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 .

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 .