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 Artery: WBC inflammation in wall Note White blood cells in the media and adventitia of the vasculitic artery Normal Artery

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 Vasculitides are typically classified by the size (and type) of the vessels they affect. 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 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 .

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 Palpable purpura is caused by rbc extravasation from small vessels that have been occluded by immune complexes. They are heavy and tend to occur in the most gravity-dependent area of the body.

Livedo Reticularis All of us develop this “lacy” vascular pattern when we are cold. However livedo reticularis is caused by relative ischemia of the capillary beds. Vasculitis is one of the causes of livedo.

Splinter Hemorrhages Splinter hemorrhages can be found in the distal nail bed and/or in the periungual area.

NEUROLOGIC Mononeuritis multiplex: check for FOOT DROP Sural nerve biopsy showing vasculitis Note that the nerve tissue is seen at the bottom of the picture. The vessel infiltration with white blood cells occurs in the vasa nervorum.

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) Cellular and Fibrous Crescent Formation in glomerulonephritis. Testicular pain is uncommon in systemic vasculitis, but when it occurs, it is relatively specific for polyarteritis nodosum (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 hepatitis pancreatitis 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 eyelearn.med.utoronto.ca/.../RedEye/10Sclera.htm http://www.uveitis.org/images/sarcoid6.jpg Retinal Vasculitis http://webmedia.unmc.edu/eye/iritis.jpg Iritis Scleritis and iritis (uveitis) present with a red eye, ocular pain, photophobia and decreased vision. Note the “ciliary flush” (erythema adjacent to the iris) in iritis. You can see exudates on the fundoscopic view of retinal vasculitis. All can be clinical manifestations of vasculitis.

Common Laboratory Findings INFLAMMATION: Elevated ESR (can be > 100) Elevated CRP Leukocytosis Thrombocytosis Anemia Low Albumin All of these laboratory findings are nonspecific features of the intense inflammatory response seen in vasculitis.

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

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) The temporal artery in this picture would be expected to have decreased pulsations, to be thickened and painful upon palpation. It is unusual to see the temporal artery abnormalities in recent times. 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 Infiltration of vessel wall with WBC large specimen (4-6 cm) multiple sections evaluated Infiltration of vessel wall with WBC Granulomata, Giant Cells Necrotic material Necrosis of the intima and media with disruption of the internal elastic lamina.

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 A. Topoisomerase (SCL-70) - Scleroderma B. Histidine tRNA synthetase (Jo-1) – ILD/PM C. Smith (Sm) - SLE D. Proteinase-3 – Wegener’s Granulomatosis E. Myeloperoxidase (MPO) MPA 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

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 Note again the fibrocellular cresent inside of Bowman’s capsule. 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 The picture shows neutrophils with fluorescent staining of the entire cytoplasm.

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) RPGN = Rapidly Progressive Glomerulonephritis (another term that describes the aggressive glomerulonephritis seen in association with vasculitis – it is not specific for MPA.

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 Neutrophils with fluorescent staining of the cytoplasm in a perinuclear distribution.

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

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 50% Renal involvement: 60% (renal arteries, interlobular arteries) Hypertension (more common) Glomerulonephritis (uncommon) Abdominal involvement 45% Arthralgias/Myalgias/Myositis 64% Testicular pain 25% Pulmonary involvement rare In PAN, note glomerulonephritis is less common than hypertension, reflecting the tendency for this disease to affect larger vessels.

Polyarteritis Nodosa ANCA 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 Vasculitides are typically classified by the size (and type) of the vessels they affect. 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