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.

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 2 cases and report a review of published cases.

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.

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.

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 was to compare the presentations and outcomes of patients with hematologic malignancies who developed MA-NDs and DI-NDs. METHODS: Cases of 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 DI-ND if they were recently exposed to one of four medications known to be commonly associated with ND or were otherwise categorized with 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 1 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.

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.

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.

Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

BACKGROUND: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. METHODS: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. RESULTS: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. CONCLUSIONS: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.

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.

Pyoderma gangrenosum study pilot registry: The first step to a better understanding.

The objective of this study was to develop a pilot physician driven patient pyoderma gangrenosum (PG) registry to summarise patient baseline demographics, PG-related medical history, treatments, and outcomes for patients with pyoderma gangrenosum. Standardised patient information was collected prospectively during clinical encounters between December 2019 and July 2021 at a single academic institution. Eligibility criteria for the study was a diagnosis of pyoderma gangrenosum determined by a PARACELSUS score of at least 10 for ulcerative patients. Main outcome measures included demographic data, PG related history and comorbidities, past and current treatments, healing outcomes, hospitalisations and recurrences of PG. The Pyoderma Gangrenosum Study (PYGAS) Registry currently includes 52 patients with 56 target lesions of four distinct PG subtypes (41 ulcerative, 12 peristomal, 2 vegetative and 1 bullous). For the 38 patients with 41 total ulcerative PG lesions, referrals to our institution most commonly came from dermatologists (42.1%). The median follow-up time in our initial registry was 5.5 months (95% CI = 4.1-11.5 months), with average time between follow-up visits at 1.1 months. These ulcers were most commonly treated with first-line systemic immunosuppressants (70.6%), such as corticosteroids or cyclosporine. Additional use of systemic immunomodulators at baseline visit was statistically significantly associated with healing (P = 0.048). This pilot study suggests that use of systemic immunomodulators has an impact on healing of PG patients. Wound care regimens are variable, and assessing their impact on treatment outcomes could be challenging. Standardisation of both wound care regimens and data collection in prospective clinical studies is necessary to assess their impact in PG treatment outcomes.

Calciphylaxis: Treatment and outlook-CME part II.

Calciphylaxis is a rare and devastating condition with important systemic ramifications. This second-part of our CME aims to educate the practicing dermatologist on the current standard of care once a diagnosis of calciphylaxis is confirmed or highly suspected. The key pathologic findings, as well as the role and limitations of biopsy, are reviewed. We aim to guide readers through the complex hospitalization and posthospitalization management of these medically vulnerable patients. Collaboration with other specialists will be discussed. Experimental and developing treatments are discussed, and the outlook of the condition is reported.

Calciphylaxis: Part I. Diagnosis and pathology.

Calciphylaxis is an uncommon but devastating disorder characterized by vascular calcification and subsequent cutaneous tissue necrosis. This results in exquisitely painful and slow healing wounds that portend exceptionally high morbidity and mortality. The diagnosis of this condition can be complicated because there are no conclusive serologic, radiographic or visual signs that this disease is manifesting. The differential of tissue necrosis is broad, and identifying calciphylaxis requires an adroit understanding of the risk factors and physical signs that should raise suspicion of this condition. Reviews on this subject are uncommon and lack directed commentary from disease experts on the best diagnostic approach for patients suffering from this disease. The goal of this article is to update practicing dermatologists on the current standard of care for calciphylaxis.

International Dermatology Outcome Measures (IDEOM): Report from the 2020 Annual Meeting.

BACKGROUND: The International Dermatology Outcome Measures (IDEOM) initiative is a non-profit organization that aims to develop evidence-based outcome measurements to evaluate the impact of treatments for patients with dermatological disease. IDEOM includes all key stakeholders in dermatology (patient, physician, industry, insurer, and government) during the process of developing such outcome measurements. SUMMARY: Here, we provide an update of IDEOM activities that were presented at the 2020 IDEOM Virtual Annual Meeting (October 23-24, 2020). During the meeting, multiple IDEOM workgroups (psoriasis, psoriatic arthritis, hidradenitis suppurativa, acne, pyoderma gangrenosum, and actinic keratosis) shared their progress to date, as well as future directions in developing and validating Patient-Reported Outcome Measures. Updates on demonstrating efficacy in clinicals trials by the US Food and Drug Administration are also summarized. KEY MESSAGES: In this report, we summarize the work presented by each IDEOM workgroup (psoriasis, psoriatic arthritis, hidradenitis suppurativa, acne, pyoderma gangrenosum, and actinic keratosis) at the 2020 IDEOM Virtual Annual Meeting.

Characterization of Legal Claims Involving Patients with Pyoderma Gangrenosum.

OBJECTIVE: To review the litigation literature related to patients with pyoderma gangrenosum (PG) to characterize the legal issues they face. DATA SOURCES: Data sources include law databases Casetext and Lexis Nexis. STUDY SELECTION: All disability and medical liability claims directly involving patients with PG were included. DATA EXTRACTION: Data extraction came directly from Casetext and Lexis Nexis. All cases extracted came from September 1965 to December 2020. This resulted in 32 cases, 18 of which were excluded because they did not mention the plaintiff having a diagnosis of PG (n = 14). DATA SYNTHESIS: The review found a total of six medical liability cases in which adverse health outcomes were reported, including prolonged suffering (2/6 cases), unnecessary treatments or procedures (2/6), exacerbation of disease (1/6 cases), and permanent scarring (1/6 cases). Despite this, two plaintiffs won their case and only one of them received any monetary award. Similarly, of the eight disability claims in the review, four were ruled in the favor of the plaintiffs and only two resulted in immediate awarding of benefits. Half of medical liability cases occurred in correctional facilities after the denial of appropriate care. CONCLUSIONS: The findings demonstrate a need for access to specialty care in incarcerated populations. Cases that occurred in a hospital setting also stress the importance of initiatives such as telemedicine to efficiently increase access to care in a cost-effective manner. Further, PG has been recognized as a severe impairment in disability claims despite patients being denied because they were deemed able to perform other work.

Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes.

IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.

Treatment of pyoderma gangrenosum: A multicenter survey-based study assessing satisfaction and quality of life.

Pyoderma gangrenosum (PG) lacks consensus regarding treatment, and no prior studies assess treatment satisfaction in PG. The objective of this study was to determine patient-reported satisfaction in the treatment of PG, and associations with satisfaction. Methodology was a multicenter cross-sectional survey for patients who received systemic medication(s) to treat PG. Thirty-five patients completed the survey (mean age: 54.0 years, 65.7% female, response rate: 81.4%). Mean (± SD) SATMED-Q score was 75.0 (±16.2, range: 67.6-85.3). Older patients (72.6 ± 23.6 for 18-39 years, 74.4 ± 16.1 for 40-59, 77.1 ± 11.6 for 60+), plus those with higher incomes (72.9 ± 20.3 for $0-49 000; 74.0 ± 17.6 for $50 000-99 000; 79.0 ± 14.6 for $100 000+) and education status (69.4 ± 14.3 for high school equivalent, 72.9 ± 15.9 for undergraduate, 91.7 ± 10.6 for graduate), were more satisfied with treatment. Ulcerative PG had higher SATMED-Q scores (79.0 ± 13.2) than other subtypes (66.2 ± 19.3). For local therapy, wound care, or pain control, 63.2%, 100%, and 75% were satisfied, respectively. The mean DLQI was 8.6 (±7.6, range: 0-29), and higher DLQI was associated with decreased satisfaction. Satisfaction with providers was positively correlated with global satisfaction (Pearson's r = 0.638). The presence of pain and/or depression influenced both SATMED-Q (72.8 ± 18.8 with pain, 78.3 ± 11.2 without; 68.2 ± 18.8 with depression, 80.1 ± 12.2 without) and DLQI scores (12.1 ± 8.1 with pain, 3.9 ± 3.4 without; 10.3 ± 7.1 with depression, 7.4 ± 8.0 without). To optimize the patient experience, non-modifiable associations should be individually considered, and potentially modifiable associations such as satisfaction with specific providers, pain, and depression, may be targeted for management.

The utility and challenges of histopathologic evaluation in the diagnosis of nonmalignant skin ulcers.

Histopathologic evaluation of cutaneous ulcers is indicated when the clinical diagnosis is unclear or when ulcers have not responded to standard of care. Many nonmalignant skin ulcers lack specific histologic findings on biopsy and pose a diagnostic challenge. While the usefulness of skin biopsies to diagnose underlying malignancy in ulcerated lesions has been demonstrated in previous studies, their utility in the diagnosis of ulcers of other etiologies has not been reported. We conducted a retrospective study of 45 nonmalignant ulcer biopsies in a 3-year period to compare the histologic diagnosis with the final diagnosis. Additionally, we assessed the diagnostic concordance among three blinded dermatopathologists when reviewing these cases. The leading histologic diagnosis from each of the three observers agreed with the final clinical diagnosis, on average, for 29.6% of the cases (average pairwise kappa = 0.15). Inflammatory ulcers had the lowest concordance between the observers and final diagnosis with an average of 26.0% of cases (average pairwise kappa = 0.06). The observers agreed with each other for 35.6% of the cases (Fleiss' kappa = 0.32). The highest agreement among observers was in the vascular/vasculopathic category (50%, Fleiss' kappa = 0.44). Our results indicate that skin biopsies alone are useful in the evaluation of nonmalignant ulcers to rule out other conditions (e.g. neoplasm) but frequently not sufficient to establish a definitive diagnosis. Additional clinicopathologic correlation is necessary in the final assessment of nonmalignant ulcers to determine the diagnosis. Future research endeavors should explore alternative approaches to more efficiently diagnose nonmalignant skin ulcers.

Perioperative management of pyoderma gangrenosum.

Pyoderma gangrenosum (PG) classically presents with an acute inflammatory stage, characterized by rapid evolution of painful ulcerations. The pathergy associated with PG lesions complicates disease management. Although PG is commonly treated with immunosuppression, some patients have refractory noninflammatory ulcers. In this subpopulation, there are case reports of successful surgical treatment. However, there is no consensus on optimal perioperative treatment for patients with PG undergoing surgery of any kind, PG related or otherwise. Therefore, we conducted a comprehensive literature review describing perioperative management practices and risk factors that may predict response to surgical intervention. We identified 126 cases of surgical intervention in patients with active PG; among these, only 16.7% experienced postoperative disease progression. No perioperative treatments or clinical risk factors were identified as statistically significant predictors of disease recurrence. Although limited by case series design and publication bias, this study is a valuable means of hypothesis generation for this rare condition.

Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions with high morbidity and mortality. Supportive care management of SJS/TEN is highly variable. A systematic review of the literature was performed by dermatologists, ophthalmologists, intensivists, and gynecologists with expertise in SJS/TEN to generate statements for supportive care guideline development. Members of the Society of Dermatology Hospitalists with expertise in SJS/TEN were invited to participate in a modified, online Delphi-consensus. Participants were administered 9-point Likert scale questionnaires regarding 135 statements. The RAND/UCLA Appropriateness Method was used to evaluate and select proposed statements for guideline inclusion; statements with median ratings of 6.5 to 9 and a disagreement index of ≤1 were included in the guideline. For the final round, the guidelines were appraised by all of the participants. Included are an evidence-based discussion and recommendations for hospital setting and care team, wound care, ocular care, oral care, urogenital care, pain management, infection surveillance, fluid and electrolyte management, nutrition and stress ulcer prophylaxis, airway management, and anticoagulation in adult patients with SJS/TEN.

Ulcerative C2 neurocutaneous dysesthesia (trigeminal trophic syndrome in an alternative distribution).

Trigeminal trophic syndrome is an uncommon condition characterized by paresthesia, itch, and self-inflicted wounds following the trigeminal dermatome(s). Similar processes adhering to cervical nerve distributions have been reported, calling into question the specificity of trigeminal trophic syndrome for the trigeminal network. Herein, we report patient with trigeminal trophic syndrome adhering to the C2 dermatome, a previously unreported distribution.