JOURNAL READING

Prurigo nodularis: an update on etiopathogenesis and therapy

“Diajukan Dalam Rangka Tugas Kepaniteraan Klinik Bagian Kulit dan Kelamin di Rumah Sakit
Umum Daerah Abepura”

Oleh
Gugun R. Lingga
0130840099

Pembimbing
dr. Titie Soepraptie, SpKK, FINSDV

RUMAH SAKIT UMUM DAERAH ABEPURA

FAKULTAS KEDOKTERAN
UNIVERSITAS CENDERAWASIH
JAYAPURA-PAPUA
2019
Jurnal Perawatan Dermatologis, 2013; 24: 458-462 ©
2013Informa Healthcare USA atas nama Informa UK Ltd.
ISSN: 0954-6634 print / 1471-1753 online DOI: 10.3109 /
09546634.2013.814759
TINJAUAN
Prurigo nodularis: pembaruan tentang etiopatogenesis dan terapi
Anna Chiara Fostini, Giampiero Girolier & Gianpaolo Tessari
Departemen Kedokteran, Bagian Dermatologi dan Venereologi, Universitas Verona, Verona, Italia
Prurigo nodularis (PN) adalah kondisi kronis, sangat pruritik yang
ditandai dengan adanya hiperkeratotik, eksoriasi, popula dan nodul
yang gatal, dengan distribusi simetris. Tidak ada data tentang
insidensi dan prevalensi PN pada populasi umum, tetapi lebih sering
dan lebih intens pada wanita. PN dapat dikaitkan dengan banyak
penyakit penyerta dermatologis dan non-dermatologis, termasuk
penyakit kejiwaan. Temuan terbaru menunjukkan asal neuropatik
dari PN, dengan perubahan serabut saraf di dermis dan epidermis.
PN memiliki dampak yang luar biasa pada kualitas hidup, dan
beberapa pilihan terapi yang efektif telah tersedia. Beberapa uji coba
terkontrol secara acak (RCT) pada terapi PN telah tersedia,
menunjukkan keampuhan fototerapi tunggal atau dengan psoralen,
dan kalsipotriol topikal dan steroid topikal dalam obat oklusif.
Thalidomide mungkin efektif, tetapi tidak ada RCT yang tersedia
dan penggunaannya tidak praktis karena kurang keamanannya.
Gabapentin, pregabalin, dan antagonis reseptor neurokinin 1,
tampaknya juga efektif dalam terapi PN, tetapi RCT masih kurang.
Kata kunci: prurigo nodular, prurigo nodularis, patogenesis, RCT,
terapi
Pendahuluan. Prurigo nodularis (PN) adalah kondisi kronis yang
berulang, sangat pruritik, yang berdampak tinggi pada kualitas hidup
pasien. Hal ini ditandai dengan adanya beberapa hingga ratusan
hiper-keratotik, papula dan nodul yang gatal, kadang-kadang
ekskoriasi atau mengalami ulserasi, dengan distribusi simetris di
bahu, di punggung, bokong dan ekstremitas atas dan bawah. Bagian
dari pertengahan punggung atas, yang dikenal sebagai 'butterfly
sign',yang khas (Gambar 1). Insidensi dan prevalensi PN pada
populasi umum tidak diketahui, karena dalam studi epidemiologi PN
sering dimasukkan dalam gangguan gatal kronis (1,2). Pada pasien
wanita PN tampaknya lebih banyak terjadi pada usia lebih dini, dan
lebih parah dari pada pasien pria (3). Diagnosis PN biasanya dibuat
berdasarkan klinis. Histologi dapat membantu, tetapi tidak spesifik,
terdiri dari epidermis yang tidak teratur atau hiperplasia
pseudoepitheliomatous, fibrosis dari papiler dermis dengan serabut
kolagen tersusun secara vertikal dan perivaskular dan infiltrasi sel-
sel radang limfosit, makrofag, eosinofil dan neutrofil (4).
1
Patogenesis belum sepenuhnya dijelaskan, dan bukti dasar untuk
terapi sangat terbatas. Tujuan dari tinjauan ini adalah untuk
menyajikan pembaruan tentang etiopatogenesis dan perawatan
berbasis bukti PN.
Metode Kami mencari artikel PubMed menggunakan kata kunci
'prurigo nodularis' dan 'nodular prurigo'. Sebanyak 394 artikel
diambil hingga Februari 2013. Kami memilih dan meninjau artikel-
artikel yang memberikan informasi yang relevan tentang
etiopatogenesis dan terapi PN. Studi terkontrol acak (RCT) dan, jika
tidak tersedia, dipertimbangkan kasus yang lebih besar.
Etiopatogenesis PN. Etiologi PN sangat kurang dipahami dan
hanya sedikit penelitian yang menggambarkan insidensi dan
hubungan komorbiditas dalam representatif kohort pasien (2,5).
Gangguan dermatologis paling umum yang terkait dengan PN adalah
dermatitis atopik, yang juga disebut sebagai 'prurigo atopik' (6).
Penyakit sistemik yang sering dikaitkan dengan PN adalah diabetes
mellitus tipe 2, kelainan tiroid, infeksi HCV, limfoma non-Hodgkin
dan kelainan psikis, khususnya depresi dan kecemasan (2,5). Dalam
beberapa kasus, tidak ada penyakit mendasar yang terdeteksi
(idiopatik PN). Deskripsi terperinci tentang kondisi yang terkait
dengan PN dilaporkan pada Tabel I. Patogenesis PN masih belum
diketahui; Namun,barubaru ini –temuan menunjukkan bahwa PN
mungkin merupakan konsekuensi dari gatal kronis yang disebabkan
oleh neuropati. Gatal neuropatik adalah sensasi pruritus yang
disebabkan oleh lesi primer atau disfungsi pada titik mana pun di
sepanjang jalur aferen sistem saraf dan sudah diketahui dalam
beberapa kondisi, termasuk neuropati postherpetic, pruritus
brachioradial, dan notalgia paresthetica (7). Karakteristik gatal
neuropatik bersamaan dengan gejala sensorik lainnya seperti
parestesia, hiperestesia atau hipoestesia, serta rasa terbakar,
kesemutan, menyengat dan panas dan dingin (7). Gejala-gejala ini
sering terjadi pada pasien PN (2). Bharati dkk. mengkonfirmasi
klinis neuropati dalam kelompok kecil pasien dengan PN, dengan
melakukan studi konduksi saraf (8).
Morfologi serabut saraf dan distribusi di kulit dengan lesi dan
non-lesi pada pasien PN telah berulang kali diperiksa. Peningkatan
produk gen protein 9,5 (PGP 9,5), faktor pertumbuhan saraf p75
(NGF) - positif dan kalsitonin gen related peptide (CGRP) –positif
dalam dermis papiler pasien dengan PN (9). Selain itu, saraf berada kulit, dan berkaitan dengan penyakit sistemik yang umum untuk PN
dekat dengan eosinofil, menunjukkan hubungan fungsional (10). (21).
Adanya peningkatan signifikan substansi P-positif pada serabut saraf Beberapa sitokin mungkin berperan dalam patogenesis PN (22).
dermis di lesi kulit pasien dengan PN, dan kulit yang terkena gatal Keterlibatan Th2- dimediasi respon peradangan dalam patogenesis
kronis, jika dibandingkan dengan kulit yang sehat/normal (11). PN telah dihipotesiskan memberikan respon berlebih pada faktor
Substansi P adalah mediator yang menginduksi, dan peningkatan transkripsi STAT-6 di lesi epidermis, yang diinduksi oleh IL-4 dan
jumlah substansi P positif pada serabut saraf dermal juga didapatkan IL-13. Namun, ekspresi STAT3 juga telah terdeteksi. Faktor
pada dermatitis atopik (12). transkripsi ini diinduksi terutama oleh IL-22, dan sedikit banyak oleh
IFN-g . Cukup menarik, IL-22 menyebabkan proliferasi keratinosit
dan sangat diekspresikan pada kulit dermatitis atopik (23). Pada
pasien PN dengan riwayat dermatitis atopik, kadar IL-31 dalam
plasma meningkat secara signifikan dan berkorelasi dengan ekspresi
IL-4 dan IL-13 (24). Pengamatan ini menunjukkan bahwa PN adalah
dermatosis dengan keterlibatan sitokin Th2, dan, bersama dengan
adanya hyperplasia serabut saraf dermal, berhubungan erat antara PN
dan dermatitis atopik.
Pengobatan PN
Pengobatan PN masih merupakan tantangan, dan itu membuat
frustasi baik untuk dokter kulit dan pasien karena, dalam sebagian
besar kasus, responsnya terbatas dan tidak memuaskan. Tidak ada
standar terapi PN, dan bukti dari RCT terbatas. Pengobatan termasuk
Keratinosit epidermis dan infiltrasi T-limfosit pada daerah
pendekatan topikal, sistemik dan pendekatan psikis (Tabel II).
kulit yang terkena pruritus mungkin akibat NGF, yang dapat
berkontribusi terjadinya neurohyperplasia, sama halnya dengan
Terapi Topikal.
pertumbuhan serabut saraf dan peningkatan regulasi neuropeptida,
terutama substansi P (11 , 13). Beberapa penelitian telah meneliti Agen topikal digunakan ketika penyakit mempengaruhi
peran serabut saraf epidermis di PN. Kepadatan serabut saraf terbatas pada daerah kulit. Secara bilateral dipasangkan RCT pada
intraepidermal PGP 9,5-positif pada lesi kulit yang gatal dengan kulit 12 pasien, perbandingan dari beta-methasone valerat 0,1% dan krim
pasien PN yang tidak gatal secara signifikan berkurang, jika pelembab menunjukan perbaikan yang signifikan pada kedua sisi
dibandingkan dengan biopsi kulit yang diambil dari relawan yang tubuh, tetapi beta-methasone valerate menunjukkan respon klinis
sehat. Pada pasien dengan pruritus yang berlangsung lebih dari 3 yang lebih tinggi (VAS 8,75-3,9 ) dibandingkan dengan krim
tahun, pengurangan serabut saraf lebih ditandai pada lesi kulit, jika pelembab untuk gatal (VAS dari 8,75 hingga 5,63). Peningkatan
dibandingkan dengan kulit non-lesi. (14) Temuan intidak yang diperoleh dengan krim pelembab mungkin terlihat pada kulit
menunjukkan bahwa kerusakan saraf terjadi disebabkan oleh xerosis yang umum pada pasien dengan PN (25). Sebuah double-
garukan kronis, karena dalam kondisi pruritus umum, termasuk blind, kanan / kiri RCT membandingkan khasiat dan toleransi 50 mg
atopic dermatitis, terjadi pertumbuhan serabut saraf epidermal / g calcipotriol salep dengan 0,1% betametason valerat salep pada 10
(12,15). Para penulis menyimpulkan bahwa berkurangnya kepadatan subjek dengan PN, menunjukkan bahwa salep kalsipotriol lebih
serabut saraf epidermis, juga ditemukan pada kulit yang tidak efektif dan nodul prurigo lebih cepat bersih dibandingkan salep beta-
terkena, mungkin terkait dengan subklinis serat kecil sensori methasone valerate (26). Dalam serangkaian kasus 11 pasien dengan
neuropati yang sudah ada sebelumnya pada PN yang mungkin pruritus kronis dan PN refrakter terhadap terapi lain, inhibitor
menjadi faktor pendorong utama (14). Namun, penelitian lain kalsineurin topikal, tacrolimus dan pimecrolimus, menginduksi
melaporkan hasil yang kontras, termasuk peningkatan jumlah saraf respons sempurna pada 3/11 pasien PN, respons parsial pada 4/11
epidermal PGP 9,5-positif pada kulit dengan lesi PN (16), dan pasien dan tidak ada efek pada pasien lain (27).
hiperproliferasi saraf kulit, dengan peningkatan NGF dan
berkurangnya ekspresi semaforin 3A, dibandingkan dengan subyek
sehat (17). Hasil yang saling bertentangan ini mungkin karena
berbeda dalam teknik penelitian, jumlah kecil dan, yang paling
penting, heterogenitas pasien. Hipotesis asal neuropatik PN juga
didukung oleh pengamatan bahwa terapi topikal dan sistemik yang
digunakan untuk gatal dan nyeri neurologis, seperti capsaicin,
gabapentin dan pre-balin, mengurangi intensitas gatal dan jumlah
lesi kulit di Pasien PN (7,8,18-20).
Selain itu, serat-serat neuropati, seperti Aδ- fibres dan C-fibres
kepadatannya rendah pada serabut saraf intra-epidermal pada biopsi

2
 Terapi Sistemik
Tidak ada penelitian yang secara resmi menyelidiki keefektifan
antihistamin oral dan steroid sistemik, serta agen imunosupresif
lainnya meskipun mereka umumnya digunakan di PN. Agen
sistemik, yang baru-baru ini diselidiki, termasuk antiepileptik
(gabapentin, pregabalin), thalidomide, antagonis neurokinin reseptor
1 (NKR1) (aprepitant), dan antagonis reseptoropioid, naltrexone.
Gabapentin dan pregabalin memblokir saluran kalsium neuron dan
meningkatkan konsentrasi asam butirat gamma-amino (GABA) di
otak. Mereka memiliki aktivitas anti-kejang, dan juga digunakan
untuk pengobatan sindrom nyeri neuropatik seperti neuropati
diabetik dan neuralgia postherpetik, dan nyeri neuropatik epilepsi
dengan cedera saraf tulang belakang. Gabapentin dan pregabalin
telah membuktikan aktivitas anti-pruritus mereka dalam pruritus
terkait dialisis, dan dalam pruritus post-burn pada RCT (28,29).
Hanya dua seri kasus yang menyelidiki penggunaan gabapentin pada
PN. Dalam serangkaian kasus sembilan pasien, lima adalah pruritus
kronis dan empat adalah oleh PN, gabapentin secara signifikan
meningkatkan rasa gatal dengan dosis 300-900mg per hari untuk 2-
10 bulan (18). Dari 30 pasien PN yang diobati dengan pregabalin (75
mg /hari selama 3 bulan), 23 (76%) menunjukkan respons lengkap,
dan terapi itu tidak berhasil pada satu kasus. Sedasi hanya muncul
pada tiga pasien (19). Gabapentin tidak dimetabolisme di hati dan
tidak berubah saat diekskresikan dalam urin. Posologi harus
dikurangi sesuai dengan pembersihan kreatinin pada pasien dengan
gangguan ginjal berat, atau pada orang tua. Penggunaan harus
diperhatikan pada wanita hamil dan menyusui karena termasuk
dalam kategori kehamilan C dan masuk dalam ASI.
selama terapi dan selama 4 minggu setelah penghentian, baik untuk
Thalidomide berperan sebagai obat imunomodulator, sebuah
wanita maupun pria.
inhibitor faktor dinekrosis tumor, sebagai depresan saraf perifer dan
Aprepitant adalah suatu selektif antagonis NKR1 afinitas –
sentral. Obat ini disetujui untuk mengobati eritema nodosum
tinggi, yang mencegah substansi P berikatan dengan reseptor.
leprosum dan multiple myeloma, tetapi juga terbukti bermanfaat
Indikasinya adalah pencegahan muntah dan mual yang akibat
dalam banyak gangguan dermatologis yang sulit disembuhkan
kemoterapi pasien kanker pada dosis 80-125 mg setiap hari selama 3
dengan terapi konvensional (30). Tidak ada RCT yang menggunakan
hari sebelum memulai kemoterapi. Sebuah studi oleh Ständer et al.
terapi thalidomide pada PN tersedia. Studi retrospektif terbesar
mengungkapkan bahwa pemberian dengan dosis 80 mg sekali sehari
termasuk 42 pasien PN yang refrakter terhadap terapi topikal,
selama 1 minggu menyebabkan penurunan yang signifikan dari
sistemik dan steroid intralesi, fototerapi dan perawatan lainnya. Tiga
pruritus pada 13 PN pasien, menunjukkan penurunan VAS rata-rata
puluh dua pasien mengalami perbaikan klinis setelah durasi rata-rata
sekitar 50% dan perbaikan klinis lesi awal (37).
pengobatan dengan thalidomide dari 105 minggu dengan dosis rata-
Naltrexone adalah antagonis kompetitif oral pada reseptor
rata 100mg perhari. Pembersihan total lesi diamati pada 1 pasien,
opioid, yang telah digunakan dalam pengobatan pruritus yang terkait
peningkatan pada 31 pasien dan tidak ada efek pada 6 pasien. Alasan
dengan berbagai penyakit dermatologis dan sistemik, seperti PN,
paling umum untuk penghentian pengobatan adalah neuropati perifer
mikosis fungoides, liken simpleks, tetapi RCT hanya ada untuk
dan sedasi, atau kurang berkhasiat pengobatannya. Temuan serupa
pruritus kolestatik, urtikaria kronis dan dermatitis atopik (38). Pada
dilaporkan pada kasus kecil lainnya menggunakan thalidomide
133 kasus pasien dengan pruritus yang disebabkan oleh peradangan
dengan dosis harian 50-200 mg (32-36). Dalam serangkaian kasus 13
penyakit kulit menunjukkan bahwa naltrexone 50-150mg/hari sangat
pasien PN yang diobati dengan thalidomide dosis rendah (50-100 mg
efektif dalam PN, pruritus karena limfoma kulit dan pruritus yang
setiap hari), 84% pasien menunjukkan respons sedang hingga baik
tidak diketahui penyebabnya (39), membuktikan efek anti-pruritus di
(32). Efek samping lain yang umum dari thalidomide adalah sembelit,
67,7% pasien.Naltrexone dikontraindikasikan pada pasien dengan
pusing, ruam, edema, kekeringan, pruritus, neutropenia, bradikardia,
hepatitis akut, gagal hati, hati yang berat dan cedera hepatoseluler
takikardia, hipotensi, sakit kepala, perubahan mood, mual,
(38).
peningkatan nafsu makan, pertambahan berat badan, disfungsi
seksual pria, amenore, kegagalan ovarium dan thrombosis. (31)
Thalidomide adalah teratogen, dan langkah-langkah kontrasepsi yang
memadai diperlukan selama 4 minggu sebelum memulai terapi,

3

Terapi Fisik
Fototerapi umumnya digunakan dalam berbagai efek inflamasi
penyakit kulit dan anti inflamasi dari paparan sinar UV untuk
mengurangi pruritus telah dipastikan di beberapa peradangan
gangguan kulit, termasuk dermatitis atopik, lichen planus ruber dan
PN(40). Radiasi UVB, pengobatan gabungan radiasi UVB dan
topikal psoralen UVA, kombinasi thalidomide dan narrowband UVB,
dan pengobatan dengan UVA dan monokromatik cahaya excimer
(308 nm) semuanya telah digunakan dengan hasil variabel dalam
pengobatan PN (41). Hammes dkk, melakukan RCT pada 22 pasien
dengan PN refrakter terhadap kortikosteroid topikal atau intralesi
yang diberikan selama setidaknya 6 bulan, dan membandingkan bath
PUVA empat kali seminggu dengan peningkatan dosis dari MED 0,2-
0,3 J / cm2 setiap tiga perawatan (maksimum 3,5 J / cm2) dengan
kombinasi bath PUVA dan targetkan UVB 308 nm radiasi excimer
laser pada tingkat 200 Hertz pada intensitas 400 mW / cm 2.
Peningkatan diperoleh pada kedua kelompok. Tidak ada perbedaan
yang signifikan dalam jumlah remisi, tetapi kelompok PUVA terapi
tunggal membutuhkan 30% lebih radiasi PUVA untuk mencapai
manfaat yang sama (40). Seri kasus lain pasien yang menggunakan
fototerapi yang dengan berbagai penyakit kulit termasuk PN, tetapi
jumlah subyek PN yang dimasukkan terlalu kecil untuk mengambil
data yang bermakna. Dalam seri kasus terbaru, 19 pasien yang
terkena PN resisten terhadap steroid topikal diobati dengan sinar UV
yang memancarkan UVA pada 390 nm, untuk jumlah rata-rata 23
perawatan fototerapi (kisaran 7-37) dengan total dosis rata-rata 6,07
J / cm2. Sekitar 80% dari mereka mengalami peningkatan kondisi
klinis setelah perawatan. Dua pasien remisi lengkap, delapan
mengalami perbaikan, lima sedikit perbaikan dan empat (21,1%)
tidak memiliki respon (41).
Kesimpulan
PN adalah penyakit kronis dan sangat melumpuhkan, yang
mungkin memiliki dampak luar biasa pada kualitas hidup. Temuan
terbaru menunjukkan asal neuropatik dari penyakit, yang mungkin
dianggap sebagai sub tipe saraf kecil neuropati namun studi lebih
lanjut diperlukan untuk lebih mendukung hipotesis ini. PN dikaitkan
dengan banyak komorbiditas dermatologis dan non-dermatologis,
tetapi data terbatas untuk mendukung adanya hubungan sebab- akibat
yang jelas. PN adalah gangguan heterogen, dan beberapa kumpulan
definisi mungkin sangat penting juga untuk percobaan terapi baru.
Beberapa RCT tentang pengobatan pada PN. Tidak ada regimen yang
tampaknya lebih efektif daripada yang lain, karena studi banding
masih kurang. Fototerapi dianggap efektif dan aman, tetapi tidak
praktis bagi banyak pasien. Hasil yang menjanjikan telah diantisipasi
dengan gabapentin dan pregabalin, tetapi RCT masih kurang. Khasiat
antagonis NKR1 perlu dipastikan dalam studi multicenter yang lebih
besar. Kemungkinan besar, pasien dengan PN perlu pendekatan
dengan terapi kombinasi, yang mencakup penekanan beberapa
mediator, termasuk sitokin dan neuromediator.
Deklarasi menarik: Para penulis melaporkan tidak ada masalah
menarik. Penulis sendiri bertanggung jawab atas konten dan
penulisan makalah.

4
Journal of Dermatological Treatment, 2013; 24: 458–462
© 2013 Informa Healthcare USA on behalf of Informa UK Ltd.
ISSN: 0954-6634 print / 1471-1753 online
DOI: 10.3109/09546634.2013.814759
REVIEW
Prurigo nodularis: an update on etiopathogenesis and therapy
Anna Chiara Fostini, Giampiero Girolomoni & Gianpaolo Tessari
Department of Medicine, Section of Dermatology and Venereology, University of Verona, Verona, Italy
Prurigo nodularis (PN) is a chronic, highly pruritic condition
characterized by the presence of hyperkeratotic, excoriated, pruritic
papules and nodules, with a tendency to symmetrical distribution. No
reliable data exist about incidence and prevalence of PN in the general
population, but it seems to be more frequent and more intense in
females. PN may be associated with many dermatological and non-
dermatological comorbidities, including psychiatric disease. Recent
findings suggest a neuropathic origin of PN, with alterations in the
dermal and epidermal small diameter nerve fibers. PN may have a
tremendous impact on the quality of life, and few effective treatment
options are available. Few randomized controlled trials (RCT) on the
therapy of PN are available, demonstrating the efficacy of
phototherapy alone or with psoralen, and of topical calcipotriol and
topical steroids in occlusive medications. Thalidomide may be
effective, but no RCT are available and its use is impractical due to
the unfavorable safety profile. Gabapentin, pregabalin and the
neurokinin receptor
1 antagonist, aprepitant, seem also to be effective in the
therapy of PN, but RCTs are still lacking.
Key words: nodular prurigo, prurigo nodularis,
pathogenesis, RCT, therapy
Introduction
Prurigo nodularis (PN) is a chronic-relapsing, highly pruritic,
condition, with a high impact on the quality of life of the patient. It
is characterized by the presence of several to hundreds hyper-
keratotic, pruritic papules and nodules, sometimes excoriated or
ulcerated, with a tendency to symmetrical distribution on the
shoulders, on the back, the buttocks and the upper and lower limbs.
Sparing of the upper mid back, known as ‘butterfly sign’, is
distinctive (Figure 1). Incidence and prevalence of PN in the general
population are unknown, because in epidemiological studies PN is
often included in chronic itchy disorders (1,2). In female patients PN
seems to be more prevalent, to occur at an earlier age, and to be more
severe than in male patients (3). The diagnosis of PN is usually made
on clinical basis. Histology can be helpful, but it is not specific, and
it includes irregular epidermal or pseudoepitheliomatous
hyperplasia, fibrosis of the papillary der-mis with vertically arranged
collagen fibers, and a perivascular and interstitial inflammatory
infiltrate of lymphocytes, macro-phages, eosinophils and neutrophils
(4). The pathogenesis is still not fully elucidated, and evidence-based
therapies are very limited. The aim of this review is to present an
update on etiopathogenesis and evidence-based treatments of PN.
Correspondence: Gianpaolo Tessari, Department of Medicine, Section of Dermatology and Venereology, University of Verona, Piazzale A. Stefani 1,
37126 Verona, Italy. Tel: +39 045 8122547. Fax: +39 045 8027315. E-mail: gianpaolo.tessari@ospedaleuniverona.it
(Received 3 June 2013; accepted 9 June 2013)
5
Methods
We searched PubMed articles using the keywords ‘prurigo
nodularis’ and ‘nodular prurigo’. A total of 394 articles were
retrieved to February 2013. We selected and reviewed those
articles providing relevant information about etiopathogenesis
and therapy of PN. Randomized controlled studies (RCTs) and,
if not available, large case series were considered.
Etiopathogenesis of PN
Aetiology of PN is very poorly understood and only few studies have
described the total incidence and the strength of association of co-
morbidities in a representative cohort of patients (2,5). The most
common dermatological disorder associated to PN is atopic
dermatitis, described also as ‘atopic prurigo’ (6). Systemic diseases
frequently associated to PN are type 2 diabetes mellitus, thyroid
disorders, HCV infection, non-Hodgkin lymphoma and psychi-atric
disorders, particularly depression and anxiety (2,5). In some cases,
no underlying disease is detected (idiopathic PN). A detailed
description of the conditions associated to PN is reported in Table I.
The pathogenesis of PN is still unknown; however, recent findings
suggest that PN might be a consequence of chronic itch induced by
neuropathy. Neuropathic itch is a pruritic sen-sation caused by a
primary lesion or dysfunction at any point along the afferent pathway
of the nervous system and it is well established in some conditions,
including postherpetic neuropa-thy, brachioradial pruritus and
notalgia paresthetica (7). A dis-tinctive characteristic of neuropathic
itch is the co-existence of other sensory symptoms as paraesthesia,
hyperesthesia or hypoesthesia, as well as burning, tingling, stinging
and heat and cold sensations (7). These symptoms are frequently
referred to by PN patients (2). Bharati et al. was able to confirm a
subclinical neuropathy in a small group of patients with PN, by
performing nerve conduction studies (8).
Nerve fibers morphology and distribution in lesional and non-
lesional skin in PN patients have been repeatedly investi-gated.
An increased number of protein gene product 9.5 (PGP 9.5), p75
nerve growth factor (NGF)-positive and calcitonin gene-related
peptide (CGRP)-positive nerve fibers in the papillary dermis of
patients with PN has been described (9). Moreover, the nerves
were in close proximity to eosinophils, suggesting a functional
relationship (10). A significant increased density of dermal
substance P-positive nerve fibers in lesional skin of patients with
PN, and also in clinically normally appearing skin affected by
chronic pruritus, if compared to the non-affected skin of the same
patients has been described (11). Substance P is a well known
mediator of itch induction and

A B
Figure 1. A 58-year old woman with prurigo nodularis, with typical
excoriated nodules distributed bilaterally and symmetrically (A). Higher
view of excoriated nodules on the breast (B).
maintenance, and an increased numbers of substance P positive
dermal nerve fibers have been documented also in atopic der-matitis
(12). Epidermal keratinocytes and T-lymphocytes infil-trating skin
areas affected by pruritus may be a source of NGF, which may
contribute to the neurohyperplasia, as well as to nerve fibers
sprouting and up-regulation of neuropeptides, especially substance
P (11,13). Fewer studies have investigated the role of epidermal
nerve fibers in PN. The density of intraepidermal PGP 9.5-positive
nerve fibres in lesional pruritic skin as well as in non-pruritic skin of
patients with PN was significantly reduced, if compared to skin
biopsies taken from healthy volunteers. In patients with pruritus
lasting longer than 3 years, the reduction of nerve fibers was more
marked in lesional skin, if compared with non-lesional skin (14).
These findings seem not to be the con-sequence of a nerve damage
induced by chronic scratching, because in common pruritic
conditions, including atopic derma-titis, there is sprouting of
epidermal nerve fibers (12,15). The authors concluded that the
reduced density of epidermal nerve fibers, also found in uninvolved
skin, is possibly related to a subclinical small-fibers sensory
neuropathy pre-existing to PN that may be the main driving factor
(14). Other studies, however, reported contrasting results, including
increased numbers of PGP 9.5-positive epidermal nerves in lesional
PN skin (16), and hyperproliferation of cutaneous nerves, with
enhanced NGF and reduced semaphorin 3A expression, compared
with healthy subjects (17). These conflicting results are possibly due
to differ-ences in investigation techniques, and the small number
and, most important, heterogeneity of patients enrolled. The hypoth-
esis of the neuropathic origin of PN is also supported by the
observation that topical and systemic treatments used in neuro-pathic
itch and pain, such as capsaicin, gabapentin and prega-balin, reduce
itch intensity and the number of cutaneous lesions in PN patients
(7,8,18–20). Moreover, small fibers neuropathies, selectively
involving Ad-fibres and C-fibres, are characterized by low intra-
epidermal nerve fiber density in skin biopsies, and are associated
with systemic diseases common to PN (21).
Some cytokines may play a role in the pathogenesis of PN (22).
The involvement of Th2-mediated inflammatory responses in the
pathogenesis of PN has been hypothesized given a high expression
of the STAT6 transcription factor in lesional epidermis, which is
typically induced by IL-4 and IL-13. However, also STAT3
expression has been detected. This transcription factor is induced
primarily by IL-22, and to less extent by IFN-g . Interestingly
enough, IL-22 promotes keratinocyte proliferation and it is highly
expressed in atopic dermatitis skin (23). In PN patients with a history
of atopic dermatitis, plasma levels of IL-31 were signif-icantly
increased and correlated with the expression of IL-4 and IL-13 (24).
These observations suggest that PN is a dermatosis with the
preferential involvement of Th2 cytokines, and they
6
Pathogenesis and therapy of PN
support, together with the presence of dermal nerve fibers
hyperplasia, the strict correlation between PN and atopic
dermatitis.
Treatment of PN
Treatment of PN is still a challenge, and it is frustrating for both
dermatologists and patients because, in the majority of cases, the
response is limited and unsatisfactory. There is no standardized
therapy of PN, and evidence from RCT is limited. Treatments
include topical, systemic and physical approaches (Table II).
Topical therapy.
Topical agents are used when the disease affects limited skin areas.
A bilateral paired RCT on 12 patients, comparing an occlusive
dressing of beta-methasone valerate 0.1% and moisturizing cream
revealed significant improvement on both sides of the body, but beta-
methasone valerate showed a higher clinical response (VAS from
8.75 to 3.9) compared with moisturizing itch relief cream (VAS from
8.75 to 5.63). The improvement obtained with mois-turizing cream
may be due to the relief to the skin xerosis which is common in
patients with PN (25). A double-blind, right/left RCT compared the
efficacy and tolerability of 50 mg/g calcipotriol ointment with 0.1%
betamethasone valerate ointment on 10 sub-jects affected by PN,
showing that calcipotriol ointment was more effective and cleared
prurigo nodules more rapidly than beta-methasone valerate ointment
(26). In a case series of 11 patients with chronic pruritus and PN
refractory to other therapies, the topical calcineurin inhibitors,
tacrolimus and pimecrolimus, induced a complete response in 3/11
PN patients, a partial response in 4/11 patients and no effect in the
other patients (27).
Systemic therapy.
No studies have formally investigated the effectiveness of oral
antihistamines and systemic steroids, as well as other immuno-
suppressive agents although they are commonly used in PN.
Systemic agents, which have been recently investigated, include
antiepileptics (gabapentin, pregabalin), thalidomide, neurokinin
receptor 1 (NKR1) antagonist (aprepitant), and the m-opioid
receptor antagonist, naltrexone. Gabapentin and pregabalin block
neuron calcium channels and increase the concentration of gamma-
amino butyric acid (GABA) in the brain. They have anti-convulsive
activity, and are also used for the treatment of neuropathic pain
syndromes such as diabetic neuropathy and postherpetic neuralgia,
and epilepsy neuropathic pain with spinal cord injury. Gabapentin
and pregabalin have proven their anti-pruritic activity in dialysis
related pruritus, and in post-burn pruritus in RCTs (28,29). Only two
case series investigated the use of gabapentin in PN. In a case series
of nine patients, five affected by chronic pruritus and four affected
by PN, gabapentin significantly improved itching at a dosage of 300–
900 mg per day for 2–10 months (18). Of 30 PN patients treated with
pregabalin (75 mg/die for 3 months), 23 (76%) showed a complete
response, and the therapy was unsuccessful just in one case. Sedation
appeared only in three patients (19). Gabapentin is not metab-olized
in the liver and is excreted unmodified in the urine. Posology should
be reduced according to creatinine clearance in patients with severe
renal impairment, or in elderly people. Caution must be used in
pregnant and lactating women because it is included in pregnancy
category C and it enters in breast milk.
Thalidomide acts as an immunomodulatory drug, a tumor
necrosis factor-a inhibitor, as well as a peripheral and central nerve
depressant. It is approved for treating erythema nodosum leprosum
and multiple myeloma, but it has also proven to be useful in many
dermatologic disorders refractory to conventional therapies (30). No
RCT on the use of thalidomide in PN are
A. C. Fostini et al.

Table I. Prurigo nodularis: reported associated diseases (2,5,6,42). onset of peripheral neuropathy and sedation, or the lack of
Cutaneous diseases efficacy (31). Similar findings were reported in other smaller case
Atopic dermatitis series using thalidomide at a daily dose of 50–200 mg (32–36).
Contact allergy In a case series of 13 PN patients treated with lower doses of
Insect bites thalidomide (50–100 mg daily), 84% of patients showed a
Nummular eczema moderate-to-good response (32). Other common side effects of
Infections thalidomide are constipation, dizziness, rash, edema, dryness,
Atypical mycobacteria pruritus, neutropenia, bradycardia, tachycardia, hypotension,
Helicobacter pylori headache, mood changes, nausea, increased appetite, weight
Hepatitis B virus gain, male sexual dysfunction, amenorrhea, ovarian failure and
Hepatitis C virus thrombosis (31). Thalidomide is teratogen, and adequate con-
Human immunodeficiency virus traceptive measures are required for 4 weeks prior to beginning
Strongyloides stercoralis therapy, during therapy and for 4 weeks after discontinuation,
Lymphoproliferative diseases and tumours both for woman and for man.
Carcinoma of the bladder Aprepitant is a selective high-affinity NKR1-antagonist,
Gastric cancer which prevents substance P to bind its receptor. Its registered
Hodgkin’s disease indication is the prevention of vomit and nausea induced by
Leiomyomatosis peritonealis disseminata chemotherapy in oncologic patients at the posology of 80–125
Lennert’s lymphoma mg daily for 3 days before starting chemotherapy. A study by
Non-Hodgkin B-cell lymphoma Ständer et al. revealed that its administration at dose of 80 mg
Miscellaneous once daily for 1 week led to a significant reduction of pruritus on
Alpha-1 antitrypsin deficiency 13 PN patients, showing a mean VAS reduction of about 50%
Aluminum overload in haemodialysis and a clinical improvement of scratch lesions (37).
Anaemia Naltrexone is an oral competitive antagonist at m-opioid receptor,
Psychiatric disorders which has been used in the treatment of pruritus associated with a
Atopy variety of dermatologic and systemic diseases, such as PN, mycosis
Etretinate treatment fungoides, lichen simplex, but RCT exist only for cholestatic
Gluten enteropathy pruritus, chronic urticaria and atopic dermatitis (38). A case series of
Hepatic dysfunction 133 patients with pruritus caused by inflammatory skin diseases
Myxoedema showed that naltrexone 50–150 mg daily was most effective in PN,
Primary sclerosing cholangitis pruritus due to cutaneous lymphoma and pruritus of unknown origin
Uremia (39), revealing an anti-pruritic effect in 67.7% of patients.
Venous stasis Naltrexone is contra-indicated in patients with acute hepatitis, liver
Diabetes mellitus I failure, severe liver insufficiency and marginal evidence of
Thyroid disorders hepatocellular injury (38).

available. The largest retrospective study included 42 PN patients
who were refractory to topical, systemic and intrale-sional steroids,
phototherapy and other treatments. Thirty-two patients experienced
clinical improvement after a median duration of treatment with
thalidomide of 105 weeks at the average dose of 100 mg daily.
Complete clearing was observed in 1 patient, improvement in 31
patients and no effect in 6 patients. Most common reasons for
treatment discontinuation were the
Physical therapy.
Phototherapy is commonly used in various inflammatory skin
diseases and the anti-inflammatory effect of UV-light exposure and
the ability of UV light to diminish pruritus has been confirmed in
several inflammatory cutaneous disorders, including atopic
dermatitis, lichen ruber planus and PN (40). Broadband UVB
radiation, sequential combined treatment of UVB irradia-tion and
topical psoralen UVA, a combination of thalidomide and
narrowband UVB, and treatment with UVA and monochromatic

Table II. Current evidence based therapies of prurigo nodularis.

Study design Type of drug No of patients References

RCT Betamethasone valerate 0.1% tape vs. moisturizing itch relief cream 12 (25)
RCT Calcipotriol ointment (50 mg/g) vs. betamethasone valerate ointment 0.1% 10 (26)
RCT Bath PUVA vs. bath PUVA + targeted UVB 308 nm excimer light 22 (40)
CS Pregabalin (75 mg p.o. daily for 3 months) 30 (19)
CS Gabapentin (300–900 p.o. mg daily) 9 (4: PN) (18)
CS Aprepitant: (80 mg p.o. daily for 3–13 days) 20 (13: PN) (37)
CS Cyclosporine microemulsion (3–5 mg/kg p.o. daily) 14 (43)
CS Roxithromycin (300 mg + tranilast 200 mg p.o. daily) 3 (44)
CS Thalidomide (50–200 mg p.o. daily) 13 (32)
CS Thalidomide 42 (31)
CS Thalidomide 48 (PN and other skin conditions) (33)
CS Thalidomide (50–100 mg p.o. daily) 6 (34)
CS Thalidomide (100–200 mg p.o. daily) 25 (1: PN) (35)
CS Intranasal butorphanol (1 mg/d) 5 (1: PN) (45)
CS Topical calcineurin inhibitors 20 (11: PN) (27)

7
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