One of the earliest observations of giant-cell arteritis (GCA) occurred in the 10th century when oculist ‘Alī ibn ‘Īsā al-Kahhal noted an association between inflammation of the temporal artery and blindness in his book, Tadhkirat.1 GCA is categorized as a large-vessel vasculitis targeting large- and medium-sized blood vessels, and the most feared complication associated with the disease is visual loss from cranial arteritis.Epidemiology
GCA is a common form of vasculitis in Europe and North America, especially in individuals aged >50 years, and mostly affects white people and women.2,3 During a 26-year period in Northern Italy, the overall age- and sex-adjusted incidence of GCA per 100,000 persons aged >50 years was 5.8; disease occurrence was higher in women than in men (7.8 vs 3.3; P <.0001).4Signs and Symptoms
Constitutional symptoms are common in GCA, and can include fever, fatigue, and weight loss. New-onset temporal headaches are an important symptom, but can include the frontal and occipital areas. Other symptoms include jaw claudication, transient monocular vision loss, and permanent visual loss. In a clinical study of 161 patients with biopsy-proven GCA, visual manifestations were present in 26.1%, and anterior ischemic optic neuropathy preceded by amaurosis fugax was present in 14.9%.5 HLA-DRB1*04-positive patients, patients with anemia, and those with low inflammatory markers had visual manifestations more frequently. One reason for the latter could be that GCA with high inflammatory markers is diagnosed earlier and treated more aggressively.
In a 2014 study, 27% of patients with GCA had diplopia at diagnosis.6 These patients had extracranial vessel inflammation assessed by vascular ultrasound more frequently, and a higher incidence of visual involvement at time of diagnosis than those without diplopia.
Investigators in a study from Olmsted County, MN, estimated that patients with GCA were 17.3 times more likely to have thoracic aortic aneurysms, and 2.4 times more likely to have isolated abdominal aortic aneurysms than sex- and age-matched individuals without GCA.7
Oral symptoms of GCA may include trismus, throat pain, dysphagia, dysarthria, chin numbness, glossitis, lip or tongue necrosis, and facial swelling.8 Hearing loss, tinnitus, vertigo, disequilibrium, and dizziness have been observed in approximately 66% of patients.9Diagnosis
Because there is an association between GCA and polymyalgia rheumatica, all patients with polymyalgia rheumatica should be evaluated for GCA. Clinical evaluation should include a thorough history and examination, as the manifestations of GCA can be highly variable. Laboratory data should include erythrocyte sedimentation rate (ESR) and C-reactive protein. Patients should also be assessed for anemia.
Temporal artery biopsy is the gold standard for GCA diagnosis. A unilateral temporal artery biopsy of at least 3 to 5 cm is preferred, and multiple 0.25- to 0.5-mm sections are necessary because of skip lesions and the potential for postfixation shrinkage.10 If the clinical suspicion is high, contralateral biopsy should be considered. A panarteritis primarily comprising lymphocytes and macrophages is the chief pathologic finding; granuloma formation may be present.11 It is important to remember that giant cells are present in 50% of biopsies, and, thus, are not a necessary feature for histopathologic confirmation.12
Temporal artery ultrasound is another modality that can aid in diagnosis. Fifty patients in Australia were examined via temporal artery ultrasound; when compared with patients who had biopsy-proven GCA, sensitivity of a halo sign was 40%; specificity was 81%; positive likelihood ratio, 2.1; and negative likelihood ratio, 0.7.13
In a study of 171 patients with suspected GCA who underwent high-field 3T magnetic resonance imaging (MRI) of arteries in the scalp, and a subsequent temporal artery biopsy as the reference test, MRI had a sensitivity of 93.6%, and a specificity of 77.9%.14 The matching negative predictive value of MRI was 98.2%, whereas the positive predictive value was 48.3%.14 This suggests that MRI can be used as the initial diagnostic procedure in GCA, with biopsies reserved for patients with abnormal MRI findings.Treatment
Glucocorticoids are the mainstay of treatment when there is a high clinical suspicion for GCA. Therapy should be started promptly, especially for patients with visual or threatened vascular complications. Within a few days of steroid initiation, systemic symptoms of malaise, anorexia, and fever begin to subside, and within the first week, ESR starts to normalize. The various steroid regimens used by different clinicians are mostly retrospective and anecdotal, and most rheumatologists use prednisone 1 mg/kg daily for nonvisual disease.
Initial therapy for patients with new visual symptoms includes higher doses of equivalent prednisone (≥80 mg daily, or 1-2 mg/kg daily).15 It is not uncommon to hospitalize patients and initiate treatment with intravenous methylprednisone 250 mg every 6 hours for the first 3 to 5 days, and then continue with high doses of oral prednisone.15 Results from a 2003 study revealed that 4% of patients who had GCA with visual symptoms had increased visual loss during their first 5 days of treatment with high-dose steroid therapy; visual impairment did not increase after those 5 days.16 There was no evidence to support that intravenous mega-dose steroid therapy was more effective in treating vision impairments in these patients compared with oral therapy.
Monitoring response and gauging treatments are important aspects of follow-up. Although clinicians use inflammatory markers, such as ESR and C-reactive protein, these biomarkers are imperfect and should not dictate steroid dose. Clinical symptoms are an important determinant for monitoring response to therapy and titrating the doses of steroids accordingly.17 Monitoring of serum interleukin-6 levels may hold promise in the future for determining corticosteroid dose adjustments in patients with GCA.18
Common side effects associated with the use of steroids include diabetes, hypertension, secondary infections, osteoporosis, myopathy, and psychiatric changes.15 Because of the cumulative toxic nature of these agents, steroid-sparing drugs have been evaluated for the management of patients with GCA.Steroid-Sparing Drugs
A multicenter, randomized clinical trial of prednisone 1 mg/kg daily plus methotrexate (median dose, 15 mg weekly) or placebo did not demonstrate the efficacy of methotrexate in GCA.19 Tumor necrosis factor inhibitors have also been shown to be ineffective.15
Recently, there has been growing interest in the use of tocilizumab for the treatment of patients with refractory GCA. An open-label clinical trial of 22 patients revealed that after a median follow-up of 6 months, ESRs and C-reactive protein levels dropped significantly.20 The median dose of prednisone decreased from 18.75 mg daily to 5 mg daily.20
GiACTA, a phase 3, randomized, double blind, placebo-controlled clinical trial investigating tocilizumab as a novel treatment for GCA, was conducted in 251 patients across 76 sites in 14 countries.21 In the GiACTA study of biopsy-proven GCA, patients were randomized 1:1:2:1 to a 26-week prednisone taper with weekly subcutaneous placebo; a 52-week prednisone taper with weekly subcutaneous placebo; weekly subcutaneous tocilizumab 162 mg plus a 26-week prednisone taper; or subcutaneous tocilizumab 162 mg every other week plus a 26-week prednisone taper. The primary comparison revealed that 56% of patients receiving weekly tocilizumab and 53.1% of patients receiving tocilizumab every other week achieved sustained remission at 12 months compared with 14% in the short-term prednisone group.21 According to the secondary efficacy comparison, each tocilizumab cohort was superior to the group receiving a long-term prednisone taper, and had a lower cumulative steroid exposure.21
Based on the results of GiACTA, the FDA approved tocilizumab in May 2017 as the first drug to specifically treat adult patients with GCA.22 The agent was granted Breakthrough Therapy designation and a Priority Review.Conclusion
GCA is one of the most common forms of vasculitis that presents in patients aged >50 years. It has a variable presentation and requires a high level of clinical suspicion, as missing the diagnosis can result in devastating consequences. Even after establishing the diagnosis, most patients have high morbidity and mortality rates because of complications from steroids. Now, with the FDA approval of tocilizumab, we hope that the clinical outcome can be altered with overall improved prognosis.
- Kawasaki A, ed. Giant Cell Arteritis. In: Krieglstein GK, Weinreb RN, eds. Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics. Leipzig, Germany: Springer-Verlag Berlin Heidelberg; 2008:227-228.
- Levine SM, Hellmann DB. Giant cell arteritis. Curr Opin Rheumatol. 2002;14:3-10.
- Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002;347:261-271.
- Catanoso M, Macchioni P, Boiardi L, et al. Incidence, prevalence, and survival of biopsy-proven giant cell arteritis in Northern Italy during a 26-year period. Arthritis Care Res((Hoboken). 2017;69:430-438.
- González-Gay MA, García-Porrúa C, Llorca J, et al. Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients. Medicine (Baltimore). 2000;79:283-292.
- Haering M, Holbro A, Todorova MG, et al. Incidence and prognostic implications of diplopia in patients with giant cell arteritis. J Rheumatol. 2014;41:1562-1564.
- Evans JM, O’Fallen WM, Hunder GG. Increased incidence of aortic aneurysms and dissection in giant cell (temporal) arteritis. A population-based study. Ann Intern Med. 1995;122:502-507.
- Paraskevas KI, Boumpas DT, Vrentzos GE, Mikhailidis PD. Oral and ocular/orbital manifestations of temporal arteritis: a disease with deceptive clinical symptoms and devastating consequences. Clin Rheumatol. 2007;26:1044-1048.
- Amor-Dorado JC, Llorca J, Garcia-Porrua C, et al. Audiovestibular manifestations in giant cell arteritis: a prospective study. Medicine (Baltimore). 2003;82:13-26.
- Sharma NS, Ooi JL, McGarity BH, et al. The length of superficial temporal artery biopsies. ANZ J Surg. 2007;77:437-439.
- Lorenz B, Borruat F-X, eds. Diagnosis of GCA. In: Krieglstein GK, Weinreb RN, eds. Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics. Leipzig, Germany: Springer-Verlag Berlin Heidelberg; 2008:241.
- Vasudevan S, Palle AR, Sylvia DS, et al. A rare case of temporal arteritis with rheumatoid arthritis and interstitial lung disease mimicking pulpo-periodontal pathology. J Indian Soc Periodontol. 2014;18:531-535.
- Black R, Roach D, Rischmueller M, et al. The use of temporal artery ultrasound in the diagnosis of giant cell arteritis in routine practice. Int J Rheum Dis. 2013;16:352-357.
- Rhéaume M, Rebello R, Pagnoux C, et al. High-resolution magnetic resonance imaging of scalp arteries for the diagnosis of giant cell arteritis: results of a prospective cohort study. Arthritis Rheumatol. 2016;69:161-168.
- Fraser JA, Weyand CM, Newman NJ, Biousse V. The treatment of giant cell arteritis. Rev Neurol Dis. 2008;5:140-152.
- Hayreh SS, Zimmerman B. Management of giant cell arteritis. Our 27-year clinical study: new light on old controversies. Opthalmologica. 2003;217:239-259.
- Ponte C, Rodrigues AF, O’Neill L, Luqmani RA. Giant cell arteritis: current treatment and management. World J Clin Cases. 2015;3:484-494.
- Roche NE, Fulbright JW, Wagner AD, et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum. 1993;36:1286-1294.
- Hoffman CS, Cid MC, Hellmann DB, et al; for the International Network for the Study of Systemic Vasculitides. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment in giant cell arteritis. Arthritis Rheum. 2002;46:1309-1318.
- Loricera J, Blanco R, Hernández JL, et al. Tocilizumab in giant cell arteritis: multicenter open-label study of 22 patients. Semin Arthritis Rheum. 2015;44:717-723.
- Stone JH, Tuckwell K, Dimonaco S, et al. Efficacy and safety of tocilizumab in patients with giant cell arteritis: primary and secondary outcomes from a phase 3, randomized, double-blind, placebo-controlled trial. Presented at American College of Rheumatology annual meeting; Washington, DC; November 11-16, 2016.
- US Food and Drug Administration. FDA approves first drug to specifically treat giant cell arteritis. www.fda.gov/newsevents/newsroom/pressannouncements/ucm559791.htm. Accessed July 27, 2017.