Dermatological Aspects of Vasculitis Jan Dutz, MD, FRCPC Professor and Head Department of Dermatology and Skin Science University of British Columbia Vancouver, Canada Conflicts of Interest u None relevant to this presentation 1 Objectives u To review clinical forms of vasculitis affecting the skin u To review new concepts in the pathophysiology of vasculitis affecting the skin u To review therapeutic options for cutaneous vasculitis 2 u Schamberg’s disease u Chronic capillaritis u Cayenne pepper color u Ankles, lower legs Pigmented purpuric dermatosis Pigmented purpuric dermatosis u Capillary involvement u RBC extravasation 3 Purpura u Minor trauma + – Acquired coag defect (coumadin, vit K def) – Platelet defect (ASA, wVF def, RF) – Poor dermis » Photo damage » Steroid » Scurvy » E-D, PXE, amyloid 4 Ecchymosis u Platelet defects/disorders u TTP 5 Cutaneous Small Vessel Vasculitis Classic palpable purpura - CSVV 6 Bolognia 4th Ed Ch 24 Bolognia 4th Ed Ch 24 7 Classic palpable purpura - SVV u Immune complex vasculitis – IgG, IgM - Idiopathic , drugs, infection - – IgA - HSP, drugs, infection – Mixed cryoglobulinemia – CTD vasculitis - SLE, RA, DM Small vessel vasculitis - SVV Purpura Postcapillary venules Fibrinoid necrosis 8 Fibrinoid necrosis Eosinophilia - Fibrin Endothelial swelling Most CSVV is idiopathic Arora A Mayo Clinic Proceed 2014 89:1515 u Incidence of LCV 4.5/100,000/year u Incidence of CSVV 2.1/100,000/year = 21 /million/yr 9 Pathophysiology Physical factors promote extravasation Milani JAMA Dermatology Online July 2017 u Prospective evaluation of children with HSP u 8/31 had linear palpable lesions 10 A potential role for platelets in coordinating inflammation Zuchtriegel PLOS Biology 2016 u Mouse cremaster model – stimulation by CCL2, TNF, IL1beta, IFN gamma Zuchtriegel PLOS Biology 2016 u Mouse cremaster model – Platelet depletion prevents Nphil transmigration 11 vWF – Not only important for clotting Zuchtriegel PLOS Biology 2016 vWF – Not only important for clotting Aymé Arterioscler Thromb Vasc Biol. 2017;37:1736- 12 Leukocytoclasis Carlson JA Am J Dermatopathol 2005 27:504 Causes of hospital-diagnosed SVV u St Vincent Hospital, Melbourne Aus - 93 Adults 1997- 2004 – 49% medications or infections – 60% resolved < 6 months Tai YJ Australas J Dermatol 2006 47:92 13 Clues to medications u University of Louisville (1997-2004) - 62 patients – 16 Medications (Antibiotics - Vancomycin) – 16 Infection – Other u Tissue eosinophilia in medication-caused disease Bahrami Arch Dermatol 2006 142:155 Henoch Schönlein Purpura u Palpable purpura u Arthritis, GI, Renal u Most common vasculitis in children – 10-20/100,000 yr u Nephritis in 30% CKD 5% u IgA in lesional skin – Sensitive – Not specific 14 Henoch Schönlein Purpura u Palpable purpura u Urticarial plaques u Non-palpable purpura Lava Clinic Rev Allerg Immunol 2017 Aug 24. 15 IgA vasculitis - Prognostic factors? u Glomerulonephritis associations – Above and below waist – Recent infection – Fever – Biologic markers of inflammation u 3/9 with skin only developed renal disease on follow up Tancrede-Bohin, Arch Dermatol 1997 133:438 IgA vasculitis - Prognostic factors? u Lesions above and below the waist u Presence of clinically apparent edema Johnson EF Br J Dermatol. 2015 May;172(5):1358 16 Adult IgA vasculitis u Increased GI and renal disease u Neutrophil to lymphocyte ratio may be a simple way to predict systemic involvement u NLR>3.34 spec 95% sens 85% Nagy JEADV 2017, 31, 1033 Who to biopsy? u Not required in children with classic HSP u Why biopsy others? – Medications – Identification of adult HSP u At 18-48 hrs HE u At 8-24 hrs IHC - Most proximal and cephalad lesion Russell JP & Gibson LE Int J Dermatol 2006 45:3 17 HSP - Treatment controversies u There is significant variation in therapy and evaluation of children with HSP – Weiss PF J Pediat 2009 155:812 u Prednisone can be used for short term control of skin but does not alter long-term outcome – Jauhola O Pediatr Nephrol 2012 ePub u Dapsone of help in decreasing recurrent skin disease – Papandreou T Eur J Dermatol 2010 20:639 Persistent SVV u Occasional SVV persists u R/O infection, cancer, CTD u A Randomized Multicenter Study for Isolated Skin Vasculitis (ARAMIS) NCT02939573 – Colchicine – Dapsone – Azathioprine 18 Persistent SVV u Occasional SVV persists u R/O infection, cancer, CTD u Long term prednisone is toxic u IVIG may provide short term relief u Rituximab may be a therapeutic option u Potential role for IL-1 inhibition, TNF inhibition, IFN gamma inhibition (JAK inhibitors) Persistent SVV Stiegler JAMA Dermatol Sept 2017 153:941 u Intolerance of azathioprine, mycophenolate mofetil, mycophenolic acid u Response to leflunomide 10 mg OD 19 Persistent SVV IL-17 pathway? u Xu H Rheumatol Int. 2016 Jun;36(6):829 IL17A gene polymorphism u Chen O Int Immunopharmacol. 2013 May;16(1):67 Increased IL17 in HSP FMF - Cutaneous Features = CSVV Think autoinflammatory dissease u Purpura u Erysipelas-like erythema - ankles u Henoch-Schönlein purpura u Angioedema u Palmoplantar erythema u Raynaud-like changes to hands Barzilai A JAAD 42:791 (2000) 20 Persistent SVV Boyer Pediatric Rheumatol 2011 9:21 u 9 YO with HSP nephritis pulmonary hemorrhage and CNS vasculitis u Partial response to anakinra Uncommon forms of CSVV u Acute hemorrhagic edema of infancy – Finkelstein Seidlmayer disease – Cocarde purpura u Urticarial vasculitis u Erythema elevatum diutinum u Cryoglobulinemic vasculitis – Mixed cryoglobulinemia 21 Acute hemorrhagic edema of infancy u Misdiagnosed as child abuse Lava Clinic Rev Allerg Immunol 22 Urticarial vasculitis u Lesions last >24 hours u Leave bruise/pigment u Burn not itch u Trunk, proximal extremities Urticarial vasculitis u In association with CTD u Normocomplementemic – 32% of SS – 70-80% of cases – 20% of SLE – Self limited – Eosinophils u Schnitzler Syndrome u HUV – Arthralgia, lymphadenopathy – Arthritis, asthma, airway – Neutrophils – Monoclonal IgM u HUVS – Associated iritis, uveitis, episcleritis – Lupus-like – Anti-C1q precipitins 23 Urticaria like lesions u Urticaria u Urticarial vasculitis u Serum sickness u HSP u SLE u Erythema multiforme Erythema Elevatum Diutinum u Red raised chronic papules u Acral joints, buttocks u Rare arthralgias u Rare gammopathy – IgA>IgG 24 Medium Vessel Vasculitis 25 Cutaneous polyarteritis nodosa u Multiple ulcers u Mostly lower legs u Nodules u Foci of livedo reticularis Cutaneous polyarteritis nodosa Necrotizing arteritis Within subcutaneous fat 26 Skip lesion Medium vessel vasculitis - MVV Livedoid change 27 Medium vessel vasculitis u Angular ulcers u Nodules u Livedo pattern Medium vessel vasculitis Atrophie blanche-like change 28 Atrophie blanche Cutaneous polyarteritis nodosa presenting as atrophie blanche u Cutaneous polyarteritis nodosa presenting as atrophie blanche – 6/29 Medium vessel vasculitis » 4/6 Neurological involvement – 2/29 Antiphospholipid antibody syndrome – 1/29 Cryoglobulinemia Mimouni D, Br J Dermatol 2003; 148: 789 29 Inflammatory retiform purpura Livedoid vasculitis/ Atrophie banche LCV with immune complexes HSP, Mixed cryo, CTD Pauci-immmune vasculitis (ANCA +) Microscopic PA GPA EGPA (Churg-Strauss) Cutaneous PAN Cutaneous PAN & MVV - Treatment u Colchicine and dapsone in combination Muramatsu JAAD 1985 13:1055 u Azathioprine u Methotrexate (reported to induce vasculitis) u Mycophenolate mofetil u Rituximab Krishnan Int J Rheum Dis 2012 15:e127 u IVIG for resistant cases Ong Br J Dermatol 2000 143: 447 30 IGIV for cutaneous vasculitis Livedoid vasculitis Kreuter JAAD 2005 51:574 IVIG as adjuvant therapy for GPA u Cochrane review 2013 - Fortin P u 1 RCT 34 pts azath +/_ IVIG – Greater fall in disease activity scores – RR of adverse events 3.5 – Cost - $8,500 per infusion 31 Cutaneous PAN – New concepts Cutaneous PAN – New concepts Elkan NEJM 2014 370 :921 32 Cutaneous PAN – New concepts Zhou Q NEJM 2014 370:911 Cutaneous PAN – New concepts Zhou Q NEJM 2014 370:911 33 Cutaneous PAN – New concepts u Patients with ADA2 protein deficiency (DAD2 CERC1 gene mutation) have features of cutaneous PAN u Response to TNFi, tocilizumab Gonzalez Santiago JAMA Dermatol 2015 151:1230 34 Cutaneous PAN – New concepts u ADA2 deficiency is associated with B cell deficiency = immunodeficiency u ADA2 deficiency is associated with increase in T1 IFN gene signature – Similarities to SAVI – Role for JAK 1,3 inhibition? u ADA2 deficiency may present as – Early onset PAN – Difficult to treat PAN – Immunodeficiency Inoue Pediatrics International (2017) 59, 751 TNFi use in childhood cut PAN 35 SAVI – A new vasculopathy u STING (Stimulator of interferon genes) -associated vasculopathy with onset in infancy u Liu Y NEJM 371: 507 (2014) SAVI – A new vasculopathy u STING (Stimulator of interferon genes) -associated vasculopathy with onset in infancy u Liu Y NEJM 371: 507 (2014) 36 SAVI – A new vasculopathy u STING (Stimulator of interferon genes) -associated vasculopathy with onset in infancy u Liu Y NEJM 371: 507 (2014) SAVI – A new vasculopathy 37 ANCA-associated vasculitis u Wegener’s granulomatosis – Granulomatous Polyangiitis (GPA) u Churg Strauss Syndrome (eGPA) u Microscopic PA u DIF - few immunoreactants = pauci immune GPA and Skin u Up to 50% have skin lesions u Multiple morphologies – SVV, MVV – Vesicles – Papules Gibson LE Int J Dermatol 2003; 42:859 38 Granulomatous polyangiitis u Churg Strauss granuloma Rituximab - ANCA-associated vasculitis u Nat Rev Rheumatol. 2010 Oct;6(10):556 u N Engl J Med. 2010 Jul 15;363(3):221-32 – RAVE study 39