Giant Cell Arteritis Part 1: Diagnosis

By Drs. Azin Ahrari (biography, no disclosures), Neda Amiri (biography, no disclosures), Mohammad Bardi (biography, no disclosures), Natasha Dehghan (biography, no disclosures)

What care gaps or frequently asked questions I have noticed

Giant cell arteritis (GCA) is the most common vasculitis in adults above 50 years of age. Mean age of onset is 79, with an incidence of 15-80 per 100,000 per year (1). The disease is more prevalent in those of Northern European descent (1).

GCA is a rheumatological emergency. Rapid diagnosis and treatment are required to reduce the risk of complications. Most common clinical symptoms of GCA are persistent new-onset headaches (including any pain above the neck), scalp tenderness, jaw or tongue claudication and constitutional symptoms. Polymyalgia rheumatica can occur concurrently (30-50%) (2). Ocular symptoms may be present in up to 40% of patients (2). GCA tends to have a subacute presentation but may occur abruptly too (3, 4).

Despite the familiarity that most physicians have with GCA, delays in diagnosis and initiation of treatment are not uncommon.  History and clinical features are key when inquiring about symptoms of GCA.  Atypical symptoms can result in a delay for diagnosis and treatment. Furthermore, a small proportion of patients may have a normal ESR/CRP.

In GCA, it is critical to obtain a temporal artery biopsy (TAB) to help confirm the diagnosis. TAB still remains the gold standard diagnostic test in North America.

1. Delay in recognition and diagnosis of GCA when presenting with atypical symptoms such as fever of unknown origin, or limb claudication
2. Not obtaining temporal artery biopsy when suspicion for GCA is high based on clinical presentation or if pre-emptive glucocorticoid therapy has been initiated prior to biopsy
3. Lack of screening or monitoring for extra-cranial large vessel vasculitis in those with confirmed diagnosis of GCA
4. Using normal CRP as “rule out” test

Data that answers these questions or gaps

Presentation

Most common manifestations of GCA are headache, jaw claudication and visual symptoms.  The headache may be unilateral or bilateral. It is often persistent, non-positional and unresponsive to analgesics. Any new headache in individuals older than 50 is concerning for GCA. GCA does not occur in individuals younger than 50, and other causes of headache should be considered.

Jaw and tongue claudication are ischemic symptoms that are brought on by chewing or talking. Patients may complain that it is hard for them to chew solid food, which may be associated with pain and fatigue in the masseter muscle. Jaw claudication is not present at rest, localized to the temporomandibular joint (TMJ) nor is it associated with clicking or popping pain over the TMJ. Jaw claudication is the most specific symptom of GCA. Visual symptoms of GCA are varied and can include acute painless loss of vision, diplopia or blurry vision.

Atypical symptoms can occur in up to 40% of cases and include cough, throat/neck pain, hoarseness, joint pain and swelling, limb claudication, myocarditis, fever of unknown origin or acute (most commonly vertebrobasilar) stroke (4-9). Large vessel involvement (such as aortitis or aortic aneurysm) in GCA may be present at diagnosis or develop during the course of the disease (10).

Biopsy

A suspected diagnosis of GCA should be confirmed with a temporal artery biopsy (or imaging) even when clinical suspicion is high (11). Ideally, TAB should be done within two weeks of initiation glucocorticoid (GC) therapy. Although sensitivity of diagnostic tests decreases following treatment with GC, biopsy may show features of GCA including giant cells, intimal hyperplasia, fragmentation of the internal elastic lamina or signs of healed arteritis weeks to months after GC therapy (12-13, 17-18). Furthermore, a study by Maleszewski et al assessing histopathologic changes in patients with GCA showed while clinical symptoms of GCA improve with treatment, vascular changes lasted longer and were present even after 12 months of treatment (14). Therefore, TAB to confirm diagnosis of GCA should be pursued in all patients regardless of duration of pre-emptive therapy.

The sensitivity of a biopsy ranges from 30-70% depending on the centre and longer biopsy lengths have shown higher sensitivity (15-17). It is important to note that a negative biopsy does not rule out GCA if clinical suspicion for the diagnosis remains high.

The EULAR guidelines for imaging in large vessel vasculitis recommend the use of ultrasound as the first test when suspecting cranial GCA (19). However, this requires appropriate equipment and expertise which is centre dependent. Currently, a study is being undertaken locally by the authors (ND and MB) to compare the diagnostic yield of ultrasound versus TAB, and to assess if ultrasound can be used to prognosticate GCA based on the degree of vascular inflammation present.

Screening for Large Vessel Involvement

In general, large vessel imaging is recommended in most patients with GCA as approximately 83% of patients can have extra-cranial large vessel involvement (18). Imaging should be performed as early as possible and ideally within 1 week of treatment as sensitivity rapidly drops with glucocorticoids. Ultrasound, PET, MRI and CTA may be used for detection of extra-cranial large vessel GCA (LV-GCA). At our centre, CTA of chest and abdomen is most readily accessible and can be done for detection of LV-GCA (19).

Acute Phase Reactants

Studies have shown that the sensitivity of CRP and ESR in GCA is 86% and 84% respectively (20).  Most often, ESR and CRP are significantly elevated in GCA given high inflammatory burden. Therefore, these tests may serve as good “rule out” tests in the majority of patients. However, caution needs to be applied when using these tests to rule out GCA. If the clinical suspicion for GCA is moderate to high, a normal CRP/ESR does not rule out the disease. In approximately 4% of patients both markers can be normal (21-22, 23, 24). In a subset of patients, ESR and CRP can be discordant. In general, CRP is preferred over ESR in all patients as ESR is affected by multiple other factors including age, gender, anemia, kidney disease, etc (24). Anemia and thrombocytosis may also be present.

What I recommend

1. Taking a detailed history: Typical symptoms of GCA include any new headache that is persistent, non-responsive to analgesics, and not positional. Other typical symptoms are jaw and tongue claudication. Lastly, GCA can manifest with varied visual symptoms including blurry vision, loss of vision, and diplopia.
2. Be aware of the atypical symptoms of GCA: fever of unknown origin, cough, hoarseness, limb claudication and stroke
3. All patients with suspected GCA need urgent assessment for investigations, treatment, and for monitoring complications.
4. In patients with clinical symptoms of GCA, normal ESR/CRP does not exclude diagnosis of GCA.
5. Large vessel imaging is recommended in most patients with GCA due to the high frequency of large vessel involvement (e.g. CTA).
6. A suspected diagnosis of GCA should be confirmed with a unilateral TAB of at least 1.5 cm in length. TAB should be ideally obtained within two weeks of GC therapy initiation.

References

1. Gonzalez-Gay MA., Vazquez-Rodriguez TR., Lopez-Diaz MJ., et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum. 2009; 61(10): 1454-146. DOI: 10.1002/art.24459. (View with CSPBC or view with UBC).
2. Salvarani C., Cantini F., Boiardi L., et al. Polymyalgia rheumatica and giant cell arteritis. N Engl J Med. 2002; 347(4):261-71. DOI: 10.1056/NEJMra011913. (Request from CSPBC or view with UBC)
3. Álvarez-Lafuente R., Fernández-Gutiérrez B., Jover JA., et al: Human parvovirus B19, varicella zoster virus, and human herpes virus 6 in temporal artery biopsy specimens of patients with giant cell arteritis: analysis with quantitative real time polymerase chain reaction. Ann Rheum Dis. 2005;64:780–782. (View)
4. Calamia KT., Hunder GG. Giant cell arteritis (temporal arteritis) presenting as fever of undetermined origin. Arthritis Rheum. 1981;24(11):1414-8. DOI: 10.1002/art.1780241113. (View with CSPBC or view with UBC)
5. Shmerling,RH. An 81-year-old woman with temporal arteritis. JAMA. 2006;295(21):2525-2534.  DOI: 10.1001/jama.295.21.2525. (Request from CSPBC or view with UBC)
6. Healy LA., Wilske KR. Presentation of occult giant cell arteritis. Arthritis Rheum. 1980;23(6):641-3. DOI:10.1002/art.1780230605. (View with CSPBC or view with UBC)
7. Hellmann, DB. Occult manifestations of giant cell arteritis. Med Rounds. 1989;2:296-301. (Request from CSPBC)
8. Hernández-Rodriguez J., Tan CD., Rodriguez ER., et al. Gynecologic vasculitis: an analysis of 163 patients. Medicine. 2009;88(3):169-81. DOI: 10.1097/MD.0b013e3181a577f3.(View with CSPBC or view with UBC)
9. Gonzalez-Gay MA., Varquez-Rodriguez TR., Gomez-Acebo I., et al. Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis. Medicine. 2009;88(4):227-35.  DOI:10.1097/MD.0b013e3181af4518. (View with CSPBC or view with UBC)
10. Brack A., Martinez-Taboada V., Stanson A., Goronzy JJ., Weyand CM. Disease pattern in cranial and large-vessel giant cell arteritis. Arthritis Rheum. 1999; 42(2): 311–317. DOI: 10.1002/1529-0131(199902)42:2<311::AID-ANR14>3.0.CO;2-F. (View with CSPBC or view with UBC)
11. Hellmich B., Agueda A., Monti S., et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79(1):19-30. DOI:  10.1136/annrheumdis-2019-215672. (Request from CSPBC or view with UBC)
12. Luqmani R., Lee E., Singh S., et al. The role of ultrasound compared to biopsy of temporal arteries in the diagnosis and treatment of giant cell arteritis (TABUL): a diagnostic accuracy and cost-effectiveness study. Health Technol Assess. 2016;20:1–238. (View)
13. McDonnell PJ., Moore GW., Miller NR., et al. Temporal arteritis. A clinicopathologic study. Ophthalmol. 1986;93(4):518–30. DOI: 10.1016/s0161-6420(86)33706-0. (Request from CSPBC or view with UBC)
14. Maleszewski JJ., Younge BR., Fritzlen JT., Hunder GG., Goronzy JJ., Warrington KJ., et al. Clinical and Pathological Evolution of Giant Cell Arteritis: A Prospective Study of Follow-Up Temporal Artery Biopsies in 40 Treated Patients. Mod Pathol. 2017; 30(6): 788–796. (View)
15.  Chu r., Foster C., Ali M., Chaba T., Soo J., Clifford A., Tervaert J., Yacyshyn E. A Ten-year retrospective review of temporal artery biopsy lengths in Alberta. Rheumatol. 2019;58(2). DOI: 10.1093/rheumatology/kez059.010. (View with CSPBC or view with UBC)
16. Schmidt WA., Gromnica-Ihle E. Incidence of temporal arteritis in patients with polymyalgia rheumatica: a prospective study using colour Doppler ultrasonography of the temporal arteries. Rheumatol. 2002;41:46–52. DOI: 10.1093/rheumatology/41.1.46. (View with CSPBC or view with UBC)
17. Ashton-Key MR., Gallagher PJ. False-negative temporal artery biopsy. Am J Surg Pathol. 1992;16(6):634–5. DOI: 10.1097/00000478-199206000-00014. (Request from CSPBC or view with UBC)
18. Dejaco, C., Brouwer, E., Mason, J., et al. Giant cell arteritis and polymyalgia rheumatica: current challenges and opportunities. Nat Rev Rheumatol. 2017;13(10):578-592. DOI:  10.1038/nrrheum.2017.142. (Request from CSPBC or view with UBC)
19. 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(5):636-643. DOI: 10.1136/annrheumdis-2017-212649. (Request from CSPBC or view with UBC)
20. Blockmans D., de Ceuninck L., Vanderschueren S., et al. Repetitive 18F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients. Arthritis Rheum. 2006;55(1):131–7. DOI: 10.1002/art.21699. (View with CSPBC or view with UBC)
21. Ypsilantis E., Courtney ED., Chopra N., et al. Importance of specimen length during temporal artery biopsy. Br J Surg. 2011;98(11):1556–60. DOI: 10.1002/bjs.7595. (View with CSPBC or view with UBC)
22. Kermani TA., Schmidt J., Crowson CS., et al. Utility of erythrocyte sedimentation rate and C-reactive protein for the diagnosis of giant cell arteritis. Semin Arthritis Rheum. 2012;41(6):866–871. DOI:10.1016/j.semarthrit.2011.10.005. (View)
23. Parikh M., Miller NR., Lee AG., et al. Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis. Ophthalmol. 2006;113(10):1842–5.DOI: 10.1016/j.ophtha.2006.05.020. (Request from CSPBC or view with UBC)

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Giant Cell Arteritis Part 1: Diagnosis

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