Review article 119

Prurigo nodularis – an update on an important disease

Athanasios Tsianakas, Claudia Zeidler, Claudia Riepe and Sonja Ständer

Department of Dermatology, Center for Chronic
Pruritus, University Hospital Muenster, Muenster,
Germany
Correspondence to Sonja Ständer, MD Department of
Dermatology, Center for Chronic Pruritus, University
Hospital Muenster, Von-Esmarch-Str. 58, 48149
Muenster, Germany
Tel: + 20 122 296 6670; fax: + 20 342 10352;
e-mail: carmen271173@yahoo.com
Received 21 January 2016
Accepted 24 April 2016
Journal of the Egyptian Women’s Dermatologic
Society 2016, 13:119–124
Prurigo nodularis (PN) is defined as a clinical pattern of mostly symmetrically papules
and nodules and belongs to the group of chronic pruritic diseases. Underlying
diseases can be skin diseases (e.g. atopic dermatitis or lichen planus), internal medical
diseases (e.g. hepatic or renal diseases), and neurological or psychiatric diseases.
Recently, new insights into the pathogenesis of PN have revealed an important role of
various neuropeptides such as substance P in the maintenance of the itch–scratch
cycle of PN. As a consequence, new clinical trials are being conducted to verify a
potential benefit by blocking these substances. However, till today, standard therapy
regimens for PN include, apart from the treatment of underlying diseases, topical
steroids, antihistamines, phototherapy, anticonvulsants, antidepressants, opioid
receptor antagonists, and, finally, immunosuppressants.
Keywords:
antihistamines, aprepitant, chronic pruritus, prurigo activity score, prurigo nodularis

J Egypt Women Dermatol Soc 13:119–124

& 2016 Egyptian Women’s Dermatologic Society
1687-1537

reported as to be among the top 20 of the most common

Introduction
Prurigo nodularis (PN) is a clinical pattern defined by
multiple, typically symmetrically distributed papules and
nodules that are often erosive and ulcerative. PN belongs
to the spectrum of chronic pruritic diseases, and
development of its itchy lesions is based on a vicious
itch–scratch cycle. Etiologically, it could be shown that
50% of the patients with PN have a concomitant atopic
disease [1]. Moreover, there are various other dermato-
logical potentially pruritic diseases such as bullous
pemphigoid and lichen planus that can lead to PN. In
addition, there is a variety of internal medical diseases
that can be associated with PN (e.g. chronic kidney and
liver diseases, tumors, diabetes mellitus, chronic iron
deficiency, and many others), as well as neurological and
psychiatric diseases [2]. Therefore, PN can be a result of
chronic pruritus of diverse origin, and thus a thorough
medical examination should always be carried out to
reveal any potential underlying disease.
Methods
An intensive literature research was performed on PN
using different electronic medical databases such as
Medline and DIMDI. The key words used were ‘prurigo
nodularis’ and ‘prurigo nodularis’ in combination with
‘epidemiology’, ‘pathophysiology’, ‘treatment’, and ‘ther-
apy’. In what follows, we would like to highlight the
pathophysiology, the clinical picture, the connection to the
underlying diseases, and the treatment options for PN.
Results
Epidemiology
There are only a few studies in the literature reporting
the frequency of PN among dermatological diseases,
mostly from Asia [3,4]. In these publications, PN is
1687-1537 & 2016 Egyptian Women’s Dermatologic Society
dermatological diseases, and its prevalence ranges from
1.82 to 3.8% [3,4]. Most often, elderly patients are
affected, but there are other reports even about affected
children [5]. Women seem to be more often affected than
men (female : male = 1.7 : 1), and the age of onset is
about 60 years [2]. There does not seem to exist a link of
PN to genetic factors [6].
Pathogenesis
Historically, for a long time histamine was thought to be
the major itch-inducing mediator of PN [7]. However,
high treatment-failure rates of the antihistaminic therapy
have led to a deeper insight into the pathogenesis of PN.
Histopathologically, increased numbers of eosinophilic
granulocytes, T-cells, and mast cells can be found in the
lesions of PN. Based on the infiltration with eosinophilic
granulocytes, there are high amounts of eosinophil
cationic protein, eosinophil-derived neurotoxin, and
eosinophil protein X in PN lesions [8]. In addition, it
could be detected that the T-cell-derived cytokine
interleukin (IL)-31 is upregulated in PN lesions [9].
This is also known from atopic dermatitis in which IL-31
serum levels even correlate with disease severity [9,10].
Furthermore, IL-31 is known to induce inflammation and
pruritus.
Most recently, there is a focus on changes of the
neuroanatomy in PN lesions. Chronic mechanical irrita-
tion by scratching seems to lead to proliferation of
keratinocytes, fibroblasts, mast cells, collagenous fibers,
and dermal nerve fibers [8,11]. Recently, an immunohis-
tochemical study has been published, in which it has
been shown that there is an increased expression of the
nerve growth factor (NGF) in epidermal keratinocytes
with PN [11]. But there exist many other neuropeptides
such as substance P, calcitonin gene-related peptide, and
DOI: 10.1097/01.EWX.0000481472.60356.9e

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120 Journal of the Egyptian Women’s Dermatologic Society
the receptor of NGF (TrkA p75NGF) that are increased
in PN lesions as well [12,13]. Increase of neuropeptides
can lead to nerve growth, but also to inflammation and
pruritus, which might be the link between the neurohis-
tological findings and the clinical picture. The itch
(reason for inflammation and pruritus)–scratch (causes
mechanical irritation with the consequence of inflamma-
tion and pruritus) cycle keeps the disease permanently
going.
Clinical appearance of prurigo nodularis
PN is typically characterized by symmetrically distrib-
uted erythematous papules, nodules, and plaques that are
highly pruritic. Their number can vary from just a few to
more than a hundred.
PN rarely occurs in circumscribed areas (typically in
neuropathic pruritus). In general, PN lesions affect the
extensor surfaces of the extremities and the trunk with a
typical butterfly sign (that means the lack of lesions at
the central back, which can be explained by the patient’s
inability to scratch these skin areas). The face is rarely
affected. For conducting clinical trials, it is important to
have a reliable measurement tool to evaluate the disease
activity. For PN, such a tool has not been made available
till now. Therefore, it is a welcome sign that just recently
a Prurigo Activity Score has been developed and
validated [14]. In addition, there are efforts to analyze
prurigo activity by a computer-based software that would
evaluate PN lesions automatically in an objective
way [15].
For a deeper understanding of the different clinical
features and pictures of PN during the time the patient
is suffering from PN, a publication by Schedel et al. [16]
should be referred. In that publication, it is clearly
presented how dynamically the lesions behave during the
course of the disease. After a nondefined time of chronic
pruritus, PN lesions appear as a consequence of chronic-
repetitive mechanical irritation (usually by scratching).
This first appearance of PN is characterized by small
papules that become bigger in size because of scratching
and develop into nodules or even plaques. These stages of
PN are therefore called papular type (Fig. 1), nodular type
(Fig. 2), and plaque type prurigo (Fig. 3). In the course,
these nodes can be massively excoriated, ulcerated (stage
of ulcerated prurigo), or show crusts resulting in scars after
healing. In some patients, no nodules but ulcerations with
fibrosated edges of elevated and hyperplastic epidermis
form resulting in the clinical picture of the umbilicated
ulcerative prurigo. This was (in former times) described as
an own entity (Kyrle’s disease).
Underlying diseases
Dermatological diseases
In up to 50% of PN patients there is an atopic
predisposition, often also showing signs of atopic
dermatitis [2]. As PN is a specific clinical skin reaction
pattern to chronic pruritus, PN can appear in many other
dermatological diseases. Sometimes the clinical picture of
PN can be so dominant that the originally underlying skin
disease can get hidden by it. Examples for underlying
Copyright r 2016 Egyptian Women’s Dermatologic Society. Unauthorized reproduction of this article is prohibited.
dermatological diseases are scabies, stasis dermatitis,
allergic contact dermatitis, lichen planus, bullous pem-
phigoid, dermatitis herpetiformis (Duhring), or even
neoplastic diseases such as cutaneous lymphoma or
multiple keratoacanthomata. Therefore, a histological
examination involving routine histology of the lesion plus
direct immunofluorescence of the surrounding skin of the
lesion should be carried out to rule out the above-
mentioned underlying diseases.
Systemic diseases
PN is an often described clinical picture of chronic renal
failure. In a study with patients suffering from chronic
renal failure, more than half of the patients showed PN
lesions [17]; in this trial, the duration of kidney disease
correlated with the probability to suffer from PN.
Metabolic diseases such as diabetes mellitus can also lead
to PN. The coexistence of chronic renal failure and
diabetes mellitus even leads to a more active stage of PN,
with umbilicated ulcerations; see Chapter ‘Clinical
appearance of PN’ by Tseng et al. [18].
Cholestatic diseases are known to lead to chronic pruritus
and in some cases to the clinical picture of PN. However,
in cholestatic pruritus, PN is an exception and patients
suffer mostly from chronic pruritus on normally looking
skin. Examples are primary sclerosing cholangitis, primary
biliary cirrhosis, choledocholithiasis, or hepatocellular
carcinoma [19].
Among viral hepatitides, hepatitis C is well-known to be
often associated with chronic pruritus [20] and can
sometimes also lead to PN [21]. Other infectious diseases
such as HIV are also well-known to frequently lead to the
appearance of PN [22].
Neurological disease
Neurological diseases are sometimes the reason of
localized PN. It is caused by irritation or damage of
cutaneous and/or extracutaneous nerves. Examples are
postherpetic neuralgia or brachioradial pruritus (often in
dermatome C6) [23,24].
Psychiatric diseases
The clinical picture of PN can be erased by the so-called
skin-picking disorder in which the patients scratch and
maltreat their skin despite lack of pruritus [25]. The
result is the appearance of PN-like lesions. In addition,
anxiety disorders, depressions, and tactile hallucinations
can also lead to chronic pruritus and thereby to PN as
well [26].
Treatment of prurigo nodularis
PN requires a multimodal itch therapy based on mainly
two arms. The first one is the treatment of the potentially
underlying disease, which can often lead to an improve-
ment in the itch (e.g. successful treatment of underlying
hepatitis C, HIV, renal and hepatic diseases). The second
arm is the symptomatic antipruritic therapy, which is
induced in parallel to the first arm and, if a causal therapy
is not possible or if it does not lead to a sufficient

Figure 1.
Papular type of prurigo.
Figure 2.
Nodular type of prurigo.
therapeutic effect, should be maintained until all PN
lesions are healed. For that, we have developed treatment
algorithms for PN treatment (Fig. 4). The different
treatment levels are explained in what follows.
Topical symptomatic treatments
Generally, clinical experience has shown that a basic
topical therapy with moisturizing emollients exhibits
antipruritic efficacy and is therefore always concomitantly
recommended. Topical emollients are most often not
completely sufficient, so that in daily practice the first-
line topical treatment of PN is the use of topical steroids.
However, there are just a few randomized clinical trials
underlining its efficacy (e.g. betamethasone valerate
Copyright r 2016 Egyptian Women’s Dermatologic Society. Unauthorized reproduction of this article is prohibited.
Prurigo nodularis Tsianakas et al. 121
Figure 3.
Plaque type of prurigo.
0.1% [27] or hydrocortisone 1% cream [28]). On the
bottom of the widespread use of topical calcineurin
inhibitors (such as pimecrolimus cream and tacrolimus
ointment) in atopic dermatitis, these substances are also
sometimes used in PN cases not accordingly responding
to topical steroids or because of the side effects of
steroids. A randomized controlled trial showed that
pimecrolimus 1% cream is as effective as hydrocortisone
1% cream in treating PN [28]. In the case of only single
PN lesion, an injection with triamcinolone acetonide is
also possible [29]. In localized neuropathic PN, such as
brachioradial pruritus, the usage of topical capsaicin is an
option. It can be either used as a cream in various
concentrations (0.025–0.3%) for up to six times daily or as
a ready to use patch [30,31].
Systemic symptomatic therapy
Antihistamines: Despite missing randomized trials for all
kinds of systemic therapies and missing approval of
systemic therapy for the treatment of PN, treatment with
antihistamines is still the number one option of
dermatologists for the systemic therapy of PN. Despite
a convincing clinical effect of antihistamines, several
patients benefit from a therapy with modern antihista-
mines. It is recommended to use high doses of
nonsedative antihistamines (dosage of four times a day)
if necessary, in addition to a sedative antihistamine at
night [32]. A combination with antileukotriene agents
such as montelukast is also possible [33]. A case series
with 12 PN patients showed successful treatment with
the antihistaminic fexofenadine 240 mg per day in
combination with 10 mg of montelukast per day [33].
UV therapy: An alternative for further systemic treatment
or addition to antihistamines and topical steroid or
capsaicin treatment is the ultraviolet (UV) phototherapy.
There are several case series and a single case report
about successful treatment regimens with UVB, (bath)
PUVA, UVB excimer laser therapy, or UVA [34–36].
However, the only randomized controlled trial is the one
that compared bath PUVA with bath PUVA in combination
122 Journal of the Egyptian Women’s Dermatologic Society

Figure 4.

Level 4 • Immunosuppressants such as cyclosporine A or methotrexate

• Opioid antagonists such as naltrexone or naloxone

disturbance, psychosomatic concomitant treatment

• Intralesional injection of triamcinolone

Basic therapy, if necessary treatment of sleep

Level 3 • Topical capsaicin (in localized PN)
• Antidepressants (SSRI, tricyclic, tetracyclic)

Level 2 • Topical primecrolimus and tacrolimus

• Anticonvulsants (such as gabapentin or pregabalin)

Level 1 • Treatment of underlying disease

• Topical steroids
• Non-sedative antihistamines
• Phototherapy

Algorithms of treatment of PN. PN, prurigo nodularis; SSRI, selective serotonin reuptake inhibitor.

with UVB 308 nm excimer light in 22 patients [37].
The combination resulted in lower cumulative PUVA
doses.
Generally, in daily practice UV therapy has many
limitations as it is time-consuming and due to its
potential carcinogenicity. Therefore, it is only appropriate
for a specific target population.
Anticonvulsants: After failure of antihistamines and UV
therapy, the group of anticonvulsants has been shown to
be effective in PN treatment. Well-known from the
therapy of chronic pruritus [38], there are several case
reports in the field of treatment of PN [39,40]. Our own
clinical experience has shown that the antipruritic
character of gabapentin seems to be superior to the one
of pregabalin (clinical observation).
For the mode of action for both substances, it is
postulated that they react as ligands of the a2–d subunits
of calcium channels of peripheral and central nociceptive
neurons. Their binding results in calcium influx with the
result of inhibition of depolarization of neuronal cells [41].
Antidepressants: Based on the results of the therapy of
chronic pruritus, it is well-known that antidepressive
agents have antipruritic properties. Both the group of the
selective serotonin reuptake inhibitors (e.g. paroxetine
and sertraline) [42–44] and the tetracyclic (e.g. mirtaza-
pine) [45,46] and tricyclic antidepressants (e.g. amitryp-
tiline, doxepin) [47,48] have been shown to be
efficacious in treating chronic pruritus. In the case of
PN as a subgroup of chronic pruritus, a two-arm, proof-of-
concept study comparing the two selective serotonin
reuptake inhibitors, paroxetine and fluvoxamine, in 50
PN patients resulted in complete healing of scratch
lesions in 14 patients and partial remission in 17 [49].
Opioid receptor antagonists: The m opioid receptor antago-
nists naloxone (intravenous dosing) or naltrexone (oral
administration) has been described to be efficacious in
treating PN, with response rates of up to 67.5% [50].
There are some randomized controlled trials reporting
the effects on pruritus in different underlying diseases
such as cholestatic pruritus [51,52]. However, potential
side effects such as dizziness, inability to drive, and
nausea have been considered and discussed with the
patients prior to the treatment initiation.
Immunosuppressive drugs: After failure or contraindication of
the above-mentioned drugs, the use of immunosuppres-
sive drugs such as cyclosporine A or methotrexate can be
considered in adults. The dose of cyclosporine A is
usually 3–5 mg/kg body weight and for methotrexate it is
7.5–20 mg once per week subcutaneously. A combination
of cyclosporine A and methotrexate (each in a drastically
reduced dosage) with the aim of reducing the side effects
of cyclosporine A can be successful. In a case series of 14
patients treated with cyclosporine A, high response rates
of greater than 90% have been detected [53]. Strong
results have also been reported in a retrospective
observation of 13 patients treated with methotrexate [54].
In addition to the case reports of the efficacious use of
thalidomide in PN [55], recently two case reports about
the use of its successor lenalidomide in treating PN have
been reported [56,57].
Other immunosuppressive drugs such as oral tacrolimus
have only been reported in single case reports, and thus
the evidence of their efficacy is highly limited [58]. The
use of systemic steroids as pulse therapy can be
considered as an initial therapy in patients with
extremely high degree of suffering. However, long-term
use is strictly contraindicated due to the known side
effects of steroids after continued treatment duration.
Future therapies: During the last few years, treatment of PN
has come under the focus of the medical community and
the pharmaceutical industry, so that several clinical trials
on the treatment of PN are currently in progress
(DRKS00005594, NCT01963793, NCT02196324). Exam-
ples are ongoing trials on neurokinin-1 receptor antagonists
aprepitant and serlopitant. As substance P as a major
pruritogenic transmitter is the ligand of neurokinin-1

Copyright r 2016 Egyptian Women’s Dermatologic Society. Unauthorized reproduction of this article is prohibited.

receptor, these receptor antagonists should have the
potential to considerably reduce chronic pruritus in PN.
Furthermore, a combination of m-opioid receptor antago-
nist and k-agonist nalbuphine is currently under observa-
tion in a clinical trial on treating PN (NCT02174419,
NCT02174432).
With respect to the pruritic properties of IL-31 and its
increase in PN lesion, a clinical trial of the recently
developed IL-4/IL-13 and IL-31 antagonists might be
promising as well.
Summary
The clinical pattern of PN should encourage the treating
physicians to find potentially underlying diseases. Suc-
cessful treatment of these diseases can lead to a rapid
improvement in PN. If this approach fails or is not
possible, a stepwise scheme has to developed to simplify
and categorize a successful treatment of PN, both
topically and systemically.
Acknowledgements
The authors thank Emily Burnett for the help in preparation of the
manuscript.
The work was supported by the Federal Ministry of Education and
Research (BMBF; no. 01KG1305)
Conflicts of interest
There are no conflicts of interest.
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