Non-Antibiotic and Non-Biologic Systemic Therapeutics

Introduction

The pathogenesis of hidradenitis suppurativa (HS) remains to be fully elucidated. Genetic susceptibility along with hormonal fluctuations and immune dysregulation are all thought to contribute to HS development. HS tends to occur in patients with comorbid conditions associated with hyperandrogenism, insulin resistance, and inflammation including acne vulgaris, hirsutism, diabetes, and polycystic ovary syndrome (PCOS). Utilizing multimodal treatment regimens including hormonal therapies (anti-androgens, anti-diabetics), systemic immunomodulators (oral retinoids), and immunosuppressants may alleviate HS symptoms and aid in recovery. This chapter discusses non-antibiotic and non-biologic systemic therapies for HS. Table 17.1 summarizes the mechanism of action, other indications, dosing regimen, contraindications, and adverse effects for the medications discussed in this chapter. Table 17.2 outlines the levels of evidence and recommendations regarding the use of these therapies according to the 2019 North American guidelines.

Table 17.1

Mechanism of Action, Other Uses, Dosage, Relative and Absolute Contraindications, and Side Effects of Systemic Non-Antibiotic and Non-Biologic Therapeutics

Medication	Mechanism of Action	Other HS-related Indications	Dosing Regimen	Absolute Contraindications	Relative Contraindications	Adverse Effects
Combined Oral Contraceptives	Inhibit ovulation via inhibiting FSH and LH. Increase SHBG.	Acne vulgaris	Estrogen content < 50 mcg/day PO. Avoid progestogen-only regimens.	Pregnancy Liver tumor Active or history of breast or endometrial cancer Ischemic/valvular heart disease History of thromboembolic disorders Smokers over age 35 Migraines with aura Valvular heart disease	Uncontrolled HTN Uncontrolled DM	Bleeding Nausea Headaches Abdominal cramping Breast tenderness Vaginal discharge Decreased libido
Spironolactone	Aldosterone antagonist, K + sparing diuretic. Androgen antagonist. Androgen biosynthesis inhibitor.	Acne vulgaris PCOS	25–50 mg/day titrate as needed to a dose of 50–200 mg/day, PO	Addison disease Serum Cr > 4 mg/dL Serum K + > 5 mmol/L Concurrent use of potassium sparing diuretics Pregnancy	Uncontrolled DM Respiratory or metabolic acidosis Hepatic disease with biliary cirrhosis or ascites Menstrual irregularity	Arrythmia Hyperkalemia Hepatotoxicity Renal failure Gynecomastia
Finasteride	Inhibitor of type II 5α-reductase that decreases DHT.	PCOS	2.5–10 mg/day PO	Pregnancy	Breast-feeding Hepatic disease	Impotence Orthostatic hypotension Decreased libido Sexual dysfunction Rhinitis Prostate cancer Depression and self-harm behavior Infertility (rare reports post-marketing)
Metformin	Inhibit hepatic gluconeogenesis and the action of glucagon by inhibiting mGPD. Increases glycolysis and peripheral glucose uptake. Increases insulin sensitivity. Promotes weight loss.	Type 2 DM PCOS	1500–2000 mg PO	Renal or hepatic insufficiency Acute hypoxia and acute cardiac disease Acidemia (lactic acidosis/ metabolic acidosis)	Iodinated contrast Acute MI Alcoholism Pernicious anemia Uncontrolled adrenal insufficiency, pituitary insufficiency, or hypothyroidism	GI disturbance Lactic acidosis B12 deficiency
Liraglutide	GLP-1 analog. Decreases glucagon release and gastric emptying. Increases glucose-dependent insulin release and satiety.	Type 2 DM Weight reduction and maintenance in obese and overweight individuals	0.6–1.8 mg injection/day	Certain types of thyroid cancer Diabetic Ketoacidosis, Type 1 DM Pregnancy History of suicide attempts or active suicidal ideation	Renal insufficiency Gastroparesis Cholelithiasis Gallbladder disease Hepatic disease Breast-feeding Pancreatitis	Palpitations Nausea Vomiting Cholecystitis Pancreatitis Renal failure Suicidal ideation Heart block
Oral Retinoids: Acitretin/Isotretinoin	Activates nuclear receptors to produce anti-keratinizing, anti-inflammatory, and anti-proliferative effects in the skin.	Acne vulgaris Severe psoriasis	0.5–0.6 mg/kg/day PO	Breast-feeding Pregnancy Acitretin should be avoided in women of childbearing age.	Visual disturbance Hepatic insufficiency	Xerosis Alopecia Teratogenic Pseudotumor cerebri Tinnitus Epistaxis Hepatotoxicity Hypertriglyceridemia Dysglycemias
Colchicine	Anti-inflammatory, disrupts microtubule polymerization. Prevents activation, degranulation, and migration of neutrophils.	Behçet	0.5 mg PO BID	Both hepatic and renal insufficiency Pregnancy Myopathy	Renal insufficiency Hepatic insufficiency Biliary obstruction Bone marrow suppression	Nausea Diarrhea Neutropenia Infertility (rare)
Methotrexate	Dihydrofolate reductase inhibitor that prevents conversion of folic acid into tetrahydrofolate, inhibiting DNA synthesis in the S-phase of the cell cycle. Causes adenosine accumulation, inhibiting neutrophil chemotaxis.	Psoriasis	Start: 15 mg/week with laboratory monitoring Dose adjustments: increase by 5 mg/week at week 8 if no response	Severe renal insufficiency Pregnancy Breastfeeding Blood disorders: blood marrow hypoplasia, leukopenia, thrombocytopenia, anemia Alcoholism Active tuberculosis	Renal or hepatic insufficiency Ascites HIV/AIDS GI disease Radiation therapy	Myelosuppression Pulmonary toxicity GI disorders Hepatotoxicity Lymphoma
Dapsone	Inhibits bacterial dihydropteroate synthetase and synthesis of dihydrofolic acid. Anti-inflammatory.	Pyoderma gangrenosum Dissecting cellulitis of the scalp Acne vulgaris	Start at 25 mg daily and titrate to 100 mg PO BID	G6PD deficiency Agranulocytosis Aplastic anemia	Cardiopulmonary disease Renal or hepatic insufficiency Allergy to sulfonamide antibiotics Neuropathy	Agranulocytosis Methemoglobinemia
Prednisone	Inhibits synthesis of leukotrienes. Diminishes production of proinflammatory cytokines. Inhibits cytotoxic T-cell activation.	Ankylosing spondylitis	10 mg/day PO	Uncontrolled DM	Warfarin use DM Infections Peptic ulcers Congestive heart failure Recent MI Glaucoma Seizure disorder	Hyperglycemia Sleep disturbances Psychomotor agitation Avascular necrosis Visual impairment
Cyclosporine ^42–44	Calcineurin inhibitor. Inhibits T-lymphocytes.	Refractory psoriasis	1–6 mg/kg/day	Active infection	Renal insufficiency Uncontrolled HTN Asthma Blood disorders: aplastic anemia	Nephrotoxicity HTN Hyperlipidemia Neurotoxicity Gingival hyperplasia Hirsutism

BID , Twice per day; Cr , creatinine; DHT , dihydrotestosterone; DM , diabetes mellitus; FSH , follicle stimulating hormone; G6PD , glucose 6 phosphate dehydrogenase; GI , gastrointestinal; GLP-1 , glucagon like peptide-1; HTN , hypertension; K + , potassium; LH , luteinizing hormone; mGPD , mitochondrial glycerophosphate dehydrogenase; MI , myocardial infarction; PCOS , polycystic ovary syndrome; PO , per os (oral administration); SHBG , sex hormone binding globulin.

Table 17.2

Evidence Levels: Non-Antibiotic and Non-Biologic Systemic Therapeutics for Hidradenitis Suppurativa

Therapy Name	Evidence Level	Recommended Use
OCPs	A	Consider in female patients with no contraindications.
Spironolactone	C	Consider in female patients with no contraindications.
Finasteride	D	Not enough evidence to make a definitive conclusion.
Metformin	C	Strongly consider in patients with obesity, insulin resistance and/or PCOS.
Liraglutide	E	Not enough evidence to make a definitive conclusion.
Isotretinoin	C	Not enough evidence to make a definitive conclusion. Consider in patients with severe concomitant acne.
Acitretin	B	Consider in patients with recalcitrant HS with failure to respond to first-line therapy.
Colchicine	B	Consider in patients with refractory mild-moderate disease who can tolerate colchicine and minocycline combination therapy.
Methotrexate	C	Not enough evidence to make a definitive conclusion.
Dapsone	B	May be effective for select patients without contraindications.
Prednisone	C	Can be used as rescue therapy or bridge-therapy to other long-term treatment option.
Cyclosporine	E	Consider in patients with recalcitrant moderate to severe HS who have failed or are not candidates for standard therapy.

Evidence Levels:

A: At least one prospective, randomized, double-blind, controlled trial without major design flaws (in the authors’ view).

B: Prospective clinical trials with 20 or more subjects; trials lacking adequate controls or another key facet of design that would normally be considered desirable.

C: Small trials with fewer than 20 subjects with specific design limitations, very large numbers of case reports (at least 20 cases in the literature), or retrospective analysis of data.

D: Series of greater than or equal to five patients reported to respond.

E: Anecdotal case reports individual case reports amounting to published experience of fever than five cases

HS , Hidradenitis suppurativa; OCPs , oral contraceptive pills; PCOS , polycystic ovary syndrome.

Hyperandrogenism and Hidradenitis Suppurativa

Small questionnaire-based studies conducted in the U.K. found that approximately 50% of women with HS report acute flares which are temporally related to menstruation. In one cross-sectional study in the Netherlands, patients reported frequent changes in disease activity during pregnancy. Furthermore, improvement in HS symptoms during pregnancy was associated with a history of premenstrual disease flares. These findings suggest that disease activity in women with HS may be strongly correlated with hormonal fluctuations.

The skin has the unique ability to synthesize androgens de novo from cholesterol in the epidermis and sebaceous glands. However, the main source of androgens are the testes, ovaries, and adrenal glands. The circulating androgens, dehydroepiandrosterone (DHEA) and androstenedione, are converted into testosterone in sebocytes, sweat glands, and dermal papilla cells. In the skin, the enzyme 5α-reductase metabolizes testosterone into a more potent androgen, dihydrotestosterone (DHT). In comparison to testosterone, DHT binds to androgen receptors with 10 times higher affinity and with greater stability. Androgen metabolism is depicted in Fig. 17.1 .

Fig. 17.1, Androgen Metabolism in the Skin.

In the skin, androgen receptors are primarily located in the dermal papillae, sebaceous epithelium, eccrine sweat epithelium, and, to a lesser degree, in basal epidermal cells and reticular dermal fibroblasts. They are also present in pilosebaceous duct keratinocytes and, to a lesser degree, in interfollicular keratinocytes, and could play a role in acne and HS via promotion of follicular hyperkeratinization. According to the acne model, hyperproliferation of the infrainfundibular keratinocytes is one of the initial and most crucial events in the development of microcomedones, and is also characteristic of HS. Infrainfundibular hyperkeratosis, hyperplasia of the follicular epithelium, and perifolliculitis lead to localized inflammation and precede follicular rupture in HS. In one study, anti-androgens were shown to decrease follicular debris at the hair follicle, raising the possibility that androgens could play a role in hyperkeratinization. Additionally, increased 5α-reductase activity in infrainfundibular keratinocytes—as opposed to interfollicular epidermal cells—suggests that DHT could affect follicular keratinization; however, this remains to be fully explored.

Androgens may also modulate the inflammatory milieu important in HS pathogenesis. It is postulated that Tumor Necrosis Factor alpha (TNF-α expression, interleukin (IL)-1β, and IL-17 are prominent inflammatory actors in HS. Multiple independent studies have indicated increased IL-17 expression in HS lesions compared with control skin. IL-17 is produced by T-helper-17 (Th17) cells, innate lymphoid cells, T cells, mast cells, and neutrophils. IL-1β, IL-6, TGF-β, and IL-2, produced by innate immune cells, can further upregulate IL-17 production. Testosterone and DHT modulate TGF-β, IL-6, and TNF-α production, indicating that there is a potential for these androgens to exacerbate HS lesions via the Th17 inflammatory pathway. In a rat model, androgens were shown to exacerbate inflammatory responses resulting in delayed skin healing. Androgens specifically promote inflammation by enhancing local TNF-α expression of TLR stimulated macrophages, thereby inducing the release of proinflammatory cytokines. Androgen receptor signaling also upregulates TNF-α expression via other avenues, including increasing the inflammatory monocyte population via upregulation of CCR2, thereby enhancing monocyte chemotaxis. Gilliver et al. conducted a study in which a 5α-reductase inhibitor administrated to a rat model resulted in significantly decreased inflammatory markers such as TNF-α and IL-6 in the skin and markedly accelerated wound healing.

Studies have demonstrated improvement in HS disease activity with the use of both antiandrogens (e.g., finasteride, flutamide, spironolactone) and oral contraceptive pills (OCPs). While the exact mechanism remains unclear, clinical evidence suggests that blocking the androgenic pathway is effective in management and will be discussed below in further detail.

Oral Contraceptives

Combined OCPs contain both progesterone and estrogen and act primarily by preventing ovulation through the inhibition of follicular stimulating hormone (FSH) and luteinizing hormone (LH). Oral estrogens produce an anti-androgenic effect by increasing the concentration of circulating sex hormone binding globulin (SHBG). SHBG binds more avidly to androgens than estrogens, rendering androgens less bioavailable to interact with the androgen receptor as demonstrated in Fig. 17.2 .

Fig. 17.2, Sex Hormone Binding Globulin Mechanism.

Several studies have evaluated the use of OCPs in HS. One study evaluated ethinyl estradiol/cyproterone (CPA) versus ethinyl estradiol/norgestrel in women with HS. There was no clinically significant difference as evaluated by visual analogue scales (VAS) and disease activity scores in response to the two treatments among the 18 patients who completed the trial, but there was significant improvement overall in comparison to baseline HS status. Seven (39%) patients’ HS lesions completely cleared while five (28%) patients improved, four (22%) remain unchanged, and two (11%) patients’ conditions deteriorated. In another case series evaluating a combination treatment of ethinyl estradiol and CPA, all 4 individuals exhibited improvement after 3 to 7 months of treatment. In both studies, free androgen index, defined as the ratio of total testosterone divided by SHBG, was decreased in response to treatment, which may explain patients’ HS improvement.

While these two studies show some promise for OCPs, more randomized-controlled studies must be conducted to better understand the potential benefits of OCPs. Small sample sizes, variable outcome measures and methods, and reporting bias limit the evidence available to make fully informed recommendations for OCPs at this time. The 2019 North American HS management guidelines suggest OCP usage as monotherapy for mild to moderate HS or in combination with other agents for more severe disease for appropriate female patients, such as those with HS flares around menses or those with PCOS. When selecting an OCP, progestogen-only regimens should be avoided as anecdotal concerns suggest that they may worsen HS. The 2015 European guidelines suggest antiandrogen therapy such as CPA in female patients with menstrual abnormalities, signs of hyperandrogenism, or upper-normal or high serum levels of DHEA, androstenedione, and/or SHBG. A comparison of HS management guidelines published by different international expert organizations can be found in Chapter 14 .

Spironolactone

Spironolactone is another antiandrogen used in HS treatment. It is an aldosterone antagonist and competitively inhibits active sodium transport. While originally used for its potassium-sparing diuretic effects, spironolactone is commonly used off-label for skin conditions such as acne vulgaris due to its anti-androgenic properties.

The anti-androgenic properties of spironolactone are most likely attributable to the structural similarities between the mineralocorticoid and androgen receptors. Although the exact mechanism of its anti-androgenic effects are unknown, spironolactone inhibits the activity of 5α-reductase in vitro, decreasing the conversion of testosterone to DHT. It also increases the level of SHBG, depleting bioavailable testosterone. An active metabolite of spironolactone also inhibits 17α-hydroxylase and desmolase, two enzymes necessary for adrenal and gonadal androgen synthesis. Spironolactone’s therapeutic effects in skin could be due to inhibition of 17α-hydroxylase within the cytoplasm of sebocytes and keratinocytes, although this has not been directly demonstrated. Spironolactone also modulates the deposition of extracellular matrix in human skin. Spironolactone’s capacity as a potential scar and keloid treatment is under investigation; preliminary results have revealed decreased collagen expression in spironolactone-treated skin.

A single center retrospective study of 67 female HS patients treated with spironolactone from 2000 to 2017 exhibited promising results. The study showed statistically significant improvement in the Numeric Rating Scale (NRS)-pain score (-1.5, P = .01), lesion count (-1.3, P = .02), and the Hidradenitis Suppurativa-Physicians Global Assessment (HS-PGA) score (-0.6, P < .001). The average daily spironolactone dose was 75 mg (range: 25 to 200 mg) and the average duration of treatment was 7.1 months (range: 0 to 28 months). There was no difference in change in NRS-pain score, lesion counts, or HS-PGA score between subjects who received less than 75 mg versus those who received greater than 100 mg daily. A sub-analysis of groups stratified by race, Body Mass Index (BMI), comorbidities, and concomitant HS treatments did not show any significant differences in treatment response.

Two smaller retrospective studies evaluated a total of 46 patients on spironolactone with 7 patients on concurrent OCPs and 17 patients on concurrent metformin. Overall, 26/46 (57%) exhibited clinical improvement. Another retrospective study reviewed 31 HS patients on different combination therapies. All six patients with mild and moderate disease on combinations containing spironolactone (combined with either isotretinoin or adalimumab) exhibited clinical improvement. Finally, another retrospective review with 64 patients found that patient response rate to antiandrogen therapy (including Diane-35 (ethinyl estradiol 35 μg and CPA 2 mg), CPA, spironolactone, and OCPs), was significantly superior to oral antibiotics (55% vs. 26%, respectively).

Spironolactone is a potent therapeutic agent to consider for patients suffering from HS. There is an ongoing investigation regarding the optimal dosage of spironolactone in the treatment of HS. Similar to OCPs, spironolactone should be considered as monotherapy for appropriate female patients (such as those with HS flares around menses or those with PCOS) with moderate HS or in combination with other agents for more severe disease.

Finasteride

There are two types of 5α-reductase enzymes; type I 5α-reductase is found in both hair follicles and apocrine glands, whereas type II 5α-reductase is found only in hair follicles. Finasteride inhibits type II 5α-reductase while dutasteride inhibits both type I and type II. While the exact mechanism of finasteride’s effects in HS is unknown, it is hypothesized that finasteride modulates HS disease activity by reducing the concentration of hair follicle DHT levels.

Khandalavala et al. conducted a systematic review in 2016 which summarized 5 publications detailing 13 individual cases of HS treated with finasteride. Notably, the cases included four male and nine female patients. Dosages ranged from 2.5 to 10 mg daily. It was effective for both men and women, especially those with metabolic or hormonal alterations present such as PCOS, metabolic syndrome, obesity, and precocious puberty. Of the 13 cases, 3 (23%) patients had complete responses and 10 (77%) patients experienced partial responses. Due to recurrence of symptoms upon cessation of finasteride therapy, some patients used finasteride continuously or as needed for up to 6 years. Khandalavala et al. suggested that finasteride could be used as a monotherapy or additional therapy for advanced HS as it could increase time between flares. In one case series of five pre-pubescent patients, including one male patient, finasteride treatment decreased the frequency and intensity of flares for all patients.

Similar to other hormonal modulators finasteride should be considered as monotherapy for appropriate female patients (such as those with HS flares around menses or those with PCOS) with moderate HS or in combination with other agents for more severe disease. There is not enough conclusive evidence at this time to make a distinction between finasteride’s efficacy in men compared to women. Therefore, finasteride could be considered for males who have other stigmata of hyperandrogenism such as androgenetic alopecia.

Insulin Resistance and Obesity

HS tends to occur in patients with comorbid medical conditions associated with insulin resistance such as diabetes and PCOS. A case control study in Spain demonstrated that patients with HS were found to have elevated levels of insulin resistance, even when controlling for age, gender, and BMI. Elevated insulin levels affect the levels of circulating insulin growth factor-1 (IGF-1) and insulin growth factor binding protein (IGFBP-3), which regulate keratinocyte proliferation and apoptosis, respectively. Typically these two factors are in balance, however, in insulin resistant states, IGF-1 increases and IGFBP-3 decreases, causing increased keratinocyte proliferation and decreased keratinocyte apoptosis, amplifying the likelihood of follicular hyperkeratinization. Increased IGF-1 also increases levels of androgens, growth hormone, and glucocorticoids through various pathways. Elevated androgens in turn increase IGF-1, and promote insulin resistance in peripheral tissues further propagating this cycle. This pathway is depicted in Fig. 17.3 below.

Fig. 17.3, Elevated insulin levels increase the levels of circulating insulin growth factor-1 (IGF-1) and decrease insulin growth factor binding protein (IGFBP-3) , which regulate keratinocyte proliferation and apoptosis, respectively. This promotes follicle plugging. Additionally, increased IGF-1 increases androgens. Increased insulin and insulin resistance may increase risk of obesity, which can affect hidradenitis suppurativa (HS) as excessive fat can secrete inflammatory markers like interleukin (IL)-6, TNF-α, inducible nitric oxide synthase, and TGF-β1.

Burghen et al. compared serum insulin and androgen levels in obese women with PCOS and control obese women. A positive correlation was found between elevated insulin levels and increased androgen levels in both groups of women. Insulin can both increase circulating androgens and decrease serum SHBG resulting in increased free serum testosterone levels. Increased insulin influences pituitary release of gonadotrophins, increasing ovarian androgen production. Notably, abnormally high insulin states decrease insulin responses in the liver and muscles but increase insulin-dependent ovarian androgen production. It is unclear whether the reverse is possible—that hyperandrogenism can cause hyperinsulinemia. Few studies have demonstrated that androgen reduction or blockade resulted in improved insulin sensitivity.

Studies have found a correlation between the severity of HS and increased BMI. The rate of long-term self-reported remission, defined as no inflammatory boils in the last 6 months, is lower in obese patients. Obesity may be strongly associated with HS and other autoimmune disorders because adipose tissue produces pro-inflammatory mediators, including IL-6, TNF-α, inducible nitric oxide synthase, and TGF-β1. In addition, obesity causes mechanical stress, increased moisture, and increased friction in skin folds, which can promote follicular hyperkeratinization and occlusion, key instigating factors of HS pathogenesis.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here