Enthesitis-related arthritis, family history, etanercept use tied to IBD risk in JIA
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Enthesitis-related arthritis and a family history of autoimmune disease are key risk factors for inflammatory bowel disease in juvenile idiopathic arthritis, according to data published in Rheumatology.
The researchers additionally found data linking etanercept (Enbrel, Amgen) to a higher incidence of IBD regardless of whether it is combined with methotrexate.
“Until now, not much was known about risk factors and independent predictors for IBD in JIA,” Joeri W. van Straalen, a PhD student at Wilhelmina Children’s Hospital, University Medical Center Utrecht, in the Netherlands, told Healio Rheumatology. “Albeit a rare comorbidity, IBD strongly reduces quality of life in children and complicates the treatment of JIA. Therefore, specific information about which JIA patients run the highest risk of developing IBD was much desired.”
To examine the risk factors for IBD among children with JIA, van Straalen and colleagues analyzed data from Pharmachild, an ongoing international observational registry established in 2011. According to the researchers, this registry includes both retrospective and prospective clinical, laboratory and demographic data from patients with JIA treated at 85 centers within the Pediatric Rheumatology International Trials Organization (PRINTO) across 31 countries.
The researchers compared characteristics between 8,942 registry patients with and without IBD, using multivariable logistic regression analysis. The incidence rates of IBD events with various disease-modifying antirheumatic drugs were also determined, as well as the differences between the treatments, assessed as relative risks.
According to the researchers, 48 patients, or 0.54% of the total, developed IBD. Among patients with JIA who developed IBD, 47.9% were more often male — 47.9% versus 32% — and HLA-B27-positive — 38.2% compared with compared with 21%, than those without IBD. They were also older at JIA onset — a median 8.94 versus 5.33 years — and more often had a family history of autoimmune disease — 42.6% versus 24.4% — and enthesitis-related arthritis — 39.6% versus 10.8% — compared with those without IBD.
Based on multivariable analysis, the strongest predictors of IBD among these were enthesitis-related arthritis (OR = 3.68; 95% CI, 1.41-9.4) and a family history of autoimmune disease (OR = 2.27; 95% CI, 1.12-4.54).
The incidence of IBD with etanercept monotherapy (RR = 7.69; 95% CI, 1.99-29.74), etanercept plus MTX (RR = 5.7; 95% CI, 1.42-22.77), and infliximab (RR = 7.61; 95% CI, 1.27-45.57) was significantly higher than MTX monotherapy. The recorded incidence with adalimumab (Humira, AbbVie) was not significantly different (RR = 1.45; 95% CI, 0.15-13.89).
“Independent predictors for IBD in JIA are enthesitis-related arthritis and a family history of autoimmune disease,” van Straalen said. “We also observed that the incidence of IBD was significantly increased on etanercept therapy, regardless of whether combined with methotrexate. Physicians might consider opting for adalimumab instead of etanercept as a first-choice biological therapy in JIA patients with enthesitis-related arthritis and a family history of autoimmune disease in order to prevent the development of IBD.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
The paradoxical occurrence of IBD in JIA treated with anti-TNF-alpha and the paradoxical psoriasis in RA treated with anti-TNF-alpha may have interferon as their common denominator. The development of lupus in RA treated with anti-TNF-alpha may also have to do with interferon.
Studies have revealed an upregulation of interferon-alpha (a type 1 interferon) regulated genes in circulating leukocytes of patients with systemic onset juvenile idiopathic arthritis who receive anti-TNF therapy. One of the most highly upregulated cytokines in IBD and mouse models of intestinal inflammation is interferon-gamma (a type 2 interferon).
A multitude of evidence has shown that type 1 interferon, IL-12, IL-15, and IL-18 are all capable of inducing interferon-gamma production from NK cells. The skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type 1 interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis.
Anti-TNF treatment prolongs type 1 interferon production by pDCs through inhibition of their maturation. The resulting type 1 interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type 1 interferon.
In lupus induced by anti-TNF drugs, a possible hypothesis, among others, is that there is an imbalance between interferon-alpha and TNF-alpha with the latter controlling the production of interferon first by inhibiting the generation of pDCs, a major producer of interferon-alpha/beta, from CD34+ hematopoietic progenitors. Blockade of TNF would therefore increase interferon production, a major player in lupus.
TNF also inhibits interferon-alpha release by immature pDCs exposed to viruses. and blockade of TNF sustains interferon-alpha secretion by pDCs. Interferon-alpha and -gamma are of distinct origins, have distinct genes, and are in separate classes. They interact with each other and TNF-alpha in a complex fashion that may explain some of the drug-induced diseases that we see in practice.
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