Old disease, new tricks. Update on giant cell arteritis
Early recognition of suspected giant cell arteritis (GCA) is paramount to prevent permanent visual loss. Recent developments such as increasing use of vascular imaging in diagnosis and the addition of tocilizumab to the treatment armamentarium have enhanced management. Patients with GCA generally have a good prognosis once they have been established on treatment.
Giant cell arteritis (GCA), also known as temporal arteritis, is a systemic medium to large vessel vasculitis that affects older people. It can cause acute irreversible visual loss, aortic aneurysm, posterior circulation strokes and peripheral artery stenosis. Rapid, accurate diagnosis is necessary to prevent sequelae. Recent advances include new vascular imaging and treatment options. Although temporal artery biopsy remains the gold standard diagnostic test, specialised noninvasive imaging modalities including positron emission tomography (PET)/CT and vascular ultrasound are increasingly being used in the diagnostic pathway. A new trial-proven corticosteroid-sparing treatment option, tocilizumab (monoclonal antibody to interleukin 6 [IL-6]), will increasingly become used in routine care.
GCA is the most common systemic vasculitis in adults. It exclusively affects people over 50 years of age and affects women more than men. It is more common in people of European descent.1-3 A recent South Australian study found the incidence in an Australian cohort was 3.2 per 100,000 person-years in people aged over 50 years, with a median age of 78 years.4 Other studies have reported a higher incidence of between 16.7 and 30 cases per 100,000 in
people aged over 50 years.1-3
The pathogenesis of GCA is not completely understood. The disease involves arterial inflammation and systemic upset. Many of the symptoms can be attributed to particular vascular territories. It commonly affects the branches of the external carotid artery including the temporal and occipital arteries (headache), maxillary and facial arteries (jaw and tongue claudication), ophthalmic artery branches (vision loss), supra-aortic branches (upper limb claudication and stroke) and the aorta. The main cytokines involved include IL-6, interferon-gamma and highly activated macrophages that lead to formation of multinucleated giant cells (giant cells are seen in around 50% of biopsies).2,3,5
GCA has a variable presentation and is a heterogeneous disease. The classic presentation includes five cardinal symptoms: headache (with or without scalp tenderness); jaw claudication; visual changes; pain consistent with polymyalgia rheumatica; and constitutional upset. Although patients generally present with one or more of these symptoms, atypical presentations are seen occasionally, including patients with arm claudication and posterior circulation stroke.
Two-thirds of patients with GCA present with headache of new onset, often with associated tenderness over the temporal artery.6 Some patients have more generalised scalp tenderness that they may notice when combing their hair.
About 30% of patients with GCA report visual symptoms such as transient or permanent monocular visual loss, diplopia and visual field defect.7 Permanent vision loss is common if GCA is untreated. Patients who have transient visual changes may have a normal fundoscopy examination. All patients with visual symptoms should be referred urgently for assessment by an ophthalmologist.7
Half of patients with GCA report fatigue and pain on chewing.5,8 This is the most specific symptom for GCA. It is important to distinguish claudication from jaw pain at rest or temporomandibular joint dysfunction.
Polymyalgia rheumatica typically presents with morning-predominant neck, shoulder and pelvic girdle pain and stiffness which improves rapidly with corticosteroid therapy. Fourteen per cent of patients with a history of this condition go on to develop GCA.6 Fifty per cent of patients with GCA also report symptoms of polymyalgia rheumatica.3
Fever, weight loss and fatigue can be a prominent feature of GCA. Some patients may present with pyrexia of unknown origin.7
Symptoms consistent with large vessel involvement
Patients may present with atypical symptoms if they have disease in their aorta or its branches. These may include unilateral upper limb claudication, chest pain secondary to complications of aortic aneursym/dissection or, occasionally, stroke if the vertebral arteries are involved.
Early recognition and diagnosis of GCA is paramount to prevent permanent visual loss. A definitive diagnosis is made based on the clinical picture (Table 1), blood test and temporal artery biopsy results or specialised diagnostic imaging in conjunction with a specialist rheumatologist and/or ophthalmologist. If symptoms persist after the patient starts therapy, reconsideration of the diagnosis is important. Table 2 describes some important differential diagnoses (note that the list is not exhaustive).2 Table 3 provides a list of suggested investigations in the primary care setting.
What to do when you suspect a diagnosis of GCA
Corticosteroid therapy should be started as soon as GCA is suspected to prevent vision loss during the diagnostic work-up. Blood tests should be part of the initial work-up in primary care. Inflammatory markers in the form of c-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) are typically elevated; however, in 4% of cases they can both be normal.9 Raised CRP level and/or ESR are nonspecific and can be elevated in infection, malignancy and due to many other causes. A full blood count may show a reactive thrombocytosis, leucocytosis and/or anaemia of chronic disease. Liver function tests may be mildly elevated.
Blood test results normalise with corticosteroid-based treatment. Care must be taken to exclude differential diagnoses such as infections and malignancy, as inflammatory markers may initially fall with corticosteroid therapy, providing false reassurance in these conditions.
Confirming the diagnosis with temporal artery biopsy or advanced GCA-specific imaging
Temporal artery biopsy remains the gold standard test to confirm a diagnosis of GCA. Recent advances in imaging, however, mean that centres with access to specialised GCA protocols are increasingly using ultrasound, PET/CT and scalp MRI as first-line tests.
Temporal artery biopsy
Temporal artery biopsy is the gold standard test, particularly when imaging in a specialist centre is unavailable. Clinically guided, unilateral (based on side of most significant local symptoms) biopsy of 2 cm is appropriate.10 Treatment should never be delayed while awaiting biopsy. A study from South Australia showed biopsy results are often positive after more than 42 days of therapy; nevertheless, when possible, we recommend performing the biopsy within two weeks at the most from starting therapy.10,11 A negative biopsy result makes GCA less likely but does not definitely exclude it, as the active artery segment is missed in around a quarter of biopsies. False-negative biopsy results can be caused by the patchy nature of disease in some patients (skip lesions) or a large-vessel-predominant (aorta, subclavian, vertebral arteries) disease pattern. If the clinical suspicion remains high after a negative biopsy result, ongoing treatment should be based on the evolving clinical picture and further investigations.
Imaging is playing an increasingly important role in GCA. It assists with making the diagnosis, assessing the distribution of disease and monitoring the patient’s response to therapy. It is crucial that it is only performed in centres with higher volumes of patients and expertise with GCA-specific protocols, given the subtlety of findings, interoperator/reader variability and the gravity of an incorrect diagnosis. Currently in Australia, some of these modalities are less available, especially in rural centres, and are not covered by Medicare rebates. When imaging in an expert centre is not available or is discordant/equivocal with the clinical picture, a temporal artery biopsy should be performed.12,13
Colour duplex ultrasonography has been used to diagnose GCA for many years in specialised centres in Europe.14 Performance is highly operator dependent, however, and in nonexpert centres more than 25% of patients with biopsy-positive GCA may be misdiagnosed.15 Scans should ideally be performed within four days of starting corticosteroid treatment and should examine the temporal, occipital, carotid, vertebral, subclavian and axillary arteries. The scan may show arterial wall thickening, stenosis and a hypoechoic halo (halo sign).15,16
Time-of-flight (TOF) PET/CT has also recently shown utility as a diagnostic tool in GCA and we are actively using it as a first-line test. A 2019 Sydney-based study showed that a specialised TOF PET/CT protocol conducted within three days of the patient starting corticosteroid therapy delivers high diagnostic accuracy with the benefit of detecting vasculitis mimics and aortitis.17
High-resolution gadolinium-enhanced scalp MR angiography can also provide good diagnostic accuracy. It may show vessel-wall oedema and increased gadolinium contrast enhancement in active disease.18
The cornerstone of treatment involves immediate initiation of corticosteroid therapy with gradual weaning over the following months to years. In the past few years, a trial-proven corticosteroid-sparing agent, tocilizumab, has been added to the armamentarium of drugs. The Flowchart summarises the management of GCA.
The initial dosage of corticosteroid can be variable between practitioners as there have been no clinical trials evaluating this. However, consensus guidelines suggest the following:19
- Uncomplicated GCA (no jaw claudication or visual impairment): start with prednisone 40 mg per day
- GCA with jaw claudication but without vision impairment: start with prednisone 60 mg/day
- Visual loss (evolving or recent or amaurosis fugax): pulse intravenous methylprednisolone 500 mg to 1000 mg on days one, two and three, followed by 60 mg daily.
There should be a marked clinical response.
Prednisone has historically been tapered over 16 to 24 months. Guidelines have suggested prednisone be tapered by 10 mg every three to four weeks until the dose is 20 mg, then tapered by 5 mg every two to four weeks until the dose is 10 mg, and thereafter tapered by 1 mg every month. However, shorter tapers of around six months may be appropriate for patients also taking tocilizumab.
Low-dose aspirin 100 mg daily is generally not added in uncomplicated cases of GCA but should be considered if there are features of ischaemia including visual phenomena, or symptoms of stroke/transient ischaemic attack or limb claudication, unless there are contraindications.19,20-22
We routinely add a proton pump inhibitor while patients are taking high-dose corticosteroids to reduce the chance of gastrointestinal ulceration. Vitamin D and calcium supplementation are also recommended for bone protection. We also screen for osteoporosis risk with bone mineral density scanning. The PBS subsidises antiresorptive therapy for those with corticosteroid-induced osteoporosis (T-score < -1.5) and prednisone dosage of more than 7.5 mg for greater than three months.
Pneumocystis prophylaxis with three times weekly trimethoprim/sulfamethoxazole should be considered in newly diagnosed patients while they are on doses of prednisone greater than 15 mg/day.23
Tocilizumab is a monoclonal antibody that inhibits IL-6. In a randomised controlled trial, it has been shown to be superior in sustaining remission to 52 weeks when combined with prednisone, compared with prednisone therapy alone.24 Use of this biologic drug has also been shown to reduce the cumulative prednisone dose given to patients. The subcutaneous formulation is currently PBS listed for a maximum 12-month course and must be prescribed by a specialist. Treatment beyond 12 months needs to be individualised, given that about 50% of patients relapse in the two years after cessation of therapy.25 As further trial data emerge it will be useful to compare biologic therapy with conventional corticosteroid-sparing agents, in terms of both efficacy and cost.26 Although patients taking tocilizumab have favourable outcomes compared with those taking prednisone alone, many patients with GCA continue to be managed with a conventional corticosteroid-sparing agent (see below). Monitoring for relapse can be difficult with tocilizumab because the mechanism of the drug normalises inflammatory markers, meaning CRP level and ESR cannot be used as reliable measures of disease activity.27
Other corticosteroid-sparing agents
There is conflicting evidence for the use of methotrexate, with a meta-analysis of three trials suggesting it may have a small corticosteroid-sparing effect.28 Rheumatologists have historically used methotrexate as a first-line corticosteroid-sparing agent, but this may change with PBS access to tocilizumab.
Leflunomide has been used historically as a second-line corticosteroid-sparing agent. A recent open-label trial showed leflunomide to be effective as a corticosteroid-sparing agent and its use was associated with a reduced risk of relapse.29
Monitoring for complications
GCA treatments are associated with side effects that can be especially pronounced in the vulnerable elderly population group who have the condition. It is important to monitor for these in primary care. Table 4 summarises some of the side effects that require monitoring.
When initiating long-term corticosteroid treatment, a detailed medical history should be taken and a thorough examination performed to assess for risk factors and pre-existing conditions that may be exacerbated by therapy, including osteoporosis, diabetes and cardiovascular risk factors.4,13
Patients treated with tocilizumab are at increased risk of developing serious infections (fungal, viral, bacterial, opportunistic). Other considerations include an increased risk of gastrointestinal perforation; therefore, prompt evaluation of patients presenting with new abdominal pain should occur. Other side effects may include hepatotoxicity, neutropenia and demyelinating disorders. Live vaccines are contraindicated in patients treated with tocilizumab.30
Monitoring for a flare in disease
Monitoring will be guided by clinical history, examination and inflammatory markers. In patients on tocilizumab, monitoring inflammatory markers is not reliable. We generally avoid escalating therapy based on elevated inflammatory markers in the absence of GCA-specific clinical symptoms or signs. In some cases, isolated elevation in markers may prompt vascular imaging to identify progressive stenotic or aneurysmal lesions that would warrant increased immunosuppression. Given there is uncertainty regarding the significance of persistent vessel-wall activity shown on PET/CT and MRI in patients with clinically inactive disease, we do not currently recommend routine vascular monitoring in the absence of serological or clinical markers of relapse.31,32
Patients with GCA generally have a good prognosis once they have been established on treatment. Relapse occurs in more than 50% of patients, but the condition is not associated with excess mortality and the risk of recurrent vision events is very low beyond the first month.33,34 Longer-term risks relate to treatment complications and aortic aneurysm/dissection. We recommend that all patients with a diagnosis of GCA undergo long-term aortic screening every two to four years even when in treatment-free remission.35
GCA is the most common form of vasculitis affecting people aged over 50 years, and the recent developments in diagnostic and treatment pathways outlined in this article should help to improve outcomes. Practice points are summarised in the Box. Advanced vascular imaging is playing an increasingly important role in the diagnostic algorithm. Although corticosteroids remain the cornerstone of initial therapy and should be started immediately in all new suspected cases to prevent vision loss, tocilizumab can be used to minimise the cumulative corticosteroid burden. Close monitoring with specialist input, careful medication titration and vigilant assessment for medication side effects is essential in all patients being treated for GCA. MT