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Effectiveness of anti-TNFα drugs in patients with Crohn's disease who do not achieve remission with their first anti-TNFα agent

Digestive and Liver Disease, In Press, Corrected Proof, Available online 2 March 2016, Available online 2 March 2016

Abstract

Background

Anti-TNF treatment is effective for Crohn's disease (CD); however, some patients did not achieve remission with these drugs.

Aims

To evaluate the short-term effectiveness of a second anti-TNF in CD patients who did not achieve remission with the first one and to assess its durability.

Methods

Patients who did not achieve remission with their first anti-TNF were included. The short-term response of the second anti-TNF was assessed, the long-term response was evaluated in patients who achieved remission (Kaplan–Meier). Cox-regression was performed to identify predictors of loss of efficacy.

Results

In all, 118 CD patients received a second anti-TNF after primary failure of the first. The first anti-TNF was discontinued because of non-response in 54% of patients and partial response in 46%. Fifty-one percent of patients achieved remission in the short-term. The probability of remission was lower in patients for whom the drug indication was perianal disease (OR = 0.3, 95% CI = 0.1–0.7, P = 0.005). The dose was increased in 33% of patients, and 37% achieved/regained remission. The probability of maintaining remission was 76%, 68% and 64% at 12, 18 and 24 months, respectively.

Conclusions

Approximately half of the patients achieved remission with a second anti-TNF after primary failure of the first, this strategy was less effective in patients with perianal disease.

Keywords: Crohn's disease, Primary failure, Primary non-responder.

1. Introduction

Crohn's disease (CD) is a chronic transmural inflammation of the gastrointestinal tract of unknown aetiology. The role of various cytokines, including tumour necrosis factor (TNF), in the inflammatory process of inflammatory bowel disease (IBD) is well known; therefore, these cytokines are the main target of therapy. Given that there is no medical or surgical cure for CD, the current goal of treatment is to induce and maintain remission [1]. The introduction of anti-TNF antibodies has strengthened the therapeutic arsenal against IBD [2] and [3]. Both infliximab and adalimumab have proven efficacious for inducing and maintaining remission in moderate to severe CD [2], [4], and [5].

Some patients, especially those with long-standing disease, fail to respond to induction therapy with this drug and are defined as primary non-responders [6] and [7]. In addition, more than 10% of patients who achieve remission lose their response annually [8] and [9]. Finally, another relevant proportion of patients have to discontinue treatment because of intolerance. Both drugs are effective in anti-TNF-naïve patients and in those in whom the other drug has failed [10], [11], [12], and [13].

In patients who lose their response to an anti-TNF drug, the physician can switch to another anti-TNF agent in an attempt to regain remission. To date, however, few studies have evaluated the effectiveness of anti-TNF drugs in CD patients who did not achieve remission with their first anti-TNF drug [13], [14], [15], [16], [17], [18], [19], [20], and [21]. This analysis focuses on CD patients with primary failure, not including secondary failure or intolerance, because it is a less studied population and there are possible differences in the production mechanism of each clinical situation.

The objectives of this study were to evaluate the efficacy of treatment of CD patients with a second anti-TNF drug after primary failure of the first, to identify predictors of remission with the second anti-TNF, and to ascertain the duration of remission in patients who achieved remission with the second drug.

2. Materials and methods

2.1. Study subjects

We performed a multicentre, retrospective, open-label trial in which the patients were enrolled in the clinics of gastroenterologists at 24 Spanish hospitals from July 2012 to October 2013. CD patients who had not achieved remission with an anti-TNF and had received a second anti-TNF were included. We contacted specialists at the study centres and asked them to send us all cases that met the inclusion criteria. Patients were excluded if the second anti-TNF was prescribed because of intolerance or loss of response to the first drug.

2.2. Data collection

The data collected were age, sex, smoking status, age of diagnosis, location of disease, behaviour (inflammatory, stenosing or fistulising), perianal disease, surgical history, concurrent use of immunomodulators, indication of anti-TNF therapy, data regarding the first anti-TNF (drug, date of initiation of first anti-TNF, induction dose, response, loss of response, dose escalation, response to escalated dose, reason for dose escalation, and adverse events with the first drug), reason for discontinuation of the first anti-TNF, data on the second anti-TNF (drug, start date, indication, induction dose, initial response, disease activity at baseline, disease activity at the last visit, loss of response, date of loss of response, dose escalation, response to escalated dose, and adverse events) and reason for discontinuation of the second treatment.

We collected data from the previous history with anti-TNF drugs because the response that the patient had to the drug could impact the efficacy of the second anti-TNF drug; and the same happens with adverse events.

2.3. Definitions

2.3.1. Disease behaviour and location

Disease behaviour was described based on the Montreal classification as inflammatory, stricturing or fistulising. Location was defined by the CD findings in the gastrointestinal tract: ileal, colic, ileocolic and/or upper digestive tract CD, with or without perianal involvement.

2.3.2. Concomitant immunomodulators

We recorded whether a patient had been on immunomodulators for at least the first six months after commencing anti-TNF therapy.

2.3.3. Smoking history

A patient was considered a smoker if he/she consumed at least one cigarette daily for at least three months prior to being admitted to the study.

2.3.4. Indication of anti-TNF therapy

The indications for anti-TNF therapy were luminal CD, perianal CD or both.

2.3.5. Evaluation of response
  • - Primary failure: Failure to an anti-TNF was considered primary failure if the patient did not achieve remission with the drug. Therefore, primary failure included both non-responders and partial responders.
  • - Remission: Response to the anti-TNF was evaluated using the Harvey–Bradshaw index [22] (HBI) at the end of the induction period for the short-term response and at the end of follow-up for the long-term response. For luminal disease, remission was defined as an HBI ≤4 points without corticosteroids. For perianal CD, complete response was defined as closure of all fistulas. As HBI is a quite simple index, there was enough data in medical reports to calculate the score retrospectively.
  • - Partial response: For luminal disease, partial response was defined as a decrease in HBI of ≥3 points. For perianal CD, it was defined as a ≥50% reduction in the number of draining fistulas.
  • - Non-response: Patients who did not show a decrease of at least 3 points on the HBI were considered non-responders for luminal disease; patients who did not achieve closure of at least 50% of fistulas were considered non-responders for perianal disease.
2.3.6. Loss of response

Loss of response was defined as a worsening of the patient's symptoms associated with endoscopic, radiographic and/or serological evidence of inflammation.

2.3.7. Dose escalation

In the case of adalimumab dose escalation was defined as a reduction in the administration interval from every other week to every week. In the case of infliximab, dose escalation was defined either as an increase in the dose of infliximab or a decrease in the drug infusion interval or, occasionally, both.

2.4. Statistical analysis

The mean and standard deviation were calculated for continuous variables when they had a normal distribution; otherwise, the median and the interquartile range (IQR) were used. The t test was used to compare quantitative variables. Univariate and multivariate analyses were performed to study the short-term response. Percentages and 95% confidence intervals were provided for categorical variables. In multivariate analysis, variables that had reached statistical significance in the univariate (P < 0.05) and those that could be relevant although did not reach statistical significance were included. Categorical data were compared between patients according to the short-term response using the χ2 test. Maintenance of long-term remission with the second anti-TNF was assessed using Kaplan–Meier analysis, in which only patients achieving short-term remission were included. Differences between survival curves were evaluated using the log-rank test. Multivariate analysis using the Cox model was performed to identify predictive factors for loss of response.

3. Results

3.1. Study population

The study population comprised 118 CD patients who received a second anti-TNF after having failed to their first drug. The main characteristics of the study population are summarised in Table 1. Median age was 39 years (IQR 32–46). Half of the patients were female (50.4%), 45.8% had ileocolic disease (54 patients), 49.6% inflammatory disease (58 patients) and 45.3% perianal disease (53 patients). We found that 25% of patients were refractory to corticosteroids (28 patients) and that 64% were corticosteroid-dependent (71 patients).

Table 1 Characteristics of the study population.

Variables n (%)
Sex (female %) 58 (50.4)
Age (years), median (IQR) 39 (32–46)
Location
 L1 28 (23.7)
 L2 27 (22.9)
 L3 54 (45.8)
 L1 + L4 4 (3.4)
 L2 + L4 2 (1.7)
 L3 + L4 3 (2.5)
Behaviour
 Inflammatory 58 (49.6)
 Stricturing 19 (16.2)
 Fistulising 40 (34.2)
Perianal disease 53 (45.3)
Smoking habit 42 (37.2)
History of CD-related surgery 70 (59.3)
Concomitant immunosuppressants 51 (45.9)
Reason for discontinuation of the first anti-TNF
 Partial response 54 (45.8)
 Non-response 64 (54.2)

L1: ileum; L2: colon; L3: ileum and colon; L4: upper digestive tract.

Seventy patients had a history of CD-related surgery (59%) and 22% of patients had undergone more than two surgeries (25 patients). The most frequent indications for surgery were treatment of perianal disease (24%) and resection of intestinal stenosis (25%).

Mean time from diagnosis of CD to the start of the first anti-TNF treatment was 103 ± 93.4 months (range, 0–458 months).

The first drug was infliximab in 71 patients (60%) and adalimumab in the remainder. The most common indication for treatment with anti-TNF was luminal disease in 67% of cases (79 patients), followed by the association of luminal and perianal disease in 20% (24 patients) and perianal disease in 13% (15 patients). The reason for discontinuation of the first anti-TNF was partial response in 54 patients (46%) and no response in 64 patients (54%). Before the switch to another anti-TNF, the dose was increased in 53 patients (45%). The median duration of treatment with the first anti-TNF before switching was 5 months (IQR 3–13).

Almost all patients (95%, 110 patients) received a standard induction regimen: infliximab 5 mg/kg at weeks 0, 2 and 6; and adalimumab 160 mg/80 mg at weeks 0 and 2 and 40 mg/kg thereafter.

Immunosuppressants were being taken concomitantly with the first anti-TNF by 57% of patients (60 patients), but only 46% continued this therapy with the second (51 patients). During the course of the disease, 95% of patients were treated with azathioprine, 12% with mercaptopurine and 35% with methotrexate; several patients were treated with various immunosuppressants over the course of their disease.

The mean HBI before starting treatment with the second anti-TNF was 9.8 ± 3.6 points (range, 5–19 points). For this analysis, 3 patients were excluded. One patient started treatment with an HBI of 3 points but with concomitant corticosteroids; another patient had an HBI of 4 points, but it was decided to start treatment for complex and long-lasting disease; and the third patient had an HBI of 0 points and endoscopic activity. The mean number of draining fistulas in patients with perianal disease at the beginning of the second anti-TNF was 2.6 ± 2 (range, 1–8 fistulas).

3.2. Short-term effectiveness

Mean follow-up after the introduction of the second anti-TNF was 26 ± 21 months (range, 1–83 months).

Remission was achieved with the second anti-TNF drug in 51% of patients in the short term (60 patients).

Among patients who did not respond to the first anti-TNF, 44% achieved remission with the second drug (28 patients); those who discontinued the first anti-TNF because of partial response achieved remission with the second drug in 59% of cases (32 patients) (P = 0.11).

Among the 39 patients who started the anti-TNF treatment for perianal CD, 50% achieved full closure of fistulas (18 patients). Of the remainder, 19% had a reduction of 50% or more in the number of draining fistulas. The remainder had no response.

Among the patients in whom the biological drug was initiated only for treatment of luminal disease, 60% achieved remission (47 patients), 25% achieved only a partial response and the remainder had no response.

The univariate analysis showed that patients who had undergone CD-related surgery had a poorer response to the second anti-TNF drug than those who did not (P = 0.036). The same was true of patients receiving the drug for perianal disease compared with those with only luminal activity (P = 0.007).

Multivariate analysis confirmed that the probability of remission with the second anti-TNF drug was lower in patients for whom the indication was perianal disease (OR = 0.3, 95% CI = 0.1–0.7, P = 0.005) and in those who did not respond to the first drug compared with those who had a partial response to the previous anti-TNF with a tendency towards borderline statistical significance (OR = 2.1, 95% CI = 0.9–4.6, P = 0.053) (Table 2).

Table 2 Association between variables and the probability of achieving remission with the second anti-TNF drug.

Odds ratio 95% confidence interval P value
Anti-TNF drug for perianal disease 0.3 0.1–0.7 0.005
Previous primary non-response 2.1 0.9–4.6 0.053
Previous CD-related surgery 0.5 0.2–1.2 0.1
Smoking habit 0.6 0.2–1.4 0.2
Concomitant immunomodulator 1.08 0.4–2.5 0.8
Fistulising behaviour 1.07 0.4–2.6 0.8

No association was found between the effectiveness of treatment with a second anti-TNF after failure of the first and age of diagnosis, duration of disease, disease behaviour, location, sequence of drugs (infliximab/adalimumab vs. adalimumab/infliximab), induction and maintenance doses, dose escalation of the first anti-TNF, degree of disease activity (according to the HBI and/or number of draining fistulas at the beginning of the second anti-TNF), use of immunomodulators or smoking history.

The overall rate of adverse events with the second anti-TNF was 9%, including infusion reaction (3 patients), injection site reaction (1 patient), infection (3 patients), flu syndrome (1 patient), headache (1 patient), neuropathy (1 patient) and lupus-like syndrome (1 patient). The adverse effect led to discontinuation of the second drug in 73% of cases (in 3 patients the adverse effect was associated with a partial response to the second anti-TNF as a cause of discontinuation of treatment).

3.3. Long-term effectiveness

The probability of maintaining the remission achieved with the second anti-TNF drug was 76%, 68% and 64% at 12, 18 and 24 months, respectively (Fig. 1).

gr1

Fig. 1 Kaplan–Meier curve for time to loss of remission.

The incidence of loss of response to the second anti-TNF was 22.5% per patient-year of follow-up. No statistically significant differences in loss of response were observed with respect to the following variables: age, sex, reason for discontinuation of the first anti-TNF, location, disease behaviour, previous history of surgery, use of concomitant immunomodulators and current smoking habit. Finally, the most common reason for discontinuing the second anti-TNF was loss of response (46%) followed by non-response (33%) (Table 3). Successive treatment following the suspension of the second anti-TNF is described in Table 4.

Table 3 Reasons for discontinuation of the second anti-TNF.

n (%)
Primary non-response 16 (33.3)
Partial response 4 (8.3)
Loss of response 22 (45.8)
Drug intolerancea 5 (10.4)
Long-term remission 1 (2.1)

a Including infusion reaction, injection site reaction, infection, flu syndrome and other.

Table 4 Successive treatment following the suspension of the second anti-TNF.

n (%)
Anti-TNF 5 (10.4)
Anti-TNF + Thiopurine 2 (4.1)
Anti-TNF + Methotrexate 1 (2.1)
Ustekinumab 2 (4.1)
Ustekinumab + Thiopurine 1 (2.1)
Vedolizumab 1 (2.1)
Thiopurine 2 (4.1)
Methotrexate 2 (4.1)
Methotrexate + Mycophenolate mofetil 1 (2.1)
Mesalazine 1 (2.1)
Corticosteroids 2 (4.1)
Aphaeresis 1 (2.1)
Hematopoietic stem cell transplantation 2 (4.1)
Surgery 21 (43.8)
Loss of follow-up 4 (8.3)

3.4. Dose escalation

The dose of the second drug was increased in 39 patients (33%) a mean of 11.9 ± 10.9 months (range, 1–40 months) after initiation of the treatment. The reasons for escalating the dose of the second anti-TNF were non-response (13%), partial response (23%), loss of response (61%) and endoscopic recurrence (2.6%). Of the patients whose dose was escalated, 21% did not respond, 42% achieved only a partial response and the remaining 37% achieved or regained remission.

Of the 5 patients who did not respond to the second drug and whose dose was increased, 1 achieved partial response and another remission. Among patients with partial response to the second anti-TNF, 55.6% (5/9) achieved remission after dose escalation. Of patients whose dose was increased because of loss of response, 45.8% had a partial response and 33.3% (8/24) regained remission. The probability of maintaining remission after dose escalation was 87% at both 12 and 48 months.

4. Discussion

Anti-TNF drugs have proven efficacious in the induction [6], [7], [23], and [24] and maintenance [2], [4], [5], and [25] of remission in CD patients. However, incomplete response and lack of response to anti-TNF drugs in CD patients is a relatively common problem. Several studies have reported that 10–40% of CD patients do not attain a clinically relevant response to anti-TNF treatment [2], [6], [7], [26], [27], and [28].

Treatment with a second anti-TNF is effective in CD patients who cannot tolerate or lose the response to their first drug [13], [15], [17], [21], [24], and [27]. However, CD patients who only achieve a partial response with no clinical remission with the first drug and those who do not respond at all represent a different challenge.

To date, few studies have analysed the effectiveness of switching to a second anti-TNF when failure of the first one was classed as primary failure. Furthermore, study populations were small, and the inclusion criteria and definitions for primary failure differed [12], [13], [15], [16], [17], [18], [19], [20], and [21]. To our knowledge, the present study is the largest study to evaluate the effectiveness of a second anti-TNF drug after primary failure of the first one.

There are no uniform criteria for the term “primary failure”; most authors consider it a non-response to anti-TNF treatment, and many others do not define it. We defined primary failure as failure to achieve remission in both partial responders and non-responders, only in a recent paper of Papamichael et al. [29] primary failure was considered both CD patients with complete absence of response to anti-TNF and those with response but non-remission. We considered that both groups experienced primary failure, because the goal when treating IBD is to achieve not only response, but also clinical remission [1], [30], [31], and [32].

The 2 largest studies on the effectiveness of that issue are discussed below. The CHOICE trial [16] evaluated safety, fistula healing, quality of life and work productivity in adalimumab-treated patients whose treatment with infliximab failed. The study population included primary non-responders. The reason for previous anti-TNF failure was determined subjectively by the treating physician, and there were no strict criteria for determining primary non-responders. The CARE trial [17] evaluated clinical effectiveness, resolution of extraintestinal manifestations and safety of adalimumab in a cohort of patients with CD, including a subgroup of patients with primary failure to infliximab. Both studies only analysed the effectiveness of adalimumab as a second anti-TNF treatment; these trials demonstrated the efficacy of a second anti-TNF after primary failure with the first agent, although neither was specifically designed to assess the response of an anti-TNF drug after previous primary failure.

In our study, 51% of patients achieved remission in the short term with the second anti-TNF drug. Our results appear to be in agreement with data for other published reports [14], [16], [17], [19], and [21]. Thus, the proportion of patients achieving short-term remission in our trial was higher than that reported in CARE [17] (29%) and CHOICE [16] (31% complete fistula closure). These better results could be accounted for by the inclusion of partial responders among patients considered to have experienced primary failure. Similarly, the efficacy results from the CHOICE [16] trial were inferior because only perianal disease was evaluated.

In this respect, our data reveal that the probability of achieving remission was lower in patients in whom anti-TNF treatment was prescribed for perianal disease. These results are in accordance with those obtained in the CARE [17] trial, in which remission rates were higher in patients with luminal disease than in patients with perianal disease.

A remarkable finding is that the effectiveness of the second anti-TNF drug depends on the reason for the treatment switch [33]. A recent meta-analysis investigated the efficacy of a second anti-TNF agent after failure or intolerance to a first drug. The remission rate was higher when the reason for withdrawing the first anti-TNF was intolerance (61%) than after secondary failure (45%) or primary failure (30%), only non-responders were considered primary failure [33]. The results of our study reveal a trend towards differences in remission rates between patients with a partial response and complete non-response to a previous anti-TNF drug (OR = 2.1, 95% CI = 0.9–4.6, P = 0.053). Fifty-nine percent of patients with a partial response to the first anti-TNF drug achieved remission with the second, while the remission rate among non-responders was only 44%.

In a recent study of Billiet et al. a model was developed to predict primary non-response to IFX in CD patients; the authors found that lower BMI, older age at first IFX and previous surgery were related with lower probability of response to IFX [34]. In our study a worse response to the second anti-TNF in patients with previous CD related surgery was found in the univariate analysis (P = 0.036), which was not confirmed in the multivariate (OR = 0.5, 95% CI = 0.2–1.2, P = 0.1).

In contrast with data from other trials [17] and [19], we found no association between the rate of remission and concomitant use of immunomodulators. Similarly, we found no association between remission and age or disease duration, whereas other authors reported that the response was better in CD patients with shorter disease duration [17]. Again, no differences in response rates were found according to the type of switch, the induction regimen or the degree of activity.

Mean follow-up with the second anti-TNF drug was 26 months, higher than in other studies [16], [17], and [33]. The one-year survival free of loss of response to the second anti-TNF drug was 76%, that is, higher than in previously published trials [14], [15], [16], [17], and [33] (Fig. 1). Dose escalation in CD patients who lost the response to anti-TNF drugs is effective and common in clinical practice [4], [5], [12], [14], [24], [35], [36], and [37]. The results of our study suggest that dose escalation may also be a therapeutic option after the loss of response or partial response to the second anti-TNF agent. Thus, one-third of the patients who had lost the response to the second anti-TNF agent regained remission after dose escalation. Furthermore, 56% of those who had a partial response achieved clinical remission after dose escalation. However, there are insufficient data to recommend dose escalation in patients who do not respond to the second anti-TNF drug and experience primary failure with the first. Larger studies are needed to confirm our results.

One possible reason for the good response to dose escalation in patients who experience a partial response might be better clearance of the drug in patients with increased inflammatory activity. Takeuchi et al. analysed the effectiveness of this strategy in patients with rheumatoid arthritis treated with different concentrations of infliximab (3, 6 and 10 mg/kg) depending on the levels of TNF in blood [38]. It is possible that these patients, who did not completely respond initially, could achieve remission with higher doses of the anti-TNF agent. Unfortunately, we did not analyse the concentration of cytokines and anti-TNF drugs in blood.

The mechanism underlying primary non-response to an anti-TNF drug and subsequent response to another anti-TNF drug is unknown. Because of the similar structure and function of infliximab and adalimumab, one would think that if there is no response to one of them, the other will also fail [39]. Differences in efficacy between anti-TNF agents may be due to differences in pharmacokinetic properties or tissue penetration [40]. In this trial, more than half of the patients achieved remission with the second anti-TNF after primary failure with the first drug, suggesting that the lack of response to one anti-TNF drug does not necessarily entail failure of another.

The present study is subject to a series of limitations, mostly related to its retrospective design. We did not measure laboratory values such as C-reactive protein, anti-TNF drug levels nor the presence of drug antibodies. Despite these limitations, this is the first study to date specifically designed to evaluate the effectiveness of a second anti-TNF agent after primary failure of the first drug.

In summary, the results of our study suggest that CD patients can be successfully treated with a second anti-TNF drug after failure of the first one (partial response or non-response). This strategy is less effective in CD patients receiving the drug for perianal disease. On the other hand, this approach is more effective in patients in whom the first anti-TNF was withdrawn owing to partial response than to complete absence of response. A significant proportion of patients lose the response to the second anti-TNF in the long term, although increasing the dose was an effective strategy for regaining response in some cases.

Conflict of interest

Dra. Chaparro has served as speaker, consultant and advisory member for, and has received research funding from MSD (U.S. and Canada) and Abbvie (U.S.). Dr. Barreiro-Acosta has served as lecture and consulting fees from MSD and Abbvie. Dr. Castro has attended scientific meetings, presentations and participation in clinical trials and financed by MSD and Abbvie. Dr. Domenech: scientific advice, conferences, support for research and/or training activities: MSD, Abbvie, Takeda (Japan), Hospira (U.S.), Kern Pharma (Spain), Ferring (Switzerland), Faes Farma (Spain), Shire Pharmaceuticals (U.S.), Tillotts Pharma (Switzerland), Chiesi (Italy), Gebro Pharma (Austria) and Otsuka Pharmaceuticals (Japan). Dr. Pérez-Calle has served as advisory boards for MSD and Abbvie. Dr. Taxonera has served as speaker, consultant or advisory board member for Merck Sharp & Dohme (U.S.) and Abbvie. Dr. Barrio reports non-financial support from Abbvie, non-financial support from MSD, non-financial support from Ferring, outside the submitted work. Dra. Saro has served as advisory member for Abbott (U.S.), Ferring, Tillotts and MSD. Dr. Bermejo has served as a speaker and consultant for MSD and Abbvie and has received research funding from MSD. Dra. Garcia-Sánchez has served as a speaker, advisor and consultant for MSD and Abbvie. Dr. Ginard: scientific advice and/or training activities for MSD, Abbvie, Janssen Cilag (U.S.) and Otsuka Pharmaceuticals. Dra. Vera has served as advisory member for de MSD, Abbvie, Shire Pharmaceuticals, and Ferring. Dr. Calvet has served as a speaker, a consultant and advisory member for, or has received research funding from MSD, Abbvie, Hospira, Pfizer (U.S.), Shire Pharmaceuticals, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma (Switzerland). Dr. Gisbert has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Kern Pharma, Takeda, Janssen, Pfizer, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma (Germany), Chiesi, Casen Fleet (Spain), Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma.

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Footnotes

a Department of Gastroenterology, La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain

b Department of Gastroenterology, Ramón y Cajal, Madrid, Spain

c Department of Gastroenterology, Clínico de Santiago, Santiago de Compostela, Spain

d Department of Gastroenterology, Virgen Macarena, Sevilla, Spain

e Department of Gastroenterology, Valme, CIBEREHD, Sevilla, Spain

f Department of Gastroenterology, Germans Trias i Pujol, CIBEREHD, Badalona, Spain

g Department of Gastroenterology, Infanta Sofía, Madrid, Spain

h Department of Gastroenterology, Fundación Alcorcón, Madrid, Spain

i Department of Gastroenterology, Clínico San Carlos, Madrid, Spain

j Department of Gastroenterology, Río Hortega, Valladolid, Spain

k Department of Gastroenterology, Central de Asturias, Oviedo, Spain

l Department of Gastroenterology, Complejo Hospitalario Universitario, Pontevedra, Spain

m Department of Gastroenterology, Hospital Universitario Miguel Servet, Zaragoza, Spain

n Department of Gastroenterology, Cruces, Vizcaya, Spain

o Department of Gastroenterology, Manises, Valencia, Spain

p Department of Gastroenterology, Cabueñes, Gijón, Spain

q Department of Gastroenterology, Fuenlabrada, Madrid, Spain

r Department of Gastroenterology, Reina Sofía, Maimónides Institute of Biomedical Research of Córdoba, Córdoba, Spain

s Department of Gastroenterology, Son Espases, Mallorca, Spain

t Department of Gastroenterology, General de Alicante, Alicante, Spain

u Department of Gastroenterology, Puerta de Hierro, Madrid, Spain

v Department of Gastroenterology, Clínico de Valencia, Valencia, Spain

w Department of Gastroenterology, Clínico Universitario Lozano Blesa, CIBEREHD, Zaragoza, Spain

x Department of Gastroenterology, Parc Tauli, CIBEREHD, Sabadell, Spain

Corresponding author at: C/ Corazón de María 50-52, 12° A, CP 28002 Madrid, Spain. Tel.: +34 913093911; fax: +34 914022299.