Australasian Journal of Dermatology
Blackwell Science, LtdOxford, UKAJDAustralasian Journal of Dermatology0004-83802005 Blackwell Publishing Asia Pty LtdNovember 2005464211220Continuing Professional Development Pro-
November 2005464211220Continuing Professional Development Program
Prurigo nodularis: A reviewMR Lee and S Shumack
Correspondence: Dr Michael R Lee, Department of Dermatology,
Royal North Shore Hospital, Pacific Highway, St Leonards, NSW
2065, Australia. Email: firstname.lastname@example.org
Michael R Lee, MB BS. Stephen Shumack, FACD.
Submitted 10 April 2004; accepted 10 March 2005.
nerve growth factor
nerve growth factor receptor
pulsed dye laser
tumour necrosis factor
-melanocyte stimulating hormone
CONTINUING PROFESSIONAL DEVELOPMENT PROGRAM
Prurigo nodularis: A review
Michael R Lee and Stephen Shumack
Department of Dermatology, Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales,
Hyde first described pruritic nodules on the extensor sur-
faces of the lower extremities in middle-aged women and
labelled the condition PN.
Since that time cases affecting
children and men have also been reported.
with PN can be divided into those who are atopic and non-
In the setting of atopy, PN has an earlier age of onset
and may be accompanied by cutaneous hypersensitivity to
various environmental allergens.
The classic lesion in PN is a firm pruritic nodule that is
hyperkeratotic, numbers from few to hundreds, and ranges
from several millimetres to 2 cm in diameter. There is a
tendency for symmetrical distribution, with a predilection
for extensor surfaces of the limbs; however, the trunk may
be involved. The face and palms are seldom affected
although no part of the body is exempt.
ment of the PN lesions is common and prominent features
include crusting and excoriations with post-inflammatory
hyperpigmented and hypopigmented macules. The skin
between the lesions is usually normal but can be xerotic or
A linear arrange-
The aetiology of PN remains unknown. There is uncertainty
as to whether PN is a primary cutaneous disease or whether
it is a pathological reaction secondary to pruritus and
scratching provoked by a separate cause.
A variety of systemic conditions have been reported to be
associated with PN (Table 1). The mechanism in the major-
ity of associated diseases that have been reported is unclear
and the link between PN and these associated disorders is
based on case reports. Psychosocial disorders such as
depression and anxiety may be postulated to be a primary
association or secondary to the itch in PN.
Prurigo nodularis is a chronic condition character-
ized by a papulonodular pruriginous eruption of
unknown aetiology. This condition is a difficult dis-
ease to treat and causes frustration to both the patient
and the treating doctor. A variety of systemic condi-
tions have been reported to be associated with pru-
rigo nodularis. The mechanism by which these
disorders may trigger prurigo nodularis is unknown.
Nerve growth factor has been implicated in the patho-
genesis of prurigo nodularis. Calcitonin gene-related
peptide and substance P immunoreactive nerves are
markedly increased in prurigo nodularis when com-
pared with normal skin. These neuropeptides may
mediate the cutaneous neurogenic inflammation and
pruritus in prurigo nodularis. Topical or intralesional
glucocorticoids are the treatment of choice. Other
topical treatments such as topical vitamin D3, and
topical capsaicin have also been reported to be effec-
tive. Oral treatments such as cyclosporin and thalido-
mide have been shown to improve both appearance
of the skin and pruritus. We review the clinical fea-
tures, associations, pathology, pathogenesis and treat-
ment of prurigo nodularis.
Key words: calcitonin gene-related peptide,
circumscribed neurodermatitis, lichen simplex
chronicus, nerve growth factor, picker nodules,
212 MR Lee and S Shumack
magnesium and phosphorous may result in microprecipi-
tation of calcium or magnesium phosphate salts in the skin
and may be the cause of uraemic pruritus.
toxicity has been considered as a cause of severe uraemic
pruritus and PN in a case series of dialysis patients.
maintenance haemodialysis patients with PN and alumin-
ium overload were treated with an aluminium chelating
agent and their skin lesions disappeared after treatment. A
case of a moderately differentiated tubular adenocarci-
noma of the stomach has been reported to be associated
Transforming growth factor-
produced by gastric malignancies and it is postulated that
this results in eosinophilia. Additionally, epidermal growth
factor, which stimulates keratinocytes, has been reported
to be elevated in gastrointestinal carcinomas that might
contribute to PN lesions.
and higher dermal levels of calcium,
is known to be
It is postulated that the extrahepatic manifestations of
hepatitis C may be attributed to the appearance of circulat-
ing immune complexes that may be deposited in the skin.
Several mechanisms for HIV involvement in PN have been
postulated. Direct viral infection of peripheral nerves by
HIV could possibly stimulate pruritus
demonstrated that viral infection of nerves can cause the
direct release of substance P.
infection may result from an immunological abnormality
within the skin. Infection with HIV is associated with a
reversal of the normal CD4 : CD8 ratio and this may result
in faulty recognition of one or more endogenous proteins.
Additionally, it has been demonstrated that there is a
reduction in the number of Langerhans cells that function
abnormally, resulting in faulty antigen processing and pre-
Patients with HIV infection also have increased
titres of IgE directed to HIV-1, levels that rise as CD4 counts
diminish. Finally, because HIV infection leads to polyclonal
activation of B-cells, the possibility of immune-complex
deposition has been proposed as a possible aetiology of
and it has been
Prurigo nodularis in HIV
PATHOLOGY AND PATHOGENESIS
Histologically, PN is characterized by marked hyperkerato-
sis, often focal parakeratosis, and marked irregular acan-
thosis that is often of pseudoepitheliomatous proportions.
The characteristic neurological changes observed include
hypertrophy and proliferation of dermal nerves.
nin gene-related peptide
and substance P
noreactive nerves are markedly increased in PN. These
neuropeptides may mediate the cutaneous neurogenic
inflammation and pruritus in PN. Table 2 outlines the neu-
ropeptides involved in PN and their actions.
There are increased numbers of Merkel cells in the
epidermis of PN nodules that have been postulated to be
a component of the neurocutaneous abnormality.
inflammatory infiltrate in the dermis includes lymphocytes,
mast cells, histiocytes and occasionally eosinophils.
Mast cells in PN lesions are increased in number and
show characteristic morphological changes such as an
enlarged cell body size and a dendritic shape compared
with the round or elongated shape seen in normal
Disorders reported in association with prurigo nodularis
Associated disorderReference no.
Focal causes of pruritus
Insect bite reactions
Folliculitis and discoid eczema
Polycythaemia rubra vera
Chronic renal failure
Gluten-sensitive enteropathy (coeliac disease)
Obstructive biliary disease
-1 antitrypsin deficiency
Hepatitis B virus
Hepatitis C virus
Neuropeptides in prurigo nodularis
Substance PIncreased Stimulates expression of intercellular adhesion molecule 1 and vascular cell
adhesion molecule 1
Activates mast cells to secrete tumour necrosis factor-
prostoglandin D2 and leucotriene B
Activate keratinocytes to secrete interleukin 1
Vasodilation and protein extravasation
Enhances chemotaxis and proliferation of fibroblasts
Enhances growth of keratinocytes
Vasodilation and protein extravasation
Induces interleukin 8 production in dermal microvascular endothelial cells
, histamine, 30–33
Prurigo nodularis: A review213
plasm with a decreased number of granules inside, sug-
gesting that many of the granules have been released into
the surrounding tissue.
Mast cells, which are known to
release NGF, are seen in close proximity to nerves
expressing increased levels of NGFr.
factor has, therefore, been implicated in the pathogenesis
of PN and its known actions are listed in Table 3.
has demonstrated that NGF is overexpressed in PN, which
could lead to neurohyperplasia.
two components: a trk high-affinity receptor and p75, a
low-affinity receptor. The expression of both subunits is
increased in the perineurium cells and Schwann cells of
the hyperplastic nerves found in lesional PN skin. This
may result in increased NGF binding and hence neural
Subsequently, neural hyperplasia could be
related to the strong itch caused by increased axon fir-
The increased NGF–NGFr interaction may not
only cause itch through neurohyperplasia but may also
contribute to the release of neuropeptides that initiate
and mediate neurogenic inflammation.
products that may contribute to pruritus in PN are listed
in Table 4.
Eosinophils containing eosinophil cationic protein,
eosinophil-derived neurotoxin/eosinophil protein X
major basic protein
are increased in lesional PN skin
and are in close proximity to afferent sensory nerves.
The eosinophilic granular basic proteins exacerbate
inflammation and are responsible for damaging nervous
and organisms such as parasites.
relationship between nerves and eosinophils suggests
The PN mast cells also have an abundant cyto-
The NGFr is made up of
Other mast cell
that eosinophil cationic protein and eosinophil-derived
neurotoxin/eosinophil protein X can be released to local
tissue and cause injury that may be manifested as itch.
Additionally, it has been reported that eosinophils can
release NGF and may contribute to the neurohyperplasia
Endothelial cells in the upper dermis of PN lesional skin
-MSH. It has been postulated that one of the roles
-MSH is to act as an immune suppressor in inflamma-
The role of
-MSH in PN is presently unknown,
although its function may be to counter the cutaneous
Dermal Langerhans cells, unlike epidermal Langerhans
cells, are increased in PN.
Langerhans cells and other dermal dendritic cells may be
implicated in the development or persistence of PN.
This suggests that dermal
Prurigo nodularis is a challenging condition to treat and
causes significant frustration to both the patient and the
treating doctor. It is important that the patient is informed
of the natural history of the disease and its resistance to
therapy. The difficulty in treating this disease is reflected in
the number of treatments. Once the itch–scratch cycle
‘takes over’, it is extremely difficult to stop.
An important first step in therapy is to identify any under-
lying associations and treat accordingly. Table 5 lists the
suggested investigations for these underlying associations.
Biopsies requesting histopathology and direct and indirect
immunofluorescence studies may be indicated, as pem-
phigoid nodularis that precedes bullous pemphigoid may
present as PN.
Serum IgE levels may be elevated in atopic
Patch testing should be performed to exclude
contact sensitivity to metals, fragrances or other chemical
Simple measures such as clipping the fingernails and rec-
ommending the use of gloves or mittens can be helpful.
Table 6 outlines the topical and systemic treatments cur-
rently used for PN. It is important to stress to the patient
the requirement to apply emollients as xerosis usually
worsens the pruritus.
Mast cell products that are mediators of itch
Mediator Mechanism underlying pruritic potencyReference
Induction of itch via H1-H3 receptor stimulation present on sensory nerve fibres
Induction of itch via proteinase-activated receptor 2 stimulation
Potentiates histamine-induced itch
Interleukin 2 activates subpopulation of cutaneous C-fibres.
Interleukin 6 acts on its receptor expressed in nerve and Schwann cells
Actions of nerve growth factor
Actions of nerve growth factorReference
Normal development and survival of peripheral
Chemotactic for neurones
Upregulates expression of substance P and
calcitonin gene-related peptide in neurones
Increases number of mast cells
Promotes myeloid progenitor cell growth
Induces proliferation and differentiation of B
Enhances histamine release by basophils
Accelerates cutaneous wound healing
Chemotactic for melanocytes
214MR Lee and S Shumack
Topical antipruritics such as 1% menthol or phenol in a
creamy base may be used to reduce the itch. Oral antihis-
tamines such as promethazine hydrochloride 25–75 mg at
night, or oral antidepressants such as doxepin 10–75 mg at
night may be administered to reduce the pruritus.
Potent topical glucocorticoid creams or ointments, such
as betamethasone dipropionate 0.5 mg/g, glucocorticoid
creams under occlusion, and intralesional glucocorticoids,
such as triamcinolone acetonide 10 mg/mL increasing to
40 mg/mL suspension, are often employed. Occlusive ban-
dages are useful as they interrupt the itch–scratch cycle.
UV light exposure has been shown to lessen the pruritus and
can be beneficial in the treatment of PN.
of UV light treatment in PN is to break the cycle of itching
and scratching. In a Scandinavian study, bath PUVA was
shown to be efficacious in 13 of 15 patients.
patients preferred 8-methoxypsoralen topical PUVA over
more painful therapies such as intralesional glucocorti-
Broadband (presumed, although not stated in the
article) UVB has been reported to be more effective than 8-
methoxypsoralen topical PUVA in cases with generalized
Cryotherapy is a useful therapeutic agent for the treat-
ment of PN.
The total time of liquid nitrogen applied to
the nodules varies from 10–30 s with two to four freeze–
thaw cycles depending on the size of the nodule. Blistered
nodules may take 2–4 weeks to heal and be replaced by
hypopigmented macules. Cryotherapy is thought to cause
destruction of sensory nerves and impairment of nerve
Treated patients may not complain of
pruritus for up to 3 months.
gery, intralesional triamcinolone acetonide 40 mg/mL
diluted 1:3 with lignocaine 1% may be an effective
method for treatment of PN.
cryosurgical erythema that develops as the thaw wears
off represents an oedematous state that facilitates the
injection of triamcinolone acetonide.
The main effect
In one study,
A combination of cryosur-
The immediate post-
Recently, topical vitamin D3 has been reported to be
effective in the treatment of PN.
lates cellular adhesion molecule expression by inhibiting
mRNA expression. Vitamin D3 also reduces the
number of epidermal FcR1
dendritic cells in PN lesions. A
double-blind, right/left comparison of calcipotriol ointment
g/g) and betamethasone valerate ointment (0.1%) in
the treatment of PN has shown calcipitriol to be more effi-
cacious in reducing the size and number of pruriginous
Capsaicin has been shown to reduce pruritus and induce
complete disappearance of lesions.
cally it induces itch and a burning sensation as well as
Capsaicin exerts its effects via binding to the
vanilloid receptor, which is located on free nerve endings.
Repeated topical application of capsaicin releases and pre-
vents specifically the accumulation of neuropeptides in
unmyelinated polymodal C-type and small myelinated A
type cutaneous nerves. Nociceptive sensations are mediated
by these nerve fibres and depleting neuropeptides from
these nerves impede the perception of pain and itch sensa-
tions, whereas tactile sensations remain.
patients with PN treated with topical capsaicin (dose range
from 0.025% to 0.3%) four to six times daily for 2 weeks up
to 10 months demonstrated complete remission of itching
in all within 12 days.
On average, concentrations of 0.05%,
0.075% and 0.1% appeared to be the most effective. After
discontinuation of capsaicin, pruritus returned in 16 of 33
patients within 2 months. Capsaicin is no longer commer-
cially available in Australia. It also should be applied four
to six times daily to prevent reaccumulation of neuropep-
tides and recurrence of itch. Capsaicin is an effective and
safe approach to the treatment of PN; however, the practi-
cality of capsaicin therapy is limited by the high application
frequency and high recurrence after discontinuation of
Vitamin D3 downregu-
When applied topi-
A study of 33
Cyclosporin has demonstrated unequivocal improvement
of PN as well as a reduction in the severity of pruritus.
Cyclosporin inhibits lymphokine
lymphocyte activation and proliferation.
Oral doses of
Suggested investigations for associated disorders in
Full blood count
Liver function tests
Urea, creatinine and electrolytes
Parathyroid hormone level
Thyroid function tests
HIV serology (if indicated)
Total serum IgE levels
Tuberculin skin testing (Mantoux test)
Skin biopsies for
– direct immunofluorescence
– microscopy (Ziehl–Nielsen stain) and culture
Current treatments available for prurigo nodularis
Topical antipruritics: menthol and phenol
Oral antihistamines: promethazine hydrochloride
Oral tricyclic antidepressants: doxepin
Topical and intralesional glucocorticoids
Narrow-band UVB, and PUVA
Topical vitamin D
Prurigo nodularis: A review215
3.5–4 mg/kg/day for periods of 24–36 weeks have demon-
strated a reduction in the severity of pruritus after
2 weeks. However, the use of cyclosporin is limited by its
side-effects of hypertension and renal damage and relapse
of disease after cessation of treatment. Regular monitoring
of the patient is required while on cyclosporin.
The first reported use of thalidomide in the treatment of
PN was in 1975.
Thalidomide inhibits polymorphonuclear
leucocyte chemotaxis and selectively inhibits TNF-
tion by enhancing degradation of TNF-
been postulated that thalidomide causes central nervous
system depression without causing incoordination, respira-
tory depression or narcosis.
effect, it causes a decreased perception of peripheral stimuli.
Thalidomide may have a direct peripheral action on the
proliferated neural tissue in the lesions causing PN.
have been reported cases where oral thalidomide at doses
of 200 mg daily demonstrated improvement of pruritus and
flattening of lesions with no serious adverse events.
not until a study of eight patients that the neurotoxic side-
effects were reported.
Seven of the eight patients developed
a predominantly sensory neuropathy mainly involving the
lower limbs after 6–14 months of thalidomide. An oral daily
dose of 150–400 mg thalidomide was initially given, after
which it was gradually reduced to a daily dose of 25–100 mg.
Their PN improved dramatically, but treatment had to be
discontinued due to sensory neuropathy. In three of the
patients followed up, the neuropathy was irreversible. An
Australian case series demonstrated improvement in pruri-
tus and a decrease in nodules in three of five patients with
PN treated with oral thalidomide.
achieved in any PN patient. This was thought to be due to
the low thalidomide doses (100–200 mg). Three adverse
events were reported, two of which were peripheral neur-
opathy. Other adverse events reported included dizziness,
angina and poor control of blood glucose levels associated
with underlying diabetes mellitus.
Zinc and iron concentrations in lesional skin have been
reported to be increased in PN.
thalidomide at a dose of 300–400 mg/day. In one patient, a
remission time of 17 months was achieved and this was
associated with a decrease in the lesional zinc and iron
concentrations towards that of uninvolved skin. In a second
patient, a lesion on the elbow demonstrated clinical
improvement for 7 months and this again correlated with a
reduction in the lesional zinc and iron concentrations.
Treatment with thalidomide decreased the lesional zinc and
iron levels towards the reference range.
have confirmed the efficacy of thalidomide with its im-
mediate pronounced effect on pruritus and significant
decrease in the size and number of skin lesions.
Sequential combined therapy with thalidomide and nar-
row-band UVB has demonstrated improvement in PN with
minimal side-effects. The side-effects of the two therapies
are distinct and not synergistic.
trial, four patients received oral thalidomide 100 mg daily
for 8–16 weeks (average 12 weeks) then narrow-band UVB
treatment was initiated. After a mean of eight narrow-band
UVB treatments (6–12 treatments), the pruritus had
Through its central sedative
Remissions were not
Four patients received oral
In a prospective open label
decreased dramatically and most lesions had disappeared.
Thalidomide therapy was ceased while narrow-band UVB
therapy was maintained until complete remission was
achieved. This occurred after an average of 32 narrow-band
UVB treatments. After a median follow up (after the end of
treatment) of 6 months (4–18 months), only one needed
topical glucocorticoids to control minor symptoms.
Thalidomide is currently an unregistered drug in Austra-
lia and prescribing is through the Special Access Scheme
on an individual basis. Its use is restricted to severe dis-
abling conditions that cause an unacceptable interference
with normal life, and only after other treatments have been
trialled and failed.
Little data have been reported on the use of laser in the
treatment of PN. One patient with PN was successfully
treated with a 585 nm PDL using a 5-mm beam at an energy
fluence of 6.5 J/cm
. Treatment was performed six times
at weekly intervals 1 hour after the application of topical
anaesthesia. After six treatment sessions the lesions
resolved. The PDL emits the wavelength that is close to one
of the absorption peaks of oxyhaemoglobin. The rationale
for the use of PDL is that one of the histological features in
PN is vascular hyperplasia and this vascular hyperplasia
may provide the PDL with a high density of oxyhaemoglo-
bin to act as its target chromophore. The treatment is well
tolerated with a low risk of scarring.
Naltrexone has been reported to have a high antipruritic
effect in patients with PN.
Opiates have been shown to
evoke or potentiate itch, independently from their hista-
The actions of the opiates results
from binding to peripheral and central opiate receptors.
As pruritus is modified by opioids, antagonizing opioids
suppress localized and systemic pruritus. In 17 patients
with PN, nine had an improvement of 50% or more
in pruritus. Naltrexone 50 mg daily orally was shown
to reduce scratching, which led to the subsequent
re-epithelialization of lesions, flattening and softening of
nodules, and final healing with some scarring and hyper-
pigmentation. Relief of pruritic symptoms can be observed
within 2–8 days.
The half-life of naltrexone is approxi-
mately 9 hours,
therefore after discontinuation of naltr-
exone, abrupt exacerbation of pruritus may occur.
Contraindications for the use of naltrexone include severe
liver insufficiency, acute hepatitis, pregnancy, breast-
feeding and opiate abuse.
A case report of an experimental oral retinoid, arotinoid
acid Ro-137410, has demonstrated a reduction in the
degree of pruritus and nodule formation.
acid is the active metabolite of arotinoid ethyl ester. It
has antitumour, antimetaplastic, differentiation-inducing,
anti-inflammatory and immunomodulatory properties.
Etretinate 50–75 mg/day has also been reported experi-
mentally to reduce the severity of pruritus and the size of
Prurigo nodularis presents as a treatment dilemma for doc-
tors and is frustrating to patients. There remain many