2019 update on pyoderma gangrenosum

Transcription

1 2019 update on pyoderma gangrenosum Kanade Shinkai, MD PhD University of California, San Francisco F106: Updates in neutrophilic and pustular dermatoses I have no conflicts of interest to disclose. I will be discussing off-label use of medications during this lecture. Harp & Ahronowitz et al (2012) Am J Clin Derm, 13: updates Diagnosis Pathogenesis Treatment Special scenarios 1

2 2019 updates Diagnosis New PG diagnostic criteria? *PG major criteria *Histopathology Using literature-based characteristic validation Comparison to other criteria ongoing Maverakis et al (2018) JAMA Derm, 154(4): Does age matter? Multicenter retrospective cohort study (n=365) Associated comorbidities (67%) Patients >65 yrs: - pathergy (36% vs 24%, p=.02) - RA, AS, malignancy, heme disorders IBD more common in <65 yrs (47.7% vs 26.6%; p<.001) Ashchyan et al (2018) JAMA Derm, 154(4): Roth et al (2019) PLOS One, Jan 25, 2019 online 2

3 2019 updates Pathogenesis Are there different pathogenic pathways? Malignancy Neutropenia Medication Autoimmune Infection Autoinflam Pathergy Immunodeficiency neutrophils T cells (Th17) cytokines genes Neutrophil recruitment Neutrophil homeostasis PG plus shock physiology 69yo M History of MDS Repeated debridement Multiple IV antibiotics (5), antifungals (2), valacyclovir: - cultures negative - lesion expanding Shock physiology Sanchez et al (2019) JAMA Derm, 155(1):

4 Does this case fit PG diagnostic criteria? *Classic ulcer *Dx of exclusion Pathergy, cribiform Systemic associations Histopathology Response to steroids Su et al (2004) IJD, 43(11): *PG major criteria NND: distinct subset of ND with shock physiology PG/ Sweet syndrome PG+shock/ Necrotizing Sweet Necrotizing Neutrophilic Dermatoses Kroshinsky et al (2012) JAAD, 67:

5 Necrotizing neutrophilic dermatoses Shock physiology mimicking necrotizing fasciitis High misdiagnosis rate (91% given antibiotics as initial rx) Morbidity: amputation, leukemoid reaction, satellite lesions Sanchez et al (2019) JAMA Derm, 155(1):79-84 Callen et al (2019) JAMA Derm, 155(1):17-18 Haag et al (2019) J Trauma Acute Care Surg, 86(2): How do we explain the necrotizing phenotype? 2 nd signal? Endo et al (2012) J Infect Chemother Zeitoun et al (2010) Scan J Infect Dis Adam and Colikoglu (2004) JEADV Sfia et al (2007) JAMA Derm IL-1 IL-8 Rantes Necrotizing neutrophilic dermatosis vs infection? Markers of infection: Tissue cultures (43-98%) Blood cultures (18-66%) Universal PCR Procalcitonin Presepsin ESR/CRP ratio (low ratio) CD64 + PCT + IL-10 Wong et al (2003) J Bone Jt Surg Endo et al (2012) J Infect Chemother Zeitoun et al (2010) Scan J Infect Dis Adam and Colikoglu (2004) JEADV Sfia et al (2007) JAMA Derm 2 nd signal? IL-1 IL-8 Rantes 5

6 Could there be a genetic basis for NND? Novel heterozygous variants in NFKB1 (p50/p105) Spectrum of phenotypes: autoimmunity/ autoinflammatory Kaustio et al (2018) J All Clin Immun, 140(3): Somatic mosaicism in NLRP3 inflammasome Regulates IL-1 cytokine production cryopyrin Adult-onset somatic mosaicism explains late onset autoinflammation Kahlenberg JM (2016) Curr Opin Rheum, 28(3): Zhou et al (2015) Arthritis Rheum, 67: Drug-induced PG Drugs associated with PG: cocaine, levamisole isotretinoin, alitretinoin PTU adalimumab, etanercept, infliximab azacitidine gefitinib/ imatinib/ sunitinib ipilimumab enoxaparin EPO, G-CSF IFN Onset: may be years after drug start, no pattern suggests drug Wang et al (2018) Am J Clin Derm, 19:

7 Levamisole-induced PG: distinct pathophysiology? Levamisole -> retiform purpura, PG (neutropenia, ANCA+, APLA) Rapid response to brief, low-dose steroids (<0.5mg/kg x 1-2 wk) Jeong et al (2016) JAAD, 74: Drug-induced neutrophilic dermatosis Similar or distinct pathophysiology? Malignancy Neutrophil recruitment Neutropenia Medication Autoimmune Infection Neutrophil homeostasis Autoinflam Pathergy Immunodeficiency Wu et al (2017) BJD, 177: Drug-induced neutrophilic dermatosis Similar or distinct pathophysiology? Neutrophil recruitment Medication Illicit drugs Keratinocyte apoptosis Neutrophil homeostasis Wu et al (2017) BJD, 177:

8 2019 updates Treatment Best practices for PG management WOUND + INFLAMMATION Additional goals: Reduce pain Evaluate for/ treat associated systemic condition(s) Bennett et al (2000) Medicine, 79:37-46 Alavi et al (2017) Am J Clin Derm, 18: Ashchyan et al (2018) JAAD, online release Dec 2018 Limited evidence for PG treatment Topical: level II evidence - clobetasol propionate 0.05% - tacrolimus 0.03 or 0.1% Systemic: level Ib evidence -prednisone - cyclosporine - TNF-alpha (infliximab) Ashchyan et al (2018) JAAD, online release Dec 2018 Partridge et al (2018) BJD, 179:

9 What s new in PG treatment? Case reports Apremilast (Laird et al, 2017, JAAD Case reports)* Tocilizumab (Lee et al, 2016, JEADV)* JAK inhibitors - Tofacitinib (JAK1/3) (Kochar et al, 2019, Clin GE & Hep)* - Ruxolitinib (JAK2) (Nasifoglu et al, 2018, BJD) Ashchyan et al (2018) JAAD, online release Dec 2018 Do PG variants require distinct treatment? GI lymphoma PAPA Peri-stomal IgA vasculitis? Harp J, Ahronowitz I, et al (2012) Am J Clin Dermatol, 13: updates Special scenarios 9

10 Special site: PG after breast surgery Bilateral PG following breast explantation Special site: PG after breast surgery Aesthetic breast implant augmentation and attempt to cover defect by pedicle flap Ehrl et al (2018) J Plast Recon Aes Surg, 71: Systematic review Median onset: post-op day 7 Risk factors: - reduction/reconstruction - malignancy (37%) - autoimmunity (17%) Treatment: 4.7 months Special site: Peri-stomal PG Afifi et al (2018) JAAD, 78(6): Systematic review (n=335) % (4.3% in IBD) Risk factors: - younger age - wound infection - bowel obstruction - hernia - female - increased BMI - autoimmune disease Onset: 23 months (mean) 10

11 Surgery for PPG: (Re)location, location, location Surgical approaches: ostomy closure: 15 cases stoma revision/relocation: 36 cases debridement: 34 cases 100% healing 86% healing* 53% healing Afifi et al (2018) JAAD, 78(6): Other surgical strategies: grafting Ishikawa et al (2015) J Ostom Continence Nurs, 42: updates Diagnosis Pathogenesis Treatment Special scenarios Alavi et al (2017) Am J Clin Derm, 18: Ashchyan et al (2018) JAAD, online release Dec

12 Future directions (Re)considering diagnostic criteria to group & define similar and distinct conditions Pathogenesis: elucidating pathways, diagnostic markers, distinguishing from infection Understanding which treatments work and whether they work broadly Q&A 12