Am J Clin Dermatol

DOI 10.1007/s40257-016-0202-8

REVIEW ARTICLE

Subcorneal Pustular Dermatosis: A Review of 30 Years

of Progress
Paula Jean Watts1 Amor Khachemoune2

Springer International Publishing Switzerland 2016

Abstract Subcorneal pustular dermatosis (SPD), also

known as SneddonWilkinson disease, is a rare, benign yet Key Points
relapsing pustular dermatosis. Its incidence and prevalence
have not been well studied. It characteristically presents as Subcorneal pustular dermatosis (SPD) is a recurrent,
hypopyon pustules on the trunk and intertriginous areas of relapsing, sterile neutrophilic pustular dermatosis.
the body. SPD is similar to two other disease entities. Both In its classical clinical presentation, SPD appears as
SPD-type immunoglobulin (Ig)-A pemphigus and annular hypopyon pustules.
pustular psoriasis clinically and histologically present
Classically seen on histology are subcorneal
similarly to SPD. Immunologic studies separate SPD-type
collections of neutrophils without spongiosis or
IgA pemphigus from SPD and pustular psoriasis. However,
acantholysis.
there is still an unclear designation as to whether SPD is its
own entity distinct from pustular psoriasis, as the once SPD is typically found on the trunk and on
thought characteristic histologic picture of psoriasis does intertriginous and flexural surfaces.
not hold true for pustular psoriasis. SPD has been reported
An association with systemic diseases has been
to occur in association with several neoplastic, immuno-
observed, which includes other neutrophilic
logic, and inflammatory conditions. Dapsone remains the
dermatoses, hematologic disorders, connective tissue
first-line treatment for SPD, although dapsone-resistant
diseases, and neoplasms.
cases have been increasingly reported. Other therapies have
been used singly or as adjunctive therapy with success, Dapsone remains the treatment of choice.
such as corticosteroids, immunosuppressive agents, tumor
necrosis factor inhibitors, and ultraviolet light therapy. This
article provides a review of the last 30 years of available
literature, with a focus on successful treatment options and 1 Introduction
a suggestion for reappraisal of the classification of SPD.
Subcorneal pustular dermatosis (SPD), also known as
SneddonWilkinson disease, is a chronic, benign yet rare
neutrophilic dermatosis (ND), which was first described by
Ian Sneddon and Darrell Wilkinson [1]. It commonly pre-
& Amor Khachemoune sents in middle-aged women as a relapsing pustular skin
amorkh@gmail.com disorder, similar to a variety of erythematous and pustular
1
diseases. Although it is typically seen in adults, there have
Kansas City University of Medicine and Biosciences, 1750
Independence Avenue, Kansas City, MO 64106, USA
been a few cases found in children [24]. Its diagnosis is
2
made on the basis of characteristic clinical and
Department of Dermatology, Veterans Affairs Medical
Center Brooklyn and SUNY Downstate, 800 Poly Place,
histopathologic findings. Clinically, in its most character-
Brooklyn, NY 11209, USA istic form, patients will present with symmetrical,
 P. J. Watts, A. Khachemoune

superficial pustular lesions commonly over normal-ap- peripheral pustules [5]. SPD pustules most characteristi-
pearing skin, which progress to form annular patterns. cally arise on normal-appearing skin, yet in some instances,
These are distinctive, sterile, flaccid pustules, which appear the pustules may appear overlying erythematous or
with hypopyon formation. It is frequently found on the inflamed skin [5]. Within the pustules, there is a separation
trunk, intertriginous regions, and flexor aspects of the of two substances, with the bottom half containing purulent
extremities. It may occur as a localized cutaneous eruption, material and the top half containing clear fluid. This is also
without systemic involvement, or it may coexist with known as a hypopyon pustule. These pustules rupture
systemic disease. Histologic findings of SPD reveal sub- spontaneously, and areas of desquamation form. They then
corneal accumulation of neutrophils. It is similar in its crust over and heal with hyperpigmentation, most often
clinical and histologic presentation to pustular psoriasis without scarring. Lesions at different stages of evolution
and immunoglobulin (Ig)-A pemphigus, thus its classifi- are classically localized to the flexural surfaces in the
cation is debatable. axilla, groin, inframammary folds, and intertriginous areas,
In this article, we aim to provide a systematic review of as well as on the trunk and proximal extremities [9]. SPD
the literature available, with a critical reappraisal of SPD. has rarely been reported to involve the palms, soles, and
We critically reviewed common medical databases nails [10]. It usually spares the face and mucosal surfaces
(PubMed and Cochrane Central) for studies addressing [11]. Atypical cases in terms of age, sex, or unusual sites
SPD management and classification. We searched for rel- have been reported wherein SPD pustules were found
evant articles containing any of the terms Sneddon involving adult men or children, or on distal extremities
Wilkinson disease, subcorneal pustular dermatosis, [12]. Usually, SPD is localized to the skin, with mild
neutrophilic pustular dermatosis, IgA pemphigus, pruritus and irritation and without constitutional symptoms
pustular psoriasis, or a combination of the above, from [13, 14]. However, cases presenting with systemic symp-
1985 to 2015. The search results were reviewed, excluding tomssuch as malaise, fever, arthralgias, abnormalities of
articles without an English translation. We summarize the hepatic enzymes, aseptic neutrophilic abscesses, or scle-
key features of SPD, including the epidemiology, clinical rosing glomerulonephritishave been reported
presentation, histology, pathophysiology, associations, and [10, 14, 15]. See Fig. 13.
differential diagnoses. The review includes the latest
information on management and therapeutic options for
SPD, as dapsone-resistant cases have been noted.

2 Epidemiology

SPD most commonly presents between the fifth and sev-

enth decades of life [5]. It is four times more common in
women than in men [2, 5] and is extremely rare in children
[6]. Predilection for a certain race has not been discussed
[1], nor has there been a geographically favored region in
terms of its incidence or prevalence [7]. In a review written
by Chimenti and Ackerman in 1981 [8], more than 200
cases had been reported by that time. A more recent review
by Bordignon et al. [7] states that the true prevalence of
SPD has not been established, because of possible misdi-
agnoses and its rare incidence.

3 Clinical Presentation

Clinically, SPD presents abruptly with or without pain and,

in some cases, pruritic superficial papules, which develop
into flaccid pustules, vesicles, or occasionally bullae. New Fig. 1 Subcorneal pustular dermatosis. Right axilla. Multiple
lesions spread within a day or two to form annular, circi- 0.22 cm erythematous, annular lesions with central erosion and
nate, or serpiginous patterns with a central clearing and scaling on the periphery
Subcorneal Pustular Dermatosis
Fig. 2 Subcorneal pustular dermatosis. Right trunk. Multiple
0.22 cm pustules overlying mildly erythematous skin, coalescing
into annular lesions with central clearing and scaling on the periphery
4 Histology
Histologic examination reveals neutrophil infiltration of the
subcorneal layer of the epidermis, with occasional eosi-
nophils. Perivascular infiltrates are seen predominantly
with neutrophils [1], as well as exocytosis of neutrophils
[11] (Fig. 4a). Sneddon and Wilkinson suggest early his-
tologic examination of lesions, as these will show poly-
morphonuclear leukocytes migrating from the dermal
capillaries [1]. A splitting of the corneal layer from the rest
of the epidermis is noted with subcorneal accumulation of
neutrophils above a normal-appearing dermis, forming a
vesicopustule. The pustules appear to sit on top of the
epidermis, usually without forming spongiosis, and with
minimal change to the epidermis other than the pustules
[13, 14] (Fig. 4b). SPD pustules are nonfollicular [11].
Parakeratosis and elongation of rete ridges are reportedly
absent [1, 5]. Acantholysis may be observed in older SPD
lesions [5, 10, 12]. Moreover, Junkins-Hopkins and Busam
[11] have reported the presence of acantholysis within and
surrounding pustules in SPD. Mitotic figures are usually
absent [13]. Infectious agents are absent in SPD, unless
secondary infection is present.
5 Pathophysiology
The etiopathogenesis of SPD remains unknown [14, 16]. It
is one of a few skin disorders resulting from unidentified
mechanisms of neutrophilic recruitment to the skin, termed
neutrophilic dermatoses (NDs). NDs are a group of
heterogenous skin diseases, with common features. A
Fig. 3 Subcorneal pustular dermatosis. Right trunk. Multiple annular
lesions with central clearing and peripheral pustules overlying mildly
erythematous skin
common histopathologic finding is polymorphonuclear
leukocyte infiltrates at various levels within the epidermis,
dermis, or panniculus [17]. They are often associated with
similar systemic diseases and are frequently seen in co-
occurrence with other NDs [18]. NDs are defined on the
basis of their clinical and histologic presentation, and are
thought to result from exaggerated neutrophilic processes,
such as activation and phagocytosis. Although neutrophils
release enzymes intended for phagolysosomes, some are
unintentionally released into the extracellular space,
resulting in injury to normal tissues [19]. Figure 5 shows
the classification of NDs as proposed by Wallach and
Vignon-Pennamen [20], and a brief description of each
condition is given in Table 1.
A trigger for aberrant neutrophil chemotaxis in SPD has
not been identified. Faulty immune mechanisms and
genetic susceptibility have been proposed. Although
attempts (as discussed below) have been made to study the
causation, no widely accepted hypothesis has been
substantiated.
Neutrophilic chemotactic factors found within vesico-
pustules of SPD have suggested a defective immune
mechanism [14, 16, 21]. These include the presence of
tumor necrosis factor (TNF)-a [16], interleukin (IL)-8,
complement fragment C5a, and IgA within vesicles
[14, 21]. Significant findings in two reports focused on the
increased level of TNF-a in blister fluid [21] and in serum
[9]. Moreover, SPD has been seen to occur with other TNF-
a-implicated diseases, such as inflammatory bowel disease,
rheumatoid arthritis, pyoderma gangrenosum (PG), and
pustular psoriasis. These associations, as well as the partial
responsiveness of SPD to anti-TNF therapy, imply that
 P. J. Watts, A. Khachemoune

Fig. 4 Histologic features of

subcorneal pustular dermatosis.
Subcorneal pustule with mild
spongiosis and acantholysis,
superficial perivascular mixed
cell infiltrate; hematoxylin and
eosin stain, 9100 (a) and
9200 (b)

TNF-a has a role in the pathogenesis of SPD [16, 21]. SPD
has also been reported to exist in association with other
immune-mediated conditions, such as myeloid disorders
and IgA monoclonal gammopathies, stressing an immune
disorder [18, 20].
Ono et al. [22] reported a case of SPD with elevated
serum levels of thymus and activation-regulated chemo-
kine/chemokine ligand 17 (TARC/CCL17). This was the
second reported case of elevated TARC/CCL17 in a pus-
tular dermatosis, as it had also been detected in a case of
acute generalized exanthematous pustulosis (AGEP). The
impression made by this finding is that SPD may have
T helper (Th)-2 properties, as TARC/CCL17 is a Th2
chemokine.
Lastly, Abreu Velez et al. [16] suggested the presence
of a likely genetic component. They found strong
positivity to human leukocyte antigen (HLA)-DPDQDR,
mast cell tryptase, CD68, and 70 kDa zeta-associated
protein (ZAP-70) in the subcorneal infiltrate and sur-
rounding blood vessels [16]. In their study, they further
highlighted the positive findings of anti-ribosomal pro-
tein S6-pS240 adjacent to the subcorneal blisters and
positivity to myeloperoxidase [16]. Additional studies
are necessary to further validate the significance of these
findings and whether this indicates a genetic
susceptibility.
6 Associations
SPD has been associated with numerous systemic and/or
extracutaneous conditions.
Subcorneal Pustular Dermatosis

Subcorneal Connective tissue diseases occurring in association with

pustular SPD include rheumatoid arthritis, systemic lupus erythe-
dermatosis matosus, and Sjogrens syndrome. SPD associated with
Superficial connective tissue diseases has been most commonly
neutrophilic IgA pemphigus observed to occur with an exacerbation of the connective
dermatosis
tissue disease [2729], rather than as an initial presenting
(epidermal
neutrophilic Other symptom. In terms of rheumatoid arthritis, both seronega-
infiltrates) pustuloses tive- and seropositive-associated cases have been descri-
bed. SPD has been reported to occur slightly more often in
Bullous
neutrophilic seropositive cases [2729]. Successful resolution of SPD is
dermatoses seen in parallel with treatment of the arthritis flares
[27, 29].
Sweet's
syndrome
Numerous overlap cases of ND and inflammatory bowel
disease have been reported [3032]. PG is the most fre-
Neutrophilic quent ND occurring with inflammatory bowel disease,
eccrine most commonly with Crohns disease [30]. SPD has been
Neutrophilic hidradenitis
dermatoses 'en reported in a case of ulcerative colitis and a few cases of
Neutrophilic Erythema
dermatosis plaques' Crohns disease [30, 33]. Sweets syndrome has also been
elevatum
(dermal diutinum seen in association with Crohns disease [30] and rarely
neutrophilic with ulcerative colitis [20]. Erythema elevatum diutinum
infiltrates) Neutrophilic
rheumatoid (EED) has been reported in a case of Crohns disease [34]
dermatitis and in a case of ulcerative colitis [35].
Granulomatous
pyoderma 6.2 Hematologic Disorders
gangrenosum
Wallach and Vignon-Pennamen [20] proposed the group-
Pyoderma
gangrenosum ing of ND in 1991, as several cases had been reported of
Deep
neutrophilic
more than one ND occurring in patients with myelopro-
dermatosis Neutrophilic liferative disorders. They stated that simultaneous forms of
(dermal and panniculitis ND have been associated with systemic conditions,
hypodermal including but not limited to hematologic disorders.
infiltrates) Aseptic Although it is not an absolute indication of systemic dis-
abscesses ease, ND coexisting simultaneously should prompt further
investigation [20]. Among those seen in association with
Fig. 5 Proposed classification of neutrophilic dermatoses [20]. other NDs are IgA monoclonal gammopathies and myeloid
Ig immunoglobulin disorders [20]. Hematologic disorders reportedly seen
specifically with SPD include monoclonal gammopathies
[1, 23], multiple myeloma [18], aplastic anemia [36], IgG
6.1 Inflammatory and Connective Tissue Diseases cryoglobulinemia [1], lymphomas [37], chronic lympho-
cytic leukemia, and chronic myeloid leukemia [20]. In
Multi-organ and systemic dysregulations have been monoclonal gammopathies and multiple myeloma, the
described in association with SPD. These include connec- most frequent paraprotein found in association with SPD is
tive tissue diseases, inflammatory bowel disease, of the IgA type, where most myeloma patients in the
hypothyroidism, hyperthyroidism, SAPHO (synovitis, general population will typically have increased IgG
acne, pustulosis, hyperostosis, osteitis) syndrome, and M-proteins [18, 38]. The period between SPD presentation
multiple sclerosis [5, 14, 15, 2326]. and myeloma has been inconsistently reported. The gam-
A case of SPD occurring in a patient with multiple mopathy may appear years after the onset of SPD [14] and
sclerosis has been reported [26]. Other reported extracu- has also been reported to occur as the primary event [18].
taneous involvement includes amicrobial lymph node
suppuration with an aseptic splenic abscess, aseptic 6.3 Neoplasms/Malignancies
leukocyte infiltration of the lung, and hepatic parenchymal
infiltration [15]. Internal organ involvement suggests SPD SPD has rarely been described with neoplasms or malig-
is an inflammatory response to internal disease. nancies. Anecdotal reports of neoplasmssuch as

Table 1 Neutrophilic dermatoses (ND) with their most notable clinical presentations and histologic features [5, 19, 20, 91]
ND Clinical presentation
SPD Abrupt presentation of grouped flaccid pustules, which
spread into annular patterns with central clearing and
peripheral pustules
IgA pemphigus Similar to SPD
Sweets Tender erythematous plaques, papules, or pustules
syndrome Systemic symptomsmalaise, fever, arthralgia,
(acute febrile hyperleukocytosis
ND)
NEH Involves the face, upper extremities, palms, and soles
Usually seen in patients receiving treatment for acute
myelogenous leukemia
EED Persistent symmetrical tender red or purple papules or
nodules
Near joints, usually on extensor surfaces
RND Symmetrical distribution of erythematous papules and
plaques over extensor surfaces
PG May present as:
Vesicobullous form
Pustular form
Superficial granulomatous
Pyostomatitis vegetans
Neutrophilic Painful subcutaneous nodules
panniculitis
EED erythema elevatum diutinum, Ig immunoglobulin, NEH neutrophilic eccrine hidradenitis, PG pyoderma gangrenosum, RND rheumatoid
neutrophilic dermatitis, SPD subcorneal pustular dermatosis
thymoma, epidermoid carcinoma of the lung, and a meta-
static apudomahave been seen in association with SPD
[10, 39]. Apudomas are rare endocrine tumors derived from
amine precursor uptake and decarboxylation (APUD) cells,
which secrete bioactive amines or polypeptide hormones.
These cells are derived from neural crest cells, which
migrate to various organs [39]. The resulting hyperplastic
tumors are called apudomas. Symptoms depend on the
tissue-specific substance released. Examples are gastrino-
mas, glucagonomas, carcinoid tumors, and pheochromo-
cytomas. The apudoma described by Villey et al. [39] was
a case of ZollingerEllison syndrome with metastasis to a
supraclavicular lymph node, which then presented with
SPD once the patient began to deteriorate 8 years after the
initial diagnosis. The patient died before treatment was
initiated for SPD.
6.4 Drug Reactions
A few cases of drug-induced SPD have been described in
the literature. These cases involved a multikinase inhibitor
[40] and a TNF-a inhibitor [41]. Sorafenib, a multikinase
inhibitor, is used to treat several malignancies, including
renal cell carcinoma, hepatocellular carcinoma, and thyroid
carcinoma. Several cutaneous toxicities have occurred with
P. J. Watts, A. Khachemoune
Histology
Subcorneal accumulation of neutrophils; hypopyon pustules
Subcorneal accumulation of neutrophils with slight acantholysis
Diffuse infiltrate of mature neutrophils with band-like pattern in
the upper dermis
Neutrophilic infiltrates surrounding and infiltrating eccrine
glands
Begins as leukocytoclastic vasculitis; later findings show
perivascular fibrosis and lymphohistiocytic infiltrate with a
few polymorphonuclear neutrophils
Diffuse superficial and deep dermal neutrophilic infiltrates
without the vasculitic changes noted with EED
Neutrophilic infiltrates found at the base of the ulceration,
usually with necrosis and fibrosing inflammation on the
borders
Neutrophils predominate in fat lobules
sorafenib, reportedly in 92 % of patients within 6 weeks of
treatment [42]. These included squamous cell carcinoma,
psoriasiform eruptions, handfoot skin reaction (HFSR),
erythema, alopecia, StevensJohnson syndrome (SJS),
keratoacanthomas, actinic keratosis, and a case of SPD
[40, 42, 43]. The patient, described by Tajiri et al. [40], had
been diagnosed with a hepatocellular carcinoma 7 years
previously and treated with radiofrequency ablation and
transarterial chemoembolization. Since the disease contin-
ued to progress, the patient was then placed on 800 mg/day
of sorafenib. He initially developed HFSR 20 days after
initiation of sorafenib, which prompted a decrease in
dosage to 400 mg/day. Once the HFSR showed improve-
ment and stable liver disease was determined, the sorafenib
was increased in dosage to 600 mg/day. Erythematous,
mildly tender, and pruritic eruptions in a circular and linear
distribution appeared on the extremities 10 days after the
dosage change. On the basis of the clinical features and
histologic analysis, the patient was diagnosed with SPD.
Sorafenib was decreased to 400 mg/day, and a strong
topical steroid was initiated. The SPD improved but per-
sisted. It resolved only with discontinuation of sorafenib
for a transarterial chemoembolization and reappeared soon
after the drug was restarted. This prompted discontinuation
of sorafenib, with complete resolution of SPD 23 months
Subcorneal Pustular Dermatosis

Table 2 Drugs associated with the development of subcorneal pustular dermatosis (SPD) or SPD-like features
Drug Onset after Clinical features Histology References
initiation

Cases diagnosed as SPD

Sorafenib 70 days Multiple erythematous eruptions Spongiosis [40]
Circular/linear pattern Vacuolar changes
Mildly pruritic and tender Subcorneal pustular formation
Extremities Neutrophil-dominant infiltrates in the
superficial epidermis
Adalimumab 4 months Multiple pustules with fluid levels Orthokeratosis overlying a thin layer [41]
Background of erythema and edema of parakeratosis containing the
vesicopustule
Annular pattern of clustering on the palms
Neutrophils within the vesicopustule
Scattered solitary pustules on the forearms,
thighs, and abdomen Acantholysis
Pruritic and painful Mild spongiosis
Palms and soles primarily, extremities, abdomen A few neutrophils in transit through
the epidermis
Cases diagnosed as a drug eruption due to variation in distribution
Isoniazid 2 weeks Widespread pustules varying in size Subcorneal pustules with [44]
Background of erythema polymorphonuclear leukocytes
Widespread pruritus Mild dermal perivascular infiltrate of
lymphocytes and plasma cells
Trunk
Gefitinib 12 weeks Follicular eruption Subcorneal pustules with neutrophilic [45]
Xerosis infiltration
Erythematous papules, erosions, fissure, Dermis with telangiectatic changes and
pustules, petechiae extravasated red blood cells
Geographic pattern Mild perivascular infiltration
Lower extremities
Paclitaxel 5 days Diffuse pustular exfoliating rash Spongiform pustules [46]
Trunk and extremities, sparing the hands and feet
Cefazolin 8h Superficial pustules with a tendency to coalesce Subcorneal pustules with a large [47]
sodium Severe pruritus number of polymorphonuclear
leukocytes
Trunk and extremities
A few acantholytic cells
Intact basal layer
Amoxicillin 12 h Recurrent localized erythema and irritation, which Intracorneal pustules primarily with [48]
progress to a pustular eruption within 4872 h neutrophils
Mild upper dermal mixed inflammatory
infiltrate
Intact basal layer

later. Similarly, a case of what was diagnosed as SPD
occurred after adalimumab therapy for rheumatoid arthritis
[41]. The eruption was mostly on the palms and soles, with
some discrete pustules appearing on the abdomen, fore-
arms, and thighs. Other adverse drug reactions with a
similar clinical and histologic picture to SPD have been
described. They presented with unusual distributions and
varying histologic findings in regard to the presence or
absence of spongiosis and acantholysis. These cases
involved isoniazid [44], gefitinib [45], paclitaxel [46],
cefazolin [47], and amoxicillin [48]. A case of subcorneal
pustules induced by dapsone and quinidine in a patient with
known SPD has also been reported [49]. Drugs associated
with the development of SPD or SPD-like features are
listed in Table 2.
6.5 Infections
In rare cases, SPD may be preceded by an infection. Cases
of urinary tract infections, upper and/or lower respiratory
tract infections, and a primary pulmonary coccidioidomy-
cosis have been reported immediately prior to presentation
of SPD [15, 50]. Reports of Mycoplasma pneumoniae
infection of acutely ill patients, confirmed with serology or

polymerase chain reaction on throat swabs, had an asso-
ciated SPD-type cutaneous eruption [15, 5154]. Lombart
et al. [51] suggest including M. pneumoniae in the work-up
for SPD, especially with children. These findings suggest a
reactive process.
7 Diagnosis of SPD
A rigid set of diagnostic criteria has yet to be established
for SPD. In 1956, Sneddon and Wilkinson described the
hallmark clinical and histologic features that SPD is known
for today [1]. These include flaccid, hypopyon pustules,
which tend to form annular patterns. Histology identifies
subcorneal pustules, which tend to sit atop a normal-ap-
pearing epidermis, filled with polymorphonuclear leuko-
cytes and occasional eosinophils. Other diagnostic features
have been inconsistently reported, such as spongiosis and
acantholysis. Sneddon and Wilkinson state that acanthol-
ysis is a rare feature [1]. Direct immunofluorescence (DIF)
and indirect immunofluorescence (IIF) findings are nega-
tive [11, 14].
Since SPD is seen in association with multisystemic
diseasesmost notably, IgA paraproteinemias and multi-
ple myelomaa screen for urine and serum paraproteins
has been suggested [9, 11]. Periodic screening of patients
who are initially negative is recommended [55].
Bacterial cultures from intact lesions of SPD are
negative.
8 Differential Diagnoses
Differential diagnoses for SPD include inflammatory con-
ditions, autoimmune diseases, drug reactions, infections,
and a paraneoplastic syndrome. Reviewed below are the
most common differentials.
SPD and SPD-type IgA pemphigus are indistinguishable
clinically and histologically [56]. IgA pemphigus is an
intraepidermal blistering disease with circulating and tis-
sue-bound IgA autoantibodies against keratinocyte cell
surfaces [56]. Circulating IgA is present in 50 % of cases
[13]. About 60 cases were reported between the year when
it was first described (1982) and 2011 [57, 58]. It is tra-
ditionally divided into two subtypesintraepidermal neu-
trophilic and SPD subtypeswith different clinical and
histologic features. Clinically, SPD-type IgA pemphigus
presents most typically on the axillae and groin, with
flaccid vesicles and pustules [59]. The pustules then coa-
lesce into an annular, circinate pattern with crusts centrally.
Pruritus is a feature in about 50 % of cases [56, 57], and
mucosal involvement is usually spared [56, 59]. Histology
reveals neutrophilic infiltration in the epidermis, clefts and
P. J. Watts, A. Khachemoune
pustules in the subcorneal region, and mild or no acan-
tholysis [11, 13, 56, 57]. Since SPD-type IgA pemphigus is
indistinguishable from SPD clinically and histologically
[56], immunologic evaluation is crucial. Several methods
are available to detect the presence or absence of tissue-
bound IgA deposits. In SPD-type IgA pemphigus, IgA is
directed exclusively against desmocollin 1, a desmosomal
component of keratinocytes [11, 13, 60]. DIF studies of
perilesional skin demonstrate IgA deposits concentrated in
the upper epidermis [2, 5, 13, 14]. A similar result is seen
with IIF using patient sera and substrates such as healthy
human skin, monkey esophagus, or other epithelia [13, 61];
however, about 50 % of IIF studies in SPD-type IgA
pemphigus are negative [13, 56]. To increase the sensitivity
and specificity of the IIF assay, cultured COS7 cells
transfected with desmocollin 13 complementary DNA
(cDNA) vectors have been used [62]. This assay is not
widely available. Immunoblotting using human epidermal
extracts fails to detect human desmocollin [58, 62]. There
are now bovine desmocollin molecules used in
immunoblotting, which detect human desmocollin to a
greater extent [62]. This assay is, however, less sensitive
than immunofluorescence with COS7 cultured cells [13].
Lastly, an enzyme-linked immunosorbent assay (ELISA)
for desmocollin 1 produced by baculovirus expression has
shown very low sensitivity for SPD-type IgA pemphigus
[13, 56, 60]. A recently developed ELISA using eukaryotic
desmocollin 13 recombinant proteins is much higher in
sensitivity and specificity than baculoprotein ELISAs [63].
Dapsone is the drug of choice for IgA pemphigus and can
be used as monotherapy [13, 59]. Colchicine or oral ster-
oids may be added [13]. Retinoids, sulfapyridine, oral
corticosteroids, adalimumab, methotrexate, and mycophe-
nolate mofetil are alternatives [13, 17].
Pemphigus foliaceus (PF) is another autoimmune bullous
condition to be considered in the differential diagnosis. It is a
superficial variant of pemphigus, found in the subcorneal
layer of the epidermis [64]. Vesicles and bullae are found on
seborrheic areas of the bodysuch as the face, scalp, upper
chest, and abdomenand less commonly on other areas of
the skin. It begins as scattered superficial blisters, which
coalesce and form scaly and crusted erosions. The pustules
and vesicles do not coalesce annularly as is commonly seen
with SPD. The epidermal blisters are similar in flaccidity to
SPD vesicopustules. Erythema, scales, and crusts form as
they heal, and mucosal membranes are commonly spared
[11]. Acantholysis is found in the granular layer. DIF reveals
intercellular and intraepidermal deposits of IgG [14]. IIF and
ELISA show IgG autoantibodies to epithelial cells, specifi-
cally to desmoglein 1 [13, 57]. PF and SPD have both been
associated with thymomas [15, 65].
SPD presents clinically similarly tobut usually in a
different distribution fromthe four types of pustular
Subcorneal Pustular Dermatosis
psoriasis: von Zumbusch, annular, exanthematic, or local-
ized patterns. Pustular psoriasis, as a group, is described as
sterile pustules over an erythematous base, with distribu-
tion varying depending on the type [65]. The annular
variant is most similar to SPD in form. This variant of
pustular psoriasis is described as an erythematous eruption,
with scaling and pustules spreading centrifugally, with
healing beginning in the centers [66]. Histopathologically,
the most commonly described features of both SPD and
pustular psoriasis are enhanced chemotaxis and infiltration
of neutrophils within the epidermis. Of importance is that
these features are notably far more significant in pustular
psoriasis than in other psoriasis variants [65]. Chemotactic
factors such as leukotrienes, complement products, and
cathepsin 1 have been found in the affected areas in pus-
tular psoriasis [65]. A slight acanthosis is noted with pus-
tular psoriasis, which has inconsistently been described in
cases of SPD [65]. Spongiosis has been inconsistently
reported with pustular psoriasis. Other histologic features
of classic psoriasissuch as psoriasiform hyperplasia,
tortuous telangiectasias in the dermal papillae, and mitotic
figuresare not seen with SPD. A familial contribution is
seen in some cases of pustular psoriasis, and one report
suggested that there was a genetic component to SPD [16].
Both pustular psoriasis and SPD usually respond to dap-
sone [6669].
Dermatitis herpetiformis (DH) should also be consid-
ered in the differential diagnosis. Classically, DH vesicles
and papules are symmetrical and grouped, with tense bullae
[11]. They are intensely pruritic, which is not a charac-
teristic of SPD. DH lesions are predominantly found on
extensor surfaces, the buttocks, the scalp, or the back.
Tissue examination reveals vesicles that contain neu-
trophils, eosinophils, and fibrin, with perivascular lym-
phocytic infiltrates [11]. DIF reveals a granular
subepidermal IgA deposition in the tips of the dermal
papillae. If it is associated with celiac disease, there is
immunoglobulin haphazardly deposited at the jejunum [2].
The target antigen is tissue transglutaminase [13].
Amicrobial pustulosis of the folds is a recurring pustular
condition with aseptic, follicular, and nonfollicular pus-
tules. Although the pustules may be similar to those seen in
SPD, this condition differs in location and histology. Pus-
tules are seen on cutaneous folds, the scalp, extensor sur-
faces, and periorificial areas of the body, and they are
usually larger than SPD lesions [70]. There is a female
predominance. Typically in association with other
autoimmune conditionsmost commonly, systemic lupus
erythematosusit relapses independently from the under-
lying autoimmune condition [70]. Although rare, it may
occur in patients receiving dapsone therapy [42]. There is
neutrophilic migration to the upper layer of the epidermis,
wherein spongiform pustules are formed, as well as
neutrophilic perivascular and periadnexal infiltrates [1, 71].
With tissue analysis, one might find either subcorneal
pustules or neutrophilic spongiosis in the epidermis, and
perivascular and perifollicular neutrophils in the dermis
[42]. Polymorphonuclear infiltrates and a few plasma cells
may be found diffusely in the dermis [70]. Vaculitis is
absent. Acanthosis and parakeratosis are present. The most
effective treatment to date is medium-dose systemic cor-
ticosteroids [70], with 0.51.0 mg/kg/day of prednisolone
being the most effective dosage reported. This condition
has also been responsive to zinc [42].
AGEP is a rare, often pruritic and burning, sudden erup-
tion of small nonfollicular pustules, triggered by a drug or
viral infection. It reveals pustules similar to those seen in
SPD [1]. It is an adverse effect of antibiotics and presents
within a few days to 2 weeks after initiation of drug therapy.
Less commonly, it may be caused by anticonvulsants,
radiocontrast dyes, viral infections, and Mycoplasma infec-
tions [55]. It typically begins on the face or intertriginous
areas, disseminates quickly, and overlies erythematous and
edematous skin [55]. Systemic manifestations, such as fever
and leukocytosis, usually present with this condition. His-
tologically, there is neutrophilic accumulation at various
levels of the epidermis, but it is usually found at the sub-
corneal level [55]. Subcorneal pustules, dermatitis, and
vasculitis suggest AGEP. There is mild acantholysis [55].
Necrotic keratinocytes, mixed neutrophil-rich interstitial
and mid-dermal infiltrates with the presence of eosinophils in
the pustules or dermis sets this pustular eruption apart from
SPD [55, 72]. This condition is self-limited.
Other differential diagnoses include fungal, viral, and
bacterial infections, though they should be easily distin-
guishable from SPD with a thorough history and physical
examination. These include candidal intertrigo, herpes
zoster, tinea corporis, bullous impetigo, folliculitis, and
miliary tuberculosis. The possibility of necrolytic migra-
tory erythema may also be considered. The differential
diagnoses are summarized in Table 3.
9 Management
Dapsone (50200 mg daily) remains first-line treatment for
SPD [5, 31]. Resolution is frequently seen within
14 weeks [17]; relapses are quite common with discon-
tinuation of the treatment. Maintenance therapy at a lower
dosage is necessary to prevent relapse. Dapsone may cause
hematologic adverse effects, such as methemoglobinemia,
hemolytic anemia, agranulocytosis, hypersensitivity syn-
drome, renal toxicity, hepatic toxicity, or peripheral motor
neuropathy [67, 73]. Hemolytic reactions and agranulocy-
tosis are dose dependent [67]. Additionally, glucose-6-
phosphate dehydrogenase levels must be checked prior to

Table 3 Differential diagnoses [2, 5, 11, 13, 16, 55, 62, 65, 72, 9295, 97, 98]
Condition
Autoimmune conditions
SPD-type IgA pemphigus
Dermatitis herpetiformis
Pemphigus foliaceus
Pemphigus vulgaris
Inflammatory conditions
Pustular psoriasis
Amicrobial pustulosis
of the folds
Other multisystemic genetic syndromes
PAPA syndrome
Clinical features
Flaccid vesicles and
pustules, which coalesce
into an annular circinate
pattern with crusts
centrally
Axillae and groin
Tense bullae
Intensely pruritic
Extensor surfaces,
buttocks, scalp, or back
Flaccid bullae
Localized or generalized
exfoliation
Oral lesions (rare)
Seborrheic areas
Mucosal erosions
Flaccid bullae, which
rupture, forming erosions
with crusts
Mouth, groin, scalp, face,
neck, extremities
Varied distribution with
pustules and erythema
Coalescent pustules
overlying erythematous
or eczematous skin
Cutaneous folds, scalp,
extensor surfaces, and
periorificial areas of the
body
1st decade of lifepainful H&E (of cystic acne): cystic space in
monoarticular arthritis
Pustule formation with
pathergy
Puberty to adulthoodPG
and nodulocystic acne
P. J. Watts, A. Khachemoune
Histologic features Pertinent findings
H&E: subcorneal pustules with mild Target antigen: desmocollin 1
or no acantholysis
DIF, IIF: IgA accumulation in the
upper epidermis
IIF utilizing desmocollin 1 cDNA-
transfected COS7 cells: fluoresces
exclusively with desmocollin 1
ELISA (using eukaryotic recombinant
desmocollin proteins): fluoresces
exclusively with desmocollin 1
Immunoblotting (with bovine
extracts): positive reactivity
H&E: subepidermal blister with Target antigen: tissue transglutaminase
neutrophilic microabscesses at the
tips of the dermal papillae
DIF: haphazard granular
subepidermal IgA deposition
IIF: rarely positive
H&E: acantholysis in granular layer Target antigen: desmoglein 1
DIF: intercellular and intraepidermal
deposits of IgG, mostly in
superficial layers
IIF: positive in most cases
H&E: suprabasilar acantholysis with Target antigen: desmoglein 3
intraepidermal blisters
DIF: chicken wire pattern
intercellular deposits of IgG, mostly
in the lower epidermis
IIF: similar to staining with DIF
H&E: intraepidermal pustules with Pustular variants include:
different stages of involvement Von Zumbusch pattern
Early lesions: subcorneal infiltrates of Exanthematic pattern
neutrophils with slight acanthosis
Annular pattern
Late lesions: scaly crusts with
Localized pattern
neutrophils between
H&E: upper epidermisspongiform Female predominance
pustules with acanthosis and
parakeratosis; dermis
polymorphonuclear infiltrates
Autosomal dominant
distended follicles, filled with Mutation in gene encoding CD2-
keratinaceous debris and bacteria binding protein 1
Subcorneal Pustular Dermatosis

Table 3 continued
Condition Clinical features Histologic features Pertinent findings

SAPHO syndrome The hallmarks are H&E: neutrophilic pseudo-abscess Genetic basis unknown
osteoarticular CRMOsubset predominating in the
manifestations: pediatric population
Synovitis
Arthrosteitis
Aseptic pustular
dermatosis
Palmoplantar pustulosis
Severe acne
Monogenic childhood pustular psoriasis
DIRA Perinatal onset H&E: acanthosis, hyperkeratosis, Autosomal recessive
Pustular dermatosis pustule formation, with extensive
resembling pustular neutrophilic infiltration in the
psoriasis dermis and epidermis
Nail changes (pitting and
onychomadesis)
Osteomyelitis
Periostitis
DITRA Sudden and severe H&E: spongiform pustules, Autosomal recessive
generalized pustular acanthosis, elongation of rete ridges,
psoriasis parakeratosis
High-grade fever
Neutrophilia
Elevated inflammatory
markers
CAMPS Childhood-onset Autosomal dominant
generalized pustulosis CARD14 mutations have also
Fevers manifested with plaque psoriasis and
Palmoplantar keratoderma pityriasis rubra pilaris
Nail pitting
Drug reaction
AGEP Pustules usually begin on H&E: subcorneal pustulesmay Usually accompanied by fever and
the face or intertriginous occur at various levels of the leukocytosis
areas and disseminate epidermis but usually found at the
rapidly subcorneal level; dyskeratosis,
Vasculitis necrotic keratinocytes, mixed
interstitial and mid-dermal
infiltrates
Fungal infection
Candidal intertrigo Intertriginous areas KOH or PAS stain: budding yeast Satellite lesions
cells and pseudohyphae
Viral infection
Herpes zoster Painful grouped vesicles on H&E: intraepidermal vesicles Prodrome: pruritus, hyperesthesia, pain
an erythematous base containing ballooned acantholytic
Varied presentation based keratinocytes, intranuclear inclusion
on location bodies
 P. J. Watts, A. Khachemoune

Table 3 continued
Condition Clinical features Histologic features Pertinent findings

Bacterial infection
Bullous impetigo Mostly the face and H&E: subcorneal bullae
extremities A few acantholytic cells, some
neutrophils, some Gram-positive
cocci
Papillary dermismixed
inflammatory cell infiltrate
Paraneoplastic condition
Necrolytic migratory Erythematous papules, H&E: parakeratosis and vacuolization Occurs in 7090 % of patients with
erythema (paraneoplastic which coalesce within the cytoplasm of the upper glucagonoma syndrome
process to glucagonoma Central vesicles, which epidermal keratinocytes Clinical findings associated with
syndrome, a pancreatic islet- leave hyperpigmentation; May see neutrophilic crust, glucagonoma include worsening
cell neoplasm) peripheral spread, spongiosis, subcorneal pustule diabetes mellitus, weight loss,
resulting in an arcuate formation, a few eosinophils, or normocytic anemia, and
pattern necrotic keratinocytes hyperglucagonemia
Anywhere, most Lab findings: increased glucagon
commonly in
intertriginous and
periorificial areas
AGEP acute generalized exanthematous pustulosis, CAMPS CARD14-mediated pustular psoriasis, cDNA complementary DNA, CRMO chronic
recurrent multifocal osteomyelitis, DIF direct immunofluorescence, DIRA deficiency of interleukin-1 receptor, DITRA deficiency of interleukin-
36 receptor antagonist, ELISA enzyme-linked immunosorbent assay, H&E hematoxylin and eosin, Ig immunoglobulin, IIF indirect
immunofluorescence, KOH potassium hydroxide, PAPA pyogenic arthritis, pyoderma gangrenosum, and acne, PAS periodic acidSchiff,
PG pyoderma gangrenosum, SAPHO synovitis, acne, pustulosis, hyperostosis, osteitis, SPD subcorneal pustular dermatosis

initiation of dapsone therapy, as deficient patients are at
increased risk of severe hemolysis with its use. Current
recommendations are a complete blood count weekly for
the first month, monthly for the next 5 months, and bi-
annually thereafter [67]. Many patients will respond to
dapsone. As such, this has been used to suggest a diagnosis
of SPD [17]. However in cases where there is an ineffec-
tive, insufficient responseor where it causes adverse
effectsother anti-neutrophilic drugs have been shown to
work, though with variable effectiveness. This includes
colchicine, sulfapyridine, and sulfamethoxypyridazine
[5, 17].
Topical corticosteroids alone or in combination with
dapsone have been successful used in a few cases
[5, 14, 24]. Similarly, oral corticosteroids alone or in
combination with dapsone have been used successfully.
This is usually the treatment of choice when patients pre-
sent either with other dermatologic conditions that are
treatable by oral corticosteroids or with associated systemic
conditions [17, 74]. Oral retinoids, such as acitretin and
etretinate, have been used with success. The effectiveness
of oral retinoids is allegedly comparable to that of dapsone,
with a quicker decline in symptoms and better tolerability
[14, 73]. Symptoms tend to resolve within 815 days of
treatment with an oral retinoid, and a maintenance dose is
needed to avoid relapse [17].
In a few reports, light therapy has been used success-
fully to treat SPD either alone or as an adjunct to other
treatment. Psoralen plus ultraviolet (UV) light therapy
(PUVA) alone or with either dapsone or a retinoid has been
used with good results [73, 75, 76]. Successful cases con-
trolled with UVB alone or with minocycline have also been
reported [77, 78]. A case managed with PUVA and a
retinoid with UVB as maintenance treatment was effica-
cious; however, relapses have occurred during treatment
with this regimen [79].
For unmanageable SPD, immunobiologic agents that
inhibit or decrease the effects of TNF-a, such as infliximab
and etanercept, have been used with some success [9].
Infliximab is a chimeric monoclonal antibody targeting
soluble and membrane-bound TNF-a, which is approved
for the treatment of rheumatoid arthritis, Crohns disease,
ulcerative colitis, ankylosing spondylitis, psoriatic arthritis,
and plaque psoriasis [80]. Bonifati et al. [81] studied
cytokines such as TNF-a, IL-1b, IL-6, IL-8, IL-10, and
interferon-c before and after infliximab therapy. Although
infliximab was not successful in treating their patient with
SPD, a potentially significant finding was observed in this
case. Proinflammatory cytokine levels found in both
lesional and non-lesional skin after infliximab therapy
decreased. IL-10, an anti-inflammatory cytokine, remained
stable before and after therapy. Secondly, there was an
Subcorneal Pustular Dermatosis
increase in IL-1b once the pustulosis reappeared. IL-1b is
an activator of TNF-a, suggesting it plays a role in the
pathogenesis of SPD. Several successful cases of
immunobiologic therapy have been reported in the litera-
ture. Resistant cases were managed successfully with
infliximab; however, most needed adjunctive therapy with
corticosteroids and/or a retinoid [9, 28, 82]. Although TNF
inhibitors have been used with good effect in the treatment
of SPD, it has not been approved by the US Food and Drug
Administration specifically for this purpose.
Cases of SPD that are atypical in terms of sex or age are
reportedly less responsive to dapsone [12]. In cases unre-
sponsive to dapsone, other possible options, aside from
those mentioned previously in this article, are vitamin E,
methotrexate, chloramphenicol, tetracycline, estrogen,
corticosteroids, potassium arsenite, and niacin [12]. Many
of these have been inconsistently effective. Long-term
follow-up is suggested, as patients have developed multiple
myeloma or psoriasis years after their cutaneous lesions
initially presented [5].
9.1 Treatment of SPD with Other Disease
Associations
Cases of SPD associated with arthritides have been con-
trolled with various combinations of dapsone, immunobi-
ologic agents, light therapy, minocycline, antimalarial
therapy, and TNF-a inhibitors. Dapsone alone has effec-
tively resolved both cutaneous and joint flares in a few
cases [27, 29, 82]. Others have failed dapsone as a
monotherapy. In a case of seropositive arthritis and SPD,
dapsone treatment alone failed to resolve the joint pain
completely; addition of hydroxychloroquine was effective
in this case [29]. A second case of seropositive arthritis and
SPD, with dapsone-induced neutropenia, was successfully
treated with minocycline, topical corticosteroids, and 31
exposures to narrow-band UVB therapy [78]. A third case
of seropositive arthritis and SPD was effectively controlled
with etanercept alone [28].
A few reports of mild M. pneumoniae upper respiratory
infections associated with SPD have responded to oral
dapsone without recurrence [51]. One patient discontinued
dapsone therapy because of nausea, and the skin lesions
were successfully treated with topical corticosteroids alone
[51]. Table 4 lists successful treatment reported in litera-
ture, with dosages, patient type, and clinical course.
10 Reappraisal
SPD and pustular psoriasis are very similar pustular con-
ditions, with long-standing debate as to whether they are in
fact the same disease or two separate entities [8388].
SPD-type IgA pemphigus, once thought to be SPD, has
been designated under the pemphigus diseases. Clinically,
all three conditions frequently present with flaccid pustules,
which can further spread into circinate or annular
arrangements. Histologically, subcorneal pustules, largely
infiltrated by neutrophils, characterize all three conditions.
Although the presence or absence of acantholysis and
spongiosis have been defined for each disease in the past,
these have not always been clear cut. Nevertheless,
immunologic assays easily detect IgA immunoreactivity
toward keratinocyte cell surface molecules in SPD-type
IgA pemphigus, separating it from SPD and pustular pso-
riasis. We agree with Chimenti and Ackerman [8], to an
extent, that no clinical or histologic feature truly distin-
guishes SPD from the annular variant of pustular psoriasis.
Clinically, neutrophil infiltration, erythema, and ster-
ile pustules characterize SPD and all forms of pustular
psoriasis. The centrifugal spread of the lesions with
pustules at the advancing edge, scaling and healing
centrally are morphologically similar to the annular form
of pustular psoriasis. Several histologic features in the
once-classic description of psoriasis that may distinguish
it from SPD are not always identified in pustular psori-
asis [89]. These include elongated rete ridges with
characteristic enlargement of their tips, elongation of the
dermal papillae with tortuous capillaries, thinning of the
epidermis, spongiosis forming spongiotic pustules of
Kogoj, microabscesses of Munro, mitotic figures, and
acantholysis. Both SPD and pustular psoriasis can be
associated with systemic diseases and drug-induced
cases. Both are associated with arthritis. Unlike psoriatic
arthritis, SPD has been reported to occur slightly more
often in seropositive arthritis.
Therapeutic options in the treatment of SPD and annular
pustular psoriasis are similar. For one, dapsone, which is
considered first-line therapy for SPD, has been used as a
successful alternative for annular pustular psoriasis
[67, 68]. Immunobiologic agents designed to inhibit the
proinflammatory cytokine TNF-asuch as adalimumab,
infliximab, and etanercepthave been used to treat pus-
tular psoriasis. These agents have also been seen to have a
good effect in the treatment of SPD. TNF-a inhibitors have
not been the most effective option for either condition, with
adjunctive treatment needed in most cases. Acitretin and
cyclosporine have also been used effectively to treat both
conditions.
Shared triggers of pustular psoriasis and SPD exist but
have yet to be further studied. TNF-a inhibitors have been
implicated in exacerbating or causing psoriasis [41]. A case
of TNF-a inhibitor-induced SPD has also been described
[41]. Additionally, sorafenib, which caused SPD in one
case, has reportedly induced psoriasiform eruptions, two of
which were pustular in nature [90, 91].
 P. J. Watts, A. Khachemoune

Table 4 Successful treatment reported in SPD cases published between 1985 and 2015
Therapy Successful regimen Patient Clinical course References

Dapsone alone 1 mg/kg/day 7-year-old male Complete clearance of [2]

lesions was close to being
achieved in 2 weeks
50 mg/day 26-year-old female with Complete clearance during [26]
multiple sclerosis dapsone therapy
Relapse with discontinuation
100 mg/day 44-year-old female with Pruritus relieved in 2 days [27]
rheumatoid arthritis Lesions resolved in 2 weeks
Arthritis resolved in
4 months
37-year-old male with Crohns Cutaneous lesions controlled [30]
disease in 6 weeks without known
recurrence
26-year-old female with Pruritus relieved in 2 days [96]
recurrent joint pain Skin lesions resolved in
3 weeks
Joint pain resolved in
2 months
Dapsone ? Dapsone 100 mg/day 39-year-old female with Complete clearance of [23]
oral steroid Corticosteroid 1.5 mg/kg/day recurring SPD ? cutaneous lesions in
IgA paraproteinemia ? PG 2 weeks
Dose dropped to 25 mg/day,
but PG recurred
Complete resolution of PG
and SPD with systemic
steroid
Dapsone ? Dapsone 50 mg/day 31-year-old female Lesions resolved over a few [12]
topical steroid ? 10 % coal tar in 1 % triamcinolone weeks
coal tar acetonide ointment
Dapsone ? Dapsone 50 mg daily 59-year-old female with history Cutaneous lesions improved [29]
topical steroid ? Topical 0.05 % clobetasol proprionate of rheumatoid arthritis slowly over 4 months
hydroxychloroquine
Hydroxychloroquine 400 mg daily
added
Oral steroid Oral prednisone 25 mg/day 93-year-old female Complete resolution in [74]
6 weeks
Topical steroid Strong topical steroid 75-year-old male with advanced Sorafenib dose decreased [40]
hepatocellular carcinoma Strong topical steroid added
treated with sorafenib, with
Cutaneous lesions showed
eruption of SPD 70 days later
improvement but persisted
until sorafenib was
discontinued
Topical steroid Topical corticosteroid alone 36-year-old female with cough 18-month follow-up showed [51]
and positive throat swab PCR complete resolution of
analysis and IgM and IgG cutaneous manifestations
titers for M. pneumoniae
Subcorneal Pustular Dermatosis

Table 4 continued
Therapy Successful regimen Patient Clinical course References

Retinoid alone Etretinate Cases with SPD alone, SPD ? Etretinate: 6 cases [73, 97]
rheumatoid arthritis, and SPD Variable dosing, ranging
? monoclonal gammopathy between 20 and
100 mg/day
Maintenance doses between
20 and 50 mg/day
Acitretin Acitretin: 2 cases received
40 mg/daycleared in
8 days, maintained on the
same dose
25 mg/daycleared in
2 weeks, maintained on
10 mg/day for 4 months
with good effect
Acitretin 10 mg/day (0.5 mg/kg/day) 12-year-old female Lesions almost completely [3]
resolved by 4 weeks, with
only erythematous lesions
on dorsal hands remaining
TNF inhibitor alone Etanercept 27-year-old female with history Dapsone started, but [28]
of rheumatoid arthritis neutropenia developed
Resolved with etanercept
therapy
TNF inhibitor ? Etanercept 50 mg twice weekly 51-year-old Caucasian female Cleared completely [9]
retinoid Acitretin 25 mg every other day added with SPD refractory to various 22 months after initiation of
upon slight flare-up therapies, including UVB therapy
TNF inhibitor ? Etanercept 50 mg twice weekly ? 61-year-old African American Marked improvement at [9]
topical steroid topical steroid as needed male, refractory to various 9-month follow-up
therapies, including PUVA
TNF inhibitor ? Single-dose infliximab 5 mg/ 79-year-old female with a Responded to 2 infliximab [82]
retinoid ? kg intravenously 7-year history of SPD infusions
oral steroid Acitretin 0.4 mg/kg/day refractory to various therapies, Methylprednisolone and
including dapsone and acitretin for 3 months
Oral methylprednisolonetaper begun
phototherapy
3 days after pustules disappeared Acitretin for 6 months
Recurrences were treated
successfully with oral
methylprednisolone
PUVA alone PUVAtaper 28-year-old male with a 6-year Twice weekly for 6 weeks [75]
history of SPD Once weekly for 1 month
Bi-weekly for 2 months
Relapse after 6 months of
discontinuation
PUVA restarted
Maintenance: once every
3 weeks
Flares up regularlystill
being followed
PUVA ? dapsone Dapsone 50 mg/day ? PUVA thrice 55-year-old male with insulin- Recurrent disease with [76]
weekly dependent diabetes mellitus dapsone alone at dosages of
and IgA paraproteinemia 100200 mg/day
PUVA added
Lesions cleared after
15 sessions
Maintenance: dapsone and
PUVA once weekly
 P. J. Watts, A. Khachemoune

Table 4 continued
Therapy Successful regimen Patient Clinical course References

PUVA ? retinoid PUVA ? etretinate
UVB Mineral oil ? UVB thrice weekly with
increasing dosage
PUVA ? retinoid, Acitretin 10 mg daily ? whole-body
UVB maintenance 8-methoxypsoralen UVA
(118 treatments)
Narrow-band UVB ?
sulphamethoxypyridazine
Narrow-band UVB alone
UVB ? minocycline Narrow-band (TL-01) UVBminimal
incremental dose thrice weekly,
31 exposures ? minocycline
100 mg/day, continued for 5 months
after completion of UVB therapy
Ig immunoglobulin, M. pneumoniae Mycoplasma pneumoniae, PCR polymerase chain reaction, PG pyoderma gangrenosum, PUVA psoralen ?
ultraviolet A, SPD subcorneal pustular dermatosis, TNF tumor necrosis factor, UVA ultraviolet A, UVB ultraviolet B
58-year-old male with a 10-year
history of SPD and IgA
monoclonal gammopathy
12-year-old male with a 5-year
history of SPD
40-year-old female
76-year-old female with IgA
and IgM gammopathy, and a
2-week history of
polyarthropathy
Etretinate 90 mg/day [73]
Maintenance: etretinate
10 mg/day
Skin lesions cleared after [77]
11 exposures
Frequency of exposure
decreased
Longest period of sustained [79]
clinical improvement was
2 months
Switched to narrow-band
UVB ?
sulphamethoxypyridazine
4 months afterward: 2nd
course of narrow-band
UVB alone
Relapses still recurring
2 months after last
treatment
Minocycline and topical [78]
steroideruption and
synovitis resolved
SPD recurred without
arthritis
Prednisolonecleared but
recurs with prednisolone
taper
UVB ? minocycline started
Maintenance: minocycline
alone

Clinical and histologic characteristics that differ between
annular pustular psoriasis and SPD cannot be ignored. The
hypopyon nature of the pustules in SPD, which has not been
described in pustular psoriasis, is one. Additionally, there are
increased findings of spongiosis, systemic symptoms, and a
higher incidence of childhood cases in annular pustular
psoriasis in comparison to SPD [6].
Nevertheless, we are not suggesting that annular pus-
tular psoriasis and SPD are the same disease; rather, what is
considered as SPD in the current literature could reason-
ably be a variant of pustular psoriasis. There are a number
of other subtypes of psoriasis that also present quite dif-
ferently from classic psoriasis; such as erythrodermic
psoriasis, guttate psoriasis, the different pustular variants
(including pustulosis of the palms and soles and acroder-
matitis continua of Hallopeau), and those with special
locations; such as scalp psoriasis, nail psoriasis, flexural
psoriasis, and psoriasis in the oral mucosa. From our
review of the literature and discussion of the above find-
ings, including the subtypes of psoriasis, we feel it would
be reasonable to suggest that a reappraisal of SPDa
pustular, cyclic, scaly, recurrent, and noninfectious type of
dermatitisshould be made, and should be reclassified as a
generalized form of pustular psoriasis.
Within this classification, we suggest several variants of
SPD. One subtype should include a benign form, wherein
the pustules are localized to the skin, and no other systemic
involvement is found. A second type should include those
that present as a reactive phenomenon, seen with connec-
tive tissue diseases and other multi-organ dysregulation. A
third subtype should include SPD as a paraneoplastic
phenomenon. Since SPD has been widely reported to occur
with solid tumors and hematologic malignancies, it is
reasonable to suggest that its presentation in some settings
may be malignancy-associated. Last, and least commonly
seen, is a drug-induced form of SPD.
Subcorneal Pustular Dermatosis
11 Conclusion
SPD is a rare, recurrent, relapsing, sterile ND. It presents
clinically with hypopyon pustules, most commonly on the
trunk, intertriginous and flexural areas. Histology reveals
subcorneal collections of neutrophils sitting atop a normal-
appearing epidermis. It is benign yet can present with
malignancies. Management begins with dapsone; should
this be ineffective or cause adverse effects, several other
options can be considered as monotherapy or as adjunctive
therapy. These include oral and topical corticosteroids,
hydroxychloroquine, retinoids, TNF-a inhibitors, minocy-
cline, sulfapyridine, sulfamethoxypyridazine, PUVA, and
UVB therapy. Less effective options include vitamin E,
methotrexate, chloramphenicol, tetracycline, estrogen,
potassium arsenite, and niacin.
This article proposes a reclassification of what we cur-
rently know as SPD. On the basis of our review of previous
debate and the literature over the last 30 years, we find that
SPD is nearly indistinguishable from the annular form of
pustular psoriasis. However, there are several characteris-
tics more often seen in one disease and less often observed
in the other. Therefore, SPD still cannot truly be considered
one and the same as this variant of pustular psoriasis. Since
there are several entities currently classified as subtypes of
pustular psoriasis, each with similar features yet different
distributions and associations, we propose a reclassification
of SPD as an additional variant of pustular psoriasis. Fur-
ther research on familial studies and on the etiology of
neutrophilic chemotaxis to the skin, for both SPD and
pustular psoriasis, may further eliminate any source of
disagreement. This would also potentially resolve the
dilemma of dapsone-resistant cases and provide direction
toward better options to treat the majority of SPD patients.
Acknowledgments We thank James A. Ramirez, MD, for providing
us with high-quality micrographic images for this review.
Compliance with Ethical Standards
Funding No funding was received for the preparation of this review.
Conflict of interest Paula Jean Watts and Amor Khachemoune have
no conflicts of interest to report.
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