Amicrobial pustulosis of the folds: A case report of a rare variant of neutrophilic dermatosis associated with systemic lupus erythematosus.

Amicrobial pustulosis of the folds (APF) is a rare neutrophilic dermatosis found in association with autoimmune diseases. We present a 49-year-old woman with a history of systemic lupus erythematosus and a recurrent pustular eruption in the cutaneous folds. Histologic examination revealed spongiform pustulosis and dermal neutrophilic infiltrate. The Gram and periodic acid-Schiff stains were negative for bacteria and fungi. A diagnosis of amicrobial pustulosis of the folds was given. While there is no standard treatment, our patient's symptoms resolved following an oral prednisone taper and have not recurred since starting colchicine. The presence of pustules and erosive plaques in skin folds in young women with autoimmune conditions should raise suspicion for APF. The combination of localized neutrophilic spongiosis with intraepidermal or subcorneal pustules in conjunction with dermal changes of a neutrophilic dermatosis is a helpful clue to the diagnosis. If the patient does not already have a diagnosis of an underlying autoimmune condition, a presentation of APF should prompt further screening consisting of a relevant review of symptoms and appropriate assessment for autoimmune antibodies, since APF may precede the diagnosis of autoimmune disorders.

Adjunctive hyperbaric oxygen treatment for challenging pyoderma gangrenosum cases.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare, difficult-to-treat neutrophilic ulcerative cutaneous condition that severely impacts those affected. Treatment options for PG are limited, and disease remission is not guaranteed. Hyperbaric oxygen treatment is a potential therapeutic option for treating various ulcerative conditions not frequently utilized for PG. CASE REPORT: We present a case of a patient with treatment-resistant PG who achieved remission with adjunctive HBOT, and then later had difficulty achieving remission without HBOT during a future flare. DISCUSSION: HBOT should be more readily considered as a treatment option for those with PG.

Characterisation of IL-1 family members in Sweet syndrome highlights the overexpression of IL-1ß and IL-1R3 as possible therapeutic targets.

Sweet syndrome (SS) as a prototypic neutrophilic dermatosis (NDs) shares certain clinical and histologic features with monogenic auto-inflammatory disorders in which interleukin (IL)-1 cytokine family members play an important role. This has led to the proposal that NDs are polygenic auto-inflammatory diseases and has fuelled research to further understand the role of IL-1 family members in the pathogenesis of NDs. The aim of this study was to characterise the expression of the IL-1 family members IL-1ß, IL-36γ, IL-33 and IL-1R3 (IL-1RaP) in SS. The expression profile of IL-1ß, IL-33, IL-36γ and their common co-receptor IL-1R3 was analysed by immunohistochemistry, in situ hybridisation and double immunofluorescence (IF) in healthy control skin (HC) and lesional skin samples of SS. Marked overexpression of IL-1ß in the dermis of SS (p < 0.001), and a non-significant increase in dermal (p = 0.087) and epidermal (p = 0.345) IL-36γ expression compared to HC was observed. Significantly increased IL-1R3 expression within the dermal infiltrate of SS skin samples (p = 0.02) was also observed, whereas no difference in IL-33 expression was found between SS and HC (p = 0.7139). In situ hybridisation revealed a good correlation between gene expression levels and the above protein expression levels. Double IF identifies neutrophils and macrophages as the predominant sources of IL-1ß. This study shows that IL-1ß produced by macrophages and neutrophils and IL-1R3 are significantly overexpressed in SS, thereby indicating a potential pathogenic role for this cytokine and receptor in SS.

Skin disorders and interstitial lung disease: Part II-The spectrum of cutaneous diseases with lung disease association.

Part 2 of this 2-part CME introduces dermatologists to noninfectious inflammatory skin diseases associated with pulmonary involvement. In many cases, dermatologists may be the first physicians recognizing respiratory complications associated with these diagnoses. Because pulmonary involvement is often the leading cause of morbidity and mortality, dermatologists should be comfortable screening and monitoring for lung disease in high-risk patients, recognizing cutaneous stigmata of lung disease in these patients and referring to pulmonary specialists, when appropriate, for prompt treatment initiation. Some treatments used for skin disease may not be appropriate in the context of lung disease and hence, choosing a holistic approach is important. Interstitial lung disease and pulmonary hypertension are the most common pulmonary complications and a significant cause of mortality in autoimmune connective tissue diseases, especially systemic sclerosis, dermatomyositis, and mixed connective tissue disease. Pulmonary complications, notably interstitial lung disease, are also common and life-threatening in sarcoidosis and vasculitis, while they are variable in neutrophilic and autoimmune blistering diseases.

Sweet Syndrome: A Review of Published Cases.

Sweet syndrome (SS), the prototypical neutrophilic dermatosis, is characterized by abrupt onset of tender plaques and nodules, classically accompanied by fever and leukocytosis. While management mainly relies on systemic corticosteroids, inadequate response can be seen in some patients that necessitates exploring other treatment options. Early diagnosis of malignancy-associated SS (MA-SS) along with detection of concomitant malignancy is crucial for improving patients' outcomes. Data regarding various clinical manifestations, extracutaneous associations, treatment, and outcomes are poorly characterized in the literature. We aimed to review all published case reports and case series to portray clinical features of SS including extracutaneous manifestations. We also describe reported treatment options and their outcomes to draw attention toward unmet therapeutic needs in the management of SS. In addition, for clinical and practical purposes, we attempted to delineate the distinction between MA-SS and nonmalignant subtypes of SS.

Reactive Neutrophilic Dermatoses in Adult-Onset Immunodeficiency due to Interferon-Gamma Autoantibody and Their Associated Factors.

BACKGROUND: Adult-onset immunodeficiency (AOID) due to interferon-gamma autoantibody is a rare, acquired immunodeficiency disease. Reactive neutrophilic dermatoses (RND), predominantly Sweet syndrome (SS), and generalized pustular eruption have been reported repeatedly. OBJECTIVES: The aims of this study were to describe the cutaneous manifestations in AOID patients and determine the incidence of RND and associated factors using a larger population size than have been previously reported. METHODS: A retrospective chart review of all confirmed AOID cases in Chiang Mai University Hospital from January 2006 to June 2020 was conducted. The demographics and characteristics of RND including type, onset, and laboratory information in every episode of cutaneous manifestations were collected. Generalized estimating equations of binary logistic regression were used to determine the indicators of RND. RESULTS: A total of 146 patients with confirmed AOID were identified. Of these, 57 cases (39%) developed at least one episode of RND. Thirteen cases (23%) of the patients experienced RND twice during the follow-up period. All recurrence of RND displayed the same cutaneous phenotype, with the exception of 2 cases who had both SS and generalized pustular eruption. Finally, 49 episodes of SS and 22 episodes of generalized pustular eruption were included in the analysis. All patients with RND had concomitant active opportunistic infections, of which most were non-tuberculous mycobacterium (NTM) infection. NTM infection (prevalence odds ratio [POR] 2.87), lymphadenopathy (POR 3.30) as well as lower serum alkaline phosphatase (ALP) level (POR 0.71 for every 100-unit increment in ALP) were found to be significantly associated with RND occurrence. CONCLUSIONS: 39% of our AOID patients experienced RND once during the course of the disease. Notable factors associated with RND occurrence were concomitant NTM infection, lymphadenopathy, and lower level of ALP.

Intravenous immunoglobulin treatment for refractory pyoderma gangrenosum.

BACKGROUND: Intravenous immunoglobulins (IVIG) have been increasingly used for various inflammatory dermatoses with success. Small case series and case reports suggest a role for IVIG in the management of refractory pyoderma gangrenosum (PG). OBJECTIVE: The objective was to study the characteristics of PG patients treated with IVIG and the efficacy and safety of IVIG for patients with refractory PG. METHODS: An analysis was performed of all patients with PG treated with IVIG from 2012 to 2022 at an Australian tertiary hospital seeing a high volume of PG patients. RESULTS: We identified 12 patients, 9 females and 3 males, with median age of 61 years (29-77) at IVIG commencement. All patients were taking systemic corticosteroid therapy prior to IVIG treatment, and all had been treated with a steroid-sparing agent-including ten patients who had been treated with a biologic agent. IVIG was used with corticosteroids in one patient, concurrently with a steroid-sparing agent in nine patients and with a biologic agent in eight patients. Eleven patients demonstrated treatment response to IVIG-six with excellent response and five with good response. Three patients had complete healing of their most active ulcer. One patient did not respond to IVIG. Nine patients were able to wean their prednisolone dose and one patient was able to cease prednisolone. Four adverse events were recorded, and only one patient had to cease treatment due to aseptic meningitis and headaches. CONCLUSION: Our experience suggests that IVIG may be an efficacious treatment for patients with refractory PG due to its pleiotropic and immunomodulatory effects, particularly for patients with malignancy or other systemic conditions where high-dose immunosuppressive agents are contraindicated.

Characterizing the presence of neutrophil extracellular traps in neutrophilic dermatoses.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of multiple inflammatory dermatoses. However, characterization of NETs in neutrophilic dermatoses was performed on very limited number of patients; this limitation precluded definitive conclusions. In this case series of 57 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different entities of neutrophilic dermatoses (17 with pyoderma gangrenosum, 37 with Sweet's syndrome and three with subcorneal pustular dermatosis). NETs were identified by double immunofluorescence on formalin-fixed paraffin-embedded skin biopsies using antibodies against elastase and citrullinated histone 3. Percentages of neutrophils showing NETs were high across all three entities (62.9% in PG, 48.5% in SS and 37.8% in subcorneal pustular dermatosis). The differences in mean percentages were significant between entities, with PG showing significantly superior percentage of NETs compared with SS. In our series, 15.8% of neutrophilic dermatoses were associated with malignancies, 10.5% with autoimmune diseases and 73.7% were idiopathic. Percentages of NETs were not statistically different between aetiologies. These findings suggest that NETs are abundantly produced in the various entities and different aetiologies of neutrophilic dermatoses. In comparison with SS, the superior percentage of NETs in PG is clinically mirrored in its greater ulceronecrotic nature.

Evaluation of neutrophil extracellular trap deregulated formation in pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a neutrophilic dermatose (ND) characterized by a dense neutrophilic infiltrate in the affected tissue. Neutrophil extracellular traps (NETs) are web-like structures released by neutrophils and composed of cytosolic and granule proteins assembled on a scaffold of decondensed chromatin. Very little is known about the role of NETosis in PG. Here, we assessed the possible implication of NETosis in the pathogenesis of PG by investigating the NETosis in the ulcers of 26 PG patients. We demonstrated that neutrophils in the PG skin lesions undergo an aberrant level of NETosis in 100% of the analysed cases (N = 26). All control and abscess biopsies were instead negative for the NETosis. In addition, neutrophils from peripheral blood of PG patients showed a significantly higher rate of spontaneous, but not induced, NETosis. Overall, this study suggests that the NETosis may contribute to systemic inflammation and tissue destruction in PG, thus representing a possible novel therapeutic target.

Skin changes in hairy cell leukemia.

Skin lesions have been reported in about 10-12% of hairy cell leukemia (HCL) patients. Most are etiologically related to autoimmune or infectious processes, although secondary cutaneous neoplasms and drug-induced lesions are also reported. However, leukemia cutis with the direct infiltration of the skin by leukemic cells is extremely rare in HCL patients. This paper reviews the epidemiology, pathogenesis, clinical symptoms, diagnosis, and approach to treating skin lesions in HCL. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skin lesions, leukemia cutis, adverse events, infectious, cutaneous, drug reactions, neutrophilic dermatoses, secondary neoplasms, and vasculitis was conducted via PubMed. Publications from January 1980 to September 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Superficial Granulomatous Pyoderma Gangrenosum Involving the Face: A Case Series of Five Patients and a Review of the Literature [Formula: see text].

BACKGROUND: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by painful and ulcerating lesions on the skin. It rarely involves the face and is often difficult to diagnose. There are few cases reported in the literature of PG involving the face. AIM: To share our experience with 5 patients in whom the final diagnosis was PG involving the face, and to review the literature. METHODS: We report a series of 5 patients with a final diagnosis of PG involving the face and reviewed relevant literature. We searched through PubMed andEMBASE using keywords such as "face" and "pyoderma gangrenosum," "blastomycosis-like pyoderma gangrenosum, vegetative pyoderma gangrenosum and granulomatous pyoderma gangrenosum." RESULTS: We report 5 patients (4 females) with pyoderma gangrenosum involving the face. All 5 had a final diagnosis of superficial granulomatous PG. All cases presented with nonhealing facial ulcer most commonly on cheeks and a common histopathology of mixed inflammatory infiltrates, multinucleated giant cells, and plasma cells with some granulomatous inflammation. CONCLUSIONS: PG can involve the face, and all 5 of our patients had the superficial granulomatous as the most common form.

Dapsone in a Large Tertiary Center: Outdated Therapeutic Option or Timeless Agent?

BACKGROUND: The ancient drug dapsone has antimicrobial and anti-inflammatory features. In dermatology, dapsone is primarily used for neutrophil-dominant skin diseases. However, real-life data assessing the long-term efficacy of dapsone across multiple dermatological diseases is missing. -Objectives: To determine the efficacy and safety of dapsone in patients with inflammatory skin diseases treated at the Department of Dermatology of the University Hospital Zurich. METHODS: The hospital database was searched for patients treated with dapsone in the last 20 years (from January 1, 1998, to December 31, 2017). Overall, 175 patients were included in our study. RESULTS: Thirty-four patients received dapsone for eosinophilic dermatoses, 82 for neutrophilic dermatoses and 59 for other dermatoses. After 3 months, 8% of all patients reached complete remission, 40.6% showed improvement, 30.3% had stable disease, and only 9.1% had disease progression. Final treatment evaluation revealed complete response in 13.2%, disease improvement in 47.4%, stable disease in 25.7% and disease progression in only 12.0%. Patients who showed remission or improvement after 3 months were significantly older than patients with stable or progressive disease. In addition, remission after 3 months was associated with a significantly lower dose of dapsone compared to improvement only. Hemolysis was the most common adverse event (21.7%). CONCLUSIONS: Our data show that dapsone is a valid treatment option in various dermatological diseases, leading to a favorable response in the vast majority of patients. In addition, it is well tolerated, safe and inexpensive. Randomized, controlled trials are needed to further elucidate the role of this high-potential drug.

Idiopathic, Refractory Sweet's Syndrome Associated with Common Variable Immunodeficiency: a Case Report and Literature Review.

PURPOSE OF REVIEW: Sweet's syndrome (SS) is classically considered a hypersensitivity reaction often associated with autoimmune disorders and malignancy. SS has also been increasingly reported to occur with immunodeficiencies. We present a case of treatment-refractory, systemic SS as the initial manifestation in a young child with common variable immunodeficiency (CVID). We also review current literature about SS and concurrent immunodeficiencies and autoimmunity in CVID patients. RECENT FINDINGS: Few case reports exist regarding the co-occurrence of Sweet's syndrome and primary immunodeficiencies. SS is characterized by a pro-inflammatory state with a neutrophil predominance resulting in a spectrum of clinical manifestations. CVID is a multifactorial antibody deficiency that can be associated with autoimmunity, which some studies have proposed to be secondary to altered CD21 expression. SS occurring in patients with CVID has been infrequently reported, and one case study demonstrated improvement of Sweet's associated skin lesions with immunoglobulin replacement. In our case, the patient had multi-system SS refractory to multiple immunomodulatory therapies. To our knowledge, this is the first report of the effective and safe use of intravenous tocilizumab and oral lenalidomide to treat SS in a child with CVID. Immunoglobulin replacement reduced the frequency of infections and may have contributed to the opportunity to wean the immunosuppressive therapies for Sweet's syndrome. Sweet's syndrome as an initial manifestation of co-occurring immunodeficiencies is rare, and providers need a high index of suspicion. In addition, treatment of SS associated with an immunodeficiency can be a challenge. Treatment with immunoglobulin replacement reduces the frequency of infections, and in some patients with concurrent SS may improve skin lesions and reduce the need for immunomodulator therapy. Further study is necessary to better understand the pathogenesis of CVID in patients with SS and to identify possible biomarkers that predict who with SS are at risk for developing hypogammaglobulinemia.

Erosive pustular dermatosis of the scalp: A neutrophilic folliculitis within the spectrum of neutrophilic dermatoses: A clinicopathologic study of 30 cases.

BACKGROUND: It is general opinion that histopathology is nonspecific and of little value in diagnosing erosive pustular dermatosis of the scalp (EPDS). OBJECTIVES: Clinicopathologic correlation of erosive pustular dermatosis of the scalp. METHODS: We reviewed the clinical and pathologic records of patients with a clinicopathologic diagnosis of EPDS between 2011 and 2016 at the Dermatopathology Unit of Turin University. RESULTS: Thirty elderly patients with EPDS were identified (22 men and 8 women). Androgenetic alopecia was present in 19 of 30 patients. Triggering factors included mechanical trauma in 10 of 30 cases, surgical procedures in 4 of 30 cases, and herpes zoster in 1 of 30 cases. Three patients were affected by autoimmune disorders. The vertex was the most common location. Disease presentation varied markedly from tiny, erosive, scaly lesions to crusted and hemorrhagic plaques, mimicking pustular pyoderma gangrenosum. The pathologic changes differed according to lesion type and disease duration. Interestingly, a spongiotic and suppurative infundibulo-folliculitis was observed in 8 of 30 cases. LIMITATIONS: This was a retrospective study. CONCLUSIONS: We believe that the primary lesion of erosive pustular dermatosis of the scalp is a spongiotic, pustular superficial folliculitis. The clinicopathologic similarities with other neutrophilic dermatoses, such as pustular pyoderma gangrenosum, suggest this condition should be included in this spectrum, where pathergy plays a pathogenetic role.

Pentoxyfilline as a treatment for subcorneal pustular dermatosis.

Subcorneal pustular dermatosis (SPD) is a rare pustular neutrophilic dermatosis in which groups of sterile pustules appear in the superficial (subcorneal) skin. This chronic condition can be associated with significant morbidity and decreased quality of life. Dapsone is the first-line therapy for SPD, but some patients fail to respond or cannot tolerate it. In these instances, patients may be treated with second-line therapies such as phototherapy, topical corticosteroids, or systemic agents including glucocorticoids, acitretin, immunosuppressive, or biologic medications. These therapies may not always be efficacious and can be associated with intolerable adverse effects. Here, we report a case of a patient who sustained long-term remission and no side effects with the novel use of pentoxifylline, a tumor necrosis factor-alpha inhibitor, as monotherapy. Pentoxifylline should be considered as a possible therapy in patients with SPD intolerant to dapsone.

Rheumatoid neutrophilic dermatitis.

Rheumatoid neutrophilic dermatitis is a rare extra-articular manifestation of rheumatoid arthritis, both seropositive and seronegative for rheumatoid factor. The condition most often presents as symmetric erythematous papules, nodules, plaques, and urticaria-like lesions in patients with severe, long-lasting rheumatoid arthritis. We report a case of a 65-year-old man with well-controlled rheumatoid arthritis, who developed rheumatoid neutrophilic dermatitis on the right lower leg. The biopsy of skin lesions revealed an intense, neutrophilic dermal infiltrate, microabscesses, and leukocytoclasis without vasculitis. The patient responded well to pulses of intravenous methylprednisolone. We present this patient due to the rarity of the disease and atypical unilateral manifestation involving the flexural surfaces of the lower leg.

Ocular pyoderma gangrenosum: A systematic review.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare, ulcerative cutaneous disorder. Ophthalmic involvement in PG is atypical, but can have devastating consequences. OBJECTIVE: We sought to characterize ocular PG to allow for earlier diagnosis and therapy. To our knowledge, this is the first systematic review summarizing this clinical variant. METHODS: A systematic review was conducted using PubMed and Web of Science. Data were extracted and studies were qualitatively assessed and analyzed. RESULTS: We identified all 34 cases of PG involving the eye and periorbital area, and categorized them into 4 different subtypes. Common presenting signs include ulceration, peripheral ulcerative keratitis, and decreased visual acuity. Although it is often difficult to biopsy ocular PG, histologic features are nonspecific. Combined therapy using corticosteroids and further surgical reconstruction as needed is the mainstay of treatment. Cases of the eye/orbit in particular should be treated aggressively, as these are more likely to relapse compared with cases of the periorbital area. LIMITATIONS: Use of case reports, paucity of ocular PG cases, and heterogeneity of studies are limitations. CONCLUSION: PG should be considered in the differential diagnosis of ulceration of ocular/periocular tissues. An aggressive, early, multimodal treatment strategy should be used to prevent relapse, especially in cases of the eye/orbit.