DeBoer, Mark D.*; Barnes, Barrett H.†; Stygles, Nicholas A.*; Sutphen, James L.†; Borowitz, Stephen M.†
Infliximab has become a treatment commonly used to induce remission among children and adolescents with inflammatory bowel disease (IBD) (1,2). As a monoclonal antibody that binds tumor necrosis factor-α (TNF-α), infliximab decreases systemic inflammation (1,3,4) and lessens disease severity (3,5,6). Long-term use of infliximab in children and adolescents results in improved growth velocity (3,7) and improved quality of life (QoL) as assessed by IMPACT III, a questionnaire assessing disease-related QoL in multiple domains of care in IBD (5,8).
Because of its effectiveness in inducing disease remission, infliximab is used increasingly as a maintenance medication for the treatment of pediatric IBD (2,5). In a recent cohort study, 79% of patients who received infliximab were continued on maintenance therapy thereafter (9). Whereas early studies documented dramatic anti-inflammatory and QoL effects as measured from the time of first treatment (1,3,6), the systemic, hormonal, and QoL effects of a single dose of infliximab during continued therapy are unclear.
Our goal was to determine the timing and magnitude of anti-inflammatory, hormonal, and QoL changes following a single infliximab infusion among a group of subjects in ongoing treatment with infliximab, comparing changes seen in those with symptoms (symptomatic group) versus without symptoms (asymptomatic group) at the time of treatment. We evaluated children and adolescents with IBD for markers of systemic inflammation, hormones related to growth and puberty, and measures of appetite and IBD-related QoL. We performed these measures just before a clinically indicated treatment (either regularly scheduled or urgently scheduled treatment), as well as 2 days and 2 weeks after treatment, with a hypothesis that greater changes would be observed among subjects experiencing symptoms compared with those without symptoms.
The present study was approved by the institutional review board of the University of Virginia. Patients seen in the pediatric gastroenterology clinic at the University of Virginia who were scheduled to receive an infusion of infliximab for clinical indications were offered a chance to participate. Interested subjects and at least 1 parent were required to sign informed consent and assent before participation. Inclusion criteria were diagnosed Crohn disease or ulcerative colitis, ages 6 to 22 years old with medically indicated need for infliximab, and a history of previous infliximab use. Exclusion criteria were previous treatment with infliximab <3 weeks before study entry and change in use of other anti-inflammatory medications from 3 days before study enrollment to 2 weeks after infliximab treatment. Blood was drawn at the time of intravenous placement before infusion (with the exception of 2 subjects, whose blood was drawn immediately following infusion and who were not included in TNF-α calculations). Blood for clinically indicated laboratory tests (including those needed for pediatric Crohn's Disease Activity Index [PCDAI] (10) determination) was delivered to the central laboratory, whereas blood samples for additional tests were brought to the general clinic research center for centrifugation and storage at −80°C. During or just following pretreatment (diphenhydramine and acetaminophen) and infliximab infusions, subjects answered questions regarding clinical characteristics, including presence of diarrhea, abdominal pain, or blood in stool during the 4 days before the clinic visit. Subjects who had presence of these symptoms in the 4 days before clinic visit were classified as being in the symptomatic group and those without were classified as being in the asymptomatic group. During the infusion, subjects filled out the IMPACT III survey (5,8). IMPACT III was used by permission (Dr Anthony Otley, Dalhousie University, Halifax, NS, Canada) and scored according to the specifications of its creators. Scores for overall IMPACT III (with a range from 35 to 175) and individual domains were then converted to a percentage possible, with higher scores associated with better QoL. We hypothesized that in addition to improved QoL, subjects would experience an increase in appetite following treatment with infliximab. Thus, during the infusion, subjects filled out a validated appetite visual-analog scale (“appetite VAS”). For this measure, subjects placed an “X” on individual 100-mm scales to gauge their present degree of appetite, hunger, fullness, intake capacity, nausea, and thirst (11). Additional clinical information, including original diagnosis of IBD and present height, weight, and disease location, was drawn from the chart. PCDAI scores were calculated only for subjects with Crohn disease.
On day 2 following infliximab infusions, subjects had a subsequent blood draw and filled out appetite VAS; on day 14, subjects had a final blood draw and completed IMPACT questionnaires and the appetite VAS. Following each blood draw, blood was allowed to clot and was spun down before being stored at 4°C, a maximum of 48 hours before being frozen at −80°C until time of testing.
Measures of erythrocyte sedimentation rate, albumin, and hematorcrit were performed at the University of Virginia Health System central laboratory using standard procedures. Additional measures were batched and performed in the general clinic research center laboratory at the University of Virginia, using a chemiluminescent enzyme immunoassay (DPC Immulite 2000, Siemens Healthcare Diagnositcs, Deerfield, IL) to measure serum levels of high-sensitivity C-reactive protein (hsCRP), high-sensitivity interleukin (IL)-6, high-sensitivity TNF-α, insulin-like growth factor (IGF)-1, thyroid-stimulating hormone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone. To facilitate intergroup comparison, IGF-1 measurements were converted to age-based z scores (Esoterix Laboratory Services, Austin, TX). Measures of LH, FSH, estradiol, and testosterone were analyzed only for subjects Tanner 3 or more. Given the low sample size, we had 80% power to detect changes in the overall group between day 0 and days 2 and 14 as low as 2.47 mg/L for hsCRP, 0.93 mg/L for high-sensitivity IL-6, 0.90 (change in z score) for IGF-1, 0.71 μIU/mL for thyroid-stimulating hormone, 0.089 ng/dL for free T4, 1.90 μIU/mL for LH, 1.26 μIU/mL for FSH, 51.6 pg/mL for estradiol, and 94.9 ng/mL for testosterone, based on the variance at baseline.
Intergroup comparisons between symptomatic and asymptomatic subjects were performed using t tests. Intragroup comparisons over time were assessed by paired t tests. All of the statistical comparisons were performed using Prizm (GraphPad Software, La Jolla, CA). Significance was considered to be P < 0.05.
We recruited a total of 24 subjects, 14 of whom were classified as being in the symptomatic group and 10 in the asymptomatic group. Subject characteristics by group are shown in online-only Table 1 (http://links.lww.com/MPG/A69). There were no differences in baseline characteristics between the symptomatic and asymptomatic groups, including additional treatment medications, time since diagnosis, or time since last infliximab infusion.
Inflammation and Disease Status
Subjects in the symptomatic group had higher PCDAI scores than subjects in the asymptomatic group (Fig. 1A). There was a nonsignificant trend in correlation between PCDAI scores and time-since-last-infliximab for the entire cohort (R2 = 0.15, P = 0.076). There were no differences between groups in hsCRP values at any time point (Fig. 1B). Overall, subjects exhibited a decrease in hsCRP by day 2 and day 14. Subjects in the symptomatic group but not in the asymptomatic group had a decrease in hsCRP at the day 2 but not the day 14 time point (Fig. 1B). There were no significant differences in IL-6 between groups or significant improvements over time (Fig. 1C). Similarly, there was no difference in baseline levels of TNF-α between groups (data not shown). When subjects were analyzed by whether they were receiving combination therapy with antimetabolites (irrespective of symptomatic status), this did not yield a significant difference in baseline levels of PCDAI, hsCRP, or other markers of inflammation (data not shown).
Hormones of Growth and Puberty
Levels of hormones by symptomatic classification are shown in online-only Table 2 (http://links.lww.com/MPG/A70). There were no differences in hormone levels between groups, nor were there significant changes in hormone levels following infliximab treatment.
IMPACT III and Appetite Scores
IMPACT III total scores for all subjects 9 to 17 years old are shown in Figure 2 and subcategories of IMPACT are shown in Table 1. Compared with asymptomatic subjects in this age range, subjects in the symptomatic group at baseline had lower scores for total IMPACT and for subcategories related to bowel symptoms and emotional symptoms. At day 14, the symptomatic group had lower scores than the asymptomatic group in subcategories for bowel symptoms and systemic symptoms. When all of the subjects (ie, including those older than 18 years) were included in the analysis, there were significant differences in total IMPACT at baseline and bowel subscore at baseline and day 14 (P < 0.05, data not shown).
Regarding change in IMPACT scores between day 0 and day 14 for subjects 9 to 17 years old, there was a significant improvement only in emotional symptoms among symptomatic subjects (Table 1). When all of the subjects (including those older than 18 years) were included in the analysis, there were significant increases in scores of total IMPACT, emotional symptoms, and social functioning in the group overall (all P < 0.05, data not shown), with a nonsignificant trend toward increased scores for bowel symptoms (P = 0.07). In this evaluation including subjects of all ages, the symptomatic group exhibited increases in scores for total IMPACT, bowel symptoms, emotional symptoms, and social functioning (data not shown). In the asymptomatic group, there was only a nonsignificant increase in the systemic symptoms subscore (P = 0.06, data not shown).
The appetite VAS measuring hunger, fullness, intake capacity, nausea, and thirst revealed no significant differences between the symptomatic and asymptomatic groups nor any significant changes between day 0, day 2, or day 14 (data not shown).
We noted rapid improvements in systemic inflammation and QoL in symptomatic but not asymptomatic subjects following a single dose of infliximab in the context of ongoing treatment. Previous reports have focused on magnitude of change between 2 weeks and 1 year after first beginning treatment with infliximab for moderate to severely affected patients with pretreatment PCDAI scores of 31 to 56 (1,4–6) and initial C-reactive protein (CRP) levels of 28 to 30 mg/L (3,4). Although early changes in CRP in these settings were striking (40%–75% decrease), later changes during maintenance treatment reflected no change or even an increase in CRP (3,4). In our sample of mildly affected children and adolescents (mean PCDAI of 8.5 overall, 13.1 in the symptomatic group), we noted a sustained decrease in hsCRP levels at both 2 days and 2 weeks, both overall and among symptomatic subjects. These decreases in hsCRP levels less than pretreatment levels at 2 weeks provide some level of expectation for changes in inflammation following a single dose of infliximab during ongoing treatment. It is not clear why these subjects exhibited symptoms despite receiving ongoing infliximab therapy. This may represent a group that does not respond optimally to infliximab from a long-term perspective. In this manner, these findings may underrepresent the effect of a single infusion of infliximab on the average patient.
Subjects who were receiving ongoing therapy with infliximab in the absence of symptoms did not demonstrate significant changes in inflammation. The lack of significant decrease in hsCRP levels in the asymptomatic group is perhaps not surprising, given lower PCDAI scores in this group and slightly (but nonsignificantly) lower initial hsCRP levels. In addition, our small number of asymptomatic subjects rendered us significantly underpowered to detect changes in hsCRP among the asymptomatic group, although we also cannot exclude the possibility of the presence of human anti-chimeric antibodies as an explanation for the lack of improvement by 14 days. Nevertheless, our observed lack of difference in the asymptomatic group is consistent with previous studies that failed to note further decreases in CRP levels during maintenance treatment (3,4) and may reflect a subset of children and adolescents with a more stable disease course.
We did not note a difference in time-since-last infliximab treatment or total number of previous infliximab doses between the symptomatic and asymptomatic subjects. A previous study randomizing subjects to regular infusions versus as-needed infusions of infliximab demonstrated a longer remission and a lower rate of relapse in the group receiving regular infusions (3). Although the majority of our subjects were receiving regularly scheduled infliximab infusions every 2 months, a subset was receiving infusions on a more periodic basis, and it remains possible that these longer intervals may have had some influence on the symptomatic status of these children and adolescents.
QoL as assessed by IMPACT III had improved by 2 weeks after infusion among all of the subjects, demonstrating tangible benefits to a single treatment, even among patients receiving continued therapy. As may have been expected, QoL was not altered significantly among those who were asymptomatic at the time of treatment but did improve among those who had been symptomatic, and this improvement applied to both the overall IMPACT III scores and subscores related to emotional symptoms and social functioning. Previous studies in children had demonstrated improvements following ongoing infliximab treatment during the course of 1 year (5,9), and a study in adults showed improved QoL 4 weeks after treatment of a single dose of infliximab in individuals naïve to therapy and with a high degree of disease activity (12). Our study is the first that we know of demonstrating improved QoL during a period as short as 2 weeks and the first evaluating changes in QoL among subjects with mild disease activity.
Systemic inflammation and IBD disease severity contribute to the regulation of hormones related to growth and puberty, as evidenced by delayed puberty and decreased growth velocity in the setting of pediatric IBD (13–19). Animal models have demonstrated that poor growth and delayed puberty are worse than seen in animals that are food restricted, suggesting a role of disease factors besides poor weight gain (20–23). In animal models, levels of LH and FSH are suppressed during systemic inflammation (24). Similarly, thyroid hormone levels can be notoriously suppressed during significant illness (“sick euthyroid” syndrome), which can improve rapidly after resolution of illness (25,26). In the setting of IBD, an important factor related to these effects is systemic inflammation (27). Levels of IGF-1 have been shown to increase as rapidly as 2 weeks following the initiation of enteral feeding in severely affected children, and striking changes in testosterone have also been observed, both coinciding with a dramatic decrease in CRP (19,28,29). These effects are confounded by the high-energy delivery that may also affect IGF-1 levels in that setting. It is not known how rapidly a decrease in systemic inflammation may affect hormones related to growth and puberty, although it was our hypothesis that we would note changes in hormonal levels during the 2-week study period. We did not note significant changes in the levels of these hormones during the time course that we studied. The present study was originally powered to detect differences in hsCRP, and it is likely that we were underpowered to detect changes in levels of hormones such as IGF-1. Additionally, 2 weeks may not have been adequate to observe significant changes in these hormones in this context. Further studies are needed to determine the effect of infliximab treatment on hormones of growth and puberty.
The present study had several weaknesses, including its observational nature. Randomized trials will be needed to determine whether QoL improvements resulted specifically from treatment with infliximab. We did not perform an analysis of serum levels of infliximab—either at baseline or at peak concentrations—and were thus not able to determine a correlation between serum levels and outcomes. Similarly, we did not measure levels of human anti-chimeric antibody, which can be useful in determining the cause of a poor response to infliximab (30). We determined symptomatic status of our subjects by asking 4 questions pertaining to recent symptoms attributable to IBD. Although these questions were rigorously applied to our subjects, it is acknowledged that this was not a validated tool, which may have confounded our results. Finally, many of the subjects filled out their IMPACT and appetite questionnaires while receiving their premedication of intravenous diphenhydramine, but they did not receive diphenhydramine before filling out their follow-up evaluation forms. It is possible that the diphenhydramine affected their initial assessment of their QoL and appetite, although this may be expected to equally affect symptomatic and asymptomatic subjects.
In conclusion, among children and adolescents in ongoing treatment with infliximab, we found evidence of a rapid decrease in hsCRP levels by 2 days and an increase in QoL scores by 2 weeks after a single dose of infliximab. These changes were present in subjects who had symptoms of disease but not in those without symptoms. Although not definitive because of the observational nature of the study, these data may offer treating physicians some guidance regarding clinical changes to expect during ongoing therapy using infliximab.
We thank Anita Vijayagopalan and Shelly Dean for their indispensable help in subject recruitment.
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