Clinical Features

Advances in Giant Cell Arteritis

Giant cell arteritis (GCA) is an immune mediated inflammatory disease of the large vessels, most commonly affecting cranial arteries but the aorta and its branches can also be involved. The inflammation initiates in the inner layers of the artery, eventually progressing to transmural inflammation, vessel occlusion and then resultant ischaemia. Patients can present with inflammatory and/ or ischaemic symptoms.

GCA is the most common systemic vasculitis among adults. Prevalence increases with age, and it is highest in people with Northern European ancestry, ranging from 18 to 29 cases for 100,000 people over the age of 50.1 It is estimated that the occurrence is likely to increase with ageing population, and it is projected that over 3 million people will be affected by GCA by 2050.2 Whilst the prevalence is highest among patients of northern European ancestry, it is important to note that patients of any ethnic background can be affected.

The most serious complication of GCA is irreversible visual loss due to anterior ischaemic optic neuropathy caused by choroidal blood vessel inflammation and ischaemia. It occurs in 15-20% of patients with GCA.3 This risk can be reduced to as low as 9% by prompt treatment (high dose corticosteroid) initiation.4 Other less common ischaemic complications include: cerebrovascular infarcts, cranial nerve palsies, infarction of tongue and scalp necrosis. The standard therapy is high dose glucocorticoids which can result in considerable toxicity especially in this often frail and elderly cohort. Thankfully there have been recent advances in therapeutics which can reduce the cumulative burden of glucocorticoids and are discussed in more detail below.

Diagnostic challenges

GCA is a challenging medical diagnosis. Clinical symptoms vary. It is often associated with a new onset headache, usually around the temples however frontal or occipital headaches can also be presenting features. Headache in itself is a non-specific symptom and other more common causes of headache such as migraine, tension headache, cervicogenic headache should be considered when evaluating patients. On physical exam, the temporal artery can be thickened and tender to palpation. Other less well recognized but much more GCA- specific features include: visual changes such as blurred vision, diplopia or visual loss (either transient or permanent). Jaw claudication is an important sign of GCA that can be easily missed. It is characterized by pain or discomfort in the jaw on chewing and is caused by impaired blood flow to the pterygoid and masseter muscles in the jaw secondary to vessel wall inflammation leading to ischaemia and pain. Ischaemic in nature, it typically radiates down the jaw on chewing. This can be easily confused with pain caused by TMJ pathology, which is usually more localized to the TMJ and is not typically associated with chewing. 40-60% of GCA patients will have symptoms of polymyalgia rheumatica (PMR) which include morning stiffness and pain affecting the shoulder and hip girdle.5 Indeed, GCA and PMR are considered to be on the spectrum of the same disease process, with PMR considered by some as a vascular inflammation limited to the adventitia. In patients with PMR who have suboptimal response to steroids, constitutional symptoms or markedly increased inflammatory markers, GCA in the form of aortitis should be considered. Subclinical GCA can be detected in patients with PMR on vascular imaging such as ultrasound, PET-CT, MRA or CTA. To aid with clinical diagnosis, the Southend GCA probability score has been validated as a risk assessment tool for suspected GCA. The cumulative, weighted score is based on several risk factors for GCA, such as age, presence of headache, ischaemic signs/ symptoms or visual changes. It can help stratify patients into low, moderate and high probability risk of having GCA (when used correctly by professionals familiar with diagnosing GCA).6

Advances in imaging

Different imaging techniques can be used to aid the diagnostic process. Temporal artery ultrasound (TAU) is used in many centres and its diagnostic value has been studied extensively. TAU is used to detect ‘halo sign’, a non-compressible hypoechoic ring artery lumen that represents vessel oedema resulting from inflammation. [Fig 1] Its sensitivity was found to be 54% with 81% specificity in TABUL study, in which TAU was compared with the gold standard temporal artery biopsy (TAB).7 It is worth mentioning that halo sign may only last for 2-3 days8 after commencing glucocorticoid therapy, thus it should not be delayed. Ultrasound is also used for detection of subacromial and subdeltal bursitis in PMR and it is included in the ACR-EULAR classification criteria for PMR. Another diagnostic tool in GCA work up is FDG-PET. Vascular inflammation is associated with increased glucose metabolism which can be detected by PET CT. This imaging modality can be used to identify aortitis in patients with marked systemic symptoms, treatment resistant disease or constitutional symptoms such weight loss or night sweats where other pathologies ( e.g. infection, malignancy) also need to be excluded.9 In PMR, increased tracer uptake is found in hip and shoulder girdle.10

High resolution MRI was found to have sensitivity of 88% and specificity of 75%.11 It detects soft tissue oedema of the wall of the blood vessels and it is helpful in assessing potential GCA-related vessel stenosis or aneurysm. It is, however, not routinely available in every centre and thus has a limited clinical utility at present.

As previously mentioned, temporal artery biopsy is the gold standard in GCA diagnosis. A positive histological result is undoubtedly the most definite diagnostic criterion. When performed by an experienced surgeon it is a relatively low risk procedure. Potential risks include infection and, rarely, potential damage to the branches of facial nerve resulting in eyebrow droop. Sensitivity of TABs is centre dependent and is often low. Potential reasons for this include presence of ‘skipped lesions’, meaning that the result can be indeed negative if the inflammation involves part of the vessel that was missed during biopsy. Delayed access to TAB can also result in lower diagnostic yield.

In summary, clinical diagnosis of GCA should be considered based on clinical signs and symptoms together with different imaging techniques. Temporal artery ultrasound is considered to be the first line diagnostic tool as it is non-invasive, fast and costeffective. If in clinical doubt, TAU can be followed by temporal artery biopsy.

As TAU images are affected after initiating treatment, development of rapid diagnostic pathways with access to ultrasound is desirable. This has shown reduction in inpatient hospitalizations, visual loss and healthcare associated costs.

Advances in therapy

As long-term glucocorticoid treatment is associated with an array of complications, especially in an older population, there is a need for new glucocorticoidsparing therapies that are safer yet effective in treatment of GCA.

Tocilizumab, an anti-IL6 receptor monoclonal antibody, showed promising results in randomizedcontrolled trials in treatment for GCA as well as PMR. It was approved for treatment of GCA in 2017, and its use is associated with higher remission rate and shorter period of glucocorticoid use. It is a self-administered subcutaneous injection given every 1 to 2 weeks or, alternatively, it can be given as an IV infusion.

In the GiACTA study, 251 patients were randomly assigned to subcutaneous tocilizumab every week or every other week, combined with 26-week prednisone taper, or placebo combined with 26 or 52 prednisone taper. Sustained remission after 52 weeks was found in 56% of patients with weekly tocilizumab group and 53% of patients that received tocilizumab every other week on 26-week prednisone taper, as compared to 14% in the placebo group with 26-week prednisone taper and 18% of placebo group with 52-week prednisone taper [12]. Thus, tocilizumab was shown to be more effective than placebo and patients could safely taper steroids over 26 weeks. Some preliminary studies have also shown that use of TOC can protect against visual loss.

Sirukumab another anti IL-6 monoclonal antibody that has similarly shown lower incidence of flares when compared to a placebo in a multi-centre, double-blind trial of 161 patients with GCA.13

Finally a recent phase 2 study showed that Mavrililumab (antigranulocyte-macrophage colonystimulating factor (GM-CSF)) plus 26-week prednisone taper was superior to placebo plus 26 week prednisone taper in a doubleblind, placebo controlled trial involving 72 patients.14 This has laid the ground work for a phase 3 study, the results of which will be eagerly awaited.

In summary, following many years of little progress in terms of diagnostics and targeted therapies the past decade has seen significant advances in terms of diagnosing and treating GCA. Furthermore there is hope of more advanced therapies becoming available in the near future. These advances will help to reduce the frequency of complications of the disease such as blindness whilst also reducing the steroid burden and associated toxicities for these patients.

References available on request

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