Neutrophilic Dermatoses

Neutrophilic DermatosesA Review of Current Treatment Options

Philip R. Cohen1,2,3

1 The University of Houston Health Center, University of Houston, Houston, Texas, USA

2 The Department of Dermatology, University of Texas-Houston Medical School, Houston, Texas, USA

3 The Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

1. Sweet Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

1.1 Clinical Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

1.2 Histologic Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

1.3 Associated Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

2. Pyoderma Gangrenosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303




3. Subcorneal Pustular Dermatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305




4. Concurrent or Sequential Neutrophilic Dermatoses in the Same Individual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

5.1 Sweet Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

5.1.1 First-Line Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

5.1.2 Second-Line Therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

5.1.3 Other Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

5.2 Pyoderma Gangrenosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

5.2.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

5.2.2 Tumor Necrosis Factor-a Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

5.2.3 Calcineurin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

5.2.4 Dapsone and Related Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

5.2.5 Cytotoxic Chemotherapies and Antimetabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

5.2.6 Other Systemic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

5.2.7 High-Dose Intravenous Immunoglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

5.2.8 Topical Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

5.2.9 Other Treatment Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

5.3 Subcorneal Pustular Dermatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

5.3.1 Dapsone and Related Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

5.3.2 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

5.3.3 Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

5.3.4 Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

5.3.5 Other Systemic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

5.3.6 Topical Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

5.3.7 Other Treatment Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

REVIEWARTICLEAm J Clin Dermatol 2009; 10 (5): 301-312

1175-0561/09/0005-0301/$49.95/0

ª 2009 Adis Data Information BV. All rights reserved.

Abstract Sweet syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosis are neutrophilic derma-

toses – conditions that have an inflammatory infiltrate consisting of mature polymorphonuclear leukocytes.

The neutrophils are usually located within the dermis in Sweet syndrome and pyoderma gangrenosum;

however, in subcorneal pustular dermatosis, they are found in the upper layers of the epidermis. Sweet

syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by pyrexia, elevated

neutrophil count, painful erythematous cutaneous lesions that have an infiltrate of mature neutrophils

typically located in the upper dermis, and prompt clinical improvement following the initiation of systemic

corticosteroid therapy. Classical, malignancy-associated, and drug-induced variants of Sweet syndrome

exist. Pyoderma gangrenosum is characterized by painful, enlarging necrotic ulcers with bluish undermined

borders surrounded by advancing zones of erythema; its clinical variants include: ulcerative or classic,

pustular, bullous or atypical, vegetative, peristomal, and drug-induced. Subcorneal pustular dermatosis is

an uncommon relapsing symmetric pustular eruption that involves flexural and intertriginous areas; it can

be idiopathic or associated with cancer, infections, medications, and systemic diseases. Since Sweet syn-

drome, pyoderma gangrenosum, and subcorneal pustular dermatosis share not only the same inflammatory

cell but also similar associated systemic diseases, it is not surprising that the concurrent or sequential

development of these neutrophilic dermatoses has been observed in the same individual. Also, it is not

unexpected that several of the effective therapeutic interventions – including systemic drugs, topical agents,

and other treatment modalities – for the management of these dermatoses are the same.

The treatment of choice for Sweet syndrome and idiopathic pyoderma gangrenosum is systemic cortico-

steroids; however, for subcorneal pustular dermatosis, dapsone is the drug of choice. Yet, tumor necrosis

factor-a antagonists are becoming the preferred choice when pyoderma gangrenosum is accompanied by

inflammatory bowel disease or rheumatoid arthritis. Potassium iodide and colchicine are alternative first-line

therapies for Sweet syndrome and indomethacin (indometacin), clofazimine, cyclosporine (ciclosporin), and

dapsone are second-line treatments. Cyclosporine is effective in the acute management of pyoderma gang-

renosum; however, when tapering the drug, additional systemic agents are necessary formaintaining the clinical

response. In some patients with subcorneal pustular dermatosis, systemic corticosteroids may be effective; yet,

systemic retinoids (such as etretinate and acitretin) have effectively been used for treating this neutrophilic

dermatosis – either as monotherapy or in combination with dapsone or as a component of phototherapy with

psoralen andUVA radiation. Topical agents can have an adjuvant role in themanagement of these neutrophilic

dermatoses; however, high-potency topical corticosteroids may successfully treat localized manifestations of

Sweet syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosis. Intralesional corticosteroid

therapy for patients with Sweet syndrome and pyoderma gangrenosum, hyperbaric oxygen and plasmapheresis

for patients with pyoderma grangrenosum, and phototherapy for patients with subcorneal pustular dermatosis

are other modalities that have been used effectively for treating individuals with these neutrophilic dermatoses.

Neutrophilic dermatoses are a group of conditions that have

a unifying characteristic: an inflammatory infiltrate that con-

sists of polymorphonuclear leukocytes (table I).[1,2] Although

several of the conditions display similar clinical morphologies

or pathologic features or both, the location of the neutrophilic

infiltrate can sometimes be useful to differentiate these der-

matoses. This article discusses, compares, and contrasts the

clinical morphology, histologic findings, associated conditions,

and treatments of three of these disorders: Sweet syndrome,

pyoderma gangrenosum, and subcorneal pustular dermatosis.

1. Sweet Syndrome

Dr Robert Douglas Sweet originally described a constella-

tion of clinical and laboratory findings he had observed in eight

women as an ‘acute febrile neutrophilic dermatosis’ in 1964.[3]

The descriptive nomenclature for the condition emphasized its

salient features: pyrexia, elevated neutrophil count, painful

erythematous cutaneous lesions characterized by an infiltrate

of mature neutrophils typically located in the upper dermis,

and prompt clinical improvement following the initiation of

systemic corticosteroid therapy.[4-7] Variants of the syndrome

include: (i) the ‘classic’ presentation, which may be associated

with upper respiratory tract or gastrointestinal infection, in-

flammatory bowel disease, and pregnancy;[8-10] (ii) the ‘malig-

nancy-associated’ presentation, in which the dermatosis is

either the presentingmanifestation of a previously undiagnosed

cancer or the recurrence of malignancy in an oncology

patient;[11-16] and (iii) the ‘drug-induced’ presentation, when the

302 Cohen

ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (5)

condition is precipitated by the patient having received a

dermatosis-associated medication.[17]

1.1 Clinical Morphology

Sweet syndrome cutaneous lesions typically present as single

or multiple, tender red papules and nodules. Larger lesions de-

velop into plaques. There is often extensive edema in the dermis

that results in the lesions having a vesicular or bullous appear-

ance. Sometimes there is central clearing and the lesions mimic

those of erythema multiforme. Pathergy may be noted, with new

lesions appearing at sites of trauma to the skin.[3]

Morphologic variants of Sweet syndrome include the de-

velopment of lesions predominantly limited to the extensor

surface of the distal upper extremities and referred to as neu-

trophilic dermatosis of the dorsal hands; in some of these pa-

tients, the lesions are pustular.[18] Another clinical variant of the

dermatosis presents as erythematous, tender, deep dermal and

subcutaneous nodules;[19] the lesions of subcutaneous Sweet

syndrome are often located on the lower extremities and mimic

erythema nodosum.[20]

Mucous membrane lesions have also been noted. These can

present as oral ulcers and various ocular lesions, including

conjunctivitis.[21] In addition to the mouth and eyes, extra-

cutaneous manifestations of Sweet syndrome can affect the

bones, CNS, ears, kidneys, intestines, liver, heart, lungs, mus-

cles, and spleen.[3,22]

In addition to the cutaneous lesions, fever is an associated

symptom in patients with Sweet syndrome. Other dermatosis-

associated symptoms may include arthralgias, general malaise,

headache, and myalgia. Leukocytosis with an elevated neu-

trophil count is also a component of the diagnostic criteria

for the condition.[3]

1.2 Histologic Findings

A diffuse infiltrate of mature neutrophils is also one of the

diagnostic criteria of Sweet syndrome. The inflammatory cells

are often located in the papillary dermis and the upper reticular

dermis. In addition, there is usually edema present between the

dermal collagen bundles. Although swollen endothelial cells

and fragmented neutrophil nuclei (referred to as karyorrhexis

or leukocytoclasia) may be present, other changes of a ‘pri-

mary’ leukocytoclastic vasculitis (such as neutrophils and fibrin

deposition in the blood vessel walls) are typically absent.

Occasionally, in older lesions, these latter features of ‘second-

ary’ leukocytoclastic vasculitis – occurring as an epiphenome-

non – have been observed.[3,18]

The spectrum of pathologic changes in Sweet syndrome

has expanded. The inflammatory infiltrate may contain

eosinophils – especially in the drug-induced variant of the

condition – or, less commonly, lymphocytes or histiocytes, or

neutrophils that look like histiocytes. The location of the neu-

trophils can also be found in the deeper dermis and the adipose

tissue (lobules, septae, or both) in the subcutaneous variant of

the dermatosis. Also, concurrent leukemia cutis may be dis-

covered in the dermis in some of the patients with hematologic

malignancy-associated Sweet syndrome.[3]

1.3 Associated Conditions

Sweet syndrome has a bona fide association with infections

(predominantly upper respiratory and gastrointestinal), in-

flammatory bowel disease (both Crohn disease and ulcerative

colitis), pregnancy, cancer (both hematologic malignancies

such as acute myelogenous leukemia and solid tumors), and

medications (most commonly granulocyte colony-stimulating

factor).[3] There is a possibly bona fide association between

Sweet syndrome and the following conditions: Behcet disease,

erythema nodosum, relapsing polychondritis, rheumatoid

arthritis, sarcoidosis, and thyroid disease (both Grave disease

and Hashimoto thyroiditis).[20,23,24] There are many other

conditions for which the validity of an association with Sweet

syndrome remains to be definitively established.[3] [See the case

reports on pages 343–345 and 331–335 of this issue, which de-

scribe Sweet syndrome in patients with celiac disease and Behcet

disease, respectively.]

2. Pyoderma Gangrenosum

Drs Brunsting, Goeckerman, and O’Leary at the Mayo

Clinic originally described pyoderma gangrenosum in 1930

Table I. Neutrophilic dermatoses

Abscess/cellulitis

Bowel (intestinal) bypass syndrome

Erythema elevatum diutinum

Halogenoderma

Leukemia cutis

Leukocytoclastic vasculitis

Neutrophilic eccrine hidradenitis

Pyoderma gangrenosum

Rheumatoid neutrophilic dermatitis

Sweet syndrome

Treatment of Neutrophilic Dermatoses 303


when they reported painful, enlarging necrotic ulcers with

bluish undermined borders surrounded by advancing zones of

erythema in five patients – four of whom had ulcerative colitis.

Several variants of the condition have subsequently been ob-

served:

1. Ulcerative or classic pyoderma gangrenosum, presenting

with painful ulceration usually located on the legs, but also

occurring anywhere, including the abdomen, genitalia, trunk,

head, and neck; it is frequently associated with inflammatory

bowel disease and rheumatoid arthritis.

2. Pustular pyoderma gangrenosum, which presents as multiple

discrete pustules surrounded by an erythematous halo on the

extensor aspects of the limbs and the upper trunk; this variant

is commonly associated with inflammatory bowel disease

(ulcerative colitis).

3. Bullous or atypical pyoderma gangrenosum, presenting as

tender vesicles that enlarge rapidly into bullae and subsequently

develop central necrosis with resulting superficial ulcers and

erosions often on the hands, arms, and face; this variant –

whose morphologic features overlap with bullous Sweet

syndrome – is often associated with hematologic malignancies

such as acute myelogenous leukemia, myelodysplastic syn-

dromes, and IgA paraproteinemias.

4. Vegetative pyoderma gangrenosum, which typically pre-

sents as solitary erosions and superficial ulcers with sinus tracts

on the trunk; this variant is chronic and slowly progressing, and

often readily responds to simple modes of therapy.

5. Peristomal pyoderma gangrenosum, which presents with

lesions occurring around abdominal stoma following ileostomy

or colostomy for either cancer or inflammatory bowel disease.

6. Drug-induced pyoderma gangrenosum, in which the lesions

appear as a consequence of the patient’s medication.[25-29]


Ulcerative or classical pyoderma gangrenosum most com-

monly presents on the lower extremities, such as the pretibial

leg. It begins as a small papule or group of papules that break

down and form small ulcers with a ‘cat’s paw’ appearance.

After the papules coalesce, necrosis occurs in the central area

and a single deep painful ulcer with a well defined, violaceous to

blue border, forms. The edge of the ulcer is undermined (worn

and damaged) and there is erythema and induration of the

surrounding skin. Healing results in scars that are frequently

cribriform.[25-28]

The morphology of peristomal pyoderma gangrenosum

is similar to that of ulcerative pyoderma gangrenosum. In

contrast, the lesions of the pustular, bullous (atypical), and

vegetative variants of this condition are characteristically

more superficial. New lesions developing at sites of minor

trauma – such as needle sticks – to the skin (pathergy) are a

common occurrence; therefore, surgical debridement of the

lesions is contraindicated.[25,26,28]

Mucosal lesions of pyoderma gangrenosum have rarely

been observed on the buccal mucosa, tongue, pharynx, larynx,

eyes, and genitalia. Extracutaneous lesions, often referred to

as ‘sterile neutrophilic abscesses,’ have most commonly been

noted in the lungs; other sites include bone (referred to as

multifocal sterile recurrent osteomyelitis), liver, spleen, heart,

skeletal muscles, and CNS.[25,28]

Patients with pyoderma gangrenosum can also have

systemic symptoms. In addition to fever, these include malaise,

arthralgia, and myalgia. Although diagnostic criteria for

pyoderma gangrenosum have been proposed, they have not

been universally accepted or validated.[25]


The pathologic findings in ulcerative (classical) pyoderma

gangrenosum are not specific and vary depending on the timing

and the site of the biopsy. However, biopsies for microscopic

evaluation and cultures (bacterial, fungal, and mycobacterial)

may be useful to exclude other conditions that clinically can

mimic pyoderma gangrenosum. Early in the disease, a biopsy

taken from the advancing erythematous border will usually

show a dermal perivascular lymphocytic infiltrate with en-

dothelial cell swelling. Later in the course of the disease, biopsy

from an area of ulceration will show a neutrophilic dermatosis

characterized by a dense polymorphonuclear leukocyte infil-

trate, and biopsy from the margin of the ulcer will show not

only perivascular lymphocytes but also thrombosis of vessels

with extravasated erythrocytes.[25-29]

Pustular pyoderma gangrenosum is also characterized by

varying pathologic features depending on the stage of disease

evolution: subcorneal accumulation of neutrophils, perifolli-

cular infiltration of neutrophils, and dense dermal infiltration

of neutrophils with subepidermal edema. The pathologic chan-

ges of bullous (atypical) pyoderma gangrenosum can also vary:

dense dermal neutrophil infiltrate with microabscess formation

from the base of the erosion and a subepidermal blister with

dermal edema from an intact bulla. Vegetative pyoderma

gangrenosum demonstrates not only neutrophils, but also his-

tiocytes within the inflammatory infiltrate; in addition, there is

granuloma formation, giant cells, and sinus tracts.[25-29]

Atypical cells in the dermal inflammatory infiltrate,

representing leukemia cutis, have occasionally been observed

304 Cohen


in the biopsies of pyoderma gangrenosum lesions from some

patients who had an associated myelogenous leukemia or

preleukemic condition.[25]


Pyoderma gangrenosum can be idiopathic. However, the

most commonly associated conditions are inflammatory bowel

disease (including both inflammatory bowel disease [Crohn

regional enteritis] and ulcerative colitis) and rheumatoid ar-

thritis. Cancer – most frequently hematologic malignancies

(leukemia, lymphoma, myeloma, myelodysplastic syndromes,

and monoclonal gammopathies) and less often solid tumors –

has also been associated with the development of pyoderma

gangrenosum. This condition has been identified in patients

with hepatitis C and as a component of PAPA syndrome

(a syndrome consisting of nonaxial destructive pyogenic

sterile arthritis, pyoderma gangrenosum, and severe cystic

acne). Drug-induced pyoderma gangrenosum has been re-

ported following the administration of gefitinib (an epidermal

growth factor receptor inhibitor), pegfilgastrim (a granulocyte

colony-stimulating factor), and propylthiouracil.[25-29]

3. Subcorneal Pustular Dermatosis

Subcorneal pustular dermatosis was first described by Sned-

don and Wilkinson in 1956. The dermatosis is a rare, relapsing,

symmetric pustular eruption that involves intertriginous areas

(such as the axillae, groin, and submammary) and also the

flexural sites of the trunk and extremities. The condition typi-

cally occurs inmiddle-aged women. In addition to the idiopathic

variant of the dermatosis, the condition can also be associated

with cancer, infections, medications, and systemic diseases.[30-32]


A pea-sized pustule arising on normal skin or a slightly ery-

thematous base is the primary cutaneous lesion. The pustules

are flaccid. They appear as half-pustular and half-clear fluid

blisters. The individual lesions coalesce rapidly to form

annular, circinate, or serpiginous patterns. The skin lesions

tend to be distributed symmetrically.[30-32]

Subsequently, the superficial flaccid pustules rupture. The

lesion then develops superficial scaling, crusting, and faint

hyperpigmentation.[30-32]


A subcorneal accumulation of neutrophils with the absence

of spongiosis or acantholysis is the salient histologic feature of

this condition. There is a superficial split between the stratum

corneum and the layers of epidermis beneath. There is minimal

distortion of the epidermis and dermis underlying the blister. In

addition to neutrophils, occasional eosinophils may be present

in the blister. In the superficial dermis, a mixed inflammatory

infiltrate may be present.[30-32]


Subcorneal pustular dermatosis is frequently associated with

monoclonal gammopathies (such as IgA or IgG monoclonal

gammopathies), multiple myeloma, and other lymphoprolifera-

tive disorders. In addition, the dermatosis has been associated

with Mycoplasma pneumoniae respiratory infection, rheumatoid

arthritis, thyroid disease (hypothyroid andhyperthyroid), inflam-

matory bowel disease (Crohn disease), autoimmune disorders

(such as systemic lupus erythematosus and Sjogren syndrome),

and other conditions such as multiple sclerosis, APUDoma (an

endocrine tumor that arises from the amine precursor uptake and

decarboxylation [APUD] cell), and SAPHO (synovitis, acne,

pustulosis, hyperostosis, osteitis) syndrome.[30-32]

In addition to monoclonal gammopathies, subcorneal

pustular dermatosis is associated with other hematologic ma-

lignancies such as chronic lymphocytic leukemia, and solid

tumors such as metastatic thymoma, and epidermoid carcino-

ma of the lung. A drug-induced variant of this condition has

also been observed in a patient with IgA myeloma who devel-

oped lesions at the injection site of recombinant human

granulocyte-macrophage colony-stimulating factor.[30-32]

4. Concurrent or Sequential Neutrophilic

Dermatoses in the Same Individual

Sweet syndrome, pyoderma gangrenosum, and subcorneal

pustular dermatosis usually occur as the only neutrophilic derma-

tosis in an individual. However, in some patients, Sweet syndrome

has developed concurrently, previously, or following the presenta-

tion of either pyoderma gangrenosum[33-37] or subcorneal pustular

dermatosis[1] (table II). Similarly, pyodermagangrenosumhasbeen

observed to occur at the same time, prior to, or after the appear-

ance of subcorneal pustular dermatosis in specific individuals

(table II).[38-46] These observations are not surprising since the cu-

taneous infiltrate is similar in all of the conditions, and all of these

dermatoses can be associated with the same systemic disorders.

5. Treatment

Systemic agents (table III), topical therapies (table IV), and

other treatment modalities (table V) have been used for the



management of patients with neutrophilic dermatoses. Some of

the individual drugs have been used in the treatment of Sweet

syndrome, pyoderma gangrenosum, and subcorneal pustular

dermatosis. However, other medications have only been in-

itiated for one or two of these conditions.

5.1 Sweet Syndrome

The skin lesions in patients with classic Sweet syndrome can

persist for weeks to months in untreated individuals. In oncol-

ogy patients with malignancy-associated Sweet syndrome, the

course of the cutaneous dermatosis can parallel the response

of the patient’s cancer. Drug-induced Sweet syndrome may

resolve spontaneously once the inciting medication has been

discontinued.[3,47-49]

5.1.1 First-Line Therapies

Systemic corticosteroids are the mainstay of therapy for

Sweet syndrome. Prednisone, at a dosage of 1mg/kg/day (usuallyranging from 30 to 60mg/day), may be given as a single morning

dose. The symptoms typically respond promptly to this therapy;

once the lesions have improved or cleared, the dosage can be

lowered by 10mg/day within a period of 4–6 weeks. Subse-

quently, the prednisone can often be discontinued; however,

some patients may require longer treatment.[3,47]

Intravenous pulse administration of methylprednisolone

sodium succinate (up to 1000mg/day) over 1 or more hours,

daily for 3–5 days, may be utilized for patients whose condition

is refractory to other therapies. Often, either a tapering dose of

orally administered corticosteroids or another immunosup-

pressant agent is also used in these individuals.[3,47]

Intralesional corticosteroids (such as triamcinolone acet-

onide at a dose ranging from 3 to 10mg/mL) can be injected

into the skin lesions as either a single injection or as multiple

sequential treatments, if necessary.[16] Also, high-potency to-

pical corticosteroids (such as clobetasol propionate 0.05% in

either a cream, ointment, gel, or foam vehicle) can be applied to

the Sweet syndrome skin lesions.[3,47]

Potassium iodide and colchicine are other first-line therapies.

Potassium iodide is administered orally. This can be in the form

of a 300mg enteric-coated tablet, three times each day, for a total

daily dose of 900mg. Alternatively, Lugol’s solution can be used;

this is a saturated solution (1 g/mL of water) of potassium iodide

(SSKI). When a ‘standard’ medicine dropper (which dispenses

20 drops/mL) is used, 1 drop of SSKI equals 0.05mL (or 50mg

when the concentration of potassium is 1000mg/mL). Treatment

with SSKI begins with 3 drops three times daily (9 drops/day,which equals 450mg/day); the medication is increased by

1 drop three times daily until a final dosage of 21 drops/day(1050mg/day) to 30 drops/day (1500mg/day) is reached.[3,47,49]

Colchicine is administered at a dosage of 0.5mg three times

daily (for a total daily dose of 1.5mg). The medication is often

limited by gastrointestinal adverse effects (such as nausea and

diarrhea). Therefore, it may be necessary to only give the

medication twice daily if these adverse effects occur.[3,47]

5.1.2 Second-Line Therapies

Second-line treatments for Sweet syndrome include indo-

methacin (indometacin), clofazimine, cyclosporine (ciclosporin),

and dapsone; the successful use of these agents has been described

in individual reports and a few larger studies. Indomethacin is

given at an oral dosage of 150mg/day for 7 days and then at

100mg/day for 14 days. Clofazimine was administered at a daily

dose of 200mg for 4weeks, followed by a daily dose of 100mg for

an additional 4 weeks.[3,47]

Cyclosporine has been used in three settings: (i) as initial

monotherapy; (ii) as second-line therapy after the failure of

other first-line treatments; or (iii) as a corticosteroid-sparing

agent. The initial oral dosage has ranged from as low as

2–4mg/kg/day to as high as 10mg/kg/day.[3,47]

Dapsone has also been used, either as a single agent for

treatment or in combination with other therapies. The initial

oral daily dose has ranged from 100 to 200mg; the higher dose

was either administered as a single dose or divided into two

equal doses.[3,47]

5.1.3 Other Therapies

Antibacterials have been used to treat patients with Sweet

syndrome. In some Sweet syndrome patients, the skin lesions

may be either impetiginized or infected with Staphylococcus

aureus. Treatment with an antimicrobial agent to which the

Table II. Concurrent or sequential occurrence of Sweet syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosisa

Sweet syndrome Pyoderma gangrenosum Subcorneal pustular dermatosis

Sweet syndrome 33-37 1

Pyoderma gangrenosum 33-37 38-46

Subcorneal pustular dermatosis 1 38-46

a Reference numbers cited in table.

306 Cohen


bacteria is susceptible often results in improvement of the

lesions. In patients whose dermatosis is related to either in-

flammatory bowel disease, treatment with metronidazole has

been useful. Similarly, when the condition is associated with

either Yersinia or Chlamydia infection, treatment with doxy-

cycline, minocycline, or tetracycline has been efficacious.[3,47]

Treatment with cytoxic chemotherapies and antimetabolites

has been described in individual case reports. Often these agents

are used as corticosteroid-sparing agents in patients with

refractory disease. Similarly, isolated reports of interferon-a(either intralesionally or systemically), immunoglobulin, and

etretinate have been published.[3,47]

More recently, successful management of Sweet syndrome

has been noted in patients treated with tumor necrosis

factor (TNF) antagonists such as etanercept, infliximab, and

thalidomide.[3] Also, in combination with oral prednisone, an

interleukin-1 receptor antagonist (anakinra) was promptly

effective in resolving the symptoms (and subsequently the

clinical lesions) of Sweet syndrome in a patient with long-

standing disease that was refractory to other therapies, in-

cluding the TNF inhibitor adalimumab.[50]

5.2 Pyoderma Gangrenosum

Systemic agents, topical therapies, and other modalities have

been used in the management of pyoderma gangrenosum.

5.2.1 Corticosteroids

Systemic corticosteroids can be sufficient to treat pyo-

derma gangrenosum, especially in patients without any

dermatosis-associated conditions. The starting dosage of oral

prednisone has ranged from approximately 0.5 to 1.0mg/kg/day(40–60mg/day) to as high as 2.0mg/kg/day. Treatment at the

higher initial dosage is continued until the lesions significantly

improve or resolve, before tapering and discontinuing the medi-

cation. Typically, 4–6 weeks of therapy are needed.[25-28,51,52]

Pulse therapy with suprapharmacologic dosages of intra-

venous methylprednisolone (1000mg/day) has been used to

treat patients with refractory disease. High-potency topical

corticosteroids (such as clobetasol propionate 0.05%) and in-

jections of corticosteroids into the border of the lesions have

also been used. However, potential exacerbation of the lesions

through pathergy should be considered before initiating

intralesional therapy.[25-28,52]

5.2.2 Tumor Necrosis Factor-a Antagonists

Adalimumab (usually 40mg subcutaneously every other week

toweekly), etanercept (50mg subcutaneouslyweekly to biweekly),

Table III. Systemic treatments for neutrophilic dermatoses

Agent Sweet

syndrome

Pyoderma

gangrenosum

Subcorneal

pustular

dermatosis

Adalimumab +

Acitretin +

Alefacept +

Anakinra +

Azathioprine + +

Chlorambucil + +

Clofazimine + +

Colchicine + + +

Corticosteroids

intravenous + +

oral + + +

Cyclophosphamide + +

Cyclosporine (ciclosporin) + + +

Danazol +

Dapsone + + +

Doxycycline + +

Etanercept + +

Etretinate + +

Hepatitis therapy +

Immunoglobulin + +

Indomethacin (indometacin) +

Infliximab + + +

Interferon-a + +

Ketoconazole +

Mebhydrolin +

Melphalan +

Mercaptopurine +

Methotrexate + + +

Minocycline + + +

Mizoribine +

Mycophenolate mofetil +

Nicotine +

Potassium iodide + +

Sulfamethoxypyridazine +

Sulfapyridine + +

Tacrolimus +

Tetracycline + +

Thalidomide + +

Tretinoin (retinoic acid) +

Vitamin E +



and infliximab (5mg/kg/week intravenously at weeks 0, 2, 6,

and then every 6–8 weeks) all seem to be effective in pyoderma

ganrenosum – especially in patients with disease-associated in-

flammatory bowel disease.[53,54] The initial reports are predomi-

nantly in patients whose dermatosis has not responded to other

therapies. Some investigators favor intravenously administered

infliximab in contrast to either adalimumab or etanercept since

the latter subcutaneously administered drugs are given more fre-

quently andmay therefore pose a greater risk for pathergy-related

new skin lesions.[25,26]

Thalidomide suppresses not only TNFa, but also basic

fibroblast growth factor and neutrophil chemotaxis. It has been

used, along with corticosteroids, to treat pyoderma gang-

renosum in dosages ranging from 50 to 200mg/day. Potentialdrug-associated adverse effects include somnolence (therefore,

it may be useful to give themedication at bedtime), birth defects

(since the medication is teratogenic), neuropathy (hence, nerve

conduction studies should be considered if symptoms occur),

and coagulopathy.[25,27,28]

5.2.3 Calcineurin Inhibitors

Prior to the advent and effectiveness of treatment of

pyoderma gangrenosum with TNFa inhibitors, cyclosporine –

either alone or in combination with systemic corticosteroids –

was an acceptable treatment for widespread disease. Cyclospor-

ine inhibits T-lymphocyte activation. Recommended starting

dosages range from 2–3 to 4–5mg/kg/day. Typically, clinicalimprovement promptly occurs after initiating therapy;

however, the drug has no impact on the incidence of disease

recurrence. Therefore, additional systemic agents are usually

needed to maintain clinical response, especially when tapering

cyclosporine therapy. When the patient is being treated with

cyclosporine, it may be prudent to monitor blood pressure

(to prevent hypertension), creatinine (to prevent renal toxicity),

lipids (to prevent hyperlipidemia), potassium (to prevent hyper-

kalemia), uric acid (to prevent hyperuricemia), and magnesium

(to prevent hypomagnesemia).[25-28,51,52]

Tacrolimus is also a calcineurin inhibitor. It has been used in

dosages of 0.1mg/kg/day. Similar to cyclosporine, it has a rapid

onset of action. In addition to systemic administration, topical

therapy with either tacrolimus or pimecrolimus has been used

to treat pyoderma gangrenosum.[25-28,55]

5.2.4 Dapsone and Related Drugs

Dapsone (50–200mg/day) and sulfapyridine (1 g twice daily)have also been used to treat pyoderma gangrenosum. These

medications have a slow onset of action andmay bemore useful

in combination with systemic corticosteroids. Before initiating

therapy, it might be useful to confirm that the patient has a

normal level of glucose-6-phosphate dehydrogenase in order to

avoid drug-induced hemolytic anemia. Periodic monitoring

of laboratory studies (complete blood cell counts and serum

Table IV. Topical treatments for neutrophilic dermatoses

Agent Sweet

syndrome

Pyoderma

gangrenosum

Subcorneal

pustular

dermatosis

Benzoyl peroxide +

Chlormethine (nitrogen

mustard)

+

Corticosteroids + + +

Hydrogen peroxide +

Nicotine +

Pimecrolimus +

Sodium cromoglicate

(disodium cromoglycate)

+

Tacalcitol (1-a, 24-

dihydroxyvitamin D3)

+

Tacrolimus +

Table V. Other treatment modalities for neutrophilic dermatoses

Modality Sweet

syndrome

Pyoderma

gangrenosum

Subcorneal

pustular

dermatosis

Hyperbaric oxygen +

Intralesional therapies

corticosteroids + +

cyclosporine

(ciclosporin)

+

interferon-a +

macrophage colony-

stimulating factor

+

tacrolimus +

Phototherapy

broad-band UVB

radiation

+

narrow-band UVB

radiation

+

psoralen and UVA

radiation

+

retinoid-psoralen

and UVA radiation

+

Plasmapheresis +

Skin grafts +

308 Cohen


chemistries) is also recommended while the patient is receiving

these medications.[25,27,28]

5.2.5 Cytotoxic Chemotherapies and Antimetabolites

Azathioprine (100–300mg/day), cyclophosphamide (1.5–

3.0mg/kg/day), methotrexate (10–30mg/week), mycopheno-

late mofetil (2–3 g/day), melphalan, and mercaptopurine have

been used,mostly in combination with systemic corticosteroids,

for treating pyoderma gangrenosum. These agents have a slow

onset of action. Each has its own potentially associated adverse

effects and monitoring. For example, if azathioprine is to

be used, consider checking the thiopurine methyltransferase

level to prevent drug-related toxicity in patients who either lack

or have low levels of the enzyme. Also, when cyclophosphamide

is used, be sure to maintain good hydration before and dur-

ing therapy to decrease the risk of developing hemorrhagic

cystitis.[25-28]

5.2.6 Other Systemic Agents

Antibacterials, clofazimine, colchicine, alefacept, potassium

iodide, nicotine, and interferon-a are additional alternatives fortreating pyoderma gangrenosum. Although cultured bacterial

organisms from the ulcer basemay represent colonizers and not

true pathogens, treatment with appropriate antibacterials may

promote more rapid improvement of the primary dermatosis.

Also, at dosages of 100mg either twice or three times daily,

minocycline and doxycycline may be helpful – especially in

combination with other therapies.[25,28]

Clofazimine (300–400mg/day) stimulates phagocytosis and

superoxide production; it also has direct antibacterial activity.

In addition, it reduces the chlorination of proteins by neu-

trophils since it is a scavenger of hypochlorus acid. It has a slow

onset of action, can cause drug-associated hyperpigmentation

and, according to one investigator, is similar in efficacy to sulfa

drugs such as dapsone.[25,27]

Colchicine (0.6mg two to three times per day) prevents

the assembly of tubulin subunits intomicrotubules. This results in

arrest of mitosis in metaphase and interference with cell motility.

Hence, the drug decreases neutrophil chemotaxis, motility, and

adhesiveness; it also interferes with lysosome degranulation. It

has been used as a single agent and in combination therapy for

treating pyoderma gangrenosum. Drug-related nausea and

diarrhea may necessitate reduction of the daily dose.[25,27]

Alefacept (15mg/week) is a genetically engineered immuno-

suppressant that inhibits T-cell activation. Its use in pyoderma

gangrenosum is based on the speculation that T-cell abnorm-

alities may play a role in the intense neutrophilic infiltrate of the

dermatosis. A recent study described four patients who were

treated weekly for 20 weeks with complete resolution (n = 1),marked improvement (n = 2), or slight improvement (n = 1) oftheir pyoderma gangrenosum.[56]

5.2.7 High-Dose Intravenous Immunoglobulin

High-dose intravenous immunoglobulin (2 g/kg/dose, givenover 2 or 3 days, each month) has been demonstrated to be

effective in the management of recalcitrant pyoderma gang-

renosum. In most of the patients, corticosteroid therapy was

initially maintained. Many of the patients were treated for

several months; however, initial improvement was usually

observed after two or three cycles of treatment.[57,58]

5.2.8 Topical Treatments

In addition to high-potency corticosteroids and calcineurin

inhibitors (tacrolimus and pimecrolimus), several other agents

have been used topically to treat pyoderma gangrenosum.

These include benzoyl peroxide, sodium cromoglicate (disodium

cromoglycate), hydrogen peroxide, nicotine, and chlormethine

(nitrogen mustard).[25-28,59]

5.2.9 Other Treatment Modalities

Other treatment modalities for pyoderma gangrenosum in-

clude hyperbaric oxygen, plasmapheresis, intralesional agents,

and skin grafts. In addition to corticosteroids and tacrolimus,

medications that have been injected into pyoderma gang-

renosum lesions (usually into intact skin at the edge of the ulcer)

include cyclosporine and macrophage colony-stimulating fac-

tor. When the ulcers are deep and extensive, either biologic

dressings, skin grafts or both have been utilized to cover the

underlying tissue at the ulcer base.[25,27,28,60]

5.3 Subcorneal Pustular Dermatosis

Systemic agents, topical therapies, and phototherapy have

been used in the management of subcorneal pustular dermatosis.

5.3.1 Dapsone and Related Drugs

Dapsone (at dosages ranging from 50 to 200mg/day) is thetreatment of choice for subcorneal pustular dermatosis. Indeed,

in association with other appropriate clinical features, a helpful

criterion for establishing the diagnosis of this condition is a

therapeutic response after initiating treatment with dapsone.

The response to therapy is slow in onset and remission; clinical

resolution may occur in about 4 weeks and long-term therapy

is necessary to maintain disease control in most patients.



However, the dose can be tapered to the minimum needed once

the condition has cleared.[30-32]

Sulfapyridine and sulfamethoxypyridazine are alternative

therapeutic options to dapsone; however, they are generally less

effective and, therefore, are not commonly used for treating

subcorneal pustular dermatosis.[30-32]

5.3.2 Corticosteroids

Systemic corticosteroids (such as prednisone in dosages ran-

ging from 50 to 100mg/day) have also successfully been used to

treat subcorneal pustular dermatosis. However, asmonotherapy,

they tend to be less effective than dapsone. Indeed, a good

response to systemic corticosteroids – associated with a failure of

the condition to improve with dapsone – is unusual and raises the

possibility that the patient has pustular psoriasis instead of sub-

corneal pustular dermatosis. Yet, when subcorneal pustular

dermatosis is associated with other dermatologic or systemic

conditions (such as pyoderma gangrenosum, multiple myeloma,

or systemic lupus erythematosus), oral corticosteroids have

effectively been used in combination with dapsone.[30-32]

5.3.3 Retinoids

Etretinate, acitretin, tretinoin (retinoic acid), and isotretinoin

have been used to treat patients with subcorneal pustular

dermatosis; however, the latter appears to not be effective. The

dosage of etretinate has ranged from as low as 0.25mg/kg/day tobetween 0.5 and 1.0mg/kg/day; patients usually receive a dosageof 20–75mg/day. Inhibition of neutrophil migration and influ-

ence on specific mediator systems are postulated as the mecha-

nisms of action of etretinate.[30-32,61]

The retinoids have been used either as monotherapy, in

combination with dapsone, or along with psoralen and UVA

(PUVA) phototherapy. Rapid and complete clinical remission

has been observed as promptly as 8–15 days after starting

therapy. However, relapses have occurred and the agent etre-

tinate was ineffective in some patients.[30-32,61]

5.3.4 Infliximab

Variable success has been reported in patients treated with

the TNFa antagonist infliximab.[31,32] In one person with severe

recalcitrant disease, clinical improvement occurred within

2 days after receiving a single intravenous dose of 5mg/kg; asecond administration was given after 14 days because of

clinical relapse. Thereafter, the patient remained in complete

remission while being maintained on acitretin at a dosage

of 0.16mg/kg/day.[62] However, the improvement was only

temporary for another patient whose disease was not controlled

after four administrations of the drug.[63]

5.3.5 Other Systemic Agents

Several other systemic agents have anecdotally been observed

to be effective for treating individual patients with subcorneal

pustular dermatosis. These include antibacterials (tetracycline

and minocycline), antifungals (ketoconazole), immunosuppre-

ssants (cyclosporine), antimetabolites (methotrexate), mizor-

ibine, mebhydrolin, vitamin E, and colchicine.[30-32]

5.3.6 Topical Treatments

High-potency topical corticosteroids (such as clobetasol

0.05%) have been used alone or in combination with dapsone;

this has been effective when the lesions were localized.[30,31] A

patient who responded to topical tacalcitol (1-a, 24-dihydroxy-vitamin D3) has been reported.[64]

5.3.7 Other Treatment Modalities

Phototherapy has been used alone or in combination with

dapsone and/or retinoids to treat subcorneal pustular derma-

tosis. The type of UV radiation has either been UVB (broad

band or narrow band) or UVA. The latter has been combined

with either psoralen (PUVA) alone or psoralen and a systemic

retinoid (Re-PUVA).[30-32,61]

6. Conclusion

Neutrophilic dermatoses are conditions that share a com-

mon cell, the neutrophil, in the inflammatory infiltrate of their

skin lesions. In Sweet syndrome and pyoderma gangrenosum,

the neutrophils are usually located within the dermis; however,

they can be present in the subcutaneous fat. In subcorneal

pustular dermatosis, the neutrophils are found in the upper

layers of the epidermis.

Sweet syndrome, pyoderma gangrenosum, and subcorneal

pustular dermatosis can all be associatedwith infections, systemic

diseases, cancer, and medications. Subcorneal pustular derma-

tosis is only localized to the skin. However, Sweet syndrome and

pyoderma gangrenosum can present with not only dermatosis-

related mucosal lesions but also extracutaneous manifestations.

The management of these neutrophilic dermatoses includes

systemic drugs, topical agents, and other treatment modalities.

Systemic corticosteroids are the treatment of choice for Sweet

syndrome and pyoderma gangrenosum – especially when the

latter is not associated with any dermatosis-related systemic

310 Cohen


conditions. However, when pyoderma gangrenosum is accom-

panied by inflammatory bowel disease or rheumatoid arthritis,

TNFa antagonists are becoming the initial therapeutic agent for

both the neutrophilic dermatosis and the underlying systemic

disease. In contrast, dapsone is the drug of choice for treating

subcorneal pustular dermatosis.

Alternative first-line therapies for Sweet syndrome include

potassium iodide and colchicine; second-line treatments are

indomethacin, clofazimine, cyclosporine, and dapsone. Cy-

closporine is effective in the acute management of pyoderma

gangrenosum; however, additional systemic agents are neces-

sary for maintaining clinical response when tapering the drug.

Although systemic corticosteroids may be effective in some

patients with subcorneal pustular dermatosis, systemic re-

tinoids (such as etretinate and acitretin) either as monotherapy

or in combination with dapsone or as a component of

Re-PUVA phototherapy have effectively been used for treating

this neutrophilic dermatosis.

Localized manifestations of Sweet syndrome, pyoderma

gangrenosum, and subcorneal pustular dermatosis may be

successfully treated with high-potency topical corticosteroids;

however, topical agents for these neutrophilic dermatoses

usually have an adjuvant role in their management. Other

treatment modalities may also be useful, such as intralesional

corticosteroid therapy for patients with Sweet syndrome and

pyoderma gangrenosum, hyperbaric oxygen and plasmapher-

esis for patients with pyoderma grangrenosum, and photo-

therapy for patients with subcorneal pustular dermatosis.

Acknowledgments

No sources of funding were used to assist in the preparation of this

review. The author has no conflicts of interest that are directly relevant to

the content of this review.

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Correspondence: Dr Philip R. Cohen, 805 Anderson Street, Bellaire, TX

77401-2806, USA.

E-mail: [email protected]

312 Cohen


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