DOI: 10.1111/exd.12648
Commentary
www.wileyonlinelibrary.com/journal/EXD
Phenotypic heterogeneity implies heterogeneous pathogenic pathways in hidradenitis suppurativa John W. Frew1,2, Dunja A. Vekic1, Jane Woods1 and Geoffrey D. Cains1,2 1 Department of Dermatology, Liverpool Hospital, Sydney, NSW, Australia; 2Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia Correspondence: Dr John W. Frew, Department of Dermatology, Liverpool Hospital, Suite 7, Level 1, 45-47 Goulburn St. Liverpool, NSW, 2170 Australia, Tel.: +61 2 8738 4560, Fax: +61 2 8738 4639, e-mail:
[email protected]
Key words: gammma secretase – Hidradenitis Suppurativa – metabolic syndrome – notch
Accepted for publication 20 January 2015
Summary of general pathogenic mechanisms
‘typical’ HS but their utility is as yet unclear in ‘atypical’ subtypes.
Hidradenitis Suppurativa is a chronic inflammatory condition manifesting in recurrent painful deep-seated nodules and abscesses with variable phenotypic presentations (1). Melnik and Plewig eloquently describe the concept of HS as an autoinflammatory disease with dysregulation of the gamma-secretase/Notch pathway (2); however, recent studies have identified ‘typical’ and ‘atypical’ HS subtypes with differing morphology (nodules, comedones), lesion distribution (axillary, submammary and gluteal) and comorbidity prevalence (1). The pathogenic hypothesis proposed by Melnik and Plewig (2) as well as reports of inconsistent responses to systemic therapies (3,4) has led to suggestions that variable phenotypic presentations are suggestive of heterogeneous pathogenic inflammatory dysregulation within the gamma-secretase/ Notch pathway paradigm (5).
The complex interaction between metabolic syndrome and HS Pascoe and Kimball describe the complex yet ‘established link’ between metabolic syndrome and HS (6). Comorbidities including insulin resistance, glucose intolerance (7), dysregulated adipokine levels (8) (indirectly measured via BMI) (9) and bacterial superinfection (10) are all possible modulators of disease activity. These associations, however, have not taken into account the heterogeneity of HS presentations and ensuing confounding relationships. The point prevalence of HS is quoted at 18% amongst bariatric surgery patients (11) with an odds ratio for metabolic syndrome of 3.89 (95% CI 1.90–7.98) for a hospital HS cohort (12). However, analysis by Canoui-Poitrine et al. (1) shows statistically significant variation in BMI between ‘subtypes’ of HS, discrepancies which may confound existing results. Miller et al. (12), adjusting for BMI, revealed significant correlation between decreased HDL/elevated TG levels and HS in this cohort, suggesting an underlying metabolic disturbance independent of BMI. The role of adipose tissue as a dynamic endocrinological organ across all BMI ranges in HS requires further investigation (7). HS occurs in individuals with normal BMI (11), with 52.6% of individuals in Canoui-Poitrine’s analysis of BMI 25 or lower (1). The rates of metabolic derangements in this ‘atypical’ subtype are less well defined than their ‘typical’ counterparts. Hence, treatment focused on metabolic comorbidities may be appropriate in
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‘Typical’ versus ‘atypical’ HS The ‘typical’ (axillary–mammary) patient is likely to be female, with mammary and axillary involvement with prominent hypertrophic scarring and lack of follicular lesions/comedones (1). They are more likely to be overweight than ‘atypical’ (specifically gluteal) counterparts. Gold et al. (7) suggest that glucose intolerance is more common amongst patients with HS, and reports of the efficacy of metformin in HS are found in patients where clinical descriptors suggest a ‘typical’ HS subtype (13). Bacteriologically, polymicrobial isolates are common, including coagulase-negative staphylococci, S. Aureus and intestinal flora (14). In contrast, ‘atypical’ HS patients (also further dichotomised into follicular or gluteal) are likely to be male with a normal BMI, a current or previous smoker, demonstrate a personal history of severe acne and a family history of HS (1). They are more likely to present with comedones and follicular lesions, with the gluteal variant less predisposed to hypertrophic scarring. Bacterial superinfection with staphylococcal species is more common in current smokers, and the relative burden of gastrointestinal flora such as E. Coli, P. Mirabilis and E. Faecalis is greater in patients with gluteal and perineal involvement (14). Comparatively, the disease is more severe and onset earlier than ‘typical’ counterparts (1) and SCC may be more prevalent in this cohort (1). Genetic studies have identified multiple pathogenic mutations in the gamma-secretase/Notch signalling pathway which overlap with PAPA/PASH and other autoinflammatory syndromes (15).
Phenotypic variance and relevance to underlying pathogenesis The gamma-secretase/Notch pathway paradigm in HS encompasses the contributing endogenous and exogenous factors including inherited syndromes, obesity and smoking (2). It also infers a possible mechanism for the heterogeneous phenotypic manifestations in this disorder (Fig. 1). Melnik and Plewig present a review of evidence which implicates gamma-secretase/Notch and ADAM10 (involved in the extracellular cleavage of notch) as pivotal in the development of epidermal cysts and comedones (2), a concept that is supported by the increased prevalence of cystic and comedonal structures in ‘atypical’ HS where pathogenic
ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2015, 24, 338–339
Commentary
Figure 1. Heterogeneous pathogenic pathways in clinical subtypes of Hidradenitis Suppurativa. The Notch/gamma-secretase complex (a), polymorphisms of which are implicated in hereditary ‘atypical’ forms of HS. Notch activity is increased by Simvastatin, with smoking decreasing Notch activity. Notch signalling is the regulatory inhibitor of MAPK (via MKP-1), a major regulator of innate immunity (b). Lesser inhibition is implied in atypical subtypes as compared to typical subtypes. TNF-a receptors are stimulated via metabolic factors mediated by adipose tissue (c), which alter gene expression as well as directly stimulate the NLRP1/3 inflammasome (d). The inflammasome is also stimulated via changes in the cutaneous microbiome (altered by smoking) via pathogen-associated molecular patterns (PAMPs) (e). The resultant stimulation of the adaptive immune system results in a cell-mediated inflammatory loop (f) contributing to the chronicity of disease..
inhibitory mutations in the gamma-secretase/Notch apparatus have been identified in some cases (15). The presence of metabolic comorbidities in ‘atypical’ HS may require acknowledgement as potential confounders in future studies as common antihyperlipidaemic agents such as simvastatin can increase Notch signalling activity (14) and association has been noted between ‘atypical’ HS and low HDL/elevated TG levels in the absence of elevated BMI (1). The association between increased BMI and ‘typical’ HS is contributed to by TNF-a, with visceral adipose tissue known to secrete large quantities of TNF-a and IL-1b (7, 8). The benefits of metformin in some cases of HS (13) can be explained via the suppression of systemic inflammation by the up-regulation of MAP kinase (MAPK) and downstream inhibition of TNF-a, IL-6 and IL-1b production as well as any potential correction of underlying insulin resistance (8, 13). The potential contribution of
TNF-related apoptosis inducing ligand (TRAIL) deficiency and the increased risk of diabetic and cardiovascular complications is currently under further investigation (16). The benefits of weight loss in ‘typical’ HS (8) too are correlated with reduction in systemic inflammation through normalisation of adipokine levels, specifically adiponectin and resistin, which contribute to the perpetuation of the inflammatory cascade in a variety of diseases (17). The effect of these metabolic factors may also be mediated through changes in the gastrointestinal and cutaneous microbiome which are known to be altered in obesity and chronic inflammatory conditions (18) and contribute to inflammasome activity (10). The role of Th-17-mediated inflammation is thought to involve the perpetuation of an ‘inflammatory loop’ as a downstream by-product of initial inflammasomal dysregulation from endogenous and/ or exogenous factors (19). The use of systemic retinoids alongside TNF-a inhibitors has been hypothesised to suppress the Th-17 pathway through regulation of dendritic cells and aid in comedonal ‘atypical’ disease through epidermal differentiation (20).
Factors influencing therapeutic efficacy in clinical trials The variance in treatment efficacy in HS is likely multifactorial, due to the specific underlying endogenous pathogenic mechanism as well as the presence or absence of exogenous exacerbants (smoking, obesity, insulin resistance) and genetic variants impacting upon the efficacy of the medication (3). It is also possible that different HS subtypes have variable response to identical treatment regimens due to the involvement of disparate pathogenic pathways and other confounding factors (Fig. 1). The variable responses to different biologic agents in recent studies (21) may be explained by the combination of HS subtypes recruited; therefore, stratification and consideration of confounders are essential for analysis of future trials.
Author contribution JWF and DAV performed the literature review. JW and GDC designed the concept for the paper. JWF wrote the paper. DAV, JW and GDC critically revised the paper. JWF, DAV, JW and GDC all approved the final version of the paper.
Funding sources The authors have no funding sources to declare.
Conflict of interests The authors have no conflict of interests to declare.
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