Vasculitis

Question 1

Mechanisms of vasculitis - cell mediated, immune complex mediated, ANCA associated

Answer 1

• Cell mediated: GCA, takayasu, primary CNS vasculitis
• Immune complex mediated: PAN, HSP, cryoglobulinemic vasculitis
• ANCA associated: granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis

Question 2

What are the typical presentations of large, medium and small vessel?

Answer 2

• Large vessel: limb claudication, bruits, asymmetric blood pressure, absence pulses
• Medium vessel: cutaneous nodules, ulcers, livedo reticularis, digital gangrene, mononeuritis multiplex, renovascular htn
• Small vessel: palpable purpura, urticaria, glomerulonephritis, alveolar haemorrhage, scleritis

Question 3

Large vessel vasculitis - compare GCA with takayasu

Answer 3

• Granulomatous arteritis in patient > 50yo = giant cell arteritis
• Granulomatous arteritis in patient < 50yo especially if female = takayasu

Question 4

How do you differentiate small vessel vasculitis

Answer 4

Immune complexes in vessels

• Cryoglobulins in blood and vessels: cryoclobulin vasculitis
• IgA dominant vessel wall deposits: HSP
• SLE or RA: SLE/RA vasculitis

Paucity of vascular Ig (often with ANCA)

• Vasculitis with no asthma or granulomas: microscopic polangiitis (pANCA, MPO)
• Granulomas and no asthma: granulomatosis with polyangiitis (cANCA-PR3)
• Eosinophilia, asthma, granulomas - churg strauss, eosinophilic granulomatous with polyangiitis (pANCA, MPO)

Question 5

Symptoms of GCA

Answer 5

• PMR
• Headache (unilateral or bilateral)
• Scalp tenderness
• Jaw claudication
• Diplopia or blindness, constitutional symptoms

Eyes: affects the POSTERIOR CILIARY ARTERIES causing anterior ischaemic optic neuritis

Question 6

Diagnosis of GCA

Answer 6

• ESR ++
• CRP
• Doppler US: halo sign , compression sign
• Temporal artery biopsy: gold standard but can have false negatives due to skip lesions

Question 7

Treatment for GCA

Answer 7

• Empirical: PO Prednisone
• If vision threatening: IV methypred 500g for 3 days while awaiting confirmatory test
• Aspirin to prevent ischaemic events
• Pred sparing include methotrexate or tocilizumab (IL6)

Question 8

Histopathology of GCA biopsy

Answer 8

• 50% granulomatous inflammation of the inner half of the media with fragmentation of the internal elastic membrane
• 60% giant cells
• Non specific pan-arteritis
• Fibrinoid necrosis not seen (a sign of PAN)
• Negative biopsy does not exclude GCA

Question 9

In a 75yo woman presenting with unilateral temporal headache, which of the following clinical features is most specific for the diagnosis of temporal arteritis?
A. Unilateral headache
B. Blurred vision
C. Jaw claudication
D. Pain and stiffness around the hips and shoulders
E. Fever

Answer 9

Jaw claudication

Question 10

58yo woman with unilateral headache, vision loss and morning stiffness has a biopsy of her temporal artery. What are the histologic findings you would expect on biopsy?

A. Large vessel giant cell vasculitis with fragmentation of elastic lamina
B. Small vessel eosinophilic vasculitis
C. Medium vessel vasculitis with fibrinoid necrosis
D. Large vessel granulomatous vasculitis with massive intimal fibrosis
E. Fibrinoid necrosis of the external and internal elastic lamina

Answer 10

A. Large vessel giant cell vasculitis with fragmentation of elastic lamina

Question 11

72yo male presents with unilateral headache, jaw pain on chewing and shoulder and hip girdle stiffness. Commenced on pred and responds initially but symptoms reoccur. Which of the following drugs would be most appropriate to add in addition to pred?
A. Adalimumab 
B. Secukinumab 
C. Tocilizumab
D. Golimumab
E. Abatacept
F. Tofacitinib

Answer 11

C

Question 12

34yo female presents with malaise, fever, arm pain, loss of appetite and blurred vision. Exam reveals reduced pulsation and low BP on the upper extremities. Pulses and BP on the lower extremities are normal. Which of the following are the most likely morphologic changes within the affected arteries?
A. Segmental necrotising inflammation
B. Necrotizing inflammation with thrombosis and abscess formation
C. Necrotising inflammation with eosinophilia
D. Granulomatous inflammation and treponemas
E. Granulmatous inflammation and AFB
F. Granulomatous inflammation

Answer 12

F- granulomatous inflammation

AFB: TB
Treponema: Syphillis

Question 13

Characteristics of takayasu

Answer 13

• Young women, especially asian, <50yo
• Triphasic presentation
  Constitutional: fever, arthralgia, weight loss
  Vessel inflammation: pain, tenderness
  Fibrotic: bruits, ischaemia

• Primarily granulomatous inflammation of aorta and its branches initially proximal subclavian artery then others
• Abdominal aorta effected eventually in 50%
• Aneurysmal dilatation or scarred stenosed vessel
• Renal involvement: Involvement of the renal arteries leads to
renovascular hypertension in > 50% cases

Question 14

Investigations for takayasu

Answer 14

• elevated ESR
• Angiography: detects vascular stenosis
• Biopsy
  Granulomatous inflammation
  Infiltrate localised to outside (rather than inside for GCA)
  T lymphocytes and NK cells

Question 15

Treatment for takayasu

Answer 15

Steroids and methotrexate are first line.
Mycophenolate, azathioprine, cyclophsphamide or biologics also used

Sometimes for irreversible stenosis- Percutaneous transluminal
angioplasty or bypass grafts

Question 16

Characteristics and symptoms of polyarteritis nodosa

Answer 16

• 40-60yo, M=F

Clinical Features

• Fever, constitutional symptoms
• Neuropathy - normally mononeuritis multiplex, sensorimotor polyneuropathy
• Rash - livedo reticularis
• Renal failure
• Renal HTN (don’t biopsy), GI involvement (especially Hep B), orchitis, iritis
• Lungs generally spared (can have infiltrates, nodules)
• Livedo reticularis, haematuria, renal failure

Bloods
- ANCA negative
(if MPO thinking of MPA)
- Hep B*
- HIV

Imaging: MESENTERIC or RENAL angiography would show stenosis and microaneurysms

Histo: focal segmental necroitising vasculitis of medium arteries (fibrinoid necrosis with predominantly neutrophils)

In PAN the Pulmonary Arter is Not involved, PANmural inflammation of the arterial wall is present and PAN is often associated with Hepantitis B.

Question 17

Treatment of PAN

Answer 17

• PAN (no HBV): steroids, cyclophosphamide, azathioprine, methotrexate, mycophenolate, infliximab

HBV associated PAN:

• Prednisone to control symptoms (lower dose with rapid taper)
• Plasmapheresis (to remove immune complexes)
• Anti-viral agents

Prognosis very poor without therapy

Question 18

Characteristicis of thromboangiitis obliterans (Buerger disease)

Answer 18

• Men <45 yo
• Inflammatory, obliterative, nonatheromatous vascular disease (small and medium arteries)
• Characterised by inflammatory thombus formation
• Strong association with tobacco use
• Intermittent claudication due to severe limb ischaemia, acute necrosis of toes and fingers often requiring amputation
• Superficial thrombophlebitis and Raynaud phenomenon in 40%
• Angiography (confirmatory test: non atherosclerotic segmental occlusion of arteries - focal stenosis or occlusion with otherwise normal proximal vessels
• Tx: stop smoking, vasodilators (eg: calcium channel blocker, sildenafil, iloprost)

Question 19

55yo female, non smoker diagnosed with systemic vasculitis affecting medium sized arterities. Biopsy shows transmural inflammatory infiltrate without giant cells and fibinoid necrosis of the media. Normal upper airway and aortic arch. Most likely dx
A. HSP
B. Temporal arteritis
C. Polyarteritis nodosa
D. Thromboangiitis obliterans
E. Granulomatosis with polyangiitis

Answer 19

C. Polyarteritis nodosa

Question 20

50ymo male with reddish blue skin lesions on legs, fever, myalgia and weight loss. PE: multiple red purple nodule on both legs. ANCA negative. Haematuria and proteinuria. Abdo US: 1-2cm fluid filled cavities in both kidneys. Which of the following is the most likely dx?
A. PAN
B. Microscopic polyangiitis
C. Churg strauss
D. HSP
E. Anti GBM

Answer 20

A PAN

Question 21

What is cANCA and pANCA?

Answer 21

• cANCA against PR3, correlated with ENT, upper respiratory tract disease, high relapse rate
• pANCA against MPO, associated with haematuria and GN

Question 22

Characteristics of GPA

Answer 22

Glomerulonephritis
Pulmonary Haeorrhage
Neuropathy
Palpable Purpura

Affects:
- LUNG + ENT: Upper and lower respiratory tract: nasopharynx (sinus pain, ulcers, saddle nose), strawberry gingivitis, lungs (SOB, cough blood)
- KIDNEY: GN, RPGN
- Eyes, skin, joints, PNS/CNS, cardiac
Essentially looking for renal-pulmonary involvement and involvement of upper and lower respiratory tract

• Strong association with cANCA and PR3
• ANCA titre in GPA useful for predicting flare of disease

Granulomatosis with polyangiitis is the ‘C’ disease: Curvy nose (saddle nose deformity), Chronic sinusitis, Cough, Conjunctivitis and Corneal ulceration, Cardiac arrhythmias, nonCaseating granulomas on biopsy, cANCA, Corticosteroids and Cyclophosphamide as treatment.
Limited GPA

Treatment: cyclophosphamide or rituximab

Question 23

Characteristics with microscopic polyangiitis

Answer 23

Similar to GPA but

• KIDNEYS: pauci immune GN –> rapidly progressive crescenteric GN
• LUNGS: pulmonary vasculitis with haemoptysis
• NOT nasopharynx
• No granulomas
• Neuropathy
• P-ANCA MPO
• Similar to PAN but does not cause microaneurysm formation in abdominal or renal vessels
• Treat like GPA
• Relapse is common

Question 24

Characteristics of churg strauss egpa

Answer 24

• Sinusitis and lung
• GI, skin, nerve, joints - peripheral neuropathy is common
• Renal less common
• Think of EGPA if stem has asthma or allergy history (eosinophilia)
• Granulomas
• P-ANCA

Question 25

Clinical features of churg strauss egpa

Answer 25

- Asthma >95%: precedes the development - Sinusitis - Lung infiltration - Peripheral neuropathy - Skin disease - Renal disease

Question 26

Renal pulmonary syndromes

Answer 26

- DDx: GPA, MPA, Goodpasture disease, SLE - Goodpasture: anti-basement membrane antibodies, linear deposition of Ig in GBMs - SLE: immune complex deposition in the glomerulus. Granular (lumpy) deposition of Ig. "full house" immunofluorescence - IgG/A/M/complement - GPA/MPA: pathophysiology unclear, immunofluorescence usually negative or "scant"

Question 27

Treatment of ANCA vasculitis

Answer 27

Induction: Steroids, CYC or rituximab or MMF (Avacopan c5a) - essentially cyclophosphamide or ritux Rituximab usually used to help with fertility Maintenance: AZA, MTX, MMF, leflunomide, rituximab SE of rituximab: hypogammaglobulinaemia Mepolizumab (IL-5) for EGPA

Question 28

Predictors of relapse in ANCA vasculitis

Answer 28

- Wegners (granulomatosis with polyangiitis) or PR3-ANCA at diagnosis - Remains ANCA positive despite treatment - Become ANCA positive during treatment - Increase in ANCA titre is of uncertain prognostic significance

Question 29

Characteristics of HSP

Answer 29

- Elevated IgA - Skin especially buttocks and legs - palpable purpura (leukocytoclastic or necrotising vasculitis), arthritis, GI tract (abdo pain), kidneys - haematuria - IgA nephropathy - Often follows respiratory infection or GIT infection and resolves on its own - NSAIDs, steroids for severe disease. Progressive renal disease usually does not respond to steroids

Question 30

All of the following vasculitis syndrome are thought to be due to immune complex deposition except? A. Cryoglobulinaemic vasculitis B. HSP C. Polyarteritis nodosa associated with hepatitis b D. Serum sickness E. Granulomatosis with polyangiitis

Answer 30

E. Granulomatosis with polyangiitis

Question 31

``` Peripheral neuropathy and mononeuritis multiplex are seen most frequently in? A. EGPA B. GPA C. Takayasu D. Drug induced vasculitis ```

Answer 31

A. EGPA Other conditions where peripheral neuropathy is seen is PAN

Question 32

Characteristics of behcets

Answer 32

Cardinal Features - Relapsing oral + genital ulcers with bilateral posterior or panuveiitis Other Features - Recurrent papulopustular lesions - EN like lesions - Non erosive mono/oligoarthritis - Pathergy - Vasculitis involving all vessels - venous tend to be thrombotic, arterial - pseudoaneurysms HLAB51 Behcet's syndrome is a complex multisystem disorder associated with presumed autoimmune-mediated inflammation of the arteries and veins. The precise aetiology has yet to be elucidated however. The classic triad of symptoms are oral ulcers, genital ulcers and anterior uveitis Epidemiology more common in the eastern Mediterranean (e.g. Turkey) more common in men (complicated gender distribution which varies according to country. Overall, Behcet's is considered to be more common and more severe in men) tends to affect young adults (e.g. 20 - 40 years old) associated with HLA B51 around 30% of patients have a positive family history Features classically: 1) oral ulcers 2) genital ulcers 3) anterior uveitis thrombophlebitis and deep vein thrombosis arthritis neurological involvement (e.g. aseptic meningitis) GI: abdo pain, diarrhoea, colitis erythema nodosum Diagnosis no definitive test diagnosis based on clinical findings positive pathergy test is suggestive (puncture site following needle prick becomes inflamed with small pustule forming) ``` Diagnostic Criteria - Oral aphthous ulcers x 3 in 12 months - Plus 2 of the following 4 features § Ocular inflammation § Genital ulcers § Pathergy reaction - Pathergy is an exaggerated skin injury occurring after minor trauma such as bump, bruise, needle stick injury. A more severe injury, such as a surgical procedure, can result in persistent ulceration in a patient with pathergy - Skin lesions: pustules, erythema nodosum -Treatment: colchicine, steroids - Associated with venous thromboses ``` • Strong HLAB51 association

Question 33

What are rare causes of ANCA associated vasculitis

Answer 33

- 10-40% of Anti-GBM antibody disease ANCA+ [mostly MPO] - Drug associated ANCA vasculitis: most commonly anti-thyroid drugs, minocycline, hydralazine, cocaine contaminated with levamisole, penicillamine, clozapine and isoniazid

Question 34

Overview of pauci immune vasculitis

Answer 34

Preceded by fever, malaise, anorexia, and weight loss for weeks to months • Wegeners- granulomatous inflammation effecting upper and lower respiratory tracts with GN • Microscopic Polyangiitis- Necrotising inflammation causing GN, pulmonary capillaritis but NO asthma/eosinophilia/granulomas • Churg-Strauss- asthma, eosinophilia and necrotising granulomatous inflammation involving respiratory tract, renal involvement less common • Renal biopsy (COMMON IN ALL THREE PAUCI-IMMUNE VASCULITIS) shows segmental necrotizing glomerulonephritis often with crescents, no granulomas/IF negative (called pauci immune)

Question 35

True about PAN- a. Can effect both arteries and veins b. Classically presents with haemoptysis c. Kidney involvement manifests as glomerulonephritis d. Characterised by absence of vasculitis in veins e. Can effect both large and small blood vessels

Answer 35

d. Characterised by absence of vasculitis in veins Causes renal HTN rather than GN

Question 36

The commonest clinical manifestation of PAN is- a. Abdominal pain b. Testicular pain c. Haemoptysis d. Hypertension e. Peripheral neuropathy

Answer 36

e. Peripheral neuropathy

Question 37

ANCA positive vasculitis is not seen in- a. Lupus nephritis b. Goodpasteur syndrome c. Use of anti-thyroid disease d. Microscopic polyangitis e. Anti- GBM antibody disease

Answer 37

a. Lupus nephritis

Question 38

Renal involvement is the least common in- a. Churg Strauss syndrome b. IgA nephropathy c. Microscopic polyangitis d. Lupus nephritis e. Polyangitis with granulomatosis

Answer 38

a. Churg Strauss syndrome

Question 39

Which of the following is true about microscopic polyangitis- a. There is a strong association with hepatitis C b. Histology shows granuloma formation c. Usually leads to saddle nose deformity of the nose d. Kidney histology often shows crescents e. Is associated with eosinophilia

Answer 39

d. Kidney histology often shows crescents

Question 40

What arteries are involved in GCA?

Answer 40

Temporal arteries Aorta Aortic branches Posterior ciliary arteries

Question 41

Complications of GCA

Answer 41

- Permanent visual loss - anterior ischaemic optic neuropathy - Aortic aneurysm, dissection - Peripheral and cerebrovascular disease: stroke, limb claudication

Question 42

Cocaine induced vasculitis

Answer 42

- Autoimmune serology negative - Skin Biopsy: small vessel vasculitis, IgA negative - Cocaine use confirmed on history - Spontaneous resolution

Question 43

Features of leukocytoclastic vasculitis

Answer 43

Mechanism - Capillary wall inflammation: extravasation of blood products and inflammatory cell debris 3 Features on Biopsy - Fibrinoid necrosis (fibrin in wall) - Neutrophil dust - leukocytoclastia - Extravasated dust IgA vasculitis = Henoch Schonlein Purpura

Question 44

Treatment of GPA and MPA

Answer 44

``` Major Organ (kidney, lung, nerve) (A) Induction (6 months) - Rituximab (better in PR3 cANCA) or cyclophosphamide - Steroid - No role for routine plasmapheresis ``` (B) Maintenance (4 years +) - Rituximab is superior to azathioprine - Azathioprine or methotrexate Minor Organ (sinus, joints) - Induction: methotrexate + steroid - Maintenance: methotrexate or azathioprine

Question 45

Treatment of EGPA

Answer 45

Major Organ (cardiac, renal, CNS, GIT) (A) Induction - Rituximab or cyclophosphamide - Steroid (B) Maintenance - Rituximab is superior to azathioprine - Azathioprine or methotrexate Minor Organ (lung, sinus, skin) - Induction: Steroid +/- Mepolizumab (IL5i) - Maintenance: Mepolizumab or azathioprine

Question 46

Which connective tissue disease are associated with vasculitis?

Answer 46

- RA - SLE - Sjogren's Syndrome

Question 47

Causes of drug induced vasculitis

Answer 47

- Cocaine (levamisole) - Propylthiouracil - Minocycline - Hydralazine - Allopurinol - Antibiotics - NSAIDs

Question 48

Cryoglobulinemia - 3 types

Answer 48

- Cryoglobulins are immunoglobulins in the serum that precipitate at temperatures below 37 degree and redissolve on rewarming 3 types of cryoglobulins: (A) Type 1: Monoclonal Ig (typically IgG/IgM) - Cryoglobulins are monoclonal Ig (typically IgG or IgM or less commonly IgA, or free light chains) - Develops in setting of protein secreting monoclonal gammopathies, eg: MGUS or B-cell lineage malignancy (eg: multiple myeloma, Waldenstrom's macroglobulinaemia, CLL) - Often associated with hyperviscosity syndrome, vascular occlusion, Raynaud phenomenon - Does not involve RF. (B) Type 2: Mixture of Monoclonal IgM (or IgG/IgA) with rheumatoid factor activity and polyclonal IgG - Mixed cryoglobulin composed of MIg(usually IgM-κ) complexed to polyclonal Ig (usually IgG) - Associated with underlying viral infections (particularly Hep C, others include Hep B, HIV), dysproteinaemias or autoimmune diseases (SLE, Sjogrens) (C) Type 3: Mixture of polyclonal IgG (all isotopes) and polyclonal IgM - Mixed cryoglobulin composed of polyclonal Ig (usually IgM and IgG) - Often due to viral URTI Clinical syndrome is cryoglobulinemic vasculitis - Characterised by Meltzer's Triad: Palpable Purpura, Arthralgia, Weakness (PAW) - Petechiae - ischaemia/infarction of digits/limbs - Renal failure - Other clinical suspicions: skin ulcers, glomerulonephritis, peripheral neuropathy • Laboratory Hallmark: cryoglobulin (cryocrit), low C4 (marker of disease activity) Treatment: removal of stimulus - steroids, plasma exchange, cyclophosphamide, rituximab, colchicine, other AZA, MTX, CYP