l a r lecture

Large vessel Arteritis

Large Vessel Arteritis Giant cell arteritis - Common in the

West, uncommon in India Takayasu’s aorto-arteritis - Has

predilection for certain geographical areas I.e. Japan, South-East Asia, India, South America, milder form in North America

Important points on GCA Commonest vasculitis Neuro-ophthalmic complications Need for careful disease

assessment to maintain an acceptable balance between risks and benefits of steroid therapy

History of GCA Ali Ibn Isa -10th century-first

description Hutchinson 1890 described painful TA Horton 1932 described histology Gilmour coined the term GCA Link between PMR and GCA

recognised by Poulley and Hughes 1960

Giant cell arteritis Affects cranial branches of arteries

arising from the aortic arch most typically the superficial temporal artery

Characterised by acute phase response

Classification criteria GCA 1. Age at disease onset 50 years 2. New headache -- New onset of or new type of localised

pain in the head 3. Temporal artery abnormality 4.Elevated erythrocyte sedimentation rate 50 mm/hour

5. Abnormal artery biopsy----Biopsy specimen with the artery showing vasculitis characterised by prominence of mononuclear cell infiltration or grannulocyte inflammation, usually with multinucleated giant cells.

*For purposes of classification, a patient with vasculitis shall be said to have giant cell (temporal arteritis if at least 3 of these 5 criteria are present.

Epidemiology Age and sex are risk factors Increasing incidence through

successive decades F:M= 2.5-3:1 Common in Caucasians of N

European stock Rare in Asians and Blacks

Epidemiology contd Variable incidence 9.3 -27/100,000

>50yrs Suggestion of cyclical pattern Association with environmental agents:

adenovirus, RSV, Mycoplasma,parvovirus B19, chlamydia pneumoniae, HPIV

Chlamydia found by PCR in TA biopsies ‘Actinic’ hypothesis

Immunogenetics Linkage to DR4 DR4 neg linked to DR3, DR8, DR13 Conserved AA sequence in 2nd

hypervariable region of DRB1 Link to DRB1*0401, Weak association with shared RA

epitope Association of relapse with DR4*0401

Immunopathogenesis Low CD8 cells Antibody to intermediate filaments Antibodies to cardiolipin and beta2

GP1 Raised IL-6 and IL-1RA, IL-10

Mechanism of arterial injury Pathology in TA suggests ongoing

immune response-infiltration with macrophages, T cells.

All layers may be involved Granuloma formation Small portion of T cells show clonal

expansion

Arterial injury Cytokine profile correlates with clinical

picture- high IFN gamma with giant cells and ischaemia, IL-2 with polymyalgia

Antigen recognition in adventitia IFNGamma--differentiation of macrophages

Giant cell formation-- activation of matrix metalloproteinases--release of angiogenic and growth factors--tissue injury

Animal model of GCA No spontaneous or induced animal

models SCID mouse allows xenogeneic

transplantation without rejection Diseased artery transplant s.c. in SCID Inflammation persisted for 6 weeks T cell depletion and adoptive transfer of

autologous T cells suggest GCA is an antigen driven T cell dependent disease

Circulating cytokines in GCA TNF alpha and IL-6 serum levels

correlate with intensity of inflammatory response in GCA

IL-1beta and IL-13 not detectable

Biopsy positivity and GCA Negative biopsies seen in Less severe ischaemic symptoms Without visual symptoms Without abnormal temporal

arteries Without constitutional syndrome

Anti-phospholipid and GCA High prevalence of anti-PL Mainly ACL not beta2-GPI Not related to ischaemic

manifestations No congenital thrombophilic risk

factors associated with GCA

Pathogenesis of GCA Wagner et al –Dendritic cells

localise in the immediate vicinity of activated CD45RO+ T cells surrounded by RHO GTPases in grnulomatous infiltrates in GCA

? Right environment for cell to cell contact, adhesion and promote internalisation of bacteria

Pathology Sup temporal, ophthalmic, posterior ciliary,

vertabral arteries commonly involved lesions patchy/segmental with lymphocytes

either limited or infiltrating all layers. There may be necrosis, granulomata with

GC, macrophages, fibroblasts Thrombus formation Calcification reported

Clinical features Headache-sudden,mainly

temporal,occipital TA-thickened, tender,red or non-

pulsatile Scalp tenderness -localised or

diffuse/ nodules,occ scalp necrosis Jaw , tongue claudication Constitutional Sx- fever, weight loss

Visual involvement Transient and permanent vision loss,

diplopia, ptosis Fundoscopy--pallor and oedema ,

scattered cotton wool exudates, haemorrhages due to optic neuritis--- optic atrophy a sequel

Permanent vision loss 0-20% Risk of vision loss higher with transient

vision symptoms & jaw claudication

Large arterial involvement 10-15% of cases--upper extremity

claudication, absent pulses, Raynaud’s, bruits over carotid, subclavian, brachials

Thoracic artery aneurysm and dissection of aorta rarely complicates GCA

Angina pectoris, congestive failure, myocardial infarction due to coronary arteritis reported

Relation between GCA and PMR PMR reported in 40-60% GCA and

initially in 20-40% GCA in PMR--0-80%--depending on

the practice of obtaining TA biopsy High Scandanavian figures PMR can occur before,

simultaneously or after GCA

Investigations Acute phase response- CRP & ESR Anemia, thrombocytosis, mild

increase in alkaline phosphatase, decreased albumin, raised globulins, mild rise transaminases

Increased von Willebrand factor Rare reports of biopsy positive

GCA with no acute phase response

Imaging Colour duplex

ultrasonography-’halo sign’ stenosis/occlusion Gallium scan Angiography Ta biopsy remains gold standard

Mimics Ta invovement in systemic vasculitis Partial response to steroids in IC SOLs

eg tumours, abscesses Migraine Opthalmic zoster Non-arteritic causes of ischaemic

Optic neuritis Important to pursue histological proof

Treatment of GCA Initially variable dose 40-80 mg daily 40 mg in pts without visual

symptoms for I month Reduced by 5 mg/1-2 wks till 20 mg

reached Further reductions by 2.5 mg/2-4

wks. Cumulative steroid dose related to

incidence of side effects.

Treatment contd Methotrexate- conflicting results

from RCTs –American vs Spanish studies

Azathioprine Cyclosporin Deflazacort I.v. Methylprednisolone Aspirin

Methotrexate in GCA 2 conflicting reports Hoffman et al –98 pts randomised to

Mtx or placebo ,12 mths–no difference in relapses,GCA related morbidity, Steroid dose, treatment toxicity

Jover et al – 24 mths- 42 pts, significant difference in steroid dose and relapses between Mtx and placebo

Takayasu definition

It is an idiopathic, inflammatory disease that produces arteritis primarily of the aorta and its branches.

Takayasu’s vs GCA

Relatively common in India

Young usually < 40 yrs Chronic onset Mainly aorta and primary

branches Complications-

retinopathy, hypertension, aortic regurgitation, critical limb ischaemia, strokes

Commonest vasculitis in the West

Elderly , rare < 50 yrs Acute onset Mainly branches of external

carotid esp temporal artery Complications- anterior

ischaemic optic neuropathy, cranial N palsies, strokes, large vessel ischaemia uncommon

Epidemiology

Incidence / Prevalence. Omstead county (Minesota) 2.6 / million /

yrSweden 1.2 / million / yrJapan 150 new cases / yr

< 40 years (majority of patients) Female preponderance.

Epidemiology

Ethnic / geographic variations:Japan / US: Neck and UL involvement.

SE Asia: Abdominal aorta & LL involvement.

HLA associationsJapanese Bw52 / Dw12 DQw1 / DR2

Korean Bw52 / DR7 / DQw52Mexico B5India B21 / B5

Linkage disequilibrium

Pathology

Focal & skip lesions common. Active phase: Granulomatous panarteritis.

Predominantly lymphoplasmacytic infiltrate with a variable number of giant cells. Mild intimal and adventitial fibrosis.

End stage: Bland fibrosis with scant or no inflammatory infiltrate. Degeneration of the internal elastic lamina. Neovascularization.

Pathogenesis

Link with TB not confirmed. Cell Mediated Immunity: gamma & delta

T lymphocyte driven endothelial damage.

Humoral Immunity: increased gamma globulin, CIC and RF.

Increased anti-aortic antibodies.

Clinical Features

Symptoms

Constitutional symptoms: nonspecific. Dizziness, syncope, visual problems, arm

claudication, cardiac symptoms- (Japan & US).

Renovascular hypertension and lower limb claudication - (SE Asia).

Signs Unequal or absent pulses, carotidynia,

vascular bruits, BP differences, aneurysms, aortic incompetence, strokes.

GEOGRAPHICAL VARIATION OF AFFECTED VESSELS

JAPAN INDIA NORTH AMERICA

Aortic arch& branches

68 38 98

Common carotid

20 7 58

Abdominal aorta

11 22 65

Renal 8 52 38

TAKAYASU CLASSIFICATION

1 Aortic arch

2a 1+ As Aorta

2b 2a+ thoracic aorta

3 Thoracic+

Abdominal aorta

4 Abdominal aorta

5 Entire aorta

TAKAYASUACR criteria Age at onset <50 yrs Claudication of extremities Decreased brachial pulse BP difference >10 mm between arms Bruit over subclavian or aorta Arteriogram abnormality- aorta or

primary branches excluding other causes

Takayasu Sharma criteria MAJOR L subclavian R subclavian Characteristic

Signs & symptoms (of at least 1 month)

Minor ESR Carotid tenderness Aortic regurgitation Annuloaortic

ectasia Pulmonary artery L midcommon

carotid

Takayasu- Uppal et al

Chief Sx No PercentageHypertension 27 60Prolonged fever 5 11.1CCF 4 8.9Others 9 20Complications Hypertension CCFAortic regurg Stroke Critical limb

ischaemia

Imaging

Angiography : gold standard USG/ doppler: Inflammation of the

vessel wall can be assessed. But certain sites cannot be visualised.

MRI / MRA: Wall thickening, mural thrombi, aortic incompetence, collateral circulation, pulmonary A involvement.

Differential Diagnosis

Vasculitides: GCA, Cogan’s, Behcet’s etc. Tuberculous, mycotic or syphilitic

arteritis. Spondarthropathies. Marfan syndrome. Ehlers-Danlos syndrome. Fibromuscular dysplasia. Sarcoid vasculopathy

Disease groups based on complications Group 1- uncomplicated Group 2- Single complication- Takayasu

retinopathy, Hypertension, Aortic regurgitation, Aortic/ arterial aneurysm

A orB depending on mild to moderate or severe complication

Group 3- presence of > 2 complications

Takayasu - Outcome 20 yr overall survival 83% 15 yr survival 66% with complications

vs 96% without complications Improvement in survival with steroids In Japanese and Indians those carrying

the haplotype A24-B52-DR2 have higher complication rates and lower steroid responsiveness

Treatment Steroids:

Initiation: 0.75-1mg/kg/d (4-12 weeks)

Maintenance: 5-15 mg/d. Immunosuppressants:

Difficulty in tapering the dose of steroid.

Azathioprine/methotrexate/cyclosporine. Usual duration of treatment: 2-3 years. Surgical treatment needed in ~ 50 %.

Response to Rx & Prognosis

Response to oral pred 20-100 % Remission 82 % Median time to remission 22 months Need for cytotoxic Rx 40 % Relapse 50 % Smouldering activity 18 % Mortality 3-35 %

CVS complicationsHypertensive crises

PTCA & surgery Ischaemic symptoms esp. stenosis ~ 70

% PTCA

Success rate 56 - 80 %

Renal.A stenosis : B.P fall in 24 hrs.Subclavian.A stenosis

BypassFailed PTCA, not amenable to PTCA

Success rate 70 % Surgery of the aortic aneurysms

Settings for suspicion of Early Takayasu’s Constitutional symptoms with limb

pains renovascular hypertension secondary hypertension hypertension in the young hypertension in women coarctation of aorta

Guidelines for prescribing of bisphosphonates in patients on corticosteroids

1. Osteoporosis: clinical guidelines for prevention and treatment, Royal College of Physicians 1999, updated July 2000.

2. Guidance on the prevention and management of corticosteroid osteoporosis, National Osteoporosis Society, in: The Sheffield protocol for the management of the menopause and the prevention and treatment of osteoporosis, 6th revised edition, 2000.

Prepared by: Rheumatology Department, Southend Hospital for the Clinical Guidelines Working Group, September 2000. Intended review date September 2001

PREVENTION OF STEROID INDUCED OSTEOPOROSIS

The best preventive measure is to avoid systemic steroids if possible.

If systemic therapy is necessary, use minimum effective doses

Consider steroid sparing agents such as methotrexate or azathioprine.

1. All patients on long term steroids should be given lifestyle advice:a)Adequate Calcium (1000mg/d) and vitamin D (800units/d) intakeb) Weight bearing exercise (20 minutes brisk walking daily)c) avoid tobacco and excess alcohol.

2. Patients who require steroid treatment with pred. at 7.5mg/day or more for 6 months or longer should have a bone density assessment using DEXA scanning.

a) If DEXA result is Normal ie T score greater than –1.0, no other treatment is recommended. b) If DEXA shows osteopaenia, ie T score between –1.0 and –2.5, then treatment should be started if there has been a previous low impact fracture.c) If DEXA shows osteoporosis, ie T score below –2.5, treatment should be started.

3. Bisphosphonates have the best supporting evidence of benefit, compared with other pharmacological treatments, and should be used first-line.

a) Cyclical etidronate, alendronate and risedronate are all licensed for the prevention and treatment of steroid induced osteoporosis.Cyclical etidronate is given as etidronate 400mg once daily for 14 days, followed by calcium 500mg once daily for 76 days, after which the 90 day cycle is repeated.b) Alendronate is given as 5mg daily, except in post-menopausal women who are not on HRT, when the dose is 10mg/day.c) Risedronate is given as 5mg once daily.

The bisphosphonates are all poorly absorbed from the gut and must be taken fasting. Alendronate can cause oesophagitis if the tablet is not cleared from the gullet. Efficacy at vertebrae is similar, but alendronate and risedronate have a faster onset of action and are more efficacious at peripheral sites than is etidronate.

4. All patients on long term steroids should have a second DEXA scan one year after the first, and subsequent scans at 1-3 year intervals depending on the results.

5. Local Notes:The best preventive measure is to avoid systemic steroids if possible. If systemic therapy is necessary, consider steroid sparing agents such as methotrexate or azathioprine.

Patients with chronic airways disease or other inflammatory conditions are likely to have reduced bone density as a result of their disease. Beware such patients who have intermittent steroid treatment for eg asthma, inflammatory bowel disease and later become insidiuosly steroid dependent.

Audit criteria1 At the time of starting steroids, patients notes should state

whether this is likely to be for greater than 6 months. Standard: 100% of patients with PMR/GCA /organ transplantation/ polymyositis

2. If treatment is likely to last or has already continued for more than 6 months, medical notes should contain information ona) patients diet, smoking and alcohol habits. Standard 100%b) the presence or absence of previous fractures. Standard 100%

3 If treatment is likely to last or has already continued for more than 6 months

a) DEXA should be performed. Standard 100%b) either dietary intake is documented at Calcium 1g and Vitamin D 800 units/d or patients are prescribed supplementation.Standard 100%

Audit criteria (cont’d)

4. If DEXA is performed, the result should be in the notes and normality /osteopaenia /osteoporosis noted. Standard 100%

5. If patient has either a)T score <-2.5 or b) T score –1.0 to –2.5 and a previous fracture, a bisphosphonate should be prescribed. Standard 100%

6. If a patient is still on steroids more than one year after a first DEXA scan, a second DEXA scan should be performed. Standard 100%