Acute myeloid leukaemia presenting with ecthyma gangrenosum as the first manifestation: A case report.

RATIONALE: Ecthyma gangrenosum (EG) is an uncommon cutaneous infection usually associated with Pseudomonas aeruginosa bacteremia in immunocompromised patients, particularly those with underlying malignant diseases. Despite its rarity, especially in immunocompetent or nondiagnosed immunodeficiency patients, EG can present as the first manifestation of an underlying immunosuppression. PATIENT CONCERNS: A 42-year-old Japanese man was admitted to our hospital with a 3-day history of a painless red macule on his right forearm and fever. DIAGNOSES: Blood culture on admission revealed the presence of Pseudomonas aeruginosa, whereas pus culture of the skin lesion showed Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus positivity. INTERVENTIONS: Additional bone marrow aspirate examination and immunophenotyping were performed to confirm the diagnosis of acute promyelocytic leukaemia with PML-retinoic acid alpha receptor. OUTCOMES: The patient was successfully treated with a 14-day course of antibiotics, and no evidence of relapse was noted. The patient achieved complete remission after treatment for acute promyelocytic leukaemia. LESSONS: It should be kept in mind that EG is an important cutaneous infection that is typically associated with P aeruginosa bacteremia and the presence of underlying immunodeficiency, such as acute leukaemia.

Pyoderma gangrenosum associated with levamisole-adulterated cocaine in a c-ANCA positive patient.

Pyoderma gangrenosum (PG) is an inflammatory, ulcerative condition that is characterized by painful ulcers that commonly present on the lower extremities. Up to half of PG cases are associated with underlying systemic disease, including inflammatory bowel disease, various autoimmune conditions, and malignancy. Another well-known association is the manifestation of PG with recreational cocaine use, especially cocaine contaminated with the adulterant agent levamisole. Once utilized for its immunomodulatory capabilities, levamisole was withdrawn from the market in 2002. It has since been repurposed to potentiate the amphetamine-like effects and duration of cocaine and has reduced preparation cost. We present a 52-year-old woman with chronic maxillary sinusitis and cocaine use disorder presenting with a two-week history of painful ulcers on bilateral lower extremities, each with a purulent base and undermined, violaceous borders. Urine toxicology was positive for cocaine and serologic studies were positive for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and lupus anticoagulant. Underlying conditions, especially that of granulomatosis with polyangiitis, were considered and ultimately ruled out. The patient's lesions exhibited a marked response with a short course of oral corticosteroids, typical of PG associated with levamisole. This case highlights the crucial role that drug abstinence plays in the prevention of recurrence.

Pyoderma Gangrenosum Occurring in the Setting of Hypercortisolism Associated With Adrenocortical Adenoma: A Pathophysiological Paradox.

Pyoderma gangrenosum (PG) is a challenging, rare, ulcerating skin disease characterized by neutrophilic abundance and absence of infection, often associated with systemic diseases. We present a 25-year old previously healthy female with a 1.5-year history of treatment refractory PG. Features of Cushing’s syndrome such as facial plethora, striae, and lipodystrophy were noted on exam, which prompted several studies that ultimately revealed an adrenal adenoma. Following surgical excision of the adenoma, symptoms rapidly resolved and systemic immunosuppressants were discontinued. This rare case highlights the importance that adrenal adenoma and resultant Cushing’s syndrome may be a driver of PG despite the pathophysiologic paradox. J Drugs Dermatol. 2021;20(1):95-97. doi:10.36849/JDD.5566.

Novel Therapeutic Approaches and Targets for the Treatment of Neutrophilic Dermatoses, Management of Patients with Neutrophilic Dermatoses and Future Directions in the Era of Biologic Treatment.

Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders characterized by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. Universally accepted and validated guidelines for the management of neutrophilic dermatoses do not exist, also given the paucity of randomized controlled study and high-quality data. However, the literature on the effective use of biologic therapies is rapidly expanding. This article reviews the epidemiology, clinical characteristics, histopathologic features, and management of pyoderma gangrenosum as well as Sweet's syndrome, sub-corneal pustular dermatoses and bowel-associated dermatosis arthritis syndrome. The use of biologic agents, including tumor necrosis factor α-inhibitors, anti-IL1, anti-IL-17, and IL-23 are discussed in detail.

Surgical Treatment of Pyoderma Gangrenosum with Negative Pressure Wound Therapy and Skin Grafting, Including Xenografts: Personal Experience and Comprehensive Review on 161 Cases.

Significance: Pyoderma gangrenosum (PG) is a rare debilitating autoinflammatory ulcerative skin disease. No gold standard has been established for the treatment of PG. The role of surgical interventions and negative pressure wound therapy (NPWT) was discussed controversially until recently as these procedures might pose a trigger to further aggravate the condition. Recent Advances: Recent advances confirm the paradigm change that a surgical approach of PG with split thickness skin grafting (STSG) secured by NPWT is a safe and valuable treatment if performed under adequate immunosuppression. We elaborate this on the hand of a broad literature search retrieving 101 relevant articles describing 138 patients complemented with our personal experience on 23 patients, including 2 patients treated with a porcine xenodressing. Critical Issues: A wide range of surgical approaches have been reported, including xenografts. Treatment was finally successful in 86%, including the xenotransplant cases. Ten percent improved and failures were mainly reported without immunosuppression. Despite halting the inflammatory process, NPWT alone, without skin grafting, does not much accelerate healing time. The best surgical approach appears to be STSG fixed with NPWT as this leads to higher skin graft take. There remains the problem of the chronic nature of PG and the recurrence after tapering of immunosuppression or trauma; therefore, a sustained immunosuppressive treatment is suggested. Future Directions: While surgical treatment is supported by the published data, the exact immunosuppression is still evolving. Due to deeper insights into pathogenesis and growing clinical reports, a broader utilization of biologic treatments and a shift from tumor necrosis factor (TNF)-alpha to interleukin (IL)-12/23 or IL-23 antibodies alone are predictable, as IL-12/23 antibodies show good clinical responses with fewer side effects. The positive results with porcine xenodressings might be due to immunological effects of the xenomaterial; they appear promising, but are preliminary and should be confirmed in a larger patient collective.

IL-17E (IL-25) Enhances Innate Immune Responses during Skin Inflammation.

IL-17E (IL-25) is a member of the IL-17 cytokine family involved in the promotion of type 2 immune responses. Recently, IL-17E has been reported to be up-regulated in distinct skin inflammatory diseases such as psoriasis and atopic and contact dermatitis. We assessed the role played by IL-17E in skin inflammation. Here, we show that IL-17E induces skin inflammation in vivo, characterized by the expression of innate immune response genes and the recruitment of innate immune cells, particularly neutrophils. Genetic deletion or IL-17E neutralization ameliorated skin inflammation induced by imiquimod application or tape stripping, with reductions in neutrophil and macrophage infiltration as assessed by t-distributed stochastic neighbor embedding-guided multiparameter flow cytometry analysis, in mice. In humans, IL-17E promotes the recruitment of neutrophils via activation of macrophages in a p38-dependent mechanism. In addition, IL-17E is up-regulated in neutrophil-rich inflammatory skin diseases, such as pyoderma gangrenosum and acute generalized exanthematous pustulosis. Our data show a role for IL-17E in skin inflammation that is unrelated to the development of type 2 immune reactions. We propose that IL-17E is an important common denominator of chronic skin inflammation, promoting innate immune cell recruitment and activation.

Pyoderma gangrenosum and tumour necrosis factor alpha inhibitors: A semi-systematic review.

Pyoderma gangrenosum (PG) is a rare ulcerative skin disease that presents a therapeutic challenge. Tumour necrosis factor alpha (TNFα) inhibitors have been reported to successfully control PG. Our aim was to systematically evaluate and compare the clinical effectiveness of TNFα inhibitors in adults with PG. A literature search including databases such as PubMed, Embase, Scopus, and Web of Science was conducted, using search terms related to PG and TNFα inhibitors. Studies and case reports were included if patients were diagnosed with PG, over the age of 18 and administered TNFα inhibitor. A total of 3212 unique citations were identified resulting in 222 articles describing 356 patients being included in our study. The study we report found an 87% (95% CI: 83%-90%) response rate and a 67% (95% CI: 62%-72%) complete response rate to TNFα inhibitors. No statistically significant differences in the response rates (P = 0.6159) or complete response rates (P = 0.0773) to infliximab, adalimumab, and etanercept were found. In our study TNFα inhibitors demonstrated significant effectiveness with response and complete response rates supporting the use of TNFα inhibitors to treat PG in adults. Our study suggests that there is no significant difference in effectiveness among infliximab, adalimumab, and etanercept.

A dermatologic perspective on autoinflammatory diseases.

Autoinflammatory diseases (AIDs) encompass a heterogeneous group of disorders pathogenetically related to an abnormal activation of the innate immunity and clinically characterised by aseptic inflammation in the affected organs in the absence of high titer of circulating autoantibodies or autoreactive T cells. In classic monogenic AIDs, the skin is frequently involved with a wide range of cutaneous lesions. Monogenic AIDs result from different mutations in a single gene, which regulates the innate immunity. These mutations cause an uncontrolled activation of the inflammasome, leading to an overexpression of interleukin (IL)- 1ß. IL-1ß is the pivotal cytokine which is responsible for the exaggerated production of cytokines and chemokines that induce the recruitment of neutrophils, key cells in autoinflammation. Paradigmatic autoinflammatory forms are the cryopyrin-associated periodic syndromes (CAPS), whose skin involvement consists of urticarial lesions. Similar IL-1ß-mediated autoinflammatory pathomechanisms also occur in deficiency of IL-1 receptor antagonist (DIRA) and deficiency of IL-36 receptor antagonist (DITRA), whose cutaneous appearance is characterised by pustular lesions, as well as in pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. Pyoderma gangrenosum, which is the cutaneous hallmark of the PAPA syndrome, is a prototypic neutrophil-mediated skin disease, manifesting as single or multiple ulcers with undermined, raised erythematous to violaceous borders. This review is focused on the CAPS, DIRA/DITRA and PAPA syndromes with emphasis on their cutaneous manifestations, as well as their histology and pathophysiology.

A Comprehensive Review of Neutrophilic Diseases.

Neutrophilic dermatoses are a group of conditions characterized by the accumulation of neutrophils in the skin and clinically presenting with polymorphic cutaneous lesions, including pustules, bullae, abscesses, papules, nodules, plaques and ulcers. In these disorders, the possible involvement of almost any organ system has lead to coin the term 'neutrophilic diseases'. Neutrophilic diseases have close clinicopathological similarities with the autoinflammatory diseases, which present with recurrent episodes of inflammation in the affected organs in the absence of infection, allergy and frank autoimmunity. Neutrophilic diseases may be subdivided into three main groups: (1) deep or hypodermal forms whose paradigm is pyoderma gangrenosum, (2) plaque-type or dermal forms whose prototype is Sweet's syndrome and (3) superficial or epidermal forms among which amicrobial pustulosis of the folds may be considered the model. A forth subset of epidermal/dermal/hypodermal forms has been recently added to the classification of neutrophilic diseases due to the emerging role of the syndromic pyoderma gangrenosum variants, whose pathogenesis has shown a relevant autoinflammatory component. An increasing body of evidence supports the role of pro-inflammatory cytokines like interleukin (IL)-1-beta, IL-17 and tumour necrosis factor (TNF)-alpha in the pathophysiology of neutrophilic diseases similarly to classic monogenic autoinflammatory diseases, suggesting common physiopathological mechanisms. Moreover, mutations of several genes involved in autoinflammatory diseases are likely to play a role in the pathogenesis of neutrophilic diseases, giving rise to regarding them as a spectrum of polygenic autoinflammatory conditions. In this review, we focus on clinical aspects, histopathological features and pathophysiological mechanisms of the paradigmatic forms of neutrophilic diseases, including pyoderma gangrenosum, Sweet's syndrome, amicrobial pustulosis of the folds and the main syndromic presentations of pyoderma gangrenosum. A simple approach for diagnosis and management of these disorders has also been provided.

T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a rare, immune-mediated skin disease classified into the group of neutrophilic dermatoses. Although a number of studies confirmed the central role of innate immunity, only few studies have investigated the possible contributing role of acquired immunity. In particular, no reports concerning T helper type 1 (Th1) and Th2 cells are available as yet. Therefore, 15 patients with PG, five with Sweet's syndrome (SS) and nine skin specimens from healthy controls (HC) were investigated, evaluating the expression of Th1-related markers interleukin (IL)-12, interferon (IFN)-γ, C-X-C motif chemokine receptor 3 (CXCR3) and C-C motif chemokine receptor 5 (CCR5), of the Th2-related molecules IL-4, IL-5, IL-13 and CCR3, of the co-stimulatory axis CD40/CD40 ligand, of IL-15 and the natural killer (NK) cell marker CD56 in skin lesions by immunohistochemistry. Patients with PG and SS showed a higher expression of Th1 markers than HC. Conversely, IL-5- and CCR3-expressing cells were less numerous in PG skin lesions compared to SS (P = 0·0157 and < 0·0001, respectively). Both CD40 and CD40L were expressed more in PG than in SS and HC (P < 0·0001 for both). Finally, the number of IL-15+ and CD56+ cells was higher in the skin of patients with PG than in those of SS and HC (P < 0·0001 for both). Our results suggest that Th2 cells are down-regulated in PG. At the same time, over-expression of the co-stimulatory axis CD40/CD40L amplifies the impairment of the Th1/Th2 balance. Both these findings might explain the most aggressive behaviour of PG in comparison to SS. Moreover, over-expression of IL-15+ and CD56+ cells may suggest a possible role of NK cells in the pathogenesis of the disease.

PAPA, PASH and PAPASH Syndromes: Pathophysiology, Presentation and Treatment.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis usually manifesting as skin ulcers with undermined erythematous-violaceous borders. It may be isolated, associated with systemic conditions or occurring in the context of autoinflammatory syndromes such as PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis) or PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis). From a physiopathological point of view, all these conditions share common mechanisms consisting of over-activation of the innate immune system leading to increased production of the interleukin (IL)-1 family and 'sterile' neutrophil-rich cutaneous inflammation. From a genetic point of view, a number of mutations affecting the proteins of the inflammasome complex (the molecular platform responsible for triggering autoinflammation) or the proteins that regulate inflammasome function have been described in these disorders. As these debilitating entities are all associated with the over-expression of IL-1 and tumour necrosis factor (TNF)-α, biological drugs specifically targeting these cytokines are currently the most effective treatments but, given the emerging role of IL-17 in the pathogenesis of these syndromes, IL-17 antagonists may represent the future management of these conditions.

Pyoderma gangrenosum-a novel approach?

Pyoderma gangrenosum (PG) represents a rare skin disorder, with several clinical variants and still not fully understood ethiopathogenesis. Often associated with inflammatory or neoplastic disease, PG is nowadays considered an inflammatory neutrophilic disease with common underlying morbidity. Modern treatment options are oriented towards key mechanisms underlying the pathogenesis of the disease, namely inflammatory mediators, and seem to be the most effective treatment currently available. Although promising, the results are not invariable and these treatments are sometimes surrounded by controversy, as recent studies have reported cases that are refractory to therapy with biological agents. It is possible that refractoriness to the use of biological agents as monotherapy stems from the fact that a single agent is not able to affect the entire inflammatory cascade, or to simultaneously influence all of its levels. Based on the pathogenesis of inflammation, we can suggest that an ideal targeted therapy should be able to induce the following changes: 1) reduction of the secretion of interleukin (IL)-1a/b from the inflammasome with subsequent blocking of its biological effect (by therapy with IL-1 receptor antagonists); 2) blocking of the activation of the secreted procytokines in their active form (by therapy with caspase-1 inhibitors; 3) blocking of the effect of the already released active cytokines (by therapy with tumour necrosis factor alpha, TNF-α, inhibitors); 4) blocking of the effector action of the cytokines on the target intracellular molecules (by therapy with kinase inhibitors). The specific therapy should aim to attack more than one link in the inflammatory cascade, in order to achieve maximum therapeutic effectiveness. Most surely, this could be achieved with combined therapy with different groups of biological agents (for example a combined therapy with IL-1 receptor antagonist and a TNF-α inhibitor). Currently, no data in the literature exist to support this statement, and there are no safety data relating to such approaches. We focus this review on the novel etiopathogenetic concepts of PG and the future therapeutic approaches based on blocking different levels of the inflammatory cascade, which seems to be the most promising weapon in the target-oriented treatment options.

Alarming consequences - autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1.

PURPOSE OF REVIEW: To give an overview about the expanding spectrum of autoinflammatory diseases due to mutations in proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) and new insights into their pathogenesis. RECENT FINDINGS: In addition to classical pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome has been described as a distinct clinical phenotype of PSTPIP1-associated inflammatory diseases (PAID) and other entities are emerging. In addition to dysregulation of IL-1ß release from activated PAPA monocytes that requires NLR family, pyrin domain containing 3 (NLRP3), PSTPIP1 mutations have an general impact on cellular dynamics of cells of the innate immune system. In addition, overwhelming expression and release of the alarmins myeloid-related protein (MRP) 8 and 14 by activated phagocytes and keratinocytes, which promote innate immune mechanisms in a Toll like receptor (TLR) 4-dependent manner, are a characteristic feature of these diseases and form a positive feed-back mechanism with IL-1ß. SUMMARY: Autoinflammatory diseases due to PSTPIP1 mutations are not restricted to the classical PAPA phenotype but might present with other distinct clinical features. MRP8/14 serum levels are a hallmark of PAPA and PAMI and can be used as screening tool to initiate targeted genetic testing in suspected cases. The feedback mechanism of IL-1ß and MRP-alarmin release may offer novel targets for future therapeutic approaches.