Faecal calprotectin (FC) shows an excellent correlation with endoscopic and histological activity of ulcerative colitis (UC) and it is the best predictor of clinical relapse. Our aim was to evaluate the usefulness of modifying the dose of mesalazine based on FC levels, in clinical practice.
MethodsRetrospective, single-centre study in UC patients in clinical remission while treated with mesalazine which dosage was decreased (DOWN) or increased (UP) according to FC levels. The main endpoint was the long-term maintenance of clinical remission.
ResultsA total of 56 patients were included (39 DOWN, 17 UP). In the DOWN group, the median baseline dose of mesalazine was 3.6 g/day and the median baseline FC was 36 μg/g. After a median follow-up of 22 months, 28% required rescue therapy. The cumulative relapse-free survival after tapering was 91% and 82% at 12 and 24 months, respectively. In the UP group, the median baseline dose of mesalazine was 2.4 g/day, with a median baseline FC of 524 μg/g. After a median follow-up of 12 months, 29% required rescue therapy. The cumulative relapse-free survival after dose increase was 86% and 72% at 12 and 24 months, respectively.
ConclusionsMesalazine dose modification based on FC monitoring seems to be a safe strategy in patients with UC in clinical remission, with a probability of clinical relapse around 20% at two years.
La calprotectina fecal (CF) ha demostrado una excelente correlación con la actividad endoscópica e histológica de la colitis ulcerosa (CU) y constituye el mejor predictor de recidiva clínica. Nuestro objetivo fue evaluar la utilidad de modificar la dosis de mesalazina en base a los niveles de CF en la práctica clínica.
MétodosEstudio retrospectivo y unicéntrico en pacientes con CU asintomáticos tratados con mesalazina cuya dosificación se disminuyó (DOWN) o aumentó (UP) según niveles de CF. El criterio de valoración principal fue el mantenimiento de la remisión clínica.
ResultadosSe incluyeron 56 pacientes (39 grupo DOWN, 17 grupo UP). En el grupo DOWN la dosis mediana basal de mesalazina fue de 3,6 g/día y la CF mediana basal de 36 μg/g. Tras una mediana de seguimiento de 22 meses, el 28% precisó tratamiento de rescate. La probabilidad acumulada de mantenerse en remisión clínica tras la disminución fue 91% y 82% a los 12 y 24 meses, respectivamente. En el grupo UP, la dosis mediana basal de mesalazina era de 2,4 g/día, con CF mediana basal de 524 μg/g. Tras una mediana de 12 meses de seguimiento, el 29% precisó tratamiento de rescate. La probabilidad acumulada de mantenerse en remisión clínica fue 86% y 72% a los 12 y 24 meses, respectivamente.
ConclusionesLa modificación de dosis de mesalazina en base a la monitorización de CF parece una estrategia segura en pacientes con CU en remisión, con una probabilidad de recidiva clínica en torno al 20% a los dos años.
Mesalazine is the most widely used drug for the treatment of ulcerative colitis (UC). It is indicated for both the induction of remission in mild or moderate flare-ups and maintenance therapy in patients who responded to induction with this drug or with corticosteroids, and is the drug of choice in both cases.1,2 In fact, several population studies have shown that approximately half of patients with UC will only use mesalazine to control their disease throughout their whole lives.3,4 The minimum effective dose recommended for maintenance therapy is 1.5−2 g/day orally,1,2,5 although higher doses are often prescribed in clinical practice, particularly when they have been used for induction of remission.
The main aim of maintenance therapy is to prevent clinical relapse. However, endoscopic remission (absence of macroscopic lesions) and histological remission (absence of neutrophilic infiltration in biopsies) have been associated with better outcomes in UC,6 including a reduction in the risk not only of clinical relapse, but also of dysplasia.7 Furthermore, with better knowledge of the natural history of the disease and having established the relationship between chronic inflammation of the mucosa and the risk of colic dysplasia, the objective of maintenance therapy has become the control of inflammatory activity and not just the symptoms. Nevertheless, colonoscopy (with or without biopsies) is an invasive, expensive, uncomfortable procedure for the patient and is not without risk. The use of biomarkers, however, makes it easier to assess disease activity as periodic testing allows non-invasive, simple and objective continuous monitoring. Calprotectin is the main cytosolic protein of neutrophils, a key cell in the pathophysiology of UC. It is stable at room temperature and easily measurable in biological samples.8 Measuring calprotectin in faeces has demonstrated a high negative predictive value for clinical relapse. High levels of faecal calprotectin (FC) in patients in clinical remission are associated with a greater risk of clinical relapse in the three to six months after testing, with a sensitivity of 90% and a specificity of 83%.9 In fact, it has been suggested that patients in clinical remission with elevated FC concentrations have a 14-fold higher risk of relapse than those with normal FC levels.10 FC has also shown a high correlation with endoscopic11 and histological12 activity.
This has all led to the recommendation to include FC monitoring in UC patients in clinical practice, and even its inclusion as a biomarker of activity in numerous controlled clinical trials.13 Although, in routine clinical practice, the dose of mesalazine is often modified based on FC levels, there is little evidence in the literature to support this. In fact, only two prospective studies have evaluated the utility of increasing the dose of oral mesalazine in patients with UC in remission but with elevated FC.14,15 There are no data available in real clinical practice and no data are available to support the reduction of mesalazine in patients in prolonged remission with persistently low FC levels. Our aim was to assess the efficacy and safety of modifying the mesalazine dose based on FC levels in patients with UC in clinical remission whose FC was periodically monitored in clinical practice.
MethodsThis was a retrospective, observational, descriptive study in asymptomatic patients with UC on oral mesalazine therapy in whom the dose was modified (up or down) according to FC levels.
Adult patients with a diagnosis of UC were identified from local data from the ENEIDA registry.16 The inclusion criteria in the study were: 1) treatment with oral mesalazine at a stable dose not lower than 1.5 g/day in the previous three months; 2) modification (increase or decrease) of the mesalazine dose based on FC levels; 3) clinical remission of at least three months at the time of dose modification; and 4) at least one clinical follow-up after the mesalazine dose modification. Stable concomitant treatment with topical mesalazine, thiopurines or biological medicinal products (anti-TNF, vedolizumab) at stable doses was permitted for at least six months prior to mesalazine dose modification. Patients with an ileo-anal pouch or ileorectal anastomosis, treatment with oral or topical corticosteroids, pregnancy or comorbidities whose symptoms could overlap with those of UC (for example, untreated coeliac disease, irritable bowel syndrome and bile acid malabsorption) were excluded.
The ENEIDA registry was approved by our centre's Ethics Committee and all patients signed the informed consent form for their inclusion in it.
Patients were grouped according to whether they had been prescribed an increased or decreased mesalazine dose into: a) subjects with low FC (<250 μg/g) in whom the mesalazine dose was reduced (DOWN group); and b) subjects with high FC (>250 μg/g) in whom the mesalazine dose was increased (UP group). As this was a clinical practice study, patients using any of the commercial brands available in Spain during the study period were included.
Because regular FC monitoring was implemented at our centre in 2015, only the period from 2016 to 2022 was analysed. The variables of interest during follow-up were persistence of clinical remission, clinical relapse and the need to intensify treatment or introduce salvage therapy after the dose change.
Clinical remission was defined as the absence of rectal bleeding and normalisation of the number of bowel movements or a partial Mayo index value <3 points, with a rectal bleeding sub-index of 0. An increase in the number of liquid or pasty stools to >3 per day and/or the presence of blood in the stool, with a partial Mayo index greater than or equal to 3, was considered a clinical relapse. Lastly, salvage therapy was defined as increasing the dose of oral or topical mesalazine (in the dose reduction group), starting topical, oral or intravenous corticosteroids or changing the dose of biologicals or starting a new biological medicinal product or immunomodulators.
Qualitative data were expressed as absolute numbers and frequencies, and quantitative data as medians and interquartile range (IQR). Kaplan-Meier survival curves were used in each group to calculate the cumulative probability of remaining in remission after modifying the mesalazine dose.
ResultsA total of 56 patients were included, 39 in the DOWN group and 17 in the UP group. The main characteristics of the two study groups are shown in Table 1. Overall, 41% of patients were female, with a median time since onset of UC of 10 years (IQR: 5–18); 53.6% had extensive UC and 30.4% left-sided UC. Mesalazine was used as monotherapy in the majority of patients (75%: 64.3% orally only and 10.7% combined topical treatment), while in 16.1% it was used in combination with thiopurines, and in 8.9% with biological medicinal products.
Baseline characteristics of the patients included by study group.
| DOWN Group (n = 39) | UP Group (n = 17) | |
|---|---|---|
| Faecal calprotectin level (μg/g) | 36 (17−82) | 524 (393−739) |
| Female | 13 (33.3) | 10 (58.8) |
| Age in years | 55 (43−65) | 52 (39−72) |
| Extent of ulcerative colitis | ||
| Proctitis | 5 (12.8) | 4 (23.5) |
| Left-sided | 12 (30.8) | 5 (29.4) |
| Extensive | 22 (56.4) | 8 (47.1) |
| Concomitant treatments | ||
| Oral mesalazine (monotherapy) | 26 (67) | 10 (59) |
| Oral and topical mesalazine | 2 (5) | 4 (24) |
| Oral mesalazine and thiopurines | 7 (18) | 2 (12) |
| Oral mesalazine and biological medicinal product | 4 (10) | 1 (6) |
| Time in clinical remission before change (months) | 17 (11−32) | 16 (11−33) |
| Baseline mesalazine dose (g/day) | 3.6 (3−4) | 2.4 (1.5−2.4) |
| Modified mesalazine dose (g/day) | 2 (1.5–2.4) | 3.2 (3−4.4) |
| Duration of follow-up after change (months) | 22 (7−31) | 12 (4−24) |
Data expressed in absolute numbers and frequencies or medians and interquartile range.
In the DOWN group, the median dose of mesalazine at the time of modification was 3.6 g/day (IQR: 3−4); the baseline FC was overall less than 100 μg/g (median: 36 μg/g, IQR: 17−82) and the median time in clinical remission before dose change was 17 months (IQR: 11−32). The mesalazine dose was reduced to 2 g/day (IQR: 1.5−2.4) as a median, and in one fifth of the patients the drug was withdrawn (Table 1). After a median post-modification follow-up of 22 months (IQR: 7−31), 23% (9/39) showed clinical relapse and 28% (11/39) required salvage therapy (Table 2). The cumulative probability of remaining in clinical remission after decreasing the mesalazine dose was 91% and 82% at 12 and 24 months, respectively (Fig. 1).
Treatments used in patients who received salvage therapy by study group.
| DOWN Group (n = 11) | UP Group (n = 5) | |
|---|---|---|
| Oral mesalazine | 6 | 2 |
| Topical mesalazine | 1 | 0 |
| Oral and topical mesalazine | 1 | 0 |
| Topical corticosteroid | 2 | 3 |
| Oral corticosteroid | 1 | 0 |
| Intravenous corticosteroid | 0 | 0 |
| Immunomodulator | 0 | 0 |
| Biological medicinal product | 0 | 0 |
Data expressed in absolute numbers.
After the dose reduction, new FC testing was performed in 32/39 patients, with a median of 2.5 tests per patient (IQR: 1−3.7); of these, 15.6% showed some value of FC > 250 µg/g. Eight of the 11 patients who required salvage therapy had new FC testing, and 63% (5/8) had at least one FC measurement > 250 µg/g. Two of the patients who received salvage therapy did so because they had high FC values, without showing clinical relapse. Of the nine patients who had a relapse, six had new FC testing and 67% (4/6) had at least one > 250 µg/g. All patients with FC values > 250 µg/g received salvage therapy and 75% (4/5) showed clinical relapse.
In the UP group, the median mesalazine dose at the time of dose modification was 2.4 g/day (IQR: 1.5−2.4); in the majority of these patients, the baseline FC was above 400 μg/g (median: 524 μg/g, IQR: 393−739) and the median time in clinical remission before dose change was 16 months (IQR: 11−33). The mesalazine dose was increased to a median of 3.2 g/day (IQR: 3−4.4), with around a quarter of the patients increasing to more than 4 g/day (Table 1). After a median of 12 months (IQR: 4−24) of follow-up after dose modification, 29% of patients (5/17) had salvage therapy prescribed despite the increased mesalazine dose (Table 2) and 23% (4/17) suffered clinical relapse. The cumulative probability of remaining in clinical remission after increasing the dose was 86% and 72% at 12 and 24 months, respectively (Fig. 2).
After the dose change, new FC values were available for 13/17 patients in the UP group, with a median of two tests per patient (IQR: 0.5–3) during follow-up. FC levels fell to below 250 µg/g in 77% (10/13) of the cases. Six patients had at least one value > 250 µg/g during follow-up; of them, three (50%) required salvage therapy. Of the four patients in the UP group who had clinical relapse, FC measurements were available during follow-up for three of them (median: 2; IQR: 1–5); 67% (2/3) of these patients had shown at least one FC value > 250 µg/g. Only one patient in the UP group received salvage therapy while in clinical remission, due to high FC values.
DiscussionAminosalicylates are proven to be effective and safe drugs for the treatment of UC.5 The main clinical practice guidelines therefore recommend oral maintenance treatment at doses not lower than 1.5−2 g/day.1,2 Despite the fact that there is insufficient evidence to support the use of induction-type doses of mesalazine for maintenance5 and that therapeutic de-escalation should be considered in asymptomatic patients,17,18 over the last twenty years there has been a tendency towards the use of high doses. This has significant economic implications for both patients and the healthcare system,19,20 and could affect adherence to treatment, which is particularly compromised when the disease is in remission.21 In fact, as long as adherence is moderate to high, no differences in the long-term risk of relapse have been observed between those who use a low daily dose (2.2–2.8 g/day) and those taking doses above 4 g/day.22 Having said that, simplification of the dosage has been shown to be a factor that improves adherence.23
FC is the best biomarker of endoscopic and histological remission in UC and is therefore the most efficient predictor of clinical relapse in the short/medium term.6,9,10,12,24,25 Despite this, only two randomised controlled studies have evaluated the use of FC levels to guide the modification of treatment with mesalazine in patients with UC in remission. Moreover, they only analysed a dose increase but not a decrease. Lasson et al. studied 91 adults with UC in remission. Those with FC > 300 μg/g were randomised to an intervention group in which the mesalazine dose was increased, or to a control group without modification of the baseline dose. After 18 months of follow-up, the clinical relapse rate in the subgroup of patients with FC > 300 μg/g was significantly lower in the intervention group than in the controls (28.6% vs 57.1%; P < .05). Furthermore, it was found that, after the intensification, FC fell to below 200 μg/g in 64% of patients.15 In our experience in clinical practice, we found very similar values, with clinical relapse in 23% of patients in the UP group and a decrease in FC to <250 μg/g in 77% during follow-up. In a controlled, randomised, open-label study, Osterman et al. examined mesalazine dose escalation in 52 patients with inactive UC and FC > 50 μg/g.14 After six weeks of follow-up, 3.8% of the controls and 26.9% of the escalated group had achieved the primary endpoint (decrease in FC to <50 μg/g without clinical relapse; P = .049). Furthermore, a higher proportion of patients in the intervention group had a reduction in FC levels to below 100 μg/g (52.6%; P = .04) or below 200 μg/g (76.9%; P = .005). Similarly, in our study, more than half of the patients in the UP group had a reduction in FC levels to below 150 and 250 μg/g.
Despite providing the only scientific evidence available on the utility of modifying the mesalazine dose in patients with UC in clinical remission, both studies are far from perfect. The number of patients included was lower than planned, not all clinical relapses were confirmed by endoscopy and adherence to treatment was not confirmed. Lastly, the study by Osterman et al. used an FC threshold much lower than that required in clinical practice, which greatly limits the application of its results in our routine practice.
According to our findings, patients whose mesalazine dose was reduced based on FC levels also showed a high likelihood of maintaining clinical remission in the medium term. However, there is no specific evidence in the literature on the utility of FC for reducing the dose of mesalazine in patients with UC in remission. Buisson et al. evaluated the risk of relapse after therapeutic de-escalation in patients with IBD with different treatments and showed that FC levels > 100 μg/g before therapeutic de-escalation were highly predictive of clinical relapse in the following year.26 Furthermore, the authors found that FC values < 200 μg/g during surveillance were highly predictive of absence of clinical relapse, while figures > 400 μg/g were associated with a high risk of relapse. In our study, the majority of patients in the DOWN group had a baseline FC of less than 100 μg/g and the cumulative probability of maintaining clinical remission after dose reduction was over 80% at two years. Furthermore, only 15.6% recorded an FC value above 250 μg/g during follow-up.
Beyond FC levels, there are other risk factors for clinical relapse to be considered before any therapy de-escalation,17 and which should also be taken into account when evaluating the success of mesalazine dose reduction. The patients in the DOWN group were in clinical remission for a long time and were all over the age of 40, which would reduce the likelihood of relapse.
We need to take some considerations into account about the proposed strategy. Firstly, the FC threshold for modifying the mesalazine dose has yet to be defined. It seems most appropriate to use the threshold of 100 μg/g for dose reduction (or withdrawal of the drug),12 while the threshold could be increased to 250 μg/g for “preventive” dose increase.14,15,26 Secondly, the frequency of FC testing needs to be established. In a meta-analysis of six studies, asymptomatic patients with FC levels above the cut-off value had a more than 80% likelihood of relapse at two to three months.25 A prospective study in patients in deep remission who had treatment with anti-TNF agents discontinued showed that FC levels were elevated up to six months before the reappearance of endoscopic activity.27 However, the optimal frequency of FC testing after treatment modification to avoid clinical relapse, whether in dose elevation or reduction, has barely been studied and only in different clinical conditions. In our opinion, given that under stable clinical and therapeutic circumstances FC is usually measured every three to six months, it seems reasonable to perform at least two or three tests at shorter intervals (two to three months) after dose modification, as has already been suggested by other authors.26
Last of all, some of the limitations of our study are those inherent to its retrospective design, such as the lack of regular FC measurement intervals, the lack of endoscopic corroboration of relapse and the lack of data on treatment adherence, an essential aspect for this type of strategy. The mesalazine doses were not pre-established and were somewhat heterogeneous in both study groups. Finally, the sample size was small, which did not allow sub-analyses to be performed in relation to certain study populations (for example, patients on monotherapy or with concomitant treatments).
In conclusion, our results suggest that modification of the maintenance dose with mesalazine guided by periodic monitoring of FC levels in patients with UC in clinical remission is an effective and safe strategy, with a likelihood of clinical relapse of around 20% at two years. This needs to be consolidated by future prospective studies that generate the necessary evidence.
Ethical considerationsThis study was conducted in accordance with the Declaration of Helsinki. The ENEIDA registry, from which the data for this study were extracted, was approved by the Ethics Committee of our centre and all patients signed the informed consent form for their inclusion in it.
FundingThis study did not receive any financial support.
Conflicts of interestGP has received fees for lectures or expert advice, has been aided in attending courses or conferences, or her unit has received donations or grants for organising events or for research projects from Ferring, Pfizer, AbbVie, Takeda and Janssen.
MM has received fees for lectures or expert advice, has been aided in attending courses or conferences, or her unit has received donations or grants for organising events or for research projects from Faes Farma, Ferring, Falk, Pfizer, MSD, AbbVie, Takeda and Janssen.
MC has received fees for lectures or expert advice, has been aided in attending courses or conferences, or her unit has received donations or grants for organising events or for research projects from Takeda, Janssen, Faes Farma and MSD.
FC has received fees for lectures or expert advice, has been aided in attending courses or conferences, or her unit has received donations or grants for organising events or for research projects from Takeda, Janssen, Faes Farma and Pfizer.
ED has received fees for lectures or expert advice, has been aided in attending courses or conferences, or his unit has received donations or grants for organising events or for research projects from Samsung, MSD, AbbVie, Takeda, Kern Pharma, Pfizer, Janssen, Celgene, Adacyte Therapeutics, Roche, Otsuka Pharmaceuticals, Ferring, Shire Pharmaceuticals, Tillots, Thermofisher, Grifols and Gebroy Gilead.
The other authors have no conflicts of interest to declare.
