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Comorbidities and Systemic Associations
Introduction
HS represents a prime candidate to bridge diseases of the integument and comorbid systemic disease, as a chronic inflammatory disease of the pilosebaceous unit characterized by inflammatory nodules, suppuration and abscess formation resulting in pain and disfigurement. In addition to its locally destructive course, HS has gained recognition for its association with individual comorbid diseases as well as all-cause mortality. Indeed, patients with HS have been observed to have a higher global comorbidity burden than both healthy patients and patients with psoriasis. Systemic disease states with Charlson Comorbidity Indices similar to HS include systemic lupus erythematosus, dermatomyositis, and ankylosing spondylitis.
The chronic inflammatory state in HS may represent shared pathways yet to be characterized, which link HS to comorbid conditions. At present, biomarker expression in tissue and serum of HS patients appears complex and its description likely remains incomplete. Cytokine expression profiles in lesional skin have demonstrated increased levels of tumor necrosis factor (TNF), interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12, IL-17, and IL-23. The serum of HS patients has also shown elevated levels of C-reactive protein, TNF, IL-17, and IL-6.
Comorbid conditions observed to be associated with HS range across almost every organ system, from the skin to the gastrointestinal tract to the cardiovascular system ( Fig. 8.1 ). HS symptoms may be the first to prompt patients to seek healthcare, providing an opportunity for comorbidity screening and the interdisciplinary management of HS patients with the goal of supporting overall health and clinical outcomes. Therefore, awareness of comorbid associations by physicians treating HS patients is highly relevant. This chapter includes an evidence-based summary of comorbid associations in HS. It is important to note that comorbidities in HS is a dynamic content area for which further evidence-based updates in the coming years may be necessary.
Associated Inflammatory Skin Diseases
Pyoderma Gangrenosum
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by painful ulcerations with undermined and violaceous borders. This rare disorder can greatly impact quality of life and can cause significant morbidity in afflicted patients. Both HS and PG exhibit intense neutrophilic predominant inflammation and have overlap in treatment modalities, including anti-TNF agents. The cytokines IL-8 and IL-17, which are involved in promoting tissue neutrophilia, are overexpressed in both disorders.
The prevalence of PG among patients with HS has ranged from 0.2% to 0.4% as compared to only 0.01% in patients without a diagnosis of HS. This represents prevalence of PG 18 times higher in HS patients. In addition, patients who have concomitant HS and Crohn’s disease (CD) are more than 21 times as likely to have PG as compared to HS patients without comorbid CD. The development of PG in HS patients typically occurs 2 to 19 years after HS diagnosis. This may implicate ongoing immune dysregulation in HS patients which ultimately contributes to the development of PG. This is an area needing further investigation.
Psoriasis
Psoriasis is another chronic inflammatory disease of the skin with similar inflammatory mediators as HS, including TNF, IL-12, IL-23, IL-17. Both diseases have also shown response to a similar profile of targeted therapies, including TNF-alpha, IL-17, and IL-12/23 inhibitors. While the two disease phenotypes are vastly different, the overlap in inflammatory pathways may be due to a link between HS and psoriasis.
Evidence for the association between HS and psoriasis has been somewhat inconsistent in the literature. In a cross-sectional study with 68,836 psoriasis patients, the prevalence of HS was found to be significantly increased in the psoriasis group (0.3%) as compared to controls (0.2%). A statistically significant association between HS and psoriasis was found in a multivariate analysis adjusting for smoking, obesity, healthcare utilization, and Charlson Comorbidity index.
However, another large population-based study found no statistically significant difference in psoriasis prevalence. The prevalence of psoriasis among HS patients was 1.0%, whereas that among controls was 0.9%. Additional studies are needed to confirm this association.
Associated Disorders of Follicular Occlusion
Acne Vulgaris and Acne Conglobata
Both acne vulgaris and HS are chronic inflammatory disorders involving the pilosebaceous unit. Acne conglobata refers to a more severe inflammatory variant which results in tender inflammatory nodules, and in some cases double comedones and sinus tract formation, which is also appreciated in HS. For this reason, HS is often also referred to as acne inversa. The prevalence of acne vulgaris/conglobata in patients with HS ranges from 4.5% to 15.2%, which is significantly higher than the prevalence noted in patients without HS (0.9% to 6.2%). The odds of a patient with HS developing acne vulgaris/conglabata is up to 5 times higher than an individual without HS. While acne vulgaris and acne conglobata can often be treated with isotretinoin, there is limited therapeutic benefit of this medication as a monotherapy in HS. A modified treatment approach should therefore be used in patients with both diseases.
Pilonidal Disease
Pilonidal disease is a chronic inflammatory disorder of the pilosebaceous unit resulting in abscesses, cysts, and/or sinus formation in the sacral region. There is considerable overlap in the clinical manifestations of this disorder with HS, perhaps pointing to common inflammatory pathways which likely contribute to their association with one another.
The prevalence of pilonidal disease in HS patients ranges from 1.4% to 2.3%, compared to 0.1% to 0.3% in non-HS patients. HS patients have 5 times the odds of developing pilonidal disease compared to non-HS patients. There is some evidence to suggest that HS patients with more severe disease are more likely to have pilonidal disease compared to HS patients with milder disease.
Dissecting Cellulitis of the Scalp
Dissecting cellulitis of the scalp (DCS) is a chronic inflammatory disorder of the pilosebaceous unit and is part of the follicular occlusion tetrad along with HS, acne conglobata, and pilonidal disease. DCS is characterized by pustules, abscesses, inflammatory nodules, and significant tunnel formation on the scalp that ultimately results in scarring of affected areas. Overlap among these four entities in the follicular occlusion tetrad may be the result of a common pathogenesis, for which the exact trigger remains to be elucidated. Hyperplasia and overactivity of the pilosebaceous unit is noted first, then followed by follicular occlusion, development of double-ended comedones, and bacterial colonization. Subsequent rupture of occluded follicles results in an inflammation response with suppuration and eventual tunneling with scarring. This shared underlying proposed mechanism may be the basis for the association between HS and DCS. Some consider DCS to be a manifestation of HS involving the scalp.
The prevalence of DCS in patients with HS is 9.2%, compared to that of 0.7% in non-HS patients representing a 13-fold higher prevalence in HS patients.
Associated Cardiovascular Disorders
Major Adverse Cardiovascular Events
Major adverse cardiovascular events (MACE) are the sum composite of myocardial infarction (MI), cerebrovascular accident (CVA), and cardiovascular mortality. This definition may vary to include heart failure, percutaneous coronary intervention, coronary artery bypass grafting, and all-cause mortality. Both psoriasis and HS are inflammatory skin disorders that have been linked to a higher risk of MACE. The association between HS and MACE is thought to be the result of an increased systemic inflammatory burden consisting of elevated circulating TNF and IL-6 that contribute to thrombosis, endothelial injury, and atherosclerosis. HS patients have been observed to have a 23% increased risk of incident MI and a similar increase in risk for the development of CVA when compared to non-HS patients. This is an adjusted risk that accounts for covariates related to MI and CVA; examples include obesity, hypertension, diabetes mellitus, and tobacco smoking. The risk of cardiovascular-related death is higher in HS patients compared to that in severe psoriasis patients, which may point to a higher systemic inflammatory burden in HS patients, more severe involvement with disease covariates, or less robust control of these covariates.
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