Dermatological Aspects of

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 u Cayenne pepper color u Ankles, lower legs

Pigmented purpuric dermatosis

Pigmented purpuric dermatosis

u Capillary involvement u RBC extravasation

3

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 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 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 u 41% as first sign u 40% will go on to multisystem thrombotic events

45 46 Necrotic skin ulceration

u 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 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