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ONLINE EXCLUSIVES

Neutrophilic Dermatoses in a Clinical Practice of Wound Care Professionals

Lapa, Tatiana MD, MScCH; Sibbald, R. Gary MD, DSc (Hons), MEd, BSc, FRCPC (Med Derm), ABIM, FAAD, MAPWCA, JM; Coutts, Patricia M. BSc, RN; Zhao, Xiu Chang MD, CCFP

Author Information
Advances in Skin & Wound Care: June 2022 - Volume 35 - Issue 6 - p 1-8
doi: 10.1097/01.ASW.0000826832.69141.e4
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Abstract

INTRODUCTION

Neutrophilic dermatoses (NDs) are inflammatory skin diseases with various clinical presentations but overlapping pathophysiology that are unified by histologic features. Heterogeneous clinical presentations make diagnosis challenging. However, it is essential to complete a comprehensive evaluation to rule out similar skin disorders and establish the diagnosis because NDs may be associated with underlying infections, inflammatory conditions, and malignancies.

Characteristic histologic features include a sterile, mostly neutrophilic infiltrate in the dermis, rarely in the epidermis (subcorneal pustular dermatosis) or hypodermis. The signs of primary or secondary vasculitic changes might also be present, depending on the ND and the stage of the disease.1–4 The spectrum of NDs includes pyoderma gangrenosum (PG), Sweet syndrome (SS), erythema elevatum diutinum (EED), subcorneal pustular dermatosis, neutrophilic dermatosis of the dorsal hands (NDDH), neutrophilic eccrine hidradenitis, bowel-associated dermatosis-arthritis syndrome, rheumatoid neutrophilic dermatitis, Behçet disease, amicrobial pustulosis of the folds, and generalized pustular psoriasis and its atypical forms.5–7

Neutrophilic dermatoses can coexist in established associations within the spectrum of autoinflammatory syndromes:

  • PASH (PG, acne, and suppurative hidradenitis)
  • PAPA (pyogenic arthritis, PG, and acne)
  • PAPASH (pyogenic arthritis, PG, acne, and suppurative hidradenitis)
  • PsAPASH (psoriatic arthritis, PG, acne, and suppurative hidradenitis)
  • PAC (PG, acne, and ulcerative colitis)
  • PASS (PG, acne, and spondyloarthritis)
  • SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis).

Further, SAPHO syndrome might be associated with a variety of dermatologic presentations, not only acne and palmoplantar pustulosis but also PG or hidradenitis suppurativa (HS).8–12

Concurrent or sequential development of more than one ND has been described in patients with malignancy: EED and PG, EED and SS, EED and vasculitis, neutrophilic eccrine hidradenitis and subcorneal pustular dermatosis, neutrophilic eccrine hidradenitis and SS, PG and subcorneal pustular dermatosis, PG and SS, PG and vasculitis, SS and subcorneal pustular dermatosis, and SS and vasculitis.13 However, the authors found no previous literature regarding coexisting PG, SS, and HS, as was documented in the patient described herein.

CASE REPORT

The patient provided written informed consent to publish all related information and associated images. A 58-year-old woman presented to a wound care clinic with multiple circumferential ulcers on both her legs. Six months prior to that visit, the patient was seen by her family doctor with spontaneous onset of multiple nodular lesions on her lower legs after mosquito bites. Lesions were red and itchy without pain. There was no improvement after a course of antibiotics (penicillin) prescribed by her primary care physician, and the patient was referred to a wound care clinic. A punch biopsy was taken in the wound clinic, showing “extensive neutrophilic infiltrate in the superficial and deep dermis;” no evidence of vasculitis or infection was observed. In the past, the patient had documented erythema nodosum and venous disease. Laboratory test results revealed increased neutrophils count 8.4 × 109/L (2.0–7.5 × 109/L) and erythrocyte sedimentation rate (ESR) 28 mm/h (0–20 mm/h). The patient was diagnosed with SS and started on oral corticosteroids (prednisone).

The patient has had regular follow-up visits in the wound clinic regarding her management of SS lesions, both existing and new. Over the following 8 years, Sweet-like lesions appeared on her feet, legs, arms, buttocks, lower abdomen, and face. A comprehensive diagnostic workup was performed to explore possible associated conditions, including myelogenous malignancies and solid tumors (complete blood count, blood chemistry, protein electrophoresis, chest X-ray, abdominal ultrasound), without any positive results. A rheumatologist saw the patient to exclude connective tissue disease, limited cutaneous polyarteritis nodosa, and systemic vasculitis associated with Sweet-like lesions; none of the rheumatologic conditions were identified. Laboratory studies consistently showed neutrophilia, ranging from 8.4 to 17.8 × 109/L with or without leukocytosis, and an elevated ESR (up to 52 mm/h) and C-reactive protein (up to 71.4 mg/L; <8 mg/L is normal). Since 2014, the patient’s hemoglobin has been 8.5 to 10 g/dL (12–16 g/dL). The patient was seen by a hematologist, who performed blood studies and bone marrow biopsy without any positive findings. The hematologist concluded that the patient has anemia of chronic disease.

In addition to SS, the patient was also diagnosed with PG and HS. Three years after the patient’s initial presentation to the wound clinic, she was admitted to a hospital because of suspected left breast cellulitis/abscess. The result of the pathology report concluded PG. Two years later, the patient raised concerns about “recurrent furuncles of the peroneal and inguinal regions;” she was diagnosed with HS and started on doxycycline. There was no recurrence of HS lesions after that.

Over the course of 8 years, the patient was prescribed various therapeutic options, including oral corticosteroids combined with dapsone (adverse effect-skin rash), doxycycline (adverse effect-hives), colchicine, and sulfasalazine. She experienced only a few short, lesion-free periods, lasting no longer than 2 to 3 months. The minimal dose of prednisone able to maintain remission was 5 mg daily. Currently, the patient is on prednisone, metformin (started recently because the patient’s hemoglobin A1c level was 7.9%, a possible adverse effect of corticosteroids), colchicine, cefalexin (lifelong infection prophylaxis after bilateral hip replacement), risedronate (for osteoporosis), pregabalin 25 mg (for neuropathic pain), pantoprazole, and vitamins D and C.

In September 2021, the patient had a large circumferential ulcer on her lower right leg (Figure 1A, B). The wound size was 26.5 cm in circumference, 6.0 cm medially, 16.0 cm laterally, and 11.0 cm posteriorly. Surrounding skin was erythematous, with moderate serous exudate. The wound did not appear to be secondarily infected. The patient reported that pain was 8 to 9 out of 10 and both nociceptive and neuropathic in nature. Local wound care provided twice weekly included compresses with normal saline and Unna boot compression bandage (a zinc oxide paste boot), superabsorber, and rolled gauze. Tacrolimus ointment was applied to the surrounding skin. Compression therapy consisted of Comprilan short-stretch compression bandage (BSN Medical, Luxembourg, Luxembourg), ensuring 15- to 20-mm Hg compression on her left leg and zinc oxide paste boot on her right leg. On the back of her right lower leg, the patient had PG-type lesions that met one major and six minor diagnostic criteria for PG.14 The major criterion was a biopsy showing a neutrophilic infiltrate, whereas the minor criteria met were the exclusion of infection; pathergy; a history of vesicle ulcerating within 4 days of appearing; clinical signs of peripheral erythema, undermining border, and tenderness at ulceration site; multiple ulcerations, at least one on an anterior lower leg; and cribriform or “wrinkled paper” scars at healed ulcer sites.

F1
Figure 1:
CIRCUMFERENTIAL ULCER ON THE LOWER RIGHT LEGA, Lateral surface. B, Medial surface.

At a follow-up appointment 4 months later, the authors observed that the wound was smaller in size (circumference 19.5 cm, medially 8.0 cm, posteriorly 10.0 cm, laterally 11.5 cm), there was less erythema, wound edges were flattening, and exudate was scant serous (Figure 2A, B). The patient reported that pain was 2 to 3 out of 10, mostly related to the dressing change, and nociceptive in nature. The patient has been followed up regularly; her local wound care Unna boot compression bandage (a zinc oxide paste boot) was replaced with a lipo-colloid contact layer with silver.

F2
Figure 2:
CIRCUMFERENTIAL ULCER ON THE LOWER RIGHT LEG: 4-MONTH FOLLOW-UPA, Lateral surface. B, Medial surface.

The next considered treatment option negotiated with the patient was the biologic agent adalimumab. The patient expressed concerns about the adverse effect of immunosuppression and asked for time to discuss this modality with her family to make an informed decision.

DISCUSSION

Sweet Syndrome

Sweet syndrome was originally described by Dr Robert Douglas Sweet in 1964 as an “acute febrile neutrophilic dermatosis.”15 Over a period of 15 years, Dr Sweet encountered eight patients with what appeared to be a new dermatologic entity. They had four distinctive features:

  • 1. fever (100–102° F);
  • 2. neutrophil polymorphonuclear leukocytosis of the blood (white blood cell count around 12,000–23,000);
  • 3. raised painful plaques on the limbs, face, and neck; and
  • 4. a dense dermal infiltration with mature neutrophil polymorphs on histology.

In addition, there was no evidence of infection and rapid and dramatic response to corticosteroids. When no steroids were administered, the active phase of the disease was 1 to 2 months. After that time, the lesions were nontender and flattened and disappeared with some residual staining within the next 3 weeks, rarely lasting up to 6 months. There was no scarring. “Sweet syndrome” became the established eponym for this acute febrile ND, and other authors agreed that SS had enough distinctive features to classify it as a new entity.16

Over the next 15 years, Dr Sweet continued to analyze similar cases he has seen himself and published worldwide.17,18 Surprisingly, not all cases presented with fever and polymorphonuclear leukocytosis in the blood while manifesting with the characteristic morphologic appearance. Gunawardena et al19 also highlighted the essential characteristics of SS as morphology and histologic features together with immediate response to corticosteroid therapy and no scarring; fever and neutrophilic leukocytosis were found less frequently than high ESR. In 1986, Su and Liu20 proposed diagnostic criteria for SS, suggesting that a definite diagnosis of SS required both of the major criteria and at least two of the minor criteria (Table 1). In 1994, Von Den Driesch21 modified the minor diagnostic criteria for SS, with two major and at least two minor criteria required for SS diagnosis (Table 2). In 2017, Nofal et al22 proposed changing the terms “major criteria” to “constant features,” which would be required for the diagnosis of Sweet-like NDs, and “minor criteria” to “variable features,” whose absence does not warrant ruling out this condition. Consequently, Nofal et al22 suggested that the abrupt onset of painful erythematous plaques or nodules in association with a dense dermal neutrophilic infiltrate is sufficient to confirm the diagnosis of Sweet-like NDs, even in the absence of any variable features and irrespective of any underlying disorder or histologic subtype (Table 3).

Table 1 - DIAGNOSTIC CRITERIA FOR SWEET SYNDROME PROPOSED BY SU AND LIU IN 198620
Major Criteria Minor Criteria
1. Morphology: Abrupt onset of tender or painful erythematous or violaceous plaques or nodules 1. Plaques are preceded by fever, infections, or general malaise
2. Histology: Predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis 2. Plaques accompanied by fever, arthralgia, conjunctivitis, or underlying malignant diseasea
3. Leukocytosis
4. Patient exhibits good response to systemic steroid therapy
aThis may be best classified as neutrophilic dermatosis associated with malignancy due to a lack of classic definition of Sweet syndrome.

Table 2 - DIAGNOSTIC CRITERIA FOR SWEET SYNDROME MODIFIED BY VON DEN DRIESCH IN 199421
Major Criteria Minor Criteria
1. Abrupt onset of tender or painful erythematous plaques or nodules occasionally with vesicles, pustules, or bullae 1. Preceded by a nonspecific respiratory or gastrointestinal tract infection or vaccination or associated with inflammatory diseases such as chronic autoimmune disorders, infections, hemoproliferative disorders, solid malignant tumors, or pregnancy
2. Predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis 2. Accompanied by periods of general malaise and fever (>38° C).
3. Laboratory values during onset: erythrocyte sedimentation rate >20 mm; elevated C-reactive protein level; segmented-nuclear neutrophils and stabs >70% in peripheral blood smear; leukocytosis >8,000 (three of four of these values necessary)
4. Excellent response to treatment with systemic corticosteroids or potassium iodide

Table 3 - DIAGNOSTIC CRITERIA FOR SWEET SYNDROME PROPOSED BY NOFAL ET AL IN 201722
Constant Features Variable Features
Clinical: abrupt onset of painful or tender erythematous papules, plaques, or nodules Clinical:
(1) fever >38° C
(2) Atypical skin lesions (including hemorrhagic blisters, pustular lesions, cellulitis-like lesions)
Histopathologic: dense dermal neutrophilic infiltrate Histopathologic:
(1) Presence or absence of leukocytoclastic vasculitis
(2) Subcutaneous variant
(3) Histiocytoid variant
(4) Xanthomatoid variant
(5) Cryptococcoid variant
Laboratory:
(1) Elevated erythrocyte sedimentation rate
(2) Elevated C-reactive protein levels
(3) Leukocytosis
(4) Neutrophilia
(5) Anemia

Classic SS usually presents in women between the ages of 30 and 50 years. It is characterized by abrupt onset of fever and malaise, the appearance of tender erythematous plaques or nodules, histologic findings with predominantly neutrophilic dermal infiltration, and laboratory findings of peripheral neutrophilia, leukocytosis, or elevated ESR or C-reactive protein.7 The clinical manifestations of classic SS promptly respond to the administration of systemic corticosteroids; however, approximately one-third of patients will experience dermatosis recurrence.

Neutrophilic Dermatoses

Neutrophilic dermatoses can be idiopathic (classic), drug-induced, or associated with malignancy. Because the original SS was described as an idiopathic condition, drug-induced, inflammation-associated, and malignancy-associated NDs should be given names distinct from SS.

Cohen23 conducted a comprehensive review of acute febrile NDs and described the occurrence of other NDs and leukemia cutis prior to, simultaneously, and after the diagnosis in patients with NDs. He divided the associated conditions as probable, possible, and yet to be established. Among the probable associations are cancer (hematologic malignancies with acute myelogenous leukemia as the most common, and solid tumors with the most common carcinomas of the genitourinary organs, breast, and gastrointestinal tract),13,23,24 infections of the upper respiratory tract (streptococcus) and the gastrointestinal tract (salmonella and Yersinia), inflammatory bowel disease (IBD) including Crohn disease and ulcerative colitis, medications (eg, granulocyte colony-stimulating factor), and pregnancy. Possible associations were found with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease (Grave disease and Hashimoto thyroiditis).23

Throughout the disease course, more than one ND may appear in the same patient. Various NDs share similar clinical and pathologic features; however, the location of an inflammatory infiltrate, consisting of mature polymorphonuclear leukocytes, enables practitioners to differentiate them. For example, localization of neutrophilic infiltrate in epidermis distinguishes subcorneal pustular dermatosis, whereas an accumulation of eosinophils in the papillary and upper reticular dermis characterizes PG and EED.23 An ulcerative pattern is uncommon in Sweet-like ND (and when present may suggest hematologic malignancy); however, ulceration is not unusual in cases of PG.

Drug-Induced Neutrophilic Dermatoses

Drug-induced NDs most commonly occur in patients who have been treated with granulocyte colony-stimulating factor, followed from most to least common by retinoids (all trans-retinoic acid and 13-cis-retinoic acid), antibiotics (minocycline, nitrofurantoin, norfloxacin, ofloxacin, quinupristin/dalfopristin, trimethoprim-sulfamethoxazole), antineoplastics, antiepileptics (carbamazepine, diazepam), nonsteroidal anti-inflammatory drugs, contraceptives, antipsychotics, diuretics, antihypertensives, antithyroid hormone synthesis drugs, and anti-HIV drugs.23

Walker and Cohen25 proposed diagnostic criteria for drug-induced NDs in 1996 (all five criteria are required for the diagnosis):

  • 1. abrupt onset of tender or painful erythematous plaques or nodules;
  • 2. dense dermal neutrophilic infiltrate without leukocytoclastic vasculitis;
  • 3. fever >38° C;
  • 4. temporal relationship between drug ingestion and clinical presentation, or temporally related recurrence after oral challenge; and
  • 5. temporally related resolution of lesions following drug withdrawal or treatment with systemic corticosteroids.

Malignancy-Associated Neutrophilic Dermatoses

Malignancy-associated NDs can occur as a paraneoplastic syndrome in patients with established cancer or whose ND-related hematologic dyscrasia or solid tumor was previously undiscovered. The dermatosis can precede, follow, or appear concurrently with the diagnosis of the patient’s cancer. Hence, the malignancy-associated type can be the cutaneous harbinger of either an undiagnosed visceral malignancy in a previously cancer-free individual or an unsuspected cancer recurrence in an oncology patient.23

Two types of NDs, PG and Sweet-like NDs, are associated with myeloproliferative disorders that have received considerable attention in the literature, namely, vesicular-bullous and acute disseminated vesiculopustular forms of PG and atypical NDs (bullous, necrotizing).13 A retrospective review of 48 cases of Sweet-like NDs treated at the Mayo Clinic between 1980 and 1992 revealed that 26 of the 48 patients had a hematopoietic, plasma cell, or malignant disorder, and many of these patients had associated anemia. In addition, 14 patients had preexisting musculoskeletal diseases (including rheumatoid arthritis), IBD, or infectious disease (urinary tract infections, upper respiratory tract inflammatory, or viral pneumonia); only eight patients had no underlying disorders (idiopathic).24

The most frequently encountered ND-associated hematologic malignancy is acute myeloid leukemia. However, other malignancies have also been associated with NDs, including lymphoma (Hodgkin and non-Hodgkin), myelodysplastic syndromes, CLL, hairy cell leukemia, myeloma, acute lymphocytic leukemia, and myeloproliferative disorders (chronic myeloid leukemia, agnogenic myeloid metaplasia/myelofibrosis, and polycythemia). Cancers of the genitourinary organs, breast, and gastrointestinal tract are the most frequently occurring ND-associated solid tumors. Some other reports include head and neck organs, pulmonary carcinoma, melanoma, and tumors with unknown primaries.26–29

Pyoderma Gangrenosum

Pyoderma gangrenosum usually occurs between the ages of 11 and 89 years. The classic variant starts as a pustule that develops into a rapidly enlarging painful ulcer with violaceous, undermined borders; surrounding erythema; and a purulent base. Several clinical variants of PG have been recognized: ulcerative, vesicular-bullous (atypical), pustular, and superficial granulomatous/vegetative. Associated systemic diseases and comorbidities were documented in 33% to 75% of patients. They include IBD, rheumatoid arthritis, asymmetric seronegative monoarticular arthritis, Behçet disease, other inflammatory or autoimmune conditions, non-Hodgkin lymphoma, a monoclonal gammopathy (typically IgA), and risk of development of multiple myeloma, leukemia, myeloproliferative diseases, and solid tumors.30,31

Following the introduction of diagnostic criteria by Maverakis et al14 and based on the Delphi method from the world’s leading experts, PG is no longer a diagnosis of exclusion. Receiver operating characteristic analysis revealed that four of eight minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively. Thus, a PG diagnosis requires one major criterion—biopsy of ulcer edge demonstrating neutrophilic infiltrate–and at least four of the eight minor criteria: (1) exclusion of infection (histology); (2) pathergy; (3) history of IBD or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least one on an anterior lower leg; (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). A skin biopsy is necessary to confirm a diagnosis of PG and exclude other diagnoses and infectious etiologies. An adequate biopsy is excisional down to the subcutaneous tissue, obtaining enough tissue for histology and culture to rule out infection (bacteria, fungi, and mycobacteria). Laboratory tests should include analyzing and detecting abnormalities in complete blood count, ESR, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies, basic metabolic panel, serum protein electrophoresis, coagulation panel, antiphospholipid antibodies cryoglobulins, cryofibrinogen, chest X-ray, and colonoscopy, as well as venous and arterial studies.

Von Den Driesh32 observed 44 patients (30 women and 14 men) with PG for 20 years. Of these, 20 patients had idiopathic PG, 14 had parainflammatory course (IBD), and 10 had PG associated with neoplastic or hemoproliferative conditions. Interestingly, over the 20-year follow-up period, no patients with idiopathic PG were diagnosed with any possibly related disease, suggesting that PG is not a cutaneous complication of underlying comorbidities but an independent disease.

Pyoderma gangrenosum and Sweet-like NDs are classified as NDs because they exhibit neutrophilic dermal infiltrate without or with little evidence of a primary vasculitis. Overall, PG and Sweet-like NDs have more common features than differences: neutrophilic infiltrate; altered immunologic reactivity; associations with malignancy, particularly hematologic; development after granulocyte colony-stimulating factor therapy; pathergy; response to immunosuppressives; and reports of coexistence in a single patient.33 However, the typical forms of these two conditions are quite distinct: PG presents with cutaneous ulceration with a purple, undermined border, whereas Sweet-like lesions are tender, erythematous, nonulcerated plaques and nodules. In clinical practice, it is not rare to observe the appearance of atypical forms of these two conditions, and concurrent and/or sequential existence of both make their diagnosis challenging.

Although NDDH is distinct from classic PG, it bears a resemblance to atypical vesiculobullous PG (hemorrhagic bullous lesions, ulcerating superficially and located on the dorsal hands), as well as bullous or atypical Sweet-like NDs.34 Characteristically, PG involves the lower extremities as deeper ulcers with overhanging borders and often excruciating pain. Histologically, atypical PG is distinguished from typical PG by the frequent presence of a diffuse neutrophilic infiltrate with associated vascular changes and, therapeutically, by faster remission. Each of these features of atypical PG is similar to NDDH. It is likely that many of the cases termed atypical SS or PG-Sweet overlap and belong to the spectrum of NDs. Cases are now increasingly recognized as NDDH when present in this distribution.7,33,35 Atypical NDs have been reported to occur frequently in patients with hematologic malignancy, and many of the published photographs of cancer-associated Sweet-like NDs closely resemble lesions of NDDH seen in the presence and absence of malignancy. Owing to the similarities of bullous SS and atypical PG, pustular vasculitis of the hands was proposed to be a variant of atypical PG.7

Cases originally described as SS lacked vasculitis, although a vascular injury might occur secondary to intense neutrophilic infiltrate and the accompanying enzymatic and cytokine cascade. This agrees with two histologic series that identified mild leukocytoclastic vasculitis or vasculitis-like changes in 18% to 30% of patients with typical SS. Malone et al36 reviewed the presence of vasculitis in Sweet-like NDs with the timing of the biopsy and found that vasculitis correlated with lesions of longer duration. Indeed, initial skin biopsy of the patients with NDDH may show a negative result for vasculitis with a subsequent positive biopsy result, suggesting a difference in lesion timing or sampling rather than a fundamental change in the disease process.7 Cohen37 and Cohen and Kurzrock38 have argued that vasculitis in Sweet-like NDs and NDDH is an epiphenomenon in which the damaged vessel is an “innocent bystander” of an inflammatory dermatosis. Although the clinicopathologic features (papillary dermal edema, brisk neutrophilic infiltrate, and leukocytoclastic vasculitis) and responsiveness to corticosteroid therapy suggest acute febrile ND, some authors have called this presentation pustular vasculitis to reflect the vascular damage.39

Lear et al33 highlighted clinical and histopathologic similarities between the lesions of SS and PG, particularly atypical bullous PG, which make it challenging to distinguish between these two conditions. It has been suggested that PG and Sweet-like NDs may represent a continuum of the spectrum of disease resulting from a single pathophysiologic phenomenon, the common denominator being an inflammatory process mediated by neutrophils. This spectrum may range from classic to atypical Sweet-like NDs to atypical to classic PG.33

Pathophysiology

The pathophysiologic hallmark of NDs is neutrophil-mediated inflammation that is initiated by the overproduction of interleukin 1β (IL-1β), which triggers the release of proinflammatory cytokines and chemokines and induces the recruitment and activation of neutrophils.5 In the lesions of HS, dysregulation of IL-1β, IL-17, and cytokines indicates an autoinflammatory process. Lima and colleagues’40 findings support the autoinflammatory origin of HS, demonstrating the localization and expression of autoinflammation-associated molecules (IL-17, caspase-1, the danger-associated molecular pattern molecules S100A8 and S100A9) in the lesions of HS. Further, it has been shown that IL-17+ cells present in perilesional skin at the early stages of HS, where they trigger the release of IL-1β by keratinocytes and initiate skin inflammation.

Similarly, overexpression of IL-1β and IL-17 was detected in two prototypic NDs (PG and SS) and in a syndromic variant of HS (PASH). Lima et al40 also discovered a dense infiltrate of neutrophils in the later stage of HS. Thus, HS can be included in the spectrum of NDs as part of the growing family of autoinflammatory diseases.41

Neutrophil-mediated skin conditions can be attributed to a spectrum of polygenetic autoinflammatory conditions based on the discovery of multiple mutations of autoinflammatory genes. Both SS and PG are prototypic forms of NDs with features that significantly overlap with autoinflammatory disorders, manifesting with the repeated episodes of sterile inflammation without high titers of circulating autoantibodies and autoreactive T cells. Pathogenesis of NDs involves dysfunctional cellular signaling mediated by the inflammasome pathway, IL-1, IL-17, and other effector molecules.5 However, the precise pathophysiologic mechanism of neutrophil-mediated skin diseases has not yet been fully elucidated, hindering the discovery of tailored treatments for patients with different NDs.

CASE REPORT TREATMENT

The described patient has three coexisting conditions: PG, Sweet-like NDs, and HS. Hidradenitis suppurativa is a chronic inflammatory disease affecting hair follicles. Clinically, HS presents with deep, painful nodules that often result in abscesses and sinus tracts with suppuration and leave hypertrophic scars. This debilitating disease affects approximately 1% of the population. The coexistence of HS and PG has been described in the spectrum of autoinflammatory syndromes such as PASH, PAPASH, and PsAPASH. In addition, SAPHO might also be associated with PG or HS.8–12

Most NDs require therapeutic intervention to normalize flare and achieve remission. Therapeutic modalities range from systemic corticosteroids to biologic agents.1,3 Mainstream treatment for Sweet-like NDs includes oral corticosteroids and topical or intralesional steroids. Alternatives to corticosteroid treatment include colchicine, dapsone, doxycycline, sulfasalazine, clofazimine, nonsteroidal anti-inflammatory agents, and cyclosporine. Management of PG includes treatment of PG lesions and underlying diseases because up to two-thirds of patients have associated conditions. Treatment options are based on the severity and extent of the PG lesions, patient preference, and comorbidities. Potent topical and intralesional corticosteroids can be sufficient for patients with limited PG. Other topical agents encompass topical tacrolimus and pimecrolimus, sodium cromoglycate, nicotine, and topical dapsone.

Pain management and local wound care are essential elements of managing patients with PG. In more severe diseases, systemic therapy with oral corticosteroids or steroid-sparing immunosuppressive agents such as cyclosporine may be needed. Other systemic treatments involve colchicine, sulfasalazine, dapsone, minocycline, apremilast, and thalidomide. Biologic therapy is a novel modality for recalcitrant disease.30,42

Treatment of HS depends on the stage and severity of the disease. At the early stage and benign course of the disease, topical and systemic anti-inflammatory drugs are beneficial. More severe variants of HS require immunosuppressive agents (tumor necrosis factor α blockers), and patients with advanced and recalcitrant lesions may benefit most from surgical treatments—the only effective curative therapy for HS–including incision and drainage, deroofing and marsupialization, limited local excision, and radical wide excision.43,44

CONCLUSIONS

Of the wide array of NDs, most are idiopathic, but NDs can also be associated with malignancy and inflammatory conditions or induced by medications. Further, NDs may have a relapsing and remitting course and coexist and overlap with each other. Even though NDs’ treatment modalities bear some similarities and focus on immunosuppression, healthcare practitioners need to recognize various NDs, their subsets, and their established associations to diagnose them correctly and exclude associated malignancies.

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Keywords:

drug-induced; hidradenitis suppurativa; idiopathic; malignancy; neutrophilic dermatoses; pyoderma gangrenosum; Sweet syndrome

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