Miscellaneous Systemic Drugs

Hereditary Angioedema

For prevention of attacks of hereditary angioedema, danazol therapy is initiated at a dose of 200 mg 2 or 3 times daily (see package insert). After edematous episodes are successfully prevented, the dose is slowly titrated downward to the lowest dose that will suppress life-threatening bouts of the disease. Long-term prophylaxis is typically obtained with doses not exceeding 200 mg daily. Alternate-day dosing regimens can also be effective. Plasma Complement 1 ( esterase ) inhibitor (C1 INH) and C4 levels rise with therapy but need not normalize totally for disease control to be achieved.

Other Dermatoses

Taking advantage of their fibrinolytic properties, the attenuated androgens have been shown to relieve the pain and heal the cutaneous ulcerations of cryofibrinogenemia, improve the spectrum of lipodermatosclerosis, and effectively treat livedoid vasculopathy.

The use of attenuated anabolic steroids has been reported in lichen sclerosus et atrophicus, chronic urticaria, Raynaud phenomenon, autoimmune progesterone dermatitis, and refractory pruritus associated with myeloproliferative disorders. It is of interest that danazol has been used for the treatment of fibrocystic breast disease, endometriosis, and notably as an adjunct to surgical excision in cases of cutaneous endometriosis.

Antimicrobial Effects

See Table 40.3 for drug mechanisms and clinical correlates for clofazimine. To date, there is no single theory to fully explain clofazimine’s antimicrobial effects. In vitro, clofazimine selectively binds to deoxyribonucleic acid (DNA) guanine residues, which are in higher concentration in mycobacteria than in humans. Whether this explains its in vivo activity is uncertain. Other proposed mechanisms of action involve the drug’s inhibition of the mitochondrial respiratory chains and inhibition of the increased production of free radicals within various cell lines. Recent in vitro work has shown that the antimycobacterial effects of clofazimine can be augmented by interferon (IFN)-γ or tumor necrosis factor (TNF)-α in certain circumstances. Perhaps cytokine-enhanced clofazimine therapy will someday be a reality for the treatment of human mycobacterial infections.

Immunological Effects

Within the immune system, clofazimine exerts its effects mainly by altering the functions of monocytes and neutrophils (polymorphonuclear neutrophil [PMN]). Among other effects on monocytes, the drug has been shown to increase the size and number of lysosomes and phagolysosomes. PMN motility and lymphocyte transformation are inhibited in a dose-dependent manner, and superoxide production is enhanced. Although phospholipase A ₂ production is also enhanced, the overall effect of the drug is usually anti-inflammatory.

Leprosy and Other Mycobacterial Infections

Clofazimine is approved for the treatment of lepromatous leprosy. It has also been used in the treatment of erythema nodosum leprosum (ENL). For multibacillary leprosy, combination drug therapy has been advocated as initial therapy to reduce the development of drug resistance. The drug has been used extensively in combination with dapsone and rifampin. Most commonly, 50 mg of clofazimine is taken daily along with an additional bolus of 300 mg monthly for at least 2 years. Different amounts of dapsone and rifampin have been recommended for concurrent use during this clofazimine course of therapy. It has been suggested that the addition of ofloxacin to this regimen may reduce the duration of therapy. In addition to leprosy, clofazimine has been used to treat tuberculosis and selected atypical mycobacterial infections.

Inflammatory Skin Diseases

Within the realm of inflammatory diseases, multiple reports discuss the use of clofazimine in the treatment of pyoderma gangrenosum (PG), in both its classic and malignant forms. Small series and case reports exist to support a trial of clofazimine in a number of other inflammatory, granulomatous, and infectious processes. The likelihood of successful therapeutic outcome, as gauged by response and remission rates, is highly variable. Although clofazimine is used for a host of dermatoses, it does not appear to be the drug of choice for any one condition.

Clofazimine is seldom used as a solitary agent, but most often in combination with other antimicrobial or anti-inflammatory drugs. It does not affect the bioavailability of dapsone. It slightly alters the pharmacokinetics of rifampin, and its levels in urine and plasma are slightly elevated with simultaneous isoniazid use; the clinical significance of these alterations is presumed negligible. Usually 50 to 300 mg is given daily; doses as high as 400 mg daily have been reported by some authors. Larger doses are usually divided 3 to 4 times daily. Attempts to taper the drug to a maintenance dose should be made after clinical response occurs.

Cutaneous Effects

Clofazimine is usually safe and well tolerated. Q40.4 The most common AE, seen with its use, is a reversible orange-brown discoloration of the skin, beginning within 2 to 4 weeks of initiating use. The cause is not only direct drug deposition but is also because of an induced hypermelanosis. Tears, sweat, hair, sputum, milk, urine, and feces can also have this discoloration. This usually resolves spontaneously within a few months of stopping therapy. Approximately 30% of patients experience a generalized xerosis, although progression to frank ichthyosis is not uncommon.

Systemic Effects

Q40.4 Rare and more serious AE can result from crystal deposition within the viscera. This usually occurs in a dose- and duration-dependent manner. Deposition within the small bowel may rarely cause a fatal enteropathy. Splenic infarction and eosinophilic enteritis have also been reported. There is one case report of cardiac dysrhythmia related to clofazimine use and a pre-existing electrolyte disturbance. Common effects of less significance include abdominal cramping, nausea, and diarrhea. Nail changes, pedal edema, and exacerbation of vitiligo have also been reported.

Neutrophilic Dermatoses

Colchicine’s value in the treatment of acute gouty arthritis and FMF is well established, including a 2009 FDA approval (Colcrys) for flares of acute gout. Use in the treatment of Behçet disease, a predominantly neutrophilic dermatosis, is also fairly well established. Although conflicting studies exist, improvement has been documented in the oral, genital, and ocular lesions of Behçet disease, as well as in associated erythema nodosum and articular complaints.

The PMN inflammatory infiltrate and enhanced leukocyte chemotaxis of Behçet disease are also seen in recurrent aphthous stomatitis where colchicine has also proven efficacious. Colchicine has shown utility in treating Sweet syndrome and case reports suggest it may be useful in treating dermatitis herpetiformis, linear immunoglobulin A (IgA) bullous dermatosis, in both children and adults, IgA pemphigus, and epidermolysis bullosa acquisita.

Vasculitis

The use of colchicine in the treatment of cutaneous leukocytoclastic vasculitis is controversial. One prospective, randomized controlled trial (RCT) showed no significant therapeutic effect with colchicine compared with placebo, but identified several patients who cleared with colchicine and relapsed with its discontinuation. Many uncontrolled reports advocate use of colchicine for treating chronic cutaneous leukocytoclastic vasculitis, citing a majority of patients achieving complete disease control or being able to taper their concurrent corticosteroid (CS) dose. A beneficial effect on the associated arthritis has also been observed. One case report describes resolution of chronic cryofibrinogenemia-related lower extremity ulcerations when colchicine was added to an unsuccessful regimen of high-dose pentoxyfylline.

Papulosquamous Dermatoses

Colchicine, with its PMN suppression and antimitotic activity, could theoretically be beneficial in treating psoriasis and palmoplantar pustulosis. In some patients, favorable results have been observed, although this therapy is considered a nonstandard option at best. Colchicine may be most effective for thin psoriatic lesions and as maintenance therapy after remission is obtained through other treatment modalities.

Other Dermatoses

Colchicine’s suppression of local inflammation caused by calcinosis in dermatomyositis and progressive systemic sclerosis (PSS) has been reported. Prolonged colchicine therapy, however, has not been shown to halt disease progression in PSS. Anecdotal reports suggest that colchicine may be efficacious for other diseases, including relapsing polychondritis, pachydermoperiostosis, with acro-osteolysis, and mild to moderate type II lepra reactions. In a single case, the inflammatory component of primary anetoderma responded to colchicine. Several studies have shown topical colchicine to effectively treat actinic keratoses, as well as condylomata acuminata.

Gastrointestinal Effects

The dose for dermatologic conditions is typically 0.6 mg 2 or 3 times daily, subsequently tapered as disease activity allows. Q40.6 For some patients, tolerance is enhanced by starting at once-daily therapy and gradually increasing the frequency over a number of weeks. Therapeutic doses of colchicine alter both jejunal and ileal function, such that abdominal cramping, hyperperistalsis, and watery diarrhea often occur with thrice-daily dosing. Diarrhea can be controlled with aluminum-containing antacids (Amphojel, Alternajel) or specific oral antidiarrheal medications, such as loperamide.

Colchicine Overdose

The therapeutic index of colchicine is narrow, generally between 0.015 and 0.03 mg/kg, with doses greater than 0.8 mg/kg being predictably fatal. Overdose can lead to a cholera-like syndrome with dehydration, hypokalemia, hyponatremia, metabolic acidosis, renal failure, and ultimately shock. Respiratory distress syndrome, disseminated intravascular coagulation, and bone marrow failure may ensue. Other toxic manifestations include hepatic failure and late central nervous system (CNS) disorders. Myopathy, hypocalcemia, alopecia, stomatitis, and porphyria cutanea tarda have been reported in acutely intoxicated patients, who ultimately survived.

Chronic intoxication may uncommonly occur after prolonged therapy with at least 1 mg daily. Complications include leukopenia, aplastic anemia, myopathy, and alopecia. Azoospermia and megaloblastic anemia, secondary to vitamin B ₁₂ malabsorption, have also been described.

Treatment is supportive. Intravenous colchicine carries serious risk, including death and is no longer available in the United States.

Use in Pregnancy and Lactation

In otherwise healthy women, colchicine use during pregnancy has been associated with lower birthweight and lower gestational age. It is classified as pregnancy Category C. However, to prevent disease relapse in women with FMF and Behçet, the literature strongly supports the ongoing use of colchicine throughout pregnancy. In these settings, studies have shown no increase in fetal malformations or miscarriages. The American Academy of Pediatrics classifies colchicine as compatible with breastfeeding, in which case it should be taken immediately after nursing.

Overall Dermatologic Uses

Niacinamide can be used for prophylaxis and treatment of pellagra caused by poor nutrition, Hartnup disease, or carcinoid tumors. Of most interest, however, is niacinamide’s reported utility in treating autoimmune bullous dermatoses, including the full spectrum of pemphigoid, pemphigus, dermatitis herpetiformis, and linear IgA dermatosis. Anecdotally, it has also been used to treat erythema elevatum diutinum, polymorphous light eruption, granuloma annulare, and necrobiosis lipoidica. Systemic niacinamide, in combination with azelaic acid, folic acid, copper, and pyridoxine, has also been marketed as a prescription dietary supplement, useful in the management of acne vulgaris.

Purported uses for topical niacinamide include improved epidermal barrier function and keratinocyte differentiation to fight signs of aging, improvement of isoniazid-induced pellagra-like skin lesions, improvement in wound healing, and anti-inflammatory and sebosuppressive effects useful in the treatment of acne vulgaris and rosacea. Topical niacinamide has also been shown to reduce the immunosuppressive effects of UV irradiation, making it an attractive additive in topical sunscreen preparations. Similarly, by reducing cutaneous immunosuppression, impeding cellular energy depletion, and promoting DNA repair, oral niacinamide has found a niche as a chemopreventive agent for nonmelanoma skin cancers.

Bullous Dermatoses

One randomized, open-label trial suggested comparable efficacy and fewer AE using the combination of niacinamide and tetracycline, compared with prednisone as first-line therapy for bullous pemphigoid. Another small review suggested that the combination of niacinamide and tetracycline derivatives may be an effective alternative to CS in pemphigus foliaceus and pemphigus erythematosus and a CS-sparing adjuvant, rather than CS alternative in pemphigus vulgaris. A more recent retrospective review of 51 patients with a spectrum of pemphigus also concluded that this combination therapy may be useful as ‘CS-sparing-sparing therapy’. Assessment of clinical response to niacinamide alone, in treating autoimmune blistering disorders and erythema elevatum diutinum, has clearly been complicated by concomitant tetracycline or erythromycin use in these studies. It has been proposed that the anti-inflammatory properties of these antibacterial agents may function synergistically with niacinamide in the treatment of diseases with excessive PMN chemotaxis. Because tetracycline alone has been reported to clear bullous pemphigoid, it is difficult to assess niacinamide’s exact contribution in treatment of bullous diseases. However, one case of localized bullous pemphigoid responding to niacinamide alone has been reported.

Skin-Cancer Chemoprevention

In a double-blind, randomized, controlled trial of 386 immunocompetent participants at high risk for skin cancer, niacinamide reduced rates of new basal cell carcinomas by 20% and new squamous cell carcinomas by 30%. Research suggests niacinamide might serve a similar role in preventing arsenic-induced skin cancers. Although more studies are warranted, enthusiasm exists for the chemopreventive use of nicotinamide in patients at high risk for skin cancer, particularly in the setting of renal transplantation.

Photodermatoses

Some researchers believe that niacinamide has a beneficial effect in the prevention of polymorphous light eruption. However, using phototesting, others failed to document this favorable response.

Dosing Strategies

In the treatment of autoimmune bullous diseases and granulomatous diseases, the dose of niacinamide has averaged 500 mg, 3 times daily. Four times daily dosing may also be considered. The concurrent tetracycline dose has typically been 500 mg, 4 times daily, although lower doses have proved to be efficacious. Minocycline 100 mg twice daily has been substituted in patients with GI distress attributed to tetracycline. There is also significant clinical experience combining niacinamide with doxycycline 100 mg twice daily. For chemoprevention purposes, the studied dose of niacinamide has been 500 mg twice daily.