1. Systemic Vasculitis: a clinical approach
Geordie Lawry MD
Chief, Rheumatology
UC IRVINE
Medicine HS Noon Conference: October 2015

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

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

9. General Approach to Vasculitis
Throw up your hands….

10. General Approach to Vasculitis
Slap at it ….

11. When should vasculitis be suspected? 1
MULTISYSTEM inflammatory disease
Significant CONSTITUTIONAL SYMPTOMS
RAPIDLY PROGRESSIVE organ dysfunction
HIGH ESR SEVERE anemia PLATELETS > 500K

12. 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 **

13. 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?

14. General Approach to Vasculitis
Gather your equipment…. Find the target…. Take aim…..
NAIL IT !

15. 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 .

16. 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

17. 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?

18. COMPLEX MEDICAL PROBLEMS 4
SYSTEMIC VASCULITIS ?
Are there additional tests which could help confirm this suspicion?
Serologic tests
Imaging studies
Tissue biopsy

19. VASCULITIS: additional testing 1
Serologic tests
ANCA
Hepatitis B surface antigen
Hepatitis C, C3 & C4
HIV
ANA
ACA, “lupus” anticoag panel

20. VASCULITIS: additional testing 2
Imaging studies
Sinus CT scan
Chest CT scan
Mesenteric angiogram

21. VASCULITIS: additional testing 3
Tissue biopsy
Temporal artery
Sural nerve
Muscle
Lung
Renal

22. 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

23. 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.

24. 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.

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

26. 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.

27. RESPIRATORY: upper Sinusitis Or……

28. RESPIRATORY: lower
Pulmonary infiltrates
Nodules
Cavities

29. 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).

30. MUSCULOSKELETAL Polyarthralgias - common Polyarthritis - less common
Myalgias - common
Myositis - biopsy may demonstrate vasculitis in muscle

31. 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

32. OCULAR Scleritis Retinal Vasculitis Iritis
eyelearn.med.utoronto.ca/.../RedEye/10Sclera.htm
Retinal Vasculitis
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.

33. 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.

34. VASCULITIS MIMICS INFECTIOUS DISEASES Endocarditis HIV DRUGS Cocaine
Methamphetamine
CHOLESTEROL EMBOLI
ANTIPHOSPHOLIPID ANTIBODY SYNDROME

35. 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

36. 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

37. Specific Entities

38. 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.

39. 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

40. 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.

41. 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!

42. 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

43. 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

44. 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

45. 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.

46. Granulomatous Polyangiitis (GPA) : Respiratory Involvement
Sinusitis
Nasal septal ulceration
Pneumonitis
few symptoms until late
usually no mediastinal lymphadenopathy
nodules that can cavitate

47. Granulomatous Polyangiitis (GPA) : Renal Involvement
85% of patients
Focal/segmental necrotizing glomerulonephritis
Usually progressive
Note again the fibrocellular cresent inside of Bowman’s capsule.

48. 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.

49. 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

50. 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

51. 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.

52. MPA: Clinical Manifestations
Renal manifestations 79%
Weight loss 73%
Skin involvement 62%
Mononeuritis multiplex 58%
Fever %
Arthralgias/Myalgias 50%
Pulmonary involvement 25%

53. MPA: ANCA P (perinuclear) ANCA Myeloperoxidase antibodies
Sensitivity/Specificity
unclear
Neutrophils with fluorescent staining of the cytoplasm in a perinuclear distribution.

54. 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

55. 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

56. 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

57. 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.

58. Polyarteritis Nodosa ANCA
Association with Hepatitis B (surface antigen)
Classic PAN is NOT associated with ANCA
ANCA

59. 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

60. Cryoglobulinemia 2

61. Cryoglobulinemia 3 PATTERN OF ORGAN INVOLVEMENT: constitutional
Cutaneous
articular
vascular
neurologic

62. Cryoglobulinemia 4 PATTERN OF LABORATORY FINDINGS: rheumatoid factor
complement C4 ↓ ↓ ↓
cryoglobulin (cryocrit)
TREATMENT:
Antiviral therapy …. clearance of hep C virus!

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

64. 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)

65. 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