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French national consensus clinical guidelines for the management of Crohn’s disease
Digestive and Liver Disease, April 2017, Volume 49, Issue 4, Pages 368-377
Crohn’s disease (CD) is a chronic and disabling condition. There is no curative medical treatment but current treatments provide increasingly sustainable control of the disease and allow patients a better quality of life. There is limited evidence supporting CD management in specific clinical situations, thus precluding an evidence-based approach.
To help clinicians in making informed treatment decisions, a group of 59 French gastroenterologists with experience in the management of CD met to develop straightforward and practical algorithms based on the European Crohn’s and Colitis Organisation (ECCO) recommendations.
This experts’ opinion was developed following a Nominal Group consensus methodology. Nine clinical situations were identified: mildly active CD; uncomplicated moderately active CD, with, and without poor prognostic factors; uncomplicated severely active CD; perianal CD with a single fistula; perianal CD with complex fistula with or without abscess; complicated CD with abscess; intestinal stricture; and post-operative CD. Two working groups were formed and proposed algorithms that were then approved by a two-thirds majority of the Nominal Group.
These algorithms represent the pragmatic consensus of a group of experts in gastroenterology on the modalities of therapeutic care in different clinical situations in CD. They are available via a web application at: www.algorithmici.com .
Keywords: Algorithm, Experts’ opinion, Treatment guidelines.
Crohn’s disease (CD) is an inflammatory bowel disease (IBD) that progresses with alternating flare-ups followed by periods of remission. It can affect any section of the digestive tract and may be accompanied by extra-intestinal manifestations in the joints, skin, eyes, hepatobiliary system, pancreas, etc.
The annual incidence of CD is 12.7 per 100,000 people in Europe, 5.0 per 100,000 in Asia and the Middle East and 20.2 per 100,000 in the US. The prevalence of CD is 322 per 100,000 people in Europe and 319 per 100,000 in the US  . In France, it affects about one in a thousand people. The annual incidence is approximately 5 per 100,000. Crohn’s disease can occur at any age, but it is usually diagnosed between the ages of 20–30 years  . It is a cryptogenic disease involving a variety of different factors including genetic predisposition and immunologic and environmental factors  .
There is no medical cure for CD, but current treatments can achieve increasingly sustainable disease control or clinical remission and improve patient quality of life. However, digestive complications such as bowel strictures, fistulae, anal fissures, abscesses, cancer, malnutrition, anemia, etc. or extradigestive complications, for example, pyoderma gangrenosum , uveitis, venous thrombosis, etc. remain a problem  .
In addition to corticosteroid and immunosuppressive therapies, biological agents are indicated in the management of CD. The use of these treatments has been the subject of multiple expert opinions and recommendations 3 4 5 6 7 . Although corticosteroids are effective on flare-ups, their side effects prohibit their use as maintenance therapy  . Immunosuppressants – azathioprine, 6-mercaptopurine, methotrexate – slow the progression of the disease and are effective in maintaining remission. However, ongoing monitoring of metabolites is maybe useful to avoid side effects and potential complications  .
Biological treatments are effective for inducing and maintaining clinical remission and reducing recourse to surgical procedures 10 11 12 13 14 15 . In France, three biologicals are indicated and reimbursed for the treatment of CD: infliximab, adalimumab and vedolizumab.
The clinical profiles of patients suffering from CD vary and treatment must be adapted to each patient’s profile. Different treatment strategies for CD are determined by the disease itself, its progression, and the therapeutic objectives for that patient. Recommendations about the definition, diagnosis and treatment of CD have been published by the European Crohn’s and Colitis Organisation (ECCO) in 2010 and actualized in 2016 [16 17] . These recommendations, in the form of consensus statements, are however sometimes quite distant from clinical practice. In order to develop a practical decision tool to inform therapeutic decisions that meets the needs of practitioners, a group of French gastroenterologists with expertise in the management of CD met to develop treatment algorithms based on international recommendations, their personal clinical experience and new treatments. The experts considered the treatment of CD in the following situations: mildly active CD; uncomplicated moderately active CD without poor prognostic factors; uncomplicated moderately active CD with poor prognostic factors; uncomplicated severely active CD; CD with a single perianal fistula; CD with complex perianal fistula, with or without abscess; CD complicated by abscess; CD with intestinal stricture; and post-operative CD.
The definitions used in the development of the algorithms were those previously defined by the ECCO in their 2010 guidelines and were not revisited by the Nominal Group  .
1.1.1 Disease activity
Clinical activity is classified as mild, moderate or severe ( Table 1 ).
|Corresponds to a CDAI between 150 and 220 and an HBI score <8||Corresponds to a CDAI between 220 and 450 and an HBI score between 8 and 12||Corresponds to a CDAI >450 and an HBI score >12|
|Example: ambulatory patient who eats normally, weight loss <10%. No sign of obstruction, fever, dehydration, abdominal mass or sensitive mass. CRP usually moderately elevated||Example: intermittent vomiting or weight loss >10%. Treatment of mild CD or sensitive mass ineffective. No apparent signs of occlusion. CRP level elevated||Example: cachexia (BMI < 18) or evidence of obstruction or abscess. Symptoms persist despite intensive treatment. CRP considerably elevated|
Defined as a Crohn’s Disease Activity Index (CDAI) of <150. This has become the standard definition used in literature reviews and clinical trials.
Defined as a CDAI decrease of 100 points or more.
Defined as a flare-up of symptoms, either spontaneously or after medical treatment, in a patient with established CD who is in clinical remission. In clinical practice, relapse is preferably confirmed by biomarker level data, imaging or endoscopy. In clinical trials, a CDAI of >150 with an increase of over 70 points has been proposed.
1.1.5 Corticosteroid-resistant CD
Patients treated with corticosteroids who have active disease despite receiving prednisolone up to 0.75 mg/kg/day over a period of 4 weeks.
1.1.6 Corticosteroid-dependent CD
Patients who are either: (i) unable to reduce corticosteroid levels below the equivalent of prednisolone 10 mg/day (or budesonide 3 mg/day) within 3 months of initiating corticosteroids, without relapsing into active CD, or (ii) have a relapse within 3 months following cessation of corticosteroids.
The assessment of corticosteroid resistance or dependence should be made after careful exclusion of disease-specific complications.
This definition of corticosteroid dependence requires that the total duration of corticosteroid therapy does not exceed 3 months before a threshold equivalent to prednisolone 10 mg/day is reached. Patients are still considered corticosteroid dependent if they relapse within 3 months following cessation of corticosteroids.
The term recurrence is used to define the reappearance of lesions following surgical resection (while relapse refers to the reappearance of symptoms).
This expert opinion was developed using a Nominal Group (NG) consensus methodology  . The NG was made up of 59 French gastroenterologists with experience in the management of CD and representative of different schools of clinical practice. Given the specialist expertise of the Groupe d’Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID), all the members of this group were asked to participate in this expert opinion. In addition, the Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux (ANGH) and the Club de Réflexion des Cabinets et Groupes d’Hépato-Gastroentérologie (CREGG) were approached and asked to appoint representatives from among their members that they felt were the most experienced in the management of IBD. The NG met in Paris on January 13, 2016. During a preparatory phase (September to December 2015) the NG Steering Committee (Y Bouhnik, L Peyrin-Biroulet, X Roblin) conducted a literature review, defined the themes submitted to the NG and proposed the frameworks for algorithms. Working group coordinators were appointed from representatives of the professional societies: G Bonnaud (CREGG), H Hagège (ANGH) and X Hébuterne (GETAID).
Two working groups addressed nine clinical situations. These situations were defined during the workshops. Group 1 addressed mild uncomplicated CD, post-operative treatment, and perianal fistulizing CD. Group 2 dealt with moderate and severe uncomplicated CD, and CD complicated by stricture and abscess. During the evaluation phase, proposals were selected based on an anonymous vote by each member of the working groups and majority choices were discussed. Consensus was determined by a two-thirds rule. If no consensus was obtained during the workshop, the NG voted again during the plenary session. Alternative choices with qualifying commentary could be added. During a second round of evaluation, algorithms developed by the two working groups were submitted, step by step, to the NG during the plenary session, and a second vote was held. Again consensus was determined by meeting a threshold of two-thirds in agreement. Failure to reach consensus was recorded.
3.1 Mildly active Crohn’s disease
Participants agreed without a vote to identify two forms in this clinical case: an ileocecal form and a colic form.
The management of the mild form begins with a local or systemic corticosteroids, depending on the location.
In the mildly active localized ileocecal Crohn’s disease the recommended first-line treatment is budesonide. Maintenance treatment is not recommended in cases of response. A corticosteroid (without voting the NG agreed to use the term ‘corticosteroids’ as short-hand for ‘prednisone or prednisolone’ in order to simplify the algorithm) is recommended for non-response. In case of corticosteroid response, establishing a maintenance treatment is not recommended.
In the mildly active colic form, the NG did not reach a consensus for the first-line treatment: 50% of participants recommend initial corticosteroid therapy and 36% recommend treatment with 5-aminosalicylic acid (5-ASA). In both options, if there is response to treatment, establishing a maintenance treatment is not recommended.
After initiation of therapy with a corticosteroid, the participants agreed, without a vote, for the same treatment approach for both ileocecal and colic forms. In case of intolerance to corticosteroids, the NG did not reach a consensus: 61% of the participants propose treatment with thiopurines while 26% prefer the anti-TNFα option (off label in mild CD). In case of corticosteroid dependence, there was a consensus that the patient be treated with thiopurines. Ongoing thiopurines are recommended if there is a treatment response. In case of intolerance or failure of thiopurines despite optimization, the NG opted (by 73% of the votes) for treatment with anti-TNFα (off label in mild CD). In the event of corticosteroid resistance or failure of optimized thiopurines, the NG recommends reconsidering the severity of the disease ( Fig. 1 ).
3.2 Uncomplicated moderately active Crohn’s disease without poor prognostic factors
Participants considered the case of a patient naïve to treatment presenting a first, moderate CD flare with right ileocolonic involvement and without poor prognostic factors. It was clarified that any smoking had no impact on the choice of treatment in this situation. The moderate form was described in the ECCO 2010  .
In this indication, the NG recommends budesonide as first-line treatment. If the patient responds to treatment, maintenance treatment is not recommended; however, monitoring is still warranted. In the absence of response, systemic corticosteroids are recommended.
In case of intolerance to corticosteroids, the NG opted for anti-TNF alpha therapy; vedolizumab is an alternative treatment in case of intolerance or contraindication to anti-TNFα. In case of response, maintenance therapy is recommended. In case of primary or secondary failure to optimized anti-TNFα, the NG recommends performing a pharmacokinetic assay (PK) of residual levels of anti-TNF alpha and neutralizing antibodies (AAA).
There was consensus that in case of corticosteroid dependence the patient should receive azathioprine treatment. In the event of response, continuing azathioprine is recommended. In the absence of response, testing levels of 6-thioguanine (6-TG) nucleotide is recommended. Depending on these results, the NG recommends switching to an anti-TNFα (or vedolizumab in case of intolerance or contraindication) with or without continuation of azathioprine. If no response, a pharmacokinetic assay of residual levels of anti-TNFα and its antibodies is recommended.
In case of corticosteroid resistance, the NG recommends anti-TNFα therapy (vedolizumab is an alternative in case of intolerance or contraindication), with the treatment being maintained if the patient responds. If unsuccessful after treatment optimization, or in case of loss of secondary response to an anti-TNFα, a pharmacokinetic assay is recommended. Depending on these results, three treatment options can be considered: vedolizumab; switching the anti-TNFα; or optimization of the anti-TNFα ( Fig. 2 ).
3.3 Uncomplicated moderately active Crohn’s disease with poor prognostic factor
The NG considered the case of a treatment-naïve patient experiencing a first flare with right ileocolonic involvement and poor prognostic factors.
These poor prognostic factors were defined as follows  : upper gastrointestinal damage, damage to the small intestine, severe ileal involvement, severe rectal involvement, perianal damage, severe lesions on endoscopy (large and/or deep ulcer), and young age at diagnosis.
Corticosteroids are recommended as first-line treatment in this indication. In patients who respond, maintenance therapy with azathioprine is recommended.
In case of intolerance to corticosteroids, the NG recommends anti-TNFα therapy and vedolizumab may be used as an alternative in case of corticosteroid intolerance or contraindication. Maintenance therapy is recommended if there is treatment response. In case of primary or secondary failure of the optimized anti-TNFα, the NG recommends performing a pharmacokinetic assay.
In case of corticosteroid dependence, no consensus was reached: 58% of the NG participants opted for azathioprine and 41% recommended an anti-TNF alpha.
If there is corticosteroid resistance, the NG advocates anti-TNF alpha (with vedolizumab as an alternative in cases of intolerance or contraindication). Consensus was not reached on the use of anti-TNFα monotherapy or in combination with azathioprine.
Maintenance therapy is recommended if there is a response to anti-TNFα therapy. In the event of primary or secondary failure of the anti-TNFα, the approach described above for this situation applies (pharmacokinetic assay) ( Fig. 3 ).
3.4 Uncomplicated severely active Crohn’s disease
Severely active CD was defined according to the ECCO 2010  .
In this situation, corticosteroids are recommended as first-line treatment. If successful, the NG recommends azathioprine maintenance therapy. The NG recommends anti-TNFα therapy (vedolizumab is an alternative in case of intolerance or contraindication) in case of intolerance to corticosteroids, corticosteroid dependence or corticosteroid resistance. Consensus was not reached on the use of an anti-TNFα as monotherapy or in combination with azathioprine.
Maintenance therapy is recommended if there is a treatment response. In case of primary failure of optimized anti-TNFα or secondary failure, the NG recommends a pharmacokinetic assay to inform the choice of three options, as described previously: vedolizumab; changing the anti-TNFα; or optimization of the anti-TNFα ( Fig. 4 ).
3.5 Perianal CD with single active superficial low fistula in the acute phase without proctitis or abscess
In this situation the NG recommends both medical and surgical treatment. However, consensus was not reached: 37% of NG members advocate antibiotic therapy alone and 35% recommend antibiotic therapy with drainage. If treatment with antibiotics alone is not efficient, the experts propose a drainage. No consensus was reached in cases of response to antibiotic monotherapy: 52% consider that no treatment is needed and 34% recommend introducing thiopurines. After draining, the question of maintenance treatment did not achieve consensus, with 42% of respondents in favor of thiopurines and 40% recommending anti-TNFα and thiopurine combination ( Fig. 5 ).
During the workshop the group had to address the question of withdrawal or not of the seton after drainage and maintenance treatment. No formal vote was taken but the group felt that there was no minimum time period for its removal.
3.6 Perianal Crohn’s disease with complex fistula with or without abscess
Initially, complex fistula without abscess and complex fistula with abscesses were discussed separately. The working group subsequently decided that the treatment would be the same in both situations and that the algorithm should describe the medical and surgical treatment in parallel.
As first-line management the NG recommends drainage with antibiotic therapy for a period of two weeks and treatment with infliximab and thiopurines combination therapy. It was clarified that the surgery could be discussed at different levels of the algorithm, similarly with a bypass colostomy in case of worsening or sepsis uncontrolled by antibiotics.
In case of response to surgical treatment, the NG, without reaching a consensus, tended towards removal of the seton (44%) or sphincter saving treatment (42%).
In case of response to combination therapy, the NG recommends a follow-up assessment at 3 months and continued treatment if there is response. In the absence of treatment response, the NG recommends treatment optimization and in case of persistent failure, the use of adalimumab in combination or not with thiopurines ( Fig. 6 ).
3.7 Crohn’s disease complicated by drainable intra-abdominal abscess, diagnosed by MRI or CT
As first-line treatment the NG recommends antibiotic therapy and, if possible, radiologically guided drainage. Response to treatment was defined by the disappearance of the abscess and resumption of patient feeding. Non-response to treatment was defined as a persistence of the abscess. In case of a response to antibiotic-associated drainage, the proposed algorithm distinguishes between two scenarios: short ileal involvement (<30 cm) and long ileal involvement (>30 cm) with or without colon involvement. The NG recommends anti-TNFα treatment in both of these situations.
In case of persistence of the abscess, no consensus was found: 56% of the NG propose a second attempt to drain the abscess while 44% prefer surgical resection without a second attempt at drainage ( Fig. 7 ).
3.8 CD with intestinal stricture
The experts identified two situations: a predominantly inflammatory stricture and a predominantly non-inflammatory stricture. However, they recognized that the distinction was theoretical and in practice it is difficult to classify patients with certainty as having one or the other. For inflammatory strictures, the NG advocates anti-TNFα treatment. Non-inflammatory strictures are distinguished as being short (<5 cm), long (≥5 cm), symptomatic or asymptomatic. For short symptomatic strictures, the NG recommends endoscopic dilatation; whereas for short asymptomatic strictures, simple monitoring is recommended. For long symptomatic strictures, the NG recommends surgery; for long asymptomatic strictures no consensus was reached: 62% of the NG recommend monitoring and 38% recommend medical treatment with an anti-TNFα.
Management approach after response to an anti-TNFα was not discussed. Management may be modulated depending on the results of the CREOLE study (ClinicalTrials.gov No. NCT01183403), a multicenter prospective observational study initiated by the GETAID. This study uses a predictive score of the clinical and radiological response to adalimumab therapy in CD patients with symptomatic stricture of the small intestine  .
In case of loss of response to an anti-TNFα, treatment optimization is recommended. In case of non-response, the experts did not reach a consensus, with 55% advocating vedolizumab and 45% recommending surgery ( Fig. 8 ).
3.9 Post-operative Crohn’s disease
The management of post-operative CD is decided 15 days post-surgery and depends on the presence or absence of risk factors for relapse, namely: active smoking, history of bowel resection for CD, fistulizing phenotype (B3 according the Montreal Classification), length of the intestinal resection (>50 cm). Three situations were considered: (i) no risk factor; (ii) one risk factor; (iii) at least two risk factors. In the absence of risk factors, no treatment is recommended. In the presence of one risk factor, thiopurines are recommended. In the presence of at least two risk factors for recurrence, an anti-TNFα (vedolizumab is an alternative in case of intolerance or contraindication) is recommended. In this situation anti-TNFα monotherapy is preferred by 64% of experts, combination therapy by 11%, and thiopurine monotherapy by 24%. There was a consensus (75%) to administer an anti-TNFα, but there was no consensus for monotherapy or combination therapy.
The second step in the management of post-operative CD is to assess the patient at 6 months. Relapse is confirmed by a Rutgeerts score higher or equal to i2 on ileocolonoscopy 6 months after the surgical intervention. In the absence of relapse, the NG recommends continuing treatment or ongoing monitoring. If there is a relapse, the therapeutic decision depends on the initial therapy prescribed after the surgery: In the absence of treatment, the NG did not reach a consensus, with 54% recommending thiopurines and 45% preferring anti-TNFα therapy (with vedolizumab as an alternative in case of intolerance or contraindication). In case of initial post-operative treatment with optimized thiopurines, the NG voted 64% for combination therapy and 35% for anti-TNFα monotherapy, with 99% of votes in favor of an anti-TNFα (vedolizumab is an alternative in case of intolerance or contraindication). If the patient was treated post-surgery with an anti-TNFα, consensus was not reached. The NG tended to recommend maintaining and optimizing the anti-TNFα (52%) rather than opting for a change of anti-TNFα, while an anti-TNFα and thiopurine combination therapy is preferred by 38% of participants ( Fig. 9 ).
The emergence of new therapies and the lengths of time to develop recommendations motivate expert groups and professional gastroenterology societies to foster a clear picture of the situation and to share their clinical experience. Treatment algorithms developed on the basis of expert opinion have recently been published for ulcerative colitis 21 22 23 24 .
A group of 59 French gastroenterologists with experience in the management of Crohn’s disease (CD) and representative of both university hospitals and private practice met to develop algorithms to improve the management of CD. This Nominal Group focused on the management of common clinical presentations of CD.
The algorithms approved by the NG show, in uncomplicated forms of CD, that the management of the first flare, with corticosteroids as first-line, remains consensual, except for the mildly colic form of CD where the use of 5-ASA is also permissible (36%), but without consensus.
The use of thiopurines is recommended in case of intolerance or corticosteroid dependence in mildly active CD. In moderately active CD, the algorithms show that practitioners prefer the use of anti-TNFα in case of intolerance or resistance to steroid therapy. In case of corticosteroid dependence therapy, the NG recommends thiopurines, even though the use of an anti-TNFα is recommended if there are poor prognostic factors. In these situations, and those of the severe active forms of CD, the NG recommends prescribing pharmacokinetic assays of residual anti-TNFα and antibody levels to inform the therapeutic decision after a primary non-response to optimized anti-TNFα. The use of anti-TNFα alone or in combination therapy (an anti-TNFα and a thiopurine) was discussed although no consensus was reached. This decision is therefore up to the practitioner.
In the perianal CD with complex fistula, the NG considered that the presence of an abscess did not change the management approach. Draining with antibiotics and treating with combination therapy (infliximab and a thiopurine) is recommended as first-line therapy. In the case of a single fistula, the NG favored antibiotics, but there was no consensus on the concomitant use of drainage.
In patients with intra-abdominal abscess, the NG reached a consensus about its management and recommended antibiotic therapy with drainage (radiologically guided if possible). Anti-TNFα therapy is recommended following resolution of the abscess. However, no consensus was found on whether to attempt a second drainage or to attempt a resection if the abscess persists.
The management of stricture generated considerable debate within the Nominal Group. The challenge being the choice of criteria characterizing the stricture: inflammation, length of the stricture, or symptoms.
Finally, the post-operative management of Crohn’s disease was discussed. The presence or absence of risk factors for relapse was decisive in determining the choice of treatment, which includes the use of thiopurines or anti-TNFα depending on the case. Relapse is confirmed by a Rutgeerts score higher or equal to i2 on ileocolonoscopy 6 months after the surgical intervention. The NG did not make a distinction between i2a and i2b scores.
These algorithms for the treatment of CD were developed using the NG method, a consensus methodology that is widely used to develop professional recommendations. This method is of great utility where professional opinion is not unanimous because of a paucity of data in the literature, a low level of evidence or conflicting data. The situations discussed in these expert recommendations meet these conditions. The algorithms developed show the consensus of gastroenterologists on the management of various CD modalities and may serve as a practical and useful tool in clinical practice, accessible via a web application: www.algorithmici.com .
Conflicts of interest
Laurent Peyrin-Biroulet (Consultant: AbbVie, BMS, Boerhinger-Ingelheim, Celltrion, Ferring, Genentech, Hospira, Janssen, Lilly, Merck, Mitsubishi, Norgine, Pharmacosmos, Pilège, Shire, Takeda, Therakos, Tillots, UCB-Pharma, Vifor. Speaking engagements: Merck, AbbVie, Ferring, HAC-Pharma, Janssen, Norgine, Takeda, Therakos, Tillots, Vifor); Yoram Bouhnik (Consultant: AbbVie, Astra Zeneca, BMS, MSD, Norgine Pharma, Roche, Sanofi, Shire, Takeda. Honoraria: AbbVie, BMS, Ferring, HAC Pharma, Mayoli-Spindler, MSD, Teva, Vifor Pharma); Xavier Roblin (AbbVie, Ferring, HAC Pharma, Janssen, MSD, Takeda, Theradiag, Speaking engagements: AbbVie); Guillaume Bonnaud (Consultant and speaking engagements: AbbVie, Covidien, Ferring, MSD, Norgine, Takeda); Hervé Hagège (Consultant and speaking engagements: AbbVie, Alfa Wassermann, Aptalis, Given Imaging, Janssen Cilag, Mayoly Spindler, MSD, Norgine, Takeda); Xavier Hébuterne (advisory board member: AbbVie, Fresenius-Kabi, Nestlé, Takeda. Educational activities: AbbVie, ARARD, Baxter, Fresenius-Kabi, MSD, Nutricia, Takeda, Vifor). The information in this article has not be previously presented at any conference.
This experts’ opinion on the management of CD was developed from a working group meeting of gastroenterologists using a Nominal Group methodology. We would like to thank the following physicians who participated in this working group: Vered Abitbol, Laurent Abramowitz, Romain Altwegg, Aurélien Amiot, Jean-Pierre Arpurt, Alain Attar, Alexandre Aubourg, Marc-André Bigard, Antoine Blain, Gilles Bommelaer, Arnaud Boruchowicz, Arnaud Bourreille, Marc Brun, Anthony Buisson, Guillaume Cadiot, Maryan-Nicolas Cavicchi, Hubert Claudez, Denis Constantini, Laurent Costes, Baya Coulibaly, Anne Courillon-Mallet, Vincent de Parades, Emilie Del Tedesco, Nina Dib, Bernard Duclos, Jean-Louis Dupas, Luc Escudié, Isabelle Etienney, Patrick Faure, Jérôme Filippi, Mathurin Flamant, Bernard Flourié, Frédéric Heluwaert, Pauline Jouët, Mehdi Kaassis, Gilles Macaigne, Georgia Malamut, Patrick Mamou, Nicolas Mathieu, Jacques Moreau, Stéphane Nahon, Stéphane Nancey, Benjamin Pariente, Anne-Laure Pelletier, Magali Picon-Coste, Hélène Pillant-le-Moult, Guillaume Pineton de Chambrun, Marie-Pierre Pingannaud, Jean-Marie Reimund, Guillaume Savoye, Agnès Senéjoux, Xavier Tréton and Lucine Vuitton.
We would also like to thank KPL for editorial assistance in the drafting of this article.
Institutional support: The working group meeting received institutional support from the Takeda Pharmaceutical Company, who did not participate in the development of the algorithms. No representative of the Takeda Pharmaceutical Company attended the Nominal Group meeting.
Organizational support: We would like to thank KPL, who helped with the organization of this meeting.
Institutional support for the working group was provided by the Takeda Pharmaceutical Company; organizational support for the working group meeting was provided by KPL.
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