VasculitisDEFINITION Vasculitis are a heterogeneous group of diseases characterized by Inflammation , necrosis and damage to blood vessel walls , often with associated organ involvement.

The vessel lumen is usually compromised, and this is associated with ischemia of the tissue supplied by the involved vessel. Any type, size, and location of blood vessel may be involved.

Vasculitis may be primary ( sole manifestation of a disease) or may be secondary( component of another primary disease)

Vasculitis may be confined to a single organ, such as the skin,or it may simultaneously involve several organ systems

Classification of Vascilites Large vessel.Giant cell arteritis &/or Polymyalgia rheumatica.• Takayasu's arteritis

Medium vessel Classical polyarteritis nodosa • Kawasaki disease (in childhood)

Small vessel • Microscopic polyangiitis • Wegener's granulomatosis • Churg-Strauss syndrome • Henoch-Schönlein purpura • Mixed essential cryoglobulinaemia

Others as Behcets disease.

PATHOPHYSIOLOGY AND PATHOGENESIS of Vasculitis

• Generally, most of the vasculitic syndromes are assumed to be mediated at least in part by immunopathogenic mechanisms that occur in response to certain antigenic stimuli

• it is unknown why some individuals might develop vasculitis in response to certain antigenic stimuli,whereas others do not.

• It is likely that a number of factors are involved in the ultimate expression of a vasculitic syndrome. These include the genetic predisposition, environmental exposures, and the regulatory mechanisms associated with immune response to certain antigens.

deposition of immune complexes in vessel walls is the most widely accepted pathogenic mechanism of vasculitis.

• The actual antigen contained in the immune complex has only rarely been identified in vasculitic syndromes.

• In this regard, hepatitis B antigen has been identified in some patients with systemic vasculitis, most notably in polyarteritis nodosa .

• The syndrome of essential mixed cryoglobulinemiais strongly associated with hepatitis C virus infection

• . The mechanisms of tissue damage in immune complex–mediated vasculitis

• antigen-antibody complexes are formed and are deposited in vessel walls .

• The deposition of complexes results in activation of complement components, particularly C5a, which is strongly chemotactic for neutrophils.

• These cells then infiltrate the vessel wall, phagocytose the immune complexes, and release their intracytoplasmic enzymes, which damage the vessel wall.

• As the process becomes subacute or chronic,mononuclear cells infiltrate the vessel wall.

• This will compromise of the vessel lumen with ischemic changes in the tissues supplied by the involved vessel.

Clinical features of Vasculitis• The clinical features of vasculitis are due to a combination of

local tissue ischaemia (caused by vessel inflammation and narrowing) and the systemic effects of widespread inflammation.

• Systemic vasculitis should be considered in any patient with

fever, weight loss, fatigue, evidence of multisystem involvement, rashes, raised inflammatory markers and abnormal urinalysis.

• Early diagnosis and management are essential to prevent irreversible organ damage.

• .

• Vasculitis may be difficult to distinguish from widespread malignancy, occult sepsis (particularly subacute bacterial endocarditis &

meningococcal septicaemia). cholesterol emboli. atrial myxoma . antiphospholipid syndrome.

• The key to recognition is the presence of multisystem involvement

Clinical Features of Vasculitis include Constitutional symptoms FeverWeight lossFatigue pururaLivido reticularisDigital infarction

MusculoskeletalArthralgiaArthritis

Cardiovascular pulselessness and ⁄or bruits common in large vessel diseaseClaudicationAneurysms

PulmonaryAlveolar hemorrhageNodules

GastrointestinalBowel ischemia and ⁄or infarction

RenalGlomerulonephritisNephrotic syndromeRenovascular involvementHypertension

NeurologicMononeuritis multiplexVisual disturbanceStrokelightheadedness

Laboratory abnormalities AnemiaEosinophiliaElevated acute phase reactionsRenal insufficiencyActive urinary sediment

Conditions That Can Mimic Vasculitis

• Infectious diseases• Bacterial endocarditis• Disseminated gonococcal infection• Pulmonary histoplasmosis• Coccidioidomycosis• Syphilis• Lyme disease• Rocky Mountain spotted fever

• Coagulopathies/thrombotic microangiopathies• Antiphospholipid antibody syndrome• Thrombotic thrombocytopenic purpura

• Neoplasms Emboli • Atrial myxoma cardiac emboli• Lymphoma cholestrol emboli• Carcinomatosis

• Drug toxicity• Cocaine

• Others• Sarcoidosis• Goodpasture’s syndrome• Amyloidosis• Migraine• Cryofibrinogenemia

Investigations in Vasculitis

• If vasculitis is suspected, the diagnosis should ideally be confirmed by tissue biopsy.

• Skin biopsies are easily obtained.• Nasal septal tissue can be taken from areas of ulceration or

granulation. • Muscle biopsy is positive in about 50% of patients with muscle

pain.

. The most important bedside test is the urine dip test for protein and blood, and subsequent microscopy, since the prognosis of vasculitis is often determined by the degree of renal involvement. In patients with abnormal renal function and active urinary sediment, renal biopsy should be considered.

• Visceral angiography to detect microaneurysms (e.g. classical polyarteritis nodosa)

is most useful where involved tissue is not available to biopsy.

• ESR usually elevated in vasculitis• CRP• C-ANCA & p-ANCA

• Antineutrophil cytoplasmic antibodies (ANCA) • are directed against enzymes present in neutrophil granules. • Two main patterns of immunofluorescence are distinguished:

cytoplasmic (c-ANCA) and perinuclear (p-ANCA).

• c-ANCA are usually directed against proteinase 3 and are particularly associated with Wegener's granulomatosis and Churg-Strauss syndrome.

• p-ANCA are usually directed against myeloperoxidase and associate with microscopic polyangiitis.

• However, positive ANCAs occur in many other diseases, including malignancy, infection (bacterial and HIV), inflammatory bowel disease, RA, lupus and pulmonary fibrosis. Therefore, the diagnosis of these conditions cannot be made or refuted on the ANCA test alone.

Large Vessel Vasculitis

1- Giant cell arteritis2- Polymyalgia rheumatica3-Takayasu's arteritis

GIANT CELL ARTERITIS (GCA)(Temporal Arteritis)

• GCA also known as temporal arteritis or cranial arteritis

• is a large vessel vasculitis predominately affecting branches of the temporal and ophthalmic arteries.

• The mean age of onset is 70 years .

• 4:1 female:male ratio.

Clinical features of Giant cell arteritis

• The onset of symptoms may be abrupt but is often insidious over the course of several weeks or months.

• The most important clinical features are: 1- Headache. This is usually the first symptom and is often

localised to the temporal or occipital region, with scalp tenderness.

2- Jaw pain. This is brought on by chewing or talking and is due to ischaemia of the masseters.

3-Visual disturbance.The most important complication of GCA is monocular

blindness which is almost never reversible

The optic nerve head is supplied by the posterior ciliary artery, vasculitis of which leads to occlusion and acute anterior ischaemic optic neuropathy.

Damage to the optic nerve results in loss of visual acuity and field, reduced colour perception and pupillary defects.

Sudden visual symptoms in one eye, leading rapidly to blindness, constitute the most common pattern.

On fundoscopy the optic disc may appear pale and swollen with haemorrhages, but these changes may take 24-36 hours to develop.

Once blindness has occurred corticosteroids have a negligible effect but are indicated to prevent blindness in the other eye.

4- There may be associated constitutional symptoms of anorexia, fatigue, weight loss, fever, depression and general malaise.

5- Occasionally presentation is with neurological complications that include transient ischaemic attacks, brain-stem infarcts and hemiparesis.

Investigations• The ESR usually elevated above 50 mm/hour in 90% of cases. ( in some

cases the ESR may be normal mainly in those with acute presentationis , in the this situation the CRP may be more helpful ,& usually elevated ).

• Temporal artery biopsy should be obtained. corticosteroid treatment should not be delayed whilst the biopsy is

organised. Characteristic biopsy findings are fragmentation of the internal elastic

lamina with necrosis of the media in combination with a mixed inflammatory cell infiltrate (lymphocytes, plasma cells and eosinophils).

However, 'skip' lesions are common and a negative biopsy does not exclude the diagnosis.

Management of GCA

• If GCA is suspected, systemic corticosteroid (prednisolone 60 mg daily) should be started immediately to prevent visual loss.

• Steroid reduction should be guided by symptoms and ESR, aiming for approximately 10 mg daily by 6 weeks. Thereafter, doses should be reduced by 1 mg per month

• Maintenance therapy is required for at least 1 year, and occasionally for the rest of the patient's life.

• Relapse occurs in 30%, and is an indication to restart high-dose steroids with additional immunosuppressive agents, typically azathioprine or methotrexate

• . Patients with known GCA should be advised to take 60 mg prednisolone and seek prompt medical advice should they experience any recurrence of headache or visual disturbance.

POLYMYALGIA RHEUMATICA (PMR)

•PMR is a clinical syndrome of muscle pain and stiffness with an increased ESR.

• It is not a true vasculitis but there is a close association with giant cell arteritis.• The prevalence is approximately 20 per 100 000 over the age of 50. •The mean age of onset is 70. •Women are affected more often than men in a ratio of 3:1.

Clinical features of PMR The cardinal features are muscle stiffness and

pain, symmetrically affecting the proximal muscles of the neck, upper arms and, less commonly, the buttocks and thighs.

There is marked early morning stiffness, often with night pain.

Constitutional features of weight loss, fatigue, depression and night sweats also occur.

On examination there may be stiffness and painful restriction of active shoulder movement but passive movements are preserved.

Muscles may be tender to palpation but there should not be muscle-wasting; if there is, then primary muscle or neurological disease is more likely

CONDITIONS THAT MAY MIMIC POLYMYALGIA RHEUMATICA

Fibromyalgia Hypothyroidism Cervical spondylosis Rheumatoid arthritis Inflammatory myopathy (particularly

inclusion body myositis) Systemic vasculitis Malignancy

Investigations in PMR

ESR is elevated above 40 mm/hour In the majority of patients

Very occasionally the ESR is low, usually in the acute situation where there has not been sufficient time for it to rise. In this situation the CRP may be elevated prior to the ESR.

There may be a normochromic, normocytic anaemia

Management of PMR

The only effective treatment is corticosteroids. prednisolone should be started at a dose of 15 mg

daily.

The majority of patients should have a dramatic response within 72 hours.

If there is no response by 72 hours or an incomplete response by 7 days, then the diagnosis is not PMR.

If there has been a good response to prednisolone, the daily dose should be reduced to 10 mg after 4 weeks and then by 1 mg per month, assuming that symptoms remain controlled.

Most patients need steroids for an average of 12-18 months and osteoporosis prophylaxis with bisphosphonates should be considered.

Some patients require steroid-sparing agents such as methotrexate or azathioprine, particularly if prednisolone cannot be withdrawn at 2 years or is needed at doses greater than 7.5 mg daily.

Approximately 15-20% of patients develop

features of giant cell arteritis at some point in the course of their disease.

TAKAYASU'S ARTERITIS

Takayasu's disease is a chronic inflammatory granulomatous panarteritis of elastic arteries.

The vessels most commonly involved are the aorta and its branches, and the carotid, ulnar, brachial, radial and axillary arteries. Pulmonary arteries are occasionally affected.

It is more common in women (female:male ratio 8:1) with a typical onset at the age of 25-30 years.

It has a world-wide distribution but is most common in Asia.

The aetiology is unknown.

.The usual presentation is with claudication and systemic symptoms of fever, arthralgia and weight loss.

Clinical examination may reveal loss of pulses, bruits, hypertension and aortic incompetence.

Laboratory investigations are usually non-specific, with high ESR and normocytic, normochromic anaemia.

Diagnosis is usually based on angiographic findings of coarctation, occlusion and aneurysmal dilatation.

Diagnostic Criteria for TA

1-Age less than 40 years.2-Claudication of extremeties.3-Decreased brachial artery pulse.4-BP difference more than 10 mmHg between

arms.5-Bruit over subclavian arteries & aorta.6-Arteriogram abnormalities: occlution or narrowing in aorta or main

branches.

Must have 3\6 criteria for diagnosis.

.The 5-year survival rate is ∼80%.

Treatment Most patients respond to initial high-dose oral

prednisolone (1-2 mg/kg daily). Additional therapy with methotrexate or

cyclophosphamide is usually required.

Reconstructive vascular surgery should be avoided during periods of active inflammation but may benefit selected patients, especially those with hypertension secondary to aortic or renal lesions

Takayasu’s is LARGE Vessel Dz

Medium – Sized Arteritis

1- Classical polyarteritis nodosa.2- Kawasaki disease.

CLASSICAL POLYARTERITIS NODOSA (PAN)

Classical PAN is a necrotising vasculitis characterised by transmural inflammation of medium-sized to small arteries.

PAN is a rare disorder with an annual incidence of 2 per million in most populations.

All age groups can be affected, with a peak incidence in the fourth and fifth decades, and a male:female ratio of 2:1.

Hepatitis B is a risk factor, and the incidence of PAN is higher in the areas, where hepatitis B infection is endemic

Clinical presentation is with myalgia, arthralgia, fever and weight loss in combination with manifestations of multisystem disease.

The most common skin lesions are palpable purpura, ulceration, infarction and livedo reticularis .

In 70% of patients arteritis of the vasa nervorum leads to neuropathy which is typically symmetrical and affects both sensory and motor function.

Severe hypertension and/or renal impairment may occur due to multiple renal infarctions.

glomerulonephritis is rare .

Diagnosis is confirmed by finding multiple aneurysms and smooth narrowing of either the mesenteric, hepatic or renal systems on angiography.

Tissue biopsy may be definitive (muscle or sural nerve), even in the absence of angiographic abnormality.

Treatment Treatment for hepatitis B-related disease is to

remove the source of the antigen, i.e. antiviral therapy.

Corticosteroids and cyclophosphamide are the treatment of choice for idiopathic disease.

Mortality is less than 20%, although relapse occurs in up to 50% of patients

Severe Skin Ulceration in PAN

Polyarteritis NodosaMicro “Berry” aneurysms

Kawasaki Disease

Kawasaki disease is an acute systemic disorder of childhood that predomintely occurs in Japan( 800 cases per million in children under the age of 5 ).

The disease resembles a viral exanthem or stevens – Johnson syndrome.

Although the causative trigger is unknown, it has been associated with Mycoplasma and HIV infection in some cases.

The clinical features often develop abruptly.

Features of Kawasaki Disease*

Fever persisting > 5 days Bilateral conjunctival congestion Erthema of lips, buccal mucosa and tongue Acute non-purulent cervical lymphadenopathy Polymorphous exanthema Erythema of palms and soles(oedema followed

by desquamation) Coronary dilatation* Five out of six clinical features, or four out of

six clinical features with evidence of Coronary dilatation, are required for diagnosis.

Cardiovascular complications include myocarditis, pericarditis, coronary aneurysms, transient coronary artery dilatation, myocardial infarction due to coronary thrombosis.peripheral vascular insufficieny and gangerene.

Investigations that favour KD include : polymorphonuclear leucocytosis,

thrombocytosis, raised ESR and CRP and circulating antiendothelial cell antibodies.

Treatment is with aspirin (5 mg/kg daily for 14 days) and intravenous gammaglobulin (400 mg/kg daily for 4 consecutive days).

Steriods should be avoided because of the risk of worsenin the coronary artery dilatation .

coronary artery changes are usually monitored weekly by two-dimensional echo for 4 weeks, by which stage most children have recovered.

The overall mortality is less than 2% Relapse is rare , but if there is coronary artery

involvement long –term follow –up is necessory.

Small Vessel vasculitis

Small Vessel Disease of Arterioles, Venules & Capillaries Microscopic polyangiitis Wegener's granulomatosis Churg-Strauss syndrome Henoch-Schönlein purpura Mixed essential cryoglobulinaemia

ANCA-ASSOCIATED VASCULITIS Microscopic polyangiitis, Wegener's

granulomatosis and Churg-Strauss syndrome can be grouped

together as 'ANCA-associated vasculitis',

Sites of Involvement of ANCA Vasculitis

1. Kidney - most common (75%-90%)2. Lung - 50%3. Skin + Kidney - 33%4. CNS - 25%

Microscopic polyangiitis (MPA)

Classic presentation is with rapidly progressive glomerulonephritis often associated with pulmonary alveolar haemorrhage.

Cutaneous and gastrointestinal involvement, similar to PAN, is common.

MPA is more common than PAN, with an annual incidence of 8 per million .

Other features include neuropathy (15%) and pleural effusions (15%).

Patients are usually p-ANCA-positive.

Wegener's granulomatosis (WG)

The annual incidence of WG is 5-10 per million. The most common presentation is with upper

airway involvement (typically epistaxis, nasal crusting and sinusitis), haemoptysis, mucosal ulceration and deafness due to serous otitis media.

Symptoms may have been present for several months and erroneously attributed to infection or allergy.

The most common ocular abnormality is proptosis, due to inflammation of the retro-orbital tissue.

This may cause diplopia due to entrapment of the extraocular muscles, or loss of vision due to optic nerve compression .

Untreated nasal disease ultimately leads to destruction of bone and cartilage.

Migratory pulmonary infiltrates and nodules occur in 50% of patients.

A minority of patients present with

glomerulonephritis.

Patients are usually c-ANCA-positive.

Pulmonary infiltration in WG

Churg-Strauss syndrome (CSS) The annual incidence is 1-3 per million . Most patients have a prodromal period for many

years, characterised by allergic rhinitis, nasal polyposis and late-onset asthma that is often difficult to control.

The typical acute presentation is with a triad comprising skin lesions (purpura or nodules), asymmetric mononeuritis multiplex and eosinophilia on a background of resistant asthma.

Pulmonary infiltrates and pleural or pericardial effusions due to serositis may be present.

Up to 50% of patients have abdominal symptoms due to mesenteric vasculitis.

Either c-ANCA or p-ANCA is present in around 40% of cases.

Management of MPA, WG and CSS

Treatment should be instituted as early as possible to prevent irreversible damage.

Remission can be induced either with oral high-dose prednisolone (1 mg/kg daily) and continuous oral cyclophosphamide (2 mg/kg daily)

or with bolus i.v. methylprednisolone and

cyclophosphamide infusion monthly.

Doses of cyclophosphamide should be reduced in the elderly and those with renal impairment.

Once remission has been induced (3-6 months) the dose of oral prednisolone is rapidly reduced and cyclophosphamide is usually replaced with azathioprine.

Co-trimoxazole is usually given at a prophylactic dose (960 mg thrice weekly) in conjunction with cyclophosphamide to prevent Pneumocystis pneumonia, unless there is a history of drug allergy.

Mesna is used with bolus cyclophosphamide to reduce the risks of haemorrhagic cystitis.

Patients who have ANCA-positive vasculitis with acute renal failure have a better outcome when also treated with adjunctive plasma exchange.

Henoch-Schönlein purpura Most common systemic vasculitis in children.

Usually occurs following an upper respiratory tract infection. About 50% of cases are preceded by URI’s. Streptococcus is often implicated.

Vaccines, insect bites, viruses have also been reported as triggers.

Occurs more often in winter, and spring. Rare in the summer

Typical presentation is with : purpura over the buttocks and lower legs. abdominal symptoms (pain and bleeding) . arthritis (knee or ankle).

Nephritis occurs in 40% of patients and may occur up to 4 weeks after the onset of other symptoms

. The diagnosis can only be confirmed by demonstrating IgA deposition within and around blood vessel walls.

Prognosis is generally good and determined by the degree and severity of renal involvement.

Although only 1% of patients develop end-stage renal failure, adverse features at presentation in adults include hypertension, abnormal renal function and proteinuria > 1.5 g/day.

Treatment Corticosteroids alone are effective for

gastrointestinal and joint involvement but nephritis usually requires treatment with both

pulse i.v. steroids and immunosuppression

Cryoglobulinaemic vasculitis

Cryoglobulins are circulating immunoglobulins that precipitate out in the cold.

They are classified into three types, types II and III are associated with cryoglobulinaemic vasculitis.

The typical clinical features are palpable

purpura over the lower extremities, arthralgia, Raynaud's phenomenon and neuropathy.

Type II cryoglobulinaemia is secondary to hepatitis C virus (HCV) infection in most patients, the virus being present in the vasculitic lesions complexed with IgG and IgM.

For HCV-positive patients, interferon-alpha is the treatment of choice; for high HCV loads, combination with ribavirin may be more effective .

CLASSIFICATION OF CRYOGLOBULINSType I

Antibody type Monoclonal IgM Associations Malignant B-cell disease, e.g.

Waldenström's macroglobulinaemia, lymphoma, myeloma.

Type II ('mixed essential') Antibody type Monoclonal IgM and anti-IgG

antibody Associations Hepatitis C, SLE, B-cell malignancy

Type III Antibody type Polyclonal IgM and anti-IgG antibody Associations RA, SLE, chronic infections

Other forms of vasculitis

Behçet's syndrome

Behçet's syndrome

This is a vasculitis of unknown aetiology that characteristically targets venules.

It is common in the countries around the Mediterranean and in Japan where there is a strong association with HLA-B51.

There is a wide range of clinical features, and the disease is characterised by unpredictable exacerbations.

There are no defining investigations and

the diagnosis is made using clinical criteria .

CRITERIA FOR THE DIAGNOSIS OF BEHÇET'S SYNDROME

1- Recurrent oral ulceration-

2- Plus two of: a- Recurrent genital ulceration

b- Eye lesions-anterior uveitis, posterior uveitis, retinal vasculitis

c- Skin lesions- erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules

d- Positive pathergy test

Oral ulcers are universal , the ulcers are usually deep and

multiple, and last for 10-30 days.occur at least three times in a 12-month period

Genital ulcers are less common (60-80%). Skin lesions are erythema nodosum or acneiform lesions

but migratory thrombophlebitis and vasculitis also occur.

pathergy reaction is hyper-reactivity at the site of minor trauma. A

positive pathergy test (a papule 2 mm or more in size developing 24 to 48 hours after oblique insertion of a needle 5mm into the skin, generally performed on the forearm)

pathergy test involves intradermal skin pricking with a needle, and is positive if a pustule develops within 48 hours.

Ocular involvement is usually bilateral and may include anterior or

posterior uveitis or retinal vasculitis.

Neurological involvement occurs in 5% and mainly involves the brain

stem, although the meninges, hemispheres and spinal cord can also be involved to cause pyramidal signs, cranial nerve lesions, brain-stem symptoms or hemiparesis.

Recurrent thromboses also occur.

Renal involvement is extremely rare.

Differential diagnosis  of oral Ulceration

Behcet's syndrome : Oral aphthae are present in almost all patients with Behcet's.

Herpes simplex Benign aphthous ulcers Inflammatory bowel disease Stevens-Johnson syndrome Systemic lupus erythematosus.Dental prosthetics and oral hygiene products can cause oral

irritation and ulceration. Medications such as methotrexatepemphigoid, pemphigus vulgaris, lichen planus, and linear IgA

disease.

TREATMEN OF BEHÇET'S SYNDROME

Treatment of oral ulceration is with topical corticosteroid preparations (e.g. soluble prednisolone mouthwashes, corticosteroid pastes).

Colchicine is sometimes effective for erythema nodosum

and arthralgia. Thalidomide (100-300 mg daily for 28 days initially) is

very effective for resistant oral and genital ulceration but is teratogenic and neurotoxic.

Systemic disease usually requires oral corticosteroids in combination with other immunosuppressive drugs like (cyclosporine , cyclophosphamide , azathioprime , mycophenolate mophetil ….).