Introduction
No clinical trials have directly compared biologics in children with inflammatory bowel disease (pIBD), with observational studies indicating only modest differences in efficacy [1]. Risk factors for adverse effects of individual preparations are important for treatment personalization. Cutaneous adverse effects of tumour necrosis factor antagonists (anti-TNF) have been widely reported, affecting up to 48% of anti-TNF treated pIBD patients [2]. Identifying patients at risk for developing adverse cutaneous effects may be beneficial for treatment sustainability.
Aims & Methods
The Czech National Prospective Registry of Biologic and Targeted Therapy of Inflammatory Bowel Disease (CREdIT) was used to identify the biologic treatment courses. PIBD patients younger than 19 years were considered eligible if they were treated with anti-TNF, vedolizumab, or ustekinumab. Baseline patient characteristics, including anthropological features, disease classification, and the reason for biologic, were collected in the registry. Data on the family and personal history of skin conditions and atopic diseases were collected at enrolment or, if missing, by systematic telephone interview. The occurrence of cutaneous adverse events, including type (atopic, psoriatic, pustulotic or other), distribution and the quality of life as assessed by validated questionnaires were prospectively collected. Observation was defined as one course of biological therapy in one patient. The primary outcome was defined as time to onset or significant worsening of the skin condition during biological therapy. Cox proportional hazard models with mixed effect were designed for potential predictors. Predictors that were statistically significant in the univariate analysis were used to build the multivariate model.
Results
Among the 544 included observations of 423 paediatric patients from 4 centres, 208 were treated with adalimumab (38%), 256 with infliximab (47%), 46 with ustekinumab (8%), and 36 with vedolizumab (7%). Most patients had CD (N=311; 74%) and were also treated with an immunomodulator at the time of initiation of biologic therapy (N=478; 78%). The primary outcome was achieved in 108 observations (atopic [9%], psoriatic [34%], pustulotic [13%]), with most of the children treated with adalimumab (50%), 47% with infliximab and 3% with ustekinumab. Female sex (hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.22–2.78), anti-TNF therapy (HR 6.97, 95% CI 2.15–22.59), and family history of atopic diseases (HR 1.77, 95% CI 1.12–2.79) were identified as predictors of the occurrence or progression of the cutaneous adverse events in univariate analysis. These predictors retained their significance in the multivariate model additionally including diagnosis, concomitant immunomodulator use and line of therapy (Table 1).
Table 1 – Multivariate Cox proportional hazard model of cutaneous adverse effect predictorsPredictor
| HR (95% CI)
| p-value
|
|---|
Female sex
| 1.82 (1.18–2.81) | 0.01 |
Family history of atopic diseases
| 1.82 (1.13–2.91)
| 0.01 |
anti-TNF therapy
| 6.84 (1.98–23.63) | <0.01 |
Crohn's disease
| 1.33 (0.75–2.36)
| 0.43 |
Biologically naïve
| 0.79 (0.46–1.37)
| 0.41 |
Concomitant immunomodulator
| 1.48 (0.76–2.88)
| 0.25
|
Conclusion
These preliminary data from the prospective multicentre study suggest that when choosing biologic treatment, the female sex, family history of atopic diseases and, in particular, anti-TNF treatment, may be considered as predictors of cutaneous adverse effects in paediatric IBD patients regarding the occurrence of cutaneous adverse reactions.
References
1. Sands BE, Irving PM, Hoops T, Izanec JL, Gao LL, Gasink C, Greenspan A, Allez M, Danese S, Hanauer SB, Jairath V, Kuehbacher T, Lewis JD, Loftus EV Jr, Mihaly E, Panaccione R, Scherl E, Shchukina OB, Sandborn WJ; SEAVUE Study Group. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn's disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet. 2022 Jun 11;399(10342):2200-2211. doi: 10.1016/S0140-6736(22)00688-2.
2. Mälkönen T, Wikström A, Heiskanen K, Merras-Salmio L, Mustonen H, Sipponen T, Kolho KL. Skin reactions during anti-TNFα therapy for pediatric inflammatory bowel disease: A 2-year prospective study. Inflammatory bowel diseases. 2014;20(8):1309-15. doi: 10.1097/MIB.0000000000000088.
Disclosure
DK: Lecture/workshop fee: Takeda, Vitabalans Oy
KZ: Consultancy: Nestlé
IC: Nothing to disclose
TL: Nothing to disclose
JS: Lectures/congress fees/consultancy: MSD, Abbvie, Takeda, Nutricia, Nestle
EK: Nothing to disclose
MH: Lectures/congress fees/consultancy: Nutricia, Nestlé
KM: Lectures/consultancy: Janssen, Eli Lilly
MD: Congress fees: Nutricia
EV: Workshop/congress fee: Biocodex, Ewopharma
MK: Nothing to disclose
JP: Nothing to disclose
JB: Lectures/congress fees/consultancy: MSD, Abbvie, Nutricia, Nestlé, Sanofi
OH: Lectures/congress fees/consultancy: MSD, Abbvie, Takeda, Nutricia, Sandoz, Eli Lilly