Significant Absorption of Topical Tacrolimus in 3 Patients with Netherton Syndrome

OBSERVATION Significant Absorption of Topical Tacrolimus in 3 Patients With Netherton Syndrome

Angel Allen, MD; Elaine Siegfried, MD; Robert Silverman, MD; Mary L. Williams, MD; Peter M. Elias, MD; Sarolta K. Szabo, MD; Neil J. Korman, MD, PhD

Background: Tacrolimus is a macrolide immunosup- limus in organ transplant recipients. None of these pressant approved in oral and intravenous formulations patients developed signs or symptoms of toxic effects of for primary immunosuppression in liver and kidney trans- tacrolimus. plantation. Topical 0.1% tacrolimus ointment has recently been shown to be effective in atopic dermatitis for Conclusions: Patients with Netherton syndrome have children as young as 2 years of age, with minimal sys- a skin barrier dysfunction that puts them at risk for in- temic absorption. We describe 3 patients treated with topi- creased percutaneous absorption. The Food and Drug Ad- cal 0.1% tacrolimus who developed significant systemic ministration recently approved 0.1% tacrolimus oint- absorption. ment for the treatment of atopic dermatitis. Children with Netherton syndrome may be misdiagnosed as having Observation: Three patients previously diagnosed as atopic dermatitis. These children are at risk for marked having Netherton syndrome were treated at different cen- systemic absorption and associated toxic effects. If topi- ters with 0.1% tacrolimus ointment twice daily. Two pa- cal tacrolimus is used in this setting, monitoring of se- tients showed dramatic improvement. All patients were rum tacrolimus levels is essential. found to have tacrolimus blood levels within or above the established therapeutic trough range for oral tacro- Arch Dermatol. 2001;137:747-750

ETHERTON syndrome is taneous absorption of the drug, with serum an autosomal recessive levels well above the therapeutic range. disorder characterized by congenital erythro- REPORT OF CASES derma, hair shaft de- Nfects, frequent infections, poor growth, and CASE 1 food allergies. The gene defect was recently localized to chromosome 5q32 and A 5-year-old boy had been born prema- identified as a mutation in the SPINK5 turely and had had congenital erythro- gene, encoding the serine protease inhibi- derma complicated by Staphylococcus au- tor LEKTI (lymphoepithelial Kazal-type reus sepsis. Continuing problems beyond related inhibitor).1 the neonatal period included erythro- From the Department of The pathognomonic cutaneous find- derma with scaling scalp, sparse hair, fre- Dermatology, Saint Louis ing in Netherton syndrome, ichthyosis lin- University Health Sciences quent otitis media, recurrent sinusitis, and Center, St Louis, Mo (Drs Allen earis circumflexa, develops in 75% of cases poor growth. Netherton syndrome was di- and Siegfried); Departments of but is not usually evident in infancy or agnosed at 9 months of age by demonstra- 2 Pediatrics and Dermatology, early childhood. A more common pre- tion of the pathognomonic hair shaft de- University of Virginia, McLean senting sign is generalized redness and fect, trichorrhexis invaginata. Initially, his (Dr Silverman); Department of scaling, which has been mistaken for atopic skin care regimen consisted of daily bath- Dermatology, University of dermatitis. The erythroderma is often ing with Cetaphil (Galderma Laborato- California–San Francisco widespread and resistant to therapy. A re- ries, LP, Paris, France) and frequent use (Drs Williams and Elias); cent report described a 20-year-old man of Aquaphor (Beiersdorf Inc, Wilton, Dermatology Service, Veterans with ichthyosis linearis circumflexa who Conn). He was unavailable for follow-up Affairs Medical Center, improved dramatically with topical tacro- care from ages 3 to 5 years. San Francisco (Dr Elias); 3 and Case Western Reserve limus treatment. We describe 3 children At age 5 years, his erythroderma was University/University Hospitals with Netherton syndrome and erythro- unresponsive to conservative topical thera- of Cleveland, Cleveland, Ohio derma treated with 0.1% tacrolimus oint- pies, including ketoconazole shampoo and (Drs Szabo and Korman). ment who experienced significant percu- 2.5% tar ointment, as well as more aggres-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 sive short trials with limited applications of lactic and sali- tolerable stinging and exudative erythroderma, which sub- cylic acid lotion and 0.1% tazarotene ointment alone and sided after 1 week without the medication. Results of patch in combination with a class 1 topical corticosteroid. Ag- tests with the study drug and the extemporaneous com- gressive treatments were used on limited areas for a maxi- pound ointment were negative. Another trial of propri- mum of 1 week because of concern about percutaneous etary 0.1% tacrolimus ointment was applied to one arm absorption. We treated this patient in a double-blinded twice a day for 7 days, with the same adverse reaction. A fashion with extemporaneously formulated 0.1% tacro- tacrolimus level determined within 48 hours of the last limus in white petrolatum twice daily on one side of the application was 23 ng/mL. Complete blood cell count, scalp and face and white petrolatum on the other side. renal function, and hepatic function were normal. The He had a marked decrease in crusting, scale, and ery- patient did not tolerate retreatment with extemporane- thema on both sides, but the tacrolimus-treated side was ously compounded 0.03% tacrolimus ointment. A 24- noted at 3-week and 8-week follow-up visits to have near- hour postapplication drug level was 8.3 ng/mL. She elected complete clearing. A total of 15 g of tacrolimus oint- to discontinue treatment with tacrolimus ointment. ment was then applied sparingly to his trunk, shoul- ders, scalp, and face twice daily. On day 5, whole-blood CASE 3 tacrolimus level was 37.2 ng/mL 2 hours after treatment (therapeutic trough range in organ transplant recipi- A 3-year-old boy had been born with facial erythema and ents, 5-20 ng/mL). Care was taken to draw the blood from a scaly patch on his left wrist. During the first week of a site that had not been treated for 2 days before the phle- life, he had developed more widespread erythematous, botomy. One week later, a second 2-hour postdose drug polycyclic, and serpiginous plaques with migratory, hy- level was 19 ng/mL with the patient receiving the same perkeratotic, double-edged peripheral scaling. At birth, dose of medication. Despite these levels, his blood pres- he had had long dark hair, which fell out after a few weeks sure, serum electrolyte levels, glucose level, complete and was replaced by sparse, brittle hair. Infancy and child- blood cell count, serum urea nitrogen level, and serum hood had been complicated by frequent otitis media and creatinine level remained within normal limits. Subse- externa; allergies to spinach, peanuts, milk, and eggs; and quently, the drug was applied twice a week, only to the erythroderma. The patient was only minimally respon- most severely involved areas, the scalp and face. On this sive to numerous topical corticosteroid preparations and regimen, postapplication blood levels monitored at 2-day antihistamines. The diagnosis of Netherton syndrome had trough times were less than 1.5 ng/mL (lower limit of been confirmed at age 2 years, when trichorrhexis in- quantitation for the assay). vaginata was found on light microscopic examination of the patient’s hair. CASE 2 At age 3 years, the patient was deemed eligible for inclusion in a clinical trial of 0.1% tacrolimus ointment A 14-year-old girl presented with trichorrhexis invagi- twice daily for the treatment of atopic dermatitis (Fu- nata, short stature, patches of ichthyosis linearis circum- jisawa Healthcare, Inc, protocol 99-0-054). The proto- flexa, and widespread congenital erythroderma associ- col not did include monitoring of laboratory measures. ated with severe pruritus and elevated IgE level. Her An average of 3 g was spread over the body and scalp with dermatitis and pruritus had been treated long-term with each application. Baseline and follow-up blood pres- applications of 0.1% triamcinolone acetonide ointment sures remained within normal limits (measured with an since early infancy. During the preceding 5 years, her age-appropriate cuff, 80/50 mm Hg at baseline and 90/55 course had been complicated by recurrent staphylococ- mm Hg at his 6-month visit). The patient experienced cal and streptococcal skin infections, flares of her eryth- rapid improvement in his skin along with decreased pru- roderma, and poor growth, falling below the fifth per- ritus and slow regrowth of his hair. After 8 months of centile for age. At chronologic age 10 years 5 months, intermittent therapy (interrupted by two 2-week courses her bone age was 6 years 10 months, which was delayed of systemic corticosteroids), a blood level was obtained 2 SDs below the mean. Adrenocortical suppression was to monitor for systemic absorption. The level, 10.2 ng/ documented, with a low morning cortisol level of 13.8 mL, was determined 30 hours after the last application nmol/L (reference range, Ͼ118.6 nmol/L). She was sub- of medication from a site that had not been treated for sequently given a lower-potency topical corticosteroid 2 days before phlebotomy. Complete blood cell count, (fluocinolone oil [Derma-smoothe FS; Hill Dermaceuti- renal function, and hepatic function were normal. The cals, Inc, Sanford, Fla]) and growth hormone replace- patient’s parents elected to discontinue use. ment, resulting in a 6-cm growth spurt during 9 months. At age 12 years, she was treated with extemporane- COMMENT ously compounded 0.1% tacrolimus ointment applied to one leg twice a day for 1 month, resulting in marked im- Despite dramatic clinical improvement with topical ta- provement. For the next 6 months, she applied the com- crolimus in these 3 cases, the risk of systemic exposure pounded ointment to a larger area, with excellent re- from percutaneous absorption is a serious concern in sponse. Blood levels were not monitored. Two months Netherton syndrome. At 11 hours after dosing, the thera- later, she was enrolled in an open-label study of 0.1% peutic trough range for oral tacrolimus (Prograf; Fu- tacrolimus ointment for the treatment of atopic derma- jisawa Healthcare, Inc) in organ transplant recipients has titis (Fujisawa Healthcare, Inc, Deerfield, Ill; protocol been defined at 5 to 20 ng/mL. The pharmacokinetics of 99-0-054). Three applications of study drug caused in- topically applied tacrolimus have been less well de-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 fined. Percutaneous bioavailability has been estimated at Serine Protease Inhibitor 0.5% to less than 5% on the basis of testing in a limited number of adults with normal skin and a rat model of SC Tryptic Enzyme damaged skin (data on file, Fujisawa Healthcare, Inc). Mean tacrolimus blood concentration–time profiles have sPLA2 Activation Desmosomal Degradation also been determined on the basis of a small number of Degraded Pro-IL-α adults with mild to severe atopic dermatitis and a smaller Processing (33 kd) Enzymes number of affected children, during an 8-day course. Peak Desquamation levels occur at 4 to 8 hours after application. Cumula- Active-IL-1α (17 kd) tive rises in blood levels were not demonstrated during Premature LB Secretion the 8 days.4 Percutaneous pharmacokinetics are un- and Cytolysis SC Thickness Defective known for Netherton syndrome. However, serum levels Barrier determined 2 to 30 hours after application in these cases reflect a high risk of systemic toxic effects. Although no Inflammation clinical signs or symptoms of tacrolimus toxic effects were Suggested pathogenesis of Netherton syndrome. SC indicates stratum

observed, exposure to high blood levels of drug was brief corneum; sPLA2, secretory phospholipase A2; IL, interleukin; and LB, lamellar in cases 1 and 2. The signs and symptoms of tacrolimus body. toxic effects in organ transplant recipients include hy- pertension, renal insufficiency, central nervous system dysfunction, hyperglycemia, and gastrointestinal tract dis- thinning of the stratum corneum. Both of these actions tress.5 These complications occur in 10% to 85% of chil- would result in a defective permeability barrier and could dren with therapeutic trough plasma drug levels, requir- account for the increased absorption and high blood lev- ing dose reduction in 33%.6,7 B-cell lymphoproliferative els of tacrolimus in these cases of Netherton syndrome. disorder is an ominous, long-term complication.8 Finally, serine proteases may also be involved in releas- In normal skin, multiple lamellar sheets of hydro- ing stratum corneum interleukin 1 from its inactive form, phobic lipids surround the nucleate corneocytes, pro- which could lead to the marked inflammation charac- viding a waterproofing shield that retards movement of teristic of Netherton syndrome. Interruption of this in- water and water-soluble substances across the stratum flammatory sequence may account for the beneficial ef- corneum.9 These lipids are delivered to the stratum cor- fects of topical anti-inflammatory drugs, such as neum interstices by a secretory organelle, the epidermal tacrolimus, in this disorder. lamellar body. After secretion, the lipids are further Clinical experience with topical tacrolimus has been metabolized to hydrophobic species and then organized limited to investigational trials in patients older than 2 into repeating membranous arrays, termed lamellar unit years with atopic dermatitis. In a well-controlled study structures. A competent skin barrier requires both suffi- of pediatric patients, 2 to 15 years of age, with moderate cient layers of stratum corneum and mature extracellu- and severe atopic dermatitis, mean and median blood lev- lar lamellar unit structures.10 In Netherton syndrome, els were below the limit of quantitation. Tacrolimus blood the stratum corneum is thin and parakeratotic. The cor- levels in the therapeutic transplant trough range were not neocytes are surrounded by incompletely processed lip- detected in any subject.12 Quantifiable blood levels in- ids and disorganized lamellae, as well as deposits of variably occurred during the first week of therapy and amorphous electron-dense materials.11 These features diminished as patients’ skin disease improved. Infants and would be predictive of a defective barrier, although bar- young children with widespread areas of active disease rier function has not been directly measured. It is well are at highest risk for significant percutaneous absorp- recognized that infants with Netherton syndrome are at tion of the drug. risk for hypernatremic dehydration, presumably On December 8, 2000, tacrolimus ointment (Pro- because of increased free water loss across an impaired topic; Fujisawa Healthcare, Inc) received approval by the skin barrier.11 Similarly, patients with Netherton syn- US Food and Drug Administration for the treatment of drome may be particularly vulnerable to increased per- atopic dermatitis in children as young as 2 years. Before cutaneous absorption of drugs such as corticosteroids marketing, an extemporaneously compounded form of the and tacrolimus. drug had been prescribed in accordance with a published The recent identification of the underlying genetic formula that use tacrolimus capsules.13 With commercial defect in Netherton syndrome, SPINK,3 affecting func- availability, tacrolimus ointment will likely become the tion of an epidermal serine protease inhibitor,1 is con- treatment of choice for children with severe or cortico- sistent with the pathogenic sequence illustrated in the steroid-dependent atopic dermatitis. Because children with Figure. Premature activation of the stratum corneum Netherton syndrome are often either misdiagnosed as hav- tryptic enzyme would result in activation of phospholi- ing only atopic dermatitis or assumed to have atopic der- pase A2. This may stimulate premature lamellar body se- matitis in association with Netherton syndrome, as in our cretion, a unique ultrastructural finding in Netherton syn- cases 2 and 3, it will be important to identify these chil- drome,8 as well as disruption of the plasma membrane, dren correctly before topical tacrolimus therapy is initi- triggering cytolysis or premature cornification. At the same ated. Sparse or brittle hair, frequent infections, and poor time, unchecked activation of the stratum corneum tryp- growth in an erythrodermic child should prompt appro- tic enzyme would lead to premature degradation of cor- priate investigation for Netherton syndrome.14 The risk of neodesmosomes, as well as premature desquamation and cutaneous tacrolimus–associated cutaneous B-cell lym-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 phoproliferative disease can be appreciated only after long- 4. Alaiti S, Kang S, Fiedler V, et al. Tacrolimus (FK506) ointment for atopic derma- term use in a large patient population. Special caution must titis: a phase I study in adults and children. J Am Acad Dermatol. 1998;38:69- 76. be taken with regard to this potential adverse effect when 5. Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and topical tacrolimus is prescribed for patients with a pri- therapeutic use in the management of organ transplantation. Drugs. 2000;59: mary immunodeficiency such as Netherton syndrome. We 323-389. also believe that the potential risk of marked systemic ab- 6. McKee M, Segev D, Wise B, et al. Initial experience with FK 506 in pediatric renal transplant recipients. J Pediatr Surg. 1997;32:688-690. sorption with associated acute toxic effects must be con- 7. Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentra- sidered in any child with extensive skin disease, or any tions and efficacy and toxicity after liver and kidney transplantation. Transplan- infant, regardless of the extent of disease, because of their tation. 1996;62:920-925. high ratio of body surface area to weight.15 If topical ta- 8. Younes BS, McDiarmid SV, Martin MG, et al. The effect of immunosuppression crolimus ointment is prescribed in any of these settings, on posttransplant lymphoproliferative disease in pediatric liver transplant patients. Transplantation. 2000;70:94-99. close monitoring with plasma drug levels is essential. 9. Elias PM, Menon GK. Structural and lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res. 1991;24:1-26. Accepted for publication February 23, 2001. 10. Williams ML, Hanley K, Elias PM, Feingold KR. Ontogeny of the epidermal per- Corresponding author: Elaine Siegfried, MD, Depart- meability barrier. J Invest Dermatol Symp Proc. 1998;3:75-79. 11. Fartasch M, Williams ML, Elias PM. Altered lamellar body secretion and stratum ment of Dermatology, Saint Louis University Health Sci- corneum membrane structure in Netherton syndrome. Arch Dermatol. 1999; ences Center, 1755 S Grand, St Louis, MO 63104 (e-mail: 135:823-832. [email protected]). 12. Paller A, Eichenfield LF, Leung DYM, Stewart D, Appell M, for the Tacrolimus Ointment Study Group. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol. 2001;44 REFERENCES (suppl):S47-S57. 13. Aoyama H, Tabata N, Tanaka M, et al. Successful treatment of resistant facial 1. Chavanas S, Bodemer C, Rochat A, et al. Mutations in SPINK5, encoding a serine lesions of atopic dermatitis with 0.1% FK-506 ointment. Br J Dermatol. 1995; protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25:141-142. 133:494-496. 2. Greene SL, Muller SA. Netherton’s syndrome: report of a case and review of the 14. Pruszkowski A, Bodemer C, Fraitag S, Telliac-Hamel D, Amoric JC, de Prost Y. literature. J Am Acad Dermatol. 1985;13:329-337. Neonatal and infantile erythrodermas: a retrospective study of 51 patients. Arch 3. Suga Y, Tsuboi R, Hashimoto Y, Yoshiike T, Ogawa H. A case of ichthyosis lin- Dermatol. 2000;136:875-880. earis circumflexa successfully treated with topical tacrolimus. J Am Acad Der- 15. Spray A, Siegfried EC. Dermatologic toxicology in children. Curr Probl Derma- matol. 2000;42:520-522. tol. 2000;12:118-122.

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