Learning Objectives:

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• Learning Objectives
• To review the clinical presentation of Giant Cell
  Arteritis, including new imaging modalities
• To review the complications of GCA, specifically
  Aortic Arch Disease
• To update current therapy and novel options for
  the future

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Giant Cell Arteritis (GCA)

• Department of Medicine
• Division of Rheumatology
• Dr. Laurence Rubin
• Dr. Rachel Shupak
• Dr. Louise Perlin
• Department of Medical Imaging
• Dr. Louis Wu

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Case Presentation

• Mr. E. M
• 64 yo retired Caucasian male
• CC
• Shortness of breath

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Additional issues

• Six month history of nausea
• Weight loss (approx. 10 kg)
• Fatigue
• Non productive cough
• Anemia (OGD, colonoscopy negative)
• CT Scan results (L. Wu)

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Past Medical History

• Partial gastrectomy for PUD
• Radical prostatectomy July 2000 (PT2 tumour)
• Long standing asthma
• Hypertension (gt35years)
• spontaneously resolved two months previously
  and discontinuation of anti-hypertensive meds

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Physical Examination

• Afebrile
• BP not recorded
• No bruits
• Diffuse wheezing
• Elevated JVP

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Laboratory Studies

• On admission
• Hgb 123, ESR 68, CRP 62
• Cultures negative
• Negative Serology (ANA, ANCA, VDRL, HBsAg)

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Diagnoses

• Giant Cell Arteritis with diffuse large vessel
  involvement (Aortic Arch and branches, Mesenteric
  vessels)
• Asthma
• Atherosclerotic Abdominal Vascular Disease

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ACR Criteria for the Diagnosis of Giant Cell
Arteritis
Table III
These criteria were formulated by the American
College of Rheumatology 32. GCA was diagnosed if
a patient with vasculitis had three of the five
criteria listed above. The presence of three or
more criteria yields a sensitivity of 93.5
percent and a specificity of 91.2 percent
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The Temporal Artery of a Patient with Giant-Cell
Arteritis
Salvarani, C. et al. N Engl J Med 2002347261-271
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Treatment

• High dose daily Corticosteroid (60 mg/day)
• Methotrexate (15?25 mg SQ weekly) FA
• Resume Antihypertensive meds
• Bronchodilators
• ASA low dose
• Bisphosphonate
• Ca, Vitamin D

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Follow Up

• Energy level improved, fatigue and cough resolved
• ESR, CRP normalized within 4 weeks
• Readmitted to Hospital with acute CHF (SOB and
  hemoptysis)
• Angio -CAD - but also ?Myocarditis resolved with
  medical therapy

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Imaging

• Dr. Louis Wu

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Etiopathogenesis of GCA/PMR

• Viral/Bacterial
• Parainfluenza, Mycoplasma, Parvo B19, Chlamydia
• Genetic
• HLA DRB104, HLADR B101 (marker for severity)
• Cellular
• CD4 T cells, Dendritic cells (immunitolerance)
• Hormonal/Cytokine
• IFNgamma, IL-1, IL-6, IL-2, MMP/NO PDGF, VEGF

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Dendritic Cells in the Arterial Adventitia
Weyand, C. M. et al. N Engl J Med 2003349160-169
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Adaptive Immune Responses in Vasculitis and the
Consequences of Arterial-Wall Injury
Weyand, C. M. et al. N Engl J Med 2003349160-169
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Recommendations

• History
• Constitutional symptoms
• New headache
• Visual change
• Amaurosis fugax
• Sudden blindness 8-15
• Diploplia
• Jaw claudication
• Peripheral claudication
• Confusion/TIA

• Physical
• BP both arms
• Palpate TA
• Bruits
• Lab
• Cbc
• ESR, CRP
• LFT

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Teaching pointIf you cant get a blood
pressure . . .
CHECK THE PULSES!
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Giant Cell Arteritis

• Complications of GCA
• Large Vessel Aortic Arch Disease

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Giant Cell ArteritisHistorical Perspective

• 1890 Hutchinson
• First clinical case
• 1932 Horton
• TA involvement, vasculitis
• 1941 Gilmour
• Non-cranial vessel involvement, aorta large
  arteries
• 1990 Ninet
• 10 collected cases of subclavian/axillary
  involvement

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Giant Cell Arteritis
PMR 15-55 develop GCA GCA 40-60 have PMR
symptoms
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Giant Cell Arteritis Differentiating
Atherosclerosis Inflammation

• Upper limb gtgt Lower limb
• Limited risk for Atherosclerosis
• Angiographic findings
• Prompt response to corticosteroid Rx

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Giant Cell ArteritisDifferentiating
Atherosclerosis Inflammation

• Long segments of smooth arterial stenosis
  alternating with areas of normal or increased
  caliber vessels
• Smooth tapered occlusion
• Absence of irregular plaques ulceration
• Anatomic distribution subclavian, axillary,
  brachial arteries ascending, thoracic aorta
  

Perruquet, Archives Int Med, Feb 1986
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10-15 Of GCA Involve Extra-cranial Vessels

• Clinical Presentation includes
• Aortic Arch Arteritis
• Aortic Dissection/Rupture
• Aortic Insufficiency
• Coronary Arteritis

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Giant Cell ArteritisAortic Arch Arteritis
Perruquet, Archives INT med 1986 Ninet, AmJMed
1990
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Giant Cell ArteritisAortic Arch Arteritis

• Investigation
• Doppler
• Angiography
• Postvertebral subclavian
• Symmetric/bilateral
• Biopsy
• CT
• Course
• Response to steroids
• Revascularization uncommon
• Ischaemic changes rare

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Giant Cell ArteritisAortic Dissection/Rupture
Literature Review (23 cases)

• Presentation
• Femalemale 194
• Catastrophic 46 no known GCA
• GCA preceded in 54 (TA/PMR (8), PMR (3))
• ESR increased in 22/23
• Pathological confirmation 23/23
• Inadequate Rx of GCA HT increases risk for AD

• Involvement
• Diffuse in 89 vs Skip lesion of TA
• Proximal aorta 85
• Mortality
• 80 in 2 weeks
• Hypertension
• 77

Liu, Shupak Chiu Seminars Arthritis Rheum 1995
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Pathological Review of 72 Cases Aortic
Extra-cranial Large Vessel Disease
Lie Seminars Arthritis and Rheumatism, 1995
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Aortic Extra-Cranial Large Vessel DiseaseGiant
Cell Arteritis

• Prevalence unknown 3-15 of all GCA cases in
  literature
• Prospective of unselected autopsies GCA was found
  in 1.7 of 889 postmortem (TA 2 sections aorta)
• Retrospective Cohort study Olmstead County
  1950-1985

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Aortic Extra-Cranial Large Vessel DiseaseGiant
Cell Arteritis

• Evans, Mayo Clinic, Ann Intern Med 1995
• 96 cases GCA
• 11 cases Thoracic Aortic aneurysm, dissection or
  both
• CT, US, angiogram or autopsy
• 6/11 sudden death from thoracic dissection (type
  1)
• 9/11 median of 5.8 years post GCA Dx
• 6/11 Abdominal aneurysm 2.5 years post Dx GCA

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Aortic Extra-Cranial Large Vessel DiseaseGiant
Cell Arteritis

• Thoracic Aneurysm RR 17.3 (95 CI, 7.9-33)
• Abdominal Aneurysm RR 2.4 (95 CI, 0.8-5.5)
• Surgical Outcome poor

Kerr, J Thoracic and CV Surgery 2000
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Giant Cell ArteritisAortic Insufficiency

• Case reports
• Klinghofer, AR 1985
• 6 cases 2
• Abstract Bowles, Hunder AR 1984
• proximal aortitis with dilatation of aortic ring
• 14 females, 4 males TA from 1950-1980
• AI at TA dx in 3 median 5 years post Dx in 13
• CHF in 5/18 3 patients died
• GCA not implicated in AI clinically in any pt

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Giant Cell ArteritisCoronary Artery disease

• Editorial Am Heart Journal 1980
• Is GCA a Cardiologists Blind Spot??
• Dominance of Atherosclerosis overwhelms less
  common treatable disorders
• Case reports true prevalence of CAD in GCA is
  unknown
• Controversy exists re relative risk CAD in GCA pts

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Giant Cell ArteritisCoronary Artery Disease

• Ray, Heart, 2005
• population based retrospective cohort
• RR 1.6 (95 CI 1.1-2.2) for CAD compared to OA
• RR 2.1 (95 CI 1.5-3.0) for CAD compared to
  Normals

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Pitfalls to Diagnosis

• Do not think of the Diagnosis
• False negative biopsy skip lesions
• Intimal proliferation may dominate over giant
  cells
• Normal ESR 10

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Giant Cell Arteritis

• Treatment

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Giant Cell Arteritis (GCA) Treatment

• Goal of GCA treatment is to prevent
• blindness
• stroke
• other manifestations of cranial and systemic
  ischemia
• EARLY DIAGNOSIS AND TREATMENT
• ARE CRUCIAL

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Giant Cell Arteritis Treatment

• HIGH DOSE CORTICOSTEROID

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Giant Cell ArteritisTreatment

• HIGH DOSE CORTICOSTEROID
• oral or intravenous?
• how high?
• once daily or divided dose?
• how to taper?
• how long to continue?
• how to monitor disease/side effects?

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Giant Cell ArteritisTreatment

• Corticosteroid Oral or Intravenous?
• anecdotal reports of visual improvement with IV
  methylprednisolone
• visual recovery rare with high dose IV or PO
  steroid
• Chevalet (J Rheum 2000271484) RCT of IV
  methylpred 240 mg vs.po prednisone at one year,
  no difference in clinical course, cumulative
  steroid dose, side effects, normalization of
  C-reactive protein
• Overall High dose ORAL prednisone

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Giant Cell ArteritisTreatment

• Cortcosteroid Dose
• 1-1.5 mg/kg body weight
• e.g., prednisone 60-80 mg po daily

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Giant Cell ArteritisTreatment

• Corticosteroid Daily or Divided Dose?
• Divided dose re
• pharmacokinetics of prednisone
• Hunder (Ann Int Med 197582615) 20 patients
  given daily vs. 20 patients given tid steroid
  trend toward better control. No difference in
  side effects including adrenal suppression
• Overall divided dose may be preferable but not
  always feasible in the population at risk for GCA

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• DIGRESSION

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Giant Cell ArteritisTreatment

• Corticosteroid Effect on Temporal Artery
  Biopsy Yield

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Giant Cell ArteritisTreatment

• Corticosteroid effect on Temporal Artery Biopsy
• retrospective case study TABx may show arteritis
  even after 14 days of steroid (Achker Ann Int Med
  1994120987)
• SCID mouse studies inflammatory indicators one
  week after dexamethasone (Brack J Clin Invet
  1997992842)
• case reports of positive TABx months and years
  after steroid (Murgatroyd Eye 200115250)
  (Guevara Arch Opthalmol 19981161252) (Evans
  Mayo Clin Pro 1994691060)

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Giant Cell ArteritisTreatment

• Corticosteroid Effect on Temporal Artery Biopsy
• Steroids should be used as soon as the
  diagnosis is suspected AND a Temporal Artery
  Biopsy should be performed as soon as it can be
  arranged.

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Giant Cell ArteritisTreatment

• Corticosteroid Disease Monitoring
• high dose for 2-4 weeks
• reduction every 1-2 weeks by a maximum of 10 of
  the total daily dose. Taper more slowly
  thereafter.
• follow
• clinical state
• ESR
• C-reactive protein
• ? Interleukin-6 (IL-6)
• ? Radiology

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Giant Cell ArteritisTreatment

• Corticosteroid Patient Monitoring
• diabetes
• hypertension
• non-arteritic vascular disease
• osteoporosis
• infection
• muscle atrophy/weakness falls
• cataracts

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Giant Cell ArteritisTreatment

• Corticosteroid Monitoring
• Have a high index of suspicion for GCA flares.
• relapse rate is high
• in 1980s 30
• current reports 50-80 in patients followed for
  12-52 months
• 125 GCA patients only ½ were able t stop
• steroids within 2 years
• acute phase reactants are insensitive and
  nonspecific
• remember pre-existing and evolving co-morbidity
  in this elderly population

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Giant Cell ArteritisTreatment

• Corticosteroids
• high relapse rate
• questionable effectiveness
• high side effect profile
• New Immunosuppressant
• Medications with Corticosteroid

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Giant Cell ArteritisTreatment

• Other options
• Azathioprine - 1986 Dasilva
• Cyclophosphamide - 1992 deVita
• Dapsone - 1993 Doury
• Cyclosporin A - 1998 Schaufelburger
• Methotrexate - 1989 Krall

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Giant Cell ArteritisTreatment

• Methotrexate with CS vs. CS alone
• Randomized placebo controlled double blind
  studies
• Jover - Ann Int Med 2001134106
• 42 patients for 2 years less number of relapse,
  less mean cumulative dose, less duration of CS
  (no diff rate or severity of side effects)
• Spiera - Clin Exp Rheumatol 200119495
• 21 patients for gt2 years no diff in cumulative
  dose, weeks to d/c steroid, Functional status,
  side effects
• Hoffman - Arthritis and Rheum 2002461309
• 98 patients for 1 year no difference in rate of
  disease relapse, cumulative CS dose,
  disease/treatment morbidity

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Giant Cell ArteritisTreatment

• Methotrexate Summary
• study results are conflicting
• use for initial disease suppression with CS is
  not routinely recommended
• Overall when disease remains active requiring
  long term steroid and/or in the face of CS side
  effect Methotrexate can be/is (anecdotally) added

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Giant Cell ArteritisTreatment

• Case Reports
• Anti -CD20 monoclonal Ab (rituximab)
• B cell lymphocyte depletion with benefit
• (Ann Rheum Dis 2005641099)
• TNF inhibitors
• 2 cases of infliximab with benefit initially but
  no sustained response (Ann Rheum Dis
  2003621116)
• occurrence of GCA in patient on Etanercept plus
  methotrexate for RA (J. Rheum 2004311467)

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Giant Cell ArteritisTreatment

• Statins
• Issues sustained GC treatment associated with
  dyslipidemia anti-inflamm properties of statins
• Garcia-Martinez Arthritis and Rheum
  200451(4)674
• 54 patients with GCA retrospectively chosen no
  statin in 37 vs statin in 17
• Results no diff in demographics, disease
  severity, CS requirement or relapse rate

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Giant Cell ArteritisTreatment

• Low Dose ASA
• Nestor Arthritis and Rheum 2004509401332
• Retrospective chart review of 175 GCA patients
  with ischemic complications in 33 (75 before
  and 25 after diagnosis)
• Findings
• Patients receiving ASA were 5 times less likely
  to experience cranial ischemic complications by
  the time of diagnosis and 5 times less likely to
  develop them after.
• Overall Add low dose ASA to GCA treatment
  regimen.

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Giant Cell ArteritisTreatment

• Summary
• HIGH dose oral prednisone daily or divided dose.
• Taper 10 of daily dose q1-2 weeks to 20 mg
  daily and then more gradual reduction to lowest
  level possible/or discontinue.
• Follow clinical response and acute phase
  reactants carefully as flares are common.
• Prophylax against/treat corticosteroid side
  effects and co-morbid medical conditions.
• Consider an immunosuppressant (e.g.,
  Methotrexate) for refractory disease
• Add low dose ASA

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