5/22/2018

1

VasculitisMartin C. Mihm M.D.

Director – Mihm Cutaneous Pathology Consultative Service

(MCPCS)

Brigham and Women’s Hospital

Director – Melanoma Program

Brigham and Women’s Hospital and Harvard Medical School

Co-Director – Melanoma Program

Dana-Farber Cancer Institute and Harvard Medical School

Conflicts of Interest

• Chairman Scientific Advisory Board –

Caliber I.D. Inc.

• Member Scientific Advisory Board –

MELA Sciences Inc.

• Consultant – Novartis

• Consultant – Alnylam

Acknowledgments

• Cynthia Magro, MD

• A. Neil Crowson, MD

• Labib Zakka, MD, MA

5/22/2018

2

General Overview

• Dermal Based

• Vascular Thrombosis

• Neutrophilic Vascular Reactions

• Lymphocytic vasculitis

• Granulomatous vasculitis

• Subcutaneous:

• Superficial migratory thrombophlebitis

• Benign cutaneous polyarteritis nodosa

Vascular Thrombosis/

Pauci-inflammatory thrombogenic

vasculopathy

Main causes of cutaneous vascular thrombosis:

Acquired or Hereditary Defects in Anticoagulation

Increased Blood Viscosity

Endothelial Cell Injury

Cutaneous Vascular Thrombosis:

CLINICAL PRESENTATION:1. Large areas of hemorrhagic cutaneous infarction

2. Ulcers

3. Atrophie Blanche

4. Digital Infarcts

5. Livedo reticularis

5/22/2018

3

Hemorrhagic Livedo

Primary Antiphospholipid Antibody Syndrome

Digitial Infarcts

Acral Based Livedo

5/22/2018

4

Atrophie

Blanche

Salient Histomorphologic Features

• Vascular thrombosis unaccompanied by inflammation with associated ischemic changes (cutaneous infarcts)

• Vascular Ectasia(livedo)

• Reactive angioendotheliomatosis (chronic ulcers)

5/22/2018

5

Pauci-inflammatorythrombogenic

vasculopathy

5/22/2018

6

Defects in Anticoagulation

• Protein C and S deficiency

• Fibrinolytic disorders

• Antithrombin III deficiency

Activated Protein C Resistance

• In activated protein C resistance, the levels of protein

C are normal, however, the ability of inactivation by

protein C of factor V is defective

• The cause in 90% of cases is a mutant factor V

resistant to protein C inactivation designated as

factor V Leiden.

• Factor V mutation is the most common genetic cause

of venous thrombosis (20 to 40% of cases)

• Heterozygotes are at a 7 fold risk while homozygotes

are at a 80 fold risk

• No risk for arterial thrombosis

Plasminogen Activator Inhibitor 4g Polymorphism

• Unlike Factor V Leiden which is not associated with an increased risk for stroke elevated levels of plasminogen activator inhibitor due to an inherent 4G polymorphism of the PAI promoter leads to excessive levels of PAI

• Of interest high levelsof PAI is seen in patients with advanced CAD and ischemic stroke

• Triglyceride levels add to the risk of stroke in patients with a 4g polymorphism

5/22/2018

7

Thrombocythemia

Monoclonal cryoglobulinemia

Cryofibrinogenemia

Cold agglutinins

Hyperviscosity states

5/22/2018

8

Endothelial cell dysfunction

• Antibodies directed at endothelium is the basis of thrombosis in the setting of collagen vascular disease (dermatomyositis, scleroderma, antiphospholipid antibody syndrome)

• Nonimmune based causes of endothelial cell dysfunction( cholesterol embolism, homocysteinuria)

5/22/2018

9

Antiphospholipid Antibody Syndrome as the prototype for immune based endothelial cell dysfunction

• Main mechanism of likely one of immune based endothelial cell injuryi.e. the antiphospholipids are directed against endothelial cell based epitope

• However other “nonimmune” based mechanisms are likely operative• Inhibition of the Protein C/S thrombomodulin complex

• Direct binding of beta 2 glycoprotein.

Antiphospholipid Antibodies

• Cardiolipin: mitochondrial based

• Phosphatidylserine and phosphatidylethanolamine are located in the inner cytoplasmic leaflet

• Phosphatidylcholine is located in the outer leaflet

• Beta 2 glycoprotein typically associated with phosphatidylserine

• During apoptosis PS/PE may be displaced to the surface and stimulate APL AB production.

Antiphospholipid Antibodies

• Accelerated apoptosis may occur in the setting of

• 1.drug therapy (antifungal agents, taxotere)

• Endotheliotropic viral infections (i.e parvovirus B19 and cytomegalovirus)

5/22/2018

10

Antiphospholipid Antibody Work-Up

• Lupus anticoagulant test

• ELISA tests: anticardiolipin (IgG, IgM,IgA), antibeta-2 glycoprotein (IgG, IgM, IgA), antiphosphatidylserine (IgG, IgM, IgA), antiphosphatidlycholine (IgG, IgM, IgA), antiphosphatidlyethanolamine (IgG, IgM, IgA)

• Index of vascular injury: factor VIII

Cholesterol Embolism

Inflammatory vascular reaction patterns

• Neutrophilic vascular reaction/Leukocytoclastic Vasculitis

• Lymphocytic Vasculitis

• Granulomatous Vasculitis

• Interface Dermatitis

5/22/2018

11

Systemic Lupus Erythematosus

• Courtesy of Dr. Cynthia Magro

• Patient History:• 48 year old female who had with systemic lupus

erythematosus, suddenly developed a hemorrhagic photodistributed rash. She complained of marked abdominal pain, pain in her legs, and arthralgias. Patient died due to gut infarction in spite of intensive therapy.

5/22/2018

12

Systemic Lupus Erythematosus

• In patients with biopsies of interface dermatitis showing concomitant vasculitis potential vascular co-factors contributing to vascular injury should be explored

• In the setting of SLE these vascular co-factors include antiphospholipid antibodies and cryoglobulins, antiendothelial cell antibodies

• Crowson AN, Magro C. The cutaneous pathology of lupus erythematosus: a review. J Cutan Pathol. 2001 Jan;28(1):1-23. Review.

5/22/2018

13

Systemic Lupus Erythematosus

• In patients with a sudden onset of the syndromic complex always assess for potential inciting triggers:

• Autoimmune viral triggers (B19, CMV,and hepatitis C)

• Drugs

• In regards to virally triggered disease the inherent endotheliotropic properties of the virus can be associated with potentially catastrophic vasculopathy

CMV

Human Herpes

B19

RT in situ PCR to assess for Viral mRNA Expression

Hepatitis C B19

Systemic Lupus Erythematosus

• References:• Crowson AN, Magro C. J Cutan Pathol. 2001

• Murphy, GF, Saavedra AP, Mihm, MC. Atlas of Nontumor Pathology 10: Inflammatory Disorders of the Skin. ARP Press, Silver Spring, 2012.

5/22/2018

14

Leukocytoclastic Vasculitis

• Clinical:Palpable purpura to one of hemorrhagic bullous lesions

• Pathology:Neutrophils around vessels with variable fibrin deposition and leukocytoclasia

• Basis: Circulating immune complexes (Arthus type III immune complex reaction) versus ANCA positive vasculitic syndrome

Palpable Purpura

Severe Leukocytoclastic Vasculitis

5/22/2018

15

Sources of Immune Complexes

• Exogeneous antigenic triggers: drug and infection

• Endogenous causes: reflect rheumatoid factor, cryoglobulins, and tumor antigen

5/22/2018

16

ANCA Associated Vasculitic Syndromes

• Pauci-immune small vessel vasculitic syndromes associated with a positive ANCA

• Cytoplasmic granular staining in neutrophils: CANCA corresponds to antibodies to proteinase 3(WG)

• Homogeneous perinuclear staining pattern:PANCA corresponds to antibodies to myeloperoxidase (MPAN)

Antineutrophilic cytoplasmic antibody

• Antibodies which are targeted against neutrophil primary granules and monocyte lysosomes

• Cytoplasmic staining (CANCA)

• Perinuclear staining (PANCA)(With[MP] and without nuclear extension[elastase, lactoferrin](Artifactual seen only with alcohol)

• Atypical ANCA (mixture of CANCA and PANCA): PSC, PBC,SLE,RA

CANCA/WG/antiproteinase 3 ABS

WG:75%;MPAN:20%;Churg

Strauss:10%

5/22/2018

17

P ANCA/ withi myeloperoxidase(mp) sp

WG:25%;MPAN:60%;Churg

Strauss:60%;without mp sp: ulcerative colitis

Churg Strauss Disease:30% ANCA is negative

10% CANCA;60% with be PANCA

Mechanisms of ANCA Induced Injury

• Accelerated apoptosis via upregulated TNF pathway triggered by a viral stimulus in neutrophils is a critical inciting factor both with onset and recrudescence

• Neutrophil granules containing the epitopes are displaced to the surface

• Antibodies bind to surface displaced antigen

• Binding of ANCA to epitope leads to neutrophil degranulation with resultant tissue damage

• Normally an influx of macrophages digest released products

• With premature degranulation there is insufficient time for macrophage influx

5/22/2018

18

Mechanism of ANCA Injury

• Endothelial killing is achieved via primed neutrophils activated by ANCA manifesting enhanced VCAM expression

• Inciting Triggers:viral infection, drugs have also been implicated classic is propylthiouracil which down modulates IL12 (antiapoptotic)

Special Variants of Leukocytoclastic Vasculitis

Urticarial Vasculitis

• Clinical features:Persistent urticarial plaques that last more than 24 hours and may be accompanied by fixed purpura

• Arthus type III immune complex reaction i.e. drug, hepatitis C and CTD

• Intrinsic abnormalities in complement activation(i.e. C1q esterase inhibitor)

• IgM gammopathy (Schnitzler syndrome: fever, osteosclerotic bone lesions, fever, and urticaria)

5/22/2018

19

Urticarial Vasculitis

5/22/2018

20

Chronic Leukocytoclastic Vasculitis

Granuloma faciale

Erythema Elevatum Diutinum

Granuloma faciale: Middle aged men, face,

no association with systemic disease

Histology: ectatic vessel with angiocentric nodular

Mixed inflammatory cells and trabeculated thin

Mantles of fibrin

5/22/2018

21

Granuloma Faciale

5/22/2018

22

Erythema Elevatum Diutinum

Erythema Elevatum Diutinum

• Known association with various diseases

• Recurrent / chronic bacterial infection (esp. streptococcal),

• HIV

• Collagen vascular diseases

• Haematological disorders

• Inflammatory bowel disease,

5/22/2018

23

PUSTULAR VASCULITIS

Definition:

Intraepithelial pustulation with accompanying

Vasculitis of leukocytoclastic subtype manifesting

clinically as a pustule on a purpuric base.

5/22/2018

24

Pustule on a purpuric base

CAUSES OF PUSTULAR VASCULITIS

• Antecedent infection(bacterid)

• Inflammatory bowel disease(bowel arthritis dermatosis syndrome)

• Drug reaction(ACE inhibitors, prednisone in patients with psoriasis, antibiotics

• COMMONEST CAUSE: BACTERID, ESPECIALLY INFECTION TRIGGERED HSP

5/22/2018

25

Granulomatous Vasculitis

GRANULOMATOUS

VASCULITIS

• In most cases GV is part of a complex hybrid dermatitis

• Granulomatous vasculitis may be accompanied by 1.palisading necrobiosis 2. extravascular neutrophilia 3. interface dermatitis

5/22/2018

26

Diffuse interstitial Granulomatous Inflammation and GV: Atypical Granuloma annulare tissue reaction

• Rheumatoid Arthritis

• Paraneoplastic (low grade B cell lymphoma)

• Infectious id:TB, B19, CMV,hepatitis C

• Interstitial palisading granulomatous drug reaction

5/22/2018

27

Suppurative and Granulomatous

Inflammation

GV with extravascular neutrophilia

• Infection

• Id reactions to infection(mycobacterium, fungus)

• Inflammatory bowel disease

• Wegener’s granulomatosis

Granulomatous Vasculitis consistent

With Limited WG

5/22/2018

28

GV with Interface Dermatitis

• Infection(viral, yersinia, streptococcus, borrelia)

• Drug

LYMPHOCYTIC

VASCULITIS

Lymphocytic vasculitis:

Angiocentric lymphocytic infiltrates accompanied

By morphologic evidence of injury

Differential diagnostic considerations

When unaccompanied by tissue eosinophilia:

Collagen vascular disease (LE, APAB,idiopathic

Perniosis)

Paraneoplastic syndrome(B cell lymphoma

At times reflecting cryofibrinogenemia)

Viral hypersensitivity syndromes

When accompanied by tissue eosinophilia

Drug hypersensitivity

Lymphocytic Vasculitis in the setting of viral infection

5/22/2018

29

Since there is no fibrin deposition

Now considered a form of Clonal T cell dyscrasia

5/22/2018

30

Degos Disease

Degos Disease

• Clinical Features:• 0.5-1 cm large papules with an atrophic porcelain-white centre

and an erythematous, teleangiectatic rim

• Begin as small erythematous papules the center of which sinks and assumes the characteristic morphology

• Occurring on the trunk and the upper extremities ; Palms, soles, scalp and face are rarely involved.

• Internal organs exhibit multiple limited infarcts of the intestine and/or the central nervous system (CNS) lungs and eyes

Degos Disease• Histopathology:

• Low power reveals prominent epidermal atrophy overlying an area of mucin deposition, shaped as an inverted triangle

• Vessels throughout exhibit thrombogenic vasculopathy with sloughing of endothelial cells and debris

• Intense mucin deposition around vessels

• Ultrastructural analysis exhibited tubuloreticular structures in keratinocytes and endothelial cells as seen in association with INFα

• Detachment of endothelial cells with debris and platelet aggregates noted

5/22/2018

31

C5b-9

MXA

MXA

Degos Disease

• Pathogenesis:• 3 possible hypotheses are proposed including: vasculitis,

coagulopathy and primary dysfunction of the endothelial cells

• MXA, a marker of INFα, parallels the pattern of C5b-9 deposition to suggest that interferon triggers complement

• Exogeneous interferon seen in severe Raynaud’s phenomenon, digital and retinal infarcts, and cutaneous ulcers

• Four cases of Degos showed overlap of INFα in all vessel endothelium and surrounding inflammatory cells and extensive C5b-9

• 3 of 4 cases had evidence of Parvovirus B19 in the endothelium

5/22/2018

32

Degos Disease

• Differential Diagnosis:• Systemic lupus erythematosus

• Progressive systemic sclerosis

• Dermatomyositis

• Crohn’s disease

• Wegener’s granulomatosis

• Perforating collagenosis

Degos Disease• Treatment:

• Most efforts with fibrinolytic and immunosuppressive therapeutic regimens like cyclosporine A, azathioprine; cyclophosphamide and corticosteroids have failed

• anticoagulants showed partial regression of the skin lesions in single cases

• Eculizumab treatment has been effective in some patients with intestinal and CNS manifestations

Eculizumab to treat Degos Disease Proven to be life saving!

5/22/2018

33

Degos Disease

• References:• Theodoridis A et al. Orphanet Journal of Rare Diseases.

2013

• Magro CM et al. Am J Clin Pathol. 2011

SUBCUTICULAR VASCULITIS

BENIGN CUTANEOUS POLYARTERITIS

NODOSA

SUPERFICIAL MIGRATORY

THROMBOPHLEBITIS

5/22/2018

34

Benign Cutaneous Polyarteritis Nodosa

• Arteritis affecting a single vessel in the subcutaneous fat

• Associations:

• Inflammatory bowel disease

• Antecedent Streptococcus infection(remission following tonsillectomy)

• Adult Still’s disease

5/22/2018

35

SUPERFICIAL MIGRATORY

THROMBOSPHLEBITIS

Presents as tender nodules on the lower

extremities

Associations Include:

Berger’s disease

Behcet’s disease

Underlying procoagulant states

Trousseau’s syndrome,

antiphospholipid AB syndrome

5/22/2018

36

5/22/2018

37

Acknowledgments

• Cynthia Magro, MD

• A. Neil Crowson, MD

• Labib Zakka, MD, MA

Thank you for your kind attention