Neutrophilic dermatoses

CONTINUING

MEDICAL EDUCATION

Neutrophilic dermatoses Pathogenesis, Sweet syndrome, neutrophilic eccrine hidradenitis, and Behc¸et disease Caroline A. Nelson, MD, Sasha Stephen, MD, Hovik J. Ashchyan, BA, William D. James, MD, Robert G. Micheletti, MD, and Misha Rosenbach, MD Philadelphia, Pennsylvania

Learning objectives After completing this learning activity, participants should be able to define and classify the spectrum of neutrophilic dermatoses; describe epidemiological features and disease associations of neutrophilic dermatoses, with particular attention to Sweet syndrome and Behc¸et disease; recognize the clinical presentation of neutrophilic dermatoses including mucocutaneous, systemic, and histopathological findings; list diagnostic criteria and a differential diagnosis for the above neutrophilic dermatoses; and discuss established and hypothesized pathological mechanisms of neutrophilic dermatoses. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders that present with unique clinical features but are unified by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. The morphology of cutaneous lesions associated with these disorders is heterogeneous, which renders diagnosis challenging. Moreover, a thorough evaluation is required to exclude diseases that mimic these disorders and to diagnose potential associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatoses may resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality. Therapeutic modalities range from systemic corticosteroids to novel biologic agents, and the treatment literature is rapidly expanding. The first article in this continuing medical education series explores the pathogenesis of neutrophilic dermatoses and reviews the epidemiology, clinical and histopathologic features, diagnosis, and management of Sweet syndrome, neutrophilic eccrine hidradenitis, and Behc¸et disease. ( J Am Acad Dermatol 2018;79:987-1006.) Key words: acute febrile neutrophilic dermatosis; Behc¸et disease; neutrophil; neutrophilic dermatosis; neutrophilic eccrine hidradenitis; pathogenesis; Sweet syndrome.

From the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Supported by a private donation from Mr Jerry and Mrs Joan Berstein. Conflicts of interest: None disclosed. Accepted for publication November 8, 2017. Correspondence to: Misha Rosenbach, MD, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104. E-mail: [email protected].

Published online April 11, 2018. 0190-9622/$36.00 Ó 2018 by the American Academy of Dermatology, Inc. https://doi.org/10.1016/j.jaad.2017.11.064 Date of release: December 2018 Expiration date: December 2021

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INTRODUCTION Key points d

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Neutrophilic dermatoses are a heterogeneous group of cutaneous inflammatory disorders characterized by a sterile, predominantly neutrophilic infiltrate on histopathology Neutrophilic dermatoses may be classified as primarily epidermal or dermal processes and may demonstrate primary or secondary vasculitic changes

Neutrophilic dermatoses (NDs) are a heterogeneous group of cutaneous inflammatory disorders characterized by a sterile, predominantly neutrophilic infiltrate on histopathology. The term ‘‘neutrophilic dermatosis’’ is used as an umbrella term to describe primarily epidermal or dermal processes with variable evidence of primary or secondary vasculitic changes.1 NDs share overlapping clinical and histopathologic features and may occur on a spectrum with features of multiple NDs occurring consecutively or concurrently in the same patient.2,3 This 2-part continuing medical education series provides an update on the pathogenesis of NDs and the epidemiology, clinical and histopathologic features, diagnosis, and management of Sweet syndrome (SS), neutrophilic eccrine hidradenitis (NEH), Behc¸et disease (BD), pyoderma gangrenosum (PG), bowel-associated dermatosis-arthritis syndrome, rheumatoid neutrophilic dermatitis, and adult Still disease. Primarily bullous, epidermal, and vasculitic NDs are beyond the scope of this review.

NEUTROPHIL BIOLOGY Key points d

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Neutrophils are the most abundant white blood cells in the circulatory system After maturation in the bone marrow, neutrophils respond to chemoattractants and migrate into the tissue where they play a key role in the innate immune system

Neutrophils, characterized by multilobulated nuclei and granule-packed cytoplasm, are the most abundant white blood cells in the circulatory system. They are continuously made in the bone marrow from pluripotent hematopoietic stem cells that differentiate into myeloid precursors and eventually granulocytes. Mature neutrophils are released from the bone marrow into the circulation and respond to chemoattractants, which promote directional migration to sites of infection and inflammation.4 The cells undergo extravasation and migration through interendothelial spaces to reach their site of action in the

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tissue. This intricate and well-orchestrated process is mediated by neutrophil expression of integrins that adhere to adhesive molecules on endothelial cells.5,6 In the tissue, neutrophils are activated to perform a variety of critical innate immune functions, including phagocytosis of microbes, cytokine production, degranulation of soluble antimicrobial substances, and production of neutrophil extracellular traps, which aid in bacterial killing.6,7 Neutrophils ultimately undergo apoptosis and are ingested by macrophages.8

PATHOGENESIS OF NEUTROPHILIC DERMATOSES Key points d

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The pathogenesis of NDs remains incompletely understood Existing evidence points to 3 main processes: altered expression of inflammatory effector molecules, abnormal neutrophil function, and genetic predisposition

PG was the first ND to be characterized in the literature in 1930.9 It was originally thought to be caused by an occult bacterial infection, but decades of evidence have failed to support this hypothesis. Similarly, since the description of BD in 1936 and SS in 1964, it has been widely accepted that these are sterile processes.10 The evidence thus far points to 3 main factors contributing to the pathogenesis of NDs: altered expression of inflammatory effector molecules, abnormal neutrophil function, and genetic predisposition. In 1981, Schr€ oder et al11 demonstrated that the chemotactic migration of normal neutrophils was strongly inhibited by sera from patients with PG and SS. Research has supported the hypothesis that aberrant signaling contributes to the pathogenesis of NDs. Granulocyte-colony stimulating factor (G-CSF), a hematopoietic growth factor that regulates the production and differentiation of neutrophils, has been shown to be elevated in the active phase of NDs and to correlate with disease activity.12,13 Kawakami et al12 demonstrated that culturing neutrophils with serum from SS patients containing G-CSF suppressed apoptosis. Moreover, exogenous administration of G-CSF, granulocyte-macrophage colony stimulating factor, and pegylated G-CSF has been extensively reported to induce NDs.14-16 Beyond the colony stimulating factors, studies have revealed altered expression of other cytokines in NDs. In 1993, Reuss-Borst et al17 showed that interleukin (IL)-6 was elevated in the acute phase of SS, along with G-CSF. In 1998, Giasuddin et al18 found

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Abbreviations used: AML: BD: EULAR: G-CSF: HLA: IBD: IL: ND: NEH: PG: SLE: SPT: SS: TNF:

acute myeloid leukemia Behc¸et disease European League Against Rheumatism granulocyte-colony stimulating factor human leukocyte antigen inflammatory bowel disease interleukin neutrophilic dermatosis neutrophilic eccrine hidradenitis pyoderma gangrenosum systemic lupus erythematosus skin pathergy test Sweet syndrome tumor necrosis factor

that IL-1a, IL-1b, IL-2, and interferon-g were significantly elevated while IL-4 was normal in patients with SS, suggesting a role for helper T cell type 1 cytokines over helper T cell type 2 cytokines. Inflammatory cell markers and other cytokines that have been reported to be overexpressed include CD3 (T cell marker), CD163 (macrophage marker), myeloperoxidase (neutrophil marker), tumor necrosis factor (TNF)-a, IL-8, IL-17, chemokine (C-X-C motif) ligand 1/2/3 and 16, Toll-like receptors, C-type lectin innate immunity receptors, and vascular endothelial growth factor.19-23 Increased expression of matrix metalloproteinases has been observed along with remodeling of the basement membrane of dermal postcapillary venules.20,21,24 Interestingly, myeloperoxidase, IL-8, regulated upon activation normal T cell expressed and secreted, matrix metalloproteinase-9, and the Fas/Fas ligand and CD40/CD40 ligand systems have all been shown to be relatively overexpressed in PG compared to SS, correlating with the increased degree of tissue destruction and inflammation observed clinically.20,21 In the absence of infection, the trigger for altered expression of inflammatory effector molecules in NDs remains incompletely understood. In 2007, Magro et al25 found evidence of clonal infiltrates in skin biopsy specimens even in the absence of myeloproliferative diseases, raising the possibility that NDs represent an overzealous response to antigenic stimuli or a neutrophilic dyscrasia. In 2013, Sujobert et al26 used fluorescence in situ hybridization to demonstrate that the neutrophils differentiated from the malignant clone in most skin biopsy specimens from patients with NDs with underlying myeloid malignancies. Differentiation of malignant clones into mature neutrophils is a well-established mechanism for drug-induced SS, including all-trans retinoic acid in acute promyelocytic leukemia27 and

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novel fms-like tyrosine kinase-3 (FLT3-3) inhibitors in acute myeloid leukemia (AML).28,29 Recently, Ortega-Loayza et al30 reported focal up-regulation of pattern recognition receptors in lesional versus nonlesional skin samples of patients with PG. In addition to aberrant signaling, a handful of studies have highlighted the potential contribution of neutrophil dysfunction to the pathogenesis of NDs. For example, an investigation by von den Driesch et al31 in 1992 revealed impairment of chemotactic activity and intracellular killing of blastospores of Candida albicans by neutrophils in 5 of 7 patients with acute SS in vitro. In 1998, Adachi et al32 discovered that neutrophils in a patient with PG with aberrant trafficking in vivo constitutively overexpressed and clustered the leukocyte integrins CR3 and CR4, which are important adhesion molecules in transmigration. Finally, there is a mounting body of evidence to suggest a role for genetics in the pathogenesis of NDs. Multiple human leukocyte antigen (HLA) types have been linked to NDs, such as HLA-B51 with BD and HLA-B54 with SS and its localized variant, neutrophilic dermatosis of the dorsal hands, in Japan.33-35 In 2010, Torrelo et al36 described the chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, an early onset chronic inflammatory condition characterized by fever and cutaneous edematous plaques with atypical or immature myeloid infiltrates on histopathology. Liu et al37 established proteosome subunit b type 8 as the causative mutation. Heterozygous mutations in the MEFV gene mutated in familial Mediterranean fever have also been identified in patients with SS and underlying hematologic disorders, generating the hypothesis that these may serve as a ‘‘second hit’’ to activate the inflammasome and trigger SS.38,39 SS and PG have each been described in the synovitis, acne, pustulosis, hyperostosis, and osteomyelitis (SAPHO) syndrome.40 Other syndromic forms of PG include pyogenic arthritis, PG, and acne (PAPA); PG, acne, and suppurative hidradenitis (PASH); and pyogenic arthritis, acne, PG, and suppurative hidradenitis (PAPASH). Mutations in proteins that form or regulate the inflammasome complex have been described in these disorders, most notably the proline-serine-threonine-phosphatase interactive protein gene that encodes CD2-binding protein 1.41 The common pathway is overactivation of the innate immune system leading to increased production of IL-1 and sterile neutrophil-rich cutaneous inflammation.42

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Table I. Drug-induced Sweet syndrome Classification

Analgesics Combination opioid Nonsteroidal antiinflammatory drugs Salicylates Anticonvulsants Antiinfectives Antibiotics Cephalosporins Lincosamides Macrolides Penicillins Quinolones Streptogramins Sulfonamides Tetracyclines Urinary antibiotics Antifungals Antimalarials Antivirals Antineoplastics Angiogenesis inhibitors Anti-CTLA-4 monoclonal antibodies Antimetabolites Antitumor antibiotics BRAF inhibitors FLT3 inhibitors Hypomethylating agents Proteosome inhibitors Topoisomerase inhibitors Tyrosine kinase inhibitors Antiplatelet agents Antipsychotics Cardiovascular agents ACE inhibitors Diuretics Vasodilators Antigout agents Hormones Antithyroid hormone synthesis Contraceptives Immunologic agents Immunostimulants Colony stimulating factors Interferons Interleukins Immunosuppressives Purine synthesis inhibitors Selective co-stimulation modulators TNF-a inhibitors Proton pump inhibitors Radiologic agents Retinoids

Medication

Reference(s)

Acetaminophen-codeine Aceclofenac, celecoxib, diclofenac, ibuprofen, and metamizole Aspirin and sulfasalazine Carbemazepine, diazepam, and gabapentin

64 49,65-67

Cephalexin Clindamycin Azithromycin Amoxicillin and piperacillin/tazobactam Ciprofloxacin, levofloxacin, norfloxacin, ofloxacin Quinupristin/dalfopristin Trimethoprim-sulfamethoxazole Doxycycline and minocycline Nitrofurantoin Ketoconazole Chloroquine Abacavir and acyclovir

49 71 49 49,72 49,73-75 76 77 78,79 80 81 82 49,83

49,68 50,69,70

Lenalidomide Ipilimumab Capecitabine, cytosine arabinoside, and gemcitabine Mitoxantrone Vemurafenib Gilteritinib, quizartinib, and sorafenib Azacitizine and decitabine Bortezomib Topotecan Dasatinib, imatinib, and nilotinib Ticagrelor Clozapine

84 85 86-88 89 90 28,29 91,92 93 94 95-97 98 99

Captopril and enalapril Furosemide Hydralazine Allopurinol

49 100 101 102 47,103 104 105

Benzylthiouracil and propylthiouracil Oral contraceptives, levonorgestrel-releasing intrauterine system

G-CSF, GM-CSF, pegylated G-CSF Pegylated interferon a/ribavirin, Interferon b1b Interleukin 2

14-16 106,107 108

Azathioprine Abatacept Adalimumab and infliximab Esomeprazole and omeprazole Iodinated radiocontrast All-trans retinoic acid and 13-cis-retinoic acid

109 110 111,112 113 114 115,116

ACE, Angiotensin-converting enzyme; CTLA4, cytotoxic T lymphocyteeassociated protein 4; FLT3, fms-like tyrosine kinase-3; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; TNF-a, tumor necrosis factor-a.

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Fig 1. Sweet syndrome. Erythematous edematous plaques on the chest and upper arm.

SWEET SYNDROME Epidemiology Key points d SS, also known as acute febrile neutrophilic dermatosis, typically presents between the ages of 47 and 57 years and is more common in women than men d SS may be categorized into classic, malignancyassociated, and drug-induced subtypes In 1964, Dr Robert Douglas Sweet coined the term ‘‘acute febrile neutrophilic dermatosis’’ to describe 8 women between 32 and 55 years of age who presented with fever, leukocytosis, painful plaques, and a dense dermal neutrophilic infiltrate on histopathology. All lacked evidence of infection and responded to systemic corticosteroid therapy.43 SS has since been described in multiple case reports and series, and several retrospective reviews containing [50 patients have been published. These reviews reported an average age of onset between 47 and 57 years.44-50 While some reported a female predominance from 3:1 to 8:1,44-49,51 others reported a near-equivalent sex distribution.46,48,50 SS may rarely occur in children.52 Investigation into the comorbid diseases and medications associated with SS has prompted its categorization into classic, malignancy-associated, and drug-induced subtypes. Classic SS describes idiopathic SS or SS occurring in association with infection, vaccination, inflammatory disorders, or pregnancy. Reviews have reported infections and inflammatory disorders in 14% to 24% and 3% to 33% of cases, respectively.45-49,50 A range of

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pathogens, including bacteria, viruses, and fungi, have been implicated in these infections, with the upper respiratory tract being the most common site.4547,50 Bacillus CalmetteeGuerin, influenza, pneumococcal, and smallpox vaccines have also been reported to induce SS.53-55 Inflammatory bowel disease (IBD) is the most commonly reported inflammatory disorder,45-47 followed by systemic lupus erythematosus (SLE) and other autoimmune diseases.56 SS has also been observed in patients with states of altered immunity such as HIV infection and after solid organ or stem cell transplantation.57-59 Finally, pregnancy has been reported in 1% to 4% of cases.44,45,47,49,51 Retrospective reviews have reported a wide range in the frequency of malignancy-associated SS (3-67% of cases).44-51 Hematologic malignancies and myeloproliferative or myelodysplastic disorders, most notably AML and myelodysplastic syndrome, have been implicated more often than solid malignancies at a ratio of 4:1 to 8:1.44,46,48,50 Little is known about the cytogenetic and molecular features of hematologic diseases associated with SS. Studies have reported an increased frequency of -5/del(5q) karyotype, FLT3 mutations, and myelodysplasiarelated features in AML associated with SS50,60 and identified M2 and M4 AML as the most common subtypes.61 A study of MDS patients determined statistically significant associations between deletion of 5q and increased mortality in patients who developed NDs.62 SS may present months to years before the diagnosis of underlying malignancy is made.44,48,63 Drug-induced SS in retrospective reviews has been reported at a rate of 1% to 27% of cases.45-50 G-CSF is the most commonly reported; however, numerous medications have been reported, including novel antineoplastic and immunologic agents (Table I).49,50,64-116 Beyond medications, localized SS has been reported after radiation therapy117 and in areas of longstanding lymphedema.118 Clinical features Key points d SS is classically characterized by the abrupt onset of painful erythematous plaques or nodules with predominantly neutrophilic infiltrates in the dermis d SS may exhibit pathergy, the development of new or worsening lesions secondary to trauma to the skin d Age, vesiculobullous morphology, leukopenia, anemia, thrombocytopenia, elevated erythrocyte sedimentation rate, the absence of arthralgia, and histiocytoid, lymphocytic, or

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Fig 2. Bullous Sweet syndrome. A, Erythematous and violaceous plaques with overlying bullae on the right wrist and dorsal surface of the hand (courtesy of Amy Forrestel, MD). B, Erythematous edematous and violaceous plaques and bullae on the leg after radiation therapy.

Fig 4. Subcutaneous Sweet syndrome. Erythematous indurated plaque on the forearm.

Fig 3. Neutrophilic dermatosis of the dorsal hands. Edematous, purulent, violaceous plaque on the dorsal surface of the hand.

d

subcutaneous histopathology are clinicopathologic features reported in association with underlying malignancy SS can present as a multisystem disease that carries a risk of mortality

The classic clinical presentation of SS is the abrupt onset of painful erythematous plaques or nodules (Fig 1).119 Retrospective reviews have reported fever in 28% to 85% of cases.44,46-48,50,51 Clinical variants include pustular and bullous SS (Fig 2),120 giant cellulitis-like SS,121 necrotizing SS,122 and neutrophilic dermatosis of the dorsal hands (Fig 3).123 While true target lesions are not seen, targetoid lesions have been reported, along with subcutaneous lesions (Fig 4).124 Pathergy, the development of new or worsening lesions secondary to trauma to the skin, has been observed in 3% to 25% of cases (Fig 5).47,50,51 Photodistributed SS has also been reported.125 Under the microscope, SS is characterized by predominantly neutrophilic

infiltrates in the dermis (Fig 6).119 Leukemia cells and secondary vascular injury are variably present.126,127 Rare histologic variants include histiocytoid SS (Fig 7),128 lymphocytic SS,129 subcutaneous SS,130 and cryptococcoid SS.131 The clinicopathologic features of SS are summarized in Table II.119-123,128-131 Several studies have sought to identify features of SS associated with malignancy. Reported clinical features include older age,44,46,48 vesiculobullous morphology,47,132 leukopenia,50 anemia,44,46,48,49,50,132,133 thrombocytopenia,44,48,50,132 elevated erythrocyte sedimentation rate,49 and the absence of arthralgia.48,50 Histiocytoid SS remains controversial. Some have contended that it instead represents a subtype of leukemia cutis with immature myeloid cells.134 Others have reported an association between histiocytoid SS and underlying hematologic malignancy.50,63,135 Others have not identified cytogenetic anomalies or association with underlying hematologic malignancy in cases of histiocytoid SS.136 One study reported lymphocytic SS as a predictive marker of myelodysplasia.129 Several studies have supported an association between subcutaneous SS and hematologic disorders.50,61,133 While SS typically presents with constitutional symptoms, overt extracutaneous involvement may

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Fig 5. Pathergy in Sweet syndrome. Lesions occurring at venipuncture sites on the wrist and dorsal hand (A) and peripheral intravenous catheter insertion site on the forearm (B).

Fig 6. Sweet syndrome histopathology. A and B, Papillary dermal edema and a predominantly neutrophilic dermal infiltrate. (Hematoxylineeosin stain; original magnification: A, 320; B, 340.) Gram, Grocott, and Fite special stains revealed no microorganisms and the tissue culture was negative (courtesy of Laura Taylor, MD).

occur and may lead to mortality. Ocular involvement including conjunctivitis, episcleritis, scleritis, iritis, choroiditis, and retinal vasculitis may be sightthreatening.137 Pulmonary SS may present with dyspnea, cough, and pleurisy with radiologic evidence of nodular, reticular, or patchy infiltration with or without effusion. Cardiac SS may present with aortic stenosis, aortitis, cardiomegaly, coronary artery occlusion, and myocardial infiltration with neutrophils.138 SS involvement of the gastrointestinal tract may obstruct the airway or the bowel.139,140 SS may infiltrate the lymphoreticular system, and SS may cause renal or liver failure.141,142 Neurologic complications include encephalitis, meningitis, headache, conscious disturbance, epilepsy, paresis, psychiatric disorders, and dyskinesia.143

Diagnosis Key points d SS is a diagnosis of exclusion d The differential diagnosis includes infectious, inflammatory, and neoplastic diseases

d

Patients with suspected SS should receive a thorough history and physical examination, a tissue culture and a sterile skin biopsy specimen should be obtained, and further evaluation should be performed to exclude alternate diagnoses and uncover any associated diseases or medications

SS is a diagnosis of exclusion. Clinical, histologic, and laboratory findings are nonspecific and cannot be used alone for a definitive diagnosis. In 1986, Su and Liu144 proposed 2 major and 4 minor diagnostic criteria for SS that have been widely adopted into clinical practice. These criteria as modified by Moschella and Davis1 are shown in Table III. In 1996, Walker and Cohen77 proposed 5 major diagnostic criteria for druginduced SS.77 These modified criteria are shown in Table IV. The differential diagnosis of SS encompasses a spectrum of infectious, inflammatory, and neoplastic disorders (Table V).1,119 When SS presents in the pediatric population, it is important to consider interferonopathies, such as CANDLE syndrome.52 The first step in the evaluation of a patient with presumed SS is a thorough history with particular

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Fig 7. Histiocytoid Sweet syndrome histopathology. A and B, Predominantly histiocytoid, neutrophilic, and lymphocytic infiltrate with scattered eosinophils. (Hematoxylineeosin stain; original magnification: A, 310; B, 340.) Histiocytoid cells were positive for CD68 (C), CD15, CD43, myeloperoxidase (D), and lysozyme. The patient’s original leukemia was positive by flow for c-kit, which was positive in scattered benign mast cells, and CD34, which was negative, and there was no cytologic atypia. Gram and periodic acideSchiff special stains revealed no microorganisms and tissue culture was negative (courtesy of Alexandra Flamm, MD).

attention to fever and other constitutional symptoms, upper respiratory tract or other infectious symptoms, vaccinations, malignancies and inflammatory disorders, drug exposure, and pregnancy status.144 The second step is a review of vital signs and a total body skin examination including mucous membranes. SS may evidence pathergy,48,51 and therefore careful attention should be directed to sites of skin instrumentation such as venipuncture sites. The laboratory investigation should include a complete blood cell count with differential. While nonspecific, C-reactive protein and erythrocyte sedimentation rate are often elevated. A sterile skin biopsy specimen and tissue culture (bacterial, fungal, and mycobacterial) extending into the subcutis of an active lesion should be performed to evaluate for histopathology consistent with SS and to exclude infection. It is important to advise the patient of the potential for skin lesions to worsen because of pathergy48,51 and bear this in mind when obtaining biopsy specimens from anatomically or cosmetically sensitive sites. There is no universally agreed upon approach to the further evaluation of SS patients for underlying associated diseases. All patients should receive

age-appropriate malignancy screening. Given the association of SS with hematologic disorders,44,46,48 a peripheral blood smear and testing for paraproteinemia is reasonable, along with obtaining a bone marrow biopsy specimen if indicated. Additional testing for IBD and systemic autoimmune or other associated diseases should be considered depending on the index of clinical suspicion. Management Key points d Systemic corticosteroids are the therapeutic criterion standard for SS d Steroid-sparing systemic agents include dapsone, colchicine, and potassium iodide d Given the lack of high-quality comparative data, treatment should be tailored to the individual patient taking into account any associated diseases or medications, other comorbidities, and the safety and tolerability of each medication Given the paucity of high-quality data, universally accepted and validated guidelines for the treatment

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Table II. Clinical and histopathologic features of Sweet syndrome Variant

Clinical Classic Pustular and bullous Giant cellulitiselike Necrotizing Neutrophilic dermatosis of the dorsal hands Histopathologic Neutrophilic Histiocytoid Lymphocytic

Subcutaneous Cryptococcoid

Features

Reference(s)

Abrupt onset of painful erythematous plaques or nodules Pustules and/or vesicles, which may coalesce into bullae Giant (#100 cm in diameter) infiltrated erythematous, vesicular, bullous, or hemorrhagic plaques Erythematous, warm, edematous lesions with deep tissue neutrophilic infiltration and soft tissue necrosis Hemorrhagic bullae, plaques, and pustules solely on the dorsal hands

119 120 121

Predominantly neutrophilic infiltrates in the dermis Predominantly mononuclear cell infiltrates in the dermis mimicking histiocytes but of myeloid lineage Predominantly lymphocytic infiltrates in the dermis with atypical mononuclear cells identified as immature granulocytes that later evolve into neutrophilic infiltrates Predominantly neutrophilic infiltrates exclusively in the subcutis exhibiting a lobular or, less frequently, septal pattern Degenerating autolyzed inflammatory cells with prominent cytoplasmic vacuolization and acellular basophilic bodies mimicking the Cryptococcus capsule and yeast, respectively

119 128

Table III. Diagnostic criteria for Sweet syndrome* Major criteria 1. Abrupt onset of typical cutaneous lesions 2. Histopathology consistent with Sweet syndrome Minor criteria 1. Preceded by one of the associated infections or vaccinations; accompanied by one of the associated malignancies or inflammatory disorders; associated with drug exposure or pregnancy 2. Presence of fever and constitutional signs and symptoms 3. Leukocytosis 4. Excellent response to systemic corticosteroids *Both of the major and 2 minor criteria are required for diagnosis.1,144

of SS currently do not exist. SS may resolve spontaneously or with treatment of an associated disease or discontinuation of an associated medication; however, disease-targeted therapy is often necessary.145 Retrospective studies have reported recurrence rates from 15% to 45%, at intervals of up to 10 years.44,46-49,51 Systemic corticosteroids are considered the therapeutic criterion standard, with excellent response being a minor diagnostic criterion.1,43,144 Typical dosing is the equivalent of prednisone 0.5 to 1 mg/kg/day, with the precise dose and taper determined based on disease severity and comorbidities. For severe disease, the authors advocate 2.0 mg/kg/day divided with a half dose in

122 123

129

130 131

Table IV. Diagnostic criteria for drug-induced Sweet syndrome* Abrupt onset of typical cutaneous lesions Histopathology consistent with Sweet syndrome Presence of fever and constitutional signs and symptoms Temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge Temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids *All criteria are required for diagnosis.1,77

the morning and a half dose at night. Pulse methylprednisolone has been reported to be efficacious in refractory disease.146 Care should be taken not to taper steroids too rapidly because this can precipitate a flare. Topical or intralesional corticosteroids may be used as adjunctive therapy or as monotherapy in mild disease.147,148 The downside to intralesional steroids is the theoretical risk of inducing new lesions via pathergy. For patients in whom systemic corticosteroids are contraindicated or a steroid-sparing agent is desired, treatment modalities include colchicine (1.5 mg/ day),145,149-151 dapsone (100-200 mg/day),145,152-155 and potassium iodide (900 mg/day).145,156 Treatment modalities for SS are summarized in Table VI.43,44,146-189 The efficacy of novel biologic agents, such as TNF-a inhibitors and the IL-1 receptor

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Table V. Differential diagnosis of Sweet syndrome

Table VI. Treatment of Sweet syndrome

Infectious disorders

Treatment

Inflammatory disorders

Neoplastic disorders

Bacterial infections (eg, cellulitis) Fungal infections (Majocchi granuloma and deep fungal infections) Mycobacterial infections (typical and atypical) Parasitic infections (eg, leishmaniasis) Viral infections (eg, orf) Arthropod bites Autoimmune connective tissue diseases (eg, lupus erythematosus) Erythema multiforme Granulomatous diseases (eg, sarcoidosis) Halogenoderma Other neutrophilic dermatoses (eg, Behc¸et disease) Panniculitides (eg, erythema nodosum) Vasculitides (eg, cutaneous small vessel vasculitis) Well’s syndrome Leukemia cutis Lymphoma cutis Metastatic carcinoma

antagonist anakinra has been reported in case reports. Given the lack of high-quality comparative data, treatment should be tailored to the individual patient taking into account any associated diseases or medications, other comorbidities, and the safety and tolerability of each medication. Evidence for SS treatment in the pediatric population is scarce; therefore, treatment is typically based on adult practice.52

NEUTROPHILIC ECCRINE HIDRADENITIS Epidemiology Key points d NEH typically occurs in patients with AML who are receiving chemotherapy, most commonly cytarabine followed by daunorubicin d NEH may occur in childhood as a benign self-limited eruption with a predilection for the summer months NEH occurs most commonly in patients with AML who are receiving chemotherapy. In 2000, a literature review by Bachmeyer and Aractingi190 of 51 published cases of NEH reported a mean age of onset of 40 years and an approximately 2:1 male to female ratio. Forty-three of 51 (84%) patients received antimitotic agents, most commonly

Local treatment modality Topical corticosteroids Intralesional corticosteroids Systemic treatment modality Acitretin/etretinate Anakinra Azathioprine Chlorambucil Clofazimine Colchicine Corticosteroids Methylprednisolone Prednisone Cyclophosphamide Cyclosporine Dapsone Doxycycliney Granulocyte and monocyte adsorption apheresis Indomethaciny Interferon-a Intravenous immunoglobulin Lenalidomide/thalidomide Methotrexate Potassium iodide Rituximab Sulfasalazine Tacrolimus Tumor necrosis factor-a inhibitors Adalimumab Etanercept Infliximab

Level of evidence*

Reference(s)

III III

145,147 145,148

III III III III III IIB

145,157 158,159 44 146 145,159 145,149-151

III III III III III III III

145,146 43,145 160-162 145,163,164 145,152-155 145,165,166 166

IIB III III III III III III III III

145,167,168 145,169 170-172 172,173 145,146 145,156 174,175 176 177

III III III

178,179 179,180 179,181-184

*Level IA, evidence from meta-analysis of randomized controlled trials; level IB, evidence from at least 1 randomized controlled trial; level IIA, evidence from at least 1 controlled study without randomization; level IIB, evidence from at least 1 other type of experimental study; level III, evidence from nonexperimental descriptive studies; level IV, evidence from expert committee reports or opinions or clinical experience of respected authorities. y Other medications in this class have been reported.

cytarabine followed by daunorubicin.190 More recently, NEH has been reported after the administration of the hypomethylating agent decitabine191 and targeted antineoplastic agents including the BRAF inhibitors dabrafenib and vemurafenib,192 the epidermal growth factor receptor inhibitor cetuximab,193 and the tyrosine kinase inhibitor imatinib.194 Medications other than antineoplastics have been reported to induce NEH, specifically acetaminophen,190 adalimumab,195 antiretroviral therapy,190 azathioprine,196 carbamazepine,197 and G-CSF.190 NEH has also been reported in states of altered immunity, such as HIV and hematologic and

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Fig 8. Neutrophilic eccrine hidradenitis. Erythematous papules on the ankle and foot.

solid malignancies.190,198,199 In young children, NEH may occur without an associated disease or medication with a predilection for the summer months.200 Clinical features Key points d NEH is characterized by erythematous edematous papules or plaques with numerous neutrophils infiltrating the eccrine gland secretory coils and epithelial necrosis on histopathology d Idiopathic plantar hidradenitis of NEH is a variant described primarily in healthy children with rapid development of tenderness of the feet The first description of NEH in 1982 by Harrist et al201 reported the eruption of erythematous edematous plaques on the left neck and shoulder of a man undergoing induction chemotherapy for AML that resolved spontaneously, recurred during a second chemotherapy course, and again resolved spontaneously. Skin biopsy specimens obtained during both eruptions revealed numerous neutrophils infiltrating the eccrine gland secretory coils with epithelial necrosis.201 A variety of clinical presentations of NEH have since been described, ranging from single to multiple asymptomatic or painful erythematous papules or plaques (Fig 8). The trunk is most often affected, but lesions may also occur on the extremities and face. The eruption manifests on average 10 days after chemotherapy initiation. It may be accompanied by fever and display pathergy.190 In childhood, NEH characteristically presents as a self-limited eruption of urticaria-like erythematous nodules and plaques on the limbs, trunk, or scalp.200 Idiopathic plantar hidradenitis of NEH is a variant described primarily in healthy children with rapid development of tenderness of the feet.202

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Fig 9. Behc¸et disease. Ulcer on the upper lip.

Diagnosis Key point d The diagnosis of NEH depends on the histopathologic examination revealing eccrine glands with degenerative vacuolar changes Because of the protean clinical manifestations of NEH, diagnosis relies on the identification of eccrine glands with degenerative vacuolar changes on histology. These changes are more often observed in secretory as compared to ductal cells and typically spare the acrosyringium. A robust neutrophilic infiltrate as described by Harrist et al201 is classic but not required for diagnosis. Eccrine squamous syringometaplasia may be observed. Special stains for infectious agents and tissue cultures are negative.190 The differential diagnosis includes SS and infection. A diversity of pathogens has been implicated in infectious eccrine hidradenitis, including Staphylococcus aureus; Enterobacter, Nocardia, and Serratia species; Mycobacterium chelonae; and HIV.203 Management Key points d NEH resolves spontaneously within days to weeks after stopping chemotherapy but may recur in subsequent cycles d Systemic corticosteroids and nonsteroidal antiinflammatory drugs have reported efficacy in reducing pain or fever; dapsone has reported efficacy in preventing recurrences NEH resolves spontaneously within days to weeks after stopping chemotherapy but may recur in subsequent cycles. Most patients are neutropenic and receive antibiotics.190 In some circumstances, treatment of NEH may be desired to relieve pain or fever. The available evidence is limited to descriptive studies (evidence level III); however, clinical response has been reported to systemic corticosteroids and nonsteroidal antiinflammatory

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Fig 10. Behc¸et disease. A, Ulcer on the scrotum. B, Purulent ulcers involving the labia majora, labia minora, and vaginal mucosa.

100,000 population along the ‘‘Silk Route,’’ extending from Japan to the Middle East and Mediterranean.207 The highest prevalence of disease is seen in Turkey at 1 in 250,208 in contrast to 0.12 to 0.33 people per 100,000 population in the United States.209 BD usually presents in the third to fourth decades of life, with an overall equal gender distribution, showing a male predominance in the Middle East and Mediterranean and a female predominance in Japan and Korea.207 The strong regional variability in BD expression closely correlates with the geographic distribution of HLA-B51, which along the Silk Route ranges from 20% to 25% in the general population and 50% to 80% among patients with BD.210

Fig 11. Behc¸et disease. Papulopustule in the antecubital fossa.

drugs.203-206 Dapsone has also been reported to prevent recurrences.206 Topical treatment is usually ineffective, likely because of the depth of the involved eccrine glands in the dermis.190

BEHC¸ET DISEASE Epidemiology Key points d BD is a rare inflammatory condition that is most prevalent along the ‘‘Silk Route,’’ correlating with the geographic distribution of HLA-B51 d BD typically presents in the third to fourth decades of life and has an equal gender distribution BD is a chronic multisystem inflammatory disorder with a prevalence of 14 to 20 people per

Clinical features Key points d BD classically presents with a triad of recurrent painful oral ulcers, genital ulcers, and uveitis d BD confers an increased risk of mortality, which is mainly related to gastrointestinal, pulmonary, large vessel, and neurologic involvement BD classically presents with a triad of recurrent symptoms, including oral ulcers, genital ulcers, and uveitis. Oral ulcers occur most commonly on the lips, buccal mucosa, tongue, and soft palate. The lesions start as erythematous papules or vesiculopustules and evolve into oval ulcers with rolled borders and a grayish yellow necrotic base surrounded by an erythematous halo within several days (Fig 9). They may cause a considerable degree of pain and difficulty with oral hygiene, eating, drinking, and speaking. Genital ulcers of BD are similar in appearance but may be deeper and heal with scarring (Fig 10). The most common sites of presentation are the labia majora in women and

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Table VII. Diagnostic criteria for Behc¸et disease International Study Group for Behc¸et Disease criteria* Major criterion Recurrent oral ulceration: minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient that recurred $3 times in one 12-month period Minor criteria 1. Recurrent genital ulceration: aphthous ulceration or scarring, observed by physician or patient 2. Eye lesions: anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis observed by ophthalmologist 3. Skin lesions: erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or acneiform nodules observed by physician in postadolescent patients not on corticosteroid treatment 4. A positive pathergy testy International Criteria for Behc¸et Diseasez Ocular lesions (2 points) Genital aphthosis (2 points) Oral aphthosis (2 points) Skin lesions (1 point) Neurologic manifestations (1 point) Vascular manifestations (1 point) Positive pathergy testx *One major and 2 minor criteria are required for diagnosis applicable only in the absence of other clinical explainations.214 y A papule [2 mm in size developing 24 to 48 hours after oblique insertion of a 20- to 25-gauge needle 5 mm into the skin, generally performed on the forearm. z Point scoring system: scoring $ 4 indicates Behc¸et disease diagnosis.215 x Optional, and the primary scoring system of the International Criteria for Behc¸et Disease does not include pathergy testing. However, where pathergy testing is conducted, 1 extra point may be assigned for a positive result.

the scrotum in men; however, the labia minora, vaginal mucosa, cervix, shaft and glans penis, and perineum may also be involved. Genital ulcers may cause severe pain, dyspareunia, difficulty with micturition, impairment of physical activity, and strictures and fistulae.211 Panuveitis is the most frequent ocular lesion in BD, with anterior uveitis, posterior uveitis, and retinal vasculitis representing other main ocular manifestations.207 BD is a multisystem disease that may have cutaneous, vascular, articular, gastrointestinal, neurologic, urogenital, pulmonary, and cardiac involvement. The most common cutaneous lesions of BD are erythema nodosumelike lesions, papulopustular lesions (Fig 11), superficial thrombophlebitis, and cutaneous pathergy.212 Pathergy is an exaggerated skin reaction induced by a minor injury, such as a needle prick.

Table VIII. Treatment of mucocutaneous involvement in Behc¸et disease Treatment

Local treatment modality Topical corticosteroids Topical pimecrolimus Carbon dioxide laser Systemic treatment modality Alemtuzumab Anakinra Apremilast Azathioprine Azithromycin Canakinumab Colchicine Corticosteroids Granulocyte and monocyte adsorption apheresis Isotretinoin Interferon-a Intravenous immunoglobulin Methotrexate Minocycline Mycophenolate Rituximab Thalidomide Tocilizumab Tumor necrosis factor-a inhibitors Adalimumab Etanercept Infliximab Ustekinumab

Level of evidence*

Reference(s)

III IB III

219 220,221 222

IIB IIA IB IB IIA IIA IB IB III

233 234,235 236 219 237 235,238,239 219,223 219 243

IIA IB III III III III III IIB III

240 219,225 244,245 231 219 245 247 219,224 248

IIB IB IIB IIB

225-229 219,230 228,231,232 241,242

*Level IA, evidence from meta-analysis of randomized controlled trials; level IB, evidence from at least 1 randomized controlled trial; level IIA, evidence from at least 1 controlled study without randomization; level IIB, evidence from at least 1 other type of experimental study; level III, evidence from nonexperimental descriptive studies; level IV, evidence from expert committee reports or opinions or clinical experience of respected authorities.

Gastrointestinal vasculitis of BD, which is more common among patients from Japan and Korea, may lead to bowel perforation and is associated with significant morbidity and mortality. Other causes of mortality are mainly related to pulmonary, large vessel, and neurologic involvement.207 Under the microscope, oral and genital ulcers may demonstrate perivascular mononuclear infiltration, while erythema nodosum, folliculitis, and thrombophlebitis histologically mirror these entities in the absence of BD. While some argue that BD is a form of vasculitis, others argue that vasculitis is secondary.213

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Diagnosis Key points d BD is a diagnosis of exclusion d The differential diagnosis is broad and includes recurrent aphthous stomatitis, HLA-B27erelated diseases, IBD, and SLE

publication of the EULAR recommendations, the efficacy of multiple agents has been reported, including alemtuzumab,233 anakinra,234,235 apremilast,236 azithromycin,237 canakinumab,235,238,239 isotretinoin,240 and ustekinumab.241,242 Treatment data are summarized in Table VIII.219-248

The diagnosis of BD is primarily based on clinical criteria and exclusion of an alternative diagnosis. The International Study Group for Behc¸et’s Disease criteria are listed in Table VII.214 The International Criteria for Behc¸et’s Disease, also listed in Table VII, were proposed to increase sensitivity but are not as widely accepted.215 The differential diagnosis of recurrent oral ulceration includes aphthous stomatitis, HLA-B27erelated diseases, IBD, and SLE. The gastrointestinal symptoms of BD may mimic IBD and the neurologic symptoms may mimic multiple sclerosis.209,216 Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome is a diagnostic consideration in patients with coexistent relapsing polychondritis.217

We thank Mr Jerry and Mrs Joan Berstein for their generous support of neutrophilic dermatosis research at the University of Pennsylvania.

Management Key points d Treatment of mucocutaneous involvement in BD should be tailored based on impact on the patient’s quality of life d Topical therapies may be adequate to control mild disease, while systemic therapies may be required to control severe disease There are few large, randomized controlled clinical trials to guide the treatment of BD.218 In 2008, the European League Against Rheumatism (EULAR) published recommendations for the management of BD.219 A complete discussion of the management of systemic BD is beyond the scope of this review. For mucocutaneous involvement, the EULAR recommendation is to tailor treatment based on impact on the patient’s quality of life. For oral and genital ulcers, topical corticosteroids and supportive care with lidocaine gel, chlorhexidine, and sucralfate suspension may be sufficient.219 More recent reports have shown improvement with pimecrolimus cream and carbon dioxide laser.220-222 Topical therapies used in the treatment of acne vulgaris can be used for acne-like lesions. Treatment of leg ulcers depends on the underlying cause.219 Systemic therapies may be indicated in cases of severe mucocutaneous disease. Colchicine is considered first-line therapy for erythema nodosum lesions.219,223 Other systemic agents include azathioprine, minocycline, thalidomide, interferona, and TNF-a antagonists.219,224,232 Since the

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