[Academic Presentation] Systemic Manifestations of Neutrophilic Dermatoses

Article reprinted from: Chinese Medical Abstracts – Dermatology

Authors: Wang Yanan, Zhao Wenling, Liu Yidi, Wu Xia, Li Li

Neutrophilic dermatoses (ND) comprise a group of disorders characterized by similar histopathological features, pathogenic mechanisms, and treatment approaches. Histologically, they are marked by perivascular and diffuse neutrophilic infiltrates in the absence of any definitive infectious etiology. Cutaneous lesions exhibit considerable heterogeneity, ranging from localized to widespread involvement; common entities include Sweet syndrome, pyoderma gangrenosum, Behçet disease, and subcorneal pustular dermatosis. Notably, beyond skin manifestations, neutrophilic dermatoses may also feature extra‑cutaneous sterile neutrophilic infiltrates, with affected organs including the lungs, musculoskeletal system, gastrointestinal tract, liver, spleen, pancreas, central nervous system, and cardiovascular system.

1 Lung

In recent years, numerous reports have documented neutrophilic dermatoses associated with pulmonary infiltrates; among these, the lung is the most common extracutaneous organ involved in pyoderma gangrenosum. Pyoderma gangrenosum has been reported to give rise to tracheobronchopulmonary disease, with bronchoscopy revealing numerous polypoid nodules distributed throughout the trachea and bronchi, exhibiting a slightly yellowish, non‑smooth surface that resembles the cutaneous lesions. Biopsy demonstrates inflammatory granulomas and necrosis, accompanied by abundant neutrophilic infiltration. In addition, Sweet syndrome may also present with pulmonary involvement; in most cases, pulmonary manifestations occur concurrently with Sweet syndrome, though occasionally they develop secondarily to it. Pulmonary complications include bilateral pulmonary infiltrates, obliterative bronchiolitis with organizing pneumonia, and pleural effusions. Clinical symptoms typically comprise fever, cough, and chest pain, while imaging findings include pulmonary nodules and reticular or patchy infiltrates. Histopathology reveals interstitial inflammation, edema, mild fibrosis, and extensive neutrophilic infiltration of the alveoli. The diagnosis of Sweet syndrome with pulmonary involvement is usually established on the basis of characteristic clinical features, histopathological examination, and response to corticosteroid therapy. Furthermore, Behçet’s disease can also manifest with pulmonary involvement, particularly pulmonary artery aneurysms. In patients with neutrophilic dermatoses and pulmonary infiltrates, both cutaneous lesions and pulmonary involvement generally improve following glucocorticoid treatment. Among deceased patients, respiratory failure remains the leading cause of mortality.

2 Bone

Neutrophilic dermatoses may be associated with multifocal aseptic bone disease, known as chronic recurrent multifocal osteomyelitis (CRMO). The onset of this condition may be linked to mutations in the LPIN2 and PSTPIP2 genes. CRMO is most commonly observed in children; it has an insidious onset and typically presents with long-bone pain, stiffness, and swelling, with or without fever; erythrocyte sedimentation rate is mildly elevated, and white blood cell counts may also be increased. Skin lesions may occur concurrently with or following the bone disease; common types include palmoplantar pustulosis and pustular psoriasis, though they can also manifest as plaque psoriasis, severe acne, Sweet’s syndrome, or necrolytic migratory erythema. CRMO and spondyloarthropathy–associated hyperostosis–psoriasis–osteomyelitis–arthritis (SAPHO) syndromes are considered part of the same disease spectrum, and some investigators even regard CRMO as the pediatric form of SAPHO. In the latter, involvement often affects the anterior chest wall and axial skeleton, with symptoms such as tenderness on palpation, joint swelling and pain, fever, leukocytosis, and an accelerated erythrocyte sedimentation rate—features similar to those seen in CRMO. Patients with CRMO generally do not respond to antibiotic therapy but are responsive to glucocorticoids, requiring low‑dose maintenance therapy to prevent relapse. Some researchers have suggested that patients with CRMO accompanied by cutaneous manifestations may also benefit from tumor necrosis factor inhibitors.

3 Joints

Arthritis is also a relatively common systemic manifestation of neutrophilic dermatoses, with an incidence ranging from approximately 15% to 62%. It typically develops after the onset of neutrophilic dermatosis, though occasionally it may precede cutaneous lesions. Joint involvement in neutrophilic dermatoses is frequently observed in Sweet syndrome and Behçet’s disease. During the course of Sweet syndrome, about one-third of patients experience arthralgia, myalgia, or arthritis; the latter presents as asymmetric, non‑erosive arthritis primarily affecting the knees and wrists. Treatment with glucocorticoids and tumor necrosis factor‑α inhibitors is effective. Approximately 50% of patients with Behçet’s disease also develop arthritis—either polyarticular or monoarticular—in a non‑erosive pattern, commonly involving the knees, wrists, and ankles; in 80% of cases, joint symptoms persist for no more than two months. Additionally, case reports have described neutrophilic dermatosis complicated by panniculitis/fasciitis induced by granulocyte colony‑stimulating factor, which may also manifest as joint pain and localized skin swelling. Laboratory findings typically show elevated erythrocyte sedimentation rate and C‑reactive protein, while histopathology reveals extensive neutrophilic infiltration. Treatment with prednisone is effective.

4 Central Nervous System

Among neutrophilic dermatoses, Sweet syndrome and Behçet disease relatively frequently involve the central nervous system. Neurologic symptoms typically appear after the cutaneous lesions have developed. In patients with Sweet syndrome complicated by CNS involvement, encephalitis and meningitis may occur, with clinical manifestations including fever, headache, seizures, altered mental status, oculomotor disturbances, uveitis, papilledema, and selective aphasia; the skin lesions resemble erythema nodosum. Cerebrospinal fluid analysis usually shows a neutrophilic pleocytosis, with negative bacterial cultures. Systemic corticosteroid therapy is effective; some authors have also suggested that dapsone may be useful in patients with neurologic Sweet syndrome who are prone to exacerbation. In Behçet disease, neurologic involvement is more common in males and generally occurs in the late stages of the illness, portending a poor prognosis. Neurologic manifestations may include acute meningitis, cranial nerve palsy, and brainstem dysfunction (including dysphagia, pseudobulbar laughter, and crying). Additionally, there have been case reports of pyoderma gangrenosum presenting with central nervous system features, such as aphasia and headache.

5 Abdominal viscera

Visceral manifestations of neutrophilic dermatoses often present as sterile abscesses, with hepatic and splenic abscesses being common. These may belong to the same disease spectrum as conditions such as pyoderma gangrenosum, Sweet’s syndrome, subcorneal pustular dermatosis, and persistent elevated erythema, collectively referred to as neutrophilic diseases. Visceral involvement can occur after or concurrently with cutaneous lesions. A previous study of 30 patients with sterile abscesses found that 20% also had a neutrophilic dermatosis, most commonly splenic abscesses. Such patients may exhibit fever, abdominal pain, and splenomegaly; they typically show leukocytosis, an elevated erythrocyte sedimentation rate, and increased C-reactive protein levels, yet bacterial cultures from splenic puncture remain negative. Treatment with corticosteroids in combination with immunosuppressants is effective. The precise pathogenesis of sterile splenic abscesses remains unclear; however, some investigators propose that sterile hepatic abscesses may arise through interleukin‑8 (IL‑8)–mediated enhancement of T‑cell regulatory functions, leading to sterile neutrophilic infiltrative skin inflammation and, secondarily, sterile hepatic abscesses. In addition to the liver and spleen, the kidneys may also develop sterile abscesses, manifesting as microscopic hematuria or sterile pyuria, which respond favorably to glucocorticoid therapy. Furthermore, sterile abscesses can occur in lymph nodes, the pancreas, and other sites.

6 Muscles

In neutrophilic dermatoses, muscle involvement is relatively uncommon. One study reported that among 136 patients with neutrophilic dermatoses, fewer than 10% experienced myalgia. When pyoderma gangrenosum is accompanied by muscle involvement, patients may present with fever, weight loss, myalgia, and weakness of the extremities; skin lesions may manifest as erythema, pustules, ulcers, or necrosis. Electromyography suggests myositis, characterized by an inflammatory infiltrate dominated by neutrophils, with destruction of muscle architecture and necrosis of muscle fibers. Other tests for infection and connective tissue diseases are all negative, and corticosteroid therapy proves effective.

7 Cardiovascular

Cardiac involvement in Sweet’s syndrome is extremely rare. However, some reports have indicated that cardiovascular infiltration can increase the mortality rate from 9% to 40%. Consequently, cardiovascular complications in neutrophilic dermatoses remain a significant clinical concern. Recently, a case of a pregnant woman with Sweet’s syndrome complicated by neutrophilic myocarditis and pericarditis was reported in the United States; she developed chest pain, pericardial friction rubs, and elevated troponin levels three days after the onset of skin lesions. Vascular involvement in Sweet’s syndrome typically manifests as atherosclerosis, aortitis, aneurysms, and coronary artery occlusion. Notably, neonates with Sweet’s syndrome may develop aortitis and thoracic aortic aneurysms. In addition, Behçet’s disease can also present with cardiovascular manifestations, including coronary arteritis, valvular heart disease, myocarditis, arrhythmias, aneurysms, occlusive arterial disease, and superficial or deep venous thrombosis. Vasculitis associated with Behçet’s disease is ANCA‑negative, while antiphospholipid antibodies may be positive; however, these findings do not correlate with disease activity and may be linked to recurrent thrombosis.

8 eyes

Ocular involvement is the most common manifestation of Behçet’s disease, observed in approximately 90% of patients; it occurs more frequently in males and tends to be more severe, with symptoms ranging from pain to even blindness. Ocular manifestations of Sweet syndrome typically include periorbital inflammation, dacryoadenitis, conjunctivitis, scleritis, keratitis, iritis, and glaucoma, and are generally managed with oral prednisone. Beyond these organ systems, systemic manifestations of neutrophilic dermatoses may also involve the fallopian tubes, lymph nodes, and the gastrointestinal tract. The systemic presentations of neutrophilic dermatoses are broad and varied; a thorough and comprehensive understanding of these systemic features can facilitate the rapid and accurate identification and diagnosis of the condition. When encountering skin disorders characterized primarily by neutrophilic infiltrates, dermatologists should, while ruling out infectious causes, carefully elicit a detailed history of systemic symptoms and perform appropriate diagnostic evaluations.

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