TINJAUAN PUSTAKA

2.1 Definisi
Dermatitis Herpetiformis (DERMATITIS HERPETIFORMIS) atau Morbus Duhring adalah penyakit autoimun, multisistem, kronis dan residif dengan manifestasi primer pada kulit berupa ruam yang bersifat polimorfik berupa makula eritema, papula, urtika, vesikula atau bula yang tersusun berkelompok dan simetris disertai rasa sangat gatal.^4,5,8  

2.2 Epidemiologi
DERMATITIS HERPETIFORMIS merupakan penyakit dermatitis vesikobulosa yang jarang ditemukan.¹ Insiden dan prevalensi DERMATITIS HERPETIFORMIS tidak diketahui secara jelas. Penelitian di Utah, Amerika, menunjukkan bahwa prevalensi DERMATITIS HERPETIFORMIS 11,2 kasus dari 100.000 populasi. Insidennya lebih sering terjadi pada laki-laki daripada perempuan dengan ratio 2:1.² Berdasarkan umur DERMATITIS HERPETIFORMIS dapat terjadi pada setiap usia tetapi paling sering pada dekade ke-2 sampai ke-4.^2-4 Rata-rata umur onset penderita DERMATITIS HERPETIFORMIS yaitu 40,1 tahun pada laki-laki dan 36,2 tahun pada perempuan.⁹ Berdasarkan ras, penyakit ini jarang terjadi pada bangsa berkulit hitam dan asia.⁴    

2.3 Etiologi dan Patogenesis

Etiologi belum diketahui secara pasti. Predisposisi genetik penyakit ini berupa ditemukannya HLA B8, HLA DR3 dan HLA DQW2.^2,3,5,8 Penyakit ini sudah lama dilaporkan bahwa DERMATITIS HERPETIFORMIS berhubungan dengan kelainan usus halus atau disebut Gluten Sensitive Enteropathy (GSE) yaitu berkisar 70-90% penderita DERMATITIS HERPETIFORMIS mempunyai GSE. Gluten adalah protein yang terdapat pada makanan yang mengandung gandum. ^3,4 Gluten diduga kuat sebagai antigen penyakit DERMATITIS HERPETIFORMIS yang dapat merangsang terbentuknya komplek imun.^2,3,4,5,6,8 Pemberian gluten akan menyebabkan peradangan mukosa usus halus sehingga menimbulkan destruksi vili dan terjadi atrofi mukosa.³   Penyakit DERMATITIS HERPETIFORMIS juga berhubungan dengan penyakit lainnya seperti pada tabel berikut ini:⁹

AUTOIMUN DISORDERS ASSOCIATED WITH DERMATITIS HERPETIFORMIS

Common

Autoimun Thyroid Disease (Tiroiditis Hashimoto)   Limfoma (Enteropathy associated T-Cell Non Hodgkin’s Lymphoma)   IDDM

Uncommon

Pernicious anemia

Rare

Addison’s Disease   Autoimun Chronic  Active Hepatitis   Alopecia areata   Myastenia Gravis   Sarkoidosis   Skleroderma Sjogren’s Sindrome Systemic Lupus Erytematosus   Vitiligo

Tabel 1. Penyakit autoimun yang berhubungan dengan

Dermatitis Herpetiformis⁹

2.4 Imunologi
Pada penderita DERMATITIS HERPETIFORMIS, 85-­90% mempunyai IgA granuler pada dermo-epidermal junction dan 10-15% sisanya mempunyai timbunan IgA linier. Jadi dilihat dari segi imunologis, DERMATITIS HERPETIFORMIS terdiri dari 3 jenis yaitu:
1. DERMATITIS HERPETIFORMIS like dengan IgA linier pada lamina lusida.
2. DERMATITIS HERPETIFORMIS like dengan IgA linier di bawah BMZ (Basal Membrane Zone).
3. True DERMATITIS HERPETIFORMIS dengan IgA granuler.

Pada penderita DERMATITIS HERPETIFORMIS, IgA ditemukan pada seluruh kulit dan juga pada mukosa mulut. Dengan perkembangan antibodi monoklonal dapat ditentukan komposisi subklas IgA yaitu IgA1. Pada penderita DERMATITIS HERPETIFORMIS juga ditemukan rantai J yaitu rantai penggabung IgA polimerik. IgA polimerik lebih sering dihasilkan oleh mukosa. Jadi mungkin dapat disimpulkan bahwa IgA pada DERMATITIS HERPETIFORMIS berasal dari mukosa. Dengan mikroskop imunoelektron terlihat bahwa IgA ditimbun pada papila dermis dekat berkas mikrofibriler. Struktur ini berfungsi sebagai kompleks komponen fibriler yang diselubungi dengan substansia amorf sehingga merupakan sistem serabut mikrofibriler elastin yang abnormal. Pada kulit normal dan perilesi juga ditemukan C3, C5, properdin dan properdin faktor .

Kadang-kadang terlihat juga Clq dan C4. Hanya 25-30% penderita DERMATITIS HERPETIFORMIS yang mempunyai IgA containing circulating immune complex dalam serumnya dengan kadar 0,331-26 ug/ml (n < 0,2 ug/ml) dan kadarnya tidak berhubungan dengan beratnya penyakit. Pembentukan kompleks imun ini dapat dirangsang dengan makanan gandum. Kadarnya meningkat dalam 90-150 menit setelah ingesti gandum. 15-35% penderita DERMATITIS HERPETIFORMIS memiliki antibodi antiretikulin dan antibodi ini hilang setelah diet bebas gluten. In vitro, gliadin gandum terikat pada serabut seperti retikulin pada kulit manusia normal dan papila dermis pada penderita DERMATITIS HERPETIFORMIS. Antibodi antiendomisium terdapat pada 60­-70% penderita DERMATITIS HERPETIFORMIS dan ini bersifat sangat spesifik sehingga menentukan diagnosis walaupun imunofluoresensi langsung dan histopatologis meragukan. Juga terdapat peningkatan insidensi antibodi antigluten, ANA, antibodi antitiroid dan antibodi anti sel parietal gaster. Hal ini menggambarkan banyak reaksi autoimun pada individu dengan haplotipe HLA B8/DR3.³    

2.5 Gejala Klinis
Perjalanan penyakit biasanya bertahap selama berminggu-minggu atau berbulan-bulan, tetapi kadang-kadang eksplosif dalam beberapa jam atau hari. Lesi awal berupa papul eritem atau plakat urtikaria. Papul dengan cepat menjadi vesikel dengan ukuran 1-10 mm. Jarang terdapat bula yang besar. Vesikel atau bula bila tidak pecah menjadi purulen. Biasanya lesi berbentuk herpetiformis dan simetris tetapi dapat juga tersebar. Pada stadium lanjut, mungkin hanya ditemukan krusta, pigmentasi dan skar berkelompok pada tempat predileksi.^3,8 Gejala yang paling menonjol adalah rasa gatal yang hebat. Penderita dapat memperkirakan tempat lesi baru akan timbul dalam 8-12 jam karena sebelumnya terdapat rasa terbakar dan tersengat. Gejala akan berkurang bila vesikel telah pecah.^2,3,4,8,9 Perjalanan penyakit ini panjang, dapat lebih dari 10 tahun. Yang khas ialah terjadinya remisi spontan selama kira-kira 1 minggu dan kemudian tiba-tiba muncul lagi sekelompok lesi. Keadaan umum penderita tidak terpengaruh.³ Predileksi lesi pada DERMATITIS HERPETIFORMIS ialah sebagai berikut:^{2,3,4,8,10,11}

• Daerah ekstensor ekstremitas yaitu tangan, lengan, siku, tungkai, lutut. Pada telapak tangan dan kaki dapat timbul bula coklat (hemoragis) terutama pada daerah yang mendapat tekanan lebih besar.

Gambar 1. Dermatitis herpetiformis pada ekstremitas ekstensor¹⁰

• Punggung bagian atas

Gambar 2. Dermatitis Herpetiformis pada punggung¹¹

• Bokong

Gambar 3. Dermatitis Herpetiformis pada bokong¹¹

• Tempat predileksi lain pada DERMATITIS HERPETIFORMIS yaitu kepala, muka, leher, batas rambut, mulut, bahu, lipat ketiak bagian posterior, dan sakrum. Lesi pada mulut jarang, tetapi penyakit ini dapat mengenai laring dan selaput lendir usus yang akan mengalami atrofi, sehingga didapatkan gejala enteritis berupa diare dan malabsorbsi pada 20% penderita. Lesi pada mukosa jarang terdapat tetapi mungkin timbul terutama bila ditemukan banyak bula.^2,3,4,10

Gambar 4. Dermatitis Herpetiformis pada kepala, muka, leher, bahu, lipat ketiak¹¹

2.6 Diagnosis
Diagnosis DERMATITIS HERPETIFORMIS dapat ditegakkan berdasarkan anamnesis, pemeriksaan fisik dan pemeriksaan penunjang.  

2.6.1 Anamnesis
Penderita DERMATITIS HERPETIFORMIS biasanya mengeluhkan rasa gatal yang hebat dan dapat memperkirakan tempat lesi baru akan timbul dalam 8-12 jam karena sebelumnya terdapat rasa terbakar dan tersengat. Gejala akan berkurang bila vesikel telah pecah.^2,3,4,8,9,10 Penyakit ini tidak mempengaruhi keadaan umum penderita. Perjalanan penyakit biasanya bertahap berminggu-minggu atau berbulan-bulan bahkan dapat lebih dari 10 tahun, tetapi kadang-kadang eksplosif dalam beberapa jam atau hari.^3,8  

2.6.2 Pemeriksaan Fisik
Lesi primer pada kulit berupa ruam polimorfik antara lain makula eritem, papula, urtika, vesikula atau bula yang tersusun berkelompok simetris. Predileksi pada DERMATITIS HERPETIFORMIS biasanya pada daerah ekstensor ekstermitas, punggung bagian atas, bokong, tetapi dapat dijumpai pada kepala, muka, mulut, leher, batas rambut, bahu, lipat ketiak bagian posterior dan sakrum.^{2,3,4,8,9,10,11}

2.6.3 Pemeriksaan Penunjang
Pemeriksaan penunjang yang dapat digunakan untuk menegakkan diagnosis adalah sebagai berikut : ^8,12

• Tes provokasi dengan kalium iodida ( tes KI)

Tes ini tidak spesifik dan telah ditinggalkan karena dapat menyebabkan erupsi yang generalisata. Pemeriksaan KI dilakukan dengan metode patch test yaitu menempelkan kalium iodida pada mukosa mulut selama 12 jam.¹³

• Pada gambaran darah tepi ditemukan peningkatan kadar eosinofil
• Pemeriksaan histopatologik

Ditemukan vesikel atau bula supepidermal, eksodus neutrofil dan beberapa eosinofil pada papiladermis sehingga terihat mikroabses pad tepi vesikula.

• Teknik imunofluoresensi langsung

Bahan pemeriksaan diambil dari lesi dan kulit sekitarnya (perilesi). Pada pemeriksaan ditemukan adanya timbunan Ig A berbentuk granular pada membran basalis dan lebih jelas terlihat di ujung papiladermis. Timbunan IgA ini sering disertai dengan C3. Adanya komplemen ini tidak dipengaruhi oleh dapson, tetapi akan menghilang setelah diet bebas gluten.

Gambar 5. IgA Granuler Penderita DERMATITIS HERPETIFORMIS pada Pemeriksaan Imunoflouresensi Langsung¹²

• Teknik imunofluoresensi tidak langsung

Pada pemeriksaan ini tidak ditemukan antibodi sirkulasi yang bereaksi dengan struktur antigen pada daerah dermoepidermal.   2.7 Diagnosis Banding DERMATITIS HERPETIFORMIS dapat dibedakan dengan :

1. Pemfigus vulgaris ;
2. Pemfigoid bulosa ;
3. Chronic Bullous Diseases of ChilDermatitis Herpetiformisood (C.B.D.C)

C.B.D.C ialah dermatosis autoimun yang biasanya mengenai anak usia kurang dari 5 tahun ditandai dengan adanya bula dan terdapatnya deposit IgA linear yang homogen pada epidermal basement membrane. Kelainan kulit berupa vesikel atau bula, terutama bula. Berdinding tegang di atas kulit yang normal atau eritematosa, cenderung bergerombol, dan generalisata. Mukosa dapat dikenai. Umumnya tidak didapati enteropati seperti pada dermatitis herpetiformis.⁵

1. Pemfigoid gestationis adalah dermatosis autoimun dengan ruam polimorf yang berkelompok dan gatal, timbul pada masa kehamilan dan masa pascapartus.^5,14

Perbedaan pemfigus vulgaris, pemfigoid bulosa dan DERMATITIS HERPETIFORMIS dapat dilihat pada tabel berikut ini :⁵

	Pemfigus Vulgaris	Pemfigoid Bulosa	Dermatitis Herpetiformis
Etiologi   Usia Keluhan  Kelainan kulit   Tanda nikolski   Tempat predileksi   Kelainan mukosa mulut   Histopatologi   Imunofluoresensi Langsung   Enteropati   Peka gluten   HLA   Terapi	Autoimun 30-60 tahun Biasanya tidak gatal Bula berdinding Kendur, krusta bertahan lama +    Biasanya generalisata         60 %   Bula intraepidermal, Akantolisis   Ig G dan komplemen di epidermis -  -  -   Kortikosteroid (prednison 60-150 mg Sehari), sitostatik	Disangka autoimun Biasanya usia tua Biasanya tidak gatal Bula berdinding Tegang  -    Perut, lengan fleksor, lipat paha, tungkai medial     10-40 %   Celah di taut dermal- Epidermal, terutama Eosinofil Ig G seperti pita di membran basal -  -  -  Kortikosteroid (prednison) 40-60 mg	Belum jelas Anak atau dewasa Sangat gatal Vesikel berkelompok, berdinding tegang  -    Simetrik:tengkuk, bahu,lipat ketiak, posterior, lengan ekstensor, daerah sakrum, bokong. jarang   celah subepidermal, terutama neotrofil   Ig A granuler di papila dermis +  +  B8, DQw2  DDS 200-300 mg sehari

Tabel 2. Perbedaan pemfigus vulgaris, pemfigoid bulosa, dan dermatitis herpetiformis⁵

2.8 Penatalaksanaan 2.8.1 Medikamentosa
Terapi medikamentosa utama pada penderita DERMATITIS HERPETIFORMIS yaitu dapson (diaminodifenilsulfon/DDS) dan sulfapiridin.² Dapson merupakan obat yang paling banyak digunakan untuk pengobatan DERMATITIS HERPETIFORMIS karena dapat memberikan perbaikan gejala penyakit ataupun tanda-tanda di kulit.^4,8,15
a) Dapson 
Pemberian dapson dengan dosis permulaan 100-150 mg/hari umumnya menghilangkan pruritus dan mencegah pembentukan lesi baru dalam 24-48 jam. Biasanya dosis tunggal sudah adekuat. Dosis pemeliharaan berkisar antara 25-400 mg/hari untuk dewasa dan 0,5-1 mg/kgBB/hari untuk anak-anak yang berumur diatas 2 tahun dan dicari dosis minimal yang dapat menekan gejala. Lesi baru kadang-kadang masih timbul, tetapi ini bukan merupakan indikasi untuk menaikkan dosis. Dapson hanya menekan gejala penyakit tanpa mempengaruhi penimbunan IgA dan komplemen pada kulit. Penemuan terakhir menyebutkan bahwa dapson menghambat reaksi yodinasi di dalam netrofil sehingga menghambat penglepasan faktor kemotaktik netrofil. Dapson tidak mempengaruhi kelainan intestinal. Teratogenitas obat ini masih dipertanyakan, sebaiknya dihindari selama kehamilan. Efek samping dapson adalah pusing, letargi, neuropati perifer, dan methemoglobinemia (berhubungan dengan dosis). Pada penderita defisiensi G-6-PD (glukosa-6-phospat dehidrogenase), pemberian preparat sulfon dapat menimbulkan anemia hemolitik berat.^2,3
b) Sulfapiridin
Preparat sulfon lain seperti sulfapiridin dapat diberikan pada penderita DERMATITIS HERPETIFORMIS bila penderita tidak tahan dapson, usia lanjut atau penderita yang mempunyai masalah kardiopulmonal. Namun sulfapiridin ini kurang efektif dibandingkan dengan dapson. Dosisnya berkisar antara 1-3 gram/hari atau 3x500 mg/hari. Dosis ini dapat diturunkan sampai 0,5-1 gram/hari. Obat ini juga hanya mempengaruhi lesi kulit tanpa mempengaruhi lesi pada saluran pencernaan. Sulfapiridin sukar larut dalam air sehingga sering menimbulkan nefrolitiasis.³ Sulfapiridin sukar didapat karena jarang diproduksi dan efek toksiknya lebih banyak dibandingkan preparat sulfa lainnya.^5,8
c) Kortikosteroid
Kortikosteroid sistemik tidak dianjurkan karena tidak efektif kecuali pada penderita yang tidak tahan atau alergi preparat sulfon. Antihistamin peroral dan obat-obat topikal dengan khasiat antipruritus seperti preparat yang mengandung mentol, kampor, fenol, dan steroid lokal dapat dipakai untuk mengurangi gejala gatal.⁸  

2.8.2 Diet Bebas Gluten
Diet bebas gluten dapat menyembuhkan kelainan usus halus atau disebut gluten sensitive enteropathy. Dengan diet bebas gluten saja kelainan usus halus ini dapat sembuh 100% dan lesi primer kulit sembuh 82%. Apabila diet bebas gluten diberikan bersama-sama dengan dapson, dosis dapson dapat dikurangi. Biasanya dengan cara ini usus halus menjadi normal kembali dalam 1 hingga 2 bulan.^2,3,6,8 Bahan-bahan makanan yang mengandung gluten seperti gandum, sereal, terigu pati (yang dimodifikasi), gandum havermut, gandum hitam, gandum Belanda, gandum kasar dan kamut atau produk olahannya merupakan makanan terlarang bagi penderita DERMATITIS HERPETIFORMIS yang berhubungan dengan kelainan usus halus atau GSE. Produk olahan yang mengandung gandum seperti:⁶
• Tepung terigu dan tepung yang terbuat dari gandum-gandum tersebut
• Pati (yang dimodifikasi) dari gandum-gandum tersebut (misalnya terigu pati)
• Berbagai macam dan bentuk pasta seperti makaroni, vermiseli, spageti, lasagne
• Bakmi
• Tepung kasar
• Barley
• Couscous
• Bulgur
• Roti
 • Biskuit (kue/roti kering)
• Cracker
• Tepung panir
• Kue-kue
• Kue tar
• Saus dan sup (yang dikentalkan dengan tepung atau roux [bahan pengental] yang mengandung gandum-gandum di atas)
• Crouton
• Snack (kroket, sosis daging cincang, gorengan bola nasi)

Makanan yang boleh dikonsumsi bagi penderita penyakit ini antara lain :
• Jagung
• Beras
• Gandum hitam
• Panicum tepung, pati atau
• Teff tepung terigu dari bahan
• Sorghum baku ini
• Quinoa
• Amaranth
• Kedelai
• Tapioka
• Maizena
 • Pati (yang dimodifikasi)
• Tepung jagung kasar (polenta)
• Kentang dan tepung kentang
• Sayuran
• Buah kacang-kacangan/kacang polong
• Buah-buahan
• Susu
• Wafel dari tepung beras
• Ikan dan daging (asal tidak diberi panir dan tidak ditaburi dengan tepung)
• Minyak
• Telur    

2.9 Prognosis
DERMATITIS HERPETIFORMIS mempunyai prognosis yang baik apabila penderita yang diketahui memiliki kelainan usus halus atau GSE juga melakukan diet bebas gluten selain pengobatan dengan dapson atau sulfapiridin. ^3,4,6,7 Berbeda dengan pemfigoid bulosa dan pemfigus vulgaris, penyakit ini tidak pernah fatal. Kalau tidak diobati, penyakit ini menetap selama bertahun-tahun dengan aktivitas rendah disertai eksaserbasi akut. Pada 10-15 % penderita dapat timbul remisi spontan. Penderita yang diobati dengan dapson dan sembuh selama bertahun-tahun, bila obat dihentikan akan kambuh dalam 72-96 jam.^2,3

READ MORE - Dermatitis Herpetiformis (DH)

Treatment of Acne Scarring

M. Alam, MD, MSCI; J. S. Dover, MD, FRCPC, FRCP

Abstract
Acne scarring is common but surprisingly difficult to treat. Scars can involve textural change in the superficial and deep dermis, and can also be associated with erythema, and less often, pigmentary change. In general, treatment of acne scarring is a multistep procedure. First, examination of the patient is necessary to classify the subtypes of scarring that are present. Then, the patient´s primary concerns are elicited, and the patient is offered a menu of procedures that may address the various components of the scarring process. It is important to emphasize to the patient that acne scarring can be improved but never entirely reversed.

Classification of Acne Scars
There are several classifications of acne scars. A recent, comprehensive and functional scheme was proposed, whereby scars are classified as rolling, ice-pick, shallow box-car, and deep box-car. Rolling scars are gently undulating, appearing like hills and valleys without sharp borders. Ice-pick scars, also known as pitted scars, appear as round, deep depressions culminating in a pinpoint base; in cross-section, they are shaped like a "v. Box-car scars have a flat, "u-shaped base. Broader than ice-pick scars, they are round, polygonal, or linear at the skin surface. Shallow box-car scars terminate in the shallow-to mid-dermis, and deep box-car scars penetrate to the reticular dermis.

Treatment Modalities for Textural Change
Among the therapeutic tools for treatment of acne scarring are resurfacing methods, fillers, and other dermal remodeling techniques. These methods can be adapted to treat specific scar types.

Resurfacing
Resurfacing options include:

• Ablative resurfacing with carbon dioxide or erbium: yttrium aluminum garnet (Er:YAG) laser, medium- depth to deep chemical peel, dermabrasion, or plasma.

• Nonablative and partially ablative resurfacing with fractional laser, infrared laser (1,320nm neodymium:YAG (Nd:YAG), 1,450nm diode, or 1,540nm erbium:Glass)

Ablative Resurfacing
Ablative resurfacing entails removal of the epidermis and partial thickness dermis, and is considered by most as the gold standard for pitted scars and some box-car scars. While ablative resurfacing is most effective if it is deep, thereby removing as much as possible of the depressed scar, it cannot be so deep as to destroy the base of the hair follicles; such destruction could impede skin regrowth, and induce scar formation at the treated site. Carbon dioxide resurfacing is the most effective but also most operator-dependent method for deep ablative resurfacing.

Dermabrasion is possibly even more effective, but this is another procedure that is very technique dependent. Deep phenol (Baker-Gordon) peels, also highly effective, have fallen out of favor because of the associated cardiac risk and the frequency of porcelain-white postinflammatory hypopigmentation. Definitive ablative resurfacing results in 2 weeks of patient downtime, during which period re-epithelialization occurs. More superficial resurfacing with the Er:YAG laser or plasma can provide recovery within 1 week, but deeper acne scars may be less improved.

Nonablative Resurfacing
Nonablative resurfacing with laser and lights warms the dermis and can provide modest improvement of acne scarring bystimulating collagen remodeling. All subtypes of acne scars can be improved by nonablative therapy. Among the lasers used for this indication are devices originally developed for otheruses, such as pulsed-dye lasers, intense pulsed light devices, and Q-switched Nd:YAG lasers. However, more recently nonablative devices have been optimized to specifically target textural irregularities. For example, a series of treatments with infrared lasers can significantly improve uneven contour associated with acne scarring. These treatments are typically uncomfortable and may require oral and/or topical analgesics.

Similarly, fractional resurfacing is quite effective in the treatment of acne scarring. Fractional resurfacing is a minimally ablative technique that creates microscopic zones of dermal injury in a grid-like pattern. Because only a small proportion of the skin surface is treated at one time, and since the stratum corneum is not perforated, recovery is quick. However, a series of treatments is needed.

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Topical Treatments for Melasma and Postinflammatory Hyperpigmentation

C.B. Lynde; J.N. Kraft, MD; C.W. Lynde, MD, FRCPC

Abstract
Hyperpigmentation disorders of the skin are common and can be the source of significant psychosocial distress for patients. The most common of these disorders are melasma and postinflammatory hyperpigmentation. Sunscreen use and minimizing sun exposure are crucial in all cases. Topical applications are the mainstay of treatment and include phenols, retinoids, corticosteroids, and their combinations.

Introduction
Hyperpigmentation of the skin is a very common problem, with many patients seeking therapies to improve their cosmetic appearance. It is the result of an increase in cutaneous melanin deposition either by increased melanin synthesis or, less commonly, by a greater number of melanocytes. The amount of color change depends on the location of the melanin deposition. Epidermal involvement appears as brown discoloration whereas dermal deposition appears as blue-grey.

Mixed epidermal and dermal depositions appear as brown-grey discolorations. The use of a Wood's lamp can often be very beneficial in determining the location of melanin deposition showing enhancement of color contrast in lesional skin for the epidermal type, but not the dermal types. The mixed type has enhancement in some areas of lesional skin, but not in other areas. Whether the melanin is deposited in the epidermis or dermis is important therapeutically because dermal hyperpigmentation is much more challenging to treat.

The most common pigmentation disorders for which patients seek treatment are melasma and postinflammatory hyperpigmentation (PIH). These conditions may have a major impact because disfiguring facial lesions can significantly affect a person's psychological and social wellbeing, contributing to lower productivity, social functioning, and self-esteem.

Melasma
Melasma is a common acquired pigmentary disorder that occurs mainly in women (more than 90% of cases) of all racial and ethnic groups, but particularly affects those with Fitzpatrick skin types IV-VI. While the cause of melasma is unknown, factors include: a genetic predisposition, ultraviolet light exposure, and estrogen exposure. Estrogen is thought to induce melasma as it often develops during pregnancy, with use of oral contraceptives, and with hormone replacement therapy (HRT) in postmenopausal women. Melasma in pregnancy usually clears within a few months of delivery.

Discontinuation of oral contraceptives or HRT, in combination with adequate sun protection, may also result in melasma clearance, although there is a paucity of literature with regard to HRT and the clearance of this condition. Melasma presents as brown to grey macules and patches, with serrated, irregular, and geographic borders. The pigmented patches are usually sharply demarcated and symmetrical. Melasma has a predilection for sun-exposed areas. The three major patterns of distribution are: centrofacial (cheeks, forehead, upper lip, nose, and chin) (66% of cases), malar (cheeks and nose) (20% of cases) and mandibular (rami of the mandible) (15% of cases). See Table 1 for the differential diagnosis.

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Practical Management Strategies for Diaper Dermatitis

S. Humphrey, MD; J. N. Bergman, MD, FRCPC; S. Au, MD, FRCPC

Abstract
Common diaper dermatitis is an irritant contact diaper dermatitis(IDD) created by the combined influence of moisture,warmth, urine, feces, friction, and secondary infection. It is difficult to completely eradicate these predisposing factors in a diapered child. Thus, IDD presents an ongoing therapeutic challenge for parents, family physicians, pediatricians, and dermatologists. This article will focus on pratical management strategies for IDD.

Introduction
IDD is a common inflammatory eruption of the skin in the diaper area created by the presence of moisture, warmth, urine, feces, and friction, and is seen in 25% of children wearing diapers.

Pathogenesis
Four key factors contribute to the development of IDD :

• Wetness : Wet diapers result in excessive hydration and maceration of the stratum corneum leading to impaired barrier function, enhanced epidermal penetration by irritants and microbes, and susceptibility to frictional trauma.

• Friction : IDD is most commonly distributed in areas with the greatest skin-to-diaper contact. Mechanical trauma disrupts the macerated stratum corneum, exacerbating barrier dysfunction.

• Urine and feces : The interaction of urine and feces is key to the pathogenesis of IDD. Bacterial ureases in the stool degrade the urea that is found in urine, releasing ammonia and increasing local pH. Fecal lipases and proteases are activated by the increased pH. They cause skin irritation and disruption of the epidermal barrier. Ammonia does not irritate intact skin; it is thought to mediate irritation by contributing to the high local pH.

• Microorganisms : candida albicans (C. albicans) and, less commonly, Staphylococcus aureus (S. aureus) infections are associated with IDD. The warm, humid, and high pH environment in the diaper provides the ideal milieu for microbial proliferation. Innate antimicrobial microflora cannot survive in a high pH environment. There is a positive correlation between the clinical severity of IDD and the presence and level of C. albicans in the diaper, mouth, and anus of infants.

Clinical Features
IDD initially presents with localized asymptomatic erythema, and can progress to widespread painful, confluent erythema with maceration, erosions, and frank ulceration. IDD commonly spares the skin folds, and affects the convex skin surfaces in close contact with the diaper including the buttocks, genitalia, lower abdomen, and upper thighs. IDD complicated by Candida presents with beefy red intertriginous plaques and satellite papules and pustules in the diaper area.IDD complicated by S. aureus appears impetiginized, with erosions, honey-colored crust, and lymphadenopathy.

Granuloma gluteale infantum and Jacquet erosive diaper dermatitis are distinctive, severe variants of IDD. Granuloma gluteale infantum presents in the setting of IDD with violaceous papules and nodules on the buttocks and in the groin.The pathogenesis of granuloma gluteale infantum is not clear. Potential risk factors include treatment with topical steroids, candida infection, and occlusive plastic diaper covers. Granuloma gluteale infantum follows a self-limited course, resolving in weeks to months, often with residual scarring. The presence of punched-out erosions or ulcerations with heaped-up borders characterizes Jacquet erosive diaper dermatitis. This uncommon and severe presentation of IDD typically occurs in the context of frequent liquid stools, poor hygiene, infrequent diaper changes, or occlusive plastic diapers.

It is imperative to consider other conditions that may occur in the diaper area. Several excellent references are available that outline the differential diagnosis of IDD. Please see Table 1 for a review of the clinical features of relevant diaper dermatoses.

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New Developments in Hormonal Therapy for Acne

J. K. L. Tan, MD, FRCPC

Abstract
Oral contraceptives (OCs) are a valuable option for the treatment of women with acne. The use of OCs can be considered across the spectrum of acne disease severity in women. In Canada, three preparations are approved for mild-to-moderate acne, and a fourth is indicated for severe acne. These formulations contain estrogen in the form of ethinyl estradiol and a progestin. In Canada, the most recently approved OC is ethinyl estradiol 0.03mg and drospirenone 3mg (Yasmin, Bayer). With the accumulating evidence on the efficacy and safety of drospirenone-containing hormonal preparations, this formulation provides dermatologists with a new treatment option for acne and other hyperandrogenic disorders.

For many years, oral contraceptives (OCs) have been used by dermatologists as a treatment option for women with acne. OCs that are indicated for use in acne are effective across the spectrum of disease severity :

1. in mild acne as an adjunct to topical therapy for female patients desiring contraception

1. in moderate acne as a form of systemic therapy

1. in severe acne

1. as a primary form of therapy

1. as one of two preferred forms of contraception in women treated with systemic isotretinoin.

From their inception, these preparations have evolved to include less estrogen and incorporate progestins with less intrinsic androgenicity. These modifications were undertaken to reduce the potential risk of thromboembolic events, hepatic tumors, hypertension, altered glucose metabolism, and androgenic side-effects.

OCs for the Treatment of Acne
In Canada, four hormonal preparations are presently indicated for the treatment of acne. These preparations all contain estrogen and progestins with either minimal androgenicity (i.e., ethinyl estradiol/ norgestimate, and ethinyl estradiol/ levonorgestrel) or antiandrogenic potential (i.e., ethinyl estradiol/ cyproterone acetate, and most recently, ethinyl estradiol/ drospirenone). Their demonstrated efficacy and long-term safety profile advocate their use in various grades of acne in women. Evidence supporting the use of these agents in acne was recently reviewed in the Journal of Cutaneous Medicine and Surgery, and is summarized briefly here.

Ethinyl Estradiol/ Norgestimate (Ortho Tri-Cyclen
Ethinyl estradiol 0.035mg with norgestimate in increasing doses, 0.180mg/ 0.215mg/ 0.250mg (Ortho Tri-Cyclen, Ortho- McNeil), was shown to be efficacious in moderate facial acne in two randomized placebo-controlled trials involving 324 subjects who were treated for 6 cycles. Significant improvements in lesion counts and investigator global assessment scores were observed. Inflammatory lesions were reduced by 56%, noninflammatory lesions by 41%, and 32% achieved excellent improvement. Norgestimate has low intrinsic androgenicity with low binding affinity for androgen receptors, whereas it is strongly selective and avidly bound to progesterone receptor sites.

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Management and Treatment of Pruritus

P. Lovell, RN, BScN; R. B. Vender, MD, FRCPC

Abstract
Pruritus, or itch, is a common sensation that causes a person to want to scratch. It is a complex process that may negatively impact quality of life and commonly occurs with skin disorders such as atopic dermatitis and urticaria. It could also be a symptom related to an underlying disease process such as cholestasis or hyperthyroidism, or simply be caused by dry skin, especially in the cold, winter months. Therapy is often aimed at eliminating the underlying cause first, followed by the management of the itchy sensation. Treatment may include prescription and over-the-counter (OTC) medications, herbal remedies, hydrotherapy, phototherapy, and ultraviolet therapy. This overview provides information regarding the various management and treatment options for pruritus.

Pathophysiology of Pruritus
Pruritus is a complex process that involves the stimulation of free nerve endings found superficially in the skin. Thesensation of pruritus is transmitted through the C-fibers in the skin to the dorsal horn of the spinal cord, and then, via the spinothalamic tract to the cerebral cortex for processing. Many chemicals have been found to be pruritogenic, therefore causing the itch sensation, including histamine, serotonin, cytokines, and opioids. There are six categories of pruritus: dermatologic, systemic, neurogenic, psychogenic, mixed, and other. Various treatment and management options exist depending on the category or cause.

Treatment
Treatment of pruritus can be categorized in several ways. A common method of grouping the various options is causativevs. symptomatic treatment. Causative treatment involves finding the underlying disorder and then correcting it, thereby eliminating the itch sensation. Symptomatic treatment involves substituting another sensation for the itch, using methods such as cooling, heating, or counter irritation (e.g., scratching). Symptomatic treatment can be used in addition to treating the underlying disease process in order to provide earlier relief. Most of the available treatment options are categorized under symptomatic therapy and management.

Prescription Medications
Prescription medications include topical and systemic antihistamines, corticosteroids, local anesthetics, and topical immunomodulators, among others. Some lower concentration preparations of these medications are available OTC.

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Dermatological Management of Human Immunodeficiency Virus (HIV)

B. L. Bartlett, MD, M. Khambaty, MD, N. Mendoza, MSc; A. M. Tremaine, MD, A. Gewirtzman, MD,S. K. Tyring, MD, PhD, MBA.

Abstract
Atypical presentations of typical dermatological conditions are common in human immunodeficiency virus (HIV). This article will focus on three specific topics: eosinophilic folliculitis, psoriasis, and cutaneous mycoses. Their unique presentations in HIV and treatments are discussed.

Introduction
Despite attempts at increasing awareness of HIV and its transmission, this infection continues to spread and remains asignificant cause of morbidity and mortality worldwide. As of 2003, there were an estimated 1 million people living in the US with HIV infection, and nearly 40,000 cases were diagnosed in 2005. HIV infection affects nearly every organ system in the body, including the skin. HIV-infected patients can pose diagnostic challenges, as their altered immune status may lead to atypical presentations of common cutaneous diseases, as well as the occurrence of uncommon or opportunistic skin disorders.

Management of cutaneous disease in sero-positive patients can also be challenging, as the dermatological manifestations may be more severe, may recur with greater frequency, and may be refractory to standard treatment. The addition of highly active antiretroviral therapy (HAART) further complicates the picture as other dermatologic manifestations may arise as part of the immune reconstitution phenomenon. The scope of issues encountered in HIV-positive patients is too broad to discuss in its entirety. This article will focus on three diseases and their management: eosinophilic folliculitis, psoriasis, and cutaneous mycoses.

Eosinophilic Folliculitis
Eosinophilic folliculitis (EF) is seen commonly in HIV with CD4 cell counts of less than 250-300/mm3. It presents as recurrent, pruritic, erythematous papules and pustules that are usually distributed on the face, shoulders, upper back, and upper extremities. The pruritus associated with EF can be severe and debilitating. Its etiology is not well elucidated, but some theories propose an infectious derivation. EF is an example of a dermatosis that is associated with immunereconstitution. It is described as a phenomenon wherein HAART triggers a generalized immune activation as viral loads decrease and CD4 lymphocytes increase. Studies have shown that EF typically flares shortly after starting antiretroviral therapy, but will resolve from 3 weeks to several months later. Clinicians should warn patients with EF that after starting HAART, their skin will likely worsen initially, then improve. EF can be difficult to manage, as response to treatment is variable and it tends to recur once treatment is discontinued. Various treatments have been employed, including: isotretinoin, UVB phototherapy, itraconazole, and metronidazole, among others, with contrasting results. The treatment of EF with potent topical corticosteroids is reportedly effective, but is accompanied by skin atrophy and hypopigmentation.

This can be a problem given the distribution of EF on the face, and can be especially challenging in dark-skinned individuals. A relatively recent case study showed promising results with topical tacrolimus. Subjects who applied daily topical tacrolimus 0.1% to the face had an average lesion clearance time of 2.6 months with an absence of residual scarring. The average remission of 12.3 months was seen in subjects with well controlled viremia on HAART. The associated pruritus subsided within days. Given these promising results and the relative safety of topical tacrolimus, clinicians may want to consider this as an alternative to corticosteroids, which can cause hypopigmentation and scarring in darkskinned patients, resulting in potential disfigurement.

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Current Concepts in the Treatment of Recurrent Aphthous Stomatitis

Altenburg, MD; C.C. Zouboulis, MD

Abstract
The treatment of recurrent aphthous stomatitis (RAS) still remains nonspecific and is based primarily on empirical data. The goals of therapy include the management of pain and functional impairment by suppressing inflammatory responses, as well as reducing the frequency of recurrences or avoiding the onset of new aphthae. For common forms of RAS, standard topical treatment options that provide symptomatic relief include analgesics, anesthetics, antiseptics, anti-inflammatory agents, steroids, sucralfate, tetracycline suspension, and silver nitrate. Dietary modifications may also support therapeutic measures. In resistant cases of benign aphthosis or aphthosis with systemic involvement, appropriate systemic treatment can be selected from a wide spectrum of immunomodulators that include colchicine, prednisolone, cyclosporine A, interferon-á, tumor necrosis factor-áantagonists, antimetabolites, and alkylating agents.

Introduction
Idiopathic aphthae are the most frequently occurring inflammatory lesions of the oral mucous membrane. Nosologically,the condition is clearly defined, but the sores are often difficult to differentiate from heterogeneously similar aphthoid ulcerations and mucosal erosions. Episodic aphthous attacks are characterized by painful lesions that range from the size of a pinhead up to several centimeters. Fibrin covered ulcerations with a hyperemic halo are typically visible on the oral mucous membrane, but they rarely appear in the genital region. Spontaneous healing is possible after many years. Common simple aphthae, with 3-6 attacks per year, heal rapidly, are not very painful, and are restricted to the oral mucosa.

They can be differentiated from complex aphthae (less than 5% of aphthosis cases), which are recurrent, present with few to unusual multiple lesions, are extremely painful, heal slowly, and can also occur in the genital region. Complex aphthosis requires the accurate diagnosis of a possible causal or associated condition, such as anemia, cyclic neutropenia, folic acid or iron deficiency, ulcus vulvae acutum, aphthous-like ulcerations in HIV positive patients, gastrointestinal diseases, such as Crohn's disease and ulcerative colitis, and Adamantiades-Behcet Disease (ABD). In ABD, which represents a malignant form of aphthosis, there is an increase in both the frequency of occurrence and severity of lesions. The diagnosis of ABD is based on several clinical criteria sets, of which the International Study Group Criteria are the most frequently used and the New International Criteria are the most recent.

Topical Therapy
Dietary and General Measures
Certain foods should be avoided as they appear to trigger the eruption of new aphthae and prolong the course of the lesions (e.g., foods that are hard, acidic, salty, or spicy, as well as nuts, chocolate, citrus fruits, and alcoholic or carbonated beverages). In addition, because surfactants and detergents can cause irritation, dental care products containing sodium lauryl sulphate should be avoided.

Local Anesthetics
Pain relief can be attained using topical lidocaine 2% gel or spray, polidocanol adhesive dental paste, or benzocainelozenges. Available combination preparations include a pump spray with tetracaine and polidocanol, and a mouth rinsesolution that uses benzocaine and cetylpyridinium chloride as the active ingredients. As well, anesthetic-containingsolutions, e.g., a viscous lidocaine 2% solution, can be applied carefully on the lesions.

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An Update on New and Emerging Options for the Treatment of Vitiligo

B. H. Mahmoud, MD, PhD; C. L. Hexsel, MD; I. H. Hamzavi, MD

Abstract
Vitiligo is an acquired leukoderma that results from the loss of epidermal melanocytes, and is characterized by macules and patches of depigmented skin. With a relatively high rate of prevalence, vitiligo occurs in localized, generalized, or segmental patterns; it can run a rapidly progressive course or remain stationary. The pathogenesis of vitiligo is not yet fully understood, but the autoimmune hypothesis is the most commonly accepted one, based on which, many treatment modalities have been described. Although many therapeutic options exist and new modalities are still emerging, treatment challenges persist, as not all patients respond to available therapies. Variables that affect the choice of treatment include the extent, distribution, and progression rate of the lesions. Another challenge is the lack of a standardized scoring system, which hampers the production of level 1a evidence studies for the treatment of this condition.

Introduction
The worldwide prevalence of vitiligo is estimated to range between 0.5% and 4%. These depigmented macules were first described more than 3,000 years ago in pre-Hindu Vedic and ancient Egyptian texts. The pathogenesis of vitiligo is complex and not yet fully understood, but it is believed to involve a combination of autoimmune, genetic, and environmental factors. The autoimmune hypothesis suggests that antibodies develop against melanocyte surface antigens. Gauthier, et al. recently proposed the melanocytorrhagy hypothesis, which is based on an in vivo observation of melanocyte detachment from the basal layer, followed by transepidermal migration, which in turn triggers melanocyte death. In addition, the neural, self-destruct, and biochemical hypotheses have also been proposed.

Evaluation of Therapeutic Options Based on Strength of Evidence
This review will primarily discuss the more recent studies on vitiligo with a high level of evidence. Reference will be made throughout the discussion regarding the strength of evidence as defined in Table 1 .

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UV Radiation, Vitamin D and Epidermal Carcinogenesis

Daniel D Bikle

Abstract
The skin is the major source of vitamin D in the body, being the site where the precursor 7-dehydrocholesterol is converted to vitamin D under the influence of UVB radiation (UVR). Unfortunately, UVR is also the major cause of nonmelanoma skin cancer (NMSC). Substantial evidence from epidemiologic and animal studies demonstrates an important protective effect of vitamin D for a number of cancers, but the evidence is weaker for NMSC. However, recent studies indicate that animals lacking the vitamin D receptor are predisposed to developing NMSC following UVR or chemical carcinogens, suggesting that vitamin D and its active metabolite 1,25-dihydroxyvitamin D3 may also be protective of NMSC. The mechanisms underlying this protective mechanism include regulation of the hedgehog and â-catenin pathways and stimulation of the DNA damage response. This article will examine the evidence supporting this potential protective action of vitamin D with respect to NMSC development.

Introduction
Over 1 million skin cancers occur annually in the USA, 80% of which are basal cell carcinomas (BCCs), 16% are squamous cell carcinomas (SCCs) and 4% are melanomas, making skin cancer by far the most common cancer afflicting humankind. Surgery is generally curative, however, it is also disfiguring and costly. UV radiation is the major etiologic agent. UV wavelengths shorter than 280 nm (UVC) are absorbed by the ozone layer and do not reach the earth. UV wavelengths longer than 320 nm (UVA) have limited ability to induce the characteristic mutations in DNA observed in epidermal cancers. Thus, UVB with a spectrum between 280 and 320 nm is the major cause of these cancers. The principle genotoxic lesions induced by UVR are cyclobutane pyrimidine dimers (CPDs) and pyrimidine(64) pyrimidone photoproducts, which if not repaired result in C to T or CC to TT mutations, the UVB 'signature' lesion. Mutations in p53 are common in both BCC and SCC (occurring in 5090% of cases), as well as in actinic keratoses, the precursor lesions to SCC. Surprisingly, patients with Li-Fraumeni Syndrome, involving mutations in p53, are not predisposed to SCC and BCC unlike other malignancies, suggesting that other gene family members, such as p63 and p73 may play important roles in epidermal carcinogenesis. Precursor lesions for BCC have not been identified but BCCs are thought to arise from interfollicular basal cells, hair follicles and sebaceous glands. Mutations in ras are much more common in SCC than BCC, whereas mutations in the hedgehog (Hh) signaling pathway, in particular in patched 1 (Ptch1), characterize BCC, but can also be found in SCC in patients also susceptible to BCC. While UVB radiation (UVR) is the major etiologic agent for these cancers, it is also the principal means by which the body obtains vitamin D. Furthermore, the skin is capable of converting the vitamin D produced to its active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), via the enzyme CYP27B1, and this conversion is potentiated by UVR at least in part via cytokines, such as TNF-á, which are increased in the epidermis by UVR.

Sun avoidance may reduce one's risk of developing skin cancer, but this practice can result in suboptimal levels of vitamin D in the body. Most tissues express the vitamin D receptor (VDR) and several, including the epidermis, are capable of producing their own 1,25(OH)2D3. Vitamin D deficiency is associated with a number of diseases including, but not limited to, osteomalacia and rickets. Increased cancer risk ranks among these diseases, with the strongest association between vitamin D deficiency and colon cancer. This, however, has not been shown for nonmelanoma skin cancers (NMSCs). Perhaps because UVR increases the risk for NMSC, the potential for vitamin D and 1,25(OH)2D3 production in the epidermis to serve as protection against UVR-induced epidermal carcinogenesis has received little attention. However, recent studies have caused us to re-evaluate the role of vitamin D in epidermal carcinogenesis, and we propose that vitamin D production in the skin may serve as a protective mechanism for the otherwise carcinogenic actions of UVR.

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Role of Topical Calcineurin Inhibitors in the Treatment of Seborrheic Dermatitis

Bethany A. Cook; Erin M. Warshaw

Abstract
Seborrheic dermatitis (SD) is characterized by erythematous pruritic patches and plaques with greasy scale that occur in sebaceous areas. It is common, affecting up to 3% of the population. Past treatments have relied on a wide variety of anti-inflammatory and antifungal agents, but corticosteroids have limited use because of long-term adverse effects. ical calcineurin inhibitors provide a safe alternative for the treatment of SD, as these drugs block the inflammatory cascade involved in the disease process and pose no risk of skin atrophy. Studies of ical pimecrolimus and tacrolimus in the treatment of SD have found that improvement occurred within 2 weeks, and if SD recurred after sping treatment, it was significantly less severe. There have been no studies of the comparative efficacy of pimecrolimus versus tacrolimus for the treatment of SD.

Common adverse effects of mild burning and irritation have been associated with the use of both of these agents. Safety profile studies are limited to studies of aic dermatitis, which show no increase in infection rate, photocarcinogenicity, or signs of immunosuppression in patients using ical calcineurin inhibitors for long-term treatment. This article reviews the clinical trials of pimecrolimus and tacrolimus in the treatment of SD, focusing on efficacy and safety.

Introduction
Seborrheic dermatitis (SD) is an inflammatory skin condition affecting approximately 1-3% of the adult population. The chronic, relapsing course, associated symptoms, and emotional impact of SD can affect quality of life. The heterogeneity of SD is evident in the variety of clinical presentations and absence of uniform diagnostic criteria. The disease is more prevalent in male than female patients, and its incidence peaks in infants, adolescents, and adults over the age of 50 years. There is a higher rate of occurrence in immunocompromised patients, ranging from 30% to 83% in HIV-positive and AIDS patients, and 18-50% in individuals with Parkinson disease.

The large proportion of people affected by SD spurs continued interest in the etiology and treatment of this condition. While studies have shown SD to be linked to a variety of endogenous and exogenous factors, the specific etiology of the condition remains elusive. The chronic course of the disease necessitates treatment that is both effective and safe to use as long-term therapy. Historically,treatment of SD has relied heavily on keratolytics, antifungals, and corticosteroids. The development of ical immunomodulatory medications has provided an alternative therapy for chronic inflammatory skin disorders, and the use of pimecrolimus and tacrolimus in SD has been investigated in several clinical trials. This article reviews the pathogenesis and current therapy of SD, focusing on recent evidence regarding the safety and efficacy of the ical calcineurin inhibitors tacrolimus and pimecrolimus. Articles evaluated for this review included manuscripts written in English referenced in PubMed, Ovid, and/or the Cochrane library with the following search terms: 'seborrheic dermatitis', 'ical calcineurin inhibitors', 'safety', 'efficacy', 'pimecrolimus', and 'tacrolimus'.

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Protein Contact Dermatitis: Allergens, Pathogenesis, and Management

Cheryl Levin; Erin Warshaw

Abstract
Protein contact dermatitis is an allergic skin reaction induced principally by proteins of either animal or plant origin. The clinical presentation is that of a chronic dermatitis, and it is often difficult to differentiate between allergic contact dermatitis and other eczematous dermatoses. One distinguishing clinical feature is that acute flares of pruritus, urticaria, edema, or vesiculation are noted minutes after contact with the causative substances. Additionally, the patch-test result is typically negative, and the scratch- or prick-test result is positive. The pathogenesis of protein contact dermatitis is unclear but may involve a type I (immunoglobulin E, immediate) hypersensitivity reaction, type IV (cell-mediated delayed) hypersensitivity reaction, and/or a delayed reaction due to IgE-bearing Langerhans' cells. Management involves avoidance of the allergen.

Introduction
The term "protein contact dermatitis" was coined by Hjorth and Roed-Petersen in 1976 to describe the condition of several food handlers with hand and forearm eczema. The responsible allergen in these patients was not a low-molecular-weight substance, as in classic allergic contact allergy, but a protein of greater molecular weight. Additionally, these patients had positive scratch-test results and (in some cases) specific immunoglobulin E (IgE) antibodies to the food they handled, which included meat, fish, cheese, vegetables, and spices, whereas patch-test results were often negative. Of 33 patients evaluated, only 6 exhibited delayed hypersensitivity; in 10 patients, scratch tests revealed the only explanation for their eczema. Most patients did not have respiratory or mucosal symptoms. The authors postulated that protein contact dermatitis was a combined type I- and type IV-mediated allergic reaction to "proteins."

In 1983, Veien and colleagues further characterized protein contact dermatitis. They defined specific criteria, including (1) a chronic recurrent dermatitis caused by contact with proteinaceous material, (2) an acute urticarial or vesicular eruption occurring minutes after contact with the causative protein, (3) immediate testing results that are usually positive, and (4) patch-test results that are often negative.

Because there is an immediate wheal and flare response, some authors have classified protein contact dermatitis as part of the "contact urticaria syndrome," a term that encompasses immunologic, nonimmunologic, and uncertain mechanismmediated contact urticaria. In this view, protein contact dermatitis is not a unique entity and may be caused by both nonimmunologic (irritant) and immunologic (allergic) mechanisms. This article will refer to protein contact dermatitis as that which is immunologically mediated. Because protein contact dermatitis is relatively rare, little is known about its epidemiology. Information from case series
indicates that protein contact dermatitis is primarily seen in chefs, veterinarians, dairy workers, and workers in other occupations in which there is significant protein exposure. The purpose of this review is to summarize the current literature on the clinical presentation, pathogenesis, and management of protein contact dermatitis.

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Pemphigus - A Treatment Update

Sue Jessop; Nonhlanhla P. Khumalo

Abstract
Pemphigus is an uncommon but potentially life-threatening chronic autoimmune bullous disorder. Antibodies are directed against antigens (desmoglein 1 and 3) in the desmosomes linking keratinocytes and against acetylcholine receptors. Conventional treatment with high-dose corticosteroids, sometimes with adjuvant immunosuppressive agents, may be associated with very serious adverse effects. There is an urgent need to establish the evidence for the safest and most effective form of treatment. A literature review has revealed 11 controlled (9 randomized) trials of treatment for pemphigus. The numbers of participants in the individual trials are small and the data cannot be pooled as they evaluate different forms of treatment. The results of these trials suggest that very high doses of corticosteroids, either as pulse therapy or in daily dosage, are not superior to moderate daily doses.

Based on evidence from the available trials, addition of an immunosuppressive agent generally does not appear to offer substantial benefit in terms of clinical response. However, a recent study demonstrated a significant reduction in corticosteroid requirements among patients receiving immunosuppressive agents. Newer therapies, such as biologic agents (in particular rituximab), calcineurin inhibitors, or immunoadsorption appear promising but there are inadequate controlled trials to establish their role clearly. Initial open-label studies suggest that specific peptide immunotherapy may offer a safe and novel approach to the treatment of pemphigus in the future. At present, treatment of an individual patient with pemphigus requires clinical judgment and should not be based purely on guidelines or on the inadequate available evidence alone. There is an urgent need for large randomized, controlled, multicenter trials of treatment in patients with pemphigus.

Background
Pemphigus is an uncommon, autoimmune blistering disorder characterized by the presence of flaccid blisters of the skin and/or mucous membranes. It may occur at any age (peak 5060 years). In the newborn it is thought to result from passive placental transfer of pathogenic antibodies from the maternal circulation. Neonatal pemphigus is usually self-limiting, resolving with the disappearance of maternal antibodies. The recognized forms of this disease are pemphigus vulgaris (PV), pemphigus vegetans, pemphigus foliaceus (PF), IgA pemphigus, and paraneoplastic pemphigus. This article reviews only the literature relating to the two most common types (PV and PF including endemic forms).

Epidemiology and Etiology
Accurate prevalence figures are limited but it has long been recognized that PV has a relatively high prevalence in people from the Mediterranean area and among those of Jewish ancestry. The two common forms, PV and PF, show a variation in relative prevalence from one geographic area to another. PF is known to have an extraordinarily high prevalence in parts of Tunisia and Brazil (the endemic, so-called 'fogo selvagem,' form of the disorder). A genetic predisposition (HLA-DRB1*0102) has been identified.

Clinical Features
PV is characterized by the presence of flaccid blisters that rupture easily, leading to erosions and crusts. Without treatment the blisters tend to spread, showing little tendency to heal spontaneously. Skin and mucosal surfaces are often both involved, although pemphigus may initially remain at one site for months to years. PF is a more superficial condition in which the cleft occurs in the outer layers of the epidermis and frequently leads to erosive or crusted lesions rather than blisters.

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