Table 1.
All included studies with pediatric patients and biologics.
| Study | N TNF | Age (Yrs) (CD, UC) |
m % (CD, UC) | Study Type | Observation Period | Country | IBD Type | Biologic | Time from Diagnosis to Biologic | Comparison-Group | Post-Assessments | Outcomes | Results |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Claßen et al., 2022 [1] | 487 | 11.9 | 59.1 | Retrospective registry | 2004–2020 | Germany, Austria, Switzerland | CD, CU, IBDu | all | 19 months | First-line vs. Second line | Laboratory markers, clinical scores, side effects, treatment failure | Patients with CD significantly benefitted from early treatment, with lower clinical scores, fewer EIMs and lower risk for treatment failure | |
| D’Arcangelo et al., 2021 [27] | 185 | 13 | 58 | Retrospective, observational cohort Single-center |
2012–2020 | Italy | CD, UC, IBDu | IFX, ADL, UST, VEDO | 2 yrs | Immediate and delayed AEs | 32.8% biologic-related Aes 10% immediate reactions, 45% delayed 14% treatment discontinuation because of AEs |
||
| Kaplan et al., 2023 [4] | 17,649 | Retrospective, observational cohort | 2006–2016 | USA | CD, UC | all | Use, discontinuation | 43% of pediatric IBD patients treated with biologic, more likely for CD, discontinuation significantly higher in UC | |||||
| TNF-α inhibitors | |||||||||||||
| Bronsky et al., 2022 [13] | 62 | 11.64–16.27 | 55–68 | Prospective observational cohort | 2013–2017 | Czech Republic | CD | IFX, ADL | 0.6–1.04 yrs | IFX vs. ADL | Up to 24 months | Treatment escalation Non-response Serious AEs |
No difference between IFX and ADL in efficacy and safety |
| Lee et al., 2015 [18] | 52 | 13.9 | 46 | Observational cohort | Canada, USA | CD | IFX (1xADL) | 0.7 yr | EEN (n = 22), PEN (n = 16) | 8 weeks | PCDAI, QoL, mucosal healing via FCP | Clinical response: 64% PEN, 88% EEN, 84% TNFi Mucosal healing: PEN 14%, EEN 45%, TNFi 62% QoL not statistically significant |
|
| Scarallo et al., 2021 [16] | 134 | 10.9, 10.3 | 65.4, 50 |
retrospective, observational (two centers) |
2008–2018 | Italy | 78 (CD) 56 (UC) | IFX, ADL | Endoscopically assessed mucosal remission | Mucosal remission in 41% of CD patients and 53.6% of UC patients, histological remission in 33.3% of CD patients and 39.3% of UC patients | |||
| Boros et al., 2023 [26] | 32 | 15.2, 16.4 | 49 | Prospective, observational follow up Single-center |
2016–2018 | Hungary | CD, UC | TNFi | 1.4 yrs, 3 yrs | Healthy controls | 2 & 6 months | Body composition, health-related quality of life, physical activity | Body composition and physical activity significantly improved after 6 months and caught up to healthy controls, no change in health-related quality of life 58% of CD 37.5% of UC patients in remission |
| Kim et al., 2021 [28] | 84 | 15 | 74.1 | Retrospective single-center | 2000–2013 | Korea | CD | TNFi | Thiopurine treatment (N = 287) | Up to 13 yrs | Disease behavior evolution | Early treatment (within 3 months after diagnosis) was associated with lower risk of disease behavior progression | |
| Walters et al., 2014 [29] | 68 | 11.8 | 61 | Retrospective multicenter | 2008–2012 | North America | CD | IFX, ADL | Within 3 months | Immunomodulator (IM) (N = 68), no IM (N 68) | Steroid-free and surgery-free remission, growth | 85.3% in remission with TNFi, significantly more than other groups, growth improved in biologic group only | |
| Ley et al., 2022 [25] | 1007 | Retrospective multicenter |
1988–2011 | France | CD | TNFi | M = 8.8 yrs | Intestinal resection, disease progression, hospitalizations |
Reduction in intestinal resection and disease progression, no change in hospitalization over time | ||||
| Choe et al., 2022 [30] | Pediatric + adult | Population-based | 2006–2015 | Korea | CD, UC | TNFi | TNFi prescription, fistulectomy, surgery | Lower odds of surgery in CD patients under TNFi therapy | |||||
| Kugathasan et al., 2017 [31] | 913 | Prospective inception cohort | 2008–2012 | USA, Canada (28 sites) | CD | TNFi | Disease complications | Early TNFi admission reduced risk for penetrating complications but not stricturing complications | |||||
| Kandavel et al., 2021 [32] | 27,321 | Retrospective cohort, multicenter | 2007–2018 | US, UK, Qatar | CD, UC, IBDu | TNFi | Use of corticosteroids | Appliance of TNFi within the first 120 days after diagnosis reduces risk for need of steroids later in CD not in UC | |||||
| Sherlock et al., 2021 [33] | 198 | 10.5 | 59.1 | Retrospective cohort, single-center |
2001–2015 | Canada | CD, UC, IBDu | 21.5 months | M = 47.8 | Biologic therapy associated with older age, higher PCDAI/ PUCAI hypoalbuminemia in UC and CD | |||
| Nuti et al., 2014 [34] | 78 | 15 | 63 | Single-center cohort | 2001–2011 | Italy | CD | IFX, ADL | 40.6 months | 1, 2, 3 yrs | Clinical activity (PCDAI), discontinuation, AEs | 81% continuation yr 1, 54% yr 2, 33% yr 3, no serious AEs | |
| Beukelmann et al., 2018 [35] | 6808 | 43 | Retrospective, cohort | US | IBD, JIA, PsA | TNFi | No TNFi use (N = 20,049) | Malignancies | TNFi use in combination with thiopurines increased the risk for malignancies | ||||
| Hradsky et al., 2021 [36] | 100 | 15 | 57–65 | Retrospective | CD | TNFi | Skin complications | After 2 yrs of treatment 35% of patients developed at least one skin complication | |||||
| Dolinger et al., 2022 [37] | 638 | Retrospective | IFX, ADL | 6 months | Skin reactions | 21% infliximab patients, 11% adalimumab patients | |||||||
| Baggett et al., 2022 [38] | 3794 | Retrospective | 2008–2020 | IFX, ADL, etanercept | Non-TNFi exposure | Incidence of psoriasis | Higher risk of psoriasis in patients treated with TNFi (highest in adalimumab) | ||||||
| Zvuloni et al., 2021 [39] | 135 | 12.9 | 56.3 | Retrospective, cohort single-center |
2015–2020 | Israel | CD, UC | IFX, ADL | MD = 1.7 yrs | Incidence of AEs | 37% of patients had AEs, psoriatiform rashes (45%), elevated transaminases (32%) and infusion reactions (13%) | ||
| Eindor-Abarbanel et al., 2022 [40] | 89 | 3.8 | 62.8 | Retrospective | 2005–2019 | United states | VEO IBD | TNFi | TNFi-naive | 1 yr | Disease course, dose, and dose interval of IFX | 39.5% of VEO IBD patients received TNFi, higher disease activity was associated with TNFi-treatment, clinical remission on first biologic agent in 61,8% | |
| Kerur et al., 2022 [41] | 294 | Retrospective, cohort Multicenter |
2008–2013 | North America | VEO IBD | IFX, ADL | 1, 3, 5 yrs | Utilization and durability of TNFi | 55% of patients treated with TNFi between 0–6 yrs old, durability 90% after one yr, 55% after 5 yrs, lower durability in UC und IBDu | ||||
| Kennedy et al., 2019 [42] | 219 pediatric | Adult + pediatric | 49 | Prospective, observational cohort, multicenter | 2013–2016 | UK, Korea, USA | CD | IFX, ADL | 2.3–3.3 yrs | 12 months | Disease activity, AEs, discontinuation, treatment failure, anti-drug antibodies | Low drug concentration the only predictor for primary non-response in week 14, and remission by week 54 62.8% ADAs in IFX, 28.5% in ADL predicted by suboptimal drug concentration in week 14 |
|
| Rodriguez Azor et al., 2023 [43] | 30 | 11.3 | 70 | Prospective observational | 2015–2020 | CD | IFX, ADL | 9.9 months | M = 27.1 months | Clinical remission, mucosal healing, laboratory markers | 87.1% in clinical remission (wPCDAI), 83% achieved mucosal healing (MINI) | ||
| Salvador-Martín et al., 2023 [44] | 340 | 11.2 | 60.3 | Observational, multicenter | Spain | CD, UC, IBDu | IFX, ADL | 6.1 months | Responders vs. non-responders | 9 yrs | Treatmtent failure | Only in adults association of HLA polymorphisms and treatment failure | |
| Cohen et al., 2019 [45] | 234 | 13 | 54.2 | Retrospective, single-center | USA | CD, UC | IFX, ADL | With and without ADAs | ADAs | 24.8% developed ADAs, 48% of those underwent dose optimization and of those 54% had undetectable ADAs on follow-up, Patients switching to another agent were not more likely to develop ADAs |
|||
| Colman et al., 2021 [46] | 89 | 12.2–17.7 | 58.7 | Retrospective cohort, single-center | 2014–2018 | USA | CD, UC, IBDu | IFX, ADL | With and without immunomodulator (IM) | 6, 12 months | Clinical and biochemical remission, discontinuation, ADAs | Significantly more patients in combination therapy with TNFi and IM were in remission after one yr than without IM (53.9% vs. 26.8%) Without IM ADAs were unlikely to reverse if titer > 329 ng/ml |
|
| Sassine et al., 2022 [47] | 639 | 14 | 56 | Retrospective cohort study | 2009–2019 | lCD | TNFi | Clinical relapse | Use of TNFi reduced risk for relapse compared to immunomodulators | ||||
| Scarallo et al., 2021b [48] | 170 | 12 | 65.6, 46.7 | Retrospective Two centers |
2008–2018 | Italy | CD, UC | IFX, ADL | 1–1.5 | Endoscopic (mucosal and histological) remission | MH was achieved by 32 patients with CD (41%) and 30 patients with UC (53.6%); 26 patients with CD (33.3%) and 22 patients with UC (39.3%) achieved HH Withdrawal of TNFi associated with relapse |
||
| Weigl et al., 2023 [49] | 13 | 52 | Retrospective | Germany | CD | TNFi | No perioperative TNFi (N = 16) | Weight, height, disease activity, infections | Improvement of weight, height after ileocecal resection, significantly more improvement in disease activity in TNFi group, no increase in infections | ||||
| Infliximab | |||||||||||||
| deBruyn et al., 2018 [11] | 180 | 14.3 | 54.4 | Retrospective, multicenter | 2008–2012 | Canada | CD | IFX | 1.5 yrs | Discontinuation, dose optimization | Dose escalation occurred in 57.3% primarily due to loss of response Annual discontinuation 3.2% per yr |
||
| Kierkus et al., 2012 [17] | 66 | 14.1 | 43.9 | Prospective cohort | Poland | CD | IFX | 5.6 yrs | 2, 6, 10 weeks | Disease activity (clinical, laboratory & endoscopic) | 33% reached clinical remission, 28% non-responders, endoscopic improvement in week 10 | ||
| Luo et al., 2017 [19] | 13 | 11.7 | 46.2 | Prospective | China | CD | IFX | 12 months | EEN (n = 13) | 8 weeks | PCDAI, growth, AEs | Significantly higher percentage of clinical response, growth, and AEs in IFX group | |
| Hyams et al., 2012 [22] | 60 | 14.5 | 53.3 | Randomized | 2006–2010 | USA, Canada | UC | IFX | 1.4 yrs | Dosing interval 8 vs. 12 weeks | 8, 54 weeks | Clinical remission, AEs | Response at week 8 73.3%, overall remission rate at week 54 was 28.6%, no serious AEs |
| Bolia et al., 2019 [23] | 204 | 12 | 50 | Retrospective | 2005–2016 | Australia | UC | IFX | Colectomy rates | Reduction in colectomy rates after introduction of IFX | |||
| Jongsma et al., 2020 [50] | 50 | Multicenter open label randomized controlled trial | CD | IFX | Conventional treatment (N = 50) Steroids/EEN | 10, 52 weeks | Clinical and endoscopic remission | Higher percentage of patients in TNFi group achieved clinical (59%) and endoscopic remission (59%) at week 10, no significant difference in week 52, less treatment escalation needed in TNFi group at week 52 | |||||
| Jongsma et al., 2020b [51] | 2015 | 9.22 | 57 | Retrospective, case–control, multicenter | 2015–2019 | Europe, Canada | CD, UC, IBDu | IFX | Start IFX < 10 yrs of age vs. >10 yrs | 1 yr | Dosing, treatment intervals, trough levels, discontinuation, clinical remission | Equal amount of patients maintained therapy with IFX, younger patients on significantly higher dosage per kg, no effect of proactive drug monitoring | |
| Church et al., 2019 [52] | 125 | 14 | 54–70 | Retrospective Single-center |
2000–2015 | Canada | SR UC | IFX | 0.7 yrs | Standard vs. intensified induction | M = 1.4 yrs | Colectomy, remission, mucosal healing, AEs | Lower chance of colectomy in intensified regimen, other long-term outcomes are similar, 66% mucosal healing, AEs were rare |
| van Hoeve et al., 2019 [53] | 35 | retrospective | 2012–2018 | CD, UC | IFX | Remission at week 52 vs. non remission | 52 weeks | Clinical, biological remission, trough levels | Trough levels just before maintenance were the only predictors for clinical and biological remission | ||||
| Schnell et al., 2021 [54] | 42 | 13.3, 14.27 | 64.3 | Prospective, controlled, single-center | Germany | CD, UC | IFX | Healthy matched controls | 2, 6, 12 months | Biological remission, trough levels, cytokines | Higher trough levels in patients responding to treatment after 6 months, no effect of comedication with azathioprine Before treatment different cytokine profiles in IBD patients and healthy controls |
||
| Cheifetz et al., 2022 [55] | 103 | Post hoc REACH trial | CD | IFX | 10, 30, 54 weeks | Clinical remission | Higher infliximab concentration at week 10 was associated with clinical remission at week 10, and 30 | ||||||
| Lawrence et al., 2022 [56] | 140 | 14,1 | 54% | trial | 2016–2018 | Canada, Scotland | IFX | Standard induction vs. Optimization-based induction | 52 weeks | Clinical remission | Higher rates of clinical remission in optimized induction | ||
| Chung et al., 2022 [57] | 85 | Single-center retrospective | CD | IFX | Pharmacokinetic model of infliximab clearance, clinical remission | CRP and Albumin predict trough levels, induction trough levels predict remission | |||||||
| Kwon et al., 2022 [58] | 30 | 13.7 | 80 | Prospective | 2020–2021 | Korea | CD | IFX | Cytokines, trough levels, clinical and biochemical remission | Higher cytokine profiles in patients not achieving remission than in patients in remission, Cut-off for higher IFX doses TNFi concentration > 27.6 pg/ml | |||
| Constant et al., 2021 [59] | 55 | 13.1 | 69 | Retrospective single-center | 2013–2019 | USA | CD | IFX | 2, 8 weeks | Laboratory markers, IFX trough levels | Baseline laboratory markers (CRP, hypoalbuminemia, ESR) significantly associated with inadequate post-induction IFX trough concentration | ||
| Merras-Salmio et al., 2017 [60] | 146 | 14.8 | 57 | Retrospective, Single-center |
2003–2014 | Norway | CD, UC, IBDu | IFX | 1.8 | IFX trough levels, IFX ADAs | 63% of patients had loss of response, trough level significantly higher in patients in remission or ongoing therapy | ||
| Dave et al., 2021 [61] | 30 | 14.3–33.5 | 60 | Part prospective, part retrospective | 2017–2019 | India | CD, UC | IFX | 5 | IFX trough level, ADAs, evaluation of iDose software | iDose predicted 70% of patients’ trough concentrations correctly Of 11 patients managed with iDose, 8 achieved clinical remission, 2 showed partial response, one developed antibody |
||
| Curci et al., 2021 [62] | 76 | 14.7 | 47.4 | Prospective, two centers |
Italy | CD, UC | IFX | 8, 22, 52 weeks | Clinical response | single-nucleotide polymorphisms (SNPs) rs396991 in FCGR3A variant had significantly lower trough levels, higher chance of ADAs and reduced clinical response | |||
| Clarkston et al., 2019 [63] | 72 | 13.6 | 65 | Prospective cohort, Single-center |
2014–2018 | US | CD | IFX | 51 days | 1 yr | Clinical response (wPCDAI), biological response, maintenance concentrations | Clinical response 64%, fecal calprotectin improvement in 54% | |
| El-Matary et al., 2019 [64] | 52 | 13.5 | 60.8 | Cohort, multicenter |
2014–2017 | Canada | fCD | IFX | 24 weeks | Fistula healing, trough levels | Correlation between pre-fourth infusion trough levels and fistula healing | ||
| Stein et al., 2016 [65] | 77 | 14.8 | 63 | Prospective single-center |
2006–2011 | US | CD | IFX | 1.66 yrs | 1 yr | Ongoing treatment with IFX CRP, ADAs, trough levels |
78% remained on IFX associated higher week 10 trough levels | |
| Drobne et al., 2018 [66] | 183 | 15.4–40 | 57 | Cohort, single-center |
2010–2015 | Slovenia | CD, UC, IBDu | IFX | 7.3, 5.7 | Trough level, CRP, fecal calprotectin | Higher trough levels were associated with lower levels of CRP and fecal calprotectin, no higher number of infections in higher trough levels | ||
| Courbette et al., 2020 [67] | 111 | 11.6 | 59 | Retrospective single-center |
2002–2014 | France | CD | IFX | 14 weeks | Clinical response, predictors for response, through levels | 38.7% in clinical remission plus 36% partial response Normal growth and normal albumin levels at first application associated with clinical response |
||
| Crombé et al., 2011 [68] | 120 | 14.5 | 45 | Retrospective registry | 1988–2004 | France | CD | IFX | 41 months | Short- and long-term efficacy, rate of resection surgery, AEs | 58% response rate, reduced risk for surgery in responder group, 13% of AEs that led to discontinuation | ||
| Adalimumab | |||||||||||||
| Cozijnsen et al., 2015 [5] | 53 | 11 | 49.1 | Observational cohort | Netherlands | CD | ADL | 3 yrs | MD = 12 months | Categorized cPCDAI, discontinuation/treatment failure | 64% remission after three months, maintained by 50% for two yrs, more IFX primary non-responders failed ADL than Patients with loss of response | ||
| Croft et al., 2021 [24] | 93 | Double blind nulticenter |
2014–2018 | 10 countries | UC | ADL | High dose induction vs. standard dose | 8, 52 weeks | Clinical remission, mucosal healing, AEs | Remission rates in ADL group better than in placebo groups, high dose induction had higher rate of remission in week 8 and week 52 | |||
| Assa et al., 2019 [69] | 78 | 14.3 | 71 | Randomized controlled trial | 2015–2018 | Israel | CD | ADL | Proactive vs. reactive drug monitoring | 8–72 weeks | Steroid-free remission, biologic remission, discontinuation | Significantly higher proportion of patients achieved steroid-free remission in the proactive group than in the reactive group (82% vs. 48%), as well as drug intensification (87% vs. 60%) | |
| Matar et al., 2020 [70] | 78 | 14.3 | 71 | Randomized controlled trial multicenter |
2015–2018 | Israel | CD | ADL | With and without immunomodulator (IM) | Sustained steroid-free remission, laboratory markers, trough levels, ADAs, AEs | No difference in steroid-free remission between groups with and without IM (73% vs. 63%), or laboratory markers, trough levels, ADAs, occurrence of AEs | ||
| Dubinsky et al., 2016 [71] | 188 | 51, 57 | Randomized controlled trial multicenter |
8 countries | CD | ADL | 3 yrs | High dose, low dose weekly | 4, 26, 52 weeks | Remission, response rate, AEs | Significantly higher proportion of patients in high dose group responded (31.4% vs. 18.8%) and achieved remission (57.1% vs. 47.9%), same rate of AEs | ||
| Payen et al., 2023 [72] | 120 | 2008–2019 | CD | ADL | Top-down vs. step-up | 12, 24 months | Steroid -, EEN-free remission, clinical remission | Top-down strategy more effective, higher serum levels of ADL, no serious AEs | |||||
| Lucafò et al., 2021 [73] | 32 | 14.9 | 62.5 | Retrospective cross sectional multicenter |
2013–2019 | Italy | CD, UC | ADL | 41.73 | 4, 52, 82 weeks | Disease activity (PUCAI, PCDAI), trough levels | Around 50% remission rate, higher trough levels in patients with sustained clinical remission | |
| Golimumab | |||||||||||||
| Hyams et al., 2017 [74] | 35 | 15 | Open-label multicenter |
2014–2015 | North America, Europe, Israel | UC | GOL | 15 yrs | 2, 4, 6 weeks | Serum concentration, clinical outcomes, AEs | 60% clinical response, 34% clinical remission, and 54% mucosal healing, no safety concerns | ||
| Vedolizumab | |||||||||||||
| Garcia Romero et al., 2021 [7] | 42 | 12.6 | 52.4 | Retrospective, multicenter | 2017–2019 | Spain | CD UC | VEDO | 2.6 yrs (CD), 4.1 yrs (UC) |
14, 30, 52 weeks | Laboratory markers, activity indices, AEs | 52.4% overall remission rate at week 14, more in UC, 84.5% remained remission in week 52 | |
| Atia et al., 2023 [75] | 142 | 13.6 | 46% | Multicenter, prospective cohort, multicenter | 2016–2022 | 6 countries | CD, UC, IBDu | VEDO | 14 weeks | Steroid-free -/EEN-free remission | 42% UC in remission under vedolizumab, 32% CD, optimal drug concentration at week 14—> 7µg/ml | ||
| Ungaro et al., 2019 [76] | 22 pediatric | adult + pediatric | Cross-sectional, two centers |
USA | CD, UC | VEDO | Clinical -, steroid-free -, biochemical remission, drug concentration | Vedolizumab concentration > 11.5 µg/mL was associated with steroid free and biochemical remission | |||||
| Colman et al., 2023 [77] | 74 | 16 | 51 | Prospective observational | 2014–2019 | USA | CD, UC, IBDu | VEDO | 33 months | Pharmacokinetic model, clinical remission, through levels | Final model includes weight, erythrocyte sedimentation rate, and hypoalbuminemia | ||
| Ustekinumab | |||||||||||||
| Yerushalmy-Feler et al., 2022 [8] | 69 | 15.8 | Retrospective, Multicenter |
Europe | CD | UST | 4.3 yrs | 3 months | Clinical remission, CRP, fecal Calprotectin, endoscopic, histological healing | Reduction in inflammatory markers, 16% endoscopic, 13% histological mucosal healing | |||
| Dhaliwal et al., 2021 [9] | 25 | 14.8 | 28 | Prospective, multicenter |
2018–2019 | Canada | UC | UST | 2.3 yrs | 26, 52 weeks | Steroid-free remission, PUCAI, endoscopic remission, AEs | 69% steroid free remission, significantly more of whom only failed TNFi treatment before (instead of TNFi and VEDO also) | |
| Dayan et al., 2019 [10] | 52 | 16.8 | 50, 20 | Observational cohort | 2014–2018 | USA | CD, UC, IBDu | UST | 4.9 yrs (CD) and 1.8 yrs (UC/IBDu) | 52 weeks | Steroid-free remission, clinical and biomarker remission | 75% maintained on UST after one yr, 50% of bio-exposed and 90% of bio-naïve in steroid free remission | |
Note: Only studies including pediatric patients receiving TNFi are included in the table. ADAs = anti-drug antibodies, ADL = adalimumab, AEs = adverse events, CD = Crohn’s disease, EEN = exclusive enteral nutrition, fCD = fistulizing Crohn’s disease, GOL = golimumab, IBDu = unclassified IBD, IFX = infliximab, IM = immunomodulator JIA = juvenile idiopathic arthritis, lCD = luminal Crohn’s disease, MINI = Mucosal Inflammation Non-invasive Index, (w)PCDAI = (weighted) pediatric Crohn’s disease activity index, PEN = partial enteral nutrition, PsA = psoriasis arthritis, PUCAI = pediatric ulcerative colitis activity index, SR UC = steroid refractory, TNFi = TNF-inhibitors, UC = ulcerative colitis, UST = ustekinumab, VEDO = vedolizumab, VEO IBD = very early onset inflammatory bowel disease, yrs = years.