DÄ internationalArchive24/2021Early Immunosuppression in Children and Adolescents With Crohn’s Disease

Research letter

Early Immunosuppression in Children and Adolescents With Crohn’s Disease

Data From the CEDATA GPGE Registry

Dtsch Arztebl Int 2021; 118: 421-2. DOI: 10.3238/arztebl.m2021.0214

de Laffolie, J; Zimmer, K; Sohrabi, K; Hauer, A C

LNSLNS

To date, failure of the first-line medical management of Crohn’s disease (CD) in children and adolescents has been followed by escalation treatment, with administration of immunomodulators, e.g., azathioprine, or biologics, such as infliximab (1). The most recent revision of the international guideline proposes stratification of the therapy, with selection of either accelerated step-up or primary treatment with biologics on the basis of predictors of poor outcome (POPO) (2). The objective of this study was to evaluate this concept of early immunosuppression with the aid of data from the largest registry of children and adolescents with chronic inflammatory bowel disease (IBD) in Europe.

Patients and method

CEDATA GPGE is a multicenter registry in German-speaking countries that has accumulated data on more than 5000 children and adolescents with chronic inflammatory bowel disease and over 50 000 documented contacts. This study included all patients with CD who fulfilled the following criteria: age 1–18 years, diagnosis at a participating center in the period 2004–2018, addition to the registry within 3 months of diagnosis (to avoid recall bias), and at least two follow-up visits. Patients with at least one predictor of poor outcome were classified as POPO positive, while those without were classed as POPO negative. The following are considered as POPO: perianal disease; a stricturing/penetrating disease pattern; severe growth retardation; extensive panenteric disease; and persistent disease activity despite adequate induction therapy. On the one hand, we ascertained the frequency of occurrence of negative outcome parameters (especially extraintestinal manifestations [EIM]), and on the other hand, we compared patients in whom administration of azathioprine or infliximab was started early with those for whom that was not the case. Kaplan–Meier analysis and Cox regression were performed, excluding medications after occurrence of the endpoint prior to analysis.

Results

Of 2980 patients in the register, 1084 met the criteria specified above and were included. The median follow-up was 10 visits (interquartile range [IQR] 5–15 visits, maximum 94 visits over a period of 769 days (median; IQR 275–1595 days, maximum 3570 days. Seven hundred nine patients (65.4%) had at least one POPO (children under 6: 70%). Although there were no differences between POPO-positive and POPO-negative patients with regard to age, sex, or diagnostic latency, they did differ in disease activity at the time of diagnosis (Paediatric Crohn’s Disease Activity Index 23.3 versus 19.3; p = 0.05).

The use of azathioprine and infliximab increased over the study period (azathioprine: 45% in 2004, 62% in 2018; infliximab: 3% in 2004, 35% in 2018). In the first year following diagnosis, POPO-positive patients were somewhat more likely than POPO-negative patients to receive infliximab (11.1% versus 7.3%; p = 0.047) and azathioprine (64.4% versus 61.5%; p = 0.35). The POPO-positive patients with abscesses, fistulas, or stenoses were given infliximab more frequently than those without such findings (37.1% versus 22.1%, p = 0.06). A similar relationship was seen between these two groups with regard to the need for surgery (17.1% versus 7.2%, p = 0.054). In patients diagnosed before 2009, early initiation of azathioprine was associated with a lower risk of surgery (odds ratio [OR] 0.59; 95% confidence interval [0.35; 0.98]; p = 0.032; Figure 1).

Association of early treatment with azathioprine with the need for surgical procedures before and after 2009
Figure 1
Association of early treatment with azathioprine with the need for surgical procedures before and after 2009

Cox regression showed that diagnosis after 2009 was the parameter associated strongly with a reduced risk of EIM (hazard ratio [HR] 0.32 [0.2; 0.51]). When the time of diagnosis (before or after 2009) was ignored, initiation of infliximab within 3 months after diagnosis was associated with a lower risk of EIM than later administration (HR = 0.27 [0.036; 2.0]). However, no such association was found for azathioprine (HR = 1.45 [0.6; 3.1]). In Kaplan–Meier analysis, the trend was also apparent at the end of the observation period for infliximab (OR 0.17 [0.05–0.61]), but not for azathioprine (OR 1.00 [0.70; 1.44]; Figure 2).

Risk of extraintestinal manifestations (EIM) after administration of infliximab and azathioprine
Figure 2
Risk of extraintestinal manifestations (EIM) after administration of infliximab and azathioprine

The predictor “persistent disease activity despite adequate induction therapy” was associated with an elevated risk of failing to achieve a steroid-free remission lasting more than 1 year (OR 1.49 [1.07; 2.07], p = 0.02).

Discussion

The data presented here indicate that the risk is reduced by early administration of infliximab. They lend emphasis to recent calls for early escalation or initial treatment with biologics in selected cases (3), with the aim of achieving adequate control of persistent disease. Our findings are confirmed by a cohort study of 825 patients in which early initiation of infliximab treatment was associated with a low rate of surgery (4). It has to be taken into account that other factors have also contributed to the decrease in operative interventions over the past 15–20 years. The reduction in the risk of extraintestinal manifestations after administration of infliximab, but not of azathioprine, indicates that early treatment with anti-tumor necrosis factor (anti-TNF) alpha-antibodies is more effective than early use of immunomodulators, as was described in a smaller group (5).

Our observation study with analysis of data from a large cohort supports the treatment concept of the international guideline. The findings may contribute to science-based, patient-centered, and needs-oriented treatment of children and adolescents with IBD.

Conclusion

The increased and early use of azathioprine or infliximab over the past 15–20 years is associated with a decrease in the need for surgical procedures in children and adolescents with Crohn’s disease. Early disease control is particularly important in patients with risk factors to minimize long-term complications and achieve remission.

Jan de Laffolie, Klaus-Peter Zimmer, Keywan Sohrabi, Almuthe Christina Hauer and the CEDATA GPGE Study Group

Department of General Pediatrics and Neonatology, University of Giessen (Laffolie, Zimmer) jan.delaffolie@paediat.med.uni-giessen.de

Health Faculty, TH Mittelhessen University of Applied Sciences, Giessen (Sohrabi)

Clinical Department of General Pediatrics, Medical University Graz, Austria (Hauer)

CEDATA GPGE—list of contributors

Dr. med. Stephan Buderus, Bonn

Prof. Dr. med. Philip Bufler, Berlin

Dr. med. Martin Claßen, Bremen

Prof. Dr. med. Jan Däbritz, Rostock

Dr. med. Söhnke Dammann, Stuttgart

Dr. med. Jan de Laffolie, Giessen

Prof. Dr. med. Almuthe Christina Hauer, Graz, Austria

Prof. Dr. med. Klaus-Michael Keller, Wiesbaden

Prof. Dr. med. Sibylle Koletzko, Munich

Dr. med. Andreas Krahl, Darmstadt

Dr. med. Martin Laaß, Dresden

Dr. med. Thomas Lang, Regensburg

Dr. med. Carsten Posovszky, Ulm

PD Dr. med. Burkhard Rodeck, Osnabrück

Dr. med. Stefan Trenkel, Potsdam

Support and sponsorship

The CEDATA GPGE registry was/is supported by the Justus Liebig University of Giessen, Medical University Graz, and the Rudolf Chaudoire Research Fund for Switzerland, Germany, and Austria. It was/is sponsored by Abbvie, Dr. Falk Pharma, Vifor, A Heart for Children (BILD hilft e.V.), and Takeda.

Conflict of interest statement

PD Dr. de Laffolie has received consultancy honoraria (Advisory Board) from Abbvie.

Prof. Hauer has received consultancy honoraria from Abbvie, MSD, Nutricia, Shire, Milupa, and Hipp and has been the beneficiary of study support (third-party funds) from Janssen.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 23 November 2020, revised version accepted on 14 April 2021

Translated from the original German by David Roseveare

Cite this as:
de Laffolie J, Zimmer KP, Sohrabi K, Hauer AC: Early immune suppression in children and adolescents with Crohn’s disease—data from the CEDATA GPGE registry. Dtsch Arztebl Int 2021; 118: 421–2. DOI: 10.3238/arztebl.m2021.0214

1.
Buderus S, Scholz D, Behrens R, et al.: Inflammatory bowel disease in pediatric patients—characteristics of newly diagnosed patients from the CEDATA-GPGE registry. Dtsch Arztebl Int 2015; 112: 121–7 VOLLTEXT
2.
Rheenen PF, Aloi M, Assa A, Bronsky J, et al.: The medical management of paediatric crohn‘s disease: an ECCO-ESPGHAN guideline update. J Crohns Colitis 2020: jjaa161. doi: 10.1093/ecco-jcc/jjaa161. Epub ahead of print. PMID: 33026087 CrossRef MEDLINE
3.
Brückner A, Werkstetter KJ, de Laffolie J, et al.: Incidence and risk factors for perianal disease in pediatric crohn disease patients followed in CEDATA-GPGE Registry. J Pediatr Gastroenterol Nutr 2018; 66: 73–8 CrossRef MEDLINE
4.
Ashton JJ, Borca F, Mossotto E, et al.: Increased prevalence of anti-TNF therapy in paediatric inflammatory bowel disease is associated with a decline in surgical resections during childhood. Aliment Pharmacol Ther 2019; 49: 398–407 CrossRef MEDLINE
5.
Walters TD, Kim MO, Denson LA, et al.: Increased effectiveness of early therapy with anti-tumor necrosis factor-alpha vs an immunomodulator in children with Crohn‘s disease. Gastroenterology 2014; 146: 383–91 CrossRef MEDLINE
Association of early treatment with azathioprine with the need for surgical procedures before and after 2009
Figure 1
Association of early treatment with azathioprine with the need for surgical procedures before and after 2009
Risk of extraintestinal manifestations (EIM) after administration of infliximab and azathioprine
Figure 2
Risk of extraintestinal manifestations (EIM) after administration of infliximab and azathioprine
1.Buderus S, Scholz D, Behrens R, et al.: Inflammatory bowel disease in pediatric patients—characteristics of newly diagnosed patients from the CEDATA-GPGE registry. Dtsch Arztebl Int 2015; 112: 121–7 VOLLTEXT
2.Rheenen PF, Aloi M, Assa A, Bronsky J, et al.: The medical management of paediatric crohn‘s disease: an ECCO-ESPGHAN guideline update. J Crohns Colitis 2020: jjaa161. doi: 10.1093/ecco-jcc/jjaa161. Epub ahead of print. PMID: 33026087 CrossRef MEDLINE
3.Brückner A, Werkstetter KJ, de Laffolie J, et al.: Incidence and risk factors for perianal disease in pediatric crohn disease patients followed in CEDATA-GPGE Registry. J Pediatr Gastroenterol Nutr 2018; 66: 73–8 CrossRef MEDLINE
4.Ashton JJ, Borca F, Mossotto E, et al.: Increased prevalence of anti-TNF therapy in paediatric inflammatory bowel disease is associated with a decline in surgical resections during childhood. Aliment Pharmacol Ther 2019; 49: 398–407 CrossRef MEDLINE
5.Walters TD, Kim MO, Denson LA, et al.: Increased effectiveness of early therapy with anti-tumor necrosis factor-alpha vs an immunomodulator in children with Crohn‘s disease. Gastroenterology 2014; 146: 383–91 CrossRef MEDLINE