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Management of giant cell arteritis

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Figure 1A. Magnified view of normal arterial wall. Blue arrow demarcates internal elastic lamina
(note its uniform organisation), yellow arrow demarcates tunica media.

______________________________

Lucas Genereux
BS

Dr Leonid Skorin Jr
OD DO MS FAAO FAOCO
Albert Lea, MN, USA

 

Giant cell arteritis (GCA) affects one in 150,000 patients over the age of 60 years.1 By the ninth decade of life, the incidence of GCA rises to 44/100,000.1 The condition occurs twice as often in women and is most commonly seen in Caucasians of Northern European decent.2

GCA, also known as temporal arteritis or cranial arteritis, results in chronic inflammation of medium-sized and large arteries, particularly the branches of the carotid arteries. The pathology behind this inflammation appears to be multinucleated giant cells (MGCs). MGCs promote degradation of the vessel’s elastic fibres of the internal elastic lamina by the release of proteinase and peroxisome enzymes3 (Figure 1). These cells also release the angiogenic factors, vascular endothelial growth factor and platelet derived growth factor, which result in the formation of a vascular bed. This bed provides nourishment for myofibroblast proliferation from the vessel tunica media.3 The combination of events ultimately results in vessel obstruction and ischaemia to downstream tissues. The most common cranial arteries involved are the temporal, ophthalmic and short posterior ciliary arteries.4

Polymyalgia rheumatica (PMR) is often found concurrently with GCA. It presents with symmetrical aching, tenderness, and stiffness of the proximal muscles of the neck, shoulders and pelvic girdle, most notably in the morning. PMR is an inflammatory disease thought to represent a different end of the GCA spectrum.5

Pharma -OL-36-GCA_figure -1b _OL Pharma -OL-36-GCA_figure -1c _OL

Figure 1B. Cross section of normal temporal artery vessel wall

Figure 1C. Positive temporal artery biopsy. Note the proliferation of the tunica media and destruction of internal elastic lamina.

Symptomatology

Sudden painless vision loss (often preceded by amaurosis fugax), temporal headache, jaw claudication, scalp tenderness, fever, occipital tenderness, dental abscess, vertigo and unexplained weight loss are all common GCA signs and symptoms. Jaw claudication and temporal headache are highly correlated with GCA diagnosis, as 30-80 per cent of diagnosed patients present with these symptoms.5 Visual related findings may also include diplopia and visual hallucinations. Vision loss is most commonly the result of anterior arteritic ischemic optic neuropathy.

While PMR causes pain in proximal joints, distal joints can also be affected in GCA patients. Peripheral arthritis with swelling and pitting oedema in the hands and feet may occur in 25 per cent of patients.6 Likewise, the carotid branches are not the only arteries involved. Some cases manifest occlusion of the subclavian and axillary arteries. This results in claudication of the arms, and weak pulses in these distributions.6

Detection and diagnosis

The American College of Rheumatology (ACR) released diagnostic criteria for GCA in 1990.5 It requires patients to meet three or more of the following criteria: age over 50 years, new onset localised temporal headache, temporal artery tenderness or decreased pulse, erythrocyte sedimentation rate (ESR) of at least 50 mm/hour and abnormal temporal artery that shows characteristic histopathologic changes of mononuclear or granulomatous inflammation.5 However, the weight that a clinician should place on these criteria is questioned.7

Muchison and colleagues performed a retrospective review of all patients who underwent a temporal artery biopsy at Wills Eye Institute in Philadelphia, Pennsylvania.7 The authors found several patients with positive temporal artery biopsies whom the criteria failed to diagnose.7 The ACR criteria should be used as a guide and clinical judgment is still vital.

Temporal artery biopsy

As shown in Figure 2, temporal artery biopsy has long been considered the gold standard for the diagnosis of GCA. How good is it? Niederkohr and Levin set out to answer this question.8 The authors performed a Bayesian analysis on patients who underwent bilateral biopsies to determine the sensitivity of a unilateral temporal artery biopsy. The reported sensitivity of unilateral temporal artery biopsy was 87.1 per cent.8 With this high degree of sensitivity, the clinician must now determine when a biopsy should be undertaken.

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Figure 2. Bifurcation of frontal branch of left temporal artery to be excised and undergo histopathologic analysis

Hassan and colleagues have reported on symptoms that are most correlated with a positive temporal artery biopsy.9 This was performed through a meta-analysis. The authors report that jaw claudication, diplopia and abnormality of palpation of the temporal artery had the highest predictive value of a positive temporal artery biopsy. Of slightly less predictive value were temporal headache, scalp tenderness, ESR over 100 mm/hour and anaemia.9 Suelves and colleagues found high association between a positive biopsy and elevated C-reactive protein (CRP).10 We recommend that a temporal artery biopsy be performed on all patients who present with any combination of these signs and symptoms.

Shortcomings

Temporal artery biopsy is the best diagnostic test we have but it does have its faults. The most problematic is the occurrence of skip lesions. A skip lesion refers to a location along the arterial wall not affected by inflammation. Skip lesions cause false negative results if they occur within the segment of the artery that was excised. Long specimen size—between 10 and 30 millimetres—decreases the risk of a skip lesion obscuring the diagnosis. If the initial biopsy is negative in patients with highly suspected GCA, the doctor must use their clinical judgment to decide the correct diagnosis. Biopsy of the other side’s temporal artery may help increase a positive yield.

Recently, Doppler ultrasound has been used to help with the diagnosis of GCA. Nesher and colleagues found that a negative halo sign on colour Doppler ultrasound has a negative predictive value of 88 per cent.11 In other words, ultrasound without a positive Doppler sign corresponded correctly with negative temporal artery biopsy in 88 per cent of cases. This ultrasound procedure is very technician-dependent but when done properly, it can be of great assistance; however, a positive halo sign did not correlate highly with a positive biopsy.

While ESR was originally deemed most valuable for diagnosis, it remains normal in two per cent to 30 per cent of confirmed GCA cases.12 It has since been discovered that elevated CRP is of higher sensitivity (97.5 per cent), than ESR (76 per cent to 86 per cent). The best way to use these tests is to run them simultaneously, resulting in 97 per cent specificity and 99 per cent sensitivity rates.12

Treatment

Corticosteroids have long been the drug of choice for treating GCA. Adding 100 mg/day of aspirin to the steroid regimen has been shown to lower the risk of loss of vision and strokes from GCA.13

The steroid regimen used depends on the initial presentation. Unwin and colleagues report that a prednisone dose between 40 and 60 mg per day is required to suppress GCA.2 When patients present with ischaemic symptoms such as jaw claudication, a dose of 60 mg/day should be initiated.5 Initiation of treatment should be prompt, as it does not alter biopsy results for the first four weeks. When patients present with visual symptoms, intravenous methylprednisolone may be a better approach. In these cases, the steroid should be given in pulsed doses of 1,000 mg per day for three days.6 A rapid response to treatment is expected. If this does not occur, the diagnosis should be reassessed.

Relapses in GCA are common and up to one third occur in the first 18 months of treatment.12 A relapse is treated with administration of the last effective steroid dose. Patients should be monitored for relapse with both ESR and CRP monthly, for up to one year after treatment has ended. An abnormal result alone does not necessitate an increase in treatment but it does call for closer clinical scrutiny.

Thoracic artery aneurysm is another risk in GCA patients. Salivarani and colleagues report these aneurysms are 17 times more likely in patients with GCA and may occur several years after the classical symptoms of GCA subside.6 As a result, they recommend a yearly chest radiograph for GCA patients.6

Once treatment is started, the next decision is when to begin reducing the dose. Treatment may be long-term and requires a slow taper. Salivarani and colleagues recommend tapering in 10 per cent deduction every four weeks.3

The chronic use of steroids can cause many side-effects. Fifty-eight percent of patients being treated with systemic steroids suffer serious complications.6 As a result, patients need to be monitored for conditions such as diabetes, osteoporosis, cataracts, ocular hypertension, Cushing’s syndrome and gastrointestinal ulcers. Practitioners need to be vigilant of these complications and proactive in preventing them. Supplementation with calcium, vitamin D and bisphosphonates can help safeguard against osteoporosis. Likewise, proton pump inhibitors such as omeprazole and esomeprazole can prevent gastrointestinal problems.

The prevalence and seriousness of steroid-induced side-effects have prompted research into alternative or adjunct means of treatment. Immunosuppressants such as methotrexate and cyclophosphamide have been investigated; however, multiple sources reject their effectiveness.2,15,16 For now, steroid with the adjunct application of low dose aspirin remains the only proven means of treatment.

With its grave consequences and rapid progression, both detection and initiation of treatment in GCA must be timely. Though temporal artery biopsy is the only means to obtain a definite diagnosis, there are ways to help confirm or reject the diagnosis. Once treatment has begun, its course may be lengthy. Corticosteroids, despite their many side-effects, continue to be the mainstay of GCA treatment.

 

  1. Quiros P. Urgent Neuro-Ophthalmic Pathologies. Yanoff & Duker Ophthalmology, 3rd ed. Maryland Heights: Mosby Elsevier, 2008: 1074-1078.
  2. Nesher G. The diagnosis and classification of giant cell arteritis. Journal of Autoimmunity 2014; 48-49: 73-75.
  3. Salvarani C, Cantini F, Boiardi L, Hunder G. Medical progress: polymyalgia rheumatica and giant-cell arteritis. New Eng J Med 2002; 347: 261-271.
  4. Weyand CM, Goronzy JJ. Arterial wall injury in giant cell arteritis. Arthritis and Rheumatism 1999; 42: 844-853.
  5. Lighthizer N, Skorin Jr L. Neuro-Ophthalmic Disease. Ocular Therapeutics Handbook: A Clinical Manual. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2011: 589-591.
  6. Charlton R. Optimal management of giant cell arteritis and polymyalgia rheumatica. Therapeutics and Clinical Risk Management 2012; 8: 173-179.
  7. Murchison A, Gilbert M,  Bilyk J, Eagle R, Pueyo V, Sergott R, Savino P. Validity of the American College of Rheumatology criteria for the diagnosis of giant cell arteritis. American Journal of Ophthalmology 2012; 154: 722-729.
  8. Niederkohr R, Levin L. A Bayesian analysis of the true sensitivity of a temporal artery biopsy. Invest Ophthalmol  Vis Sci 2007; 48: 675-680.
  9. Hassan N, Dasgupto B, Barraclough K. Easily missed? Giant cell arteritis. BMJ 2011; 342: d3019.
  10. Suelves AM, Espana-Gregori E, Avino J, Rohrweck S, Diaz-Llopis M. Analysis of factors that determine the diagnostic yield of temporal artery biopsy. Archivos De La Sociedad Espanola De Oftalmologia  2013; 88: 127-129.
  11. Nesher G, Shemesh D, Mates M, Sonnenblick M, Abramowitz H. The predictive value of the halo sign in color doppler ultrasonography of the temporal arteries for diagnosing giant cell arteritis. J Rheumatol 2002; 29: 1224-1226.
  12. Behbehani R. Clinical approach to optic neuropathies. Clinical Ophthalmology 2007; 1: 233-246.
  13. Nesher G, Berkun Y, Mates M, Baras M, Rubinow A, Sonnenblick M. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis & Rheumatism 2004; 50: 1332-1337.
  14. Unwin B, Williams CM, Gilliland W. Polymyalgia rheumatica and giant cell arteritis. American Family Physician 2006; 74: 1547-1554.
  15. Hoffman GS, Cid MC, Hellmann DB. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis & Rheumatism 2002; 46: 5: 1309-1318.
  16. Yates M, Loke YK, Watts RA, Macgregor AJ. Prednisolone combined with adjunctive immunosuppression is not superior to prednisolone alone in terms of efficacy and safety in giant cell arteritis: meta-analysis. Clinical Rheumatology 2013; 33: 227-236.

 



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