Systemic Vasculitis:
a clinical approach
Geordie Lawry MD
Chief, Rheumatology
UC IRVINE
Medicine HS Noon Conference: October 2015
Objectives 1
• List the 4 clinical features which should
prompt you to CONSIDER A
DIAGNOSIS of systemic vasculitis
• List the “Big 5” essential questions in
patients with SUSPECTED GIANT
CELL ARTERITIS
• Describe what is meant by
PULMONARY RENAL SYNDROME
Objectives 2
• List at least 3 ORGANS / SITES commonly
involved in:
CRYOGLOBULINEMIC VASCULITIS
GRANULOMATOUS POLYANGIITIS (GPA)
MICROSCOPIC POLYANGIITIS (MPA)
CLASSIC POLYARTERITIS NODOSA
GIANT CELL ARTERITIS
Objectives 3
• List at least 2 ANCA VASCULITIS
SYNDROMES, associated ANCA
pattern / target antigens
• List at least 2 vasculitides which are
NOT ASSOCIATED WITH ANCA
• List at least 3 or more conditions
that can MIMIC THE CLINICAL
FEATURES OF VASCULITIS
VASCULITIS: Talk Outline
• Introduction and Definitions
• Approach to vasculitis
• Specific Disorders:
– Giant Cell Arteritis
– Granulomatous polyangiitis (Wegener’s)
– Microscopic Polyangiitis
– Polyarteritis Nodosa
– Cryoglobulinemia
• Take Home
VASCULITIS: principles 1
group of clinical syndromes
characterized by inflammation
of blood vessels
Normal Artery
Artery: WBC
inflammation in wall
VASCULITIS: principles 2
systemic diseases that can affect many
different organ systems
can be difficult to diagnose: challenging
clinical picture even for experienced
clinicians
can be life-threatening
VASCULITIS: classification
www.wegenersgranulomatosis.net/imageRJN.JPG
General Approach to
Vasculitis
Throw up your hands….
General Approach to
Vasculitis
Slap at it ….
When should vasculitis be
suspected? 1
• MULTISYSTEM inflammatory disease
• Significant CONSTITUTIONAL
SYMPTOMS
• RAPIDLY PROGRESSIVE organ
dysfunction
• HIGH ESR
SEVERE anemia
PLATELETS > 500K
When should vasculitis be
suspected? 2
CLINICAL FEATURES PARTICULARLY
SUGGESTIVE of small vessel
inflammation:
• SKIN: palpable purpura *
• LUNGS: pulmonary infiltrates /
hemoptysis
• KIDNEY: active urinary sediment
• NEURO: foot drop **
What is the approach to
a patient suspected of
having vasculitis?
WHAT IS YOUR
APPROACH TO ANY
COMPLEX MEDICAL
PROBLEM?
General Approach to
Vasculitis
Gather your equipment….
Find the target….
Take aim…..
NAIL IT !
COMPLEX MEDICAL PROBLEMS 1
HISTORY: PATIENT’S STORY
get careful CHRONOLOGY
…….PROBLEMS
PHYSICAL EXAM: BODY’S STORY
thoughtful, thorough
……..MORE PROBLEMS
LABORATORY: BEHIND-THE-SCENES STORY
Basic CBC, CHEMS, LFTs, UA/micro, CXR
……..MORE PROBLEMS
COMPLEX MEDICAL PROBLEMS 2
Develop a strategy: PROBLEM LIST
CREATE PROBLEM LIST
……… LIST EVERYTHING [split don’t lump]
PRIORITIZE PROBLEM LIST
……… WHAT’S THE BIG GORILLA(S) HERE?
“WORK” the PROBLEM LIST
COMPLEX MEDICAL PROBLEMS 3
“WORK” the PROBLEM LIST
• Think of 3 explanations for each problem
Create a differential diagnosis
• What are the major organs involved?
• Do they inter-relate?
Do the patient’s, body’s and the behind-thescenes stories fit together in some way?
COMPLEX MEDICAL PROBLEMS 4
SYSTEMIC VASCULITIS ?
• Are there additional tests which could
help confirm this suspicion?
• Serologic tests
• Imaging studies
• Tissue biopsy
VASCULITIS: additional testing 1
Serologic tests
• ANCA
• Hepatitis B surface antigen
• Hepatitis C, C3 & C4
• HIV
• ANA
• ACA, “lupus” anticoag panel
VASCULITIS: additional testing 2
Imaging studies
• Sinus CT scan
• Chest CT scan
• Mesenteric
angiogram
VASCULITIS: additional testing 3
Tissue biopsy
• Temporal artery
• Sural nerve
• Muscle
• Lung
• Renal
Common Clinical
Manifestations
• Systemic
– Fever, sweats,
weight loss
• Respiratory
– Sinusitis / Epistaxis
– Pulmonary infiltrates
• Skin
– Palpable Purpura
• Neurologic
– Mononeuritis Multiplex
• Musculoskeletal
– Arthralgia / arthritis
– Muscle pain /
claudication
• Gastrointestinal
– Abdominal Pain
– Bloody stools
• Renal
– Glomerulonephritis
– Hypertension
CUTANEOUS
Palpable Purpura
Livedo Reticularis
Splinter Hemorrhages
NEUROLOGIC
• Mononeuritis multiplex:
check for FOOT DROP
Sural nerve biopsy showing vasculitis
RESPIRATORY: upper
• Sinusitis
• Or……
www.conseils-orl.com/.../sommaire_epistaxis.htm
RESPIRATORY: lower
• Pulmonary infiltrates
• Nodules
• Cavities
GENITOURINARY
•
•
•
•
Glomerulonephritis
Hypertension
Hematuria
RBC casts
• Testicular pain
(especially PAN)
www.bio.davidson.edu/.../Cresgn.jpg
MUSCULOSKELETAL
• Polyarthralgias - common
• Polyarthritis - less common
• Myalgias - common
• Myositis - biopsy may demonstrate
vasculitis in muscle
GASTROINTESTINAL
• Mesenteric ischemia
– pain 30 minutes after eating
– bloody diarrhea
– bowel perforation
• hepatitis
• pancreatitis
• cholecystitis
library.med.utah.edu/WebPath/COW/COW125.html
OCULAR
Scleritis
Retinal Vasculitis
Iritis
http://www.uveitis.org/images/sa
rcoid6.jpg
eyelearn.med.utoronto.ca/.../RedE
ye/10Sclera.htm
http://webmedia.unmc.edu/eye/iritis.jpg
Common Laboratory Findings
INFLAMMATION:
Elevated ESR (can be > 100)
Elevated CRP
Leukocytosis
Thrombocytosis
Anemia
Low Albumin
VASCULITIS MIMICS
• INFECTIOUS DISEASES
– Endocarditis
– HIV
• DRUGS
– Cocaine
– Methamphetamine
• CHOLESTEROL EMBOLI
• ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
Questions?
• In the ACR diagnostic criteria for Giant Cell
Arteritis (Temporal Arteritis), a patient needs
to be greater than what age?
A.
B.
C.
D.
E.
> 40 years
> 50 years
> 60 years
> 70 years
> 80 years
Questions?
• In the ACR diagnostic criteria for Giant Cell
Arteritis (Temporal Arteritis), a patient needs
to be greater than what age?
A.
B.
C.
D.
E.
> 40 years
> 50 years
> 60 years
> 70 years
> 80 years
-Almost all are > 60
-Average age is 70
Specific Entities
www.wegenersgranulomatosis.net/imageRJN.JPG
Giant Cell Arteritis
ACR Criteria (3 of 5)
•
•
•
•
Age > 50
New onset headache
ESR (Westergren)  50
Abnormal artery biopsy
(mononuclear cell infiltrate,
granulomatous inflammation,
usually multinucleated giant cells)
• Temporal artery
abnormality (tender or
decreased pulse)
Arthritis Rheum. 1990;33:1122.
Giant Cell Arteritis
(Other clinical manifestations)
• Visual loss, jaw/tongue claudication, scalp
tenderness
• Fever, weight loss
• PMR symptoms (proximal muscle pain)
• 10% with large vessel involvement (e.g.
subclavian artery)
• Blindness (ischemic optic neuropathy) is
major complication to avoid
GCA:Biopsy
• Temporal artery biopsy
– large specimen (4-6 cm)
– multiple sections evaluated
• Infiltration of vessel wall with
WBC
• Granulomata, Giant Cells
• Necrotic material
GCA: Therapy
• Corticosteroids mainstay of therapy
(~1 mg/kg)
– Calcium and vitamin D
– Consider bisphosphonates
• Try to prevent visual loss with therapy:
– Treat, then biopsy!
Questions?
• The confirmatory antibody for a positive CANCA in a patient suspected of having
Wegener’s Granulomatosus is:
A.
B.
C.
D.
E.
Topoisomerase
Histidine tRNA synthetase
Smith
Proteinase-3
Myeloperoxidase
Questions?
• The confirmatory antibody for a positive CANCA in a patient suspected of having
Wegener’s Granulomatosus is:
A.
B.
C.
D.
E.
Topoisomerase
Histidine tRNA synthetase
Smith (Sm)
Proteinase-3
C is the 3rd letter
Myeloperoxidase
of the alphabet:
Pr-3 C-ANCA
Granulomatous Polyangiitis
(GPA) … formerly Wegener’s
• Necrotizing vasculitis that affects the small
vessels of the respiratory tract and renal
system: PULMONARY-RENAL SYNDROME
• Age ~ 40s: M > F 2:1
Granulomatous Polyangiitis (GPA)
ACR Criteria (3 of 5)
• Nasal or oral inflammation (oral ulcers or bloody nasal
drainage)
• Abnormal chest radiograph (nodules, fixed infiltrates,
cavities)
• Urinary sediment (> 5 RBC/ hpf or casts)
• Abnormal Biopsy: showing vasculitis
• Proteinase-3 antibodies
Arthritis Rheum 1990;33:1101.
Granulomatous Polyangiitis
(GPA) : Respiratory Involvement
• Sinusitis
– Nasal septal ulceration
• Pneumonitis
– few symptoms until late
– usually no mediastinal
lymphadenopathy
– nodules that can
cavitate
Granulomatous Polyangiitis
(GPA) : Renal Involvement
• 85% of patients
• Focal/segmental
necrotizing
glomerulonephritis
• Usually progressive
www.bio.davidson.edu/.../Cresgn.jpg
Granulomatous Polyangiitis
(GPA) : ANCA
• AntiNeutrophil Cytoplasmic Antibody
– C (cytoplasmic staining) ANCA
– Proteinase 3 (C is the 3rd letter)
• Pulmonary-renal disease
– sensitivity of 95%
– specificity of 95%
• Limited disease…
– lower sensitivity and specificity
Granulomatous Polyangiitis (GPA):
Tissue Biopsy
• Yield of biopsy
– Lung
• Open – highest yield
• Bronchoscopy - lower yield
– Sinus - 40% yield
– Renal
• Vasculitis rarely seen
• Focal proliferative GN is the typical finding
Granulomatous Polyangiitis
(GPA) : Rx
• Prior to cyclophosphamide, 80-90% mortality
• With cyclophosphamide, 5-10% mortality
• Concern about long-term toxicity of PO
cyclophosphamide (bladder especially)
• IV CYTOXAN no significant bladder risk
• Rituximab: very effective for induction &
maintenance
• Azathioprine for maintenance
Microscopic Polyangiitis
(MPA)
• Systemic vasculitis with predominant
small vessel involvement
• Separate disease from PAN (Initially thought to
be a variant of PAN)
• Usually RPGN and sometimes with
pulmonary hemorrhage
• More common than PAN (both are rare)
MPA: Clinical Manifestations
•
•
•
•
•
•
•
Renal manifestations
Weight loss
Skin involvement
Mononeuritis multiplex
Fever
Arthralgias/Myalgias
Pulmonary involvement
79%
73%
62%
58%
55%
50%
25%
MPA: ANCA
• P (perinuclear) ANCA
• Myeloperoxidase antibodies
• Sensitivity/Specificity
unclear
MPA: Epidemiology & Rx
• Ave. age 57
• Males > Females (slightly)
• Cyclophosphamide decreases mortality
• IV CYTOXAN no significant bladder risk
• Rituximab: very effective for induction &
maintenance
• Azathioprine for maintenance
Polyarteritis Nodosa
• Necrotizing vasculitis of medium & small arteries
• Age ~ 40s; M > F
• Constitutional symptoms are common
– fever
– weight loss
50%
50%
• Vasculitis can be variable in distribution making
diagnosis difficult
Polyarteritis Nodosa
ACR Criteria (3 of 10)
•
•
•
•
Wt loss > 4 kg
Livedo reticularis
Testicular pain
Myalgias, weakness or
leg tenderness
• Mononeuropathy or
polyneuropathy
•
•
•
•
Diastolic BP > 90
 BUN or Creatinine
Hepatitis B virus
Arteriographic
abnormality
• Biopsy of small or
medium artery
containing PAN
Arthritis Rheum. 1990;33:1088
Classic PAN: Manifestations
• Mononeuritis multiplex
• Renal involvement:
50%
60%
(renal arteries, interlobular arteries)
– Hypertension (more common)
– Glomerulonephritis (uncommon)
•
•
•
•
Abdominal involvement
Arthralgias/Myalgias/Myositis
Testicular pain
Pulmonary involvement rare
45%
64%
25%
Polyarteritis Nodosa
• Association with
Hepatitis B (surface
antigen)
• Classic PAN
is NOT associated with
ANCA
ANCA
Cryoglobulinemia 1
•
•
•
•
•
Paradigm of small vessel vasculitis
Association with hepatitis C infection
Damage is immune complex-mediated
Cryoprecipitate Hepatitis C Ag – Ab
Complement fixing: C4 consumption
C4 levels VERY low
Cryoglobulinemia 2
Cryoglobulinemia 3
PATTERN OF ORGAN INVOLVEMENT:
• constitutional
• Cutaneous
• articular
• vascular
• neurologic
Cryoglobulinemia 4
PATTERN OF LABORATORY FINDINGS:
• rheumatoid factor
• complement C4 ↓ ↓ ↓
• cryoglobulin (cryocrit)
TREATMENT:
• Antiviral therapy …. clearance of hep C virus!
VASCULITIS: classification
www.wegenersgranulomatosis.net/imageRJN.JPG
VASCULITIS OF SMALL >> MEDIUM-SIZED
VESSELS:
• drug-induced small vessel vasculitis
(hypersensitivity vasculitis),
• Henoch-Schönlein purpura (IgA vasculitis),
• ANCA-associated vasculitis
(granulomatosis with polyangiitis [Wegener’s],
microscopic polyangiitis, eosinophilic granulomatosis
with polyangiitis [Churg Strauss syndrome]),
• infection-related vasculitis
(bacterial endocarditis, poststreptococcal vasculitis
and glomerulonephritis) plus hepatitis C-related
cryoglobulinemia)
• vasculitis associated with CTD
(SLE, RA, Sjögren's)
VASCULITIS OF MEDIUM-SIZED VESSELS:
• classic polyarteritis nodosa (PAN)
VASCULITIS OF LARGE VESSELS:
• Giant cell arteritis
• Takayasu arteritis
MIMICS OF VASCULITIS:
• infectious, thrombotic, and embolic disorders