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 MAINRITSAN
AAV – New Concepts
Merkel P ARTHRITIS & RHEUMATOLOGY 2017 69; 1054
u GWAS study of AAV – HLA associations, SERPINA1, PTPN22 u Separate associations for PR3 ANCA and MPO ANCA
40 AAV – New Concepts
Kronbichler Rheumatology 2017;56:704
u CRP, baseline Cr, cutaneous and GI involvement correlate with VTE risk
AAV – New Concepts
Danlos Autoimmunity Reviews 16 (2017) 1036
u AAV and IgG4 disease overlap
41 Neutrophils
u Migrate from blood and kill bacteria u Phagocytosis - killing by proteolytic enzymes u Degranulation = killing of extracellular bacteria
u A & C - Naïve cells are round u B & D - Activated (IL-8, PMA, LPS) cells are ruffled and have protrusions u E & F - protrusions are smooth fibers ( 15 nm) with globules (25 nm) without ECM
42 NETs in SVV
u Medium and Small Vessel Vasculitis is characterized by anti-neutrophil cytoplasm antibodies (ANCA) to PR3 and to myeloperoxidase (MPO) u ANCA can prime respiratory burst in neutrophils u ANCA induces NET formation
Jenne, D Nature Medicine 15, 623 - 625 (2009)
Composition of NETs - Immunostaining
Neut elastase DNA Histone-DNA Elastase Histones
Elastase 30-60 min post IL-8
43 ANCA induce NETs
NETs promote ANCA Documented role in SVV
NETs induce MXA - Promote ANCA?
MPO-DNA complexes
44 Anti-phospholipid antibody syndrome
u Over half have livedo reticularis u 41% as first sign u 40% will go on to multisystem thrombotic events
45 46 Necrotic skin ulceration
u Calciphylaxis u Athero-emboli u Cryoglobulinemia/Cryofibrin oginemia u Catastrophic APLAS u Other necrotizing vasculitis (PAN) u Oxalosis
Necrotic skin ulceration
Stone & Nousari, Curr Opin Rheumatol 13:23 (2001)
47 A relatively new syndrome?
48 Br J Dermatol. 1999 May;140(5):948- 51
Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children
Levamisole adulterant in cocaine
u Associated with reversible neutropenia – CMAJ. 2010 Jan 12;182(1):57-9 u Retiform purpura and neutropenia – J Am Acad Dermatol. 2010 Sep;63(3):530-5 u Earlobe purpura – Ann Intern Med. 2010 Jun 1;152(11):758-9 u Anti-neutrophil elastase antibodies (atypical ANCA) – J Cutan Pathol. 2010 Aug 24
49 Levamisole adulterant in cocaine
u Literature review of 32 patients
u Location of eruption – Lower extrem 88% – Face 78% – Ears 69% u Neutropenia 63% u ANCA 94% u Histology – Vasculopathy 48% Arora Am J Med Sci 2013 345: 45 – Vasculitis 14% – Both 53%
Cocaine associated vasculitis
u Vasculopathy with C5-9 activation and endothelial death u Vasculitis with ICAM-1 expression
Magro Am J Dermatopath 2013 35:722
50 Magro Am J Dermatopath 2013 35:722
D Dimer – A way to monitor small vessel damage
Kirchhof JAMA Dermatol. 2014 Apr 2.
51 D Dimer – A way to monitor small vessel damage
Kirchhof JAMA Dermatol. 2014 Apr 2.
D Dimer – A way to monitor small vessel damage
Kirchhof JAMA Dermatol. 2014 Apr 2.
52 Purpura
u Simple hemorrhage – Petechiae – Ecchymoses u Inflammatory hemorrhage – Palpable purpura – Early erythema u Occlusion – Little erythema – Branching/stellate purpura
Is it a vasculitis?
u Small vessel vasculitis – Palpable purpura – Vesicles, pustules – Urticaria – Non-palpable lesions - macules, patches – Splinter hemorrhages
53 Is it a vasculitis?
u Medium vessel vasculitis – Nodules – Ulcers – Livedo reticularis – Digital infacts – Papulonecrotic lesions
Approach to cutaneous vasculitis
u Active lesions for >3 weeks? u Systemic signs/Sx? – Biopsy lesions 24-48 hrs old – H&E IF (IgA) u CBC, BUN, CR, LFT, UA, ESR u RF, ANA, C3, C4 CH50, cryoglob, ANCA u SPEP u CXR u Stool Guiac
54 Biopsy yields
u Nodules - “deep punch”, excision - 95% u Ulcer edges - 50% u Livedo reticularis - 25%
Cutaneous lupus Cutaneous dermatomyositis Morphea Type 1 IFN in the skin Auto-inflammatory disorders SKIN Neutrophils in the skin
Vascular predominant disorders Type 1 IFN and neutrophils around vessels
55 56