Introduction
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized
by mucosal inflammation that extends in a continuous manner from the rectum through
various lengths of the colon. Individuals with UC commonly experience alternating
phases of spontaneous flares, drug-induced remission, and varying degrees of chronic
disease activity [1 ]
[2 ]
[3 ]. The disease is associated with debilitating physical symptoms, such as bloody diarrhea,
urgency, fecal incontinence, and abdominal pain, as well as psychological distress,
which can substantially impair health-related quality of life (QoL) and general life
satisfaction [3 ]
[4 ]. Even during periods of clinical remission, inflammation may continue, leading to
persistent urgency, IBS-like symptoms, post-inflammatory complications including neoplasia,
and extraintestinal manifestations, such as peripheral arthritis, primary sclerosing
cholangitis, and pyoderma gangrenosum, which can occur in approximately one-third
of patients [5 ].
The global burden of UC is substantial and continues to grow, with an estimated five
to seven million people affected worldwide in 2023 [6 ]
[7 ]
[8 ]. This increasing prevalence is driven by multiple factors, including environmental
changes [9 ] and lifestyle adaptations [10 ] in both high- and low-income countries. In the former, the growing number of cases
among older individuals and demographic aging pose major challenges, with age-associated
changes in the immune system, sarcopenia, and comorbidities adding complexity to UC
management. The burden of UC in Germany is also considerable, with a recent analysis
of health insurance claims data indicating a prevalence surpassing 0.5% [11 ]. The etiology of UC remains elusive, although a range of factors including genetic
predisposition, environmental influences, luminal factors, and mucosal immune dysregulation
have been demonstrated to contribute to its pathogenesis [12 ].
In the absence of a cure for UC, the primary therapeutic goals in treatment have evolved
from providing symptomatic relief to achieving and sustaining steroid-free mucosal
healing with well-tolerated medication. This approach aims to avoid surgical interventions,
reduce the use of systemic steroids, decrease the likelihood of colorectal cancer,
and improve quality of life [13 ]
[14 ]. Since the 1950s and continuing to this day, the approach to managing UC has been
structured around a step-up treatment model, with 5-aminosalicylic acid (5-ASA) therapies
playing a central role. This class includes sulfasalazine, olsalazine, balsalazide,
and mesalazine (also known as mesalamine). Among these, mesalazine has become the
most widely used and extensively studied due to its improved safety profile and targeted
drug delivery [14 ]
[15 ]
[16 ]
[17 ]. The current manuscript will focus exclusively on mesalazine.
The most recent national and international guidelines, including those from the European
Crohn’s and Colitis Organisation (ECCO) [16 ], the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS)
[18 ], the American College of Gastroenterology (ACG) [14 ], and the British Society of Gastroenterology (BSG) [19 ], consistently recommend mesalazine as the first-line treatment of choice for patients
with mild-to-moderate UC. Mesalazine is also recommended as first-line therapy for
these patients in a recent international expert consensus statement, which additionally
points to the development of new ambitious outcomes such as histological remission
and disease clearance [20 ]. While guideline development groups are continually assessing the role of mesalazine
as the treatment landscape broadens to include more biologics and small molecules,
the most recent guidelines still do not recommend early intervention with these newer
therapies in mild-to-moderate cases. Instead, they suggest tailoring the dose of mesalazine
to the severity and phase of the disease, starting with higher doses that are maintained
long enough to reduce the risk of relapse [14 ]
[15 ]
[16 ]
[18 ]
[21 ]. This restraint is based not only on the scarcity of evidence on comparative effectiveness
but also on the well-established high effectiveness of mesalazine and its favorable
safety profile. Given that over 85% of UC patients have mild-to-moderate disease [22 ], mesalazine remains the cornerstone of UC treatment.
The primary aim of this manuscript is to review the recommendations for mesalazine
use in the most recent German clinical practice guideline [18 ], clarify why mesalazine continues to be the first-line treatment of choice, and
provide expert, practical advice for translating these recommendations into daily,
evidence-based clinical practice. We will also conduct a systematic search of the
literature to identify evidence on whether and how to continue mesalazine treatment
alongside newer therapies. The secondary aim is to provide an overview of the many
mesalazine products currently on the market in Germany, including their drug release
profiles, dosage forms, and strengths in order to support patient-individualized mesalazine
therapies.
Our overview and findings will be useful to IBD specialists seeking to optimize the
effectiveness and efficiency of UC treatment by highlighting the differences between
the various mesalazine products and their distinct characteristics.
Continuing role of mesalazine as first-line therapy in mild-to-moderate UC
The management of mild-to-moderate UC has relied on a step-up approach, in which decisions
to intensify treatment are guided by clinical symptoms, including non-response or
intolerance to initial therapies. This approach can be visualized as a treatment pyramid
([Fig. 1 ]), with mesalazine (oral and rectal, both as mono and combination therapies) being
the recommended first-line treatment at the base of the pyramid, followed by escalation
to low-bioavailability/colonic-release corticosteroids, systemic steroids, immunosuppressants,
and biologics/small molecules, with surgery at the tip [16 ]
[18 ]
[23 ]
[24 ].
Fig. 1 Treatment pyramid for ulcerative colitis [16 ]
[18 ]
[23 ]
[24 ].
While mesalazine has always played a central role in this step-up approach, the advent
of biologics and small molecule therapies has broadened the range of treatment options
available. This has led to discussions about the potential benefits of top-down strategies,
which would involve starting treatment with more aggressive drugs. The rationale for
top-down therapy – which has been discussed more extensively in patients with Crohn’s
disease [16 ] – is to induce remission more quickly. However, as we will outline in the following
sections, substantial evidence shows that mesalazine can rapidly induce clinical remission
within as little as two weeks, followed by lasting steroid-free clinical, endoscopic,
and histologic remission. Indeed, unlike in Crohn’s disease, there is less evidence
that early initiation or early treatment escalation with these newer therapies has
any benefit for patients with mild-to-moderate UC [25 ].
Additionally, mesalazine has been shown to have a safety profile comparable to that
of placebo [16 ]
[23 ]
[24 ], whereas most biologics and small molecule therapies come with more substantial
risks. These include an increased risk of infections, infusion and hypersensitivity
reactions, a slightly increased risk of certain cancers for some therapies and, in
the case of JAK inhibitors, risks such as blood clots, elevated liver enzyme, and
increased cholesterol levels [26 ]
[27 ]
[28 ]
[29 ]
[30 ]. Mesalazine therefore continues to be recommended as the first-line therapy of choice
for inducing and maintaining remission in mild-to-moderate UC across all of the major
UC guidelines [14 ]
[15 ]
[16 ]
[18 ]
[21 ], including the most recent update of the German Guideline on Ulcerative Colitis.
German guideline recommendations and advice for everyday clinical practice
Induction of remission in mildly to moderately active proctitis
Table 1
Box 1 . Induction treatment of mildly to moderately active proctitis
‡ Adapted from Kucharzik et al., 2024 [18 ].
Summarized recommendations (and related reference numbers from the guideline)‡
3.5
Treat proctitis initially with rectal mesalazine ≥1 g/day using suppositories; alternatively,
use rectal foams or enemas.
3.6
If rectal monotherapy with mesalazine fails, combine it either with rectal steroids
or oral mesalazine.
For proctitis (Box 1 ), the German guideline recommends starting with rectal therapy using mesalazine suppositories
at a dose of at least 1 g/day. Mesalazine foam or enemas can be used instead, but
these are described as alternatives because they may not be as well tolerated by patients.
If treatment with rectal mesalazine fails, the guideline recommends that it should
be combined with either topical steroid therapy or oral mesalazine-releasing preparations
(≥3g/day). In cases where oral mesalazine is used as add-on treatment, the guideline
notes that once-daily dosing with mesalazine granules in particular appears to be
beneficial. If this approach also fails, the guideline advises confirming therapy
adherence and endoscopic findings, and, if necessary, applying the principles used
to treat severe ulcerative colitis of any extent [18 ].
Translating the recommendations into evidence-based clinical practice
In patients with proctitis only, the guideline recommends initiating treatment with
rectal mesalazine suppositories. However, oral therapy alone is commonly prescribed.
Why is this the case, and what is the optimal approach?
Rectal mesalazine is strongly recommended as the first-line treatment for proctitis
because it delivers high concentrations of the active drug directly to the site of
inflammation, offering superior effectiveness to oral therapy alone. However, local
therapy may be underutilized due to several factors, including clinician familiarity
and comfort with oral regimens, patient reluctance or discomfort with rectal administration,
and potential time constraints in fully explaining rectal therapy options during consultations.
To address this, clinicians should actively consider and discuss rectal mesalazine
as a primary treatment option for proctitis, emphasizing its effectiveness and generally
favorable tolerability. Providing clear instructions and reassurance about the use
of suppositories, foams, or enemas can help increase patient acceptance.
What advice should I give to my patients on how best to administer rectal mesalazine?
Proper application techniques are crucial: suppositories should be inserted blunt
end first after warming by hand and moistening with water [31 ]. Foams should not be expelled prematurely but should be retained for at least 10–15
seconds after application. Mesalazine enemas should be applied while patients are
lying on their left lateral side, and they should maintain this position for about
30 minutes to ensure maximum absorption.
How and when should treatment failure with initial rectal mesalazine be determined?
The guideline does not specify the exact signs or duration for determining when initial
treatment of proctitis with rectal mesalazine has failed. However, clinical practice
generally considers a lack of symptom improvement or worsening of symptoms within
two to four weeks as indicative of treatment failure. Persistent bleeding, ongoing
inflammation, and patient-reported outcomes are key indicators to assess the effectiveness
of the therapy. In cases where patients are unable to retain a rectal enema for at
least 30 minutes, suppositories may be used as an alternative and may be better tolerated.
If these options are not effective or feasible, it may indicate severe disease requiring
escalation to topical or systemic corticosteroids or other treatments.
What is the best combination treatment and dosage if initial rectal mesalazine for
proctitis fails?
The guideline does not explicitly state which combination should be preferred. However,
clinical practice suggests that the choice often depends on patient preference. Adding
oral mesalazine is often preferred due to its broader reach within the digestive tract,
which can address inflammation beyond the rectum. However, some patients also prefer
rectal treatment only and combine topical steroids and rectal mesalazine, using one
drug in the morning and the other in the evening. Topical steroids can be effective
but may be reserved for patients who do not respond adequately to combined oral and
rectal mesalazine therapy, bearing in mind that long-term use of systemic steroids
should be avoided due to side effects.
The guideline does not provide a specific dosage for adding oral mesalazine when rectal
mesalazine treatment is insufficient. In German clinical practice, doses of 2 to 4.8
g/day tend to be used to achieve optimal therapeutic effects, often depending on which
mesalazine formulation is chosen (see also Section 4 “Overview of mesalazines and
differences”). The exact dosage may be adjusted based on the mesalazine formulation
used, as well as the patient’s response, tolerance, and disease severity.
Induction of remission in mildly to moderately active UC of at least rectosigmoid
extent
This category encompasses all forms of active UC that extend proximally beyond the
rectum. It thus includes proctitis (E1 according to the Montreal classification),
left-sided colitis (E2), and extensive colitis (also known as pancolitis, E3). Importantly,
the German guideline divides its recommendations in this category into two subcategories:
those for “left-sided colitis” and for “extensive colitis”. The term “left-sided colitis”
is used to refer to disease extending up to the splenic flexure [18 ]
[32 ], and thus the recommendations in this subcategory also apply to proctosigmoiditis.
Mildly to moderately active left-sided colitis
Table 2
Box 2 . Induction treatment of mildly to moderately active left-sided colitis
‡ Adapted from Kucharzik et al., 2024 [18 ].
Summarized recommendations (and related reference numbers from the guideline)‡
3.7
Treat initially with rectal mesalazine (≥1 g/day, enema or foam) in combination with
oral mesalazine (≥3 g/day).
3.8
Prefer rectal mesalazine therapy over topical steroid therapy.
3.9
Prefer daily single-dose administration of oral mesalazine.
For induction treatment of mildly to moderately active left-sided colitis (Box 2 ), the German guideline recommends a combination of rectal mesalazine (≥ 1 g/day,
enema or foam) and oral mesalazine (≥3 g/day) for initial treatment. The guideline
explains that this combination is favored over oral mesalazine monotherapy due to
its higher response rates and faster onset of action, pointing to a systematic review
and meta-analysis from 2012 [33 ]. In the event of intolerance to rectal application, however, the guideline notes
that oral monotherapy may be considered. The guideline recommends that rectal mesalazine
should be preferred over topical steroid therapy.
The guideline also underscores the crucial role of treatment adherence in mesalazine
therapy. It encourages physicians to discuss dosing options and formulations with
patients, such as once-daily dosing and the choice between tablets or granules. In
doing so, daily single-dose administration of oral mesalazine is recommended due to
its equivalence in effectiveness to multiple daily doses, with the added benefit of
simplifying the treatment regimen, which may improve adherence. Moreover, the guideline
emphasizes the necessity of administering sufficiently high doses of mesalazine (at
least 3 g/day) for all patients with mild-to-moderate disease, citing evidence that
patients with moderate disease may benefit from a higher initial dose of 4.8 g/day
[34 ].
Extensive mildly to moderately active UC
Table 3
Box 3 . Induction treatment of extensive mildly to moderately active UC
‡ Adapted from Kucharzik et al., 2024 [18 ].
Summarized recommendation (and related reference number from the guideline)‡
3.11
Treat initially with oral mesalazine (≥3 g/day) in combination with rectal mesalazine
treatments such as enemas or foams.
For induction treatment of extensive mildly to moderately active UC (Box 3 ), the recommendation is essentially the same as that for left-sided colitis. As with
left-sided colitis, the guideline points to evidence of the superior efficacy of combining
oral mesalazine with rectal therapy compared to oral monotherapy. Once again, the
guideline explicitly emphasizes the importance of ensuring adequate dosing of mesalazine,
of at least 3 g/day.
Translating the recommendations into evidence-based clinical practice
Is the therapeutic effect of mesalazine dose-dependent? What about side effects?
Yes, the therapeutic effect of mesalazine appears to be dose-dependent. Higher doses
of mesalazine (>3 g/day) have been shown to be more effective in inducing remission
in patients with mild-to-moderate UC. A 2018 systematic review and network meta-analysis
by Nguyen et al. found that while standard-dose mesalazine (2–3 g/day) is usually
sufficient for inducing remission in mild UC, higher doses are preferable for moderate
cases [35 ]. A more recent network meta-analysis conducted by Barberio et al. (2021) involving
11,733 patients, showed that higher doses of oral mesalazine (≥3.3 g/day) were significantly
more efficacious than lower doses for sustainable induction of remission [36 ]. Among the 20 included RCTs that used high-dose oral mesalazine, nine used 4.8 g/day,
one 4.5 g/day, six 4 g/day and four 3.6 g/day [36 ]. This evidence supports the use of higher doses during the induction phase to maximize
the chances of achieving remission, aligning with the German guideline’s recommendation
for higher induction doses of 3 g/day or greater. In contrast, the side effects of
mesalazine therapy are not dose-dependent [37 ]
[38 ] and have been shown to be similar to placebo [26 ]
[38 ]
[39 ]
[40 ].
How quickly and what kind of response should be expected from mesalazine treatment?
The German guideline does not explicitly define the duration of a rapid response.
Achieving rapid clinical response in UC is crucial and should be considered an immediate
treatment target because symptomatic relief is highly prioritized by patients, as
emphasized by the STRIDE-II statement [41 ]. According to STRIDE-II, physicians should consider changing treatment if there
is no significant improvement within approximately four weeks or no improvement at
all after two weeks when using mesalazine. Studies investigating different oral mesalazine
products at higher daily doses (4 g/day or 4.8 g/day), with or without rectal mesalazine,
suggest that nearly half of patients with mild-to-moderate UC may be able to achieve
symptom resolution within two weeks [42 ], and as many as one-third may reach clinical remission within the same period [43 ]. The expected improvements in symptoms indicating a rapid clinical response to mesalazine
include reduced bowel movement frequency, less bleeding, and decreased abdominal pain
[41 ].
Can first-line treatment with mesalazine be optimized to avoid treatment failure?
Optimization of mesalazine treatment generally involves maximizing oral doses of the
drug, combining oral with rectal therapies to improve effectiveness and potentially
avoid the need for steroids or other escalating therapies, as well as opting for simple
once-daily treatment [23 ]. Several studies have demonstrated that using optimization approaches from the beginning
of therapy can help prevent the progression of disease, avoid the need for therapy
escalation, reduce side effects, and save costs [28 ]
[44 ].
Incorporating a treat-to-target strategy into clinical practice can further optimize
mesalazine use. The recent OPTIMISE study underscores the value of guiding treatment
strategies using measurable targets such as mucosal healing rather than focusing only
on symptomatic relief [45 ]. This approach not only aims to achieve deeper remission states but also facilitates
personalized, dynamic therapy adjustments based on non-invasive markers such as fecal
calprotectin combined with clinical symptoms (PRO-2) [45 ].
In patients who respond well to induction therapy with mesalazine, how long should
induction therapy be continued?
The German guideline does not specify the exact duration of induction therapy with
mesalazine in patients with mild-to-moderate UC. However, evidence from a recent non-interventional
prospective Dutch study [46 ] suggests that a longer duration of induction therapy (>6 months) is associated with
a substantially reduced risk of recurrence, particularly among patients receiving
higher (≥4 g/day) doses of mesalazine. These findings confirm earlier similar findings
supporting a duration of at least three months [47 ]. In summary, if patients are responding to therapy, continuing the recommended induction
dose of mesalazine for six months or more is a reasonable, evidence-based approach,
particularly given the favorable safety profile of mesalazine [26 ]
[38 ]
[39 ]
[40 ].
When and how should mesalazine therapy be de-escalated?
De-escalation refers to reducing the intensity or dosage of therapy once remission
is achieved. After the initial induction period and once clinical remission is achieved,
the higher dose of mesalazine is generally continued for an additional period to stabilize
remission and achieve at least endoscopic remission or even complete deep healing
(i.e., clinical remission plus complete endoscopic and histological healing) [41 ], with evidence supporting a total duration of induction therapy of at least six
months [46 ]. After this period, the dose can be reduced to a maintenance level (≥2 g/day) to
sustain remission. Further de-escalation is not recommended by the German guideline,
which explicitly recommends offering patients long-term treatment with ≥2 g/day of
mesalazine due to its potential cancer protection effects and favorable safety profile.
We will discuss these topics more below in the section on maintenance and long-term
mesalazine therapy.
Escalating mesalazine induction treatment
Table 4
Box 4 . Escalating mesalazine induction treatment
‡ Adapted from Kucharzik et al., 2024 [18 ].
Summarized recommendations (and related reference numbers from the guideline)‡
3.10a/3.12
Use systemic steroid therapy (0.5–1 mg/kg body weight/day of prednisolone equivalent)
if the approaches recommended in 3.5–3.9 and 3.11 fail or if a severe form of UC is
already present at diagnosis.
3.10b
Budesonide MMX 9mg/day is a recommended option in mild-to-moderate left-sided colitis
if the patient does not respond to or tolerate mesalazine.
If the recommended first-line induction treatments for mildly to moderately active
left-sided colitis or extensive mildly to moderately active UC fail, or if a severe
form of UC is already present at diagnosis, the German guideline recommends systemic
steroid therapy (0.5–1 mg/kg body weight/day in prednisolone equivalents) (Box 4 ). In patients with mild-to-moderate left-sided colitis, however, the guideline specifically
recommends budesonide MMX 9 mg/day [18 ].
Translating the recommendations into evidence-based clinical practice
Should budesonide MMX 9 mg/day be tried before systemic steroid therapy?
The German guideline makes a specific recommendation for budesonide MMX in the case
of patients with mild-to-moderate left-sided colitis in whom the recommended first-line
treatments have been insufficient. Budesonide MMX is distinct from other systemic
steroids because it is metabolized extensively on the first pass through the liver,
which significantly reduces its systemic availability, thereby focusing its effects
more locally within the gastrointestinal tract and minimizing broader side effects
[48 ]
[49 ]. In everyday clinical practice, it is therefore advisable to consider budesonide
MMX first in these patients, on a case-by-case basis, before moving on to systemic
steroids. If a sufficient response is not achieved within 2–4 weeks depending on baseline
disease activity, treatment escalation to systemic steroids should be considered.
How to know if first-line mesalazine treatment is insufficient?
The German guideline states that steroid therapy with budesonide MMX or systemic steroid
treatment should be initiated if clinical symptoms worsen during treatment or if bleeding
persists for more than two weeks [18 ]. More generally, according to STRIDE-II, physicians should consider changing treatment
if there is no significant improvement within approximately four weeks when using
optimized mesalazine [41 ].
When escalating to budesonide MMX 9 mg/day, should it be added to oral and/or rectal
mesalazine, or should it be given as monotherapy?
To our knowledge, only one study has looked at this specific question to date: a multicenter,
prospective, real-world evidence cohort study conducted in Europe and Canada [50 ]. It found that adding budesonide MMX to optimized mesalazine treatment might be
the best therapeutic approach to induce clinical remission compared to budesonide
MMX monotherapy. Just over 60% of patients in the add-on treatment group achieved
the primary endpoint of clinical benefit (improvement of ≥3 points in the UCDAI clinical
subscore) compared to 33% in the monotherapy group, a substantial and statistically
significant difference. Similar results were found for clinical remission (UCDAI clinical
subscore ≤1) and symptom resolution (RB = 0, SF ≤1, and no urgency). Although only
numerically different, higher percentages of patients who had budesonide added at
least 14 days after mesalazine optimization achieved all three endpoints [50 ], suggesting that at least two weeks of mesalazine therapy optimization might be
beneficial before adding budesonide MMX.
Maintenance of remission in mild-to-moderate UC
Table 5
Box 5 . Maintenance of remission in mild-to-moderate UC
‡ Adapted from Kucharzik et al., 2024 [18 ].
Summarized recommendations (and related reference numbers from the guideline)‡
3.13
Use mesalazine to maintain remission in patients who have responded to induction treatment
with mesalazine or steroids.
3.14
The route of mesalazine administration in maintenance treatment should depend on the
extent of disease. Proctitis and left-sided colitis should primarily be treated with
rectal therapy.
3.15
Use combined oral/rectal mesalazine therapy as second-line treatment.
3.16c
Prefer mesalazine over sulfasalazine.
3.21
Do not use corticosteroids for maintenance of remission.
For maintaining remission in patients with mild-to-moderate UC (Box 5 ), the German guideline recommends mesalazine for all patients who have responded
to induction treatment with mesalazine or steroids. In patients with proctitis or
left-sided colitis, the guideline recommends monotherapy with rectal mesalazine as
the first-line maintenance treatment. However, it acknowledges the challenges in adherence
with rectal therapy and points to data indicating that patients with IBDs prefer not
to be treated with suppositories or enemas [51 ]. For this reason, the guideline states that an alternative to rectal application
is oral mesalazine formulations with a good release profile in the left-sided colon.
In patients with more extensive UC, the guideline recommends monotherapy with oral
mesalazine.
If rectal or oral monotherapy fails, the guideline recommends combination treatment
with oral and rectal mesalazine. Because of its more favorable safety profile, mesalazine
should be preferred over sulfasalazine. Corticosteroids should not be used for maintenance
of remission.
Translating the recommendations into evidence-based clinical practice
What role does therapy optimization play in maintenance treatment?
In patients with left-sided colitis who indicate that they may have difficulty adhering
to daily use of suppositories or enemas, it is reasonable to use combination treatment
for maintenance, especially if combination treatment was already being used for induction.
While the guideline states that monotherapy with oral mesalazine is an alternative
in such cases, combination therapy allows for intermittent (twice per week) use of
rectal mesalazine, which might be more acceptable to these patients. Above all, the
choice of maintenance therapy should be thoroughly discussed with the patient and
be based on patient preferences to ensure adherence [52 ]. Evidence shows that non-adherence to mesalazine therapy in quiescent UC is associated
with a fivefold greater risk of recurrence [53 ]. Thus, selecting a regimen that the patient can consistently follow is crucial for
long-term disease management.
Is it beneficial to continue with mesalazine even after escalating to biologics/small
molecules?
To address this question, we conducted a systematic search of the literature published
from 1995 onwards, which yielded 740 results. Title and abstract screening, performed
independently by two authors, identified 18 potentially relevant records. After independent
full-text review by two authors, 12 papers met the inclusion criteria and were included
in the analysis. A detailed description of the search strategy, inclusion/exclusion
criteria, results, and reasons for exclusion is provided in the Supplementary Appendix.
The search did not identify any RCTs specifically designed to assess whether continuing
mesalazine is beneficial after escalation to biologics or small molecules in UC. The
available evidence comes from retrospective analyses of clinical trials, population-based
cohorts, and real-world settings. These studies showed no consistent evidence of short-term
clinical benefit, such as improved rates of remission or mucosal healing, nor did
they indicate an increased risk of harm, including any safety concerns, associated
with concurrent mesalazine use. None of the included studies were powered or designed
to investigate long-term outcomes such as colorectal cancer prevention.
Based on this evidence, we do not recommend a universal approach. Instead, we suggest
that the decision to continue mesalazine after escalation should be individualized.
In clinical practice, factors such as patient preference, disease history, previous
response to mesalazine, and the potential (albeit inconsistently demonstrated) chemoprotective
effect against colorectal cancer may support continuing treatment in selected patients.
Given the favorable safety profile of mesalazine and the absence of evidence for harm
in combination therapy, offering patients the option to continue mesalazine may be
reasonable in cases where it aligns with patient needs and preferences.
Table 6
Box 6 . Duration of maintenance therapy with mesalazine
‡ Adapted from Kucharzik et al., 2024 [18 ].
Summarized recommendations (and related reference numbers from the guideline)‡
3.16d
Maintenance therapy should last at least two years.
3.18
Offer long-term treatment with mesalazine with a view towards cancer prevention
The German guideline recommends that maintenance therapy with mesalazine should last
at least two years to reduce the risk of future relapses. It also recommends offering
patients mesalazine treatment beyond two years due to its potential benefits in preventing
colorectal cancer (Box 6 ).
Translating the recommendations into evidence-based clinical practice
How long should maintenance treatment last, and why?
The German guideline recommends long-term mesalazine (≥2 years) treatment not only
to reduce the risk of relapse but also for its chemopreventive properties against
colorectal cancer.
Reducing relapse risk : The German guideline recommends a minimum of two years for maintenance therapy with
mesalazine. This recommendation is based on a controlled study showing that patients
in remission for one to two years who continued on mesalazine therapy for an additional
12 months had a reduced incidence of relapses compared to those on placebo. Although
this benefit was not observed in patients who had been in remission for more than
two years, the statistical limitations of the study and lower dose of mesalazine (1.2
g/day) prevent definitive conclusions about the long-term benefits of maintenance
therapy [18 ].
Prevention of colorectal cancer : Long-term maintenance therapy with mesalazine may have the potential to prevent
colorectal cancer, although the evidence remains weak. Nevertheless, due to the excellent
safety profile of long-term mesalazine compared to biologics or small molecules, the
German guideline recommends offering long-term treatment with mesalazine with a view
towards cancer prevention. Chronic intestinal inflammation is a major risk factor
for colorectal cancer in UC patients, and weak evidence indicates that ongoing mesalazine
therapy is associated with reduced colorectal cancer risk [54 ]
[55 ]. This potential effect is thought to be mediated through the induction of apoptosis
and decreased proliferation or modulation of carcinogenic gut microbiota and potentially
of biofilm formation in colorectal mucosa [56 ]
[57 ]
[58 ].
This putative preventive effect applies broadly to all UC patients [59 ]
[60 ]
[61 ], except those with isolated proctitis [59 ]
[60 ]
[62 ]
[63 ]
[64 ]
[65 ]
[66 ]
[67 ]
[68 ]
[69 ]
[70 ]
[71 ]
[72 ]. The guideline contrasts this with the more limited evidence for a cancer protection
effect of immunosuppressives like azathioprine and anti-TNF therapies in cancer prevention
while highlighting their less favorable safety profile compared to mesalazine.
Summary of dosage recommendations for maintenance of remission
Table 7
Box 7 . Dosage recommendations for maintenance of remission
‡ Adapted from Kucharzik et al., 2024 [18 ].
Summarized recommendations (and related reference numbers from the guideline)‡
(3.16a)
For oral mesalazine: use ≥2 g/day
For rectal mesalazine alone: use ≥1 g/day
For combined oral/rectal mesalazine therapy: oral 1.6–3 g/day plus rectal 1–4 g twice
per week
(3.16b)
Prefer once-daily dosing
(3.17)
Consider E. coli strain Nissle 1917 as a potential alternative to mesalazine
The guideline specifies the following dosing regimens for mesalazine (Box 7 ): for oral administration, a minimum of 2 g/day is recommended; for rectal application
alone, at least 1g/day is recommended. For those receiving combined oral/rectal therapy,
the oral dose should range from 1.6–3 g/day with an additional 1–4 g of rectal mesalazine
administered twice per week. The guideline also recommends opting for once-daily dosing
to enhance patient adherence. While the non-pathogenic E. coli strain Nissle 1917 is recognized as a potential alternative to 5-aminosalicylates
for maintaining remission in ulcerative colitis, the guideline notes that in clinical
practice, mesalazine is more commonly used due to its larger body of supporting data
and its potential effect in cancer prevention (see Recommendation 3.18) [18 ].
Overview of mesalazines and differences
Whether administered orally or rectally, mesalazine works by delivering the active
anti-inflammatory component, mesalazine, directly to the site of inflammation in the
colon. Regardless of the formulation or route of administration, systemic absorption
is low, ensuring that the drug primarily acts locally in the gastrointestinal tract,
which results in very few side effects and excellent tolerability [16 ]
[18 ]
[73 ]. Although the precise mode of action is unknown, mesalazine may reduce inflammation
in the colon by inhibiting enzymes involved in the formation of inflammatory mediators
like prostaglandin and leukotrienes [74 ].
Mesalazine has been shown to have a safety profile comparable to placebo [16 ]
[23 ]
[24 ]. Its side effects are relatively mild and include headache, nausea, and abdominal
pain, with rare but more serious effects like pancreatitis and nephritis. Importantly,
higher doses of mesalazine do not appear to increase the risk of side effects [38 ]. In patients with UC, regular monitoring is important, with routine laboratory testing
(e.g., creatinine, urea, AST, ALT, lipase, urinalysis) at least annually, even for
asymptomatic patients. Several mesalazine formulations are available, each designed
to optimize drug release at specific locations in the gastrointestinal tract. Although
the German UC guideline notes comparable efficacy across products [18 ], no head-to-head RCTs have been conducted to confirm this. Differences mainly concern
their release profiles, influenced by pH dependency, prolonged-release mechanisms,
and gastrointestinal factors such as transit time or inflammation. These distinctions,
along with variations in excipients, may be relevant for patients with dietary preferences,
comorbidities, or specific scheduling needs.
As of January 2025, a total of five mesalazine products, each with several formulations
and doses, are available in the German market and approved for induction and maintenance
treatment of UC. Listed in alphabetical order, these are: Asacol, Claversal, Mezavant,
Pentasa, and Salofalk. The following section will provide an overview of these products,
including their drug release profiles, dosage forms, strengths, as well as excipients
and other ingredients.
Drug-release profiles and kinetics of the different formulations
Each mesalazine formulation employs specific mechanisms to ensure appropriate drug
release and therapeutic efficacy. These can be grouped into three categories ([Table 8 ]):
Table 8 Drug-release profiles and kinetics of different mesalazine formulations (alphabetical
order).
Site of release
Commercial product
pH release profile
duodenum
jejunum
ileum
ascending colon
transverse colon
descending colon
sigmoid colon
rectum
Asacol enteric-coated tablets 75 ]
[76 ]
pH-dependent
•
•
•
•
•
Asacol modified-release tablets 77 ]
pH-dependent
•
•
•
•
•
Claversal micro-pellets (enteric-coated granules) 78 ]
pH-dependent
•
•
•
•
•
Claversal enteric-coated tablets 79 ]
pH-dependent
•
•
•
•
•
Mezavant enteric-coated, prolonged-release tablets 80 ]
pH-dependent
•
•
•
•
•
Pentasa prolonged-release granules 81 ]
Time-dependent
(not pH-dependent)
•
•
•
•
•
•
•
•
Pentasa prolonged-release tablets
(0.5 g, 1 g) [81 ]
[82 ]
Time-dependent
(not pH-dependent)
•
•
•
•
•
•
•
•
Salofalk Granu-Stix (prolonged-release granules) [83 ]
(0.5 g, 1 g, 1.5 g, 3 g) [83 ]
pH-dependent
•
•
•
•
•
Salofalk enteric-coated tablets
(0.25 g, 0.5 g, 1 g) [84 ]
[85 ]
[86 ]
pH-dependent
•
•
•
•
•
Eudragit coatings (pH-dependent). Six mesalazine formulations rely exclusively on enteric coatings with Eudragit that
dissolve at pH levels typically found in the ileum or colon: Asacol enteric-coated
tablets [75 ]
[76 ], Asacol modified release tablets [77 ], Claversal micro-pellets (enteric-coated granules) [78 ], Claversal enteric coated-tablets [79 ], Salofalk Granu-Stix prolonged-release granules, and Salofalk enteric-coated tablets
[83 ]
[84 ]
[85 ]
[86 ]. Their enteric coatings help protect the drugs from being released too early in
the stomach and ensure that it reaches the intended location in the gastrointestinal
tract. The site of release for Asacol is the terminal ileum and colon [75 ], whereas for Claversal and Salofalk it is the mid to distal ileum and colon [79 ]
[84 ]. There are limited data on the extent to which these formulations are affected by
other changes in gut conditions, such as diarrhea. One study from the Netherlands
suggests that diarrhea had a significant effect on drug-release for Claversal, and
Salofalk, and Asacol enteric-coated tablets [87 ].
Multi-matrix systems (MMX) (pH-dependent). MMX systems, used for example in Mezavant enteric-coated, prolonged-release tablets,
combine pH-dependent release with a slow-release matrix [80 ]
[88 ].Specifically, Mezavant uses a combination of lipophilic and hydrophilic matrices
[88 ]. This ensures extended drug release in the colon, allowing for a prolonged therapeutic
effect and consistent drug delivery over time [80 ]
[88 ]. To the best of our knowledge, there are no data on whether diarrhea affects drug
release.
Ethylcellulose coating (time-dependent). Two mesalazine formulations, Pentasa prolonged-release granules and Pentasa prolonged-release
tablets, use a time-dependent, prolonged-release mechanism that is independent of
pH [81 ]
[82 ]. It consists of ethylcellulose-coated microgranules that release mesalazine slowly
throughout the gastrointestinal tract (duodenum to rectum), ensuring a more uniform
distribution of the drug over a larger area of the intestines. The release of mesalazine
in Pentasa is not significantly affected by diarrhea [87 ].
Excipients/other ingredients
There are large differences among the five mesalazine products in terms of their excipients
and other ingredients ([Table 9 ]). Understanding these differences is important for tailoring treatment to individual
patient needs. For example, patients with lactose intolerance or sensitivities to
sweeteners like aspartame may require specific formulations. Others on sodium-restricted
diets may benefit from products with lower sodium content. Discussing these options
with patients may improve satisfaction, adherence, and, ultimately, treatment outcomes.
Table 9 Excipients and other ingredients in oral mesalazine products currently available in
Germany (alphabetical order) for the treatment of mild-to-moderate ulcerative colitis.
Brand
Formulation
Excipients and other ingredients (apart from mesalazine)
* Composition of 250 mg and 500 mg tablets differs slightly
Asacol
Enteric-coated tablets [75 ]
[76 ]
Lactose monohydrate (152.8 mg [800 mg] / 76.4 mg [400 mg]), carboxymethyl starch sodium
(type A) (Ph.Eur.), talcum, povidone (25000), magnesium stearate (Ph.Eur.) [plant-based]
(E 572), triethyl citrate, methacrylic acid-methyl methacrylate copolymer (1:2) (Ph.Eur.),
iron (III) hydroxide oxide × H2O (E 172), iron (III) oxide (E 172), macrogol 6000
Modified-release tablets [77 ]
Magnesium stearate (E470B), methacrylic acid-methyl methacrylate copolymer (1:2),
triethyl citrate, yellow iron oxide (E172), red iron oxide (E172), macrogol, microcrystalline
cellulose, glycerol monostearate (40–55), hypromellose, corn starch, polysorbate 80,
potassium dihydrogen phosphate, colloidal silicon dioxide, carboxymethyl starch sodium
(type A)
Claversal
Micropellets (enteric-coated granules) [78 ]
Microcrystalline cellulose, dispersible cellulose powder, citric acid, ascorbic acid,
butylated hydroxyanisole, hypromellose, methacrylic acid-ethyl acrylate copolymer
(1:1) MW: approx. 250,000 (Eudragit L 100–55); methacrylic acid-methyl methacrylate
copolymer (1:2) MW: approx. 135,000 (Eudragit S 100), triethyl citrate, talcum, titanium
dioxide, sucralose (Ph.Eur.), maltodextrin, tropical fruit flavor L-129243 Givaudan
Enteric-coated tablets [79 ]
Sodium carbonate, microcrystalline cellulose, highly dispersed silicone dioxide, glycine,
povidone, croscarmellose sodium, calcium stearate, methacrylic acid-methyl methacrylate
copolymer (1:1), methacrylic acid-methyl methacrylate copolymer (1:2), methacrylic
acid-ethyl acrylate copolymer (1:1) dispersion 30%, talcum, triethyl citrate, titanium
dioxide (E 171), iron (III) oxide (E 172), iron (III) hydroxide oxide (E 172), macrogol
6000
Mezavant
Enteric-coated, prolonged-release tablets [80 ]
Tablet core: Carmellose sodium, carnauba wax, stearic acid (Ph.Eur.), silicone dioxide
hydrate, sodium carboxymethyl starch (Type A) (Ph.Eur.), talcum, magnesium stearate
(Ph. Eur.) [plant-based]; Film coating: Talcum (Ph.Eur.), methacrylic acid-methyl
methacrylate copolymer (1:1) and (1:2) (Ph.Eur.), triethyl citrate, titanium dioxide
(E171), iron (III) oxide (E172), macrogol 6000
Pentasa
Prolonged-release granules [81 ]
Povidone, ethylcellulose
Prolonged-release tablets [81 ]
[82 ]
Povidone K30, ethylcellulose, magnesium stearate (Ph.Eur.), talcum, microcrystalline
cellulose
Salofalk
Granu-Stix (prolonged-
release granules) [83 ]
Aspartame (E 951), carmellose sodium (Ph.Eur.), citric acid, highly dispersed silicone
dioxide, hypromellose, magnesium stearate (Ph.Eur.) [plant-based], methacrylic acid-methyl
methacrylate copolymer (1:1) (Ph.Eur.) (MW: approx. 135,000) (Eudragit L 100), methylcellulose,
microcrystalline cellulose, polyacrylate dispersion 40% (Eudragit NE 40 D; contains
2% nonoxinol 100), povidone K 25, simethicone, sorbic acid (Ph.Eur.), talcum, titanium
dioxide (E171), triethylcitrate, vanilla custard flavor (contains sucrose)
Enteric-coated tablets 1g* [84 ]
[85 ]
[86 ]
Microcrystalline cellulose, povidone K25, croscarmellose sodium, methacrylic acid-methyl
methacrylate copolymer (1:1) (Ph.Eur.), methacrylic acid-methyl methacrylate copolymer
(1:2) (Ph.Eur.), calcium stearate (Ph.Eur.) [plant-based], talcum, macrogol 6000,
hypromellose, highly dispersed silicone dioxide, iron (III) hydroxide oxide × H2O,
titanium dioxide (E 171)
Available mesalazine dosage forms and strengths
A wide range of dosage forms and strengths of mesalazine exist, including tablets,
granules, suppositories, rectal foam, and enemas/rectal suspensions. An overview of
these is given in [Table 10 ] (oral forms) and [Table 11 ] (rectal forms).
Table 10 Currently available mesalazine oral dosage forms and strengths (alphabetical order).
Brand
Dosage form
Strengths
Licensed max. daily induction dose
Asacol
Enteric-coated tablets [75 ]
[76 ]
0.4 g, 0.8 g
3.6 g, 4.8 g
Modified-release tablets [77 ]
1.6 g
4.8 g
Claversal
Micropellets (enteric-coated granules) [78 ]
1.5 g
3 g
Enteric-coated tablets [79 ]
0.5 g
3 g
Mezavant
Enteric-coated, prolonged-release tablets [80 ]
1.2 g
4.8 g
Pentasa
Prolonged-release granules [81 ]
1 g, 2 g, 4 g
4 g
Prolonged-release tablets [81 ]
[82 ]
0.5 g, 1 g
4 g
Salofalk
Granu-Stix (prolonged-release granules) [83 ]
0.5 g, 1 g, 1.5 g, 3 g
3 g
Enteric-coated tablets [84 ]
[85 ]
[86 ]
0.25 g, 0.5 g, 1 g
3 g
Table 11 Currently available mesalazine rectal dosage forms and strengths (alphabetical order).
Brand
Dosage form
Strengths
Licensed max. daily induction dose
Asacol
Suppositories [89 ]
1 g
1 g
Claversal
Suppositories [90 ]
[91 ]
0.25 g, 0.5 g, 1 g
1.0–1.5 g, 1.0–1.5 g, 1 g
Rectal foam [92 ]
1 g
2 g
Enema [93 ]
4 g/60 g
4 g
Pentasa
Suppositories [94 ]
1 g
1 g
Rectal suspension [95 ]
1 g/100 ml
1 g
Salofalk
Suppositories [96 ]
[97 ]
[98 ]
0.25 g, 0.5 g, 1 g
1.5 g, 1.5 g, 1 g
Rectal foam [99 ]
1 g
2 g
Enema [100 ]
[101 ]
2 g/30 ml, 4 g/60 ml
4 g
Considerations for patient-individualized mesalazine therapies
Given the variety of available products and formulations, several points should be
considered when tailoring mesalazine treatment to individual patient needs. First,
not all brands offer both oral and rectal formulations, limiting options for combination
therapy. Unless absolutely necessary, we do not recommend mixing oral mesalazine formulations
from different manufacturers or rectal mesalazine formulations from different manufacturers
due to a lack of supporting evidence. Additionally, the release of most mesalazine
products, except for one, is pH-dependent, which could potentially pose challenges
for patients with irregular gut pH levels due to gastrointestinal conditions or medications,
although this has not been systematically assessed in clinical trials or clinical
practice. Such factors might also affect patients with frequent diarrhea, potentially
altering the effectiveness of treatment for all formulations. To prevent potential
allergic reactions, physicians should consider each product’s excipients and other
ingredients, taking into account patient sensitivities and preferences. Optimizing
therapy ideally involves selecting the highest optimized dose with the simplest regimen
to improve adherence and treatment outcomes. Correct use of suppositories, foam, and
enema should be explained in detail, and patient preferences should be considered.
To consolidate these points and other practical recommendations discussed throughout
the paper, [Table 12 ] provides a summary of the do’s and don’ts of mesalazine therapy in mild-to-moderate
UC, offering clinicians a practical resource for translating the German UC guidelines
into evidence-based daily practice.
Table 12 Do’s and don’ts of mesalazine therapy in mild-to-moderate UC.
DO’S
DON’TS
DO use mesalazine as first-line therapy in treatment of mild to moderative UC.
DO use rectal mesalazine more often as combination therapy, not just for ulcerative
proctitis.
DO recommend once-daily dosing of mesalazine to improve adherence.
DO always use rectal mesalazine with oral mesalazine for induction therapy when inflammation
extends beyond the rectum.
DO prefer rectal mesalazine therapy over rectal steroid therapy in proctitis.
DO advise patients on the correct use of rectal mesalazine and to empty their bowel
before treatment.
DO instruct patients on how to insert suppositories correctly: warm them in your hands,
briefly immerse them in water before insertion, and insert the blunt end first.
DO instruct patients to administer enema and foam while lying on their left lateral
side and remain resting for approximately 30 minutes.
DO routine laboratory testing annually to check for side effects (e.g., creatinine,
urea, AST, ALT, lipase, urinalysis).
DO use mesalazine to maintain remission in patients who have responded to induction
treatment with mesalazine or steroids.
DON’T overlook the excellent therapeutic effect of mesalazine in induction therapy for
mild-to-moderate UC of any extent.
DON’T underdose oral mesalazine for induction of remission. Use at least ≥3 g/day.
DON’T split the mesalazine dose. Use it once daily.
DON’T remove rectal mesalazine foam device too early – ensure it remains in place for at
least 10–15 seconds in the anus to optimize its effectiveness.
DON’T use creams or oils for inserting suppositories.
DON’T mix oral mesalazine formulations from different manufacturers with each other or
rectal mesalazine formulations from different manufacturers with each other due to
a lack of evidence, unless absolutely necessary.
DON’T stop mesalazine maintenance treatment too early. Use it for at least two years.
