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Systemic Vasculitis: a clinical approach
Geordie Lawry MDChief, 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 VASCULITISGRANULOMATOUS POLYANGIITIS (GPA)MICROSCOPIC POLYANGIITIS (MPA)CLASSIC POLYARTERITIS NODOSAGIANT 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 ESRSEVERE anemiaPLATELETS > 500K
When should vasculitis be suspected? 2
CLINICAL FEATURES PARTICULARLYSUGGESTIVE 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-the-scenes 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
• Skin– Palpable Purpura
• Neurologic– Mononeuritis Multiplex
• Musculoskeletal– Arthralgia / arthritis– Muscle pain /
claudication
• Respiratory– Sinusitis / Epistaxis– Pulmonary infiltrates
• 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
http://www.uveitis.org/images/sarcoid6.jpg
Retinal Vasculitis
http://webmedia.unmc.edu/eye/iritis.jpg
Iritis
Scleritis
eyelearn.med.utoronto.ca/.../RedEye/10Sclera.htm
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. > 40 years
B. > 50 years
C. > 60 years
D. > 70 years
E. > 80 years
Questions?
• In the ACR diagnostic criteria for Giant Cell Arteritis (Temporal Arteritis), a patient needs to be greater than what age?A. > 40 years
B. > 50 years
C. > 60 years
D. > 70 years
E. > 80 years
-Almost all are > 60
-Average age is 70
Specific Entities
www.wegenersgranulomatosis.net/imageRJN.JPG
Arthritis Rheum. 1990;33:1122.
Giant Cell ArteritisACR 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)
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 C-ANCA in a patient suspected of having Wegener’s Granulomatosus is:A. Topoisomerase
B. Histidine tRNA synthetase
C. Smith
D. Proteinase-3
E. Myeloperoxidase
Questions?
• The confirmatory antibody for a positive C-ANCA in a patient suspected of having Wegener’s Granulomatosus is:A. Topoisomerase
B. Histidine tRNA synthetase
C. Smith (Sm)
D. Proteinase-3
E. Myeloperoxidase C is the 3rd letter 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
Arthritis Rheum 1990;33:1101.
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
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 79%• Weight loss 73%• Skin involvement 62%• Mononeuritis multiplex 58% • Fever 55%• Arthralgias/Myalgias 50%• Pulmonary involvement 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 50%– weight loss 50%
• Vasculitis can be variable in distribution making diagnosis difficult
Arthritis Rheum. 1990;33:1088
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
Classic PAN: Manifestations
• Mononeuritis multiplex 50%• Renal involvement: 60% (renal arteries, interlobular arteries)
– Hypertension (more common)– Glomerulonephritis (uncommon)
• Abdominal involvement 45%• Arthralgias/Myalgias/Myositis64%• Testicular pain 25%• Pulmonary involvement rare
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
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