Prognostic significance of endoscopic remission in patients with active ulcerative colitis treated with oral and topical mesalazine: a prospective, multicenter study.
ABSTRACT It has been recommended that the treatment of active ulcerative colitis (UC) should be continued until complete healing of endoscopic lesions. However, the evidence supporting this recommendation is scanty. Aims of the present study were to assess the rate of patients with active UC who achieve clinical but not endoscopic remission after treatment with oral plus topical mesalazine and to compare the rate of relapse in patients with clinical/endoscopic remission and those with only clinical remission.
Patients with active mild or moderate UC were eligible. All patients received mesalazine, 4 g/day orally and 2 g/day per rectum for 6 weeks. Those achieving clinical remission underwent colonoscopy: afterwards, all received maintenance treatment with oral mesalazine, 2 g/day orally for 1 year. Clinical remission was defined as normal frequency of bowel movements with formed stools, no abdominal pain, and no blood in the stools. Endoscopic remission was defined as normal-appearing mucosa or only mild redness and/or friability, without either ulcers or erosions.
In all, 81 patients were enrolled. Sixty-one (75%) achieved clinical remission. Endoscopic activity was still present in five (8%). The cumulative rate of relapse at 1 year was 23% in patients with clinical and endoscopic remission and 80% in patients with only clinical remission (P < 0.0001).
Persistence of endoscopic activity is quite infrequent in patients with active UC achieving clinical remission after a 6-week treatment with oral plus topical mesalazine, but is a very strong predictor of early relapse.
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ABSTRACT: Inflammatory bowel diseases (IBD) are chronic and disabling conditions. Accumulating evidence indicates that we need to look beyond clinical symptoms as current therapeutic strategies have not modified the course of IBD. Therapeutic goals for IBD have evolved from a mere control of symptoms to mucosal healing (MH). Achieving deep remission (clinical remission, biomarker remission and MH) might be the only way to alter disease course in IBD patients. In Crohn's disease (CD), deep remission has been recently defined as Crohn's Disease Activity Index <150 and complete MH. In ulcerative colitis (UC), there is no proposed definition of deep remission. It could be defined as clinical and endoscopic remission in UC. These definitions remain to be validated in large prospective studies. In the near future, the concept of deep remission might include transmural healing in CD and histologic healing in UC. Advances in drug development have provided highly effective treatments for IBD, making deep remission a realistic goal. Whether IBD patients may benefit by experiencing a 'deep' remission beyond the control of clinical symptoms, which might ultimately impact on important outcomes such as the need for surgery and the development of disability, needs to be evaluated in future disease modification trials.Current Gastroenterology Reports 03/2013; 15(3):315.
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ABSTRACT: Background and Objectives. Mucosal healing (MH) is considered an important therapeutic goal in ulcerative colitis (UC). We evaluate the severity of intestinal inflammation and clarify the relation between MH and long-term outcomes. Methods. The study group comprised 38 patients with UC in clinical remission on total colonoscopy who were followed up for at least 5 years. Clinical remission was defined as a Mayo score of 0 for both stool frequency and rectal bleeding. Colonoscopic findings were evaluated into 4 grades according to the Mayo endoscopic subscore (MES). Results. During clinical remission, the MES was 0 in only 24% of the patients, 1 in 40%, 2 in 26%, and 3 in 10%. Seventy-six percent of the patients thus had active disease on colonoscopy. After initial colonoscopy, the cumulative rate of remission maintenance was 100% in MES 0, 1 in 93%, 2 in 70%, and 3 in 50% at 6 months and 78%, 40%, 10%, and 0%, respectively, at 5 years (P < 0.001). Conclusion. Many patients with UC in clinical remission have active lesions. Patients with a higher MES have a higher rate of recurrence. To improve long-term outcomes, an MES of 0 should be the treatment goal.Gastroenterology Research and Practice 01/2013; 2013:192794. · 1.62 Impact Factor
- Côlon & Rectum 6(2).
Prognostic Significance of Endoscopic Remission in Patients
with Active Ulcerative Colitis Treated with Oral and Topical
Mesalazine: A Prospective, Multicenter Study
Gianmichele Meucci, MD,** Renato Fasoli, MD,†Simone Saibeni, MD,‡Daniela Valpiani, MD,§
Renzo Gullotta, MD,kEnrico Colombo, MD,¶Renata D’Inca', MD,** Maddalena Terpin, MD,††
and Giovanni Lombardi, MD‡‡on Behalf of the IG-IBD
Background: It has been recommended that the treatment of active ulcerative colitis (UC) should be continued until complete healing of endo-
scopic lesions. However, the evidence supporting this recommendation is scanty. Aims of the present study were to assess the rate of patients
with active UC who achieve clinical but not endoscopic remission after treatment with oral plus topical mesalazine and to compare the rate of
relapse in patients with clinical/endoscopic remission and those with only clinical remission.
Methods: Patients with active mild or moderate UC were eligible. All patients received mesalazine, 4 g/day orally and 2 g/day per rectum for 6
weeks. Those achieving clinical remission underwent colonoscopy: afterwards, all received maintenance treatment with oral mesalazine, 2 g/day
orally for 1 year. Clinical remission was defined as normal frequency of bowel movements with formed stools, no abdominal pain, and no blood in
the stools. Endoscopic remission was defined as normal-appearing mucosa or only mild redness and/or friability, without either ulcers or erosions.
Results: In all, 81 patients were enrolled. Sixty-one (75%) achieved clinical remission. Endoscopic activity was still present in five (8%). The
cumulative rate of relapse at 1 year was 23% in patients with clinical and endoscopic remission and 80% in patients with only clinical remission
(P < 0.0001).
Conclusions: Persistence of endoscopic activity is quite infrequent in patients with active UC achieving clinical remission after a 6-week treat-
ment with oral plus topical mesalazine, but is a very strong predictor of early relapse.
(Inflamm Bowel Dis 2011;000:000–000)
Key Words: ulcerative colitis, mesalazine, endoscopic remission, mucosal healing
scopic demonstration of mucosal healing has not been con-
ntil recently, treatment of active ulcerative colitis
(UC) has focused on improving symptoms and endo-
sidered a necessary endpoint in patients achieving clinical
However, recent data suggest that concentrating
exclusively on clinical outcome measures may not be
adequate to achieve long-term treatment success. Indeed,
achievement of endoscopic remission has been shown to
correlate with a reduced risk of colectomy,3,4hospital
admissions, and need for immunosuppressive treatments.4
Recently, a panel of experts recommended that the pri-
mary endpoint for therapeutic trials in patients with mildly
to moderately active UC should be induction of remission,
defined as complete symptom resolution and endoscopic
healing.5Moreover, some experts at present recommend that
the treatment of active UC should be continued until com-
plete healing of endoscopic lesions is observed,6although
no consensus exists on this topic.2,7In fact, the evidence
supporting practical value associated with repeat endoscopy
to monitor treatment progression is limited, and no consen-
sus exists on how endoscopic remission should be assessed.7
Mesalazine is currently the mainstay of treatment for
patients with mild or moderate UC flares,2and combined
treatment with oral and topical formulations appears to be
Received for publication June 2, 2011; Accepted July 5, 2011.
From the *Divisione di Gastroenterologia, Ospedale Valduce, Como, Italy,
†Servizio di Gastroenterologia ed Endoscopia Digestiva – Unita ` Complessa di
Medicina, Ospedale Costantino Cantu `, Abbiategrasso, Italy,
Gastroenterologia, Universita ` degli Studi e IRCCS Policlinico, Milano, Italy,
§Centro di Gastroenterologia ed Endoscopia Digestiva, Ospedale Morgagni
Pierantoni, Forlı `, Italy,
Clinica San Carlo, Paderno Dugnano, Italy,
Generale ad Indirizzo Gastroenterologico, Azienda Ospedaliera G. Salvini,
Garbagnate Milanese, Italy,
Gastroenterologiche, Universita ` di Padova, Padova, Italy,
Gastroenterologia ed Endoscopia Digestiva, Azienda Ospedaliera ‘‘Ospedale
Civile di Legnano,’’ Legnano, Italy,
Digestiva, Ospedale ‘ ‘Casa Sollievo della Sofferenza’’ IRCCS, San Giovanni
Gastroenterology, Ospedale San Giuseppe, Via San Vittore 12, 20123 Milano,
Italy (e-mail: firstname.lastname@example.org).
Published online in Wiley Online Library (wileyonlinelibrary.com).
kUnita ` di Gastroenterologia ed Endoscopia Digestiva,
¶Unita ` Operativa di Medicina
**Dipartimento di Scienze Chirurgiche e
‡‡UOC Gastroenterologia ed Endoscopia
C 2011 Crohn’s & Colitis Foundation of America, Inc.
Inflamm Bowel Dis
associated with maximum clinical improvement and an ear-
lier clinical response compared with treatment with either
formulation alone.8–10Conversely, data on the rate of endo-
scopic remission in patients treated with this regimen are at
The aims of the present study were: 1) to assess the
rate of patients with active UC who achieve clinical but
not endoscopic remission following treatment with oral
plus topical mesalazine, and 2) to compare relapse rates in
patients achieving both clinical and endoscopic remission
versus those with clinical remission only.
PATIENTS AND METHODS
Eligible patients were those with active mild or moder-
ate UC extending beyond the rectosigmoid junction. Patients
requiring systemic steroids, those with previous or ongoing
immunosuppressive treatment, and those with proctitis were
This was a prospective, multicenter study. Study design
is shown in Figure 1. All patients underwent baseline colono-
scopy, followed by 6-week treatment with mesalazine, 4 g/day
orally and 2 g/day rectally. Patients achieving clinical remis-
sion underwent a second colonoscopy; following this, and
regardless of endoscopic remission status, all of them received
maintenance treatment with oral mesalazine, 2 g/day for
12 months. Patients who did not achieve clinical remission
were assessed as treatment failures, were no longer eligible
for inclusion in study, and were treated as appropriate.
Patients achieving clinical remission were followed for 1 year
by means of monthly telephone interviews and clinical visits
every 3 months.
Disease activity was evaluated by means of the Mayo
Index11(Table 1). Clinical remission was defined as normal
frequency of bowel movements with formed stools, no abdom-
inal pain, and no blood in the stools, i.e., a value of 0 on the
6-point Mayo subscore.12Clinical relapse (both at baseline
and in patients attaining clinical remission) was defined as a
worsening of bowel function plus reappearance of rectal
For assessment of endoscopic activity, the Mayo endo-
scopic subscore was used. Before starting the study a formal
assessment of interobserver concordance among all participant
endoscopists was carried out. This assessment revealed an
excellent degree of concordance in separating grades 0–1 from
grades 2–3 ((kappa 0.71) but a poor one in defining the single
four grades, as well in distinguishing grade 0 from grade 1
(kappa values between 0,31 and 0,57) (Meucci et al, unpubl.
obs.). Therefore, we decided to define endoscopic remission as
a Mayo endoscopic subscore ?1, i.e., normal-appearing mu-
cosa or only mild redness and/or friability, without either
ulcers or erosions. A subanalysis in which only patients with
normal mucosa were considered in endoscopic remission was
For statistical analysis, data were input into a statistical
software (Intercooled Stata, College Station, TX). The rate of
clinical relapse was calculated by means of the Kaplan–Meier
method. For comparison of the rate of relapse in patients with
and without endoscopic remission the log-rank test was used.
For the assessment of factors associated with the rate of clini-
cal remission, endoscopic remission, and clinical relapse, mul-
tivariate analyses were performed using a logistic step-wise
regression model or Cox regression model, as appropriate. In
logistic analysis, all parameters showing a P-value lower than
FIGURE 1. Study design.
TABLE 1. Components of the Mayo Score
11–2 stools/day more than normal
2 3–4 stools/day more than normal
3 4 stools/day more than normal
1Visible blood with stool less than half the time
2Visible blood with stool half of the time or more
3Passing blood alone
Mucosal appearance at endoscopy
0Normal or inactive disease
1Mild disease (erythema, decreased vascular pattern, mild
2 Moderate disease (marked erythema, absent vascular
pattern, friability, erosions)
3Severe disease (spontaneous bleeding, ulceration)
Physician rating of disease activity
Inflamm Bowel Dis
Meucci et al
0.1 at univariate analysis were included and those showing a
P-value higher than 0.3 removed, according to an automated
backward stepwise procedure. For all tests, P < 0.05 was con-
sidered statistically significant.
In all, 81 patients were enrolled from nine participat-
ing institutions; patient baseline data are shown in Table 2.
As shown in Figure 2, 74 patients had evaluable data at 6
weeks. Three patients were switched to more aggressive
treatments because of worsening of symptoms, one patient
was found not to be affected by UC, and the three remaining
patients were lost to follow-up. Following 6 weeks of oral
and topical mesalazine treatment, 61 patients achieved clini-
cal remission (75.3% intention to treat, 78.2% per protocol).
At multivariate logistic regression analysis no correlation
was found between the rate of clinical remission and clinical
or demographic variables such as gender, age, disease exten-
sion and duration, the degree of baseline endoscopic activity,
duration of previous remission, number of relapses in the
last year, smoking habits, and previous appendectomy.
Among 61 patients achieving clinical remission,
endoscopic examination showed endoscopic remission (as
defined above) in 56 and persistence of endoscopic activity
in only five (8.2%). Again, no correlation was found at
logistic regressions analysis between the rate of endoscopic
remission and clinical or demographic variables such as
gender, age, disease extension and duration, the degree of
baseline endoscopic activity, duration of previous remis-
sion, number of relapses in the last year, smoking habits,
and previous appendectomy. However, all five patients not
achieving endoscopic remission were affected with left-
sided colitis, as compared with 42 out 56 of those achiev-
ing endoscopic remission (P ¼ 0.58 at two-sided chi-square
test). Among 13 patients not achieving clinical remission,
eight underwent repeat colonoscopy as part of their subse-
quent clinical work-up: in all, persistence of endoscopic
UC activity was confirmed.
As shown in Figure 3, the cumulative rate of clinical
relapse at 1 year was 23% in patients with clinical and en-
doscopic remission and 80% in patients with only clinical
remission (P < 0.0001). Among 56 patients achieving
endoscopic remission as defined above, the endoscopic pic-
ture was graded as grade 0 (normal-appearing mucosa) in
28 and as grade 1 (mild redness and/or friability, without
either ulcers or erosions) in the remaining 28. The cumula-
tive risk of relapse at 1 year in these two groups were 26%
and 19%, respectively, a nonsignificant difference (P ¼
0.47). At Cox regression analysis, the only variable associ-
ated with a lower risk of relapse was achievement of endo-
scopic remission (P ¼ 0.001).
Our data confirm that combination oral and topical
mesalazine is highly effective in patients with mildly to
moderatelyactive UC.Indeed, therate ofpatients
TABLE 2. Patient Baseline Data
- left-sided colitis
- extensive colitis
6-point Mayo clinical subscore
Mayo endoscopic subscore
48.6 years (19–79)
FIGURE 2. Enrollment and outcomes.
FIGURE 3. Cumulative risk of clinical relapse according to endo-
Inflamm Bowel DisEndoscopic Remission in UC
achieving clinical remission was 75% in our study, a figure
that is very close to that reported in two previous therapeu-
tic trials,9,10and slightly lower than reported in a trial
including only patients with left-sided colitis.8In all the
above-mentioned trials the oral dosage of mesalazine
ranged from 2–4 g/day and treatment duration from 6–8
weeks, thus not differing substantially from dosages and
duration in the present study.
Moreover, persistence of endoscopic inflammation
appears to be quite infrequent in patients with active UC
achieving clinical remission following a 6-week treatment
with oral and topical mesalazine. Indeed, among 61
patients achieving clinical remission only five (8%) showed
persistence of endoscopic disease activity despite complete
resolution of symptoms. In 2007, Kornbluth et al13
observed persistence of endoscopic inflammation in as
many as 42% of patients achieving clinical remission after
treatment with oral mesalazine. However, a different defini-
tion of endoscopic remission (sigmoidoscopic score of 0,
i.e., completely normal mucosa) was used in that study. In
the present study we decided to use a looser definition
(endoscopic score <2) on the basis of the results of our pre-
liminary assessment of interobserver concordance among
participant endoscopists, which revealed a very poor degree
of concordance in differentiating grade 0 from grade 1. We
believe that our definition of endoscopic remission was
more appropriate for the reasons outlined below. At any
rate, very few discrepancies between the rates of clinical
and endoscopic remission have been reported in most trials
evaluating the efficacy of mesalazine (either orally, topically,
or in combination) in patients with ulcerative colitis.10,14–16
These findings are in keeping with previous observations
showing that, in most patients with UC, endoscopic and
clinical activity coincide and endoscopic assessment adds lit-
tle to clinical indices of disease activity.12,17On the other
hand, significant discrepancies between the rates of clinical
and endoscopic remission have been reported in UC patients
treated with other therapeutic regimens, such as oral cortico-
However, persistence of endoscopic activity in the
context of clinical remission was found to be a strong pre-
dictor of early UC relapse. In fact, four out of five patients
not achieving endoscopic remission relapsed within 3
months, whereas as many as 77% of those achieving endo-
scopic remission maintained stable remission for as long as
1 year after completing the acute phase treatment. This is
in accordance with the previous finding that even persist-
ence of inflammation only at the histological level is a
strong predictor of relapse as well.22–24In previous studies
the frequency of previous relapses and young age was
found to be associated with a higher risk of relapse22,25,26
but these associations could not be confirmed in the present
study. It must also be noted that in half of our patients
achieving endoscopic remission as above defined the endo-
scopic picture was classified as grade 1; nevertheless, the
rate of clinical relapse in this subset of patients was even
slightly (albeit largely not significantly) lower than in
patients with an endoscopic score of 0. Therefore, we
believe that it is appropriate (at least for prognostic pur-
poses) to consider in endoscopic remission not only
patients showing a completely normal mucosa, but also
those in whom only mild redness and/or friability, but not
erosions or ulcers, are detectable.
Some limitations of the present study need to be
addressed. First, no formal assessment of patients’ adher-
ence to treatment was made. In fact, while very high
degrees of adherence to oral mesalazine have been reported
in clinical trials, ‘‘real-world’’ adherence has been found to
be quite low.27–31Since the present was a prospective,
pragmatic study, a high degree of nonadherence can there-
fore be supposed. However, there is no plausible reason to
suppose a lower adherence to treatment among patients not
achieving endoscopic remission when compared with
patients achieving it. Therefore, we believe that this limita-
tion does not affect the main results of the study.
Second, it has been recently proposed to differentiate
patients showing only erythema from those with friability
and to exclude friability from the definition of endoscopic
score 1.32In the present study, no attempt was made to op-
erate such a distinction. Whether a difference in relapse
rate exists between patients with only erythema and those
with friability should be a topic for subsequent research.
In conclusion, our data suggest that the majority of
patients with active UC achieve both clinical and endo-
scopic remission (or only persistence of minimal signs of
inflammation) after combination treatment with oral and
assessment in this subset of patients could not be required.
However, a minority of patients exist in whom marked en-
doscopic signs of inflammation persist despite complete
symptoms disappearance, and in these patients early relapse
is extremely frequent. Further research is needed to deter-
mine if other risk markers can be used to identify patients
who would be good candidates for joint clinical and endo-
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Inflamm Bowel Dis Endoscopic Remission in UC