Confluent and reticulated papillomatosis: Response to minocycline

Confluent and reticulated papillomatosis: Response to minocycline CPT Andrew D. Montemarano, MC, USA, a Mitra Hengge, MD, b COL Pumima Sau, MC, USA, a and MAJ Mark Welch, MC, U S A c Washington, D.C.,

Bethesda, Maryland, and Heidelberg, Germany Background: Confluent and reticulated papillomatosis (CRP) of Gougerot and Carteaud is an uncommon disorder of unknown cause for which a variety of Ireatments have been proposed. Objective: We attempted to evaluate the effectiveness of oral minocycline. Methods: Nine patients with CRP were treated with oral minocycline, 50 mg twice a day, for 6 weeks. The average follow-up period was 11 months. Recurrence rate, side effects, and effectiveness of therapy were assessed. Results: All patients except two had a 90% to 100% response to therapy. Recurrences were noted in three patients, all of whom responded to re-treatment with minocycline. None of the nine patients had an adverse reaction. Conclusion: Minocycline, 50 mg twice a day, is safe and effective for CRP. (J AM ACAD DERMATOL1996;34:253-6.) In 1927, Gougerot and Carteaud I described the clinical features of confluent and reticulated papillomatosis (CRP). Histologic examination reveals hyperkeratosis with thinning of the granular layer, acanthosis, and papillomatosis. The dermis shows perivascular inflammation. Electron microscopic studies have shown an alteration of comified cell structures, an increase in the number of Odland bodies in the stratum granulosum, and an increased number of melanosomes in the stratum comeum. 2 Hamilton et al.3 reviewed 16 patients with CRP and found a mean age at onset of 21 years (range, 14 to 36 years), a predilection for blacks, and a femaleto-male ratio of 2.5:1. The cause of CRP is unknown. Miescher 4 proposed that CRP was a disorder of kerafinization and cited successful treatment with oral retinol. Successful treatment with etrefinate and isotretinoin has been offered as further evidence to support a defect in From the Department of Dermatology, Walter Reed Army Medical Center, Washingtona; in private practice, Bethesdab; and the Dermatology Service, 95th Combat Support Hospital, Heidelberg. e The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the United States Army. Reprints not available from the authors. Correspondence: CPT Andrew D. Montemarano, Dermatology Service, Walter Reed Army Medical Center, Washington, DC 20307. 16/1/68158

keratinization. 5-7However, no defect has been found. Many authors have noticed an association with endocrine imbalance. Obesity, menstrual irregularities, diabetes, pituitary abnormalities, and thyroid disease have been observed. 8 A clinical resemblance to tinea versicolor in some patients, and the finding of yeast forms on K O H examination, led to a proposal that C R P is an abnormal host response to Malassezia furfur (Pityrosporum orbiculare).9 Successful treatment with topical selenium sulfide 2.5% has supported this contention. 9-11 Many other treatments have resulted in variable success. These include salicylic acid, urea, hydroquinone, low-voltage radiation, miconazole cream, clotrimazole cream, oral ketoconazole, liquid nitrogen, 5-fluorouracil, correction of any underlying endocrine abnormality, topical steroids, abrasive pads, oral tetracycline, and oral erythromycin. 8 No single treatment is considered superior in all patients. In response to anecdotal reports of success with oral minocycline, 12-16 we attempted to determine efficacy prospectively. MATERIAL AND METHODS

Nine patients with CRP were included. The patients were interviewed regarding onset of disease, family history, symptoms, coexistent diseases, menstrual history, medications, prior treatments, and response to therapy. Ix)cation of the lesions, photosensitivity, obesity, and 253

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e t al.

T a b l e I. Summary of patients Assorted

Follow-up

Responseto minocydine*

period/

Laboratory

Recurrences

evaluation

Case

Age (yr)/

No.

Sex/~ee

Duration

1

23/F/ Asian

4 yr

Acanthosis nigricans, diabetes, obesity

Selenium sulfide 2.5% (75% improved; recurred in 2 mo)

75% impmvement; no change in Acanthosis nigricans

4 mo/none

2

27/M/ black

4 mo

Obesity, seizure disorder, phenytoin

None

100%

7 mo/none

3

21/M/ black

3 yr

Obesity

None

27 mo/none

4

36/M/ black

10 yr

KOH, neg

28/M/ black

3 mo

Selenium sulfide 2.5% (no change) None

4 mo/none

5

Pruritus, acanthosis nigricans, obesity None

90% (hyperpigmented macules) 90% (hyperpigmented macules)

Glucose, 161 mg/dl TFFs, nl Bact Cx, NG Fung Cx, NG KOH, neg Insulin, 268 ~tU/ml Glucose, 92 TFTs, nl Bact Cx, NG Fung Cx, NG KOH, neg KOH, neg

11 mo/at 10 mo

6

26/M/ black

13 mo

None

None

7

15/M/ black

7 mo

None

None

100%

2 mo/none

8

18/M/ black

3 yr

Obesity

100%

26 months/ treated at 16 mo

9

42/F/ white

8 mo

Obesity

Selenium sulfide 2.5% (no change) None

Glucose, 94 mg/dl KOH, neg Glucose, 96 mg/dl TFTs, nl Bact Cx, NG Fung Cx, NG KOH, neg Glucose, 76 mg/dl TF'I's, nl Bact Cx, NG Fung Cx, NG KOH, neg KOH, neg

100%

16 mo/treated every 3-5 mo

Medications

Prior trealments

50% (scaly papules and macules) 90% (hyperpigmented macules)

3 mo/none

Fung Cx, NG KOH, neg

Bact Cx, Bacterialculture;Fung Cx, fungalculture;NG, no growth;hi, normal;Tb'Ts, thyroidfunctiontests.

*50 mg p.o.b.i.d, for 45 days.

presence of acanthosis nigricans were noted. Laboratory evaluations included potassium hydroxide preparations, bacterial and fungal cultures from skin scrapings, randomly obtained serum glucose levels, thyroid function tests, and insulin levels if appropriate. All but two patients underwent biopsy. All patients were treated with oral minocycline, 50 mg

twice a day, for 6 weeks. Any previous therapies were stopped at least 1 month earlier. If a partial response was noted after 6 weeks, another 6-week course was offered. Response to treatment was evaluated at 4 to 6 weeks. If the patient could not return and the response was complete, follow-up was obtained by telephone. Re-

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Montemarano et al.

255

Fig. 1. Case 8. A, Confluent reticulated papillomatosis on back of black man, before treatment. B, After 4 weeks oral minocycline, 50 mg twice daily, the patient had 90% response. After minocycline for 2 additional weeks, lesions completely cleared.

sponse was assigned a numeric value as follows: 0 = No improvement; 25%=noticeable decrease in surface area of lesions; 50% = at least half of the lesions healed; 75% = almost all of the palpable lesions healed; 90% = no more palpable lesions, only posfinflammatory hyperpigrnentation; 100% =without evidence of disease. RESULTS Demographic data and results are summarized in Table I. Seven men and two women were treated. The average age at diagnosis was 26.2 years (range, 15 to 42 years). Seven of the patients were black, one was Asian, and one was white. One patient (case 9) described a similar eruption in her son, but he was unavailable for examination. None of the other patients had a family history of the disease. The duration of disease varied from 3 months to 10 years. Fivepatients had their serum glucose levels evaluated. One patient (case 1) was found to have diabetes associated with hyperinsulinemia. She also had axiUary acanthosis nigricans. Only one other patient was found to have acanthosis niglicans (case 4). He was obese, but his serum glucose level was normal (insulin levels were not measured). Four patients underwent thyroid studies, and all results were nor-

mal. None of the women had menstrual irregularities. Two thirds of the patients were obese. In all nine patients potassium hydroxide preparation was negative. Bacterial and fungal cultures were negative in the four patients thus evaluated. No evidence of photosensitivity was found. Only one patient had associated pruritus. All patients responded within 6 weeks. One patient (case 5) was treated for an additional 6 weeks with no further improvement. Four patients completely healed, three had a 90% response, One had a 75% response, and one had a 50% response. This last patient decided to forego further treatment. No adverse reactions to minocycline were observed. The average observation period was 11.1 months (range, 2 to 27 months). Three cases recurred. One patient (case 8) had been disease free and active in college football for 18 months after treatment (Fig. 1). During a 3-month period he gained 20 pounds and noted a recurrence. He was treated at a remote facility with tetracycline and the condition responded, albeit by his accounts, much more slowly than with minocycline. Another patient's skin lesions (case 9) completely cleared with minocycline treatment, but recurred every 3 to 5 months. Each recurrence completely cleared with a 1-week course of minocycline. The patients with

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Montemarano et aL

residual hyperpigmented macules noticed fading over time. DISCUSSION

Minocycline, a lipophilic synthetic derivative of tetracycline, was proposed as treatment of C R P in 1965 by Carteau& 12 A n additional five patients who responded to minocycline have been reported. 13-16 Initially, all patients' disease cleared with minocycline, 100 mg/day, but recurrences were common. Poskitt and Wilkinson 16described one patient whose condition cleared with minocycline, 100 mg/day. Subsequent recurrences were controlled with 50 m g every other day. Although treatment failures tend to be underreported, we have not encountered any documented case of C R P unresponsive to minocycline. Reluctance to treat with minocycline m a y stem from the lack o f any clear reason w h y it should work. A bacterial cause of C R P has never been documented. The frequent onset of C R P in adolescents or young adults, the occasional association with obesity, and the predilection for the seborrheic areas o f the trtmk suggest an association with sebum production or an alteration of sebum by resident bacteria. Minocycline is effective in ameliorating acne, in part, by inhibiting the growth of Propionibacterium acnes, a normal inhabitant of skin. 17 It m a y be that C R P represents an abnormal host response to P. acnes or other resident flora and that the effectiveness of minocycline in C R P stems from its antibiotic properties. The tetracyclines are also effective in m a n y noninfectious conditions. Humbert et al. 17 reviewed their anfiinflammatory and immunosuppressive properties. They have been shown to inhibit lymphocyte transformation, suppress antibody production, suppress neutrophil chemotaxis, inhibit complement, and inhibit lipase and collagenase activity. In addition, tetracyclines have been shown to inhibit protein synthesis in mammalian tissue by competing with amino-acyl-transfer R N A for binding to the ribosome messenger R N A complex. 18 Cells with rapid protein synthesis are most susceptible to this form of inhibition. Although our' study was neither controlled nor double blinded, we believe that minocycline is a safe

Journal of the American Academy Of Dermatology February 1996

and effective therapy for CRP. The efficacy m a y be due to a~, antianabolic, immunosuppressive, or antibiotic effect. REFERENCES

1. Gougerot H, Carteand A. Papillomatose pigmentee inominee. Bull Soc Fr Derm Syph 1927;34:719-21. 2. Jimbow M, Talpash O, Jimbow K. Confluent and reticulated papillomatosis: clinical, light, and eleclron microscopic studies. Int J Dermatol 1992;31:480-3. 3. Hamilton D, Tavafoghi V, Shafer JC, et al. Confluent and reticulated papillomatosis of Gougerot and Carteaud. J AM ACADD~MATOL 1980;2:401-10. 4. Miescher G. Erythrokeratodermia papillaris et reticularis. Dermatologica 1954;108:303-14. 5. Buynzeel-Koomen CAFM, DeWit RFE. Confluent and reticulated papillomatosis successfully treated with the aromatic etretinate. Arch Dermatol 1984;120:1236-7. 6. Hodge JA, Ray MC. Confluent and reticulated papillomatosis: response to isotretinoin.J AMACADD~VL~TOL1991; 24:654. 7. Baalbaki SA, Malak JA, A1-Khars MAA. Confluent and reticulated papillomatosis: treatment with etretinate. Arch Dermatol 1993;129:961-3. 8. Nordby AC, Mitchell AJ. Confluent and reticulated papillomatosis responsive to selenium sulfide. Int J Dermatol 1986;25:194-9. 9. Roberts SOB, Lachapelle JM. Confluent and reticulated papillomatosis and Pityrosporum orbiculare. Br J Dermatol 1969;81:841-5. 10. Yesudian P, Kamalam S, Razack A. Confluent and reticulated papillomatosis: an abnormal host response to Malassezia furfur. Acta Derm Venereol (Stockh) 1973; 53:381-4. 11. Friedman SJ, Albert HL. Confluent and reticulated papillomatosis of Gougerot and Carteaud: treairnent with selenium sulfide lotion [Letter]. I AM ACAO DERMATOL 1986;14:280-2. 12. Carteaud MA. Un cas de papillomatose papuleuse confluent et reticulee de Gougerot et Carteaud completement blanchie par antibiotiques. Bull Soc Fr Derm Syph 1965; 72:396-7. 13. Petit A, Evenou P, Civatte J. Papillomatose confluent et reticulee de Gougerot et Carteaud tmitement par minocycline. Ann Dermatol Venereol 1989;116:29-30. 14. Sassolas B, Plantin P, Guillet G. Confluent and reticulated papillomatosis: treatment with minocycline. J AM ACAD DERMATOL1992;26:501-2. 15. Fuller LC, Hay RJ. Confluent and reticulated papillomatosis of Gougerot and Carteaud clearing with minocycline. J Invest Dermatol 1994;19:343-5. 16. Poskitt L, Wilkinson JD. Clearance of confluent and reticulated papillomatosis of Gougerot and Carteaud with minocycline. Br J Dermatol 1993;129:351-3. 17. Humbert P, Treffel P, Chapuis J-F, et al. The teWacyclines in dermatology. J AM ACADDERMATOL1991;25:691-7. 18. Beard NS, Armentrout SA, Weisberger AS. Inhibition of mammalian protein synthesis by antibiotics. Pharmacol Rev 1969;21:213-43.