Clinics in Dermatology (2014) 32, 376–388

Neutrophilic dermatoses as systemic diseases Lola Prat, MD, Jean-David Bouaziz, MD, PhD ⁎, Daniel Wallach, MD, Marie-Dominique Vignon-Pennamen, MD, Martine Bagot, MD, PhD Université Paris Diderot, Sorbonne Paris Cité; AP-HP, Paris, France Service de Dermatologie et Service d’Anatomo-Pathologie, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France

Abstract Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal polymorphonuclear leukocytes. The main clinical forms of ND include Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and their atypical or transitional forms. ND are often idiopathic, but they may be associated with myeloid hematologic malignancies (Sweet syndrome), inflammatory bowel disease or rheumatoid arthritis (pyoderma gangrenosum), and monoclonal gammopathies (erythema elevatum diutinum, subcorneal pustular dermatosis). The possible infiltration of internal organs with neutrophils during the setting of ND underlies the concept of a neutrophilic systemic disease. ND may be seen as a polygenic autoinflammatory syndrome due to their frequent association with other autoinflammatory disorders (monogenic or polygenic) and the recent published efficacy of interleukin-1 blocking therapies in their management. © 2014 Elsevier Inc. All rights reserved.

The neutrophilic dermatoses (ND) are a group of disorders characterized by skin lesions for which histologic examination reveals intense inflammatory infiltrates composed primarily of neutrophils with no evidence of infection. ND mainly include Sweet syndrome (SS), pyoderma gangrenosum (PG), subcorneal pustular dermatosis (SPD), other well-defined entities, and their atypical or transitional forms. The concept of ND relies on four premises: 1. The existence of transitional and overlap forms 2. A similar histopathologic feature characterized by an infiltrate of normal polymorphonuclear leukocytes 3. The possible occurrence of extracutaneous neutrophilic symptoms (the neutrophilic disease) 4. A frequent association with multisystemic diseases1

⁎ Corresponding author. Tel.: +33142494680; fax: +33142494620. E-mail address: [email protected] (J.-D. Bouaziz). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.004

The diagnosis of extracutaneous neutrophilic manifestations of ND is often difficult because it requires intensive investigations to rule out an infectious or neoplastic process. ND may be associated with a variety of systemic disorders including especially myeloproliferative disorders, monoclonal gammopathies (mainly IgA type), inflammatory bowel disease, and rheumatoid arthritis (RA).2,3 The classical sterile infiltration of the skin that occurs in ND may also be observed in many organs including the lungs, bones, joints, digestive tract, liver, spleen, pancreas, central nervous system, heart, and blood vessels4; furthermore, some patients may suffer from aseptic systemic abscesses without cutaneous involvement.5 In 2006, researchers proposed a clinical and histologic classification according to the localization of the neutrophilic infiltrate and divided ND in three groups: ND “en plaques” characterized by a dermal neutrophilic infiltrate (SS, erythema elevatum diutinum [EED]), superficial ND characterized by an epidermal neutrophilic infiltrate (SPD), and deep ND characterized by

Neutrophilic dermatoses Table 1

377

Summary of neutrophilic dermatosis, extracutaneous involvement and associated diseases

Type of Neutrophilic Dermatosis Extracutaneous Involvement Dermal neutrophilic dermatosis AFND (Sweet syndrome) Arthralgias, myalgias, polyarthritis seronegative or seropositive, CRMO, myositis, recurrent encephalitis with ND (neuro-Sweet), meningitis, rarely peripheral neuropathy, abnormalities of hepatic enzymes, aseptic neutrophilic abscesses (liver, spleen, pancreas, digestive tract) BOOP, pleural effusion, lung nodular lesions, aneurysm of ascending aorta, myocardium infiltration Periorbital and orbital, inflammation, dacryoadenitis, conjunctivitis, episcleritis, scleritis, limbal nodules, peripheral ulcerative keratitis, iritis, glaucoma, and choroiditis Proteinuria, hematuria, renal insufficiency, rarely glomerulonephritis EED

Arthralgias Sclerosing glomerulonephritis

NEH

Dermal and hypodermal neutrophilic dermatosis Pyoderma gangrenosum Nodular pulmonary lesions, with or without cavitation, noninfectious necrotizing tracheitis, CRMO, polyarthritis seronegative or seropositive, “colitis arthritis” Abnormalities of hepatic enzymes and digestive aseptic neutrophilic abscesses Myositis, cardiac involvement, keratitis, episcleritis, rapidly progressive renal failure, sclerosing glomerulonephritis, pyosalpinx

Associated Diseases AML, lymphomas, myelodysplastic syndromes, chronic leukemias, myelomas G-CSF, bortezomib Solid tumors, IBD (CD N UC), RA, Behçet disease, relapsing polychondritis, thyroid diseases

IgA gammopathy, hepatitis B, streptococcal infections, HIV, polycythemia vera, myelodysplastic syndrome, hairy cell leukemia, mixed cryoglobulinemia Induction chemotherapy in AML++, CML, Hodgkin lymphoma, various solid tumors

IBD (UC N CD) RA, ankylosing spondylitis, relapsing polychondritis, AML, polycythemia vera, monoclonal gammopathy, Waldenström macroglobulinemia, large granular lymphocytic leukemia, myelofibrosis, and non-Hodgkin lymphoma G-CSF, IFN-α2b

Neutrophilic panniculitis

Melanoma treated with vemurafenib, Crohn's disease, myelodysplastic syndrome treated by azacitidine, CML treated by imatinib, RA

Skin aseptic abscesses

Crohn's disease

Epidermal neutrophilic dermatosis SPD Arthritis, abnormalities of hepatic enzyme and digestive aseptic neutrophilic abscesses, sclerosing glomerulonephritis

IgA pemphigus

Monoclonal gammopathies (IgA type), lymphomas, multiple myelomas, aplastic anemia, CML Solid tumors (metastatic thymoma, epidermoid carcinoma of the lung) G-CSF Mycoplasma pneumoniae respiratory infection RA, IBD, autoimmune disorders (Sjögren syndrome, SLE), thyroid disease, SAPHO Monoclonal gammopathy, typically of the IgA class, B cell lymphomas, myeloma, and CD30+ anaplastic large cell lymphoma Cryoprecipitate IgG, CD, gluten-sensitive enteropathy

378

L. Prat et al.

Table 1 (continued) Type of Neutrophilic Dermatosis Extracutaneous Involvement Dermatosis arthritis syndrome

Arthritis, erythema nodosum

Associated Diseases Ileojejunal bypass, inflammatory bowel diseases

AFND, acute febrile neutrophilic dermatosis; AML, acute myelogenous leukemia; BOOP, bronchiolitis obliterans organizing pneumonia; CD, Crohn's disease; CML, chronic myelogenous leukemia; CRMO, chronic recurrent multifocal osteomyelitis; EED, erythema elevatum diutinum; G-CSF, granulocyte colony-stimulating factor; IBD, inflammatory bowel disease; IFN, interferon; ND, neutrophilic dermatosis; NEH, neutrophilic eccrine hidradenitis; RA, rheumatoid arthritis; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis; SLE, systemic lupus erythematous; SPD, subcorneal pustular dermatosis; UC, ulcerative colitis.

a dermal and hypodermal infiltrate (PG).1 The purpose of this contribution is to describe the ND clinical spectrum, the neutrophilic systemic disease, and the most frequent diseases associated with the ND (see Table 1 for a summary).

The neutrophilic dermatoses: Cutaneous clinical features Acute febrile neutrophilic dermatosis or SS, the prototype of the neutrophilic dermatoses en plaques (dermal ND) Sweet syndrome Acute febrile neutrophilic dermatosis was described by Robert Douglas Sweet in 1964 and soon came to be known as SS.6 It is characterized by fever; neutrophilia (with blood polymorphonuclear leukocyte level greater than 10,000/ mm3); painful, erythematous 0.5 to 12 cm papules or plaques (Figure 1) on the extremities, face, and neck; and a dense dermal neutrophilic infiltrate.6 Additional criteria for SS include absence of infection and responsiveness to corticosteroid.6 Microscopic examination reveals a dense dermal infiltrate of mature neutrophils with edema. The infiltrate is usually localized to the upper portion of the dermis but may extend into the subcutaneous tissue as recently reported in association with myeloid disorders (neutrophilic panniculitis or subcutaneous SS).7 Other typical histologic features may include a mixture of lymphocytes and eosinophils, vascular endothelial swelling, and erythrocyte extravasation. Changes of a primary leukocytoclastic vasculitis are typically absent

Fig. 1

Clinical picture of idiopathic Sweet syndrome.

but may be observed as an epiphenomenon in old lesions or in some localizations.8,9 Most cases are considered to be idiopathic,10 but SS can be associated with different disorders. The association between malignancy and SS was first recognized in the early 1970s. Ten to 20% of SS cases occur in the setting of an underlying malignancy, most commonly myelogenous acute leukemia,11 but also lymphomas, myelodysplastic syndromes, chronic leukemias, myelomas, and other myeloproliferative disorders. In addition, SS can occur after treatment with granulocyte colony-stimulating factor (G-CSF) in patients with hematologic disorders. An association with solid tumors is rare but has been reported. SS has also a bonafide association with inflammatory bowel disease (both Crohn's disease and ulcerative colitis), Behçet disease, relapsing polychondritis, RA, and thyroid disease (both Graves disease and Hashimoto thyroiditis). Most cases occur between 30 and 60 years of age. A prior upper respiratory tract infection is frequently associated with idiopathic SS, but a prodrome is not typically seen in malignancy-associated SS. The cutaneous lesions in patients with underlying malignancies frequently have atypical features including pustular, vesicular, bullous, and even ulcerating lesions, as well as the more typical plaques and nodules.11 Generalized pustular lesions may occur in association with chronic myeloid leukemia.12 Oral mucosal lesions are rare and occur more frequently in malignancy-associated SS.13 The frequency of SS extracutaneous manifestations varies, but they may occur in more than 50% of the cases associated with an underlying hematologic malignancy.11 The most common systemic symptoms are arthralgias and myalgias, but SS can involve many organs including the lung.14 Massive swelling of the tongue15 and cutaneous pathergy have been reported in patients with underlying hematologic disorders.16 Erythema elevatum diutinum In 1894, Henry Radcliffe-Crocker and investigators coined the name “erythema elevatum diutinum” (EED), a chronic inflammatory dermatosis characterized by brownish red, elevated lesions occurring symmetrically over extensor surfaces of the interphalangeal joints, elbows, ankles, and knees.17 A predominantly acral distribution with truncal sparing is characteristic. Most cases begin in the middle age, but the age at onset can vary from 6 months to 75 years. There is no sex predilection or familial association.17

Neutrophilic dermatoses The pathologic findings in EED correlate with the age of the lesion at the time of biopsy.18 The cause of EED is unknown, but the dermatopathologic process begins with a leukocytoclastic angiitis. Leukocytoclastic vasculitis may be accompanied by bullae formed secondary to epidermal necrosis. Later lesions show nodules with vasculitis, dermal aggregates of neutrophils, and granulation tissue formation.19 The final stage of EED is a nodule with fibrosis and infiltration by histiocytes and macrophages. The disease may be associated with a variety of underlying processes, including hepatitis B, streptococcal infections, ulcerative colitis, Crohn's disease, RA, recurrent bacterial infection, collagen vascular diseases, polycythemia vera, myelodysplastic syndrome, hairy cell leukemia, mixed cryoglobulinemia, and HIV infection, but IgA gammopathy is by far the most frequent disease associated with EED.10,20 Other ND en plaques Other ND en plaque include: 1. The neutrophilic eccrine hidradenitis, which is clinically very similar to SS. It commonly occurs in patients receiving chemotherapy for acute myelogenous leukemia, and the distinction with SS is usually made by the histologic examination that reveals neutrophils in and around the eccrine coil.21 2. The neutrophilic rheumatoid dermatitis that occurs in patients with severe, seropositive RA.22 Clinical symptoms are erythematous plaques and periarticular nodules. 3. The granulomatous PG, which is a rare variant of PG characterized by a vegetating, unique plaque that slowly extends and that may be hollowed out by a very superficial ulceration.23

PG, the prototype of the deep ND (dermal and hypodermal ND) Pyoderma Gangrenosum PG was first described in 1930.24 Active lesions are characterized by chronic evolutive ulcerations with violaceous, undermined borders (Figure 2). Five clinical variants are currently recognized: classic (ulcerative), bullous,

Fig. 2 Pyoderma gangrenosum in a patient with relapsing polychondritis.

379 pustular, vegetative, and peristomal cases.25 The diagnosis of PG is generally made clinically because the histologic findings are not diagnostic, and appropriate cultures should be taken and infection should be ruled out. Characteristically, PG presents with pustules or nodules that progress to ulcers with central necrosis. The lesions have undermined, dusky borders and are surrounded by violaceous, erythematous haloes.24 The lesions are exquisitely tender and heal with cribriform scarring. There is a female predominance in nonmalignancy-associated PG.26 Men are more commonly affected in malignancy-associated PG and have a worse prognosis.27 The average age of onset of the disease is 40 years, and only 4% of patients are younger than 15 years.3 The histology is determined by the type of lesion for which a biopsy was taken (ulcerative, vegetative), the stage of the lesion, and the portion of the lesion sampled. More than 50% of patients with PG have an associated systemic disease,28 including ulcerative colitis, Crohn's disease, RA, relapsing polychondritis, and hematologic malignancies.28 Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, are the systemic diseases most frequently reported in association with PG. This association was seen in up to 41% of PG cases published in the last three decades.25 In a recent prospective study of 2402 French patients with inflammatory bowel diseases, 0.75% of patients had PG, without any association between the severity of inflammatory bowel diseases and the presence of PG.29 PG is also frequently associated with various arthritis forms, most commonly seronegative arthritis of a single, large joint,30 but classical forms of RA and ankylosing spondylitis are also commonly associated.28 The clinical severity of the arthritis is unrelated to PG activity.31 PG has also been reported after the administration of interferon-α2b in a patient with chronic granulocytic leukemia32 and after the administration of G-CSF in a patient with myelodysplastic syndrome (MDS).33 Approximately 7% of patients with PG have an associated hematologic malignancy, most commonly acute myelogenous leukemia (AML).34 Overlaps between PG and SS are typically found in patients with a myeloproliferative disorder.35 Other associated hematologic disorders include monoclonal gammopathy (usually IgA subtype), Waldenstrom macroglobulinemia, large granular lymphocytic leukemia, myelofibrosis, and non-Hodgkin lymphoma.10 Systemic involvement of PG affecting the liver, lungs, meninges, and kidneys (rapidly progressive renal failure associated with monoclonal gammopathies) has been reported.36 Primary PG of the lung preceding cutaneous PG has been described in two patients.37,38 Other deep ND Other deep ND include the neutrophilic panniculitis, characterized by painful, inflammatory subcutaneous masses,39 and skin aseptic abscesses characterized by nodules or subcutaneous masses that fluctuate and from which spontaneous sterile pus may drain.40

380 Neutrophilic panniculitis has been reported to be associated with RA,39,41,42 with Crohn's disease,43 MDS,44 and MDS treated by G-CSF or azacitidine,45 with CML treated by imatinib,46 and with metastatic melanoma treated by vemurafenib.47,48 In a recent review, extracutaneous aseptic abscesses were well described in 29 French patients involving abdominal lymph nodes, liver, lung, pancreas, and brain. Only 20% of the patients in this cohort had an associated “skin” ND.5

SPD (Sneddon-Wilkinson disease), the prototype of the superficial ND (epidermal ND) Subcorneal pustular dermatosis SPD is a rare and chronic condition, described for the first time in 1956 by Sneddon and Wilkinson.49 Criteria for the diagnosis of SPD include a new onset of pustular eruptions without systemic symptoms, absence of existing psoriasis, subcorneal neutrophilic pustules without spongiosis, and responsiveness to dapsone.50 It is characterized by a symmetric pustular eruption that involves intertriginous areas (such as the axillae, groin, and submammary), and also the flexural sites of the trunk and extremities51-53 (Figure 3). New waves of pustules spread in an annular or gyrate pattern, leaving a ring-shaped scale. Classically, SPD occurs in women between the ages of 40 to 70 years.54 A subcorneal accumulation of neutrophils with the absence of spongiosis or acantholysis is the salient histologic feature of the condition. There is a superficial split between the stratum corneum and the layers of epidermis beneath, and a 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, with perivascular infiltrate.53 SPD may be associated with many systemic disorders, including monoclonal gammopathies, lymphomas, and multiple myelomas. The paraprotein in SPD is usually of the IgA type.50 IgG-cryoglobulinemia, IgA myeloma, and IgG myeloma have also been described with SPD.55 Also, SPD

L. Prat et al. has been reported to occur in association with aplastic anemia.56 In addition to monoclonal gammopathies, SPD is associated with other hematologic malignancies such as chronic lymphocytic leukemia, solid tumors such as metastatic thymoma, and epidermoid carcinoma of the lung. SPD has also been associated with Mycoplasma pneumoniae respiratory infection, RA, thyroid disease, inflammatory bowel disease, autoimmune disorders (such as systemic lupus erythematosus and Sjögren syndrome), and other conditions such as multiple sclerosis, apudoma syndrome (an endocrine tumor that arises from the amine precursor uptake and decarboxylation cells), and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.53 IgA pemphigus In 1979, the case of a patient with a condition similar to SPD, but with epidermal IgA deposits in a “pemphigus-like” pattern, was reported.57 Other cases of the condition were named intraepidermal neutrophilic IgA dermatosis,58 “intraepidermal IgA pustulosis,”59 or more commonly, IgA pemphigus. IgA pemphigus includes two subgroups, intraepidermal and subcorneal, with different target autoantigens. A monoclonal IgA is often associated (as in the initial case) and dapsone is often efficient, as in SPD. IgA pemphigus is considered as a continuum between the ND and autoimmune bullous skin diseases. Cases of IgA pemphigus have been recently reviewed.60 Other superficial ND Deep pustules on an inflammatory basis may represent the initial lesions of ulcerative PG or the superficial component of pustular-bullous PG or atypical SS. Isolated pustules, sometimes with an erythematous or violaceous component, have been described as pustular vasculitis and are part of the “dermatosis arthritis syndrome” (pustulosis, erythema nodosum, and arthritis) in patients with an ileojejunal bypass or with inflammatory bowel diseases.61 Bullous forms of PG and sometimes bullous forms of SS can occur and are mainly associated with myeloproliferative disorders. One report described three new cases and summarized previously published cases of a recently described entity called “amicrobial pustulosis of skin folds.” 62 Patients with autoimmune diseases, especially lupus erythematosus, experienced recurrent attacks of aseptic pustules in major and minor skin folds.

Extracutaneous neutrophilic involvement: The neutrophilic disease Lung

Fig. 3 Erythema and aseptic pustules in the setting of subcorneal pustular dermatosis (Sneddon-Wilkinson disease).

Culture-negative pulmonary lesions in patients with ND have been reported in patients with SS, PG, and SPD. Most patients had fever, and pulmonary symptoms were

Neutrophilic dermatoses characterized by cough, dyspnea, or chest pain. One patient had aseptic abscesses in many organs, especially the lung, without skin lesions, which underlines the possibility of a neutrophilic systemic disease without skin ND.63 The most recent review of the literature about SS with lung involvement, in 2006, reported 23 cases.64 In SS, skin and pulmonary lesions were generally concomitant, but in some cases, skin lesions appeared before pulmonary involvement of SS. Chest radiograph was always abnormal, disclosing patchy infiltrates, homogenous opacity in one segment or lobe, or bilateral interstitial pneumonia. Some patients had pleural effusion preceding or accompanying lung involvement. Open-lung biopsy or transbronchial biopsy when performed disclosed massive neutrophilic infiltrates that formed a suppurative exudate in the alveoli. Analysis of fluid obtained by bronchoalveolar lavage from six patients showed a predominance of neutrophils. Cases of bronchiolitis obliterans organizing pneumonia associated with SS have been reported.65 None of the patients who had biopsy-proven bronchiolitis obliterans organizing pneumonia were found to have an underlying malignancy. In one case, SS with pulmonary and muscle involvement appeared a few days after the initiation of all-trans retinoic acid for the treatment of promyelocytic leukemia.66 Pulmonary involvement in SS may occur more frequently, because many steroid-responsive lung infiltrates are not examined.65 SS with pulmonary involvement were more frequently associated with hematologic malignancy (12/23 patients in one review64). A total of 32 cases of PG with pulmonary involvement have been reported in a recent review.67 The most frequent lung alterations were nodular lesions with or without cavitation. Hematologic malignancies were reported in 13 cases (myelodysplastic syndrome or monoclonal gammopathy). In one case, PG was associated with a noninfectious necrotizing tracheitis.68 Patients with ND and lung involvement were treated with systemic corticosteroids after empirical antimicrobial or antifungal therapy had failed. Both the cutaneous and pulmonary lesions rapidly improved. Many patients died of respiratory failure, septicemia, toxic shock syndrome, or intracerebral hemorrhage.69

Bone A 1972 contribution reported a syndrome of acquired, culture-negative, multifocal osteomyelitis in children and named it “subacute and chronic symmetric osteomyelitis.”70 In 1986, the association between ND and multifocal, aseptic bone lesions in children was termed chronic recurrent multifocal osteomyelitis (CRMO).71 Fever, arthralgias, and myalgias were often present. The diagnosis of CRMO was made in conjunction with bone pain, tenderness, and swelling around a joint at one or multiple sites and lasting between 1 and 2 weeks, mild periosteal reaction, sometimes radiolucent metaphyseal lesions, and an increased uptake at the metaphyseal ends of the involved bones. This disease

381 predominantly affects the metaphyses of long bones, with only rare reports of epiphysis or apophysis involvement.72 Other sites reported include the mandible sternum, clavicle, vertebrae, and the frontal and sphenoid bones. In most cases, bone biopsies showed acute inflammation or chronic inflammatory changes, fibrosis, and excessive resorption of bony trabeculae. Slightly elevated ESRs and sometimes increased white blood cell count are noted. Skin ND lesions associated with CRMO include psoriasis, palmoplantar pustulosis, PG, and SS.73 Many authors have suggested that CRMO and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome belong to the same clinical spectrum, with CRMO being the pediatric form of SAPHO.73 The two syndromes share numerous characteristics, including osteitis, a unifocal or multifocal presentation, hyperostosis, and pustulosis, which all occur in a generally healthy individual. Skin DN lesions associated with SAPHO include palmoplantar pustulosis, nonpalmoplantar pustulosis, psoriasis vulgaris, acne, PG, SS, and SPD.73 Patients are refractory to antibiotic therapy but dramatically respond to systemic steroids and may need to be maintained on lowdose steroids to prevent relapses.

Joints Articular manifestations are frequently reported in the context of ND. They occur in approximately 50% of patients with SS and PG. They are less common in SPD and EED. Arthralgias reported in these diseases occur before, during, or after the onset of ND. They are characterized by episodic, pauciarticular, asymmetric, large joints, and lower extremity involvement. Radiographs are frequently normal or show soft-tissue swelling. In addition to the well-defined rheumatologic inflammatory disorders associated with ND (RA and ankylosing spondylitis), three main different dermatoarthritis syndromes can be individualized.74 The first pattern was mainly described by Holt et al75 and corresponds to a chronic, progressive, seronegative destructive polyarthritis with axial or peripheral involvement, or both. This polyarthritis has been observed mainly in PG and usually antedated the PG. Hidradenitis suppurativa or acne conglobate could also be observed. In all cases, the pattern was symmetric with small- and large-joint involvement. The clinical and radiologic pattern of joint disease was not typical of RA or ankylosing spondylitis. The course of the arthritis was progressive despite treatment of ND. The second pattern of arthritis reported in ND was a seronegative, nondestructive polyarthritis that paralleled the course of skin flares. A third group of patients had clinical characteristics of arthritis matching criteria that were fully established by Wright and Watkinson,76 who named it “colitis arthritis,” first recognized in patients with PG who had inflammatory bowel disease. In this condition, a recurrent acute synovitis occurred usually in a monoarticular distribution. The attacks were of short duration and almost never associated with residual joint deformity or radiologic change.

382

Central nervous system In 1983, the case of a patient with SS, neurologic signs, and psychiatric symptoms was reported; however, the cerebrospinal fluid analysis was normal, and the link between SS and neurologic abnormalities was not clearly established. The term benign recurrent encephalitis or neuroSweet disease with ND (NSD) was introduced in 1999 by Hisanaga et al,77 who described patients with erythematous plaques of SS and encephalitis. The most common neurologic diseases in SS were encephalitis and meningitis (disturbance of consciousness, headache), and rarely peripheral neuropathy. The initial episodes of neurologic symptoms usually followed SS skin symptoms; but in a few cases, the neurologic findings preceded the onset of dermatologic involvement.78 Abnormal signal intensities on MRI were demonstrated in various central nervous systems regions. The differential diagnosis between NSD and neuro-Behçet disease may be difficult because the two diseases may share common clinical features. In 2006, in a large, retrospective study, diagnostic criteria of NSD and criteria to allow the distinction between NSD and neuro-Behçet disease were established.78 In brief, NSD is characterized by its age of onset (30-60 years of age in NSD vs 20-30 in neuro-Behçet disease), the absence of central nervous system site predilection involvement (basal ganglion and brainstem in neuro-Behçet disease), highly systemic glucocorticoid responsiveness and infrequent neurologic sequelae (frequent in neuro-Behçet disease), classical sign of skin SS without vasculitis (vasculitis is frequent in skin lesions of Behçet disease), specific ocular findings (episcleritis and conjunctivitis in NSD vs uveitis in Behçet disease), specific human leukocyte antigen association (CW1 vs B54 in Behçet disease), and absence of other specific signs of Behçet disease, mainly thrombosis.78 Pituitary involvement has been reported in a patient with PG who was treated with prednisone, which produced a dramatic improvement of the pituitary pseudotumor.79

Intra-abdominal viscera Hepatic involvement has been frequently suggested in SS. Reviews have reported increased levels of alkaline phosphatase (50% of cases) and transient increased levels of aspartate transaminase and gamma glutamyl transferase.80 Abnormalities of hepatic enzymes returned to normal when steroids were started. Aseptic neutrophilic abscesses have been reported in lymph nodes, spleen, pancreas, liver, and digestive tract. 81 The patients had SS, PG, SPD, or subcutaneous abscesses. Fever and acute abdominal pain leading to surgical procedure was observed. In a few cases, the diagnosis could be performed by percutaneous aspiration of mesenteric lymph nodes, endoscopic retrograde cholangiopancreatography, or by rectal and liver biopsies. The pancreatic involvement was suggested by enzymatic abnor-

L. Prat et al. malities and/or echography disclosing pancreas defects.82 Biopsies showed neutrophilic infiltration without vasculitis. Associated diseases were monoclonal gammopathy, Fanconi anemia, acute myelogenous leukemia, and Crohn's disease.74 The disease was usually severe and was controlled by steroids. Some patients required immunosuppressive therapy. In one case, thalidomide was used with a good result.83

Muscle Muscle involvement is usually considered to be an uncommon manifestation of ND. In a series of 136 patients with ND, fewer than 10% of patients had myalgias.84 One patient had PG with lung involvement (bilateral infiltrates), liver involvement, and a severe sterile neutrophilic myositis as the first manifestation of an acute myelogenous leukemia.85 Patients with a true myositis and SS have also been reported.66,86 Most patients had SS that followed induction of chemotherapy for an acute myelogenous leukemia. Muscle involvement was characterized by a marked swelling and pain, an increase of serum creatine phosphokinase,86 and signs of myositis and fasciitis on magnetic resonance imaging.66 Biopsy of the deltoid muscle performed in one case showed scant degenerated and necrobiotic muscle cells, which were separated from one another by a heavy, partly leukocytoclastic neutrophilic infiltrate.86 Muscular involvement and cutaneous lesions resolved when corticosteroid therapy was introduced.86

Heart and blood vessels Aneurysm of ascending aorta was described, with probably a rupture, revealing at autopsy a neutrophilic infiltrate within the aortic wall.87 In one patient with SS and myositis, autopsy was performed after he died of myocardial infarction. It revealed segmental neutrophilic infiltrates in the media of the abdominal aorta.86 There has also been a report of a myocardial neutrophilic infiltration in a patient with SS and a MDS.88 Cardiac involvement has been demonstrated at autopsy in one case of bullous PG associated with a MDS that evolved to an acute myelogenous leukemia.89

Eye Ocular manifestations of 20 patients with SS were reviewed in 2008.90 Ocular SS manifestations included periorbital and orbital inflammation, dacryoadenitis, conjunctivitis, episcleritis, scleritis, limbal nodules, peripheral ulcerative keratitis, iritis, glaucoma, and choroiditis. Of the 20 cases, half were bilateral and 7 cases happened in malignancy-associated SS. Biopsies of ocular tissue were infrequent, but in the seven cases when ocular tissue was analyzed, the histopathology was similar to that of the cutaneous lesions. Oral prednisone was the mainstay

Neutrophilic dermatoses treatment in half of the cases and was efficient even if relapses occurred. Nine of the 20 patients analyzed had extracutaneous manifestations, primarily arthralgia, but also polyneuropathy, pulmonary involvement, and sterile infiltrates including pharyngitis, laryngitis, otitis media, and mastoiditis. A 60-year-old woman with RA, PG, and SS, who had a peripheral ulcerative keratitis and episcleritis successfully treated with oral cyclosporine was reported.91

Kidney Renal involvement in ND is rarely reported, presenting mostly as proteinuria,92-94 hematuria,95 renal insufficiency,96 and more rarely as glomerulonephritis or even death from renal failure.97 Most of the reported cases in the literature were SS, whereas only 3 cases linked PG with renal failure. The first case was a child with three types of ND (EED, SPD, and PG) who experienced development of sclerosing glomerulonephritis.98 The second case was a patient with PG and pulmonary involvement, who also had aseptic leukocyturia, and cystoscopy demonstrated intravesical purulent debris that disappeared with steroid therapy.99 The third case was a patient with vulvar and renal neutrophilic involvement.93

Fallopian tube The case of a 28-year-old woman with abdominal pain during pregnancy revealed a right pyosalpinx with histologic features consistent with PG (neutrophilic infiltrate with moderate vasculitis).100 Although cases of skin PG have already been reported during pregnancy, this is the only case reported with fallopian tube localization.

Systemic diseases frequently associated with ND Hematologic disorders Acute myelogenous leukemia AML may be associated with ND (more frequently SS, but sometimes PG), and ND may reveal an AML. Recently, the same cytogenetic anomaly in the neutrophils infiltrating the skin and in the bone marrow in myeloid malignancies has been demonstrated, and hence is indicative of a clonal neutrophilic dermatosis.101 A case of SS with folliculitis and neutrophilic panniculitis after remission of an AML with an increased level of endogenous G-CSF has been reported.102 Neutrophilic dermatosis of the dorsum of the hands, a subtype of SS, has been described in patients undergoing chemotherapy for AML.103 SS, in the setting of AML, may also occur after treatment with all trans retinoic acid104 or with cytosine arabinoside. Neutrophilic eccrine dermatosis,

383 an eccrine variant of SS, is associated with AML after the induction of chemotherapy, but it can also be rarely associated with AML before the treatment.105 Leukemia, other The association between ND and other forms of leukemia is relatively rare. Acute lymphoblastic leukemia may be rarely associated with PG,106 with neutrophilic eccrine hidradenitis after chemotherapy107 and with SS.10 Chronic leukemias (chronic myelogenous leukemia and chronic lymphoblastic leukemia) may be associated with SS or neutrophilic eccrine hidradenitis.10 Lymphoma Although rare, both Hodgkin and non-Hodgkin lymphomas (more than 30 cases) were reported in association with SS,10,108 sometimes with an atypical histiocytoid histologic feature.109 Cases of bortezomib-induced SS for the treatment of lymphomas have also been reported.110 Monoclonal gammopathies and multiple myeloma Benign IgA monoclonal gammopathies are strongly associated with PG, EED, and SPD, and overlapping forms of these DN may exist in this setting.111 Multiple myeloma is known to be associated with SS, predominantly in patients secreting an IgG paraprotein and after G-CSF administration.112 A patient with Sjögren syndrome with an IgG of undetermined significance that later became a multiple myeloma had initially an SS. In this patient, skin lesions relapsed after G-CSF treatment.113 There is an association between the administration of bortezomib, a proteasome inhibitor, and lenalidomide (both used for the treatment of multiple myeloma) with the development of ND, in particular, SS.114,115 Myelodysplastic syndrome Relationships between MDS and SS,116 and a case of SS after azacitidine treatment for MDS have been described.117 A case of SS of the oral cavity with neutrophilic infiltrate revealed the same chromosomal 20q deletion in the neutrophilic infiltrate than in the bone marrow.118

Inflammatory bowel diseases and neutrophilic dermatosis Inflammatory bowel disease is frequently associated with PG (1%-3%), which is often pustular, and most rarely with SS.119,120 PG is more frequent in ulcerative colitis (5%-12%) than in Crohn's disease (1%-2%), and the cutaneous lesions are often more severe and resistant to therapy, requiring more aggressive treatment than in PG not associated with inflammatory bowel disease.121,122 Peristomal PG is a rare variant of PG and is usually seen in patients with ulcerative colitis or Crohn's disease. Effective treatment is important because peristomal PG is

384 extremely painful, may interfere with adhesion of the stomal appliance, and may potentially cause loss of the stoma. Systemic corticosteroids are the most common therapy, and several case reports have shown successful treatment with infliximab. Recently, the efficacy of monoclonal antibodies targeting the interleukin (IL)-12/IL-23 has been reported for the treatment of peristomal PG.123 SS is more frequent in patients with Crohn's disease than in patients with ulcerative colitis, and they are gladly pustular with palmoplantar pustulosis.124 Aseptic abscesses syndrome is characterized by deep abscesses with a predilection for the spleen, accompanied by fever, abdominal pain, and a raised leukocyte count. Aseptic abscesses are associated with inflammatory bowel disease in 66% of cases, in particular Crohn's disease. Twenty percent of patients with aseptic abscesses have ND skin lesions primarily PG and SS.125

Rheumatoid disorders Rheumatoid arthritis The recruitment of a large number of activated neutrophils plays an important role in chronic inflammation in RA; thus, neutrophilic disorders with neutrophilic activation are often associated with RA,126 which include PG, EED, SS, pustular panniculitis, and SPD. IL-8, which is able to attract neutrophils and lymphocytes, is elevated in the serum of patients with RA and may play a role in the induction of these neutrophilic conditions. There is no prevalence of seronegative (no circulating rheumatoid factor) or seropositive polyarthritis in the development of PG127: Seropositive RA has been associated with PG, averaging a 12% occurrence (ranging from 4% to 50%) in report series about PG. In the same series, 15% revealed an association with seronegative polyarthritis.26,27,75,128,129 The ulcerative form of PG has been associated with RA and a seronegative polyarthritis.31 One author theorized that PG represents an independent disease and not a cutaneous manifestation of an underlying disease, such as RA.27 This theory is based on the observation that episodes of PG occur during times of stability or remission of such underlying diseases. RA (seropositive or seronegative) is also associated with an entity described for the first time in 1987: rheumatoid neutrophilic dermatosis, characterized by nontender erythematous, urticaria-like papules, plaques, or nodules with lesions often symmetric.130 Vesicular formation may be observed, as well as tense blister formations.131 Finally, there is an association between RA treated by adalimumab (a TNF-α blocker) and palisaded neutrophilic and granulomatous dermatitis.132 Ankylosing spondylitis Ankylosing spondylitis is known to be associated with SS.133 One patient had Crohn's disease and ankylosing spondylitis with skin lesions of SS with a psoriasiform aspect.134 A case of anterior chest wall arthritis and

L. Prat et al. clavicular osteomyelitis associated with SPD showed that ND skin lesions in ankylosing spondylitis may be involved in a broad spectrum of lesions including the so-called SAPHO syndrome.135

Pathophysiology, perspectives, and conclusion Currently, the pathophysiology of ND is poorly understood, but the current knowledge of ND suggests that they should be categorized within the spectrum of “polygenic” autoinflammatory diseases. The exact term autoinflammatory disease encompasses an enlarging group of inflammatory disorders defined as Mendelian genetic diseases (monogenic diseases) of the innate immune system that involves mutations in molecular platforms called inflammasomes, resulting in an excessive inflammatory cytokine production by the innate immune cells (in particular, IL-1) in response to danger signals. The neutrophilic disease shares many clinical features of monogenic inflammatory disorders including fever, arthralgias, and neutrophilic infiltration of the skin and visceral organs. Several monogenic inflammatory diseases have clinical features that include DN skin lesions or aseptic neutrophilic visceral involvement. The PAPA syndrome (pyogenic sterile arthritis, PG, acne) is an autosomal dominant autoinflammatory disorder due to a mutation in the PSTPIP1 gene and presents with typical PG lesions.136 The acronym PASH syndrome was recently proposed in patients with a clinical triad of PG, acne, and suppurative hidradenitis.137 This syndrome belongs to the group of autoinflammatory diseases, although no specific mutation of a gene involved in the innate immune system was found in these patients. The presence of an autosomal recessive form of CRMO with SS lesions, the Majeed syndrome, caused by mutations in the LPIN2 gene, is in favor of SS and CRMO belonging to the spectrum of polygenic autoinflammatory diseases.138 Inflammatory diseases in which selective mutations of genes implicated in the innate immune system increases the risk for development of the disease were called polygenic autoinflammatory diseases. The best example is Crohn's disease, in which selective mutations of the NOD2/CARD15 gene (a gene mutated in a monogenic inflammatory disease called Blau syndrome) increased by far the disease susceptibility.139,140 DN are frequently associated with Crohn's disease. The extreme efficacy of IL-1 blocking therapies in some autoinflammatory monogenic diseases (cryopirin associated periodic syndrome, deficiency of IL-1 receptor antagonist syndrome) suggests that the efficacy of IL-1 blocking therapies may be a diagnostic criterion for an autoinflammatory disease). Although corticosteroids remain the mainstay treatment for most ND, the efficacy of IL-1 blocking agents (anakinra) in neutrophilic panniculitis141 and in SS142 has been recently published. If DN has no hallmark of an autoimmune disorder (absence of detectable autoantibodies

Neutrophilic dermatoses and absence of an antigen-specific T cell response), some recent findings may, however, also implicate the adaptive immune system in its pathogenesis. For example, cytokines implicated in T cell polarization such as IL-17 have been found overexpressed in ND skin lesions,143 and a recent contribution reported the possible efficacy of anti–IL-12/ IL-23 antibodies in refractory cases of ND,144 reflecting the possible complexity of ND mechanism. We could also speculate that IL-6 may also be a potential target for the treatment of ND. IL-6145 indeed is a key cytokine for the development of myeloma, and IL-6 blocking agents (tocilizumab) have been approved for the treatment of RA, and these two diseases may be associated with ND. In conclusion, the clinician should be aware that ND may be important clinical signs of an underlying systemic disorder and that the systemic symptoms that occur in the setting of a well-proven ND may reveal neutrophil infiltration of a “systemic” organ.

References 1. Wallach D, Vignon-Pennamen M-D. From acute febrile neutrophilic dermatosis to neutrophilic disease: Forty years of clinical research. J Am Acad Dermatol. 2006;55:1066-1071. 2. Johnson ML, Grimwood RE. Leukocyte colony-stimulating factors. A review of associated neutrophilic dermatoses and vasculitides. Arch Dermatol. 1994;130:77-81. 3. Huang W, McNeely MC. Neutrophilic tissue reactions. Adv Dermatol. 1997;13:33-64. 4. Vignon-Pennamen MD, Wallach D. Neutrophilic disease: A review of extra-cutaneous neutrophilic manifestations. Eur J Dermatol. 1995;5: 449-455. 5. André MFJ, Piette J-C, Kémény J-L, et al. Aseptic abscesses: A study of 30 patients with or without inflammatory bowel disease and review of the literature. Medicine (Baltimore). 2007;86:145-161. 6. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;76:349-356. 7. Chan MP, Duncan LM, Nazarian RM. Subcutaneous Sweet syndrome in the setting of myeloid disorders: A case series and review of the literature. J Am Acad Dermatol. 2013;68:1006-1015. 8. Cohen PR. Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. 9. Cohen PR. Skin lesions of Sweet syndrome and its dorsal hand variant contain vasculitis: An oxymoron or an epiphenomenon? Arch Dermatol. 2002;138:400-403. 10. Hensley CD, Caughman SW. Neutrophilic dermatoses associated with hematologic disorders. Clin Dermatol. 2000;18:355-367. 11. Cohen PR, Talpaz M, Kurzrock R. Malignancy-associated Sweet’s syndrome: Review of the world literature. J Clin Oncol. 1988;6:1887-1897. 12. Feliu E, Cervantes F, Ferrando J, et al. Neutrophilic pustulosis associated with chronic myeloid leukemia: A special form of Sweet’s syndrome. Report of two cases. Acta Haematol. 1992;88: 154-157. 13. Clemmensen OJ, Menné T, Brandrup F, et al. Acute febrile neutrophilic dermatosis—a marker of malignancy? Acta Derm Venereol. 1989;69:52-58. 14. Bourke SJ, Quinn AG, Farr PM, et al. Neutrophilic alveolitis in Sweet’s syndrome. Thorax. 1992;47:572-573. 15. Bamelis M, Boyden B, Sente F, et al. Sweet’s syndrome and acute myelogenous leukemia in a patient who presented with a

385

16.

17.

18.

19.

20. 21.

22. 23.

24.

25.

26. 27. 28.

29.

30.

31.

32.

33.

34. 35.

36.

37.

sudden massive swelling of the tongue. Dermatology (Basel). 1995; 190:335-337. Cooper PH, Innes Jr DJ, Greer KE. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) and myeloproliferative disorders. Cancer. 1983;51:1518-1526. Hansen U, Haerslev T, Knudsen B, et al. Erythema elevatum diutinum: Case report showing an unusual distribution. Cutis. 1994; 53:124-126. Yiannias JA, el-Azhary RA, Gibson LE. Erythema elevatum diutinum: A clinical and histopathologic study of 13 patients. J Am Acad Dermatol. 1992;26:38-44. Sangüeza OP, Pilcher B, Martin Sangüeza J. Erythema elevatum diutinum: A clinicopathological study of eight cases. Am J Dermatopathol. 1997;19:214-222. Franks Jr AG. Skin manifestations of internal disease. Med Clin North Am. 2009;93:1265-1282. Flynn TC, Harrist TJ, Murphy GF, et al. Neutrophilic eccrine hidradenitis: A distinctive rash associated with cytarabine therapy and acute leukemia. J Am Acad Dermatol. 1984;11(4 Pt 1):584-590. Scherbenske JM, Benson PM, Lupton GP, et al. Rheumatoid neutrophilic dermatitis. Arch Dermatol. 1989;125:1105-1108. Wilson-Jones E, Winkelmann RK. Superficial granulomatous pyoderma: A localized vegetative form of pyoderma gangrenosum. J Am Acad Dermatol. 1988;18:511-521. Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma (ecthyma) gangrenosum: Clinical and experimental observation in five cases occurring in adults. Arch Dermatol Syph. 1930;22:655. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum: A comprehensive review. Am J Clin Dermatol. 2012;13:191-211. Ko CB, Walton S, Wyatt EH. Pyoderma gangrenosum: Associations revisited. Int J Dermatol. 1992;31:574-577. Von den Driesch P. Pyoderma gangrenosum: A report of 44 cases with follow-up. Br J Dermatol. 1997;137:1000-1005. Bennett ML, Jackson JM, Jorizzo JL, et al. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore). 2000;79:37-46. Farhi D, Cosnes J, Zizi N, et al. Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: A cohort study of 2402 patients. Medicine (Baltimore). 2008;87:281-293. Charles CA, Leon A, Banta MR, et al. Etanercept for the treatment of refractory pyoderma gangrenosum: A brief series. Int J Dermatol. 2007;46:1095-1099. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: Classification and management. J Am Acad Dermatol. 1996;34:395-409. [quiz 410–412]. Montoto S, Bosch F, Estrach T, Blade J, et al. Pyoderma gangrenosum triggered by alpha2b-interferon in a patient with chronic granulocytic leukemia. Leuk Lymphoma. 1998;30:199-202. Lewerin C, Mobacken H, Nilsson-Ehle H, et al. Bullous pyoderma gangrenosum in a patient with myelodysplastic syndrome during granulocyte colony-stimulating factor therapy. Leuk Lymphoma. 1997;26:629-632. Duguid CM, O’Loughlin S, Otridge B, et al. Paraneoplastic pyoderma gangrenosum. Australas J Dermatol. 1993;34:17-22. Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders. Atypical forms of pyoderma gangrenosum and Sweet’s syndrome associated with myeloproliferative disorders. J Am Acad Dermatol. 1983;9:751-758. Akatsuka T, Kawata T, Hashimoto S, et al. Rapidly progressive renal failure occurring in the course of pyoderma gangrenosum and IgA (lambda) monoclonal gammopathy. Intern Med. 1997;36:40-43. Brown TS, Marshall GS, Callen JP. Cavitating pulmonary infiltrate in an adolescent with pyoderma gangrenosum: A rarely recognized extracutaneous manifestation of a neutrophilic dermatosis. J Am Acad Dermatol. 2000;43(1 Pt 1):108-112.

386 38. Kitagawa KH, Grassi M. Primary pyoderma gangrenosum of the lungs. J Am Acad Dermatol. 2008;59(5 Suppl):S114-S116. 39. Sutra-Loubet C, Carlotti A, Guillemette J, et al. Neutrophilic panniculitis. J Am Acad Dermatol. 2004;50:280-285. 40. Kato S, Hosomi E, Amano F, et al. The efficacy of intensive granulocyte and monocyte adsorption apheresis in a patient with Crohn’s disease complicated by extensive subcutaneous aseptic neutrophilic abscesses. J Crohns Colitis. 2012;6:787-791. 41. Magro CM, Crowson AN. The spectrum of cutaneous lesions in rheumatoid arthritis: A clinical and pathologic study of 43 patients. J Cutan Pathol. 2003;30:1-10. 42. Tran TA, DuPree M, Carlson JA. Neutrophilic lobular (pustular) panniculitis associated with rheumatoid arthritis: A case report and review of the literature. Am J Dermatopathol. 1999;21:247-252. 43. Yosipovitch G, Hodak E, Feinmesser M, et al. Acute Crohn’s colitis with lobular panniculitis—metastatic Crohn’s? J Eur Acad Dermatol Venereol. 2000;14:405-406. 44. Becherer K, Golda N, Feldman M, et al. Neutrophilic panniculitis associated with myelodysplastic syndrome with abnormal nuclear forms. J Cutan Pathol. 2009;36:1024-1026. 45. Kim I-H, Youn J-H, Shin S-H, et al. Neutrophilic panniculitis following azacitidine treatment for myelodysplastic syndromes. Leuk Res. 2012;36:e146-e148. 46. De Masson A, Bouvresse S, Clérici T, et al. Recurrent neutrophilic panniculitis in a patient with chronic myelogenous leukaemia treated with imatinib mesilate and dasatinib. Ann Dermatol Venereol. 2011; 138:135-139. 47. Monfort J-B, Pagès C, Schneider P, et al. Vemurafenib-induced neutrophilic panniculitis. Melanoma Res. 2012;22:399-401. 48. Kim GH, Levy A, Compoginis G. Neutrophilic panniculitis developing after treatment of metastatic melanoma with vemurafenib. J Cutan Pathol. 2013;40:667-669. 49. Sneddon IB, Wilkinson DS. Subcorneal pustular dermatosis. Br J Dermatol. 1956;68:385-394. 50. Lutz ME, Daoud MS, McEvoy MT, et al. Subcorneal pustular dermatosis: A clinical study of ten patients. Cutis. 1998;61:203-208. 51. Reed J, Wilkinson J. Subcorneal pustular dermatosis. Clin Dermatol. 2000;18:301-313. 52. Bordignon M, Zattra E, Montesco MC, et al. Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) with absence of desmoglein 1 and 3 antibodies: Case report and literature review. Am J Clin Dermatol. 2008;9:51-55. 53. Cheng S, Edmonds E, Ben-Gashir M, et al. Subcorneal pustular dermatosis: 50 years on. Clin Exp Dermatol. 2008;33:229-233. 54. Chimenti S, Ackerman AB. Is subcorneal pustular dermatosis of Sneddon and Wilkinson an entity sui generis? Am J Dermatopathol. 1981;3:363-376. 55. Murphy GM, Griffiths WA. Subcorneal pustular dermatosis. Clin Exp Dermatol. 1989;14:165-167. 56. Park BS, Cho KH, Eun HC, et al. Subcorneal pustular dermatosis in a patient with aplastic anemia. J Am Acad Dermatol. 1998;39(2 Pt 1): 287-289. 57. Wallach D, Foldès C, Cottenot F. Subcorneal pustulosis, superficial acantholysis and monoclonal IgA. Ann Dermatol Venereol. 1982;109: 959-963. 58. Huff JC, Golitz LE, Kunke KS. Intraepidermal neutrophilic IgA dermatosis. N Engl J Med. 1985;313:1643-1645. 59. Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol. 1992;27(6 Pt 1):993-1000. 60. Tsuruta D, Ishii N, Hamada T, et al. IgA pemphigus. Clin Dermatol. 2011;29:437-442. 61. Jorizzo JL, Apisarnthanarax P, Subrt P, et al. Bowel-bypass syndrome without bowel bypass. Bowel-associated dermatosis-arthritis syndrome. Arch Intern Med. 1983;143:457-461. 62. Marzano AV, Ramoni S, Caputo R. Amicrobial pustulosis of the folds. Report of 6 cases and a literature review. Dermatology (Basel). 2008; 216:305-311.

L. Prat et al. 63. Andre M, Aumaitre O, Marcheix JC, et al. Aseptic systemic abscesses preceding diagnosis of Crohn’s disease by 3 years. Dig Dis Sci. 1995; 40:525-527. 64. Astudillo L, Sailler L, Launay F, et al. Pulmonary involvement in Sweet’s syndrome: A case report and review of the literature. Int J Dermatol. 2006;45:677-680. 65. Longo MI, Pico M, Bueno C, et al. Sweet’s syndrome and bronchiolitis obliterans organizing pneumonia. Am J Med. 2001; 111:80-81. 66. Christ E, Linka A, Jacky E, et al. Sweet’s syndrome involving the musculoskeletal system during treatment of promyelocytic leukemia with all-trans retinoic acid. Leukemia. 1996;10:731-734. 67. Batalla A, Pérez-Pedrosa A, García-Doval I, et al. Lung involvement in pyoderma gangrenosum: A case report and review of the literature. Actas Dermosifiliogr. 2011;102:373-377. 68. Merke DP, Honig PJ, Potsic WP. Pyoderma gangrenosum of the skin and trachea in a 9-month-old boy. J Am Acad Dermatol. 1996;34: 681-682. 69. Thurnheer R, Stammberger U, Hailemariam S, et al. Bronchial manifestation of acute febrile neutrophilic dermatosis (Sweet’s syndrome). Eur Respir J. 1998;11:978-980. 70. Giedion A, Holthusen W, Masel LF, et al. Subacute and chronic “symmetric” osteomyelitis. Ann Radiol (Paris). 1972;15:329-342. 71. Gamble JG, Rinsky LA. Chronic recurrent multifocal osteomyelitis: A distinct clinical entity. J Pediatr Orthop. 1986;6:579-584. 72. Van Howe RS, Starshak RJ, Chusid MJ. Chronic, recurrent multifocal osteomyelitis. Case report and review of the literature. Clin Pediatr (Phila). 1989;28:54-59. 73. Tlougan BE, Podjasek JO, O’Haver J, et al. Chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome with associated neutrophilic dermatoses: A report of seven cases and review of the literature. Pediatr Dermatol. 2009;26:497-505. 74. Vignon-Pennamen MD. The extracutaneous involvement in the neutrophilic dermatoses. Clin Dermatol. 2000;18:339-347. 75. Holt PJ, Davies MG, Saunders KC, et al. Pyoderma gangrenosum: Clinical and laboratory findings in 15 patients with special reference to polyarthritis. Medicine (Baltimore). 1980;59:114-133. 76. Wright V, Watkinson G. The arthritis of ulcerative colitis. Medicine (Baltimore). 1959;38:243-262. 77. Hisanaga K, Hosokawa M, Sato N, et al. “Neuro-sweet disease”: benign recurrent encephalitis with neutrophilic dermatosis. Arch Neurol. 1999;56:1010-1013. 78. Hisanaga K, Iwasaki Y, Itoyama Y. Neuro-Sweet disease: Clinical manifestations and criteria for diagnosis. Neurology. 2005; 64:1756-1761. 79. Chanson P, Timsit J, Kujas M, et al. Pituitary granuloma and pyoderma gangrenosum. J Endocrinol Invest. 1990;13:677-681. 80. Fett DL, Gibson LE, Su WP. Sweet’s syndrome: Systemic signs and symptoms and associated disorders. Mayo Clin Proc. 1995;70: 234-240. 81. Actis GC, Ottobrelli A, Lavezzo B, et al. Recurrent necroinflammatory disease of multiple organs and colon. Systemic presentation of inflammatory bowel disease or gut involvement during systemic disorder. Dig Dis Sci. 1996;41:2100-2105. 82. Hastier P, Caroli-Bosc FX, Bartel HR, et al. Pyoderma gangrenosum with hepatopancreatic manifestations in a patient with rheumatoid arthritis. Dig Dis Sci. 1996;41:594-597. 83. Costa I, Castanet J, Taillan B. et al (Aseptic adenitis in pyoderma gangrenosum). Ann Dermatol Venereol. 1994;121:550-552. 84. Moreland LW, Brick JE, Kovach RE, et al. Acute febrile neutrophilic dermatosis (Sweet syndrome): A review of the literature with emphasis on musculoskeletal manifestations. Semin Arthritis Rheum. 1988;17:143-153. 85. Marie I, Levesque H, Joly P, et al. Neutrophilic myositis as an extracutaneous manifestation of neutrophilic dermatosis. J Am Acad Dermatol. 2001;44:137-139.

Neutrophilic dermatoses 86. Attias D, Laor R, Zuckermann E, et al. Acute neutrophilic myositis in Sweet’s syndrome: Late phase transformation into fibrosing myositis and panniculitis. Hum Pathol. 1995;26:687-690. 87. Muster AJ, Bharati S, Herman JJ, et al. Fatal cardiovascular disease and cutis laxa following acute febrile neutrophilic dermatosis. J Pediatr. 1983;102:243-248. 88. Shimizu K. Neutrophilic infiltration of the myocardium in a patient with myelodysplastic syndrome. Am J Hematol. 1998;58: 337-338. 89. Koester G, Tarnower A, Levisohn D, et al. Bullous pyoderma gangrenosum. J Am Acad Dermatol. 1993;29(5 Pt 2):875-878. 90. Gottlieb CC, Mishra A, Belliveau D, et al. Ocular involvement in acute febrile neutrophilic dermatosis (Sweet syndrome): New cases and review of the literature. Surv Ophthalmol. 2008;53:219-226. 91. Wilson DM, John GR, Callen JP. Peripheral ulcerative keratitis—an extracutaneous neutrophilic disorder: Report of a patient with rheumatoid arthritis, pustular vasculitis, pyoderma gangrenosum, and Sweet’s syndrome with an excellent response to cyclosporine therapy. J Am Acad Dermatol. 1999;40(2 Pt 2):331-334. 92. Gunawardena DA, Gunawardena KA, Ratnayaka RM, et al. The clinical spectrum of Sweet’s syndrome (acute febrile neutrophilic dermatosis)—a report of eighteen cases. Br J Dermatol. 1975; 92:363-373. 93. Marzano AV, Ishak RS, Lazzari R, et al. Vulvar pyoderma gangrenosum with renal involvement. Eur J Dermatol. 2012;22: 537-539. 94. Sitjas D, Puig L, Cuatrecasas M, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome). Int J Dermatol. 1993;32:261-268. 95. Matta M, Malak J, Tabet E, et al. Sweet’s syndrome: Systemic associations. Cutis. 1973;12:561-566. 96. Von den Driesch P. Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol. 1994;31:535-556. [quiz 557-560]. 97. Unis ME, Hill GS. Sweet’s syndrome associated with acute renal failure. Cutis. 1987;40:139-142. 98. Su L-H, Chiu H-C, Hsiao C-H. Multiple neutrophilic dermatoses occurring in a pediatric patient with glomerulonephritis. J Am Acad Dermatol. 2005;52(2 Suppl 1):28-30. 99. Cartier H, Plantin P, Leroy JP, et al. Pyoderma gangrenosum, subcorneal IgA pustulosis and recurrent neutrophilic pleural and pulmonary diseases in a patient with IgA gammopathy. Ann Dermatol Venereol. 1995;122:97-101. 100. Dinulescu M, Vigy P, Droitcourt C, et al. Pyoderma gangrenosum and aseptic pyosalpinx in a pregnant patient. Ann Dermatol Venereol. 2007;134:179-180. 101. Sujobert P, Cuccuini W, Vignon-Pennamen D, et al. Evidence of differentiation in myeloid malignancies associated neutrophilic dermatosis: A fluorescent in situ hybridization study of 14 patients. J Invest Dermatol. 2013;133:1111-1114. 102. Uhara H, Saida T, Nakazawa H, et al. Neutrophilic dermatoses with acute myeloid leukemia associated with an increase of serum colony-stimulating factor. J Am Acad Dermatol. 2008;59(2 Suppl 1): S10-S12. 103. Walling HW, Snipes CJ, Gerami P, et al. The relationship between neutrophilic dermatosis of the dorsal hands and sweet syndrome: Report of 9 cases and comparison to atypical pyoderma gangrenosum. Arch Dermatol. 2006;142:57-63. 104. Levi I, Raanani P, Shalmon B, et al. Acute neutrophilic dermatosis induced by all-trans-retinoic acid treatment for acute promyelocytic leukemia. Leuk Lymphoma. 1999;34:401-404. 105. Roustan G, Salas C, Cabrera R, et al. Neutrophilic eccrine hidradenitis unassociated with chemotherapy in a patient with acute myelogenous leukemia. Int J Dermatol. 2001;40:144-147. 106. Bakhshi S, Sethuraman G, Singh MK, et al. Atypical pyoderma gangrenosum as a manifestation of childhood acute lymphoblastic leukemia. Pediatr Dermatol. 2005;22:543-545. 107. Kanzaki H, Oono T, Makino E, et al. Neutrophilic eccrine hidradenitis: Report of two cases. J Dermatol. 1995;22:137-142.

387 108. Woodrow SL, Munn SE, Basarab T, et al. Sweet’s syndrome in association with non-Hodgkin’s lymphoma. Clin Exp Dermatol. 1996;21:357-359. 109. Hünermund A, Wendel A-M, Geissinger E, et al. Typically atypical: Histiocytoid Sweet syndrome, associated with malignancy. J Dtsch Dermatol Ges. 2011;9:666-669. 110. Thuillier D, Lenglet A, Chaby G, Royer R, Vaida I, Viseux V, et al. Bortezomib-induced eruption: Sweet syndrome? Two case reports. Ann Dermatol Venereol. 2009;136:427-430. 111. Decaux O, Laurat E, Perlat A, Cazalets C, Jego P, Grosbois B. Systemic manifestations of monoclonal gammopathy. Eur J Intern Med. 2009;20:457-461. 112. Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol. 2003;48:497-507. 113. Harada Y, Egi Y, Honda Y, Shirota T, et al. Multiple myeloma with Sweet disease developing from monoclonal gammopathy of undetermined significance and Sjögren syndrome. Rinsho Ketsueki. 2001; 42:1176-1180. 114. Tanguy-Schmidt A, Avenel-Audran M, Croué A, et al. Bortezomibinduced acute neutrophilic dermatosis. Ann Dermatol Venereol. 2009; 136:443-446. 115. Van Regenmortel N, Van de Voorde K, De Raeve H, et al. Bortezomib-induced Sweet’s syndrome. Haematologica. 2005;90(12 Suppl):ECR43. 116. Reina D, Cerdà D, Roig D, et al. Sweet syndrome associated with myelodysplastic syndrome: Report of a case. Review of the literature. Rheumatol Clin. 2013;9:246-247. 117. Trickett HB, Cumpston A, Craig M. Azacitidine-associated Sweet’s syndrome. Am J Health Syst Pharm. 2012;69:869-871. 118. Van Loon K, Gill RM, McMahon P, et al. 20q- clonality in a case of oral sweet syndrome and myelodysplasia. Am J Clin Pathol. 2012; 137:310-315. 119. Larsen S, Bendtzen K, Nielsen OH. Extraintestinal manifestations of inflammatory bowel disease: Epidemiology, diagnosis, and management. Ann Med. 2010;42:97-114. 120. Rothfuss KS, Stange EF, Herrlinger KR. Extraintestinal manifestations and complications in inflammatory bowel diseases. World J Gastroenterol. 2006;12:4819-4831. 121. Trost LB, McDonnell JK. Important cutaneous manifestations of inflammatory bowel disease. Postgrad Med J. 2005;81: 580-585. 122. Bernstein CN, Blanchard JF, Rawsthorne P. The prevalence of extraintestinal diseases in inflammatory bowel disease: A populationbased study. Am J Gastroenterol. 2001;96:1116-1122. 123. Fahmy M, Ramamoorthy S, Hata T, Sandborn WJ. Ustekinumab for peristomal pyoderma gangrenosum. Am J Gastroenterol. 2012;107: 794-795. 124. Sommer S, Wilkinson SM, Merchant WJ, et al. Sweet’s syndrome presenting as palmoplantar pustulosis. J Am Acad Dermatol. 2000;42 (2 Pt 2):332-334. 125. André MFJ, Aumaître O, Grateau G, et al. Longest form of CCTG microsatellite repeat in the promoter of the CD2BP1/PSTPIP1 gene is associated with aseptic abscesses and with Crohn disease in French patients. Dig Dis Sci. 2010;55:1681-1688. 126. Yamamoto T. Cutaneous manifestations associated with rheumatoid arthritis. Rheumatol Int. 2009;29:979-988. 127. Sayah A, English 3rd JC. Rheumatoid arthritis: A review of the cutaneous manifestations. J Am Acad Dermatol. 2005;53:191-209. [quiz 210–212]. 128. Powell FC, Schroeter AL, Su WP, et al. Pyoderma gangrenosum: A review of 86 patients. Q J Med. 1985;55:173-186. 129. Hickman JG, Lazarus GS. Pyoderma gangrenosum: A reappraisal of associated systemic diseases. Br J Dermatol. 1980;102: 235-237. 130. Nakamura T, Higashi S, Tomoda K, et al. Cutaneous nodules in patients with rheumatoid arthritis: A case report and review of literatures. Clin Rheumatol. 2011;30:719-722.

388 131. Fujio Y, Funakoshi T, Nakayama K, et al. Rheumatoid neutrophilic dermatosis with tense blister formation: A case report and review of the literature. Australas J Dermatol. 2012. [Epub ahead of print]. 132. Stephenson SR, Campbell SM, Drew GS, et al. Palisaded neutrophilic and granulomatous dermatitis presenting in a patient with rheumatoid arthritis on adalimumab. J Cutan Pathol. 2011;38:644-648. 133. Mansouri S, Abourazzak FE, Aradoini N, et al. Ankylosing spondylitis associated with Sweet’s syndrome: A case report. J Med Case Rep. 2013;7:16. 134. Petermann A, Tebbe B, Distler A, et al. Sweet’s syndrome in a patient with acute Crohn’s colitis and longstanding ankylosing spondylitis. Clin Exp Rheumatol. 1999;17:607-610. 135. Belfiore N, Caporali R, Borroni G, et al. Anterior chest wall arthritis and osteitis associated with Sneddon-Wilkinson disease. Clin Exp Rheumatol. 1997;15:667-669. 136. Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002; 11:961-969. 137. Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)—a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-415. 138. Ferguson PJ, Chen S, Tayeh MK, et al. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent

L. Prat et al.

139.

140.

141.

142.

143.

144.

145.

multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet. 2005;42:551-557. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599-603. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411: 603-606. Lipsker D, Perrigouard C, Foubert A, et al. Anakinra for difficult-totreat neutrophilic panniculitis: IL-1 blockade as a promising treatment option for neutrophil-mediated inflammatory skin disease. Dermatology (Basel). 2010;220:264-267. Kluger N, Gil-Bistes D, Guillot B, et al. Efficacy of anti-interleukin-1 receptor antagonist anakinra (Kineret®) in a case of refractory Sweet’s syndrome. Dermatology (Basel). 2011;222:123-127. Marzano AV, Cugno M, Trevisan V, et al. Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases. Clin Exp Immunol. 2010;162:100-107. Guenova E, Teske A, Fehrenbacher B, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011;147:1203-1205. Hitzler JK, Martinez-Valdez H, Bergsagel DB, et al. Role of interleukin-6 in the proliferation of human multiple myeloma cell lines OCI-My 1 to 7 established from patients with advanced stage of the disease. Blood. 1991;78:1996-2004.