Drug-induced and malignancy-associated neutrophilic dermatoses in patients with hematologic malignancies: A single institution experience.

INTRODUCTION: Neutrophilic dermatoses (NDs) often occur secondary to inflammatory conditions, medication exposure, and hematologic malignancy. While malignancy-associated NDs (MA-NDs) have been well-reported among those with hematologic cancers, little is known about drug-induced NDs (DI-NDs) within this population. The objective of this study is to compare the presentations and outcomes of patients with hematologic malignancies who developed MA-NDs and DI-NDs. METHODS: Cases of neutrophilic dermatosis (ND) occurring between 2013 and 2023 among those with hematologic malignancies were identified from the electronic medical records of our institution. Patient characteristics, recent medication exposures, cancer mutations, and disease outcomes were reviewed. Patients were categorized with drug-induced ND (DI-ND) if they were recently exposed to one of four medications known to be commonly associated with ND or were otherwise categorized with malignancy-associated ND (MA-ND). We report a descriptive analysis of cases of DI-ND and MA-ND. RESULTS: We identified 52 patients with ND and co-occurring hematologic malignancy including 16 cases of DI-ND (30.8%) and 36 cases of MA-ND (69.2%). The most common ND in both groups was Sweet's syndrome. Chronic underlying conditions including solid tumors, inflammatory disorders, chronic viral infection, and tobacco use were more common among those with MA-ND. Among those with DI-ND, tyrosine kinase inhibitors were the most commonly associated drugs (43.8%). The most common cancer mutation among those with DI-ND was FLT3 (43.8%) while the most common mutation among those with MA-ND was TP-53 (19.4%). Among those who had died at the time of data collection, 90.0% of those with DI-ND and 66.7% of those with MA-ND died within one year of ND diagnosis. CONCLUSION: Most cases of ND occurring with hematologic malignancies develop secondary to cancer rather than drug exposure. Different cancer mutations may predispose to DI-ND and MA-ND. Further research is needed to establish diagnostic criteria for DI-ND and to determine the pathogenic role of specific cancer mutations, particularly FLT3, in the development of ND.

Anti-nuclear matrix protein 2 antibody-positive amyopathic dermatomyositis presenting in a patient with prostate cancer: A case report.

Nuclear matrix protein (NXP-2) positive amyopathic dermatomyositis (DM) may present without classic symptoms like muscle weakness, dysphagia, and edema, and mimic conditions like cutaneous lupus. Given DM's association with malignancy and interstitial lung disease, prompt and accurate diagnosis is important. Testing for myositis-specific antibodies aids diagnosis in ambiguous cases.

Approach to the Atypical Wound.

The heterogeneity of atypical wounds can present diagnostic and therapeutic challenges; however, as the prevalence of atypical wounds grows worldwide, prompt and accurate management is increasingly an essential skill for dermatologists. Addressing the underlying cause of an atypical wound is critical for successful outcomes. An integrated approach with a focus on pain management and patient engagement is recommended to facilitate enduring wound closure. Advances in treatment, in addition to further research and clinical training, are necessary to address the expanding burden of atypical wounds.

IL-12/IL23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis causing chronic and recalcitrant painful ulcerations. Pathogenic mechanisms are yet poorly understood limiting therapeutic options, however, IL-12/IL-23 inhibition via ustekinumab has previously been associated with positive outcomes. We aimed to elucidate the dysregulated immune landscape of PG and lesional skin changes associated with IL-12/IL-23 blockade. We applied spatial transcriptomics and comparative computation analysis on lesional biopsies from two patients obtained before and after IL-12/IL-23 blockade with ustekinumab. Our data indicate lesional PG skin exhibits complex patterns of inflammation, including a not previously described major infiltration of B cells and establishment of tertiary lymphoid structures. In both patients, IL-12/IL-23 blockade led to marked clinical improvement but was associated with amelioration of contrasting inflammatory pathways. Notably, plasma cell markers and tertiary structures were recalcitrant to the treatment regime suggesting that B cells might play a role in the refractory nature of PG.

Pyoderma Gangrenosum of the Genitalia, Anus, and Perineum: Two Case Reports and a Review of Published Cases.

ABSTRACT: Pyoderma gangrenosum is an inflammatory skin disease that presents with rapidly progressive ulcers with violaceous, undermined borders. Despite most commonly affecting the lower extremities, pyoderma gangrenosum can rarely present in the genital, anal, and perineal regions. We describe two cases and report a review of published cases.

Inflammatory and vaso-occlusive ulcers: Part I - clinical presentation and diagnosis.

In this CME, we review two specific categories of ulcers: inflammatory (where inflammation is the primary pathologic process leading to ulceration) and vaso-occlusive (where occlusion is the primary process). Inflammatory ulcers include pyoderma gangrenosum and vasculitides, whereas livedoid vasculopathy, calciphylaxis and Martorell ulcers are vaso-occlusive ulcers. Determining the causes of ulcers in these conditions may require laboratory evaluation, biopsy and imaging.

Inflammatory and vaso-occlusive ulcers: Part II - Management.

In the second part of this CME, we present an approach for the management of inflammatory and vaso-occlusive ulcers and highlight the need for further research in this field. The three overarching principles for management are etiology-specific treatment, ulcer care, and consideration of patient comorbidities and risk factors for poor healing. Both etiology-specific treatment and management of patient comorbidities and risk factors often require collaboration with providers from other specialties. Ulcer care is governed by TIME, or tissue debridement, infection control, management of moisture imbalance and epithelial edge advancement. As wound healing is a dynamic process, management should be adapted to changes in the status of the ulcer.

Perioperative management and clinical outcomes of peristomal pyoderma gangrenosum.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum mainly affecting stoma sites of patients with inflammatory bowel disease. While surgical treatments are often used to assist healing, little is known about the relationship between surgical interventions and the rate of recurrence of peristomal pyoderma gangrenosum. The aim of this study was to identify patient and clinical factors associated with peristomal pyoderma gangrenosum recurrence following surgical intervention. A multi-institutional retrospective case series and literature review was conducted to evaluate patient characteristics and perioperative treatment. Patients of any age with peristomal pyoderma gangrenosum undergoing surgical operations related to their pyoderma gangrenosum or due to another comorbidity were included. Descriptive statistics were used to characterize demographic information. Associations were evaluated using Wilcoxon's rank-sum test for continuous variables and Fisher's exact test for categorical data. Thirty-seven cases were included, 78.3% of which had a history of inflammatory bowel disease. Overall, 13 (35.1%) cases experienced recurrence at 30 days. There was no significant association identified between patient demographics, stoma location, surgical intervention, or perioperative treatment with rate of recurrence at 30 days post-operation. While no clinical risk factors or treatments were associated with recurrence, our work underscores the importance of a multidisciplinary approach to this disease to address gastrointestinal, dermatologic, and surgical components of treatment.

Deep Vein Thrombosis and Healing Outcomes in Patients With Pyoderma Gangrenosum.

This single-center prospective case-control study assessed the association between deep vein thrombosis and healing outcomes in patients with pyoderma gangrenosum.

Mortality and Autopsy Findings in Patients with Pyoderma Gangrenosum: A Multi-Institutional Series.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with an increased risk of mortality compared to the general population. The causes of this increased risk are not well understood. Misdiagnosis is common in PG, and many studies are limited by the inclusion of misdiagnosed cases. The goal of this study was to review autopsy findings, identify causes of death, and identify factors that may worsen outcomes among deceased patients confirmed to have PG. METHODS: Data was retrospectively reviewed from the electronic medical records at five academic hospitals. A search was conducted for deceased patients with a diagnosis of PG who had an autopsy performed between 2010 and 2020. We report a descriptive analysis of 11 patients and their clinical characteristics, causes of death, and autopsy findings. RESULTS: The average age of death was 62.9 years. Seven patients had at least one underlying condition known to be associated with PG including inflammatory bowel disease, inflammatory arthritis, or a hematologic disorder. The most common cause of death was infection (n = 6, 54.5%), followed by pulmonary embolism (n = 3, 27.3%), and myelodysplastic syndrome (n = 2, 18.2%). Six patients (54.5%) were taking systemic steroids at the time of death. CONCLUSION: The development of PG may shorten life expectancy among those with underlying conditions associated with PG, and common treatments for PG may contribute to the risk of fatal complications. Awareness of the risk of infection, thrombosis, and malignancy among those with PG is necessary for proper management. Further research is needed to explore the relationship between PG and thromboembolism.

A core domain set for pyoderma gangrenosum trial outcomes: an international eDelphi and consensus study from the UPGRADE initiative.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. OBJECTIVES: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. METHODS: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. RESULTS: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. CONCLUSIONS: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.

Evaluation of Inclusion and Exclusion Criteria for Pyoderma Gangrenosum in Clinical Research: A Systematic Review.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare, inflammatory dermatologic disease that, as a diagnosis of exclusion with nonspecific histologic features, is difficult to diagnose. As pharmaceutical interest in potential treatments for PG increases, the need for standardized diagnostic criteria to ensure reproducibility, comparability, and external validity of PG research is required. In this study, we aim to characterize the inclusion and exclusion criteria used in the diagnosis of PG in clinical research studies as well as the eligibility of PG in clinical trials. METHODS: A systematic review was conducted to characterize the PG inclusion and exclusion criteria in research studies. An additional search of the USA and international clinical trials databases was conducted as well to capture eligibility criteria for PG trials. RESULTS: Our study revealed a broad range of inclusion and exclusion criteria used to establish the presence or absence of PG. Based on eight distinct categories used to characterize inclusion criteria for research studies, diagnosis by a dermatologist (n = 25, 31.6%), no inclusion criteria listed (n = 21, 26.6%), and clinical and histopathologic features consistent with PG (n = 20, 25.3%) were most common. For current clinical trials, six categories were used to characterize inclusion criteria, of which clinical and histopathologic features consistent with PG (n = 5, 31.3%), identification based on diagnosis of PG (n = 4, 25.0%), and clinical features consistent with PG (n = 3, 18.8%) were the most common. CONCLUSION: This systematic literature review highlights the range of heterogeneity in diagnostic and eligibility criteria used in PG-directed clinical research and current clinical trials and illustrates the need for the development of consensus guidelines and a rigorous framework to enable high-quality future trials for PG.

What can inherited immunodeficiencies reveal about pyoderma gangrenosum?

Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.