Tetracycline

I report a patient with phenylketonuria who presented with pemphigus foliaceus or tinea amiantacea. The rash resolved with treatment with tetracycline and niacinamide. This article outlines the uses and mechanisms of this therapy with particular attention to its use in pemphigus, treatments, and scalp findings of pemphigus foliaceus and the dermatological manifestations of PKU.

**********

Case Report

A 38 year old white female presented with a six-month history of body and scalp rash. She had phenylketonuria (PKU) which had not been recognized in the neonatal period and her diet had not been modified, resulting in mental handicap. Physical examination revealed crusted red erosions with scale on her body (Figures 1, 2, 3) and pityriasis amiantacea (Figure 4) in her scalp. Potassium hydroxide preparations of her body and scalp did not reveal hypae. A biopsy of a body erosion showed acantholysis and intraepidermal clefting with an infiltrate of eosinophils suggesting a diagnosis of pemphigus. A subsequent biopsy for direct imnunofluorescence highlighted desmoglein (1) antibodies confirming a diagnosis of pemphigus foliaceus.

[FIGURE 1-4 OMITTED]

She was treated with tetracycline 500 mg three times a day and niacinamide 500 mg four times a day due to logistical complications of other therapies. In addition, fluocinolone acetonide oil (Dermasmoothe FS) was applied to her scalp at night under a shower cap and washed out in the morning with fluocinolone acetonide solution 0.01%.

The scalp rash resolved over several months and her treatment was discontinued. Her body rash resolved over the course of several months and her tetracycline and niacinamide were tapered by 500 mg each over a six-month period with no recurrence of her skin rash.

Discussion

The patient's scalp rash, PKU, and therapeutic course make this case notable. No report has noted coincident PKU and pemphigus foliaceus or tinea amiantacea. Tetracycline and niacinamide is rarely used in this condition. This article outlines the uses and mechanisms of this therapy with particular attention to its use in pemphigus, treatments, and scalp findings of pemphigus foliaceus and the dermatological manifestations of PKU.

Tetracyclines and niacinamide are used to treat various skin conditions1. Nicotinamide inhibits polymorphonuclear cell and eosinophil chemotaxis and blocks IgE-mediated histamine release and mast cell degranulation leukocyte protease release. Both agents inhibit lymphocyte blast transformation in vitroz.

For bullous pemphigoid, tetracycline and niacinamide is widely used, similar in effect to prednisone and mostly side effect free (3). They have been used to treat cicatricial pemphigoid (4), linear IgA dermatosis (5), ocular cicatricial pemphigoid (6), erythema elevatum diutinum (7), dermatitis herpetiformis (8) (sometimes with heparin (9)), and lichen planus pemphigoides (10).

Minocycline is also used. Minocycline and nicotinamide have treated pemphigoid gestationis (11), pemphigus vegetans with esophageal involvement (12), bullous pemphigoid (13), and oral pemphigus vulgaris (14). Minocycline can induce side effects. Severe drug-induced pneumonitis occurred with minocycline and nicotinamide therapy of a bullous pemphigoid (15).

Various treatments exist for pemphigus foliaceus. Mild pemphigus vulgaris and pemphigus foliaceus can be treated with topical corticosteroids (16). Oral corticosteroids, dapsone, cyclophosphamide, and azathioprine are often used. Severe cases can be treated with extracorporeal photochemotherapy (17), mycophenolate mofetil (18), and intravenous immunoglobulins (19). Hydroxychloroquine is another option (20) especially in children with photodistributed lesions (21).

Tetracycline alone (22) or with niacinamide can treat pemphigus. They have effectively treated pemphigus foliaceus alone (23) and associated with bullous impetigo (24). They might help long-term treatment of pemphigus vulgaris (23). One study has questioned its effectiveness as monotherapy for pemphigus variants (26). This combination is not the standard therapy for pemphigus, as it is for bullous pemphigoid.

Pemphigus variants commonly involve the scalp (27). Childhood pemphigus foliaceus typically causes scalp erythema and scaling; sometimes, blisters and oozing are present, commonly misdiagnosed as impetigo or seborrheic dermatitis (28). While this patient's scalp was not biopsied, the crusts on erythematous plaques were consistent with pemphigus foliaceus. After resolution of the body and the completion of oral treatment concluded the scalp rash did not recur. Even if her tinea amiantacea was a manifestation of seborrheic dermatitis, it would be of note because it occurred with PKU and pemphigus foliaceus of the body.

Classical PKU is caused by a deficiency of phenylalanine hydroxylase, resulting in increased levels of phenylalanine and derangements in aromatic amino acid metabolism. PKU has been linked to seborrheic dermatitis (29). This link might relate to the increased sebum excretion rate in female PKU patients, an increase that may be related to a depletion of midbrain dopamine and release of the sebotrophic hormone (30). It might also relate to and its concomitant problems in biotin metabolism. PKU is also linked to pseudoscleroderma (31), hypopigmentation (32), reticulosarcoma-like skin lesions (33), dysgammaglobulinemia (34), and iatrogenic skin lesions (35). Macular anetoderma, secondary to lichen sclerosus et atrophicus, acanthosis nigricans with apocrine hydrocystoma (36), and infantile acrodermatitis enteropathica (37) have occurred with PKU.

This case underlines an interesting (if chance) association of skin diseases and the need to be flexible in dermatological therapy. Due to their mild side effects, tetracycline and niacinamide merit a trial in patients with mild pemphigus foliaceus in whom topical medications and strong oral medications are difficult to deploy.

References

(1.) Chaidemenos GC. Tetracycline and niacinamide in the treatment of blistering skin diseases. Clin Dermatol 2001; 19:781-5.

(2.) Wolverton SE. Comprehensive Dermatologic Drug Therapy. Philadelphia: W.B. Saunders Company, 2001:426-444.

(3.) Khumalo NP, Murrell DF, Wojnarowska E Kirtschig G. A systematic review of treatments for bullous pemphigoid. Arch Dermatol 2002; 138:385-9.

(4.) Kreyden OP, Borradori L, Trueb RM, Burg G, Nestle FO. Successful therapy with tetracycline and nicotinamide in cicatricial pemphigoid. Hautarzt 2001; 52:247-50.

(5.) Chaffins ML, Collison D, Fivenson DE Treatment of pemphigus and linear IgA dermatosis with nicotinamide and tetracycline: a review of 13 cases. J Am Acad Dermatol 1993; 28:998-1000.

(6.) Dragan L, Eng AM, Lam S, Persson T. Tetracycline and niacinamide: treatment alternatives in ocular cicatricial pemphigoid. Cutis 1999; 63:181-3.

(7.) Kohler IK, Lorincz AL. Erythema elevatum diutinum treated with niacinamide and tetracycline. Arch Dermatol 1980; 116:693-5.

(8.) Zemtsov A, Neldner KH. Successful treatment of dermatitis herpetiformis with tetracycline and nicotinamide in a patient unable to tolerate dapsone. J Am Acad Dermatol 1993;28:505-6.

(9.) Shah SA, Ormerod AD. Dermatitis herpetiformis effectively treated with heparin, tetracycline and nicotinamide. Clin Exp Dermatol 2000; 25:204-5.

(10.) Fivenson DP, Kimbrough TL. Lichen planus pemphigoides: combination therapy with tetracycline and nicotinamide. J Am Acad Dermatol i997;36:638-40.

(11.) Loo WJ, Dean D, Wojnarowska E A severe persistent case of recurrent pemphigoid gestationis successfully treated with minocycline and nicotinamide. Clin Exp Dermatol 2001;26:726-7.

(12.) Sawai T, Kitazawa K, Danno K, Sugie N, Machizuki T, Sugiura H, Uehara M. Pemphigus vegetans with oesophageal involvement: successful treatment with minocycline and nicotinamide. Br J Dermatol 1995; 132:668-70.

(13.) Kawahara Y, Hashimoto T, Ohata K. Eleven cases of bullous pemphigoid treated with combination of minocycline and nicotinamide. Eur J Dermatol 1996:6; 427429.

(14.) Hausermann P, Gutersohn T, Beltraminelli H, Schiller P, Buchner SA, Rufli T. Oral pemphigus vulgaris. Successful treatment with minocycline and nicotinamide. Hautarzt 2002; 53:813-5.

(15.) Hara H, Fujitsuka A, Morishima C, Kurihara N, Yamaguchi Z, Morishima T. Severe drag-induced pneumonitis associated with minocycline and nicotinamide therapy of a bullous pemphigoid. Acta Derm Venereol 1998; 78:393-4.

(16.) Dumas V, Roujeau JC, Wolkenstein P, Revuz J, Cosnes A. The treatment of mild pemphigus vulgaris and pemphigus foliaceus with a topical corticosteroid. Br J Dermatol 1999; 140:1127-9.

(17.) Azana JM, de Misa RF, Harto A, Ledo A, Espana A. Severe pemphigus foliaceus treated with extracorporeal photochemotherapy. Arch Dermatol 1997; 133:287-9.

(18.) Katz KH, Marks JG Jr., Helm KE pemphigus foliaceus successfully treated with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol 2000; 42:514-5.

(19.) Toth GG, Jonkman ME Successful treatment of recalcitrant penicillamine-induced pemphigus foliaceus by low-dose intravenous immunoglobulins. Br J Dermatol 1999; 141:583-5.

(20.) Hymes SR, Jordon RE. pemphigus foliaceus. Use of antimalarial agents as adjuvant therapy. Arch Dermatol 1992; 128:1462-4.

(21) Metry DW, Hebert AA, Jordon RE. Nonendemic pemphigus foliaceus in children. J Am Acad Dermatol 2002; 46:419-22.

(22.) Calebotta A, Saenz AM, Gonzalez F, Carvalho M, Castillo R. Pemphigus vulgaris: benefits of tetracycline as adjuvant therapy in a series of thirteen patients. Int J Dermatol 1999; 38:217-21.

(23.) Chaffins ML, Collison D, Fivenson DE Treatment of pemphigus and linear IgA dermatosis with nicotinamide and tetracycline: a review of 13 cases. J Am Acad Dermatol 1993; 28:998-1000.

(24.) Izu K, Yamamoto O, Masuyuki K, Asahi M, Komai R, Yasumoto S, Hashimoto T. A case of pemphigus foliaceus associated with bullous impetigo successfully treated with tetracycline and nicotinamide. J UOEH 2001; 23:59-67.

(25.) Fimiani M, Rubegni P, Flori ML, De Aloe G, Andreassi L. Treatment of pemphigus senilis with tetracycline plus nicotinamide: long term follow-up. J Am Geriatr Soc 1997; 45:256-8.

(26.) Alpsoy E, Yilmaz E, Basaran E, Yazar S, Cetin L. Is the combination of tetracycline and nicotinamide therapy alone effective in pemphigus? Arch Dermatol 1995; 131:1339-40.

(27.) Yamamoto S, Kanekura T, Gushi A, Sekiyama M, Shimada T, Shimada K, Kanzaki T. A case of localized pemphigus foliaceus. J Dermatol 1996; 23:893-5.

(28.) Jones SK, Schwab HP, Norris DA.. Childhood pemphigus foliaceus: case report and review of the literature. Pediatr Dermatol 1986; 3:459-63.

(29.) Schulpis KH, Nyalala JO, Papakonstantinou ED, Leondiadis L, Livaniou E, Ithakisios D, Georgala S. Biotin recycling impairment in phenylketonuric children with seborrheic dermatitis. Int J Dermatol 1998; 37:918-21.

(30.) Burton JL, Goolamali SK, Shuster S. An abnormality in sebaceous function in phenylketonuria. Br Med J 1975;1 (5948):19-20.

(31.) Nova MP, Kaufman M, Halperin A. Scleroderma-like skin indurations in a child with phenylketonuria: a clinicopathologic correlation and review of the literature. J Am Acad Dermatol 1992; 26:329-33.

(32.) Bechelli LM, Goncalves RP, Tanaka AM, Pagnano PM. Cutaneous dyschromia in three cases of phenylketonuria. Quantitative ultrastructural study of the basal layer of the epidermis. Ann Dermatol Venereol 1978; 105:165-73.

(33.) Exss R, Weber HP. Reticulosarcoma-like skin lesions in phenylketonuria. Monatsschr Kinderheilkd 1975; 123:120-3.

(34.) Riva E, Fiocchi A, Agostoni C, Biasucci G, Sala M, Banderali G, Luotti D, Giovannini M. PKU-related dysgammaglobulinaemia:the effect of diet therapy on IgE and allergic sensitization. J Inherit Metab Dis 1994; 17:710-7.

(35.) Francois B, Diels M, de la Brassinne M. Iatrogenic skin lesions in phenylketonuric children due to a low tyrosine intake. J Inherit Metab Dis 1989; 12 Suppl 2:332-4.

(36.) Zeligman I, Houston FM, Scott CI. Macular anetoderma, secondary to lichen sclerosus et atrophicus, acanthosis nigricans and apocrine hydrocystoma in a man with phenylketonuria. Birth Defects Orig Artic Ser 1971; 7:256-8.

(37.) Ermacora E, Benelli MG. Acrodermatitis enteropathica in a phenylketonuric infant. Minerva Dermatol 1968; 43:523-4.

NOAH SCHEINFELD MD DEPARTMENT OF DERMATOLOGY, ST. LUKE'S ROOSEVELT HOSPITAL CENTER NEW YORK, NY

ADDRESS FOR CORRESPONDENCE:

Noah Scheinfeld, MD

Department of Dermatology

St. Luke's Roosevelt Hospital Center

090 Amsterdam Ave. Suite 11D

NYC, NY 10025

E-mail: Scheinfeld@rcn.com

Phone: (212) 523-3888

Fax: (212) 523-3808

COPYRIGHT 2003 Journal of Drugs in Dermatology
COPYRIGHT 2003 Gale Group