A United States Expert Consensus to Standardise Definitions, Follow-Up, and Treatment Targets for Extra-Intestinal Manifestations in Inflammatory Bowel Disease

Benjamin Cohen; Ashwin N. Ananthakrishnan; Edward L. Barnes; Abhik Bhattacharya; Jean-Frederic; Colombel; Raymond K. Cross; Marcia S. Driscoll; Anthony P. Fernandez; Christina Ha; Hans Herfarth; Sara Horst; Jason Hou; M. Elaine Husni; Daniela Kroshinsky; Kristine A. Kuhn; Careen Y. Lowder; George Martin; Deep Parikh; Christopher J. Sayed; Lisa Schocket; Bernadette C. Siaton; Priyanka Vedak; Michael H. Weisman; Florian Rieder


Aliment Pharmacol Ther. 2022;55(9):1179-1191. 

In This Article

Abstract and Introduction


Background and Aims: Extra-intestinal manifestations (EIMs) are a common complication of inflammatory bowel diseases (IBD), affecting up to half of the patients. Despite their high prevalence, information on standardised definitions, diagnostic strategies, and treatment targets is limited.

Methods: As a starting point for a national EIM study network, an interdisciplinary expert panel of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives was assembled. Modified Delphi consensus methodology was used. Fifty-four candidate items were derived from the literature review and expert opinion focusing on five major EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis) were rated in three voting rounds.

Results: For use in a clinical practice setting and as part of the creation of a prospective registry of patients with EIMs, the panel developed definitions for erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis; identified the appropriate and optimal subspecialists to diagnose and manage each; provided methods to monitor disease course; offered guidance regarding monitoring intervals; and defined resolution and recurrence.

Conclusions: Consensus criteria for appropriate and optimal means of diagnosing and monitoring five EIMs have been developed as a starting point to inform clinical practice and future trial design. Key findings include straightforward diagnostic criteria, guidance regarding who can appropriately and optimally diagnose each, and monitoring options that include patient and physician-reported outcomes. These findings will be used in a national multicenter study network to optimise the management of EIMs.


Extra-intestinal manifestations (EIMs) represent a significant yet understudied complication of inflammatory bowel diseases (IBD). EIMs are diagnosed in up to 50% of IBD patients[1] and are associated with morbidity, markedly decreased quality of life, increased complexity of decision-making for providers, and at times even mortality.[2,3]

Despite their prevalence and significance for patients, the diagnosis and management of EIMs have received only limited attention in the literature, especially in the United States (US). Consistent definitions have yet to be established and can vary widely based on whether the gastroenterology or subspecialty literature is followed.[4,5] Retrospective studies often rely on metrics like patient reports or the International Classification of Disease (ICD) code for diagnosis and are inherently limited by their retrospective nature.[6–9] Subanalyses of clinical trials lack standardised definitions of EIMs, are heterogeneous, and are of limited sample size.[10] There have been few randomised control trials (RCTs), and prospective studies have only been carried out for some of the EIMs, which typically are of small sample size and use widely different definitions of EIMs and treatment success.[11–16] None of the indices for EIMs in IBD have been developed following accepted methodologies. A 2017 systematic review of the use of biologics to treat all EIMs, including metabolic bone disease and anemia, only identified 22 studies, the majority of which were noninterventional.[17] The heterogeneity of EIM definitions and outcomes meant that grading studies or conducting a meta-analysis was not possible and led the authors to identify EIMs as a significant unmet need in the literature.[17]

This scattered and nonsystematic approach has led to conflicting reports and ongoing uncertainties in clinical practice. For example, a retrospective study found a higher rate of EIMs in patients on vedolizumab, whereas a subanalysis of the GEMINI trial reported a decreased likelihood of joint-related EIMs.[10,12] Diagnosis and management of EIMs is thus largely based on the expert opinion of individual providers as opposed to rational data-driven management, as indicated in the first guideline published in 2015 in Europe.[13] Although a very important and useful guide, this work does not comment on several items critical for clinical practice. Due to limitations in the literature itself, how and by whom these entities should be diagnosed and treated is often vague, and the means of assessing for improvement or worsening, resolution, and recurrence are not always clearly outlined. In addition, there is little guidance regarding monitoring intervals for EIMs. At the time, this consensus was initiated, no guidelines in the United States had been published.

To address this unmet need, we assembled a multidisciplinary panel of experts across the US and conducted a modified Delphi consensus panel to standardise definitions and treatment targets of five major EIMs in the clinical practice setting. The manifestations included in this study are erythema nodosum (EN), pyoderma gangrenosum (PG), uveitis, peripheral arthritis, and axial arthritis, which were selected based on prevalence and impact on quality of life. This work intends to provide clarity for the practicing provider, set the groundwork for a national multicenter EIM study network, and facilitate future, much-needed prospective studies and clinical trials of EIMs that will impact most IBD patients in their lifetime.