What Is Known
- Clinical practice in paediatric inflammatory bowel disease care differs among centres and regions based on local expertise and resources.
- From personal communications, these differences are known, but were never quantified.
What Is New
- This is the first survey covering all substantial areas of diagnostic and therapeutical approach to paediatric inflammatory bowel disease.
- Results of such survey may contribute to improvement of local clinical practice and form basis for future research projects.
Over the last several years, practice-oriented international guidelines for the diagnosis and management of inflammatory bowel disease (IBD) in children were generated (1–7). These evidence-based guidelines or if evidence is missing consensus reports of highly experienced key opinion leaders in the field aim to help clinicians in their daily practice, especially when differential diagnostic questions arise or particular treatment algorithms are needed for an individual patient. Once these guidelines are presented and published, it is of utmost interest to implement them. However, local resources (availability of diagnostic methods, access to care) individual experience and practices, as well as national or regional regulations (ie, reimbursement of drugs) might interfere with the proposed algorithms of guidelines and recommendations. The objective of the present project is to compare current clinical practice to recently published guidelines and to study the existence of local differences by evaluating results from a survey on “Clinical practice in paediatric IBD” among the most experienced IBD centres around the world using International Paediatric IBD networks. On the basis of a literature search (Appendix 1, Supplemental Digital Content 1, http://links.lww.com/MPG/B567), several surveys on subareas of diagnostic or therapeutical approaches in paediatric IBD were identified, along with a couple of complementary studies on epidemiological or phenotypic characteristics of paediatric IBD, quality of life (QOL), and transition care (8–17). Although several studies are available on diagnostic or therapeutical subtopics, such as colonoscopy in patients with colitis (9), use of enteral nutrition and dietary treatment (10,16,17), impact of complementary and alternative medicine (8), and use of immunosuppressants and biologicals in IBD (13–15), no study to date addressed the general clinical practice/practical approach to IBD patients among Paediatric gastroenterologists (Paed GIs).
MATERIALS AND METHODS
Between September, 2016 and March, 2017, a closed voluntary survey was performed among members of Porto IBD working group and IBD interest group of ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition), PIBD-NET (Paediatric Inflammatory Bowel Diseases Network), Canadian IBD network (CIDsCANN), and the Society for Paediatric Gastroenterology and Nutrition of German-speaking countries (GPGE), using a Surveymonkey web-based questionnaire. Members of these groups were repeatedly encouraged by email to fill in the questionnaire. No incentives were offered for participation in the survey. There were basically four types of answers required, depending on the wording of questions: questions asking on proportion of patients experiencing certain diagnostic/therapeutical procedures; multiple choice; questions asking for “yes”/“no”/“I do not know”; and questions, where subjective wording of the answer was required and given as full text. For some questions, written comments by respondents were allowed in order to specify the answer in detail. The questions appeared in fixed order and were not randomized. In the results section, only general comments on diagnostic and therapeutical approach are given. Complete responses including written comments as well as the analysis according to region and size of the centre are reported as an online supplementary material (Appendix 2–4, Supplemental Digital Content 2–4, http://links.lww.com/MPG/B568, http://links.lww.com/MPG/B569, http://links.lww.com/MPG/B570). As most of the generated data are from Europe, USA, and Canada, we cannot comment on other regions. Graphical presentation of data was partly processed by R-project statistical software version 3.4.4 (www.r-project.org) using packages maptools, maps, and map data.
Responses from 106 paediatric IBD centres (14 from USA, 8 from Canada, 3 from Australia and New Zealand, 1 from Japan, and the remaining [N = 80] from Europe and Israel—see Appendix 5, Supplemental Digital Content 5, http://links.lww.com/MPG/B571) were collected on 13 questions concerning the diagnostic approach (focused on initial diagnosis, use of endoscopy, imaging, laboratory methods, and cancer surveillance), and 50 questions on the therapeutical approach (focused on experience with conventional treatment as well as biological therapy, unusual therapeutical strategies, surgery and other aspects, regarding both induction and maintenance phases of the disease as well as regular monitoring of disease course and identification of patients experiencing relapse). Total number of unique IBD centres to whom the questionnaire was sent was 162. On the basis of this number, the calculated response rate is (106/162) × 100 = 65.4%. In Europe, we asked members from 24 countries and we received answers from 77 centres in 18 countries—see Appendix 5 (Supplemental Digital Content 5, http://links.lww.com/MPG/B571). Majority of centres had less than 100 newly diagnosed IBD patients per year (Fig. 1). Not all participants responded to all questions, but the overall response rate per question was 84% (mean 90 responses per question). Numbers of responding centres are given in each figure in the online supplementary material (Appendix 2, Supplemental Digital Content 2, http://links.lww.com/MPG/B568).
Diagnostic Approach (Questions Q27–Q39)
With regard to initial diagnostic evaluation combining endoscopy, imaging, and serology, majority of centres reported to fulfil the revised Porto criteria for the majority of patients (Fig. 2). Magnetic resonance enterography (MRe) is the preferred method (over wireless capsule enteroscopy [WCE]) of small bowel (SB) imaging (91%) with 79% of centres using an IBD-specific MRe protocol. In 58% of centres, a SB ultrasound is also routinely performed at the time of diagnosis. In 53% of centres, anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA) are routinely measured in the majority of patients at the time of diagnosis. Follow-up control endoscopy after induction therapy is routinely performed (in at least half of the patients) in only 16% (in Crohn disease [CD]) and 14% (in ulcerative colitis [UC]) of centres. However, in line with the current guidelines, prior considering major treatment changes a full endoscopic work-up is performed in 87% (CD) and 84% (UC) of centers. Yearly cancer-surveillance endoscopies are performed starting at diagnosis in primary sclerosing cholangitis-UC (PSC-UC) in only 16% of centres and in UC patients after 8–10 years of disease duration in 68% of centres. In half of the centres (53%), this evaluation is done in cooperation with adult GIs. Regional differences within European and North American regions regarding surveillance endoscopic programmes for PSC-IBD and UC are reported as supplementary material (see Appendix 3, Supplemental Digital Content 3, http://links.lww.com/MPG/B569).
Therapeutic Approach (Q40–Q89)
Crohn Disease (Q59–Q74)
In keeping with the recent guidelines on medical therapy of paediatric CD, in luminal CD, exclusive enteral nutrition (EEN) is used as first-line induction therapy in vast majority of centres (in contrast to steroids and other therapies [mainly anti-TNF])—see Figure 3A. Clear regional differences are apparent for first-line induction therapies of active luminal CD. European and Canadian centres mainly use EEN, whereas US centres declare to use it to a much lesser extent (Fig. 4A). In case biological therapy is indicated, IFX is considered as first-line biological in luminal CD in 70% of centres, whereas in 26%, ADA and IFX are regarded as equal. For the therapy of patients with perianal fistulizing disease, IFX was the preferred anti-TNF (85%). Less than 4% of centres always start with ADA both in luminal and in perianal CD. There are substantial regional differences for first-line anti-TNF, especially in Europe, where answers favouring IFX vary between 0% (France, Spain) and 100%.
For maintenance of remission, 9% of centres regularly use 5-aminosalicylates (5-ASA; not necessarily in monotherapy) with an additional 20% of centres reporting an occasional use. There are major regional differences for 5-ASA use in CD patients, with approximately half of U.S. centres reporting regular use whereas the majority of European and Canadian centres hardly ever use 5-ASA in CD. However, there are regional differences even within Europe, where some countries also report 5-ASA use in CD (Poland, Finland, Germany, Austria, Czech Republic, and Switzerland). Budesonide, probiotics, and special diets are practically not used by the majority (>84%) of centres, but there is at least some experience with partial enteral nutrition (PEN) in almost 40% of centres, especially in USA and some European countries, like Finland, Portugal, Switzerland, Denmark, Lihuania, and Ireland. Majority of centres use immunomodulators (IMM) in the majority of patients since diagnosis, preferentially azathioprine/6-mercaptopurine (AZA, 6-MP), or—to a lesser extent—methotrexate (MTX; Fig. 3B). IMM are used from CD diagnosis onwards in many European countries (mainly AZA/6-MP), but to a much lesser extent in USA and Canada (AZA/6-MP are used rarely; Fig. 4B). The choice between thiopurines and MTX is based in only a minority of centres (5%) on sex (AZA/6-MP given preferentially to girls, MTX to boys). In case of IMM intolerance, approximately 36% of centres choose other IMMs; however, the majority steps up to anti-TNF therapy (mainly IFX [28%] and in 22% of centres, ADA and IFX are regarded as equally efficacious). On the contrary, in IMM failure, less than 13% of centres switch to another IMM and the majority (71%) prescribes IFX.
Combotherapy is more frequent with IFX than ADA. IFX is used in combination with IMM in 86% of centres (in 70% in the majority of patients), whereas in ADA-treated patients, concomitant IMM is used in less than half of the patients in 45% of centres. Approximately half of the centres tend to stop IMM in the majority of patients regardless of type of anti-TNF (after mean of 6 months, range 3–12 [exceptionally 24] months). Canada and some European countries (Spain, Portugal, Czech Republic, Poland, the Netherlands, and Denmark) use concomitant IMM therapy with IFX in the majority of patients, but only few countries (Spain, Portugal, Czech Republic, and UK) use the same approach in ADA-treated patients.
Ulcerative Colitis (Q75–Q84)
As per the recently updated paediatric UC guidelines, the majority of UC patients, is treated with 5-ASA; however, prescribed as a once daily dose in more than 70% of centres. 5-ASA is continued as a concomitant therapy in more than 90% of centres in case IMM is used. Along with IFX, 25% of centres do not use concomitant 5-ASA. Less than 40% of centres have experience with occasional use of probiotics in UC, but more than 50% of centres use it in pouchitis (approximately 40% of centres in the majority of patients). Majority of centres use AZA/6-MP for maintenance of remission. MTX is used to much lesser extent probably because of lack of data and in accordance with recent guidelines. As in CD, in Europe, AZA/6-MP is used to much higher extent for UC maintenance therapy than in USA and Canada. When IFX fails (by mechanism that allows switch to other anti-TNF), approximately 3/4 centres switch to ADA, at least in some patients, despite this therapy is currently not approved for paediatric UC. Nineteen percentage of centres have experience with golimumab. In acute severe colitis (ASC), IFX (61%) is preferred over cyclosporine (14%) or any other medication (tacrolimus, mycophenolate) as a second-line therapy.
Unconventional Therapy (Q40–Q47)
In CD, majority of centres have experience with regular or episodic top-down strategy and more than half have used vedolizumab and/or ustekinumab (Fig. 3C). Tofacitinib, natalizumab, and abatacept are used episodically. In UC, 57% of centres tried vedolizumab. In some European countries, there is no experience with non-anti-TNF biologics, possibly because of local regulations or lack of resources. In the majority of European as well as in USA and Canadian centres (in both in almost all centres), there is substantial experience with these, both in CD and UC. As data from clinical practice, both from adults and children, accumulate over time, now almost 24% of centres use biosimilars in anti-TNF-naive CD patients and additional 16% even switch from originator to biosimilar. In UC, the experience is similar (21% and 15%, respectively). European centres have substantially higher experience with biosimilars compared with USA and especially Canada, possibly because of the fact that biosimilars were originally not approved by Health Canada. Almost 27% of centres have experience with thalidomide in CD, but only 7% in UC. Some centres (27% in CD and 22% in UC) have experience with unusual therapeutical strategies, like bone marrow/stem cell transplant, immunotherapy, faecal transplant (intestinal microbiota transplantation), leukocyte apheresis, worms, and so forth. More than 3/4 of centres used specific antibiotic (ATB) combinations, either in CD (52%) and/or in UC (53%).
Surgery (Q48, Q49, Q85–Q89)
More than 60% of centres perform endoscopic dilation of strictures in CD (52% in inflammatory disease and/or 34% postoperatively). More than 1/4 of centres do not use setons (or use them very rarely) in complex perianal CD, despite this is recommended by recent guidelines in complex perianal disease (1). After ileocaecal resection (ICR), approximately half of centres have a specific protocol for follow-up. In patients without postoperative residual disease, AZA monotherapy is the preferred treatment (38%); however, other strategies are also used, that is metronidazole, anti-TNF (each 10%), PEN, MTX, 5-ASA (each less than 4%). Nine percentage of centres do not use any therapy in this clinical setting. When residual disease is present, however, the vast majority of patients is treated with anti-TNF (51%) or AZA (28%) in accordance with recent guidelines (1). Only 14% of centres do not perform endoscopic evaluation after ICR. In 44%, it is performed regularly (usually 6–12 months after ICR) and in 37% based on clinical/laboratory markers and risk assessment. After colectomy in UC, most of the centres prefer ileopouch anal anastomosis (IPAA; 72%) over ileorectal anastomosis (4.5%) or permanent stoma (1%).
Therapeutical Monitoring (Q50–Q58)
In CD, a clinical activity index is regularly used in the majority of centres, at least in some patients during outpatient visits (paediatric crohn's disease activity index (PCDAI) in 78% and wPCDAI in 58%). Paediatric ulcerative colitis activity index (PUCAI) is well established in both ambulatory UC (used in 86% of centres) and in ASC (calculated on a daily basis in 69% of centres, at least in some patients). Faecal calprotectin, as a valuable laboratory marker for evaluation of disease activity both in CD and UC, is monitored in 53% of centres for the majority of both CD and UC patients at each outpatient visit. Access to therapeutical drug monitoring varies between centres. Approximately 10% of centres do not monitor (regularly or episodically) levels and antibodies to IFX. For ADA and AZA, the numbers are even higher (22% and 24%, respectively). There is more experience with regular therapeutical drug monitoring (both of biologics and AZA) in some European countries compared with North America, but there are substantial differences within Europe (highest rates in France, UK, and Poland).
Differences According to Centre Size
Regarding selected questions, there do not seem to be any substantial clinically relevant differences between answers from smaller (<50 newly diagnosed patients per year) and larger centres. Centre size does not seem to play a major role for the indication of surveillance endoscopies, use of EEN, IMM, IFX, and 5-ASA in CD and concomitant IMM neither in IFX nor in ADA-treated patients, including withdrawal in patients in remission. There is also no substantial difference in the use of AZA in UC and IFX in ASC. Smaller centres seem to have more experience with PEN in CD; they use more AZA than 6-MP or MTX and also use slightly more anti-TNF in case of IMM failure. On the contrary, they have less experience with non-anti-TNF biologics and biosimilars and with therapeutical drug monitoring of both biologics and AZA metabolites. Visual presentation of the data is available in Appendix 4, Supplemental Digital Content 4, http://links.lww.com/MPG/B570.
According to the results of this survey, the vast majority of centres report to fulfil the Porto diagnostic criteria recommended as gold standard in 2005, and updated in 2014 (18,19). This confirms the trend that had been analysed within the EUROKIDS registry between 2004 and 2009, showing a significant increase in rates of complete diagnostic workup in paediatric IBD over time (20).
According to the results of our survey, ASCA/ANCA measurement is not performed routinely. These antibodies may be helpful in differentiating between UC and CD, especially in IBDU (IBD unclassified) patients (19). According to a recent large prospective study on prediction of complicated disease course in paediatric CD, serological markers may be useful in predicting complications of CD (21).
Small Bowel Imaging
It is obvious that MRe has become a standard of small bowel examination in the majority of participating centres. This is in accordance with current diagnostic recommendations as it can detect CD complications as fistulas, abscesses, and strictures (19). WCE is used as a first-line method in a neglectable number of centres. Only half of the centres routinely use small bowel ultrasound (the majority without a specific protocol). A possible explanation may be that this method is very expertise-dependent and in centres with quick access to endoscopy and imaging, it may be omitted in order to speed up the diagnostic process.
Due to an introduction of the Porto diagnostic criteria, full upper and lower endoscopy including multiple biopsies have become standard in IBD centres. The routine use of endoscopy to evaluate the efficacy of induction treatments, however, is still not accepted in a majority of centres, neither for CD nor UC. This is likely because of ethical considerations related to repeated general anaesthesia and risks of endoscopy. Capacity of the centre, and in some countries, also economical aspects may play a role. It will be interesting to see how far the situation is changing over time as mucosal healing is becoming the optimal treatment target. In contrast, once a major change of treatment is considered, the majority of centres do not hesitate to evaluate possible disease progression endoscopically. For cancer surveillance, a majority of centres are used to perform regular endoscopies after 8–10 years of disease duration in UC, but for PSC, the paediatric approach differs from that in adults and in PCS-UC patients, the recommended yearly endoscopies following diagnosis are usually not done. One reason might be that the occurrence of malignancy is not frequent, especially not in very young PSC patients. It may be advantageous to involve an adult GI in surveillance programs, which is done in approximately half of the centres.
Despite current guidelines on CD management recommending EEN as first-line therapy in luminal CD (3), still approximately 10% of centres prefer corticosteroids for induction of remission. There are also centres that use anti-TNF regularly in newly diagnosed luminal CD. General experience with “top-down strategy” is also frequent, probably mainly in patients with fistulizing CD, however, we did not ask exactly the reason for “top-down strategy” in our questionnaire. IFX is preferred as first line biologic in naïve patients, which might be because of the historically higher experience when compared with ADA, mode of delivery, or better adherence to therapy. However, in 25% of centres, both anti-TNFs are regarded as equal. This is in accordance with the current ESPGHAN recommendation stating that both IFX and ADA show comparable efficacy and adverse-event profiles (3). 5-ASA is still used in some centres as a maintenance therapy in CD, despite its unproven effect in this indication. There is substantial experience with PEN for maintenance of remission. PEN seems to be an alternative for some patients. Available data as well as current guidelines consider it as an option to maintain remission in selected CD patients concomitantly with other medication (3). Despite increasing availability of various biologics, the majority of paediatric patients are still treated with IMM (preferentially AZA/6-MP) as cornerstone of maintenance therapy. In some centres, MTX is preferred in boys, probably because of fear of lymphoproliferative diseases on AZA/6-MP (22). In case of IMM intolerance, biologics are not the only choice and other IMM are being considered in one-third of centres. However, in case of IMM failure, physicians tend to start biologics more frequently, despite the fact that MTX seems to be effective both in AZA/6-MP failures and intolerance, at least as shown in retrospective paediatric studies (3). In ADA-treated patients, concomitant IMM is used to a lesser extent than with IFX. This might be because of the fact that some of the previous data have shown only little benefit by adding AZA to ADA treatment (23,24) or IFX as chimeric antibody may be perceived as more immunogenic. In half of the centres, concomitant IMM treatment is stopped within some months of combination therapy, probably because of reported risks of prolonged combination (hepatosplenic T-cell lymphoma [HSTCL] and other complications), especially with AZA (3,22).
In UC, not surprisingly, 5-ASA is used as the cornerstone of therapy, in combination with IMM. In the vast majority of centres, AZA is preferred over MTX in accordance with current guidelines (4). Despite ADA still being off-label for paediatric UC, the majority of centres uses it in patients who fail on IFX therapy. IFX is preferred to other drugs as a rescue therapy in patients with ASC.
Refractory disease courses or loss of response on long-lasting anti-TNF therapy leads many centres to use unconventional treatment strategies or drugs approved for adults only. More than half of centres have, thus experience with non–anti-TNF biologics (vedolizumab and/or ustekinumab) and a substantial amount of centres has used thalidomide, ATB combination therapy, or other unusual therapeutical strategies. Despite scarce data from large paediatric clinical trials, these drugs show reasonable efficacy and safety in paediatric clinical practice and observational studies (25–28). Although only little time has elapsed since biosimilars were introduced to the market and despite initial doubts in the paediatric community because of lacking data on efficacy and safety in children (2), in approximately one-third of centres, there is already substantial experience with biosimilars, including switch. The most likely cause is the reduction of treatment costs (29–31).
Surgery has become a standard and well established treatment modality in IBD patients. Especially subtotal colectomies and ICR are routinely performed in IBD centres. In accordance with recent paediatric guidelines, in UC surgery, IPAA is preferred over ileorectal anastomosis (4). Following ICR, most centres perform regular endoscopic evaluation and choose postoperative maintenance treatments based on presence of residual disease or recurrence of inflammation in the anastomosis—as suggested in the current guidelines (1,32).
Clinical (especially PUCAI) and laboratory (faecal calprotectin) monitoring of the disease course has become a standard in ambulatory care (33–35). As biological therapy is used to a large extent in paediatrics, therapeutical drug monitoring (especially of infliximab [IFX]) is useful for any “treat to target strategy” or decision on switch to other biologicals, both within or out of class (36,37).
Subanalysis of data according to region, confirm personal experience and communications from involved experts on the preferential use of EEN as a CD induction treatment in Europe and Canada as opposed to USA. Possible reasons may be a lack of experience with enteral nutrition, compliance issue, and higher costs of EEN when compared with corticosteroids. On the other hand, USA centres report experience with PEN as a maintenance therapy that is comparable to other regions. Also IMM (especially AZA/6-MP) are used to a much higher extent (also along with anti-TNFs, mainly IFX) in Europe, which is a change of approach when compared with the pre-biologics era, where 84% of centres in USA reported to use AZA/6-MP in paediatric IBD patients (14). Currently, in North America biologics are probably more frequently used, either from diagnosis onwards, as a top-down therapy, or when the first relapse occurs. According to a recently published survey performed among PIBD-NET members, North Americans more often used anti-TNF than other regions and anti-TNF monotherapy was also more common in North America. When used in combination, MTX was more common than thiopurines (38). In almost all USA and Canadian centres responding there is also wide experience with the use of non-anti-TNF biologics. These strategies may avoid IMM that can be perceived as risky in the paediatric population. For this reason, also MTX may be more popular than AZA/6-MP in North America, as is shown by our data. Subanalysis according to centre size shows that smaller centres have less experience with non-anti-TNF biologics and with therapeutical drug monitoring, both possibly because of lack of resources and/or clinical expertise.
Strength and Limitations of the Survey
The fact that neither diagnostic nor therapeutic approaches to paediatric IBD have ever been analysed in such an extent among experts from various IBD centres worldwide via a detailed survey is a strength of our study. On the other hand, limitations are that potentially desirable answers might have been given instead of what occurs in daily clinical practice. Moreover, different countries have different regulations and health insurance policy. These factors may also influence the clinical practice, but were not identified by our survey. Furthermore, we are aware of a potential bias in that the more motivated and experienced colleagues might have answered. Verification of some aspects of this survey could be done by detailed search in published data on paediatric IBD, but these focus only on selected aspects of clinical practice. Moreover, data from clinical trials not always reflect every day clinical practice (real-life experience).
The majority of centres follow both the Porto diagnostic criteria as well as current paediatric guidelines regarding medical and surgical IBD management. There are, however, regional differences in clinical practice, and overall the situation could be improved in specific diagnostic and/or therapeutical aspects.
This work was supported by Centre for Paediatric Gastroenterology and Nutrition, Prague, Czech Republic.
We would like to thank to all the contributors who filled the online Surveymonkey questionnaire.
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