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A. D’Errico and D. Malvi
Medical Treatment of Ulcerative Colitis:
Does Traditional Therapy Still Have a Role?
Fernando Rizzello, Marco Salice, Carlo Calabrese, Marta Mazza,
Andrea Calafiore, Lucia Calandrini, Hana Privitera Hrustemovic,
Massimo Campieri, and Paolo Gionchetti
6.1 Introduction and Definitions
Ulcerative colitis (UC) is a chronic inammatory disease which involves
the colonic mucosa continuously starting from the rectum and progressively
involving the entire colon. Its etiology is still unknown, although numerous
studies have claried the inammatory mechanisms involved in the pathogenesis,
allowing the development of new targeted drugs.
Correct medical treatment requires the evaluation of disease extension, activity and
behavior [1].
The Montreal classication allows extent to be dened into three subgroups:
proctitis (when the inammation is limited to the rectum), left-sided colitis
(distal to the splenic exure), and extensive or pancolitis (proximal to the
splenic exure) [2]. Drug formulation is chosen based on the disease extent:
suppositories for proctitis, enemas for left-sided colitis and tablets for extensive
colitis. Furthermore, patients with extensive colitis have a higher risk of
colectomy or of developing colorectal cancer, justifying the need for strict
disease control and histological surveillance [3–5].
Many disease activity indices have been proposed, but none has been adequately validated; the Truelove and Witts clinical index and the Mayo composite score are the scores most used in clinical trials. In clinical practice, the
Truelove and Witts score is used mainly to identify a severe relapse while the
Mayo score is used in mild-to-moderate activity (Tables 6.1 and 6.2) [6, 7].
6
F. Rizzello (*)
Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi
Hospital
Bologna, Italy
e-mail: fernando.rizzello@unibo.it
G. Poggioli (Ed), Ulcerative Colitis,
Updates in Surgery
DOI: 10.1007/978-88-470-3977-3_6, © Springer-Verlag Italia 2019
93
94
Table 6.1 The Truelove and Witts index
Mild Moderate* Severe
Bloody stools/day <4 4 or more If ≥6 and
Pulse <90 bpm ≤90 bpm >90 bpm or
Temperature <37.5°C ≤37.8°C >37.8°C or
Hemoglobin >11.5 g/dl ≥10.5 g/dl <10.5 g/dl or
ESR <20 mm/h ≤30 mm/h >30 mm/h
* Moderate: between mild and severe
ESR, erythrocyte sedimentation rate
Table 6.2 The Mayo score
Stool frequency Rectal bleeding Endoscopic ndings Physician global
0 Normal number
of stools for this
patient
1 1–2 stools more
than normal
2 3–4 stools more
than normal
3 5 or more stools
more than normal
No blood seen Normal or inactive disease Normal
Streaks of blood in the
stool less than half the
time
Obvious blood in the
stool most of the time
Only blood passed Spontaneous bleeding,
Erythema, decreased
vascular pattern, mild friability
Marked erythema, absent
vascular pattern, friability,
erosions
ulcerations
F. Rizzello et al.
assessment
Mild disease
Moderate disease
Severe disease
The major limitation of the Truelove and Witts severity index is that it is not
sufciently discriminative to measure changes in disease activity.
The Mayo score is a composite quantitative score ranging from 0 to 12
points, divided into 3 clinical items plus the endoscopic ndings. The denition
of remission, response and worsening is not uniform in the different studies
and none of these denitions has been formally validated. Studies evaluating
the efcacy of biological drugs in active UC have dened: clinical remission as
a total Mayo score of ≤2 points with no individual subscore >1 point; clinical
response as a decrease from baseline in the total Mayo score of ≥3 points and
≥30%, and a decrease in the rectal bleeding subscore of ≥1 point or an absolute
rectal bleeding subscore of 0 or 1; and mucosal healing as an absolute endoscopy
subscore of 0 or 1 [8–12].
The denition of refractoriness is crucial in order to avoid side effects,
overtreatment and a delay in disease control. Treatment refractoriness must
6 Medical Treatment of Ulcerative Colitis: Does Traditional Therapy Still Have a Role?
95
be dened after checking the correct dosage, duration, formulation, patient
compliance and complications. Patients will be dened as treatment-refractory
in the case of active disease despite:
• mesalamine at a correct dosage and formulation after 2–4 weeks;
• oral prednisone or methylprednisolone 0.75–1 mg/kg after 2 weeks [13];
• intravenous (IV) hydrocortisone 400 mg or methylprednisolone 1 mg/kg IV
after 3–5 days [13];
• azathioprine (AZA) 2.5 mg/kg or 6-mercaptopurine (6-MP) 1.5 mg/kg after
3 months [13];
• cyclosporine 2 mg/kg IV after 4–7 days [13];
• iniximab (IFX), adalimumab (ADA), golimumab (GOLI), vedolizumab
(VEDO) after 4–10 weeks [8–12 2×].
Steroid dependency is dened as a disease relapse during the 3-month dosage
tapering or 3 months of steroid weaning [13].
6.2 Management of Mild-to-moderate Activity
5-aminosalicylic acid (5-ASA), also called mesalamine, the active anti-inammatory part of sulfasalazine introduced in inammatory bowel disease (IBD)
treatment by Nana Svartz in the 1930s, is the rst-line treatment for mild-tomoderate active UC [14]. The different formulations, such as suppositories, enemas and tablets, and different dosages and release mechanisms allow administering the drug directly to the inamed area, optimizing efcacy and limiting
side effects [15].
Steroids could also traditionally be administered orally and topically [16]. The
introduction of oral and topical low-bioavailability steroids – such as beclomethasone dipropionate (BDP) or budesonide (BUDE) – improved safety and maintained efcacy [17–25]. The combination treatment using mesalamine and BDP
has been demonstrated to be more effective than either one alone [26]. However,
steroids are used mainly in cases of mesalamine refractoriness or intolerance.
6.2.1 Proctitis
The rst-line therapy for active mild-to-moderate proctitis involves mesalamine
suppositories 1 g once daily for 6–8 weeks [27]. Numerous studies and systematic
reviews have demonstrated that mesalamine suppositories:
• are more effective than a placebo or oral mesalamine formulation [28];
• better tolerated than enemas [29];
• given in a single administration have similar efcacy to a divided dose and
are better tolerated [30].
96
F. Rizzello et al.
Topical steroids are less effective than topical mesalamine and are recommended for patients refractory to mesalamine [31].
The association between oral and topical mesalamine formulation or topical
mesalamine and topical steroids is more effective than either one alone but,
also in this case, the combination treatment is recommended only in refractory
patients [32].
In cases of refractoriness to mesalamine plus steroid topical combination
therapy, systemic corticosteroids, biologics and/or immunosuppressors are indicated [33].
6.2.2 Left-sided and Extensive Colitis
Oral plus topical mesalamine is the rst-line therapy in active mild-to-moderate
left-sided UC. The combined route is more effective than oral or topical alone
[32], and both are superior to placebo [31, 32, 34].
No conclusive data are available comparing the efcacy of topical mesalamine
and topical steroids but mesalamine seems to be superior to traditional steroids
[31] and equivalent to topical BDP [35].
No differences have been reported in terms of efcacy between different
topical mesalamine dosages (1, 2, or 4 g) [36]; however, despite the fact that no
differences have been reported when comparing different enema volumes and
liquids, or foam enemas, in clinical practice enemas capable of covering the
entire disease extension are recommended.
A dosage of ≥2 g/day of oral mesalamine is more effective than a lower dosage [34], except in cases of moderate activity where a higher dosage of 4.8 g/
day is recommended [37].
Mesalamine is as effective as sulfasalazine but is better tolerated, in particular
at higher dosages [3]. Sulfasalazine maintains its role in patients with associated
spondyloarthropathies. A once-daily dose is more effective than divided doses
with better compliance and similar side effects [38–40].
In clinical practice, additional therapy should be started if no clinical benet
is obtained after 2 weeks of treatment, while 4–8 weeks of treatment are required
in order to have complete clinical and endoscopic remission [40, 41].
As previously mentioned, in cases of mesalamine failure, the combination
of topical mesalamine plus topical steroids is recommended [32]. Oral BDP 5
mg/day for 4 weeks instead of systemic corticosteroids could be a valid add-on
therapy in patients refractory to mesalamine [19, 42].
Oral BUDE 9 mg MMX formulation for 8 weeks was tested in two
controlled clinical trials for mild active left-sided and extensive UC. BUDE was
signicantly superior to a placebo in both studies but not superior to mesalamine
2.4 g/day and non-MMX BUDE 9 mg/day [43, 44]. When BUDE was used as
add-on therapy in patients not adequately controlled by mesalamine 2.4 g/day,
it was signicantly more effective than a placebo [45].
6 Medical Treatment of Ulcerative Colitis: Does Traditional Therapy Still Have a Role?
97
In clinical practice, BDP and BUDE could be used for patients refractory
to mesalamine as an alternative and before using systemic steroids in cases of
multi-refractoriness.
Systemic steroids are superior to mesalamine in patients with extensive colitis [46, 47]. Baron proposed steroid dosages in the 1960s in a small study com-
paring three different dosages of prednisolone: 40 mg per day was as efcacious
as 60 mg and had a better safety prole, similar to 20 mg per day [48].
6.3 Management of Severe Activity
Management of a patient with severe active UC is independent of the disease
extent. In the past, severe active UC was a life-threatening disease and death
occurred in almost 30% of episodes until the introduction of the intensive
intravenous steroid regimen by Truelove in the 1970s [49].
After hospital admission, a patient’s medical history must be carefully
collected and any infective complications must be ruled out. A joint medical
and surgical evaluation is strongly recommended. Intravenous steroids
(hydrocortisone 400 mg/day or methylprednisolone 0.75–1 mg/kg/day) as a
bolus injection [50] are the mainstays of treatment for severe active UC but
the possibility of an urgent colectomy must be evaluated (i.e., in cases of
perforation, septic complications, toxic megacolon or a history of repeated
severe attacks) [49].
No data are available regarding the correct steroid dosage or type of steroids;
however, a meta-analysis seemed to suggest that the risk of colectomy is
independent of steroid dosage [51].
Other measures are:
• uid and electrolyte supplementation as needed;
•
nutritional support mainly in malnourished patients and possibly by enteral
rather than parenteral nutrition. The initial concept of bowel rest has been
superseded [52], and enteral nutrition is associated with fewer side effects
than parenteral nutrition [53];
• topical therapy with mesalamine or corticosteroids, or both [49];
broad spectrum antibiotics mainly when a systemic infection is suspected
•
since they are not effective in improving the disease outcome [54–56];
• blood or albumin transfusion;
•
subcutaneous prophylactic low-molecular-weight heparin in order to reduce
the risk of thromboembolism [57].
Travis et al. demonstrated that, after 3 days of steroid treatment, patients
with >8 bloody stools per day or between 3 and 8 bloody stools per day and
C-reactive protein >45 mg/l had an 85% risk of colectomy [58]. Based on these
data, called the Oxford criteria, rescue therapy should be started earlier.
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F. Rizzello et al.
Lichtiger rst proposed rescue therapy in patients with active severe UC who
failed to respond to intravenous corticosteroids. Intravenous cyclosporine 4 mg/
kg was tested in a small open-label study precociously interrupted because of the
strongly positive results [59] Two subsequent consecutive studies showed that IV
cyclosporine 4 mg/kg/day was as effective as IV cyclosporine 2 mg/kg/day [60]
and that IV cyclosporine 4 mg/kg/day was as effective as IV methylprednisolone
40 mg/day [61]. Numerous small open-label studies have conrmed the efcacy
of cyclosporine but have also reported infectious complications causing a patient’s
death. Pooling the data of these studies, cyclosporine is effective in 76–85% of
patients in order to avoid colectomy in the short term. The major problem of
cyclosporine treatment is the ineffectiveness of maintaining remission [62–64].
Combining it with AZA improves the maintenance of remission [65], tapering
steroids and switching to oral cyclosporine 5–8 mg/kg/day until the thiopurine
takes effect. When combining three immunosuppressors, such as steroids,
cyclosporine and AZA, the risk of severe and life-threatening infection is higher
than when using a single drug.
In the biological era, IFX has been demonstrated to be as effective as rescue
therapy in steroid-refractory severe active UC patients. Jarnerot has demonstrated
that a single dose of IFX 5 mg/kg is more effective than a placebo in avoiding
colectomy for 3 months. [66]. Other studies have suggested that a three-dose
induction is more effective in preventing colectomy [67], mainly reducing the
duration of the induction period [68]. When comparing IFX and cyclosporine,
both drugs are equally effective, rapid and safe [69, 70] but IFX is more effective
in maintaining remission [71].
Based on the data obtained by pooling the results of 10 studies regarding thirdline rescue therapy, Narula et al. recently suggested that this method is possible
(28.3% colectomy rate at 3 months and 42.3% at 12 months) with an acceptable
risk (6.7% serious infections and 1% mortality) [72, 73]. However, this approach
should be reserved for highly selected patients in a tertiary referral center [74].
6.4 Maintenance of Remission
The main outcome of maintenance treatment is clinical and mucosal remission
without steroids. Oral mesalamine at a dosage of at least 2 g once daily is
the rst-line treatment in patients who responded to mesalamine during the
induction phase [34]. Selected patients with proctitis or left-sided colitis may
be treated with topical mesalamine (suppositories or enemas, respectively) 3
g/week alone or combined with oral mesalamine in cases of inefcacy of the
former alone [33].
Thiopurines are indicated at a dosage of 2–2.5 mg/kg/day for AZA or 1–1.5
mg/kg/day for 6-MP in patients refractory or intolerant to mesalamine, patients
6 Medical Treatment of Ulcerative Colitis: Does Traditional Therapy Still Have a Role?
99
who experienced a moderate-to-severe relapse who required steroids and/
or cyclosporine or tacrolimus, and patients who were steroid-dependent. The
evidence supporting the use of thiopurines as a maintenance treatment in UC
is of poor quality and comes from retrospective series. The major problems
in thiopurine treatment is poor tolerability and action slowness, requiring 3
months before the effectiveness can be judged, using steroids or cyclosporine as
a bridge therapy [75–78].
6.5 Special Situations
The identication of the tumor necrosis factor (TNF) as a pivotal key of the
inammatory process and the introduction of monoclonal antibodies – also called
“biologics”, based on in vivo biotechnological production – as a therapeutic
option in chronic inammatory diseases has profoundly modied the treatment
of UC.
In fact, patients with chronically active moderate UC refractory or intolerant
to steroids could also be treated with IFX (5 mg/kg IV at week 0, 2 and 6)
or ADA (160 mg subcutaneously at week 0 and 80 mg at week 2) or GOLI
(200 mg subcutaneously at week 0 and 100 mg at week 2) [8–13]. All these
monoclonal antibodies are more effective in inducing and maintaining clinical
response than a placebo, but no head-to-head studies could help in identifying
the best monoclonal antibodies. Furthermore, they are effective in maintaining
remission at different administration schedules (Table 6.3).
Patients who failed to respond to a rst anti-TNF course were dened as
“primary failure”, and treatment with VEDO should be considered.
Patients who lost the clinical response, mainly because they developed
neutralizing anti-drug antibodies, could regain the response by optimizing
the dosage used (10 mg/kg instead of 5 mg/kg) [79] or reducing the schedule
interval (every 4 weeks instead of 8 weeks), or both, during IFX treatment or by
reducing the schedule interval (weekly treatment) during ADA treatment [80].
No dosage optimization was used during GOLI treatment. In this case, a switch
to VEDO is also possible [81]. In cases of allergic reaction or other drug-related
side-effects (i.e., paradoxical psoriasis), switching to VEDO is mandatory [81].
Integrins are pivotal molecules involved in the process in which leukocytes
move from the circulation to the site of inammation; VEDO is a monoclonal
antibody against alpha4-beta7 integrin expressed mainly in the endothelium of the
intestinal vessels. As previously mentioned, VEDO is also effective in inducing
and maintaining clinical response in patients with moderate-to-severe UC.
Table 6.4 summarizes the efcacy in the induction and maintenance of IFX,
ADA, GOLI and VEDO. Once again, in this case, no head-to-head studies are
available to help clinicians choose between TNF-blockers and VEDO.
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