

Western Europe Southern Asia

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Proctitis Mild-to-moderate active ulcerative colitis Left-sided or

Mesalazine suppository* Mesalazine suppository Oral mesalazine ≥2 g per Oral

Mesalazine suppository* Oral mesalazine ≥2 g per day†**

Mild-to-moderate but refractory active ulcerative colitis might require

Figure 2: Suggested treatment approach algorithm for mild-to-moderate ulcerative colitis

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Moderate-to-severe active ulcerative colitis

Adequate primary response Primary non-response Secondary loss of response

If non-anti-TNF therapy If anti-TNF therapy used as first line

Low or no antidrug Elevated antidrug Low or no antidrug

Figure 3: Suggested treatment approach algorithm for moderate-to-severe ulcerative colitis

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Surgery ileostomy, and finally stoma closure. A modified two

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