Utilization and Clinical Outcome Following 5-Aminosalicylate Therapy for Crohn's Disease in Children

While efficacy supporting 5-aminosalicylate (5-ASA) use for the induction and maintenance of remission for Ulcerative Colitis (UC) has been well established in adult as well as several pediatric studies [1-6], evidence regarding 5-ASA use in Crohn's Disease (CD) for induction or maintenance of remission, or to prevent relapse after surgically induced remission, is conflicting and weak [7-12]. Despite the absence of strong supporting data, 5-ASA compounds are commonly prescribed for CD in general clinical practice. A 2014 Swiss Cohort study including adults and children found that among 1420 patients with CD 59% of patients had been treated with 5-ASA at some time [13].

From our large prospective, inception cohort of children newly diagnosed with CD which included patients from 30 pediatric centers in North America managed by independently practicing pediatric gastroenterologists we aimed to:
(1) Describe the prevalence of 5-ASA utilization 
(2) Describe clinical outcomes at 1-3 years following therapy with 5-ASA ± corticosteroids (CS) 
(3) Identify clinical and demographic factors associated with clinical remission

Disease activity and outcome measures for 5-ASA use

Statistical analysis

Institutional Review Board (IRB)

Deriving the study population and utilization of 5-ASA

Figure 1: Study patient derivation and initial treatments received at 30 days following diagnosis.

Table 1A: Use frequency alone or in combination at 30 days following diagnosis.

Table 1B: Most frequent treatment combinations at 30 days^***.

*Total > 1297 due to patients receiving multiple treatments
***combinations also included patients receiving rectal therapies
**The above 9 most frequent treatment combinations represent the regimens for 88% (1143) of the 1297 patients. There were 22 additional combinations which account for the remaining 12% of patients (154).

In order to analyze 1 year outcomes data following 5-ASA use, we identified the subset of individuals for whom 5-ASA ± CS was prescribed as the only therapy by 30 days followed diagnosis (n=484). Forty-four of these patients were excluded from further analysis because of incomplete data, leaving 440 subjects (34% of all patients with CD in this study with >1 year of follow up) who form our study group. Of these patients, 177 received 5-ASA without CS and 263 received 5-ASA with CS at 30 days following diagnosis Figure 1.

Demographic and clinical characteristics at diagnosis of study population

Table 2: Distribution of characteristics at diagnosis for all Crohn's Disease patients with at least one year of follow-up and for the subsets of study patients who received 5-ASA ± corticosteroids in the first 30 days from diagnosis.
CD-Crohn's Disease; CS-Corticosteroids; PGA-Physician's Global Assessment of disease severity; 
PCDAI-Pediatric Crohn's Disease Activity Index; ESR-Erythrocyte Sedimentation Rate.
Data expressed as mean ± standard deviation or frequency (percent).
* p<0.05, ** p<0.01, *** p<0.001 comparing patients receiving 5-ASA alone vs. 5ASA + CS.

Clinical outcomes at 1 year

Clinical outcomes at 2 - 3 years

PCDAI

Table 4: Univariate and multivariate logistic regression analysis of remission at one year4 following diagnosis of Crohn's Disease for study groups (N=440): results show Odds Ratios (OR) and 95% confidence intervals (95% CI) for potential risk factors at diagnosis and therapy in first 30 days.

1. Forward selection model including therapy, PGA, ESR and ALB (N=365)
2. Forward selection model including therapy, PGA and ANYLAB (N=404)
3. Full model including therapy and PGA (N=440)
4. Remission at one year following diagnosis=PGA inactive, not receiving Corticosteroids (CS), and no rescue with immunomodulators, biologics or surgery during first year; N=108 in remission, N=332 not in remission
* p<0.05, ** p<0.01, *** p<0.001.

For most children with CD who present with moderate to severe symptoms, and often with growth delay, current therapy frequently includes the early use of immunomodulators and biologics [19,20] which indeed, has been associated with improved clinical outcomes at one year following diagnosis of very ill children [21]. More difficult, however, is choosing initial therapy in those children who present with mild disease for whom there is parental and sometimes clinician reluctance to use therapies associated with potentially more significant side effects. 5-ASA therapy, which is perceived to have a more favorable side effect profile, is often used per anecdotal evidence as well as sparse published data [13] for patients with milder disease despite minimal data in the pediatric (or adult) Crohn's disease literature to support this practice.

In this prospective multicenter observational registry study, we aimed to provide data on 5-ASA utilization among children newly diagnosed with CD. We also aimed to describe clinical outcomes in patients following 5-ASA treatment. At 30 days following a CD diagnosis which is the first data collection point in our study design, 5-ASA appears to be the most frequent initial treatment prescribed with over half (53%) of all patients receiving 5-ASA either alone or in combination. Furthermore, over one-third (37%) of patients received only 5-ASA ± CS in the first 30 days following diagnosis. Outcomes data show that 25% of all study subjects who started on only 5-ASA +/- CS had clinically inactive disease without the need for CS or step up therapy at 1 year following diagnosis. When stratified by PGA at diagnosis and/or need for CS at 30 days, 1 year outcomes varied considerably. CS-free remission or response at 1 year without step up therapy was as high as 58% for the subgroup of patients with mild PGA at diagnosis whom were not given CS initially. Among patients with moderate/severe PGA at diagnosis who were given initial CS (undoubtedly reflecting a sicker population), only 18% achieved primary or secondary outcome. We did not find that disease location, age, or gender influenced outcomes. 

When looking at outcomes data after 2-3 years, favorable outcomes diminished considerably. Patients started on only 5-ASA +/- CS at diagnosis whom had clinically inactive disease without the need for CS or step up therapy at 2 and 3 years, were 22% and 16%, respectively. The subset who were most likely to have a favorable outcome at 2 and 3 years were those receiving 5-ASA only without CS and who had mild PGA at diagnosis. For this subset, remission or response was noted to be 46% and 34% at 2 and 3 years, respectively.

As this was not a controlled study with a single preparation of 5-ASA we are only able to give dosing data in aggregate. The mean 5-ASA dose was about 50 mg/kg/day. Given that efficacy in adult patients with ulcerative colitis may be improved with higher dosing schedules [22] as well as some adult CD studies that provide data on dose [12]. It is possible that dosing greater than 50 mg/kg/day might be more effective.

The main strengths of our study are the size of the population studied and the breadth of an experience from multiple institutions reflecting true real world experience. However, our study is not a randomized, case-control clinical trial. All treatment choices were dictated by physician discretion and were not protocol based including doses and specific formulations of 5-ASA compounds, use of rectal therapies, and decision to start or move to alternative therapies. Therefore, placebo effect and/or selection bias should be considered. While placebo effect has been demonstrated in adult clinical trials of inflammatory bowel disease [23,24], similar studies have not been conducted in pediatrics and therefore, we have no data on the potential size of this effect in our population. We did note, however, that standard laboratory measures of disease activity normalized in many patients who achieved an inactive PGA suggesting improvement of inflammation.

In addition, adherence was not systematically monitored and can be a significant confounder. And other markers that may potentially correlate with clinical outcomes that have gained more uniform use were not systematically collected throughout the study period and were not included in our analysis. Such markers include C-reactive protein, fecal calprotectin, X-ray computed tomography and/or magnetic resonance enterography and repeat endoscopic examinations to document mucosal healing. The use of PGA as an outcome variable is not ideal though reasonable correlation with PCDAI has been demonstrated [16]. Since PGA was all that was available for many of the study subjects, it was therefore utilized for our study analysis. We presented PCDAI data when available.

Given that over half of children newly diagnosed with CD are receiving 5-ASA medications as part of their initial therapy, it is important to develop evidence on efficacy or futility. It is highly unlikely that future placebo controlled trials of 5-ASA will be conducted in children and therefore observational registry data may be all that is available. pediatric literature and clinical experience, most pediatric practitioners would agree that use of 5-ASA monotherapy is not appropriate for pediatric patients with CD who demonstrate moderate to severe phenotypical features including extensive small bowel disease, stricturing or penetrating disease, or disease that impacts on growth or pubertal development [19-21]. Our data suggest the possibility of clinical utility in select patients with initially mild disease, though further exploration of specific compounds as well as dosing schedules would be helpful. For patients with more significant disease activity, however, our outcomes data (1-3 years following diagnosis) suggests that the use of 5-ASA as primary therapy does not appear to be efficacious. The development of newer risk stratification tools including serology, genetics and microbiome analysis may help identify patients at lower risk for progressive disease [25].

Early support for the present study came from an unrestricted grant provided by Janssen Ortho-Biotech. There was no external funding from 2012 to the close of the Registry. 

We would like to acknowledge participants of the "Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry" for enrolling patients, collecting and submitting data to the centralized data management center.

Bella Zeisler, Trudy Lerer, report no conflicts of interest. Jeffrey Hyams reports the following disclosures: Janssen Ortho Biotech-research support, advisory board. Consultant Abbvie, Celgene, Takeda, Lilly, Boerhinger Ingelheim, Astra Zeneca. Shire- research support.

Bella Zeisler - Design of work, interpretation of data, drafting and revising work, final approval and accountability.
Jeffrey Hyams - Acquisition of data, design of work, interpretation of data, drafting and revising work, final approval and accountability.
Trudy Lerer - Design of work, interpretation of data, statistical analysis drafting and revising work, final approval and accountability.

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