1. UPDATES IN DIAGNOSIS AND
MANAGEMENT OF VASCULITIS

2. OVERVIEW
 Basic facts
 Definition and Classification
 Patient perspective
 Management
 Evidence based recommendation
 Newer therapy
 Monitoring
 Complications
 Summary

3. VASCULITIS: BASIC FACTS
• Vasculitis affects all ages, although some types
are restricted to certain age groups
• Vasculitis tends to affect Caucasians, although
many African-Americans are affected
• Vasculitis has a genetic component, but is not
heritable
• Vasculitis is a chronic relapsing
disease, although some patients experience
prolonged remission

4. DEFINITION AND CLASSIFICATION

5. VASCULITIS: DEFINITION
Pathologist
Inflammatory destruction of
blood vessels
• Infiltration of vessel wall with
inflammatory cells
– Leukocytoclasis
– Elastic membrane disruption
• Fibrinoid necrosis of the vessel
wall
• Ischemia, occlusion, thrombosis
• Aneurysm formation
• Rupture, hemorrhage
Rheumatologist
A clinicopathologic
process characterized by
inflammatory destruction
of blood vessels that
results in occlusion or
destruction of the vessel
and ischemia of the
tissues supplied by that
vessel.

6. VASCULITIS: CLASSIFICATION
• Large-vessel vasculitis
– Giant cell arteritis, Takayasu‟s arteritis
– Behcet‟s disease, Cogan‟s syndrome
• Medium-vessel vasculitis
– Polyarteritis nodosa
– Buerger‟s disease, Central nervous system
vasculitis, Kawasaki‟s disease, Rheumatoid vasculitis
• Small-vessel vasculitis
– Wegener‟s, microscopic polyangiitis, Churg-Strauss
– Cryoglobulinemic vasculitis, Henoch-Schönlein purpura,

7. VASCULITIS: CLASSIFICATION
• Large-vessel vasculitis
– Aorta and the great vessels (subclavian, carotid)
– Claudication, blindness, stroke
• Medium-vessel vasculitis
– Arteries with muscular wall
– Mononeuritis multiplex (wrist/foot drop), mesenteric
ischemia, cutaneous ulcers
• Small-vessel vasculitis
– Capillaries, arterioles, venules
– Palpable purpura, glomerulonephritis, pulmonary
hemorrhage

8. ANCA-ASSOCIATED VASCULITIDES
 Wegener’s granulomatosis: granulomatous
inflammation involving the respiratory tract and
necrotizing vasculitis affecting small to medium-
sized vessels
 Microscopic polyangiitis: Necrotizing vasculitis
affecting the small vessels.
 Churg-Strauss Syndrome: Eosinophil-rich and
granulomatous inflammation involving the medium-
sized vessels, and associated with asthma and
eosinophilia

9. Wegener‟s
Churg-
Strauss
MPA
Necrotizing Granuloma
Hypereosinophilia
•Sinusitis
•Subglottic stenosis
•Pulmonary nodules
•Orbital pseudotumor
•Asthma
•Pulmonary infiltrates
•Myocarditis
•Pulmonary capillaritis
•Glomerulonephritis
•Sensory neuropathy
•Mononeuritis multiplex

10. PATIENT PERSPECTIVE

11. VASCULITIS: PATIENT PERSPECTIVE
Herlyn K, Arthritis Rheum 2010; 659

12. VASCULITIS: PATIENT PERSPECTIVE
Pain
Disease-Specific
• Sensory neuropathy
• Cutaneous ulcerations
• Arm claudication
Non-specific
• [Arthritis]
• Vertebral fracture
Fatigue
Vasculitis-induced
• Loss of proprioception
Glucocorticoid-induced
• Muscle loss, Weight gain
• Emotional liability
Immunosuppression-induced
• Cognitive impairment
• Drug-associated fatigue

13. MANAGEMENT

14. • Diagnosis of a systemic vasculitis is often a diagnosis of
exclusion, based on recognition of the clinical syndrome
– e.g. Churg-Strauss: adult onset asthma x 2 years, followed by
atypical pneumonias, followed by peripheral nerve involvement
• Biopsy of involved organ is the most straightforward method
of establishing a diagnosis
– Biopsy may be helpful to exclude infection/malignancy
• Other tests may be suggestive, but not diagnostic
– ESR, CRP
– CT: pulmonary hemorrhage, cavitary lesions
– Bronchoscopy: pulmonary hemorrhage (hemosiderosis)
– Urinalysis: for patients with kidney vasculitis
– ANCA (antineutrophil cytoplasmic antibodies)
– Angiogram (including MRA, CT-angiogram)
VASCULITIS: DIAGNOSIS

15. PRINCIPLES OF TREATMENT
 Identify drives
 Infection, drugs, malignancy
 Induce and maintain remission
 Minimise drug toxicity

16. • Remission induction:
– Cyclophosphamide 2mg/kg po qd x 3-6 months
[or 15 mg/kg IV q 2 wk x3 then q 3 weeks x 6-12 months]
– Prednisone 1mg/kg po qd x 1 month, then taper
– [Bactrim, Calcium, Vitamin D]
• Remission maintenance (minimum 2 years)
– Methotrexate 20-25 mg po q week + folate
– Azathioprine 2mg/kg po qd
– Mycophenolate mofetil 1.5 g po BID
– Leflunomide 20-30 mg po BID
VASCULITIS: TREATMENT

17. „STANDARD‟ THERAPY: „ADD-ON‟ THERAPY
CYC
? improve effective
+ reduce toxicity
IV methyl prednisolone
Plasma exchange
Intravenous immunoglobulin
TNF blockade
AZA/MTX
0 3 6 9 12 15 18 24 months
Prednisolone
CYC; cyclophosphamide, AZA; azathioprine, MTX; methotrexate

18. REDUCE CYCLOPHOSPHAMIDE EXPOSURE
 Switch to alternative on remission
 IV pulse instead of daily oral
 Alternative induction for non-severe disease
18

19. GENERALISED (CYCAZAREM)
80
95
5
0
25
50
75
100
percentage
3 months 6 months Died
Jayne, N Engl J Med 2003
Time from remission to relapse (months)
1614121086420
Survival
1.0
.9
.8
.7
.6
Group
Cyclophosphamide
Azathioprine
Remission Relapse
Oral CYC + prednisolone Continued CYC vs. AZA

20. CYCLOPSde Groot et al, Ann Int Med 2009

21. Months from entry
20181614121086420
Survivaltofirstrelapse
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
LIMB
Cyclophosphamide
Methotrexate
Survivalto1strelapse
EARLY SYSTEMIC (NORAM):
METHOTREXATE (MTX) VS. CYCLOPHOSPHAMIDE (CYC)
MTX
CYC
P = 0.02
EUVAS
%
0
10
20
30
40
50
60
70
80
90
100
MTX CYC
91.5 95.5
Remission Relapse
de Groot et al, Arthritis Rheum 2005

22. Generalised vasculitis –
cyclophosphamide (3-6 months)
Time (months)
183-60
Glomerularfiltrationrate(ml/min) 80
70
60
50
40
De Groot, ASN 2006
Jayne, New Eng J Med 2003
Time to remission
Months from entry
181614121086420
1.0
.8
.6
.4
.2
0.0
LIMB
Daily oral
Pulse
Time to remission, BVAS =0 Recovery of renal function

23. REMISSION MAINTENANCE
 Azathioprine ≅ methotrexate
 How long ?
23

24. LESS CYCLOPHOSPHAMIDE - INCREASES
RELAPSE RISK

26. IMPROVE: CUMULATIVE INCIDENCE OF RELAPSE
0.000.250.500.751.00
0 1 2 3 4 5
Time (years)
AZA MMF
Hiemstra, Am Soc Nephrol 2009

27. EVIDENCE BASED
RECOMMENDATIONS

28. EULAR RECOMMENDATIONS FOR CONDUCTING CLINICAL
STUDIES AND/OR CLINICAL TRIALS IN SYSTEMIC
VASCULITIS: FOCUS ON ANCA-ASSOCIATED VASCULITIS.
 For clinical trials or studies, patients with vasculitis should be
categorised into clearly defined activity states. The following
terms are recommended to use:
remission, response, refractory disease and relapse
 Comprehensive disease assessment in vasculitis requires the
recording of disease activity, damage and function. Use form
of the Birmingham Vasculitis Activity Score, the Disease
Extent Index, the Vasculitis Damage Index and the Short Form
36
Ann Rheum Dis. 2007;66:605-617.

29.  Given the high mortality of untreated systemic vasculitis, the
use of placebo must in general be restricted as an adjunct to
standard therapy for induction treatment.
 Biomarkers such as CRP and/or ESR should be determined
regularly as serologic markers of disease activity, but results
must be interpreted in the context of the clinical findings.

30. EULAR RECOMMENDATIONS FOR THE MANAGEMENT OF
PRIMARY SMALL AND MEDIUM VESSEL VASCULITIS.
 Anti-neutrophilic cytoplasmic antibody (ANCA) testing
(including indirect immunofluorescence and ELISA) should be
performed in the appropriate clinical context
 A positive biopsy is strongly supportive of vasculitis and
should be performed to assist diagnosis and further evaluation
for patients suspected of having vasculitis
 Use of a structured clinical assessment, urine analysis and
other basic laboratory tests at each clinical visit for patients
with vasculitis
Ann Rheum Dis. 2008;68:310-317.

31.  Combination of cyclophosphamide (intravenous or oral) and
glucocorticoids for remission induction of generalised primary
small and medium vessel vasculitis
 a combination of methotrexate (oral or parenteral) and
glucocorticoid as a less toxic alternative to cyclophosphamide
for the induction of remission in non-organ threatening or non-
life threatening ANCA-associated vasculitis
 Use of high-dose glucocorticoids as an important part of
remission induction therapy

32.  Plasma exchange for selected patients with rapidly
progressive severe renal disease in order to improve renal
survival
 Remission-maintenance therapy with a combination of low-
dose glucocorticoid therapy and, either
azathioprine, leflunomide or methotrexate
 Use of antiviral therapy for the treatment of hepatitis C-
associated cryoglobulinaemic vasculitis
 A combination of antiviral therapy, plasma exchange and
glucocorticoids for hepatitis B-associated PAN

33. EULAR RECOMMENDATIONS FOR THE MANAGEMENT OF
LARGE VESSEL VASCULITIS.
 A temporal artery biopsy should be performed whenever a
diagnosis of giant cell arteritis is suspected, but this should not
delay the treatment; a contralateral biopsy is not routinely
indicated
 Early initiation of high-dose glucocorticoid therapy for
induction of remission in large vessel vasculitis
 An immunosuppressive agent should be considered for use in
large vessel vasculitis as adjunctive therapy
Ann Rheum Dis. 2008;68:318-323.

34.  Monitoring of therapy for large vessel vasculitis should be
clinical and supported by measurement of inflammatory
markers
 The use of low-dose aspirin in all patients with giant cell
arteritis
 Reconstructive surgery for Takayasu arteritis should be
performed in the quiescent phase of disease and should be
undertaken at expert centres

35. NEWER THERAPY

36. NEWER THERAPIES, BIOLOGIC OR NON-BIOLOGIC ?
 IVIg
 Anti-TNF
 Rituximab
 ATG
 Alemtuzumab
 Abatacept
 Mycophenolic acid
 Mycophenolate mofetil
(Cellcept)
 Enteric coated MPA
(Myfortic)
 Leflunomide
 Deoxyspergualin

37. RITUXIMAB

38. RITUXIMAB FOR REFRACTORY VASCULITIS N = 63
Jones, Arthritis Rheum 2009

39. RITUXIMAB IN ENT/EYE DISEASE (N=32)
Pre-RTX Post-RTX
Martinez del Pero et al, Clin Otolaryngol 2009

40. RITUXIMAB - RANDOMISED TRIALS IN ANCA
ASSOCIATED VASCULITIS
 RITUXVAS (EUVAS)
 New, with renal involvement
 N=44
 12 month data reported 2008
 RAVE (US)
 New/relapsing renal/non-renal
 N=197
 6 month data reported 2009

41. RITUVAS - BASELINE CHARACTERISTICS
RTX CYC Both
Patients 33 11 44
Age 68 67 68
PR3/MPO-ANCA 20/13 5/6 25/19
GFR (ml/min/1.73m2) 25 15 21
Dialysis 24% 9% 20%
Jones, New Engl J Med 2010

42. RITUXVAS – REMISSION (BVAS = 0 FOR 6 MONTHS)
0.000.250.500.751.00
0 100 200 300 400
Time (days)
Cyclophosphamide Rituximab
Jones, New Engl J Med 2010
RTX CYC
Sustained
remission
25/33
(76%)
9/11
(82%)
No
sustained
remission
2
incomplete
response
6 deaths
1
incomplete
response
1 death
Time to Remission

43. RITUXVAS – SAFETY
RTX CYC
SAEs 31 (42%)
1.0 /pat yr
12 (36%)
1.1 /pat yr
Infections 21 (39%)
0.66/pat yr
7 (21%)
0.60/pat yr
Death 6 (18%) 2 (18%)
0.000.250.500.751.00
ProportionFreeofSAE
0 50 100 150 200 250 300 350
Time (days)
CYC RTX
Time to first SAE
Jones, New Engl J Med 2010

44. RELAPSE
RTX
N=33
CYC
N=11
Relapse 7 (21%) 2 (18%)
Major 1 (3%) 2 (18%)
Minor 6 (18%) 0 (0%)
Jones, ACR/ASN 2010

45. RAVE = US TRIAL

46. RAVE DESIGN
 197 new (49%) or relapsing WG/MPA
creatinine < 4.0mg/dl, no lung haemorrhage
 Randomised, double-blind
rituximab 375mg/m2/wk x4 vs. oral CYC
 Primary end-point
remission and steroid withdrawal at 6 months
Stone J et al, N Engl J Med 2010

47. RAVE – REMISSION RATES
* p=0.01
%patients
p=ns p=ns
Stone J et al, N Engl J Med 2010

48. RAVE RESULTS
 Efficacy
 Nephritis and alveolar haemorrhage similar response
 Safety
 Similar AE rates
 18 month data end 2010
Stone J et al, N Engl J Med 2010

49. MONITORING

50. VASCULITIS: MONITORING
• Large-vessel vasculitis
– MRI/MRA chest/abdomen/pelvis every 6-12 months
• Medium-vessel vasculitis
– Mesenteric angiogram to assess disease activity
– EMG/NCV to monitor nerve damage
– Wound care for cutaneous ulcers
• Small-vessel vasculitis
– Chest CT every 6-12 months
– Blood and urine tests every 1-4 weeks

51. COMPLICATIONS

52. VASCULITIS: LONG-TERM DAMAGE
• Large-vessel vasculitis
– Blindness, Stroke
– Claudication: “Angina” of the arms
• Medium-vessel vasculitis
– Foot drop: inability to lift a foot
– Wrist drop: inability to lift a hand
– Cutaneous ulcerations
• Small-vessel vasculitis
– Oxygen dependence
– Renal insufficiency/failure

56. SUMMARY

57. VASCULITIS: SUMMARY
• The systemic vasculitides are chronic
diseases, characterized by relapse and remission
• Achieving remission requires intense monitoring by
a multidisciplinary team with expertise in these
diseases
• Even after achieving disease remission, patients
will continue to suffer from the chronic, irreversible
consequences of both the disease and its therapies
• Pain and fatigue are common consequences of
vasculitis that are independent of disease activity
and generally fail to respond to immunosuppression

58.  Cyclophosphamide induction has been optimised
 Remission maintenance with AZA or MTX, MMF
less effective
 Rituximab alternative to CYC and preferred for
relapsing/refractory disease. ? Maintenance of
remission after RTX

59. Thank you