Cutaneous and Urticarial - PowerPoint Presentation

Slide1

Cutaneous and Urticarial Vasculitis

Roger W. Fox, M.D.

Professor of Medicine/Pediatrics

University of South Florida

Division of Allergy and Immunology

Slide2

Cutaneous Vasculitis

Rare, or uncommon clinical diagnosis

Spectrum of presentation: clinical characteristics of

cutaneous

vasculitis

may overlap with

urticaria

Systemic diseases with

cutaneous

vasculitis

constitute the majority of cases, but there are cases of

cutaneous

vasculitis

without a systemic disorder

Constitutional symptoms often accompany the rash when associated with a systemic disorder

Laboratory tests and skin biopsy are diagnostic

Allergist/Immunologist most commonly are consulted to evaluate

urticarial

vasculitis

Slide3

Cutaneous

Vasculitis

Palpable

Purpura

Slide4

Urticarial

Vasculitis

Slide5

Urticarial Vasculitis:

Clinical Features

Nonpruritic

urticarial

-like lesions and palpable

purpura

Individual lesions persist 24-72 h (chronic

urticaria

lesions persist < 24 h)

Vasculitis

is a rare cause of chronic

urticaria

(<5%)

Diagnosis: Skin biopsy

and laboratory

Slide6

Cutaneous Vasculitis

Slide7

Leukocytoclastic Vasculitis

Slide8

Cutaneous Vasculitis

Classified

Small

vessels(typical of

urticarial

vasculitis

) and/or medium sized vessels (usual signs of medium size

vasculitis

are:

purpura

with necrosis,

livedo

reticularis

, subcutaneous nodules, ulcerations, digital ischemia)Inflammatory infiltrate on skin biopsy; mostly neutrophils, but eosinophils can be presentDirect immunofluorescence dermopathology assay: IgG, IgM, IgA and C3, fibrin depositionLaboratory investigation: Complement studies, cryoglobulins, anti-neutrophil cytoplasmic antibodies (ANCA), ANA, CBC, ESR, serum protein electrophoresis

c-ANCA, anti-

proteinase

3 (PR3) associated with Wegener’s;

p-ANCA, anti-

myeloperoxidase

(MPO) associated with

Churg

-Strauss

Slide9

Vasculitis

Cutaneous

vasculitis

often presents as palpable purpuric lesions that may be generalized or limited to the lower extremities or other dependent areas.

Urticarial

lesions, ulcers, and

hemorrahagic

blisters also occur.

May involve other organs

 liver, kidney, brain, and joints.

 

Abbas K et al. Cellular and molecular immunology.6

th

Edition.

Slide10

Direct

Immunofluorescence

Examination of a Skin-Biopsy

Specimen.

Kroshinsky D et al. N Engl J Med 2011;365:252-262

Slide11

Cutaneous

Vasculitis

:

Histopathology Criteria

Blood vessel damage (post-capillary

venule

in dermis)

Endothelial swelling

Fibrinoid

necrosis

Leukocytoclasis

(nuclear fragments)

Extravasation of RBCs

Perivascular inflammation

Complement components (

immunoflorecence); immune complexes deposition

Slide12

Cutaneous Vasculitis

Urticarial

vaculitis

- small vessels; C3,

IgG

,

IgM

*

Lupus

vasculitis

- small and medium-sized vessels; C3,

IgG

,

IgM

*Cryoglobinemias- both size vessels; IgM+Hypersensitivity vasculitis (drug)- small vessel fibrin, C3+Polyarteritis nodosa (both, C3, IgG*), granulomatous polyangiitis (both, C3, IgG*) Henoch-Schonlein purpura (both, IgA+)

*perivascular and BMZ +perivascular

Slide13

Urticarial

Vasculitis

(UV) Differential Diagnosis

Chronic Idiopathic/Autoimmune

Urticaria

Idiopathic UV

Systemic Diseases-SLE

Infections- Hepatitis B/C (

cryoglobulinemia

)

Serum Sickness and Drug Hypersensitivity

Vasculitis

Hypocomplementemic

Urticarial

Vasculitis Syndrome (HUVS)Churg-Strauss SyndromeSchnitzler Syndrome- IgM gammopathyMalignancies, immunologic and hematologic diseases reported

Slide14

Serum Sickness

Chief manifestations

 1 to 3 weeks after starting use of an offending agent.

Fever

Urticaria

Lymphadenopathy

Arthralgias

Middleton’s. Allergy principles and practice. 7

th

Edition

.

Slide15

Serum Sickness

Slide16

Hypocomplementic

Urticarial

Vasculitis

Syndrome

(HUVS)

Urticaria

vasculitis

Arthralgias

/arthritis

Abdominal pain

Angioedema

Uveitis,

scleritis

, conjuncitivitis (unusual in SLE)Proliferative glomerulonephritis (resembles SLE)COPD, pleuritis (unusual in SLE)Rarely, cardiovascular involvement: pericarditis, valvular diseaseCNS involvement: aseptic meningitis, neuropathies

Slide17

HUVS: Lung Transplant for COPD

Slide18

Clinical Photographs of the Patient.

Kroshinsky D et al. N Engl J Med 2011;365:252-262

Slide19

Skin-Biopsy Specimen from a

Lesion

(

Hematoxylin

and Eosin).

Kroshinsky D et al. N Engl J Med 2011;365:252-262

neutophilic infiltration and leukocytoclasis

Slide20

Immunoflorescence

: HUVS C3, C1q and

IgG

Slide21

HUVS vs SLE

Granular deposition of

immunoreactants

along basement-membrane zone (characteristic of cutaneous lupus)

However, in conjunction with

perivascular

immunoreactivity

, suggests HUVS

Urticarial

vasculitis

and low complement levels are commonly associated with

extra-

cutaneous

involvement as in SLE. HUVS has profoundly low complement levels

Slide22

Vasculitis

:

Henoch-Schonlein

Purpura

Small vessel

vasculitis

with

IgA

immune complexes

Classic triad of palpable

purpura

, arthritis, colicky abdominal pain.

Monitor for chronic nephritis

Usual course 4-6 weeks

Slide23

Cutaneous

Vasculitis

Drugs may be implicated in

cutaneous

vasculitis

Direct

immunofluorescent

changes in these lesions suggest immune-complex deposition.

Drugs implicated: Allopurinol, thiazides, sulfonamides, other antimicrobials, several NSAIDs, interferons and anti-TNF

α

; metformin and sulfonylurea antidiabetic drugs.

The presence of eosinophils in the perivascular infiltrate of skin biopsy may indicate a higher probability of a drug etiology. 

http://emedicine.medscape.com/article/1049474-overview

Slide24

Hypersensitivity Syndrome

Drug-induced

Slide25

Churg-Strauss Syndrome

“Allergic

angiitis

and

granulomatosis

”

Almost exclusively in individuals with asthma and allergic rhinitis; systemic

vasculitis

with

eosinophilia

, associated with fever, malaise, weight loss.

The pulmonary involvement dominates the clinical picture. Asthma is a defining feature and precedes the onset of

vasculitis

. Skin, heart, peripheral nervous system, GI tract and kidney can be involved.

Slide26

Cutaneous

Vasculitis

:

Laboratory

CBC with differential

Sedimentation rate

C-reactive protein

Complement studies

Autoantibody profiles

Liver and renal function

Serum protein electrophoresis

Slide27

Treatments for Cutaneous

Vasculitis

Corticosteroids

Hydroxychloroquine

Dapsone

Immunomodulating

drugs

Slide28

Schnitzler Syndrome

Slide29

Chronic

urticaria

with daily fevers X 6

mos

Slide30

Schnitzler Syndrome

Onset as an adult (acquired disorder), although recently a gain of function mutation has been found in the NLRP3/CIAS-1 gene (1 patient)

Characterized by:

Recurring fevers

Neutrophilic urticaria

Monoclonal IgM gammopathy

Joint/bone pain

Similar presentation to MWS (no hearing loss)

May evolve into IgM multiple myeloma or Waldenstrom

’

s macroglobulinemia

Slide31

Neutrophilic

Urticaria

Slide32

Autoinflammatory Syndromes

Past 10 years

Newly identified classification of disease

Dysregulation of innate immunity

Recurrent fevers is common feature

Innate immunity recognize “danger"

Uncontrolled cytokine-mediated inflammation (IL-1

B

)

Slide33

33

Muckle-Wells Syndrome (MWS)

Moderate in severity of inflammation - more intense and long-lasting inflammation flares

Characterized

by

urticarial

rash with onset at birth

,

deafness

and

amyloidosis

Sensorineural

hearing loss

Amyloidosis caused by build up of serum amyloid

A (SAA) protein in kidneys which can lead to kidney failure

Shinkai K, et al. Clin Exper Derm 2007;33:1-9.

Urticarial-like skin eruption in MWS

Reprinted from

Arth Rheum

2004 Feb; 50(2)607-612, Hawkins RN, et al. “Spectrum of Clinical Features of Muckle-Wells Syndrome and Response to Anakinra” with permission from Wiley InterScience.

Slide34

34

NLRP3 Inflammasome pathway

The

inflammasome

is a large complex of proteins, the most important of which is NLRP3

1

Mutations in the NLRP3 gene (a.k.a. CIAS1), which encode the cryopyrin (NALP3) protein, cause

“

autoinflammatory

”

diseases with a spectrum of onset and severity (MWS, FCAS)

2,3

Symptoms and pathology result from overexpression of Interleukin-1



3

*Ilaris is not FDA approved for NOMID

NOMID = Neonatal Onset Multisystem Inflammatory Disease; MWS = Muckle Wells Syndrome;

FCAS = Familial Cold Auto-Inflammatory Syndrome

NLRP3= Nucleotide-binding oligomerization domain, leucine-rich-repeat family, pyrin domain containing 3

NALP3=NACHT leucine-rich repeat protein; CIAS1=Cold Induced Autoinflammatory Syndrome 1

1

Neven B, et al. Nat Clin Pract Rheum 2008;4(9):481-489.

2

Hoffman HM, et al. Arthr Rheum 2008;58(8):2443-2452.

3

ChurchLD, et al. Nat Clin Pract Rheum 2008;4(1):34-42.

NLRP3 Inflammasome

Slide35

Urticarial lesions on trunk (A). Within 24 hours of commencing anakinra, these lesion had resolved (B).

Schnitzler Syndrome J Allergy Clin Immunol 2008;121:261

Slide36

Characteristics of

Autoinflammatory

Disorders

Periodic fevers

Associated with a constellation of other symptoms and physical exam findings

Arthralgias/arthritis

Malaise

Lymphadenopathy

Rashes or urticaria

Markers of autoimmunity are negative (e.g. ANA, an expression of adaptive immunity)

Slide37