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Palisaded neutrophilic and granulomatous dermatitis

Palisaded neutrophilic and granulomatous dermatitis
Literature review current through: Jan 2024.
This topic last updated: Jun 29, 2022.

INTRODUCTION — Palisaded neutrophilic and granulomatous dermatitis (PNGD) is an inflammatory cutaneous disorder of unknown etiology that usually manifests as skin-colored to erythematous papules or plaques on the extremities (picture 1A-B). PNGD typically occurs in association with systemic disease. Rheumatoid arthritis and systemic lupus erythematosus are the most common associated diseases.

The clinical features, diagnosis, and management of PNGD will be reviewed here. Other neutrophilic dermatoses are reviewed separately. (See "Neutrophilic dermatoses".)

HISTORY — The term PNGD was first proposed in 1994 in a report describing a papular eruption on the extremities in several patients with systemic lupus erythematosus, rheumatoid arthritis, or uncharacterized collagen vascular disease [1]. Biopsies of involved skin revealed histopathologic findings consistent with an evolving immune complex disorder (see 'Histopathology' below). Prior cases of PNGD were classified under other names, including Churg-Strauss granuloma [2], linear subcutaneous bands [3], rheumatoid papules [4], superficial ulcerating rheumatoid necrobiosis [5], and cutaneous extravascular necrotizing granuloma of Winkelmann or Winkelmann granuloma [6].

EPIDEMIOLOGY — PNGD is rare. A 2008 literature review identified only 97 reported cases [7]. PNGD usually develops in adults; rarely, children are affected [7,8]. Women are affected more frequently than men, an observation that may be related to the association of PNGD with autoimmune diseases [7]. (See 'Associated disorders' below.)

PATHOGENESIS — The pathogenesis of PNGD is unknown. Proposed theories for etiopathogenesis include abnormal neutrophil activation, circulating immune complex deposition, a delayed-hypersensitivity-type reaction, and a low-grade, small-vessel vasculitis [8]. Some authors have proposed that the clinical and histologic features of PNGD are manifestations of an evolving immune complex-mediated process [1]. In accordance with this theory, PNGD may represent an underlying leukocytoclastic vasculitis that acquires granulomatous features as the condition progresses [1,7].

CLINICAL MANIFESTATIONS — PNGD is typically characterized by skin-colored to erythematous, smooth, papules and plaques on the elbows and extremities (picture 1A-B) [1,8]. The papules and plaques are sometimes ulcerated or umbilicated. Other clinical manifestations include nodules, linear cords, urticarial or edematous plaques, erythematous or violaceous patches, and annular or gyrate papules and plaques. Associated scale is an infrequent finding.

Approximately one-half of patients with PNGD have involvement of the upper extremities [7]. Other potential sites of involvement, in order of decreasing frequency, are the lower extremities, trunk, and the head and neck [7].

PNGD is usually asymptomatic. However, pruritus or mild tenderness may occur [9].

ASSOCIATED DISORDERS — PNGD usually develops in association with an underlying systemic inflammatory disorder [10]; rarely, PNGD occurs in the absence of systemic disease [11]. The onset of the associated systemic disease usually predates the diagnosis of PNGD [12].

The most common associated conditions are connective tissue disorders and arthritides, particularly systemic lupus erythematosus and rheumatoid arthritis [1,7,8,12]. The association among lupus patients is more pronounced among those who have lupus nephritis [13]. Other connective tissue disorders that have been present in patients with PNGD include limited systemic sclerosis [7], undifferentiated connective tissue disease, and vasculitides or vasculopathies, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, erythema elevatum diutinum, Takayasu arteritis, and mixed cryoglobulinemia [8]. PNGD has also been reported in association with ankylosing spondylitis [14] and adult-onset Still's disease [15].

There are occasional reports of PNGD in patients with hematologic disorders, including acute myelogenous leukemia, chronic myelomonocytic leukemia (CMML), multiple myeloma, and lymphoma [6,16,17]. At least four patients with CMML-associated PNGD have been found to have an SRSF2 mutation [18].

Other infrequently associated conditions include sarcoidosis [19-21], ulcerative colitis [22], celiac disease, type 1 diabetes [23], Behçet syndrome [15], multiple sclerosis, cellulitis [24], subacute bacterial endocarditis, hepatitis, streptococcal infections, and acquired immune deficiency syndrome (AIDS) [7,8]. There is one report of a patient with PNGD who presented with hypercalcemia in the absence of any identifiable underlying disease [25].

The possibility of drug-induced PNGD has been proposed based upon occurrences of PNGD after the initiation of tumor necrosis factor (TNF) inhibitor [26,27] or allopurinol therapy [28]. However, the patients received these drugs for rheumatoid arthritis or acute myelogenous leukemia, disorders that have been associated with PNGD.

HISTOPATHOLOGY — The histologic findings of PNGD are consistent with the evolution of an immune complex-mediated disorder [1]. Diffuse, pan-dermal infiltrates composed of neutrophils, nuclear debris, strands of amorphous deeply basophilic material with leukocytoclastic vasculitis, and palisaded granulomas are seen (picture 2) [1]. The prominence of each of these findings may vary based upon the stage of disease. Palisaded granulomas may be most prevalent in mature lesions of PNGD [1]. Dermal mucin can be minimally increased, especially among those with an associated connective tissue disease, and fibrosis is not a prominent feature.

Some authors have described histopathologic features unique to patients with chronic myelomonocytic leukemia (CMML)-associated PNGD: a dense, wedge-shaped, dermal infiltrate with foamy and multinucleated histiocytes and focal areas of necrobiotic collagen [18].

DIAGNOSIS — The diagnosis of PNGD is made based upon correlation of the clinical and histologic findings. A skin biopsy should be performed in all patients. A 4 mm punch biopsy taken from a site of skin involvement is usually sufficient.

The diagnosis is most easily made in patients with all of the following features:

A skin-colored or erythematous papular eruption on the extremities

Histologic findings of a neutrophilic infiltrate with leukocytoclastic vasculitis, palisaded granulomas, and collagen degeneration

A known diagnosis of a systemic inflammatory disease associated with PNGD (eg, systemic lupus erythematosus or rheumatoid arthritis)

Patients [1] with cutaneous and histologic features of PNGD who lack a diagnosis of an associated systemic disease should be evaluated for systemic disease (see 'Associated disorders' above). In addition to a review of systems and physical examination with particular attention to signs and symptoms of systemic lupus erythematosus or rheumatoid arthritis, a reasonable initial work-up includes a chest radiograph and the following serologic studies [8]:

Antinuclear antibodies

Antineutrophil cytoplasmic antibody

Rheumatoid factor

Cyclic citrullinated peptide antibodies

Complete blood count with differential

Rarely, PNGD has occurred in the absence of detectable systemic disease [11].

DIFFERENTIAL DIAGNOSIS — PNGD should be distinguished from other cutaneous granulomatous disorders that may exhibit overlapping clinical features. Examples include granuloma annulare, interstitial granulomatous dermatitis, and interstitial granulomatous drug reaction. A skin biopsy is useful for distinguishing PNGD from these diseases:

Granuloma annulare Granuloma annulare is a cutaneous disorder characterized by localized or generalized nonscaly erythematous papules or plaques on the trunk or extremities (picture 3). Biopsies of granuloma annulare usually demonstrate a lymphocytic infiltrate, collagen degeneration, and mucin deposition in an interstitial or palisaded pattern (picture 4A-B). (See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

Interstitial granulomatous drug reaction – Interstitial granulomatous drug reaction (IGDR) typically manifests as erythematous to violaceous annular or nonannular plaques with predilection for the inner upper arms, proximal inner thighs, trunk, and intertriginous skin. Histologic findings include an interstitial lymphohistiocytic infiltrate, fragmentation of collagen, interface dermatitis, tissue eosinophils, and atypical lymphocytes [29]. Vasculitis is typically absent. Multiple drugs have been implicated. Examples include calcium channel blockers, beta-blockers, lipid-lowering agents, angiotensin converting enzyme inhibitors, diuretics, and nonsteroidal antiinflammatory agents [29].

Interstitial granulomatous dermatitis – Interstitial granulomatous dermatitis may present as skin-colored or erythematous rope-like linear cords, patches, plaques, or papules (picture 5). Histopathologic examination typically reveals a histiocytic infiltrate in the dermis, foci of degenerated collagen, and granulomas [8]. Vasculitis is usually absent.

Some authors have proposed that PNGD and interstitial granulomatous dermatitis are part of the same clinicopathologic spectrum based upon overlap in clinical features, a shared association with systemic disease, and overlap in the histologic findings [30]. Others have proposed a new unifying term (reactive granulomatous dermatitis) to encompass PNGD, interstitial granulomatous dermatitis, and interstitial granulomatous drug reaction [8,12,31,32].

MANAGEMENT — PNGD is a non-life-threatening cutaneous disorder that often resolves spontaneously or with treatment of the underlying associated disease. Therefore, treatment specifically for PNGD often is not necessary. (See 'Prognosis' below.)

Because of the rarity of PNGD, there are no prospective therapeutic clinical trials evaluating the efficacy of interventions for persistent PNGD. Clinical experience suggests that PNGD may improve with oral dapsone [33,34], oral hydroxychloroquine [8], or systemic glucocorticoid therapy [7,35]. Local therapies that may result in improvement include topical corticosteroid and intralesional corticosteroid therapy [34,36,37].

Other therapies have been proposed. A patient with rheumatoid arthritis who developed tocilizumab-associated PNGD improved during treatment with baricitinib [38].

PROGNOSIS — Prognostic data on PNGD are limited. Spontaneous resolution of PNGD can occur within a period as short as a few weeks or after longer periods of time [7]. In a review of 92 reported cases of PNGD, 20 percent of the 25 patients with available clinical response data had evidence of spontaneous resolution. Treatment responses were favorable among the remaining 20 patients; 80 percent responded to systemic treatment, which in most cases was directed at the underlying disease [7]. Recurrence after resolution is possible [7,9].

SUMMARY AND RECOMMENDATIONS

Pathogenesis – Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a rare cutaneous disorder that usually occurs in association with systemic disease. It is postulated that the pathogenesis of PNGD involves an immune-complex mediated leukocytoclastic vasculitis that progresses to develop granulomatous features. (See 'Epidemiology' above and 'Pathogenesis' above.)

Clinical manifestations – The most common clinical manifestations of PNGD are skin-colored to erythematous smooth papules or plaques (picture 1A-B). The upper extremities are the most frequent site of involvement. PNGD is usually asymptomatic, but may be associated with pruritus or tenderness of involved skin. (See 'Clinical manifestations' above.)

Associated disorders – Rheumatoid arthritis and systemic lupus erythematosus are the most common underlying diseases in patients with PNGD. PNGD may also occur in association with other connective tissue disorders, hematologic disorders, and other diseases. (See 'Associated disorders' above.)

Diagnosis – The diagnosis of PNGD is made based upon the detection of consistent clinical and histologic findings. Therefore, a skin biopsy is required for diagnosis. The characteristic histologic features are an intense neutrophilic dermal infiltrate, leukocytoclastic vasculitis, palisaded granulomas, and collagen degeneration (picture 2). (See 'Histopathology' above and 'Diagnosis' above.)

Management – PNGD usually resolves spontaneously or during treatment of the underlying disease. The best approach to persistent PNGD is unclear. Clinical experience suggests oral dapsone, hydroxychloroquine, systemic glucocorticoids, and topical or intralesional corticosteroids may be beneficial treatments. (See 'Management' above and 'Prognosis' above.)

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