Giant Cell Arteritis and Temporal Artery Biopsy

Raymond Cho, MD; Mark Lucarelli, MD, FACS

Establishing the diagnosis

Etiology

Systemic granulomatous vasculitis involving medium to large arteries

Most commonly the thoracic aorta, cervical arteries, and branches of the external carotid arteries
Activated dendritic cells attract T-lymphocytes (mainly CD4) infiltration, macrophages exposed to IFN-γ form multinucleated giant cells

Cytokine production including IFN-γ, IL-1b, IL-6, matrix metalloproteinases (MMP)
Exact etiology unclear

Some genetic predisposition, associated w/ HLA-DR4 haplotype
Suggestion of infectious origin (mycoplasma, chlamydia, parvovirus B19, burkholderia)
Age-related changes in the immune system and affected arteries might be important in disease pathogenesis.

Figure 1. H&E photomicrograph of a medium sized artery with giant cell arteritis; note the multinucleated giant cells (arrow).

Epidemiology

Incidence 18 per 100,000 in individuals over 50 years old (Salvarani, Ann Intern Med 1995)
Elderly (mean age at presentation 71 years)
Female > male (2–6 times greater); women account for 65%-75% of patients
Most common in white people of northern European descent
Unusual in Hispanic, Asian, and African-American populations

History

Headache (present in 67%)
Jaw claudication (present in 50%)
Tongue claudication
Scalp tenderness
Systemic weakness, malaise, weight loss, fever
Polymyalgia rheumatica (present in 40%–50%)
Throat pain
Nonspecific neck/shoulder/muscle pain
Loss of vision
Diplopia
Eye pain
In indeterminate specimens, CD68 staining for macrophages may be helpful

Clinical features

Ophthalmic: Ischemic complications in 25% of giant cell arteritis (GCA) patients

Anterior ischemic optic neuropathy (AION): Accounts for about 80% of vision loss attributable to GCA

Decreased vision: Often worse than 20/200, 21% NLP

Can be preceded by transient vision loss

Visual field defect: Typically central or altitudinal
Afferent pupillary defect
Swollen optic nerve head with pallor

Optic atrophy usually evident after 3–6 weeks

Posterior ischemic optic neuropathy (PION)

Same as above, but optic nerve head initially appears normal

Central retinal artery occlusion (CRAO) or cilioretinal artery occlusion

Vision loss, afferent pupillary defect, cherry red spot

Choroidal infarction
Ischemic cranial nerve palsy

Oculomotor nerve (nerve III) typically pupil-sparing

Extraocular muscle infarction
Ocular ischemic syndrome

Hypotony due to decreased aqueous production

Amaurosis fugax
Horner syndrome

Neurologic

Ischemic stroke, transient ischemic attack (TIA), spinal cord infarction, mono/polyneuropathies, sensorineural hearing loss
GCA can be “occult” (isolated ocular complications without other neurological findings) in 21%–38% of cases (Hayreh, Am J Ophthalmol 1997)

Vascular

Superficial temporal artery tenderness, lack of pulsation
Thoracic/abdominal aortic aneurysm, coronary ischemia, intestinal infarction, pulmonary artery thrombosis, renal failure
Upper or lower extremity claudication

Testing

Erythrocyte sedimentation rate (ESR)

Nonspecific marker of inflammation
Usually elevated (> 50 mm/hr in 85%–95% of patients)
“Normal” ESR level subject of debate

Miller formula (Miller, Br Med J 1983)

Men: Age divided by 2
Women: Age plus 10 divided by 2

C-reactive protein (CRP)

Usually elevated (> 2.45 mg/dL)

When combined with elevated ESR, specificity is 97% (Hayreh, Am J Ophthalmol 1997)
4% of patients with confirmed GCA had normal ESR and normal CRP at time of diagnosis (Kermani, Semin Arthritis Rheum 2012)

Thrombocytosis

65% of patients with permanent vision loss have thrombocytosis (Liozon, Am J Med 2001)

Fluorescein angiogram

AION: Delayed filling of optic disc or peripapillary choroid, choroidal nonperfusion
CRAO: Delayed filling of CRA

Duplex ultrasound of temporal artery

Arterial edema represented by hypoechoic haloes immediately adjacent to arterial wall
Sensitivity 75%, specificity 83% (Ball, Br J Surg 2010)
A systematic review and meta-analysis of 20 studies showed sensitivity of 68% (57%–78%; 95% CI) and specificity of 81% (75%–86%; 95% CI) (Rinagel, Autoimmune Rev 2019).
Can be considered as noninvasive alternative to biopsy

Temporal artery biopsy (TAB)

Gold standard for definitive diagnosis of GCA

Sensitivity 85–95% (Kermani, Ann Rheum Dis 2013)
Positive predictive value 90%–100%

Histopathologic findings

T-lymphocyte and macrophage infiltrates of the vessel media and internal elastic lamina
Giant cells might or might not be present
Intimal thickening with disruption of internal elastic lamina
Areas of unaffected tissue (skip lesions) in 21%–28% of cases

Recommendations for biopsy length significantly

Breuer (Clin Exp Rheumatol 2009) found increased biopsy length improved positivity rates: ≤ 5 mm (19%), 6–20 mm (79%), > 20 mm (89%)
Recent systematic review of literature (Buttgereit, JAMA 2016) recommends specimen length of “at least 1 cm.”
In a recent series of 240 temporal artery biopsies (Grossman, Scand J Rheumatol 2017), the TAB positivity rate was similar among all ranges of biopsy length (<5 mm 70%, 5-9 mm 71%, 10-14 mm 69%, 15-19 mm 69%, 20 mm 73% (p= ns).
A case-control study of 545 consecutive patients who underwent TA biopsy (Oh, Anz J Surg 2018) found a cut-off point of > 15 mm increased the odds of a positive TAB by 2.25 compared with TAB < 15 mm (P= 0.003)
Clinical judgment is warranted in the absence of a clear evidence-based minimum TA biopsy length

Contralateral biopsy might be required if first biopsy negative (controversial).

Positivity rate of second biopsy 9% (Hayreh, Am J Ophthalmol 1997)
Bilateral biopsy can increase diagnostic sensitivity by up to 12.7% (Breuer, J Rheumatol 2009) but is generally not recommended as a primary approach.

Systemic steroids can affect histopathologic findings, but should not be withheld prior to biopsy due to risks associated with treatment delay.

Biopsy within 1–2 weeks of initiating steroid treatment might optimize diagnostic yield.
Histopathologic evidence of GCA can still be seen after 6 months or more of steroid treatment (Narváez, Semin Arthritis Rheum 2007).

Complications of procedure

Bleeding, infection, pain, scarring, alopecia
Scalp necrosis
Damage to temporal branch of facial nerve (brow paralysis)

Temporal artery biopsy remains the gold standard for diagnosis of GCA, but significant debate has emerged over whether temporal artery biopsy is necessary

Clinicians should consider whether a positive or negative biopsy result will alter patient management

If clinical suspicion is strong, treatment may be indicated regardless of TAB result.
Temporal artery biopsy may not be required in patients with typical disease features and characteristic ultrasound or MRI findings (Dejaco, Ann Rheum Dis 2018)
In paucity of signs and symptoms consistent with GCA, diagnostic yield of TAB is extremely low.

Medico-legal ramifications: Positive TAB can justify risks of long-term steroid use

Figure 2. Temporal artery biopsy. (A) Scalp incision aided by preoperative doppler testing. (B) blunt dissection in subcutaneous fat and superficial temporal fascia to identify artery. (C) 2-cm arterial specimen to be obtained. (D) Deeper dissection demonstrates deep temporal fascia under the correct arterial plane.

American College of Rheumatology criteria

(Hunder, Arthritis Rheum 1990)

3 out of 5 of the following (sensitivity/specificity 93.5%/91.2%):

Age at onset > 50 years
New headache
Temporal artery abnormalities (on exam or ultrasound)
ESR > 50 mm/hr
Positive temporal artery biopsy

Risk factors

Increasing age
Smoking and atherosclerosis: Increases risk in women but not men
Low body mass index
Early menopause
Relative adrenal hypofunction
Genetic susceptibility suggested by several studies

Differential diagnosis

Nonarteritic ischemic optic neuropathy
Other optic neuropathies (infectious, inflammatory, infiltrative, compressive, toxic)
Nonarteritic central artery occlusion
Central retinal vein occlusion
Other causes of headache/jaw pain (trigeminal neuralgia, dental conditions)

Patient management: treatment and follow-up

Natural history

Disease course is chronic
Visual prognosis depends on vision at presentation

Incidence of blindness 7%–25%
Vision loss due to AION or CRAO usually irreversible
Features associated with poor visual prognosis: Older age, fever, weight loss, amaurosis, diplopia, jaw claudication

65% of untreated patients develop bilateral ischemic optic neuropathy.

Vision loss in second eye typically occurs within 10 days of first.
Failure to diagnose GCA is a significant cause of litigation against ophthalmologists.

Medical therapy

Systemic corticosteroids: First line therapy

Administration:

Oral prednisone, typically 1 mg/kg/day
IV administration for severe vision loss or amaurosis: Methylprednisolone 250 mg IV Q6 h for 3 days, then oral prednisone 80–100 mg/day

Initiate steroids while awaiting biopsy results to avoid delay in treatment
Follow ESR and clinical symptoms

Symptoms typically respond within days
Several weeks of steroids usually required before ESR/CRP normalize
Visual improvement unusual, especially in AION and if delayed
Decision to treat or stop treatment should be based on the complete clinical picture

Taper corticosteroids slowly: A 1–2 year course typical

Other medications

Aspirin is often prescribed to prevent thrombotic complications.

Efficacy in preventing blindness unproven

Steroid-sparing agents:

Adjunctive Methotrexate may reduce cumulative glucocorticoid dosing by 20%–44% and relapses by 36%–54% (Buttgereit, JAMA 2016)
Methotrexate and IL-6 antagonist, Tociluzimab may each prevent the likelihood of relapse (Berti Semin Arthritis Rheum, 2018)
In an RCT (Stone, NEJM 2017) Tociluzimab showed sustained remission at 52 weeks in 56% of weekly tociluzimab (with 26 week prednisone taper) vs 14% for the placebo (with 26 week prednisone taper)

Preventing and managing treatment complications

Steroid-related complications

Inability to taper drug without flare of disease
Hyperglycemia
Aseptic necrosis of the hip
Hypertension
Osteoporosis
GI bleeding
Weight gain
Cushingoid facies
Depression

Prevention

Limit long-term use
Discuss side effects with patient before use
Monitor for side effects (hyperglycemia, hypertension, osteoporosis, etc.) and treat as appropriate

Disease-related complications

Ocular

Permanent loss of vision
Diplopia

Neurologic

Transient ischemic attack, stroke
Vertigo
Hearing loss
Mononeuritis multiplex

Coronary ischemia
Aortic aneurysm or dissection
Renal failure
Mesenteric ischemia
Tongue claudication/ischemia

Temporal artery biopsy technique

Mark frontal branch of superficial temporal artery (STA) on symptomatic side, starting in preauricular region and extending toward forehead/brow:

Locate artery by palpation or Doppler ultrasound.
Incision should be at least as long as planned length of biopsy segment.
Stay as distal to main STA trunk as possible.
Shave scalp overlying STA if necessary.

Infiltrate with local anesthetic, avoiding direct intravascular injection.
Prep and drape surgical site in standard sterile fashion.
Create skin incision parallel to artery, either directly overlying or slightly to either side.
Bluntly dissect through subcutaneous fat to expose superficial temporalis fascia, also known as temporoparietal fascia.

Superficial fascia is loose and areolar, as contrasted with underlying deep temporalis fascia, which is fibrous and glistening.

Identify artery lying within superficial temporalis fascia.

Spreading fascia with blunt-tipped instrument parallel to artery can assist in locating artery.

Open fascia overlying the artery and dissect the artery from surrounding tissues:

Avoid undue penetrating or crushing trauma to the specimen (e.g., with toothed forceps).
Ligate and divide arterial branches as necessary.

Double-ligate the artery both proximally and distally with braided nonabsorbable suture (for example, 4-0 or 5-0 silk), leaving adequate specimen length between ligation points.

Ligating the artery early during procedure can limit intraoperative bleeding.

Excise specimen and send in standard tissue fixative for pathologic examination.
Obtain meticulous hemostasis.
Close incision with deep and/or superficial skin sutures.
Apply topical antibiotic ointment and dressing as desired.
Instruct patient on proper wound care and precautions.

References and additional resources

Ball EL, Walsh SR, Tang TY, et al. Role of ultrasonography in the diagnosis of temporal arteritis. Br J Surg 2010;97:1765-71.
Berti A, Cornec, D, Medina Inojosa J, et al. Treatments for giant cell arteritis: Meta-analysis and assessment of estimates using the fragility index. Semin Arthritis Rheum 2018; 48:77-82.
Breuer GS, Nesher G, Nesher R. Rate of discordant findings in bilateral temporal artery biopsy to diagnose giant cell arteritis. J Rheumatol 2009;36:794-6.
Breuer GS, Nesher R, Nesher G. Effect of biopsy length on the rate of positive temporal artery biopsies. Clin Exp Rheumatol 2009;27:S10-3.
Bury D, Joseph J, Dawson TP. Does preoperative steroid treatment affect the histology in giant cell (cranial) arteritis? J Clin Pathol 2012;65:1138-40
Calvo-Romero JM. Giant cell arteritis. Postgrad Med J 2003;79:511-515.
Dejaco C, Ramiro S, Duftner C, et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis 2018; 77:636-643
Duhaut P, Pinede L, Demolombe-Rague S, et al. Groupe de Recherche sur l’Artériteà Cellules Géantes. Giant cell arteritis and cardiovascular risk factors: a multicenter, prospective case-control study. J Arthritis Rheum. 1998;41(11):1960.
Fraser JA, Weyand CM, Newman NJ, Biousse V. The treatment of giant cell arteritis. Rev Neurol Dis 2008;5(3):140-152.
Grossman C, Ben-Zvi I, Brashack I, BornsteinG. Association between specimen length and diagnostic yield of temporal artery biopsy, Scand J Rheumatol 2017; 46: 222-225.
Hayreh S, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997;123;285-96.
Hayreh S, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol 1998;125;509-20.
Hayreh S, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 1998;125;521-6.
Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122-8.
Kale N, Eggenberger E. Diagnosis and management of giant cell arteritis: a review. Curr Opin Ophthalmol. 2010;21:417-422.
Gonzalez-Gay MA, Martinez-Dubois C, Agudo M, et al. Giant cell arteritis: epidemiology, diagnosis, and management. Curr Rheumatol Rep 2010;12:436-42.
Karassa F, Matsaga MI, Schmidt WA, et al. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med 2005;142:359-69.
Kent RB, Thomas L. Temporal artery biopsy. Am Surgeon 1989;56:16-21.
Koening CL, Katz BJ, Hernandez-Rodruiguez J, et al. Identification of a Burkholderia-like strain from temporal arteries of subjects with giant cell arteritis. Arthritis Rheum 2012:64:S373
Liozon E,Hermann F, Ly K, et al. Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients. Am J Med 2001;111:211-7.
Miller A, Green M, Robinson D. Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J 1983;286:266.
Mizen TR. Giant cell arteritis: diagnostic and therapeutic considerations. Ophthalmol Clin North Am 1991;4:547-56.
Narváez J, Bernad B, Roig-Vilaseca D, et al. Influence of previous corticosteroid therapy on temporal artery biopsy yield in giant cell arteritis. Semin Arthritis Rheum 2007;37:13-9.
Oh LJ, Wong E, Gill AJ, et al. Value of temporal artery biopsy length in diagnosing giant cell arteritis. Anz J Surg 2018;88:191-195.
Pineles SL, Arnold AC. Giant cell arteritis. Int Ophthalmol Clin 2007;47:105-119.
Quinn EM, Kearney DE, Kelly J, et al. Temporal artery biopsy is not required an all cases of suspected giant cell arteritis. Ann Vasc Surg 2012;26:649-54.
Varma D, O’Neill D. Quantification of the role of temporal artery biopsy in diagnosing clinically suspected giant cell arteritis. Eye 2004;18:384-8.
Vilaseca J, Gonzalez A, Cid MC, et al. Clinical usefulness of temporal artery biopsy. Ann Rheum Dis 1987;46:282-5.
Rahman W, Rahman FZ. Giant cell (temporal) arteritis: an overview and update. Surv Ophthalmol 2005;50:415-28.
Rinagel M, Chatelus E, Jousse-Joulin S, et al. Diagnostic performance of temporal artery ultrasound for the diagnosis of giant cell arteritis: a systematic review and meta-analysis of the literature. Autoimmune Rev 2019; 18:56-61.
Salvarani C, Gabriel SE, O’Fallon WM, et al. The incidence of giant cell arteritis in Olmsted County, Minnesota: apparent fluctuations in a cyclic pattern. Ann Intern Med 1995;123:192-4.
Stone JH, Tuckwell S, Dimonaco M, et al. Trial of Tociluzimab in giant cell arteritis. NEJM 2017; 377: 317-328.
Swannell AJ. Polymyalgia rheumatic and temporal arteritis: diagnosis and management. Br Med J 1997;314:1329-32.
Zhou L, Luneau K, Weyand CM, et al. Clinicopathologic correlations in giant cell arteritis: a retrospective study of 107 cases. Ophthalmol, 2009; 116: 1574-1580.