Rheumatology - Vasculitis

Question 1

What is vasculitis? How is it classified?

Answer 1

The vasculitides are a group of systemic autoimmune conditions characterised by blood vessel wall inflammation. Damage is caused by ischaemia and necrosis of the tissue supplied.

Vasculitis is classified based on the size of the vessel it affects - small, medium or large or whether it expresses specific autoantibodies.

Vasculitis can arise as a primary process or secondary to other autoimmune diseases - especially RA and SLE.

Question 2

What clinical features suggest a patient has systemic vasculitis?

Answer 2

Systemic vasculitis is suggested by:

• symptoms referable to > 1 organ
• constitutional symptoms (e.g. fever, weight loss, anorexia)
• increased ESR and CRP

Question 3

What is the most common form of vasculitis? What is PAN associated with?

Answer 3

Wegener’s granulomatosis (a form of small vessel vasculitis associated with c-ANCA) and giant cell arteritis are the 2 most common vasculitides.

Certain vasculitides are common at the extremes of age. For example, Kawasaki disease is almost paediatric whereas GCA generally occurs in the over 60s.

Some vasculitides are also associated with specific infections - e.g. PAN and hepatitis B.

Question 4

What vasculitides are associated with granulomatous (caseating) necrosis of blood vessel walls?

Answer 4

These all have G in their name:

• GCA (large)
• BueGers (medium)
• ChurG-Strauss (small)
• WeGener’s (small)

The only 2 exceptions are PAN (medium) and Takayasu’s arteritis (large)

Question 5

What pathological feature is often seen in vasculitis?

Answer 5

There is no exclusive pathology in vasculitis but leukocytoclastic vasculitis is often seen.
This is a characteristic histological appearance resulting from dissolution of leukocytes.

Suitable sites for biopsy are: blood vessels (e.g. superficial temporal arteries in suspected GCA), involved skin or other organs - e.g. kidney, lung, muscle

Question 6

What antibodies are associated with vasculitis?

Answer 6

1) Antineutrophil cytoplasmic antibodies (ANCA)
2) RhF
3) Anti-double stranded DNA antibodies (Anti-dsDNA)

NB - only ANCA antibodies are associated with primary vasculitis and used to distinguish between the 2 types of small vessel vasculitis. RhF and SLE associated antibodies are used to diagnose vasculitis secondary to other autoimmune diseases

Question 7

What are ANCA antibodies?

Answer 7

Antineutrophil cytoplasmic antibodies are circulating antibodies directed against cytoplasmic components of neutrophils.

They are classified according to the pattern of nuclear staining:

i) cytoplasmic (cANCA) associated with antibodies to proteinase 3 which are strongly associated with WG
ii) perinuclear (pANCA) directed against myeloperoxidase associated with other primary small vessel vasculitides and some other conditions

Question 8

What conditions are pANCA antibodies associated with?

Answer 8

They are associated with the “PURGE” diseases:

• PAN, microscopic Polyangitis (or Churg-Strauss)
• UC
• RA with vasculitis
• Glomerulonephritis
• Endocarditis with HIV

Question 9

What is rheumatoid factor?

Answer 9

Rheumatoid factors (RhFs) are antibodies directed against the Fc component of immunoglobulin (Ig). They occur in many patients with RA and are also found in many other vasculitides and chronic infections.

Question 10

What are the primary large vessel vasculitides?

Answer 10

• Giant cell arteritis (GCA) and polymyalgia rheumatic (PMR)

- Takayasu’s arteritis

Question 11

What is the link between GCA and PMR?

Answer 11

The aetiology of GCA and PMR remains unclear. Both share common epidemiological, clinical and serological features although GCA is a granulomatous large vessel vasculitis, whilst PMR is an inflammatory disorder classically manifesting with shoulder and pelvic girdle muscular pain and stiffness in the absence of weakness.

Both conditions are more common in women over 50 and are associated with HLA-DR4 and HLADRB1 alleles, suggesting a genetic predisposition.

Question 12

What is the clinical presentation of GCA?

Answer 12

Symptoms usually include the following:

• mild or severe, unilateral, temporal headaches often of abrupt onset
• burning sensation and tenderness over the scalp
• claudication of the jaw/ tongue muscles producing pain on chewing in 33-50% of cases
• systemic manifestations
• features of large vessel involvement: limb claudication
• symptoms of PMR

Question 13

What is a serious complication of GCA?

Answer 13

Visual disturbances are the most serious complication of GCA. These can include blurring of vision, diplopia or amaurosis fugax. These are initially transient and ultimately progress to complete visual loss if not recognised and treated.

They occur in up to 20% of patients and reflect the arteries supplying the retina and/ or optic nerve.

Question 14

What are the examination findings of GCA?

Answer 14

• ipsilateral temporal artery tenderness, thickened and irregular with reduced or absent pulsations
• scalp tenderness
• visual field defect
• relavent afferent pupillary defect
• anterior ischaemic optic neuritis (pale swollen optic disc with haemorrhages)
• asymmetry of pulses and blood pressure
• arterial bruits

Question 15

What are the clinical features of polymyalgia rheumatica?

Answer 15

PMR is characterised by relatively abrupt onset of pain and stiffness in the shoulder and pelvic girdle. Symptoms are typically worse after periods of inactivity and there are few physical signs.

NB - restricted movement, weakness and tenderness are NOT features of PMR and should prompt consideration for other diagnoses (e.g. frozen shoulder, OA, or inflammatory myositis)

Question 16

What investigations should be performed for GCA/ PMR?

Answer 16

There are no specific serological testes for GCA or PMA, but:

• ESR and CRP are usually raised, ESR typically > 60mm/h
• temporal artery biopsy is gold standard; arterial wall thickening with mononuclear cell infiltration or granulomatous infiltration with giant cells causing vessel occlusion
• duplex ultrasonography may show characteristic “hypoechoic halo”, vessel occlusion and stenosis
• muscle enzymes, EMG, muscle biopsy all normal in PMR

Question 17

Can GCA be diagnosed in the absence of positive biopsy?

Answer 17

Yes. Negative biopsy does not exclude GCA as skip lesions may occur. GCA should be diagnosed even with a negative biopsy if the clinical and biochemical features suggest the diagnosis.

Also, the biopsy often remains positive for 2-6 weeks after treatment is started so institution of corticosteroid therapy should not be delayed.

Question 18

How should GCA and PMR be managed?

Answer 18

GCA and PMR are very sensitive to steroids.
GCA:
- 60mg of prednisolone should be started without delay, and IV methylprednisolone should be used if there is visual disturbance
- treatment should continue for at least 12-24 months
- monitor CRP and ESR
- low dose aspirin may reduce the rate of visual loss and CVA in GCA

PMR:
- 10-20mg of prednisolone daily is usually sufficient

Question 19

What is Takayasu’s arteritis?

Answer 19

This is a rare disorder (also called “pulseless disease”) is characterised by inflammation and stenosis of large sized arteries with frequent involvement of the aortic arch and its branches producing aortic arch syndrome.

Its aetiology remains unclear but it is similar to GCA with focal granulomatous arteritis.

Question 20

What are the clinical features of Takayasu’s arteritis?

Answer 20

Clinical manifestations include:

• absent pulses - carotid, radial or ulnar arteries
• constitutional symptoms (fever, weight loss, anorexia)
• bruits: aortic, carotid and subclavian
• hypertension: majority of cases

Question 21

How should Takayasu’s arteritis be investigated?

Answer 21

ESR and CRP are typically raised, with anaemia and leucocytosis.

Aortic arch angiography and MR angiography are the imaging techniques of choice. They both reveal diffuse narrowing of the aorta and main arteries.

Question 22

Management of Takayasu’s arteritis

Answer 22

Treatment is with high dose corticosteroids (60-80mg) with gradual dose reduction guided by inflammatory markers.

Additional immunosuppression may be required in certain cases using azothioprine, methotrexate or cyclophosphamide.

Surgical intervention may be required for critical carotid or renal artery stenosis or significant aortic regurgitation.

Question 23

What is polyarteritis nodosa? What is the characteristic pathological feature?

Answer 23

This is one of 2 medium vessel vasculitides (the other being Kawasaki’s disease) that is characterised by necrotising immune complex inflammation of vessel walls.

Pathologically, it involves destruction of the arterial media and internal elastic lamina resulting in aneurysmal nodules.

Question 24

What infection is associated with PAN?

Answer 24

PAN is of unknown aetiology but is associated with hepatitis B infection in 30% of cases.

Question 25

What are the clinical features of PAN?

Answer 25

Clinical features often include constitutional symptoms such as fever, weight loss, and anorexia. PAN can also affect the following sites:

• kidneys: immune complex vasculitis in the arterioles of the glomeruli, renal lesions, and hypertension
• coronary arteries: ischaemic heart disease
• musculoskeletal system: myalgia, arthralgia, or arthritis
• GIT: nausea, vomiting or abdominal pain
• CNS: stroke
• PNS: peripheral neuropathy, areflexia, monoeuritis multiplex

Question 26

How should PAN be managed?

Answer 26

Systemic disease (constitutional symptoms + symptoms reflecting >1 organ involvement) should be treated with a combination of corticosteroids and cytotoxic chemotherapy.

HBV infection should be treated promptly.

Question 27

What is Kawasaki disease? What are the clinical features and how is it treated?

Answer 27

This disease is also called mucocutaneous lymph node syndrome. It is an acute, self limiting illness affecting infants and young children. It is characterised by acute necrotising vasculitis of medium sized vessels.

Clinically, the syndrome manifests by

1) fever, haemorrhagic oedema of the conjunctiva, lips and oral mucosa and cervical lymphadenopathy
2) It can be a cause of coronary artery vasculitis with aneurysm formation

It is treated with aspirin and IVIg.

Question 28

How are small vessel vasculitides classified?

Answer 28

The small vessel vasculitides are distinguished based on whether they are associated with ANCA antibodies or not.

ANCA positive: these constitute Wegener’s granulomatosis and microscopic polyangitis:

• cytoplasmic staining usually directed against proteinase 3 (c-ANCA) is Wegener’s
• perinuclear staining directed against myeloperoxidase in microscopic polyangitis, and also a subset of patients with Churg-Strauss (amongst other conditions)

ANCA negative: these include hypersensitivity vasculitis, HSP and cryoglobulinaemia.

Question 29

What is Wegener’s granulomatosis?

Answer 29

This is a disease of unknown aetiology that is characterised by necrotising granulomatous vasculitis of the small vessels affecting the lungs and kidneys.

It affects both sexes equally, can occur at any age (commonly in middle age) and has an estimated annual incidence of between 10 to 20 million people. It is one of the most common vasculitides next to giant cell arteritis.

Question 30

What are the clinical features of Wegener’s?

Answer 30

The main feature of Wegener’s are respiratory tract signs and symptoms especially of the paranasal sinuses and lungs. Necrotising glomerulonephritis (sometimes with immune complex deposition) is also common.

Microscopically, Wegener’s is associated with fibrinoid necrosis of small arteries and veins, early infiltration by neutrophils, mononuclear cell infiltrate and granuloma formation with giant cells.

Question 31

What are the investigations for Wegener’s?

Answer 31

• ESR and CRP: typically raised in proportion to disease activity
• renal function: requires close monitoring
• urinalysis: proteinuria, microscopic haematuria and casts
• cANCA: positive in majority of cases
• plain chest X-ray, CT chest, and CT/MRI of the nasal sinuses: check for respiratory tract involvement
• biopsy of affected tissue (nasal, lung or renal): shows necrotising vasculitis with granuloma formation

Question 32

How is Wegener’s managed?

Answer 32

Corticosteroids and cyclophosphamide - first line therapy.

Rituximab (anti-CD20 monoclonal antibody which depletes B cells) may be as effective as cyclophosphamide in inducing remission.

Corticosteroid and cyclophosphamide sparing therapy (e.g. azathioprine, methotrexate) may be used for maintenance therapy.

Question 33

What is microscopic polyangiitis? What renal disease does it typically cause?

Answer 33

Microscopic polyangiitis is a necrotising vasculitis that predominantly affects the kidneys causing rapidly progressive glomerulonephritis.

Approximately 50% of patients have lung involvement presenting as haemoptysis, pleurisy, or asthma. Frank pulmonary haemorrhage is rare but potentially fatal.

Other features include arthralgia, vasculitis or purpuric rashes, hypertension, mononeuritis multiplex and peripheral neuropathy.

Question 34

What is leucocytoclastic vasculitis? What is the aetiology of these disease?

Answer 34

This is also caused hypersensitivity vasculitis, and is a group of immune complex mediated vasculitides characterised by acute inflammation of small blood vessels; the multiple lesions tend to be of the same age.

The main clinical feature is palpable purpura which coalesce to form plaques or ecchymoses, especially on the lower limbs. There can also be joint, renal or GIT involvement.

It may be precipitated by exogenous antigens such as drugs (penicillin, sulphonamides, thiazides), foods or infectious organisms. It can also occur as a complication of systemic illnesses, such as connective tissue disorders or malignancies.

Question 35

What are the 2 clinical syndromes of leucocytoclastic vasculitis?

Answer 35

1) Henloch - Schonlein purpura - most common in young children
2) Serum sickness

Question 36

What are the clinical features of HSP?

Answer 36

HSP is most common in young children and is a systemic vasculitis characterised by deposition of IgA containing immune complexes. It affects small vessels and is a clinical syndrome of leucocytoclastic vasculitis.

Clinically, haemorrhagic urticaria is seen on the extensor surfaces or the arms, legs and buttocks, with fever, arthralgias and GIT and renal involvement (often similar to an IgA nephropathy).

It can sometimes be post streptococcal in origin. It is associated with antecedent upper respiratory tract infection.

Question 37

What is serum sickness?

Answer 37

Serum sickness is a syndrome seen experimentally, where rabbits, after serial injections of bovine serum albumin, develop generlised deposition of antigen-antibody complexes in the heart, joints and kidney.

Serum sickness is now rare in humans, but in the past it was caused by therapeutic administration of various antitoxins (foreign serum containing specialised antibodies prepared by immunisation of animals such as horses).

Question 38

What is Churg-Strauss syndrome?

Answer 38

Chrug-Strauss syndrome is a necrotising vasculitis considered by some to be a variant of PAN. It is characterised by prominent involvement of pulmonary vasculature, marked peripheral eosinophilia and clinical manifestations of asthma.

pANCA positivity is seen in most patients.

Treatment is with corticosteroids and cyclophosphamide.

Question 39

What is cryoglobulinaemic vasculitis?

Answer 39

This is an immune complex mediated vasculitis usually arising in patients with mixed cryoglobulinaema types I and II. There is a strong associated with hepatitis C infection. Females are affected more commonly than males.

Clinical presentation:

• purpura
• arthralgia
• glomerulonephritis
• chronic renal failure, hypertension and leg ulcers: in long standing disease
• liver failure and B cell lymphoma are rare associations

Question 40

What is Behcets disease?

Answer 40

Behcets is a condition of unknown aetiology characterised by disordered regulation of the inflammatory response with vasculitis of veins and arteries of all sizes, hypercoagulability and neutrophil disorders.

It occurs with greater prevalence in the Middle East and Central Asia. Males are more commonly affected with peak age of onset in the 20s.

Question 41

What is the clinical presentation of Behcets?

Answer 41

Diagnosis remains predominantly clinical.
Mucocutaneous:
- oral aphthous ulcers (occurring on >3 occasions during a 12 month period with >2 of the following “hallmark” features)
- ano-genital ulcers
- erythema nodosum

Eyes:

• relapsing anterior and posterior uveitis
• retinal vasculitis

Joints:
- arthalgia or non deforming mono or polyarthritis

The International Study Group for Behcets Disease sets the diagnostic criteria.

Question 42

What differential diagnosis should be considered in Behcets?

Answer 42

• herpes simplex virus: recurrent oro-genital ulceration
• sarcoidosis: erythema nodosum, uveitis and pulmonary involvement
• IBD: oral/ peri-anal ulcers, GI involvement
• seronegative arthritis: arthritis, uveitis

Question 43

What is Buerger’s disease?

Answer 43

Buerger’s (or thrombophlebitis obliterans) is an acute inflammation involving small to medium sized arteries of the extremities, extending to adjacent veins and nerves.

It occurs with greater frequency in young men and in the Jewish population. It results in painful ischaemic disease often resulting in gangrene. It is clearly exacerbated by heavy cigarette smoking.

Question 44

Briefly summarise the treatment of vasculitis?

Answer 44

Treatment depends on the size of the vessel affected.

Limited small vessel involvement has a good prognosis and the patient can be observed.

Small/ medium artery vasculitis, systemic upset +/- major organ involvement requires high dose steroids +/- cyclophosphamide (for renal involvement) +/- IVIg in Kawasaki’s disease.