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Journal of Clinical Immunology Jul 2023Loss-of-function (LOF) mutations in NFKB1, coding for p105, may cause common variable immunodeficiency due to dysregulation of nuclear factor kappa-light-chain-enhancer...
Loss-of-function (LOF) mutations in NFKB1, coding for p105, may cause common variable immunodeficiency due to dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κΒ) pathway. Monoallelic LOF variants of NFKB1 can predispose to uncontrolled inflammation including sterile necrotizing fasciitis or pyoderma gangrenosum. In this study, we explored the impact of a heterozygous NFKB1 c.C936T/p.R157X LOF variant on immunity in sterile fasciitis patients and their family members. The p50 or p105 protein levels were reduced in all variant carriers. Interleukin-1β (IL-1β) and interleukin-8 (IL-8) levels were elevated in vitro, potentially contributing to the very high neutrophil counts observed during fasciitis episodes. Phosphorylation of p65/RelA was reduced in p.R157X neutrophils suggesting defective activation of canonical NF-κB. Oxidative burst after NF-κB-independent phorbol 12-myristate 13-acetate (PMA) stimulation was similar in both p.R157X and control neutrophils. Comparable amounts of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex subunits were found in p.R157X and control neutrophils. However, a compromised oxidative burst was observed in p.R157X neutrophils following activation of NF-κB-dependent mechanisms following stimulation of toll-like receptor 2 (TLR2) and Dectin-1. Neutrophil extracellular trap formation was not affected by p.R157X. In summary, the NFKB1 c.C936T/p.R157X LOF variant has an impact on inflammation and neutrophil function and may play a role in the pathogenesis of sterile necrotizing fasciitis.
Topics: Humans; NF-kappa B; Neutrophils; Fasciitis, Necrotizing; Respiratory Burst; Inflammation; NF-kappa B p50 Subunit
PubMed: 36892687
DOI: 10.1007/s10875-023-01461-3 -
BioRxiv : the Preprint Server For... Apr 2024Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis causing chronic and recalcitrant painful ulcerations. Pathogenic mechanisms are yet poorly understood...
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.
PubMed: 38746177
DOI: 10.1101/2024.04.26.591387 -
Frontiers in Veterinary Science 2023Dogs with allergic dermatitis often suffer concurrent skin and ear infections. The objective of this study was to retrospectively quantify the number of systemic and...
INTRODUCTION
Dogs with allergic dermatitis often suffer concurrent skin and ear infections. The objective of this study was to retrospectively quantify the number of systemic and topical antimicrobial transactions in dogs with allergic dermatitis, following administration of oclacitinib or a glucocorticoid, compared to dogs that did not receive a pruritus therapy when there is an initial diagnosis of pyoderma. A secondary objective was to demonstrate that dogs on oclacitinib use fewer antimicrobials and concomitant therapies over time and have improved quality of life.
MATERIALS AND METHODS
This was a retrospective case-control study using a large, centralized database to identify canine patients receiving pruritus therapy along with a concurrent diagnosis of pyoderma. For the second objective, 58 client-owned dogs diagnosed with allergic dermatitis were enrolled in a prospective owner and dog quality of life and treatment satisfaction (QoL&TS) study that also evaluated concomitant therapy use over time. In Part A, data consisted of anonymous transaction records from 1,134 hospitals across the United States, representing pyoderma visits between December 2018 and December 2019. Odds ratios comparing the relative odds of having additional antimicrobial agent transactions were calculated, given initial pruritus therapy compared to dogs that did not receive pruritus therapy. Parametric bootstrapping was used to calculate goodness-of-fit statistics. In part B, dogs entered the study on Day 0 and returned for examination on Days 14, 21, 30, and 60. Owner determination of QoL&TS was performed on Days 0, 1, 3, 14, 21, 30, and 60. On Days 0, 14, 21, and 60, a veterinarian assessed concomitant therapies and dermatitis severity scoring. Least Squares Means and Standard Errors for QoL&TS, and Dermatitis Vet VAS (Visual Analog Scale) Scores were calculated using a Linear Mixed Model Approach for Repeated Measures (α = 0.05). The percent reduction in therapies was also calculated.
RESULTS
Dogs that received oclacitinib (n = 5,132) or a glucocorticoid ( = 7,024) had reduced odds (OR: 0.8091; = 0.0002 and OR: 0.7095; < 0.0001, respectively) of having a follow up antimicrobial drug transaction after initial antimicrobial therapy compared to dogs with no pruritus therapy at the initial visit ( = 12,997). In part B, oclacitinib demonstrated a statistically significant improvement in QoL&TS scores over time QoL ( < 0.05). Veterinarian assessment showed a 70% reduction in dermatitis severity over time ( < 0.05), supporting oclacitinib's anti-inflammatory effects. Oclacitinib therapy was also associated with an 83% reduction in concomitant treatments, including a 100% reduction in systemic antimicrobial therapy over eight weeks.
DISCUSSION
Dogs receiving oclacitinib showed no increase in antimicrobial therapy transactions compared to glucocorticoid recipients at the initial pyoderma diagnosis. Having a pruritus therapy at the index pyoderma visit reduced the odds of subsequent antimicrobial transactions. In addition to reducing concomitant therapy usage, oclacitinib improved owner and pet QoL, suggesting a paradigm shift in treatment success that could reshape allergic pruritus therapy recommendations. The study provides empirical evidence of oclacitinib's reduction in antibacterial therapy, supporting its therapeutic value and antimicrobial stewardship.
PubMed: 37745208
DOI: 10.3389/fvets.2023.1207582 -
Internal and Emergency Medicine Nov 2023Behçet's disease (BD) is a heterogeneous multifactorial autoinflammatory disease characterized by a plethora of clinical manifestations. Cutaneous lesions are...
Behçet's disease (BD) is a heterogeneous multifactorial autoinflammatory disease characterized by a plethora of clinical manifestations. Cutaneous lesions are considered hallmarks of the disease. However, their evolution over time and a thorough description are scarcely reported in non-endemic regions. The aim of this study was to detail BD skin manifestations and their evolution over time in Italy, as well as the dermatological prognostic impact of specific cutaneous features in long-standing disease. Data were collected in a double fashion, both retrospectively and prospectively, from the AutoInflammatory Disease Alliance (AIDA) international registry dedicated to BD, between January 2022 and December 2022. A total of 458 Italian patients were included. When assessing skin manifestations course, the constant or sporadic presence or absence of cutaneous involvement between onset and follow-up was considered. Oral ulcers (OU) (88.4%) and genital ulcers (GU) (52.6%), followed by skin involvement (53.7%) represented the most common presenting mucocutaneous manifestations at disease onset. Up to the time of enrolment into the AIDA registry, 411 (93.8%) patients had suffered from OU and 252 (57.9%) from GU; pseudofolliculitis (PF) accounted for the most common skin manifestation (170 patients, 37.1%), followed by erythema nodosum (EN) (102 patients, 22.3%), skin ulcers (9 patients, 2%) and pyoderma gangrenosum (4 patients, 0.9%). A prospective follow-up visit was reported in 261/458 patients; 24/148 (16.2%) subjects with skin involvement as early as BD onset maintained cutaneous lesions for the entire period of observation, while 120 (44.1%) patients suffered from sporadic skin involvement. Conversely, 94/113 (83.2%) with no skin involvement at disease onset did not develop skin lesions thereafter. At follow-up visits, cutaneous involvement was observed in 52 (20%) patients, with a statistically significant association between PF and constant skin involvement (p = 0.031). BD in Italy is characterized by a wide spectrum of clinical presentations and skin manifestations in line with what is described in endemic countries. Patients with skin disease at the onset are likely to present persistent cutaneous involvement thereafter; mucocutaneous lesions observed at the onset, especially PF, could represent a warning sign for future persistent skin involvement requiring closer dermatological care.
Topics: Humans; Behcet Syndrome; Retrospective Studies; Prospective Studies; Oral Ulcer; Italy; Registries
PubMed: 37803193
DOI: 10.1007/s11739-023-03410-9 -
Archives of Dermatological Research Jun 2024Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome is a rare condition characterized by clinical features of all three dermatologic conditions. The...
BACKGROUND
Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome is a rare condition characterized by clinical features of all three dermatologic conditions. The management of PASH syndrome is difficult, with no consensus on treatment guidelines. Since PASH syndrome can increase morbidity and adversely impact quality of life, better characterization of effective therapies is needed.
METHODS
A retrospective cohort study was conducted to identify all patients with pyoderma gangrenosum (PG) treated at The Ohio State University Wexner Medical Center between 2015 and 2021. PG diagnosis was confirmed via PARACELSUS score. Subsequent chart review identified eight patients with concomitant hidradenitis suppurativa (HS) and acne who were clinically diagnosed with PASH syndrome.
RESULTS
Eight patients were clinically diagnosed with PASH syndrome based on their clinical presentation at our institution. Seven patients had failed some type of medical therapy prior to presentation, including topical corticosteroids, oral corticosteroids, oral antibiotics, and biologics. One patient had also tried surgical drainage at an outside institution. Six patients were effectively treated with biologics, usually in combination with other therapies. One patient experienced improvement of her skin lesions after diagnosis and treatment of her underlying hematologic malignancy.
CONCLUSIONS
Medical management with biologics in combination with corticosteroids and/or antibiotics was effective in the management of most patients. Diagnosis and treatment of an underlying condition should be prioritized in refractory cases. If workup is negative, surgical management may be considered. Further investigation with a greater number of patients is required to develop management guidelines for PASH syndrome.
Topics: Humans; Pyoderma Gangrenosum; Female; Retrospective Studies; Acne Vulgaris; Hidradenitis Suppurativa; Adult; Male; Anti-Bacterial Agents; Young Adult; Middle Aged; Biological Products; Treatment Outcome; Quality of Life; Syndrome; Adolescent; Adrenal Cortex Hormones
PubMed: 38878169
DOI: 10.1007/s00403-024-03125-7 -
Cureus Apr 2024Pyoderma Gangrenosum (PG) is a distinctive dermatologic condition characterized by recurrent inflammatory ulcers, often manifesting with violaceous borders and...
Pyoderma Gangrenosum (PG) is a distinctive dermatologic condition characterized by recurrent inflammatory ulcers, often manifesting with violaceous borders and undermined edges. We describe a 40-year-old male who presented with acute on chronic necrotic ulcer of the left index finger following foreign body penetration. Despite multiple emergency department visits and treatments for presumed recurrent cellulitis, including various debridements, his condition persisted without symptomatic relief. A high index of clinical suspicion, due to recurrent presentations and potential pathergy, prompted an excision biopsy which confirmed Pyoderma Gangrenosum (PG). Regrettably, due to delays in appropriate management, the patient chose amputation because of intolerable pain, highlighting the critical importance of timely diagnosis for optimal patient outcomes.
PubMed: 38716010
DOI: 10.7759/cureus.57762 -
Cureus Jul 2023Pyoderma gangrenosum (PG) is a rare, poorly understood, non-infectious, autoimmune phenomenon. It is an inflammatory neutrophilic dermatosis characterized by...
Pyoderma gangrenosum (PG) is a rare, poorly understood, non-infectious, autoimmune phenomenon. It is an inflammatory neutrophilic dermatosis characterized by hyperactivity of the skin and the development of papules and pustules that rapidly progress to painful ulcerations with a violaceous and necrotic border. Approximately three to six cases of PG per million of the population occur per year and in the case of postoperative pyoderma gangrenosum (PPG), it is only one to three cases per million operated people. We are presenting a 41-year-old patient with a clinical presentation of PPG, developed in the surgical site on the sixth postoperative day (POD 6) following open appendectomy for acute appendicitis. Initial treatment was for surgical site infection (SSI) with wound opening, regular dressings, and broad-spectrum antibiotics. Due to unresponsiveness to therapy and the unexpected postoperative course with the progression of skin lesions, we suspected PPG. Corticosteroid therapy was introduced in a shock dose, once daily intravenous (IV), with superb results and stopping the spread of the process after only two days. Considering the rarity of PPG, especially when it first occurs postoperatively, we believe that the image of skin changes with superficial spreading and characteristic violaceous ulcerations can be of crucial importance for early diagnosis. A multidisciplinary approach with a mandatory examination by a dermatologist is important in order to make an early diagnosis and prevent wrong treatment, with the potential worsening of the patient's condition. Atraumatic wound care and negative pressure wound therapy are recommended. Patients at risk should perioperatively receive corticosteroids and postoperatively be closely observed for the potential development of PPG. Debridement is not recommended, and surgical treatment and further tissue trauma are undesirable and even prohibited.
PubMed: 37469578
DOI: 10.7759/cureus.42016 -
Journal of Veterinary Science Nov 2023A recent increase in the occurrence of canine skin and soft tissue infections, including otitis externa and pyoderma, caused by antimicrobial-resistant and has become...
BACKGROUND
A recent increase in the occurrence of canine skin and soft tissue infections, including otitis externa and pyoderma, caused by antimicrobial-resistant and has become a significant public and veterinary health issues.
OBJECTIVE
We investigated the virulence potentials associated with the occurrence of canine otitis externa in and
METHODS
In this study, the prevalence of genes encoding leukocidins, exfoliative toxins, and staphylococcal enterotoxins (SEs) was investigated using previously characterized (n = 26) and (n = 19) isolates derived from canine otitis externa. Susceptibility to cathelicidins (K9CATH and PMAP-36) and hydrogen peroxide (HO) was also examined in both staphylococcal species.
RESULTS
A high prevalence of genes encoding leukocidins (, , and ), exfoliative toxins (, , and ), and SEs was identified in both and isolates. Notably, isolates possessed higher number of SE genes, especially newer SE genes, than isolates harboring clusters. Although no significant differences in susceptibility to K9CATH and HO were observed between the two isolate groups, isolates exhibited enhanced resistance to PMAP-36 compared to isolates.
CONCLUSIONS
These findings suggest that high a prevalence of various toxin genes together with enhanced resistance to cathelicidins may contribute to the pathogenicity of and in canine cutaneous infections.
Topics: Animals; Dogs; Otitis Externa; Anti-Bacterial Agents; Exfoliatins; Methicillin-Resistant Staphylococcus aureus; Cathelicidins; Virulence; Hydrogen Peroxide; Leukocidins; Enterotoxins; Virulence Factors; Republic of Korea; Staphylococcal Infections; Dog Diseases; Microbial Sensitivity Tests
PubMed: 38031521
DOI: 10.4142/jvs.23087 -
The Journal of Dermatological Treatment Dec 2023
Topics: Humans; Pyoderma Gangrenosum; Antibodies, Monoclonal, Humanized; Behcet Syndrome
PubMed: 37449310
DOI: 10.1080/09546634.2023.2235040 -
International Wound Journal Dec 2023Pyoderma gangrenosum (PG) is a non-infectious, neutrophilic dermatosis that was difficult to diagnose in clinical practice. Today, the PARACELSUS score is a validated...
Pyoderma gangrenosum (PG) is a non-infectious, neutrophilic dermatosis that was difficult to diagnose in clinical practice. Today, the PARACELSUS score is a validated tool for diagnostics. Based on this score, patients with clearly diagnosed PG were examined with regard to predilection sites. In this retrospective study, the data of patients from the University Hospitals of Essen and Erlangen were analysed in whom the diagnosis of PG could be clearly confirmed using the PARACELSUS score. A total of 170 patients, 49 men (29%) and 121 women (71%) with an average age at first manifestation of 55.5 years, could be included in the analysis. The predilection sites were identified as the lower legs in 80.6% of the patients and the extensor sides in 75.2%. Other localisations of PG were the thighs in 14.1%, mammae and abdomen in 10.0% each, back and gluteal in 7.1% each, feet in 5.9%, arms in 4.7%, genital in 3.5% and head in 2.9%. This retrospective study is the first to identify a collective of PG patients with the highest data quality using the PARACELSUS score. It could be shown that PG can basically occur on the entire integument. However, the predilection sites of PG, which have now been reliably identified for the first time, are the lower legs and in particular the extensor sides.
Topics: Male; Humans; Female; Middle Aged; Pyoderma Gangrenosum; Retrospective Studies; Foot; Diagnosis, Differential; Hospitals, University
PubMed: 37528508
DOI: 10.1111/iwj.14323