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L  A  R Lecture
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L A R Lecture

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  • 1. Large vessel Arteritis
  • 2. 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
  • 3. 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
  • 4. 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
  • 5. Giant cell arteritis
    • Affects cranial branches of arteries arising from the aortic arch most typically the superficial temporal artery
    • Characterised by acute phase response
  • 6. 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.
  • 7. 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
  • 8. 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
  • 9. 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
  • 10. Immunopathogenesis
    • Low CD8 cells
    • Antibody to intermediate filaments
    • Antibodies to cardiolipin and beta2 GP1
    • Raised IL-6 and IL-1RA, IL-10
  • 11. 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
  • 12. 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
  • 13. 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
  • 14. 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
  • 15. Biopsy positivity and GCA
    • Negative biopsies seen in
    • Less severe ischaemic symptoms
    • Without visual symptoms
    • Without abnormal temporal arteries
    • Without constitutional syndrome
  • 16. 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
  • 17. 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
  • 18. 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
  • 19.  
  • 20. 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
  • 21. 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
  • 22. 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
  • 23. 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
  • 24. 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
  • 25. Imaging
    • Colour duplex ultrasonography-’halo sign’
    • stenosis/occlusion
    • Gallium scan
    • Angiography
    • Ta biopsy remains gold standard
  • 26. 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
  • 27. 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.
  • 28. Treatment contd
    • Methotrexate- conflicting results from RCTs –American vs Spanish studies
    • Azathioprine
    • Cyclosporin
    • Deflazacort
    • I.v. Methylprednisolone
    • Aspirin
  • 29. 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
  • 30. Takayasu definition
    • It is an idiopathic, inflammatory disease that produces arteritis primarily of the aorta and its branches.
  • 31.  
  • 32. 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
  • 33. Epidemiology
    • Incidence / Prevalence.
    • Omstead county (Minesota) 2.6 / million / yr
    • Sweden 1.2 / million / yr
    • Japan 150 new cases / yr
    • < 40 years (majority of patients)
    • Female preponderance.
  • 34. Epidemiology
    • Ethnic / geographic variations:
    • Japan / US: Neck and UL involvement.
    • SE Asia: Abdominal aorta & LL involvement.
    • HLA associations
    • Japanese Bw52 / Dw12 DQw1 / DR2
    • Korean Bw52 / DR7 / DQw52
    • Mexico B5
    • India B21 / B5
    • Linkage disequilibrium
  • 35. 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.
  • 36. 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.
  • 37. 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.
  • 38. GEOGRAPHICAL VARIATION OF AFFECTED VESSELS 38 52 8 Renal 65 22 11 Abdominal aorta 58 7 20 Common carotid 98 38 68 Aortic arch& branches NORTH AMERICA INDIA JAPAN
  • 39. TAKAYASU CLASSIFICATION 1 Aortic arch 2a 1+ As Aorta 2b 2a+ thoracic aorta 3 Thoracic+ Abdominal aorta 4 Abdominal aorta 5 Entire aorta
  • 40. TAKAYASU ACR 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
  • 41. 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
  • 42. Takayasu- Uppal et al
  • 43. 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.
  • 44. Differential Diagnosis
    • Vasculitides: GCA, Cogan’s, Behcet’s etc.
    • Tuberculous, mycotic or syphilitic arteritis.
    • Spondarthropathies.
    • Marfan syndrome.
    • Ehlers-Danlos syndrome.
    • Fibromuscular dysplasia.
    • Sarcoid vasculopathy
  • 45. 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
  • 46. 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
  • 47. 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 %.
  • 48. 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 complications
    • Hypertensive crises
  • 49. PTCA & surgery
    • Ischaemic symptoms esp. stenosis ~ 70 %
    • PTCA
    • Success rate 56 - 80 %
    • Renal.A stenosis : B.P fall in 24 hrs.
    • Subclavian.A stenosis
    • Bypass
    • Failed PTCA, not amenable to PTCA
    • Success rate 70 %
    • Surgery of the aortic aneurysms
  • 50. 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
  • 51. 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
  • 52. 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.
  • 53. 1. All patients on long term steroids should be given lifestyle advice: a)Adequate Calcium (1000mg/d) and vitamin D (800units/d) intake b) 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.
  • 54.
    • 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.
  • 55.
    • 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.
  • 56.
    • Audit criteria
    • 1 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 on
    • a) 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%
  • 57.
    • 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%
  • 58. 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
  • 59. 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.
  • 60. 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.
  • 61. 1. All patients on long term steroids should be given lifestyle advice: a)Adequate Calcium (1000mg/d) and vitamin D (800units/d) intake b) 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.
  • 62.
    • 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.
  • 63.
    • 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.
  • 64.
    • Audit criteria
    • 1 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 on
    • a) 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%
  • 65.
    • 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%

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