Clinical, serologic, and genetic factors associated with pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease patients.
BACKGROUND
Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis.


METHODS
We performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used.


RESULTS
We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10) and TIMP3 (5.6 ×10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10], ITGAL [0.03]) as well as SOCS5 (9.64 × 10), CD207 (3.14 × 10), ITGB3 (7.56 × 10), and rs6828740 (4q26) (P < 5.0 × 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97).


CONCLUSIONS
Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies.
*F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; †Department of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars Sinai Medical Center, Los Angeles, California; ‡Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland; §Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; ‖Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut; ¶Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; **Universite de Montreal and the Montreal Heart Institute, Research Center, Montreal, Canada; ††Mount Sinai Inflammatory Bowel Disease Center, University of Toronto, Toronto, Canada; ‡‡Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California; and §§Medical Genetics Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Adam
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Weizman
Brian
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Huang
Dror
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Berel
Stephan R
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Targan
Marla
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Dubinsky
Phillip
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Fleshner
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Ippoliti
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Kaur
Deepa
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Panikkath
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Brant
Ioannis
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Oikonomou
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Duerr
John
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Rioux
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Silverberg
Jerome I
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Rotter
Eric
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Vasiliauskas
Talin
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Haritunians
David
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Dalin
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Dermot P B
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McGovern
D000328:Adult; D000974:Antibodies, Antinuclear / Q000097:blood*; D015415:Biomarkers / Q000032:analysis*; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D004893:Erythema Nodosum / Q000097:blood / Q000209:etiology* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000150:complications* / Q000235:genetics; D008297:Male; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017511:Pyoderma Gangrenosum / Q000097:blood / Q000209:etiology* / Q000473:pathology
D000974:Antibodies, Antinuclear; D015415:Biomarkers; D004247:DNA