The Association Between Crohn's Disease and HS

Hidradenitis suppurativa is a chronic, autoinflammatory skin disease. Shalom et al. demonstrate in a large cross-sectional study an association between Crohn’s disease and hidradenitis suppurativa, but not with ulcerative colitis. This association supports the hypothesis that a similar pathogenic mechanism contributes to both diseases, providing new possibilities for functional studies and therapy development. Patients with hidradenitis suppurativa may have undiagnosed Crohn’s disease.


Hidradenitis suppurativa (HS) is a chronic, autoinflammatory disease, recurrent, debilitating affecting the hair follicles that usually presents after puberty with painful, deep-seated, inflamed lesions, most commonly in the axillary, inguinal, and anogenital regions. But can affect other areas of the body (Zouboulis et al., 2015). An association between HS and inflammatory bowel disease, comprising Crohn’s disease (CD) and ulcerative colitis, has long been suspected, but never validated. Shalom et al. (2016) provide epidemiological evidence for this association.


Hidradenitis suppurativa is associated with Crohn’s disease but not with ulcerative colitis

Shalom et al. (2016) report the results of a large cross-sectional study of 3,207 patients with HS and 6,412 age- and gender-matched controls in a population-based database in Israel of more than 4,300,000 enrollees. The inflammatory bowel disease diagnoses were made by gastroenterologists, and all files of patients with inflammatory bowel disease were reviewed manually by a dermatologist to confirm the HS diagnoses. The investigators demonstrate a significant association between HS and CD (odds ratio = 2.03, 95% confidence interval: 1.14–3.62, P = 0.01) but not ulcerative colitis (odds ratio = 1.82, 95% confidence interval: 0.81–4.05, P = 0.15), both in univariate and adjusted multivariate analyses. 


An immunopathogenic link between hidradenitis suppurativa and Crohn’s disease HS and CD share interesting clinical and pathogenic similarities. Clinically, both diseases present with sterile abscesses in perineal and inguinal areas, sinus tracts, and associated arthritis, and both respond well to tumor necrosis factor alpha inhibitors. Pathogenically, an aberrant immune response is thought to play important roles in both of these chronic inflammatory diseases.


Contemporary evidence suggests that CD is associated with disrupted immune tolerance that accompanies shifts in common gut flora (dysbiosis), and it has been hypothesized that chronic gut inflammation is the result of abnormal immune responses in genetically susceptible individuals to microorganisms that reside in the gut (Maloy and Powrie, 2011). This hypothesis is supported by the finding that several risk loci are associated with regulation of the innate immunity and intracellular processing and killing of bacteria in CD (e.g., NOD2, ATG16L1, IRGM) (Ventham et al., 2013). For example, NOD2-deficient mice display increased loads of commensal microbiota and altered ratios of microbiota (Rehman et al., 2011).


Specific microorganisms may also play a role in maintaining homeostasis or inducing pathology, and they have been studied extensively in vitro and in vivo. For example, Faecalibacterium prausnitzii appears to have anti-inflammatory properties in the gut. Stimulation of peripheral blood mononuclear cells with this bacterium induced very low levels of the proinflammatory cytokines IFN-γ and IL-12, and this was paralleled by high levels of IL-10. F. prausnitzii is therefore considered important for maintaining gut homeostasis. As a consequence of dysbiosis, pathological strains may arise in microbiota. For example, the gut adherent-invasive Escherichia coli are capable of adhering to epithelial cells and are able to invade and replicate intracellularly. These E. coli strains even survive and replicate within macrophages, without triggering host cell death, leading to the release of large amounts of tumor necrosis factor-α (Barnich and Darfeuille-Michaud, 2007). It, therefore, remains unclear whether dysbiosis precedes the disease or is the consequence of the inflammatory milieu.


It is tempting to speculate that HS, in a fashion similar to CD, is initiated by an abnormal response to bacteria in the skin of genetically predisposed individuals, although a genetic association with NOD2 has not been demonstrated in patients with HS (Schneider-Burrus et al., 2008). Moreover, patients with HS display normal quantities of F. prausnitzii in their gut, whereas patients with psoriasis and patients with CD have a decreased presence of F. prausnitzii (Eppinga et al., 2016).


The skin microbiome is, however, also driven by environmental factors, and the responses vary, depending on body site characteristics such as sebaceous gland density, moisture content, temperature, and endogenous (e.g., host genetics) factors. In turn, the skin innate immune system is an important host factor regulating the composition and balance of the skin microbiota. The microorganisms on the skin and the immune system interact continuously, and imbalances in the commensal ecosystem may cause skin pathology, such as HS, via changes in skin immunity, epithelial dysfunction, or overgrowth by pathogenic species. On the other hand, little is known about the skin microbiota in HS. Swabs from abscess discharges and HS-affected skin lesions are mostly negative, and in cases where bacteria were cultured, only skin commensals were identified (Ring et al., 2015). Preliminary evidence, however, suggests that the skin microbiota may contribute to HS in several ways (Guet-Revillet et al., 2014). First, overgrowth of commensal bacteria may aggravate the disease by causing a chronic infection or by triggering innate inflammatory pathways by engaging with Toll-like receptors, NOD-like receptors, or inflammasomes. DNA and RNA from dead commensal bacteria are capable of activating the innate immune system in conjunction with proinflammatory signals generated by scattered dermal keratin filaments. Secondly, the immune response to skin commensal bacteria may be altered and the triggering threshold lowered, which resembles the pathogenic concept of CD as a response to the gut microbiota. Robust data on the skin microbiota in HS are however currently lacking. Thirdly, and less likely, the composition of the skin microbiota in HS may be altered toward containing more pathogenic species.


HS might be misdiagnosed as cutaneous Crohn’s disease in daily clinical practice HS and CD occur together more often than thought previously. Perianal HS and perianal CD are clinically quite similar, and both can form inflammatory draining tunnels in the skin. To differentiate between these diseases, especially in the perianal area, can therefore be challenging. Moreover, histology is not always helpful because in both diseases granuloma formation and lymphoid follicles can be present. We argue that in patients with CD, inflammatory lesions in the inguinal region are likely to be misdiagnosed as cutaneous Crohn’s even though true cutaneous CD (metastatic CD) is very rare. To differentiate between HS and CD, we recommend imaging techniques such as magnetic resonance imaging. We argue that in true CD, fistulas originate from the bowel in the anogenital region, although, in contrast to HS, sinus tracts do not penetrate the anal sphincter. We furthermore propose that histological staining with pan-keratin antibodies may help to differentiate between the two diseases, because keratin remnants derived from ruptured cysts are often present in the dermis of HS-affected skin.


Shalom et al. (2016) are to be commended for providing useful data that may help to unravel HS pathogenesis and alert dermatologist as well as gastroenterologists of their possible coexistence.


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