IBD and Pediatric Arthritis: Exploring the Link

Risk factors for the development of inflammatory bowel disease (IBD) among patients with juvenile idiopathic arthritis (JIA) included the subtype of JIA, family history, and medication use, a large international study revealed.

In a multivariate analysis, the enthesitis-related arthritis subtype of JIA was associated with an almost fourfold increased risk for IBD (OR 3.68, 95% CI 1.41-9.40), and a family history of autoimmune disease was linked with a twofold greater risk (OR 2.27, 95% CI 1.12-4.54), according to Joeri van Straalen, PhD, of University Medical Center Utrecht in The Netherlands, and colleagues.

And among patients with a known onset date of IBD, almost half were exposed to etanercept (Enbrel) within the 3 months before gastrointestinal symptom onset, the investigators reported in Rheumatology.

JIA consists of seven distinct subtypes: oligoarthritis, rheumatoid factor (RF)-positive polyarthritis, RF-negative polyarthritis, psoriatic arthritis, enthesitis-related arthritis, undifferentiated arthritis, and systemic arthritis. Each has a distinct phenotype, pathophysiology, genetic pattern, and disease course.

IBD has been reported at much higher incidence rates among JIA patients than among the pediatric population in general (1.31 per 1,000 patient-years vs 0.23 per 1,000 patient-years).

Little is known about risk factors and JIA characteristics among patients who develop IBD, but previous studies have suggested that etanercept use may increase risk, while methotrexate exposure may be protective.

To examine these concerns, van Straalen and colleagues analyzed data from the largest worldwide pharmacovigilance cohort of JIA patients (PRINTO), which includes patients from 31 countries.

The analysis included 8,942 JIA patients, among whom 48 cases of IBD were reported: 13 with ulcerative colitis, 22 with Crohn’s disease, and 13 with indeterminate colitis. Median follow-up was 5.4 years.

Boys were more likely than girls to develop IBD. Other characteristics that differed between patients with and without IBD included:

• Family history of autoimmune disease, 42.6% vs 24.4% (P<0.01)
• Age at onset of JIA, 8.94 vs 5.33 years (P<0.01)
• Enthesitis-related JIA, 39.6% vs 10.8% (P<0.01)
• HLA-B27 positivity, 38.2% vs 21% (P=0.02)

But on multivariate analysis, only family history and enthesitis subtype were significant; no significant associations were seen for female sex (OR 0.70, 95% CI 0.33-1.48), age at JIA onset (OR 1.05, 95% CI 0.96-1.15), or HLA-B27 positivity (OR 0.81, 95% CI 0.33-2.02).

Among the autoimmune diseases in first- and second-degree relatives most commonly reported were psoriasis in 25%, rheumatoid arthritis in 18%, and Hashimoto’s thyroiditis in 10%.

The median time from JIA onset to IBD development was 4.2 years, and the median age at IBD diagnosis was 13.7 years.

A total of 27 patients had a known onset date for their IBD, with 13 having been treated with etanercept. Mean duration of etanercept use at the time of IBD onset was 382 days.

In six of these patients, no disease-modifying antirheumatic drug exposure had occurred within 3 months of IBD onset, with four having previously withdrawn from methotrexate treatment and two having stopped etanercept.

Relative risks for IBD were significantly increased in patients receiving these medications:

• Etanercept monotherapy, RR 7.69 (95% CI 1.99-29.74)
• Etanercept plus methotrexate, RR 5.70 (95% CI 1.42-22.77)
• Infliximab (Remicade), RR 7.61 (95% CI 1.27-45.57)

No significant increase was observed for adalimumab (Humira).

In discussing their findings, the investigators noted that the strongest predictor of IBD was enthesitis-related arthritis, which is similar to spondyloarthropathy in adults and is recognized as being associated with IBD. The other strong risk factor, family history of autoimmunity, confirmed previous observations on a genetic link with IBD.

As to the association with etanercept, with or without methotrexate, the authors cautioned that it’s unclear if this relationship can be considered causal. Some previous research has suggested that in JIA patients being treated with etanercept, an underlying subclinical IBD could become manifest, as etanercept has been shown to be ineffective for Crohn’s disease. Moreover, in one study of IBD in JIA, most cases occurring during etanercept treatment improved after stopping the medication.

Unlike etanercept, both infliximab and adalimumab have demonstrated efficacy in IBD. In this study, no increased risk was observed for adalimumab, but “surprisingly,” the authors noted, the risk was increased for infliximab. However, two of the three cases had previously been treated with etanercept. The researchers also pointed out that the dosage of infliximab is lower for JIA than for IBD, which might permit the development of anti-infliximab antibodies and loss of treatment efficacy.

Nonetheless, “it might be suggested to consider adalimumab as the biologic of choice for treatment of enthesitis-related arthritis patients with a family history of autoimmune disease,” they concluded.

Limitations to the study included the fact that the IBD onset date was missing for some patients, who therefore were not included in the analysis, as well as the lack of data on dietary and environmental influences.