Tetracyclines and Their Use in Autoimmune Bullous Diseases and Epidermolysis Bullosa

Fig. 50.1

Diagram of the structure of tetracyclines

As early as the 1960s, tetracycline was studied and used as a modality of treatment in rosacea and acne [2]. Currently, the tetracycline group of drugs, including its derivatives minocycline and doxycycline, is being used to treat a myriad of inflammatory dermatologic conditions that do not necessarily have a bacteriologic etiology. These inflammatory and non-bacteriologic diseases include neutrophilic disorders, such as pyoderma gangrenosum and Sweet syndrome; granulomatous diseases such as sarcoidosis, foreign body granulomas, and cheilitis granulomatosa; papulosquamous disorders such as lichen planus; ulcerative disorders such as chronic wounds; and bullous disorders including autoimmune and inherited bullous disorders [3]. The anti-inflammatory properties of tetracycline have become well established. The anti-inflammatory activity of the tetracycline group of drugs involves the inhibition of matrix metalloproteinases (MMPs), downregulation of inflammatory cytokines, inhibition of leukocyte chemotaxis and activation (including degranulation of neutrophils), and antioxidation [3]. Recently, a drug called incyclinide has been developed that would contain the anti-inflammatory properties of tetracycline and not possess its antibacterial activity [5]. Currently, clinical studies are being conducted on incyclinide, and it has been proven by toxicology studies to be relatively safe. In one study, incyclinide, also referred to as CMT-3 or Col-3, was used in Kaposi sarcoma due to the drug’s ability to downregulate matrix metalloproteinases (MMPs). MMP-2 and MMP-9 have been found in increased amounts in Kaposi sarcoma [4–6].

50.2 Tetracyclines in Autoimmune Bullous Disorders

In the case of autoimmune bullous disorders, a pathophysiologic mechanism of this disease is that MMPs, particularly MMP-2, MMP-9, and MMP-13, are found in increased amounts in the lesional skin of bullous pemphigoid. MMPs have been found to inactivate α[alpha]1-proteinase inhibitor, which inhibits elastase from enzymatic degradation. Hence, the tetracycline group of drugs helps prevent destructive enzyme activity in the skin by protecting α[alpha]1-proteinase inhibitor from degradation by the MMPs, which are downregulated by tetracycline. Aside from their ability to inhibit MMPs, tetracycline, its derivatives minocycline and doxycycline, and chemically modified tetracyclines (CMT) have also been postulated to be effective in the autoimmune bullous group of diseases for their ability to inhibit leukocyte activation and chemotaxis. These two mechanisms are primarily involved in the pathophysiology of autoimmune bullous disorders [3].

Currently, evidence for the effectiveness of the tetracycline group of drugs in autoimmune bullous disorders is based mostly on case reports, case series, nonrandomized clinical trials, and an open-label randomized controlled trial. Results of these studies have not been consistent, in that some have shown effectiveness of the drug while others have not [7–9]. Further studies, particularly large randomized controlled trials, would be ideal to significantly demonstrate the use of tetracyclines in autoimmune bullous disorders and, just as important, to demonstrate the manner in which the drug is to be ideally given. This includes dosages and mode of administration—whether it is to be given as monotherapy or in conjunction with another anti-inflammatory drug, such as nicotinamide. To date, an open-label randomized controlled trial by Fivenson et al. showed that treatment using a combination of 500 mg nicotinamide three times daily and 500 mg tetracycline four times daily for bullous pemphigoid was not statistically significantly different from treatment with prednisone. The authors have concluded that combination treatment of nicotinamide and tetracycline for bullous pemphigoid is a sound alternative to prednisone [9]. However, the study had low numbers of patients and was therefore underpowered to detect a true difference.

Despite the need for further studies to establish the effectiveness of tetracycline in autoimmune bullous disorders, this drug has become a popular alternative treatment in patient populations where side effects from other drugs such as systemic corticosteroids or disease-modifying anti-rheumatologic drugs (DMARDs) need to be avoided or minimized. Tetracycline therapy, particularly in autoimmune blistering conditions, has become an acceptable treatment modality among elderly individuals, particularly those with osteoporosis, diabetes mellitus, and hypertension. This drug has also been given in combination with immunosuppressive treatment for more rapid tapering of the latter [7].

Tetracycline has been used in the treatment of bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, pemphigus foliaceus, linear IgA disease, dermatitis herpetiformis, and lichen planus pemphigoides [3, 10, 11]. Based on studies that have been done, it has been used in combination either with systemic corticosteroids, topical corticosteroids, or with nicotinamide. For tetracycline, doses range from 500 to 2,000 mg daily, with the highest possible dose given as 500 mg four times daily. Minocycline is usually given as 100–200 mg daily, although 50 mg daily dose has also been taken. Doxycycline is usually given as 200–300 mg daily. Finally, nicotinamide, which is usually used in combination with tetracycline, is given at doses ranging from 500 to 2,000 mg daily. With nicotinamide, the starting dose would be 500 mg daily; the dose is then eventually increased up to 2,000 mg daily. In a treatment modality that involves combination therapy with tetracycline and nicotinamide, either drug is gradually tapered down one at a time once blister formation has been suppressed. This is done in a course of several months to prevent flares or relapse of blisters [12, 13].

The use of the tetracycline group of drugs is not without its own share of risks and adverse effects. They should not be used in children until the second set of teeth are erupting because of staining of enamel. Tetracycline must be avoided in patients with renal impairment as it has been shown to be nephrotoxic. It has also been noted to cause gastrointestinal toxicity among patients. Meanwhile, doxycycline and minocycline must be avoided in cases of hepatic impairment. These two tetracycline derivatives are also associated with photosensitivity, vestibular problems, and hyperpigmentation. Despite improvement of the bullous conditions being treated, long-term treatment with minocycline results in hyperpigmentation of the skin, nail bed, or mucosa. Fortunately, this drug-induced hyperpigmentation is reversible once minocycline therapy is ceased, but it may take many months in elderly people with thin skin who have been on corticosteroids, compared to young people with acne [10, 12, 14] (Fig. 50.2).