Diagnosing Cutaneous vasculitis - PowerPoint Presentation

Slide1

Diagnosing Cutaneous vasculitis

By: Dr. Donna Braham

Slide2

Objectives

Classify Vasculitis

Know when to consider Vasculitis

Rule out mimickers of Vasculitis

Diagnose cutaneous small vessel vasculitis – In

particular Henoch–

Schönlein

Purpura

, Essential

Cryoglobulinemic

vasculitis and Cutaneous

Leukocytoclastic

angiitis

Slide3

Vasculitis

S

pecific

pattern of inflammation of the blood vessel wall and it can occur in any

size vessel and in any organ

system of the body.

Cutaneous vasculitis may be:

(

1) a skin-limited

disease

(

2) a primary cutaneous vasculitis with secondary systemic

involvement

(

3) a cutaneous manifestation of a systemic vasculitis

Slide4

Cutaneous Vasculature

Small

vessels

(

Superficial

and mid dermis of the

skin

)

:

Arterioles

Capillaries

P

ostcapillary venules

Medium

-sized

vessels

(

Deep

dermis or

subcutis

):

S

mall arteries

Veins

Large

vessels include the aorta and named arteries.

Slide5

Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis

Small Vessel Vasculitis

Granulomatosis

with

Polyangiitis

(GPA) -Wegener’s

Granulomatosis

Eosinophilic

Granulomatosis

with polyangiitis (EGPA) - Churg-Strauss SyndromeMicroscopic Polyangiitis (MPA)Henoch-Schonlein purpura (HSP)Essential Cryoglobulinemic vasculitisCutaneous Leukocytoclastic angiitis (CSVV)

Medium-sized Vessel Vasculitis

Polyarteritis

Nodosa

Kawasaki Disease

Large-sized Vessel Vasculitis

Giant cell (temporal)

arteritis

Takayasu

arteritis

Slide6

Epidemiology

The incidence of biopsy-proven cutaneous vasculitis of all types is 15–60 patients per million per

year.

Cutaneous

vasculitis occurs in all age groups

mean

age in adults, 47 years; mean age in children, 7

years

Much more common in adults than in children

S

light female predominanceThe majority of children have Henoch–Schönlein purpura which is associated with pesticide and drugs.All are more common in whites compared with other populations Genetic and environmental factors, including infection, drugs, and silica play a role

Slide7

Pathogenesis

Immune

complex-mediated inflammation

P

olyarteritis

nodosa

,

C

ryoglobulinaemia

Henoch-Schönlein purpuraAutoantibody-mediated inflammation (ANCA)Wegener's granulomatosis Churg-Strauss syndrome Microscopic polyangiitisNecrotizing glomerulonephritisCell-mediated inflammation GCA

Slide8

Immune complex-mediated vasculitis

Circulating

antigens (e.g. infectious agents, medications, neoplasms) induce antibody formation

.

Binding

of antibodies to circulating antigens creates immune complexes.

Immune

complex deposition within postcapillary venules activates complement and subsequently leads to an increase in adhesion molecule expression on the endothelium.

Complement

split products (C3a and C5a) induce mast cell degranulation and neutrophil

chemotaxis.

Slide9

Immune complex-mediated vasculitis

Mast cell degranulation leads to increased vascular dilation and permeability, enhancing immune complex deposition and leukocyte tethering to endothelium

Neutrophils release

proteolytic

enzymes (such as collagenases and

elastases

) and free oxygen radicals that damage the vessel wall.

In addition, formation of the membrane attack complex (C5–C9) on the endothelium leads to the activation of the clotting cascade and the release of cytokines and growth factors with ensuing thrombosis, inflammation and angiogenesis.

Slide10

Autoantibody-mediated inflammation

-Anti

-

neutrophillic

cytoplasmic autoantibodies

The autoantibodies activate neutrophils

The activated neutrophils are then primed by cytokines to show MPO and PR3 on their surfaces

They then adhere to the endothelial walls of blood vessels and release oxygen radicals and enzymes that damage the surrounding tissues

Slide11

Slide12

Clinical Presentation

V

ary

from a benign loco-regionally restricted

process

to systemic

necrotising

vasculitis leading to life-threatening conditions

.

C

onstitutional symptoms (the B-symptoms) Fatigue, weight loss, night sweats and low grade feverSystemic symptoms develop in 5–25% of patients with CSVVArthralgias and arthritis 15–65%Genitourinary 3–7%Gastrointestinal involvement 3–5%In general, signs or symptoms of gastrointestinal, renal or neurologic involvement should increase the clinical suspicion for a systemic vasculitis. In one study, the presence of paresthesias or fever and the absence of painful lesions were identified as risk factors for an associated systemic disease

Slide13

Slide14

Slide15

Think Vasculitis if?

Unexplained systemic

illness

Symptoms

of organ system

ischaemia

Nephritic

syndrome

Slide16

Cutaneous Small Vessel Vasculitis

The skin lesions of CSVV usually appear 7–10 days after the triggering event.

In

systemic

vasculitic

syndromes, signs of systemic involvement often precede the appearance of associated cutaneous

lesions.

The

lesions favor dependent sites, as well as areas under tight-fitting clothing, reflecting the influence of hydrostatic pressure and stasis on the pathophysiology

.

In general, the lesions are asymptomatic, but they may itch, burn or sting.

Slide17

Cutaneous Small Vessel Vasculitis

P

alpable

or macular

purpura

U

rticarial papules

Pustules

Vesicles

Petechiae targetoid lesions

Slide18

Small and medium-sized

(“mixed”)

Cryoglobulinemia

-Types

II and III

ANCA

-associated

Microscopic

polyangiitis

Wegener’s

granulomatosisChurg–Strauss syndromeSecondary causesInfectionsInflammatory disorders (e.g. AI-CTD)PetechiaePalpable purpuraLivedo racemosaRetiform purpuraUlcersSubcutaneous nodulesDigital necrosis

Slide19

Medium-sized Vessel

Polyarteritis

nodosa

(PAN)

Classic

(systemic) PAN

Cutaneous

PAN

Livedo

racemosaRetiform purpuraUlcersSubcutaneous nodulesDigital necrosis

Slide20

Large Vessel

Temporal Arteritis

Early

– erythematous or cyanotic skin, alopecia,

purpura

, tender nodules on

frontotemporal

scalp

Late

– Ulceration and/or gangrene of

frontotemporal scalp or tongueTakayasu’s arteritisErythematous subcutaneous nodules +/− ulceration, pyoderma gangrenosum-like lesions on the extremities (lower > upper)May have evidence of small and/or medium-sized vessel vasculitis

Slide21

Mimics of vasculitis

Infections

Embolic disorders

Malignancy

Drugs

Slide22

Conditions that may cause secondary vasculitis

Idiopathic

50

%

Infections

15–20

%

Connective tissue diseases 15–20

%

Drugs

10–15%Neoplasms 2–5%Genetic disorders RareImmunodeficiency syndromesFamilial Mediterranean fever and other periodic fever syndromes

Slide23

Infection

Bacterial

Beta-hemolytic streptococci, especially group

A

Mycobacterium

leprae

Neisseria

meningococcus

(in chronic meningococcemia

)

Mycobacterium tuberculosisAtypical mycobacteriaSeptic vasculitisInfective endocarditisViralUpper respiratory tract infectionHepatitis C > B ≫ A, including vaccinesHIVParvovirus B19

Slide24

Inflammatory disorders

Autoimmune

connective tissue

diseases

Rheumatoid

arthritis

SLE

Sjögren’s

syndrome

Inflammatory bowel diseaseBehçet’s diseaseHypergammaglobulinemic purpura of WaldenströmSeronegative spondyloarthropathiesSarcoidosisCystic fibrosisPrimary biliary cirrhosisBowel-associated dermatosis–arthritis syndromeGluten enteropathy (adult HSP)

Slide25

Drug-exposure

Common

Allopurinol

Bortezomib

Cephalosporins

, esp.

cefaclor

D

-

penicillamine

G-CSFHydralazineMethotrexateMinocyclineNSAIDsOral contraceptivesPenicillinsPhenytoinPropylthiouracil/other antithyroid agentsQuinidineQuinolonesSerum (e.g. ATG)StreptokinaseSulfonamidesThiazides

Uncommon

ACE inhibitors

TNF

-α

inhibitors

Beta

-

blockers

Cocaine

adulterated with

levamisole

COX

-2

inhibitors

Furosemide

Interferons

Leukotriene inhibitors

Macrolide antibiotics

Quinine

Retinoids

Sirolimus

Sulfonylureas

Vancomycin

Warfarin

Rare

Amiodarone

Aspirin

Atypical antipsychotics

Gabapentin

Insulin

Leflunomide

Mefloquine

Metformin

Methamphetamine

3,4

-

methylenedioxymethamphetamine

Phenothiazines

Radiographic

contrast

media

Rituximab

SSRIs

Tocolytics

(e.g.

ritodrine

,

terbutaline

)

Vitamins

Food

/drug

additives

SSKI

Slide26

Neoplasms

Plasma cell

dyscrasias

Monoclonal

gammopathies

Multiple myeloma

Myelodysplasia

Myeloproliferative

disorders

Lymphoproliferative

disordersHairy cell leukemiaSolid organ carcinomas (adults with IgA-positive vasculitis)

Slide27

Skin Biopsy

W

ithin

the first 24 to 48 hours of

appearance

> 48 to 72 hours may have a predominantly mononuclear rather than

neutrophilic

infiltrate

Perilesional

skin for direct immunofluorescence (DIF)

~80% of cases of CSVV DIF demonstrates deposition of C3, IgM, IgA and/or IgG in a granular pattern within the vessel wallsImmunoglobulin deposition is highest (up to 100%) in skin lesions present for ≤48 hours. 30% of samples obtained 48–72 hours after lesion onset, DIF will be negative for immunoglobulins, and only C3 will be detected in lesions present for >72 hours. In ANCA-positive vasculitis, the DIF of lesional skin is usually negative.

Slide28

Histology

Leukocytoclastic

vasculitis

Transmural

infiltration of the walls

of

postcapillary

venules

by

neutrophilsFibrinoid necrosis of the damaged vessel wallsLeukocytoclasia (degranulation and fragmentation of neutrophils, leading to the production of nuclear dust)Extravasated erythrocytes, and signs of endothelial cell damageNeovascularization of the adventitia, in the form of small capillaries, is commonly seen in older lesions of medium-sized vessel vasculitis

Slide29

Prognosis

D

epends

upon the severity of systemic

involvement

~ 90% spontaneous

resolution of cutaneous lesions within several weeks or a few

months

10

% will have chronic or recurrent disease at intervals of months to

yearsAverage duration of disease activity is 28 months The presence of arthralgias or cryoglobulinemia and an absence of fever may portend chronicity Autoimmune connective tissue disease or neoplasm, will also affect prognosis

Slide30

Treatment

First-line therapy

Discontinue

incriminated drugs

Supportive care

Treat underlying infections, neoplasms

NSAIDs

Antihistamines

Second-line therapy

Colchicine

(0.6 mg bid–tid)Dapsone (50–200 mg/day)CorticosteroidsHydroxychloroquineThird-line therapyAzathioprine (2 mg/kg/day)MethotrexateIVIgCyclosporineCyclophosphamidePlasmopharesis

Slide31

Henoch–Schönlein

Purpura

CSVV with vascular IgA deposition

Most

commonly occurs in children <10 years of

age

1

to 2 weeks following an upper respiratory tract

infection

20–50% of HSP patients have positive antistreptolysin O titers, no causal role for group A β-hemolytic streptococci has been demonstrated.Genetic polymorphisms may predispose to more severe disease HLA-B35 positivity may predispose to renal diseaseAbsence of ICAM-1 469 K/E variant have less severe gastrointestinal involvementMay be associated with an underlying malignancy in adults

Slide32

HSP Classic Tetrad

Purpura

(100%)

Intermittent palpable

purpura

S

ymmetrically

distributed on the buttocks and lower extremities, but may also involve the trunk, upper extremities and face

Arthritis and

arthralgias

(75%)Knees and anklesAbdominal pain and/or melena (50–75%) May precede the purpura Colicky abdominal pain (65%)Gastrointestinal bleeding (30%) VomitingHematuria (40–50

%)

M

icroscopic

hematuria (40%

)

Proteinuria

(25%)

Nephritis is

clinically evident within 3

months

1

–3% of children will develop long-term renal

impairment

Orchitis

is a rare form of involvement in young boys.

Fever ~

20% of adults and 40% of

children

Slide33

Prognosis

Individual lesions usually regress within 10 to 14

days

Complete resolution

of skin involvement over a period of several weeks to

months

Recurrences

of skin disease are observed in 5–10% of

patients

Poor prognostic factors

include:Renal failure at the time of onsetNephrotic syndromeHypertension Decreased factor XIII activity

Slide34

Adult HSP

Necrotic

skin lesions are present in 60% of adults while cutaneous necrosis is observed in <5% of

children

30% will develop chronic renal insufficiency

P

urpura

above the

waist

FeverElevated ESR60–90% of patients with neoplasm-associated IgA vasculitis will have cancer of a solid organ - lung

Slide35

Diagnosis

Leukocytoclastic

vasculitis of the small dermal blood

vessels

DIF

demonstrates perivascular IgA, C3 and fibrin

deposits,

IgA ANCA may be present in some

patients

80% of all adults with CSVV may demonstrate some vascular IgA deposition and IgA deposition can be seen in other diseases (e.g. drug hypersensitivity), a diagnosis of HSP is supported by IgA predominance in the correct clinical settingEULAR/PReS:Palpable purpura and at least one of the following must be present:arthritis (acute, any joint) or arthralgiadiffuse abdominal painany biopsy demonstrating predominant IgA depositionrenal involvement (hematuria and/or proteinuria)Evidence of medium-sized vessel disease or widespread lesions (including the face) may indicate an underlying IgA paraproteinemia

Slide36

Treatment

First-Line – Supportive care

Second-Line

therapy

Dapsone

Colchicine

Corticosteroids

Azathioprine

±

Corticosteroids

Cyclophosphamide ± CorticosteroidsCyclosporine ± CorticosteroidsAntihistaminesThird-Line therapyIVIgRituximabMycophenolate mofetilCorticosteroids + tacrolimusAminocaproic acidPlasmapharesisFactor XIII

Slide37

Slide38

Cryoglobulinemic Vasculitis

Cryoglobulins

are cold-

precipitable

immunoglobulins

that can be divided into three subtypes, all of which have cutaneous

manifestations

Palpable

purpura

, typically on the lower extremitiesMyalgias and arthralgias (70%)Associated with mixed serum cryoglobulins (IgM and IgG), most commonly in the setting of HCV infectionPeripheral neuropathy (Sensory – 40%) Glomerulonephritis (Membranoproliferative -25%)GI or Hepatitis (30%) – Viral or autoimmune hepatitis

Slide39

CLASSIFICATION OF CRYOGLOBULINS

Subtype

Molecular composition

Associations

Pathophysiology

Clinical manifestations

I

Monoclonal

IgM

>

IgGPlasma cell dyscrasias, lymphoproliferative disordersVascular occlusionRaynaud’s phenomenon, retiform purpura, gangrene, acrocyanosis

II

Monoclonal

IgM

(>

IgG

) against polyclonal

IgG

HCV, HIV, autoimmune connective tissue diseases,

lymphoproliferative

disorders

Vasculitis

Palpable

purpura

,

arthralgias

, peripheral neuropathy, glomerulonephritis

III

Polyclonal

IgM

against polyclonal

IgG

Slide40

Diagnosis

T

ests

for

cryoglobulins

can be falsely negative and need to be assayed during clinical flares on more than one

occasion

T

he

blood sample should be kept at 37°C while being transported to the laboratory.

70% of patients have circulating RF activity20% have antinuclear antibodies15% of patients with mixed cryoglobulinemia have a monoclonal gammopathy as detected by serum protein electrophoresis and/or immunofixation electrophoresisHBV, HCV and HIV serologies should be evaluated =/- viral load complement levels (C4 levels) - do not necessarily correlate with the severity of the diseasePathologyDIF, granular deposits consisting predominantly of IgM and C3 in a vascular pattern are observed in the papillary dermis

Slide41

Treatment

Directed

toward any underlying

disease

All

patients with HCV-associated mixed

cryoglobulinemia

should be treated with interferon-α plus

ribavirin

R

esolution of the cutaneous (100%), renal (50%), and neurologic (25–75%) manifestationsInterferon-α alone may improve the cutaneous vasculitis (50–100%), but is less effective in reversing the neurologic or renal involvement In rare cases, interferon may trigger or worsen the peripheral neuropathy. Second-line therapyCorticosteroid + CyclophosphamideThird-line therapyIVIgRituximab (± ribavirin, IFN)Plasmaphoresis

Slide42

Summary

Think

Vasculitis

if: Unexplained

systemic

illness, Symptoms

of organ system

ischaemia

, Nephritic syndrome

Biopsy early lesions (24-48hrs) and send

perilesional skin for Direct immunofluorescenceAlways consider mimickers of Vasculitis first - Infections, embolic disorders, malignancy and drugsSearch for Secondary causes of CSVV – Infections, connective tissue diseases, drugs, neoplasms, rarely genetic disorders Clinical Tetrad of HSP – palpable purpura, arthritis/arthralgia, abdominal pain and hematuria

Slide43

References

Jennette

JC, Falk RJ. Small‐vessel vasculitis. N

Engl

J Med 1997;337:1512–23

.

Curr

Rheumatol

Rep. 2005 Aug;7(4):270-

5

Lupus (1998) 7, 280± 284 Pathogenesis of vasculitisBolognia Dermatology 3rd Ed. By Jean BologniaEULAR Textbook on Rheumatic Diseases, Johannes Bijlsma

Slide44

Slide45

Slide46

Slide47

Major categories of non‐infectious vasculitis

Large vessel vasculitis

Giant cell arteritis

Takayasu

arteritis

Medium‐sized vessel vasculitis

Polyarteritis

nodosa

Kawasaki disease Small vessel vasculitis ANCA‐associated small vessel vasculitis     MPA     WG     CSS     Drug‐induced ANCA‐associated vasculitis Immune complex small vessel vasculitis     Henoch–Schönlein purpura     Cryoglobulinaemic vasculitis     Lupus vasculitis     Rheumatoid vasculitis     Sjögren's syndrome vasculitis     Hypocomplementaemic urticarial vasculitis     Behcet's disease     Goodpasture's syndrome     Serum sickness vasculitis     Drug‐induced immune complex vasculitis     Infection‐induced immune complex vasculitis Paraneoplastic small vessel vasculitis     

Lymphoproliferative

neoplasm‐induced vasculitis

    

Myeloproliferative

neoplasm‐induced vasculitis

    Carcinoma‐induced vasculitis

Inflammatory bowel disease vasculitis

Slide48

Slide49

Slide50

Pathogenesis

CSVV - mediated

by immune complexes that form in the presence of antigen excess.

Immune

complex deposition in postcapillary venules activates complement, which, in turn, induces mast cell degranulation and neutrophil

chemotaxis

. Neutrophils release

proteolytic

enzymes and free oxygen radicals, leading to damage of the vessel wall (Fig. 24.1A). Increased adhesiveness between inflammatory cells and the endothelium, due to enhanced expression of adhesion molecules (e.g.

selectins

, LFA-1), also plays a role in the pathogenesis of cutaneous vasculitis

Slide51

General clinical

Feature

Signs or presenting disorders

Type of vasculitis

Constitutional symptoms

Low grade fever, fatigue, malaise, anorexia, weight loss

GCA, GPA, MPA,

eGPA

, PAN, less commonly other vasculitis.

Polymyalgia

rheumatica

Proximal muscle pain with morning stiffness

GCA

Myalgias

Diffuse

PAN , GPA, MPA,

eGPA

Non-destructive oligoarthritis

Joint swelling, warmth, painful range of motion, migratory

PAN, MPA,

eGPA

, GPA, hypersensitive vasculitis

Skin lesions

Livedo

reticularis

, necrotic lesions, ulcers, nodules, digital tip infarcts

Any medium-vessel vasculitis

Palpable

purpura

,

urticaria

-like

Any small-vessel vasculitis

ENT symptoms

Sinusitis, otitis, hearing loss

GPA,

eGPA

, MPA

Cranial symptoms

Headache

GCA, TAK, GPA

Multiple

mononeuropathy

(

mononeuritis

multiplex)

Injury to two or more separate peripheral nerves (e.g. drop foot, wrist drop)

PAN,

eGPA

and GPA MPA,

Renal

Involvement

Renal artery involvement

PAN, TAK

Glomerulonephritis

MPA, GPA,

cryoglobulinaemia

,

Henoch-Schönlein

purpura

Gastrointestinal involvement

Abdominal pain, nausea,

diarrhoea

, bleeding

GPA,

eGPA

, PAN,

Henoch-Schönlein

purpura

Cardiovascular involvement

Hypertension

Any type of vasculitis

Ocular involvement

Visual disturbance

GCA, TAK, GPA

Scleritis

,

episcleritis

, uveitis

Behçet’s

disease, GPA

Pulmonary involvement

Asthma

eGPA

Infiltrates

GPA,

eGPA

Slide52

Eosinophilia and elevated

IgE

in the blood and tissues (in situ) are characteristically associated with allergic

angiitis

and

granulomatosis

eg

.

Churg

–Strauss syndrome’; CSS

Slide53

Pathogenesis of Vasculitis

Slide54

Slide55

Anti-

neutrophillic

cytoplasmic autoantibodies

P

rimarily

directed against intracellular

neutrophilic

proteins (e.g. proteinase-3, myeloperoxidase), which can translocate to the neutrophil’s cell surface following primary activation by cytokines such as tumor necrosis factor (TNF)-α.

Binding

to the surface of neutrophils results in neutrophil-mediated vessel

damage. Because the vessel damage in ANCA-positive vasculitides is directly mediated by neutrophils rather than by immune complex deposition, they are referred to as “pauci-immune” vasculitides. Formation of ANCA may be related to an impairment in neutrophil apoptosis which results in a prolonged opportunity for autoantibody development

Slide56

In medium-sized vessel vasculitis, the affected blood vessels reside within the reticular dermis or

subcutis

. As a result, the latter typically presents with

livedo

racemosa

,

retiform

purpura

, ulcers, subcutaneous nodules and/or digital necrosis. In general, the presence of ulcers or necrosis suggests deeper arterial involvement. The combination of palpable purpura (or other signs of CSVV) plus signs of medium-sized vessel disease points to a “mixed” pattern of vasculitis (see Table 24.1), as is seen in ANCA-associated vasculitides, mixed cryoglobulinemia, or autoimmune connective tissue disease-associated vasculitis. Since polyarteritis nodosa affects only medium-sized vessels, it rarely presents with cutaneous signs of small vessel involvement.Arthralgias and arthritis as well as constitutional symptoms such as fever, weight loss and malaise can be manifestations of vasculitis of any size vessel2. For patients with systemic involvement, presenting symptoms and signs (e.g. abdominal pain, paresthesias, hematuria) will vary according to the affected organs.

Slide57

Small Vessel (Cutaneous small vessel vasculitis)

Henoch

–

Schönlein

purpura

Acute

hemorrhagic edema of infancy

Urticarial

vasculitis

Erythema elevatum diutinumSecondary causes of CSVV:Drug exposureInfectionsMalignancies, most often hematologic