Description

• A rare disorder of the skin that is characterized by the abrupt onset of painful, edematous, and erythematous lesions (papules, plaques, or nodules) (1). The lesions are often accompanied by fever and leukocytosis.
• Histologically characterized by diffuse dermal infiltration of mature neutrophils, leukocytoclasis, papillary dermal edema, and an absence of vascular infiltration (vasculitis)
• Classified into three main subtypes
  • Classic (idiopathic): majority of cases; often follows 1 to 3 weeks after an upper respiratory tract/GI infection; also associated with inflammatory bowel disease (IBD) (Crohn disease and ulcerative colitis), systemic lupus erythematosus (SLE), and pregnancy
  • Malignancy associated: may precede, appear simultaneously, or follow a hematologic malignancy or a solid tumor; more commonly associated with hematologic malignancies, most commonly acute myelogenous leukemia, followed by myelodysplastic syndrome
  • Drug induced: Multiple drugs have been implicated including cytokines, vaccines (influenza, BCG, small pox, pneumococcal), antiepileptics, antipsychotics, anti-inflammatory drugs (celecoxib, diclofenac), antihypertensives, antimicrobials (minocycline, ofloxacin, nitrofurantoin, trimethoprim-sulfamethoxazole), immunosuppressives, antineoplastics, retinoids, ticagrelor, and oral contraceptives (levonorgestrel/ethinyl estradiol). The cytokine, G-CSF, is most frequently reported; usually occurs ~2 weeks following drug exposure, with recurrence when reexposed to the drug
• Extracutaneous manifestations of the disease have been reported in almost every organ system.

Epidemiology

• Manifests at any age, classic peaks at 30 to 60 years of age
• Often based on subtype
  • Classic: 80% are women; 75–90% have a prior upper respiratory infection (URI); 30% recurrence
  • Drug induced: 71% are women; 67% recurrence
  • Malignancy associated: underlying hematologic malignancy: 50% are women; underlying solid tumor: 59% are women.
• There is no racial predilection.

Etiology and Pathophysiology

• Pathogenesis is multifactorial. Theorized factors include hypersensitivity reactions, cytokine dysregulation, and infection.
• This may include an imbalance and dysregulation of neutrophils and Type 1 T helper cells with a hypersensitivity reaction to bacterial, viral, or tumor antigen; or the effect of cytokines, specifically G-CSF, GM-CSF

Genetics
Abnormalities in chromosome 3q. In Japanese patients, HLA B-54 has been linked.

Risk Factors

Female sex, upper respiratory tract infection, pregnancy, hematologic malignancy, myelodysplastic syndrome, solid neoplasias, medications (antiepileptics, oral contraceptives, antimicrobials, antihypertensives, immunosuppressives, antineoplastics, anti-inflammatories, ticagrelor), inflammatory conditions (IBD), autoimmune diseases

Commonly Associated Conditions

• Upper respiratory/GI infection
• IBD (both Crohn disease and ulcerative colitis)
• Pregnancy
• Neutrophilic dermatoses, including erythema elevatum diutinum, neutrophilic eccrine hidradenitis, and pyoderma gangrenosum
• Hematologic cancers most frequently associated with acute myelocytic leukemia, myelodysplastic syndrome
• May occur in settings of patients with hematologic disorders
• Paraneoplastic syndrome
• Drug-induced dermatosis secondary to all-trans retinoic acid, G-CSF, and imatinib
• Simultaneously with leukemia cutis