Hidradenitis suppurativa is a chronic relapsing disorder of the folliculopilosebaceous units (FPSUs). Its negative impact on quality of life is extreme, mainly due to the lack of early recognition, accurate diagnosis, and appropriate management. The support structure of the FPSUs is defective. Under the influence of endogenous reproductive hormones, exogenous hormones, androgens and their precursors in dairy products, and other dietary factors, the follicular unit is plugged and distended by retained keratin. Friction, shearing forces, and pressure lead to rupture and leakage of the ductal contents from the weakened FPSU, causing an inflammatory reaction mediated mainly by the innate immune system. Therapy requires patient comprehension and cooperation, counseling, aggressive hormonal and dietary modification, avoidance of the trauma that leads to rupture, active multimodal anti-inflammatory therapy, and early unroofing and debridement. The full therapeutic program is needed to avoid the aggressive surgery required if the condition is not diagnosed early and managed appropriately.
Background
Hidradenitis suppurativa (HS) is a chronic, inflammatory, scarring condition involving primarily the intertriginous skin of the axillary, inguinal, inframammary, genital, and perineal areas of the body. It is also referred to as acne inversa (AI).
HS/AI has been erroneously linked to the apocrine sweat glands. The first pathogenic change is in the follicular portion of the folliculopilosebaceous unit (FPSU) .
HS/AI is characterized by recurrent inflamed deep-seated acneiform nodules that result in abscesses and chronic draining sinus tract formation leading to scarring, disfigurement, and life-altering disability. The lesions classically occur in areas of the skin that host FPSUs.
HS/AI is frequently misdiagnosed as “boils,” resulting in delayed diagnosis, fragmented care, and progression to a chronic, disabling condition.
Diagnostic Criteria
- 1.
Typical lesions: Deep-seated painful nodules (blind boils) in early primary lesions, or abscesses, draining sinuses, bridged scars, and “tombstone” open comedones in secondary lesions.
- 2.
Typical topography: Axillae, groin, genitals, perineal and perianal region, buttocks, and infra- and intermammary areas.
- 3.
Chronicity and recurrences.
These three criteria must be met to establish the diagnosis.
These recurrent “boils” do not respond to standard antibiotics like “boils” caused by bacteria. Instead of “pointing” vertically and discharging onto the surface, HS/AI lesions are rounded and tend not to burst. Instead, they rupture horizontally under the skin and tend to track subcutaneously. HS/AI is chronic; 90% of patients in one study had the disease an average of 19 years .
Questions help differentiate HS from other disorders ( Table 1 ).
| 1. Does anyone in your family have the same symptoms? |
| 2. Do the “boils” recur in the same spots? |
| 3. Do you smoke or use tobacco products? |
| 4. Do your “boils” flare before your menstrual period? |
| 5. Have the treatments received been helpful? |
| 6. Do you get a fever with these “boils”? |
| 7. Do you have infections elsewhere? |
Diagnostic Criteria
- 1.
Typical lesions: Deep-seated painful nodules (blind boils) in early primary lesions, or abscesses, draining sinuses, bridged scars, and “tombstone” open comedones in secondary lesions.
- 2.
Typical topography: Axillae, groin, genitals, perineal and perianal region, buttocks, and infra- and intermammary areas.
- 3.
Chronicity and recurrences.
These three criteria must be met to establish the diagnosis.
These recurrent “boils” do not respond to standard antibiotics like “boils” caused by bacteria. Instead of “pointing” vertically and discharging onto the surface, HS/AI lesions are rounded and tend not to burst. Instead, they rupture horizontally under the skin and tend to track subcutaneously. HS/AI is chronic; 90% of patients in one study had the disease an average of 19 years .
Questions help differentiate HS from other disorders ( Table 1 ).
| 1. Does anyone in your family have the same symptoms? |
| 2. Do the “boils” recur in the same spots? |
| 3. Do you smoke or use tobacco products? |
| 4. Do your “boils” flare before your menstrual period? |
| 5. Have the treatments received been helpful? |
| 6. Do you get a fever with these “boils”? |
| 7. Do you have infections elsewhere? |
Differential diagnosis
HS/AI has an extensive differential diagnosis ( Table 2 ). The appearance, age of onset, typical locations, poor response to antibiotics, and lack of signs of systemic sepsis – these can help distinguish this condition, so the diagnosis should be fairly obvious. Anogenital Crohn disease and HS/AI may be associated and confused with each other .
| • Infections |
|
|
| • Tumors |
|
| • Miscellaneous |
|
|
The most common differential diagnoses are the follicular pyodermas – folliculitis, furuncles, and carbuncles.
The varied sites of involvement and the rather nonspecific lesions take patients to many specialists. Patients seen in emergency departments are often treated with simple incision and drainage and a short course of antibiotics. This is generally ineffective in controlling the disorder and discouraging for patients . Delayed diagnosis (averaging 7 years) is common.
Prevalence and epidemiology
HS/AI is not “rare.” Estimates of global prevalence range between 1% and 4%. Most authors report no racial differences but the female to male ratio is 3.3:1. Women are affected under the breasts (22%) and in the groin (93%); men are affected on the buttocks (40%) and perianal area (51%) . The average age of onset is 23 years. Its onset occurs earlier in those with a family history, and is unusual after menopause. In men, it can continue into old age and is often more severe, and rare squamous cell carcinoma is more common in men.
Etiology
The development of HS/AI depends upon a combination of factors.
Genetic factors
A 35–40% positive family history may reflect inadequate family reporting. An autosomal dominant inheritance pattern has been noted, but no specifically genetic defect has been found. Von der Werth suggests that HS/AI is most likely a heterogeneous disease, probably with several genes involved.
Infection
Bacteria have long been considered in the pathogenesis of HS/AI. It is generally agreed that bacteria do not have a major direct role in the etiology of HS/AI but, as secondary invaders, may share in the pathogenesis of the chronic relapsing lesions causing some of the destructive processes that are seen . Septicemia and systemic illness in this disorder are exceptionally rare.
Hormonal factors
A strong relationship exists between sex hormones and HS/AI. The female preponderance suggests a greater sensitivity of females to androgens. There are no elevations in serum androgens in the vast majority of HS/AI patients. End-organ sensitivity is likely responsible. This highlights the role of FoxO1 in repressing the androgen receptor. Increased access to the androgen receptor is mediated by insulin and insulin-like growth factor-1 (IGF-1), both chronically raised by dietary factors .
In women, the onset of HS/AI occurs around menarche, flares premenstrually and following exposure to androgenic progestins like medroxyprogesterone acetate (MPA) or levonorgestrel , but improves with pregnancy and fades after menopause.
Antiandrogen therapy helps HS/AI patients of both sexes. Finasteride, a selective inhibitor of the type II isomer of 5α-reductase, reduces the levels of 5α–DHT. It was used to improve six of seven adults with HS/AI and three children, one with premature adrenarche and one with polycystic ovarian syndrome .
Immune factors
The disease does not usually produce acute systemic inflammatory effects. There is no fever, rare lymphadenopathy, no septicemia, and occasional local cellulitis, cultures are usually sterile, and, if the offending material beneath the surface is removed, the disease heals without further difficulty and without antibiotics. This is strongly suggestive of inflammation mediated on the local level by the innate immune system. Consider a simple ingrown hair. Flick out the ingrown hair and the inflammation fades.
The immune systems accelerate the disorder. A pathologic examination of excised early lesions demonstrates a wide variety of immune responses involving the innate and acquired (adaptive) immune systems. A vast catalog of T lymphocytes and cytokines are assembled . Unfortunately, cooling the inflammation does not cure the disease.
Mechanical factors
Weakness in the support structure of the follicular portion of the FPSU likely predisposes to follicular rupture caused by local trauma. ( Fig. 1 ) Patients worsen their lesions by pinching them. Obesity contributes to these increases in pressure and shear forces, but the relationship of obesity to dietary habits that raise plasma glucose and insulin levels is more important. This sensitizes the androgen receptors, increases the plugging of pores, causes insulin resistance, and enhances obesity . HS/AI affects thin people but overweight patients have more severe disease.
Smoking
Smoking is strongly associated with HS/AI; smokers are generally more severely affected than nonsmokers . Nicotine promotes follicular plugging .
Diet
The androgen receptors that control growth are normally closed to circulating androgens. Elevated insulin (from the combination of high glycemic carbohydrate load and dairy whey) and IGF-1 (induced by casein in milk) open these receptors and expose them to circulating androgens . Androgens from any source can then access previously inaccessible androgen receptors. Stimulation of follicular androgen receptors results in ductal keratinocyte overproduction and retention hyperkeratosis. Androgen sources include the adrenals, ovaries and testes, molecular precursors in dairy products, the androgenic progestins in birth control pills, the levonorgestrel-containing intrauterine device (IUD), intramuscular MPA injections, and contraceptive implants.
Drugs
HS can be triggered or flared by lithium.
Pathogenesis
The pathogenesis of the disease consists of follicular plugging, ductal rupture, and secondary inflammation leading to the downstream changes. HS/AI is subject to genetic, mechanical, hormonal, and other influences . ( Fig. 1 ) The sequential story is likely as follows, though some links remain to be proven.
Patients with HA/AI show an area of weak structural support at the junction of the sebaceous glands and the follicular duct . When hormonal overstimulation of ductal keratinocyte production results in a tight and expanding plug in the duct, centrifugal pressure is applied to this area, and the wall of the duct leaks and ruptures sideways, deep in the dermis. The intraductal follicular contents leak out, stimulating the innate immune system. Healing processes attempt to repair the normal anatomy of the FPSU. ( Fig. 1 ) When repair fails, the follicular fragments stimulate three separate reactions.
The first reaction is the inflammatory response, triggered by the innate immune system. This causes purulence and tissue destruction. It leads to foreign body reactions and extensive scarring.
Second, epithelialized sinuses may develop, postulated to evolve from stem cells (derived from the FPSU) that survive the destruction .
Third, an invasive proliferative gelatinous mass (IPGM) is produced in most cases, consisting of a gel in which are embedded both inflammatory cells and, it is postulated, the precursors of the epithelialized elements described above.
Continuous growth of these hormonally stimulated remnants beneath the surface perpetuates the communicating sinuses and inflammatory mass and provides increasing volumes of invading material. The inflammation in the dermis and subcutis will not settle until this material is eliminated.
The onset of the usual lesion occurs as an apparently random, small, red, indurated papule, pustule, or nodule that may resolve without leaving any mark. Onset may take weeks or months, causing vague itching to mild to moderate pain. Acute, severe, even frightening onset may present large, deep, painful lesions, restricting activities. They are generally intertriginous and involve the axillae, inguinal areas, inner thigh, perianal and perineal areas, mammary and inframammary area, buttocks, pubic region, scrotum, vulva, chest, scalp, and the retro-auricular region. The groin, axillae, and under the breasts are involved in women, the axillae, groin, and perianal area in men .
Nodules can last anywhere from 7 to 15 days resolving, persisting, or draining to the surface with pain resolution. Patients may present active papules, nodules, and draining sinuses in one area (the groin) and sheets of perifollicular papulopustules elsewhere (around the breasts or buttocks). These lesions come and go.
Secondary lesions develop because the process persists. The subcutaneous coalescence and lateral extension of actively invading epithelial sinuses and proliferative mass, with rupture to the surface, may result in the formation of chronic interlinked sinuses draining serous, purulent, bloody, or a mixed fluid, with or without odor. Persistent ulcerations and even red granulation tissue may surround a sinus opening. With healing, hypertrophic scars and eventually dense rope-like linear fibrotic bands develop. Sinus tracts, some hardly visible, drain serous fluid, or form swollen, painful, and very inflamed subcutaneous networks.
Tertiary lesions from aberrant healing form small pitted or cribriform scars, indolent epidermoid cysts, and sinus tracks that may become hypertrophic and fibrous. These involve entire zones, underlying a solid plaque of thick, bridged, rope-like scars. These can result in contractures, lymphatic obstruction, lymphedema, lymphangiectasia, and verrucous lymphangiomas.
“Tombstone” comedones arise from a burned-out FPSU that has lost its deeper portions. Continued keratinization of the residual follicular stump results in an indolent, shallow, and permanently dilated pore.
Clinical course
The mean age of onset is 22.1 years; it lasts about 19 years , can remit or partially remit with pregnancy and breastfeeding, and can be very variable. Usually a benign, mild, chronic but intermittently painful disease, HS/AI has acute exacerbations, premenstrual flares, resolution after menopause, remission for weeks to months, or continuous or intermittent flares. Solid plaques of coalescent nodules, sinuses, and scars host smelly discharge, pain, and debility.
New deep painful nodules last 10–30 days. Patients may present with a certain degree of severity and remain in that range, severe disease usually starting with severe disease from the beginning.
The difficulty with mobility ranges from minor soreness to inability to walk or sit without pain. Odor from drainage may be significant and require diapers, leading to social withdrawal, depression, and dysfunctional lives . The physical extent of HS/AI can be classified using Hurley’s clinical staging.
Hurley’s stages ( Table 3 )
Revuz documented 68.2% of patients in Hurley’s stage I, 27.6% in Hurley’s stage II, and 3.9% in Hurley’s stage III . From a practical point of view, a patient with Hurley’s Stage III really has all three stages and may present with burned-out Stage III but active Stage I or II lesions.
| Stage I – abscess formation, single or multiple without sinus tracts and cicatrization (scarring) |
| Stage II – recurrent abscesses with tract formation and cicatrization, single or multiple widely separated lesions |
| Stage III – diffuse or near diffuse involvement, or multiple interconnecting tracts and abscesses across entire area. |
Morbidity/quality of life
HS/AI has a profoundly negative impact on patients’ physical, social, and economic lives, with a higher morbidity index than urticaria, neurofibromatosis, psoriasis, atopic dermatitis, mild to moderate psoriasis, or alopecia. Many become socially isolated or reclusive due to the pain, malodorous discharge, intimate sites of eruptions, inappropriate medical care due to incorrect diagnosis, the numerous lesions, long and continuous duration, and pelvic area involvement . HS/AI patients, mainly women, lose an average of 2–7 days of work per year (or their jobs).
Associated diseases
HS/AI is associated with severe acne (acne conglobata), dissecting cellulitis of the scalp, and pilonidal cysts .
Chronic inflammation can cause SAPHO, a syndrome of synovitis, acne, pustulosis, hyperostosis, and osteitis .
Associations include ulcerative colitis (8%) and Crohn disease (17%). Crohn disease can mimic the appearance of advanced, scarred HS/AI, and may form perianal and perirectal sinuses . Pyoderma gangrenosum is more common than reports suggest. There are numerous other associations.
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