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Addressing current treatment challenges in Crohn's disease in real life: A physician's survey
Digestive and Liver Disease, Volume 46, Issue 12, December 2014, Pages 1066–1071
In recent years several trials have addressed treatment challenges in Crohn's disease. Clinical trials however, represent a very special situation.
To perform a cross-sectional survey among gastroenterologists on the current clinical real life therapeutic approach focussing on the use of biologics.
A survey including six main questions on clinical management of loss of response, diagnostic evaluation prior to major treatment changes, preference for anti-tumour necrosis factor (TNF) agent, (de-)escalation strategies as well as a basic section regarding personal information was sent by mail to all gastroenterologists in Switzerland (n = 318).
In total, 120 questionnaires were analysed (response rate 37.7%). 90% of gastroenterologists in Switzerland use a thiopurine as the first step-up strategy (anti-TNF alone 7.5%, combination 2.5%). To address loss of response, most physicians prefer shortening the interval of anti-TNF administration followed by dose increase, switching the biologic and adding a thiopurine. In case of prolonged remission on combination therapy, the thiopurine is stopped first (52.6%) after a mean treatment duration of 15.7 months (biologic first in 41.4%).
Everyday clinical practice in Crohn's disease patients appears to be incongruent with clinical data derived from major trials. Studies investigating reasons underlying these discrepancies are of need to optimize and harmonize treatment.
Keywords: Anti-TNF agent, Crohn's disease, Loss of response, Step-up strategy, Thiopurine, Treatment de-escalation.
The introduction of tumour necrosis factor (TNF) inhibitors more than 10 years ago in the treatment of Crohn's disease (CD) represented a major therapeutic breakthrough  . Since the first double-blind, placebo-controlled trial with infliximab (IFX)  numerous pivotal trials on the efficacy of infliximab, adalimumab (ADA) and certolizumab pegol (CTZ) in inducing and maintaining clinical response and remission and achieving mucosal healing have been published, , , , , and .
Since the early days, concerns regarding safety, above all opportunistic and severe infections and also neoplastic diseases have been raised and . Even after extensive worldwide experience with anti-TNF therapy in IBD and other indications, such as rheumatological or dermatological diseases, there still is some uncertainty about potential risks, , , , and . In the last years, there is an increasing trend towards an earlier introduction of Anti-TNF agents (which is associated with a better efficacy  ) either via a rapid step-up and or top down  approach, to avoid prolonged steroid exposure and minimizing CD-associated morbidity and the need for surgery. Since the SONIC-trial  the initial use of anti-TNF in combination with a thiopurine has been advocated at least in patients with high-risk characteristics for a disabling disease course. This approach has consecutively also been included in treatment guidelines  . Aside from treatment optimization de-escalation of therapy after variable duration of clinical remission and associated factors predicting success have been studied, , and .
In parallel, the question of applying the best clinical strategy when confronted with loss of response (LOR) in patients receiving maintenance anti-TNF therapy has emerged. LOR occurs in a significant fraction of patients and has been reported to occur in about 20–50% of patients within the first year of therapy and . Switching anti-TNF has been shown to be an effective strategy in case of LOR and drug intolerance, , , and but should be omitted simply for the reason of a more convenient route of drug administration  . However, prior to switching, dose intensification ideally guided by anti-TNF trough levels and anti-drug antibodies measurement should always be considered, due to both, the still limited number of biologic agents available and the high success rates (about 50–70%) of dose intensification in regaining response, , and . Even after failure of two anti-TNF agents, there may be considerable rates of response and remission using a third one  . Nonetheless, at this point in time only in the US and Switzerland such a third agent is available without a specific reimbursement application.
Even with similar treatment guidelines in the US (ACG) and Europe (ECCO) attitude towards anti-TNF treatment and immunosuppression in CD patients may differ between physicians (depending on their experience), treatment facilities (specialized centre, hospital and private practice) and countries. The few studies having looked at adherence to guidelines among gastroenterologists have revealed equivocal results and . However, the treatment of CD appeared to be appropriate in most patients according to cohort studies from Switzerland and Europe and .
Despite a multitude of randomized trials, clinical real life differs: looking at a selection of pivotal IBD trials, less than a third of unselected real life IBD patients would have been actually suited for inclusion  . We thus aimed to obtain a comprehensive overview on the clinical practice of GI specialists in Switzerland involved in the care of CD patients in the biologics era with a special focus on the current use of anti-TNF agents, including their position in the therapeutic armamentarium and to gain insights on how the published treatment paradigms are currently addressed in a real-life setting.
2. Materials and methods
A questionnaire was sent to all Swiss gastroenterologists by conventional mail. There is no approved and regularly updated list of all actively practising gastroenterologists maintained by an official institution, such as the Swiss Society of Gastroenterology (SGG). However, facilitated by the relatively small size of the country, there is a comprehensive list of all Swiss gastroenterologists available, used for various purposes, such as invitation to educational events in and outside of Switzerland or information on announcements for research grants or prices. In total, after discarding those gastroenterologists on the list without valid mail address (either directly available on the list or after a search in an online phone book, harbouring the complete official and up-to-date Swiss telephone registry), the questionnaire was sent to 318 gastroenterologists in April 2012. Physicians were asked to return the questionnaire either by conventional mail, fax or email (after scanning) until the end of 2012. This questionnaire included six questions addressing the following parameters: step-up strategy (question V), preference for any specific TNF antagonist (question IV), diagnostic evaluation antecedent to any major treatment change (question III), addressing loss of response (questions I, II) as well as de-escalation strategy in the event of prolonged remission on combination therapy (question VI). It also included a basic section about practice characteristics of the respondent, such as age, gender, years in gastroenterology (GI) practise, practise setting, numbers of IBD patients seen/followed and treated with anti-TNF per year (Supplementary Table S1).
The main outcome – the percentage of Swiss gastroenterologists voting for a given option (questions IV–VI), voted sequence of given options (question I), mean rating (question II and three III) or mean interval (question VI, 2nd part), respectively – was analysed both globally as well as stratified according to the number of IBD patients seen and treated with anti-TNF agents per year, years in clinical practice and practice setting. Statistical analyses were performed with SPSS (Version 21; IBM, Armonk, NY, USA) and Prism (Version 6, GraphPad Software, La Jolla, CA, USA). To investigate potential differences between the pre-specified subgroups Chi-Square testing was used. Regarding the interval on prolonged remission prior to stopping one or both medical treatments D’Agostino & Pearson omnibus normality test was used, revealing a non-normal distribution. Consecutively Kruskal–Wallis test was used to evaluate whether there are any differences in mean values between the subgroups. Mann–Whitney test was then applied to directly compare between subgroups.
3.1. Response rate and characteristics of responders
Out of 318 Swiss gastroenterologists invited to participate in the survey 120 (37.7%) responded and were analysed. The mean age of the responding GI specialists was 48.4 ± 9.8 years (89.1% male) with a mean professional experience as a gastroenterologist of 15.1 ± 9.3 years. About a third of gastroenterologists provide clinical care in each of the following sections: private practice (32.5%), smaller hospitals (district hospital 26.7% and private hospital 5.8%), as well as larger hospitals, such as university hospitals (20%) or large non-university hospitals (15%). Further information on baseline characteristics of gastroenterologists according to practise setting is given in Table 1 .
|Private practice||District hospital||Private hospital||Large non-university hospital||University hospital|
|Number of gastroenterologists||39 (32.5%)||32 (26.7%)||7 (5.8%)||18 (15%)||24 (20%)|
|Mean age (overall 48.4 years)||54.4||49.5||47.4||44.4||40.5|
|Mean practice experience (overall 15.1 years)||20.2||15.7||15.6||11.7||8.4|
|Male gender (overall: 89.1%)||94.4%||90.6%||71.4%||77.8%||87.5%|
|IBD patients followed|
|1–30||15 (38.5%)||20 (62.5%)||4 (57.1%)||11 (61.1%)||11 (45.8%)|
|31–100||20 (51.3%)||11 (34.4%)||3 (42.9%)||4 (22.2%)||6 (25%)|
|>100||4 (10.3%)||1 (3.1%)||0||3 (16.7%)||7 (29.2%)|
|IBD patients treated with anti-TNF|
|1–10||23 (60.5%)||21 (65.6%)||4 (57.1%)||8 (44.4%)||10 (47.6%)|
|11–30||13 (34.2%)||10 (31.3%)||3(42.9%)||6 (33.3%)||6 (28.6%)|
|31–100||2 (5.3%)||1 (3.1)||0||4 (22.2%)||5 (23.8%)|
|>100||1 (2.6%)||0||0||0||2 (9.5%)|
IBD, inflammatory bowel disease; TNF, tumour necrosis factor.
3.2. Preferred step-up strategy
After lack of response to systemic steroids, budesonide, 5-aminosalicylates or an inability to taper these agents, the majority of Swiss gastroenterologists (90%) use a conventional step-up strategy with a thiopurine as a first-line therapy. Only 7.5% of responders use anti-TNF therapy alone, 2.5% use combination therapy (thiopurine combined with anti-TNF) as a first-line therapy. We did not observe any statistical differences in the strategy with regard to any of the pre-specified subgroups (number of IBD patients seen and treated with anti-TNF per year, years in clinical practice and practice setting). Notably, there is not an increased primary use of anti-TNF (either as mono-therapy or in combination with thiopurine) in referral centres versus smaller hospitals or private practice (Supplementary Figure S1). Based on the data from the SONIC trial we calculated the efficacy of the treatment strategies according to the practicing physicians from our survey as well as the efficacy gap, assuming that in the comparison group all 1000 imaginary patients would have received a combo-therapy (Supplementary Figure S2).
3.3. Preference for a specific anti-TNF agent
Almost half (41.2%) of Swiss gastroenterologists have no preference for a specific anti-TNF agent. Among responders having a preference for a given anti-TNF, IFX is by far the preferred anti-TNF agent (47.1%), while 10.9% and 0.8% stated ADA and CTZ, respectively, to be their initial agent of choice ( Fig. 2 ). IFX is significantly more preferred in those physicians seeing less than 30 IBD patients per year (57.4% vs. >30 Pat: 37.3%;p = 0.03) and those treating less or equal than 10 patients with anti-TNF per year (57.6% vs. >10 Pat: 35.2%;p = 0.02). The preference according to the pre-specified subgroups is shown in Table 2 .
|Preference for specific agent||All gastroenterologists||IBD patients followed per year||IBD patients treated with anti-TNF per year|
|Adalimumab||13 (10.8%)||4 (6.6%)||9 (15.3%)||5 (7.6%)||8 (14.8%)|
|Certolizumab||1 (0.8%)||1 (1.6%)||0||1 (1.5%)||0|
|Infliximab||57 (47.5%)||35 (57.4%)*||22 (37.3%)*||38 (57.6%)*||19 (35.2%)*|
|No Preference||49 (40.8%)||21 (34.4%)||28 (47.5%)||22 (33.3%)||27 (50%)|
IBD, inflammatory bowel disease; TNF, tumour necrosis factor.
Significant differences with respect to infliximab are depicted with asterisks;p = 0.021 (≤30 vs. >30 patients seen per year),p = 0.015 (≤10 vs. >10 patients treated with anti-TNF per year.
3.4. Assessments prior to any major treatment change
Regarding the routine diagnostic evaluations performed before any major change in the treatment strategy, endoscopy, faecal calprotectin and clinical judgement are considered as equally adequate tools (5.19, 5.15 and 5.25 mean value of all answers on a scale from 1 “not adequate” to 6 “fully adequate”). Magnetic resonance imaging (MRI) is somewhat less preferred to the other given modalities with a mean value of 4.16 as depicted in Fig. 1 . There are no significant differences in the evaluation of these diagnostic options according to the prespecified subgroups of Swiss gastroenterologists (Supplementary Figure 3).
3.5. How to address loss of response
In case of LOR, the most preferred strategy is shortening the interval between anti-TNF administrations. In the questionnaire two almost identical questions aimed at investigating the preferred treatment approaches when facing LOR. While in the first question the preferred sequence of all given treatment strategies to address LOR had to be stated (from 1 to 7 for most preferred to least preferred, respectively), in the second question responders were to rate all given strategies on a scale from 1 to 6 (with lowest and highest agreement, respectively). With regards to the separate evaluation of every proposed strategy (question II), Swiss gastroenterologists favour three options to optimize treatment by modifying the application of anti-TNF to a similar extent: shortening the interval (mean value of all answers from the scale from 1 to 6: 5.4), increasing by doubling the dose (5.0) and switching to another anti-TNF (4.9). Adding a thiopurine (3.9), initiating a full anti-TNF re-induction (3.6), adding corticosteroids (3.5) or referring the patient to surgery (3.5) is considered inferior. Adding methotrexate (2.9) is not among the preferred strategies ( Fig. 2 A). However, looking at the preferred sequence of all these given strategies to address LOR (question I), a clearer preference of shortening the interval becomes evident: this strategy is voted as best option by the vast majority of gastroenterologists (46.9%). Doubling the dose (20.4%) and switching the anti-TNF agent (4.4%) are less often referred to as being the best approach. The latter receives even less approval as best option than starting a full re-induction of anti-TNF (5.3%) or adding prednisone (15.9%, Fig. 2 B). We did not find any significant differences in the preference of the step-up strategy according to IBD patients seen or treated with anti-TNF per year, practice setting (hospital vs. general practice) as well as years of clinical experience.
3.6. Prolonged remission on combo therapy – how to de-escalate, and when
In case of prolonged remission on combination therapy the gastroenterologists stop the thiopurine first in most cases (50.8%). In contrast, 40.0% prefer to primarily stop the anti-TNF agent. Only 4.2% continue both therapies indefinitely despite prolonged remission on combination therapy, while only 1.7% of responders stop both medications at the same time. The mean interval of prolonged remission considered adequate for treatment de-escalation is 15.7 months, with a wide range from 6 to 48 months. Regarding the interval of prolonged remission with combo-therapy considered sufficient, substantial heterogeneity is observed among physicians stopping either one or both drugs ( Fig. 3 ). There is no significant difference in the preference for a de-escalation treatment strategy in the pre-specified subgroups. However, the time on combo-therapy considered sufficient prior to de-escalation is significantly longer in those physicians seeing less than 30 IBD patients per year (mean 17.5 vs. 13.5 month,p = 0.017) and treating less than 10 IBD patients with anti-TNF, respectively (mean 17.4 vs. 13.2 month,p < 0.01). In contrast, no significant differences regarding the interval are observed according to hospital setting or years in practice. With regard to the latter, there is nevertheless a trend towards a shorter interval in physicians <10 years in practice (14.4 vs. 17.4 years in those >10 years of professional experience,p = 0.067). Of note, although not significant, physicians who de-escalate within a year after initiation of treatment by trend have a stronger preference to stop the immunosuppressant first, compared to those de-escalating after 1 year of combo-therapy with a trend towards stopping the anti-TNF agent first (immunomodulator first 61.1% vs. 43.8%; anti-TNF first 38.9% vs. 50%; stop both 0% vs. 6.3% for de-escalation ≤12month vs. > 12 month;p = 0.08).
We here report the results of a six-item survey regarding important treatment paradigms in CD. Despite first pivotal clinical trials addressing elements covered in this survey, a common ground of all contained issues is a lack of sufficient evidence to define the optimal clinical strategy at the present time. Yet, even if there was more evidence, the obvious differences between real-life medicine and ideal world of clinical trials  raises concerns regarding general transferability of clinical trial data to the practicing physician. Therefore, not only data on how specific treatment challenges in CD should be addressed based on clinical trials, but also on how these challenges in fact are addressed in real life are essential to identify future needs and treatment gaps to set the stage towards an optimization in the treatment of IBD.
The preference for an immunosuppressant as the first-line step-up-option is striking, with 9 out of 10 Swiss gastroenterologist voting for this approach. However, this question did not contain any patient characteristics and one may speculate that the answer would have differed substantially, if any indicators of a disabling disease course would have been given. Moreover, the answer does not allow drawing any conclusion, on when the treating physician would go for a next step in case of providing suboptimal clinical, biochemical or endoscopic response. The magnitude of the preference for a conventional step-up approach is nonetheless striking – especially considering the liberal reimbursement situation in Switzerland – and may appear somewhat “outdated”. However, using an immunosuppressant agent first with or without a corticosteroid is completely in line with major CD-treatment recommendations and guidelines, , and . This practice is not in contradiction to the increasing body of evidence, that anti-TNF based strategies are more effective in achieving crucial CD endpoints  and the recently published data on thiopurines, revealing no benefit of an early introduction regarding the primary endpoints and . Although the top-down approach has been shown to be superior in inducing remission, reducing the need for steroids and achieving mucosal healing, there was no clinical benefit regarding long-term remission rates beyond 52 weeks between early combined immunosuppression (top-down) and conventional management (bottom-up) groups  .
Another key finding of our survey is the fact, that with only few exceptions, there are no major differences in the management and preferences between gastroenterologists practising in secondary (private practise) or tertiary (large non-university or university hospitals) care. However, those physicians having more experience in the treatment of IBD patients clearly reveal to have less preference for a specific agent. Interestingly – in contrast to what one might assume based on the difference in the application mode between IFX and ADA/CTZ – the preference for the i.v. agent is even stronger in physicians in private practice compared to their colleagues in a hospital setting. This holds true despite the fact, that potential obstacles associated to IFX, such as the need for an infusion unit with monitoring for potential infusion reactions and fixed treatment schedules, evidently are more of an issue in private practice.
Regarding the preferred treatment options to address LOR there apparently is somewhat a discrepancy between the answers forquestion I(preferred sequence of all given options) andquestion II(each option to rate independently). Sequencing the order of preferred options more clearly emerges the preference of shortening the interval. This choice is in line with current treatment recommendations to optimize treatment in LOR, , , and . However, the independent rating for every option given (question II) is indicative of an overuse of switching the anti-TNF agent by gastroenterologists participating in this survey. Adding prednisone is among the least preferred strategies in question II (3.6). Nevertheless, adding prednisone is voted as the third best option in the sequential vote, being even the most preferred strategy in one out of six gastroenterologists (15.9%). This is remarkable, as adding corticosteroids in LOR has not been shown to be effective in this setting, thus it is not included in treatment recommendations  . On the other hand, a watchful waiting approach in LOR patients with mild symptoms has been recommended and , as the symptoms of LOR may be transient without any further change of clinical management. Thus, the short-term addition of steroids indeed may be considered an adequate symptomatic bridge.
In case of prolonged remission the vast majority performs a de-escalation of medical treatment, which may be considered in line with the current evidence from the literature, despite a growing advocacy to “never stop combo-therapy” especially in North America  . In contrast to one of the very few trials prospectively investigating treatment de-escalation  the majority of gastroenterologists in our survey stop the immunosuppressive agent first, in line with another European study  . The wide range of the interval considered sufficient to initiate withdrawal of medical treatment (up to 4 years in our survey) is in line with the current unequivocal body of evidence from the literature with a wide range between six  and at least 27 month  .
As with all surveys, this study has several limitations. Results from a questionnaire have always to be interpreted with caution, as a genuine image of reality cannot necessarily be presumed: Answering a questionnaire is not equal to clinical practise. The response rate of 38% may appear low. However, the rate is in line respectively rather above the typical response rates from survey studies in physicians, , , and , known to be notoriously lower than in patient surveys  . More importantly, we believe in accurate representativity of our sample. Our results do not reflect the current clinical procedural standard from a selection of clinical opinion leaders from IBD referral centres but were obtained to a high extent from gastroenterologists in private practice or smaller hospitals. Switzerland is an ideal country to obtain this empiric data, due to the small size of the country and the limited number of GI specialists in active clinical practice, allowing the acquisition of an image representative for the whole country. Moreover, in this country there is a substantial clinical experience with three anti-TNF agents registered for CD (apart from the US the only country in the world), including a relatively liberal reimbursement policy. The latter enables gastroenterologists in Switzerland to virtually always introduce anti-TNF in CD if considered clinically indicated which is why our results are not to be interpreted to be derived by substantial economic pressure.
Unfortunately, based on this survey, we are not able to draw any conclusions regarding the underlying reasons for differences in the preference for a specific agent (such as higher and longer experience with infliximab including the amount of available data, subjective perception of different clinical effectiveness, desire to regularly follow the patient within the fixed infusion interval, or simply monetary considerations). However, in spite of all we believe, that survey studies as our currently reported one, are of critical value in assessing how efficiently and consequently data generated from large controlled clinical trials and consecutively entering therapeutic guidelines, translate into real life therapeutic practice. Our results clearly illustrate and reinforce the notion that not always what is supported by evidence-based medicine is accepted by physicians at the “clinical front” and implicated in everyday clinical practise. More importantly, these results underline the need for further investigations on the reasons for these discrepancies, including their consequences on clinical outcome parameters or cost issues. Regarding these endpoints, we have to bear in mind, that due to the diverging patient characteristics in clinical practise and pivotal clinical IBD trials  the conclusions derived from these trials may not necessarily be translated into everyday clinical practice, substantiating the need for trial design models at the closer edge of clinical real-life, such as for instance cluster randomized trials with less restrictive inclusion criteria.
In summary, the vast majority of all Swiss gastroenterologists still apply a conventional step-up approach. Among those physicians having a specific preference for an anti-TNF agent (58.2%), IFX is by far the most commonly stated agent. In case of LOR dose intensification prior to switching of the anti-TNF agents is the most frequently used strategy. If prolonged remission has been achieved, stopping the immunosuppressant first is preferred. Despite substantial heterogeneity, those GI specialists seeing more IBD patients and using anti-TNF therapy more often are applying de-escalation within a significantly shorter interval of remission. In conclusion, we here present a comprehensive overview on the clinical practice of gastroenterologists in Switzerland regarding common and yet insufficiently resolved treatment paradigms in CD, aiming to capture the current pace of clinical reasoning and decision-making in the care of CD patients. Our results indicate that there is a discrepancy between real-life clinical practice and implications derived from recent pivotal studies, such as the SONIC-, STORI- or “Top Down-Trial”.
Conflict of interest
We acknowledge the IBDnet, Swiss Research and Communication Network on Inflammatory Bowel Disease, and the SIBDCS, Swiss Inflammatory Bowel Disease Cohort Study, endorsed by the Swiss National Science Foundation, SNF (Grant No. 3347CO-108792) for critical support of this work in general and the development and distribution of the questionnaire in specific.
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a Division of Gastroenterology & Hepatology, Triemli Hospital, Zurich, Switzerland
b Division of Gastroenterology & Hepatology, University Hospital Zurich, Zurich, Switzerland
c Division of Gastroenterology & Hepatology, Seespital Horgen, Horgen, Switzerland
d Division of Gastroenterology & Hepatology, Medical University Hospital Liestal, Liestal, Switzerland
e Division of Gastroenterology & Hepatology, University Hospital Lausanne, Lausanne, Switzerland
f Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Vandoeuvre-lès-Nancy, France
g Clinic de la source, Gastroenterology, Lausanne, Switzerland
1 These authors contributed equally to this work.
© 2014 Editrice Gastroenterologica Italiana S.r.l., Published by Elsevier B.V.