The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial : Journal of Pediatric Gastroenterology and Nutrition

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Clinical Trials: Gastroenterology: Inflammatory Bowel Disease

The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial

Matar, Manar; Shamir, Raanan∗,†; Lev-Zion, Raffi; Broide, Efrat†,§; Weiss, Batia†,||; Ledder, Oren; Guz-Mark, Anat∗,†; Rinawi, Firas∗,†; Cohen, Shlomi†,¶; Topf-Olivestone, Chani#; Shaoul, Ron∗∗; Yerushalmi, Baruch††; Assa, Amit∗,†

Author Information
Journal of Pediatric Gastroenterology and Nutrition: August 2020 - Volume 71 - Issue 2 - p 237-242
doi: 10.1097/MPG.0000000000002728
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Abstract

What Is Known/What Is New

What Is Known

  • Up to 85% of children and adolescents with Crohn disease may experience some degree of growth deficiency at presentation.
  • Infliximab treatment has been shown to allow catch up growth and reduced steroid use in pediatric patients with Crohn disease.
  • The positive effect of adalimumab on linear growth is less described.

What Is New

  • Adalimumab treatment resulted in a significant improvement of linear growth after 72 weeks of treatment in children with Crohn disease.
  • Diminished improvement in growth velocity was associated with ongoing inflammatory activity and the presence of perianal disease.
  • Adalimumab treatment normalized weight and body mass index after 72 weeks of treatment.

Up to 85% of children and adolescents with Crohn disease (CD) experience some degree of growth deficiency at diagnosis (1), whereas in 10% to 56% growth is significantly impaired (2). Growth impairment in inflammatory bowel disease (IBD) is characterized by delayed skeletal maturation and a delayed onset of puberty, and is usually described in terms of height-for-age standard deviation (SD) score (z score) or by variations in growth velocity over a period of at least 3 to 4 months (3). Height velocity, expressed either as a centile or as an SD score for age and sex, is the most sensitive parameter by which growth impairment is recognized (3).

The pathophysiology of growth impairment in children with IBD is attributed to a variety of causes including insufficient intake, increased energy, and protein expenditure (4); delayed puberty (5); and the direct effect of inflammatory cytokines on the growth plate (6). Nevertheless, the most important mechanism is probably the effect of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 6, on the growth hormone/insulin-like growth factor-1 axis, by downregulation of the growth hormone receptor and upregulation of postreceptor inhibitory proteins (7).

Pharmacologic treatment of children and adolescents with IBD should also mitigate the detrimental effect of inflammation on growth and nutrition. Achieving early clinical remission in children with IBD correlates with improved outcomes and therefore allows a window of opportunity for optimization of growth. An aggressive approach of treating the individual child with IBD with early biologic treatment, including utilization of therapeutic drug monitoring (TDM) has been shown to have a positive effect on disease outcomes (8), and thus may also improve growth velocity.

Infliximab treatment has been shown to allow catch-up growth and to reduce corticosteroid use in pediatric patients with CD (9–11); however, the positive effect of adalimumab (ADL) on linear growth is less described and most data are available from retrospective cohort studies with a very limited number of patients. Recently, a post-hoc analysis of the IMAgINE 1 trial (12) demonstrated that ADL therapy significantly improved and even normalized height velocity at weeks 26 and 52 in patients with baseline growth impairment.

Our aim in this post-hoc analysis of the PAILOT (Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment) randomized controlled trial was to assess the effect of ADL treatment on linear growth in children with moderate-to-severe CD, naïve to biologics, who were followed from week 4 post-ADL initiation until week 72.

METHODS

Study Design

The methodology of the PAILOT trial has been previously described (13). In brief the PAILOT trial was a randomized controlled trial performed in multiple Israeli pediatric centers between July 2015 and December 2018, with the aim to evaluate whether proactive TDM is more effective than reactive TDM in children with CD who were treated with ADL. Patients were enrolled if they were 6 to 17 years old with moderate-to-severe CD, naïve to biologic treatment, who responded to ADL induction at week 4. At each visit (weeks 4, 8, and every 8 weeks thereafter) anthropometric measures (height, weight, and body mass index [BMI]) were taken along with pediatric Crohn disease activity index (PCDAI), serum biomarkers, fecal calprotectin (Liaison Calprotectin, Diasorin, Saluggia, Italy), ADL trough concentration (TC), and antiadalimumab antibodies. Patients were randomized into either a proactive arm in which low ADL TC prompted ADL intensification regardless of disease activity or a reactive arm in which treating physicians were exposed to TC and antiadalimumab antibody results only if clinical or biologic (C-reactive protein [CRP] >0.5 mg/dL or fecal calprotectin >150 μg/g) loss of response has occurred. In both groups, ADL was intensified to achieve a TC of at least 5 μg/mL. ADL pharmacokinetic analysis was performed at a central laboratory (Sheba Gastroenterology Laboratory, Ramat Gan, Israel) using a drug tolerant enzyme-linked immunosorbent assay as described by Ben-Horin et al (14).

Anthropometric Measures

In this post-hoc analysis we assessed changes in linear growth, weight, and BMI from baseline at week 4 post-ADL initiation until week 72. Growth was expressed as height z score, height velocity, and height z score change per month (the rate or slope of linear growth change). Underweight was defined according to the World Health Organization standards as weight for age <–2 SDs, undernourished as weight for height <−2 SD, overweight as weight for height >+1 SD, obesity as weight for height >+2 SD, growth impairment as height for age between −1 SD and −2 SD and stunting as height for age <–2 SD. Height velocity was calculated as present height [cm] − height 6 to 12 months previously [cm] divided by interval [months] between measures × 12, adjusted for age and sex and expressed as SD according to accepted norms (15). We also analyzed the associations between these changes and disease characteristics, PCDAI, inflammatory biomarkers, fecal calprotectin, ADL TC, and the presence of concomitant immunomodulator (IM) treatment. In the absence of Tanner stage assessment, we defined patients with significant growth potential according to age at baseline: boys younger than 16 years and girls younger than 14 years. In subsequent analyses, patients were stratified into 2 groups based on growth impairment versus no growth impairment (height z score of <−1 vs ≥−1) at baseline. Patients who had significant change in height z score from baseline (defined as a minimal change in height velocity of +0.01 z score/month) versus patients who did not.

Statistical Analysis

Continuous variables were evaluated for normal distribution using histogram, Q-Q plots, and Kolmogorov-Smirnov test and reported as median (with interquartile range [IQR]) for nonnormally distributed variables or mean (±SD) for normally distributed variables. Categorical variables were reported as frequency and percentage. Correlations between different variables and anthropometric measures were assessed using chi-square test or Fisher exact test for categorical variables and analysis of variance , independent sample T test, Kruskal-Wallis or Mann-Whitney test for continuous variables, as appropriate. Generalized estimating equation was used for repeated measures analysis to evaluate changes in anthropometric measures over time which was expressed as B (the difference between defined time points compared with the reference group) with 95% confidence interval (CI). All reported P values are 2 sided. P values <0.05 were considered significant. Data were analyzed using SPSS (IBM SPSS statistics, version 25.0, IBM Corp, Armonk, NY).

The study was approved by the local institutional review board of each participating center. Informed consent forms were signed by both parents and assent was obtained from patients ≥14 years old (clinicaltrials.gov NCT02256462).

RESULTS

Out of 78 patients (29% girls; mean age 14.3 ± 2.6 years), 66 patients (85%) had completed 72 weeks of ADL treatment (25% girls; mean age of 15.6 ± 2.5 years) and thus had repeated anthropometric measurements from week 4 throughout week 72. Twelve patients (15%) had discontinued ADL treatment during the study period for either loss of response or adverse events and therefore had a limited follow-up, insufficient to assess the long-term effect of ADL on growth. This subgroup was analyzed separately. The baseline characteristics of the main cohort (patients who completed the study period) are depicted in Table 1.

T1
TABLE 1:
Cohort characteristics at baseline

Height

At baseline, out of the overall cohort, 21 (27%) patients had growth impairment (height z score <1 SD) and 12 (15%) had stunting (height z score <2 SD) with a total of 33 patients (42%) with either growth impairment or stunting. Of the 21 patients with growth impairment at baseline, 4 patients (19%) had not completed the study period and remained impaired at the time of ADL discontinuation, whereas only 8 (38%) were not impaired at week 72. Of the 12 patients with stunting at baseline, 2 patients (17%) had not completed the study period and remained stunted at the time of ADL discontinuation, whereas only 4 (33%) had not fulfilled the definition of stunting at week 72. Analysis of the 66 patients who continued ADL treatment throughout week 72 demonstrated that the baseline median height z score was −0.62 (IQR −1.6–0.15) and −0.33 (IQR −1.3–0.5) at week 72, P = 0.005 (Fig. 1A and B). The median change of height z score/month (rate of change) was +0.014 (95% CI 0.004–0.024); P = 0.006.

F1
FIGURE 1:
Height z score changes from week 4 following adalimumab (ADL) induction to the end of the study (week 72). A, Dot plot of all 66 patients’ height z scores at all study visits. B, The change of median height z scores (with interquartile range [IQR]) at all study visits. SD = standard deviation.

Height velocity was not available at baseline as most patients were not measured consistently for height before ADL initiation. During the 72 weeks of ADL therapy, median height velocity was −0.32 (IQR −1.5–0.8) at week 26, with an improvement to +0.11 (IQR −1.1–1.3) at week 72.

Out of 66 children who completed the study period, 46 (70%) had significant growth potential at baseline: 6 of 46 (13%) girls younger than 14 years, 40 of 46 (87%) boys younger than 16 years. Median height z score increased from −0.68 (IQR −1.6–0.1) to −0.30 (IQR −1.1–0.4), P = 0.009. The median change in height z score/month in this subgroup was similar to the overall cohort: +0.014 (95% CI 0.005–0.024), P = 0.006. Median height velocity at week 26 was −0.25 (IQR −1.3–0.9) and 0.41 (IQR −0.6–1.5) at week 72.

Repeated measure analysis demonstrated that patients with fistulizing perianal disease had reduced growth improvement when compared to patients without perianal disease (B = −0.025, 95% CI −0.05–0.003; P = 0.02). Other disease characteristics at baseline were not associated with growth velocity including sex, age, disease location, and disease behavior (data not shown). There was a significant association between PCDAI and erythrocyte sedimentation rate at baseline (week 4) and height z score changes (P = 0.043 and P = 0.048), respectively, and a trend toward an association with CRP (P = 0.06). Sustained clinical remission (PCDAI <10 at all visits) and sustained normal CRP (CRP ≤0.5 at all visits) were significantly associated with changes in height z score (P = 0.05 and P = 0.001, respectively). There was no significant correlation between sustained low fecal calprotectin and height z score changes (sustained fecal calprotectin of, P = 0.56 and sustained fecal calprotectin of ≤150 μg/g, P = 0.23). ADL TC and concomitant therapy with an IM had no significant effect on linear growth. Similarly, patients who were randomized to interventions based on proactive TDM did not differ from patients in the reactive TDM group in terms of linear growth.

When stratifying the entire cohort of patients (n = 78) to patients with growth impairment/stunting at baseline (z score <−1, n = 33, 42%) versus no growth impairment (z score ≥−1, n = 45, 58%), the only variable which was significantly associated with growth impairment at this time point was lower weight z score at baseline (P < 0.001). Neither disease characteristics nor measures of disease activity at baseline were associated with growth impairment. Analysis of patients who completed the study period (n = 66, z score <−1, n = 27, 41%; z score ≥−1, n = 39, 59%) showed that both groups demonstrated significant improved growth from baseline to week 72 (children who had growth impairment at baseline with a delta of +0.32 SD and children without growth impairment at baseline with a delta of +0.22 SD) with no significant difference between the 2 groups, P = 0.21.

When stratifying the cohort to those with significant improvement in linear growth during follow-up (n = 41) to those without (n = 25), variables which predicted significant growth improvement were lower PCDAI at week 4 (median of 10, IQR 0.0–16.2 vs 20, IQR 5.6–24.3; P = 0.04), erythrocyte sedimentation rate at week 4 (20.5 ± 20 vs 30.1 ± 17; P = 0.05), sustained clinical remission at all visits (PCDAI <10; P = 0.05) and sustained normal CRP (≤0.5 mg/dL; P = 0.001). Disease characteristics including age at enrollment, fecal calprotectin, and ADL TC did not differ between the 2 groups.

Of the 12 patients who did not complete the study period, 3 (25%) discontinued therapy due to adverse events (peripheral neuropathy, pancreatitis, and worsening arthritis), 3 (25%) developed complications and were referred to surgery, and 6 (50%) lost response to ADL treatment. Disease characteristics at baseline did not differ between this subgroup and the patients who completed the study period. The median time to treatment discontinuation was 32 weeks (IQR 16–42). The median change of height z score /month was +0.007 (95% CI 0.0009–0.01), P = 0.2, with almost no improvement of height z score from baseline to the end of follow-up: −0.85 (IQR −1.8–0.8) to −0.80 (IQR −1.6–0.9), P = 0.7. Height velocity could not have been calculated for this subgroup due to insufficient follow-up period (<6 months). The rate of change in linear growth per month in this subgroup significantly differed from patients who did not discontinue ADL (P < 0.001).

Weight and Body Mass Index

Out of the entire cohort, 6 patients (8%) were underweight (weight z score <−2) and 6 (8%) were undernourished (BMI z score <−2) at baseline. Of the underweight patients at baseline, 1 did not complete the study period and remained underweight at the time of ADL discontinuation, whereas 4 patients (66%) improved and did not fulfill the definition of underweight at week 72. The patients with undernutrition at baseline were the same patients with underweight and had similar proportion of response shown for underweight. Only 2 patients (3%) were overweight at baseline and none were obese, whereas at the end of the study 4 of those who completed 72 weeks were overweight (6%) and 3 obese (5%).

The median changes of weight z score/month in patients who completed the study period was +0.025 (95% CI 0.015–0.034) P = 0.025, with an overall increase from −0.54 (IQR −1.2–0.15) at baseline to −0.1, (IQR −0.9–0.6) at week 72, P < 0.001. The median change of BMI z score/month was +0.02 (95% CI 0.008–0.031), P = 0.001, with an overall increase from −0.4 (IQR −1.0–0.5) to 0.0 (IQR −0.8–0.9), P = 0.005 (Figs. 2 and 3).

F2
FIGURE 2:
The change of median weight z scores (with interquartile range [IQR]) at all study visits. SD = standard deviation.
F3
FIGURE 3:
The change of median body mass index (BMI) z scores (with interquartile range [IQR]) at all study visits.

Variables associated with improved weight z score during the study period included L3 phenotype (B = 0.047, 95% CI −0.5–0.6; P = 0.04), PCDAI at baseline (P = 0.01), and sustained clinical remission at all visits (P = 0.04). Other disease characteristics at baseline were not associated with improved weight z score including sex, age, disease behavior, perianal disease, and inflammatory markers (data not shown). Inflammatory markers, fecal calprotectin levels, ADL TC, or type of TDM (proactive vs reactive) during follow-up were not associated with improved weight z score.

Male patients improved BMI z score more significantly than female patients (B = 0.25, 95% CI −0.3–0.8; P = 0.01). Other variables associated with improved BMI z score during the study period included PCDAI at baseline (P = 0.005) and sustained clinical remission at all visits (P = 0.04). Other disease characteristics at baseline were not associated with improved weight z score including age, disease location, disease behavior, perianal disease, and inflammatory markers (data not shown). Fecal calprotectin levels, ADL TC, or type of TDM during follow-up were not associated with improved BMI z score.

For the 12 patients who did not complete the study period, the median change of weight z score/month was +0.019 (95% CI 0.01–0.03), P = 0.04, whereas the median change of BMI z score/month was +0.018 (95% CI 0.007–0.03), P = 0.01, both not significantly different from the overall cohort.

DISCUSSION

The current post-hoc analysis of the PAILOT randomized controlled trial demonstrated that children with moderate to severe CD who responded to ADL induction experienced a significant positive effect on linear growth after 72 weeks of treatment. Improved linear growth was negatively associated with measures of disease activity at week 4 and during follow-up. A novel finding of this study is that perianal disease was associated with reduced growth improvement. This finding may result from insufficient suppression of inflammatory cytokines as it has been shown that perianal disease is associated with a significant increase in inflammatory cytokines, predominantly TNFα, and interleukin 6 (16), which were implicated as the driving force behind growth impairment in children with IBD (17).

In contrast to linear growth, weight and BMI not only improved but in fact normalized after 1 year of ADL treatment. Children with growth potential (girls younger than 14 years and boys younger than 16 years) did not differ in linear growth improvement from the overall cohort and age was not associated with improved linear growth, implying that pediatric patients with CD continue to growth even at late adolescence, plausibly due to delayed puberty. We also demonstrated that growth impairment/stunting at baseline (which affected 42% of our cohort, well within the reported range (2)), was associated with low median weight z score and that lower height velocity during treatment could be predicted by increased disease clinical and biological activity at the end of induction and during treatment. Nevertheless, lower fecal calprotectin as a single marker and exposure to higher TC of ADL were not associated with improved growth velocity. It may be that re-establishment of growth is not dependent on the achievement of deep remission and that significant reduction of inflammatory burden is sufficient to encourage improvement in growth.

Treatment with anti-TNF agents in the RISK cohort has shown superiority over treatment with IM in terms of linear growth (18). In fact, pediatric patients receiving IM did not improve their linear growth at all, whereas patients receiving early anti-TNF therapy improved their height z score by a median of +0.25 at 1 year. Most studies evaluating the effect of anti-TNF agents on linear growth were in infliximab-treated patients. The first randomized controlled trial using infliximab in children, the REACH trial (19) reported an improvement of +0.5 height z score at 1 year of treatment. It was further demonstrated by Walters et al (10) that height velocity improvement under infliximab therapy is dependent on pubertal stage. Interestingly, despite the fact that Tanner stage was not assessed in the present study, linear growth was not age dependent. This finding may be attributed to a plausible delay in puberty and bone age in the study population (5) resulting in continuation of linear growth even at late puberty. The findings from the REACH study were consolidated by further studies showing similar results (20,21) but also highlighting the associations of early anti-TNF therapy with improved linear growth and a greater effect in boys (20), which may be related to the male pubertal growth spurt occurring later and lasting longer. Most of patients in our cohort had short disease duration (a median of 6 months), possibly contributing to the positive effect, but we could not confirm a sex preference.

The effect of ADL on growth velocity is less described. In a post-hoc analysis of the IMAgINE 1 trial (12) it was shown that ADL therapy in pediatric patients with CD significantly improved and normalized linear growth rate at weeks 26 and 52 but only in patients with baseline growth impairment. Interestingly, in our cohort, both children with growth impairment and without growth impairment demonstrated similar improvement in growth rate across the study period, although growth impaired children trended toward a greater improvement. The lack of significant difference between the 2 groups may have been a result of a relatively small sample size. Growth improvement was significantly greater at week 26 in week 4 responders to induction therapy compared with nonresponders. These results were consistent with a previous report (22) that demonstrated significant improvement in linear growth only in children who achieved remission under ADL treatment but not in those who did not, with a greater effect in children receiving background IM therapy. In contrast, our study did not demonstrate a beneficial effect of concomitant therapy of ADL and an IM on linear growth. In line with these 2 studies which showed greater improvement in postinduction responders we further demonstrated that partial responders and patients with ongoing inflammatory activity during ADL treatment have a diminished effect of ADL on linear growth, emphasizing the importance of achieving complete clinical remission and normalization of inflammatory markers. Nevertheless, reduction of fecal calprotectin was not associated with improved growth, implying that to reestablish adequate growth, deep remission including mucosal healing may not be necessary.

Looking at the long-term effect of ADL therapy, data from the IMAgINE 2 showed that patients with linear growth retardation at IMAgINE 1 continued to improve their linear growth after the initial increase, with linear growth rate approaching the median height velocity of the unaffected reference population after 4 years of treatment (23).

Our findings regarding normalization of weight and BMI z scores at 1-year of ADL treatment are consistent with previous reports (17,21), reflecting the rapid suppression of inflammatory cytokines by anti-TNF therapy which results in a change from catabolic to anabolic status.

The strengths of this post-hoc analysis derive from the stringent scheduled measurement of anthropometric measures, ADL TC, and fecal calprotectin over a period of 72 weeks. The study is limited by the lack of data on Tanner stage, bone age, mid-parental height, and caloric intake, which could have enabled a more accurate interpretation of the study results. The study was also not powered by its design to identify statistically significant effects of ADL on growth. Moreover, patients did not undergo endoscopic evaluation during the study period and mucosal healing was assessed indirectly via fecal calprotectin.

In conclusion, ADL treatment resulted in a significant improvement of linear growth after 72 weeks of treatment. Nevertheless, in contrast to weight and BMI, linear growth did not normalize during the study period. Diminished improvement in growth velocity was associated with ongoing inflammatory activity and the presence of perianal disease, emphasizing the importance of achieving complete remission in patients with growth impairment.

Acknowledgments

The statistical analysis was performed by Dr. Tomer Ziv (PhD), statistician, Tel-Aviv University, Tel-Aviv, Israel. The analyses of adalimumab pharmacokinetics were performed by Miri Yavzori and Dr. Orit Picard at the Sheba Gastroenterology Laboratory, Ramat-Gan, Israel.

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Keywords:

adalimumab treatment; delayed puberty; inflammatory bowel disease; linear growth impairment

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