Transcript Cutaneous and Urticarial Vasculitis

Roger W. Fox, M.D.
Professor of Medicine/Pediatrics
University of South Florida
Division of Allergy and Immunology
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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
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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
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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 present
Direct immunofluorescence dermopathology
assay: IgG, IgM, IgA and C3, fibrin deposition
Laboratory 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
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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.6th
Edition.
Direct Immunofluorescence Examination of a Skin-Biopsy Specimen.
Kroshinsky D et al. N Engl J Med
2011;365:252-262
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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
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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
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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 Syndrome
Schnitzler Syndrome- IgM gammopathy
Malignancies, immunologic and hematologic
diseases reported
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Chief manifestations
 1 to 3 weeks after
starting use of an
offending agent.
Fever
Urticaria
Lymphadenopathy
Arthralgias
Middleton’s. Allergy principles and practice. 7th Edition.
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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 disease
CNS involvement: aseptic meningitis,
neuropathies
Clinical Photographs of the Patient.
Kroshinsky D et al. N Engl J Med 2011;365:252-262
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
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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
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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
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Drugs may be implicated in
cutaneous vasculitis
Direct immunofluorescent
changes in these lesions
suggest immune-complex
deposition.
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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
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“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.
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CBC with differential
Sedimentation rate
C-reactive protein
Complement studies
Autoantibody profiles
Liver and renal function
Serum protein electrophoresis
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Corticosteroids
Hydroxychloroquine
Dapsone
Immunomodulating drugs
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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
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Similar presentation to MWS (no hearing loss)
May evolve into IgM multiple myeloma or
Waldenstrom’s macroglobulinemia
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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-1B)
 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
 Amyloidosis caused
loss
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.
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 The inflammasome is a large
NLRP3 Inflammasome
complex of proteins, the most
important of which is NLRP31
 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
1Neven
B, et al. Nat Clin Pract Rheum 2008;4(9):481-489. 2Hoffman HM, et al. Arthr Rheum 2008;58(8):2443-2452.
et al. Nat Clin Pract Rheum 2008;4(1):34-42.
3ChurchLD,
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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
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Periodic fevers
Associated with a constellation of other
symptoms and physical exam findings
Arthralgias/arthritis
 Malaise
 Lymphadenopathy
 Rashes or urticaria
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Markers of autoimmunity are negative (e.g.
ANA, an expression of adaptive immunity)