Giant cell arteritis – current state of play

27th February 2023, Dr Chee L Khoo

We might see one case every 5 years in primary care. It might not be common but a missed diagnosis can be devastating. Patients rarely present to emergency department or the vascular surgeon without presenting to primary care first. Giant cell arteritis (GCA) is now thought of as a systemic inflammatory disease. Although glucocorticoids remain the mainstay of treatment , in the last few decades, new knowledge have dramatically changed the way we diagnose and treat GCA. We better look at the innovations that have come up over the last few decades.

New-onset headache, reflecting the involvement of temporal arteries and their branches, is the prototypical manifestation of GCA, along with the serum increase of acute phase reactants (CRP and ESR). Many of these patients have polymyalgia rheumatica (PMR) which is an inflammatory condition characterised by the abrupt onset of symmetrical pain and stiffness over the neck and the shoulder and hip girdles. Symptoms tend to be worse in the morning, and significantly impacts daily activities. About 50% of patients with GCA concomitantly show PMR features [1]. Conversely, up to 20% of patients with a diagnosis of PMR develop GCA [2].

Not all GCA have classical symptoms. We need a high index of suspicion when faced with no classical symptoms. We can divide symptoms into cranial and systemic symptoms:

Cranial symptoms

Even though GCA-related headache is traditionally thought to be located over the temples, it can also be frontal, occipital, or generalised [3]. Involvement of cranial arteries can also cause scalp tenderness, dysphagia, and jaw and tongue claudication. Occlusion of temporal arteries or their branches can lead to ischemic skin necrosis or even ulcers of the tongue is rare.

Physical examination may reveal thickened or prominent temporal, facial or occipital arteries but the absence of prominent arteries does not rule out GCA.

Visual symptoms may include abrupt, self-limiting partial visual field defects (amaurosis fugax) and are the most feared clinical manifestation of GCA, as they might foretell the development of irreversible ischaemic complications. The most common mechanism underlying sight loss is caused by inflammatory occlusion of the posterior ciliary artery, a branch of the ophthalmic artery leading to anterior ischemic optic neuropathy. Up to 20% of patients with GCA develop permanent loss of vision [4-7]. Once established, visual loss is rarely reversible and the other eye is affected in 50% within one week. Keep in mind that amaurosis fugax is not only caused by GCA. Amaurosis fugax is associated with atherosclerotic disease.

Ischaemic strokes can occur with GCA but is not common. It makes up <0.5% of all CVAs in the general population and is usually the result of occlusion of the occipital arteries.

Systemic symptoms

Low grade fever, weight loss and fatigue is present in at least 50% of patients with GCA. GCA is one of the most frequent causes of fever of unknown origin in the elderly. Other less common symptoms include non-productive cough (from involvement of the pharayngeal and bronchial arteries), limb claudication and burning sensation over the inflamed arteries.

Investigative findings

Elevated CRP and ESR (usually both but not always) is present in about 95% of patients with GCA. The chronic inflammatory process featured by GCA may also lead to normochromic anaemia, leukocytosis, and thrombocytosis, which are often observed in patients with GCA [8,9]. Liver function tests can be abnormal in up 30% of cases [10].

The newer biomarkers are being investigated. While interleukin-16 (IL6) plays a prominent role in the pathogenesis, there is no evidence of its correlation with disease activity. Nonetheless, tocilizumab (an anti-IL6 agent) has shown remarkable efficacy. Other promising biomarkers include osteopontin, calprotectin and pentraxin although more studies are ongoing.

Temporary artery biopsy is the gold standard and have a 100% specificity but sensitivity is not as great due to sampling issues. If your index of suspicion is high, steroid therapy should not be delayed while waiting for the biopsy.

Current European guidelines suggest that ultrasound (US) should be chosen as the first diagnostic test at disease onset, because of its low invasiveness and the ready availability of results. Once again, we should not delay corticosteroid treatment if the suspicion of GCA is high although the sensitivity of US is reduced by up to 50% after 4 days of treatment (11). Thus, US should be obtained within one week of commencement of treatment.

Other investigative modalities like PET, CT and MRI scans are useful to quantify the degree of inflammation as well as to exclude extra-cranial artery involvement as well as to rule out other causes of inflammation. 

Management

The mainstay of treatment is still glucocorticoids. i) dampening the deranged inflammatory process to avoid acute ischemic complications; ii) preventing disease relapses using the lowest effective dose (if any) of glucocorticoids; iii) preventing long-term vascular damage (i.e., aneurysm and stenosis).

Current European guidelines recommend a starting dose of 1 mg/kg per day of prednisone-equivalent, without exceeding a daily dose of 60 mg as no evidence suggests additional benefit. If transient or permanent visual loss is present, intravenous pulses of methylprednisolone (0.25 – 1 g for up to three days) may be administered before starting oral glucocorticoids to prevent damage progression or contralateral involvement. The induction dose of oral glucocorticoids must be maintained ideally for two to four weeks and in any case at least until remission is established [12]. After that, tapering should be started.

In patients who is unable to be tapered off their glucocorticoids, an non-steroidal immunosuppressant might be necessary. Methotrexate, azathioprine, cyclophosphamide and leflunomide have been used with success but await larger randomised trials are required.

Newer biologic disease modifying anti-rheumatic agents are still being investigated for the more resistant cases.

Recurrence /relapses

Though response to glucocorticoids is often satisfactory, GCA relapses during and after treatment tapering can be observed in more than 50% of patients. GCA relapses range from subclinical inflammation that can be detected only with laboratory tests and imaging to clinically overt manifestations. Of note, ischemic complications are extremely rare during relapses. Several studies have shown that the presence of pronounced systemic inflammation at disease onset is associated with a higher risk of relapse. Extra-cranial large vessel involvement has also been associated with such an unfavorable disease course.

Beyond the acute vascular complications, there are longer term vascular complications. Aortic  aneurysms can complicate the history of patients with GCA in up to 20% of cases. Unlike atherosclerosis-related aneurysms, GCA-related ones are more commonly seen in the thoracic aorta rather than in the abdominal tract.

In summary, while GCA is not common, the symptoms can be fairly vague. GCA is not something most of us would think about when an older patient presents with new onset headaches, muscle pains, low grade fever, weight loss. It is even harder to spot the imminence of large vessel arteritis but it requires a high index of suspicion. It is prudent that we commence treatment while waiting for confirmation. Over the last 30 years as a GP, I have diagnosed half a dozen GCA and on each occasion based on minimal symptoms. On each occasion, the specialist was rather sceptical about the diagnosis before confirmatory tests. Trust your judgement.

References:

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  13. Farina N, Tomelleri A, Campochiaro C, Dagna L. Giant cell arteritis: Update on clinical manifestations, diagnosis, and management. Eur J Intern Med. 2023 Jan;107:17-26. doi: 10.1016/j.ejim.2022.10.025. Epub 2022 Nov 4. PMID: 36344353.