Giant cell arteritis
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1964 (Published 30 May 2019) Cite this as: BMJ 2019;365:l1964
- Karina Lazarewicz, consultant rheumatologist1,
- Pippa Watson, consultant rheumatologist and honorary senior lecturer2
- 1Rheumatology, Manchester University Foundation Trust, Trafford Hospital, Manchester, UK
- 2Rheumatology, Manchester University Foundation Trust, Wythenshawe Hospital, Manchester, UK
- Correspondence to K Lazarewicz karinalazarewicz{at}yahoo.co.uk
What you need to know
Giant cell arteritis (GCA) is a medical emergency that requires immediate treatment with glucocorticosteroids
Headache is the most common presenting symptom but is not always present
Refer patients with suspected GCA and visual symptoms such as blurring, diplopia, or visual loss immediately to ophthalmology specialists, as untreated GCA with eye involvement can lead to loss of eyesight
Refer patients without visual symptoms urgently to rheumatology specialists
The mainstay of treatment is high dose prednisolone; in some patients with refractory or relapsing disease, tocilizumab can be added to prednisolone to treat GCA and act as a steroid sparing agent
Giant cell arteritis (GCA) is an inflammatory disease that affects medium and large blood vessels, classically the extracranial branches of the external carotid arteries. Inflammation in the wall of the affected artery may cause headache, scalp tenderness, jaw and tongue pain, and visual disturbances, but can also present with systemic or other less common symptoms, so that diagnosis can be challenging. It is a rare disease affecting 2.2 per 10 000 patient-years in the UK.1 Consequences can be serious if the diagnosis is delayed, and may include visual loss, stroke, and aortic aneurysm. Many patients with GCA first present to their general practitioner or local emergency department. The most common presenting symptom of GCA is headache (76%)1 but given its relative rarity, other causes of headache are much more common in these settings. Glucocorticosteroids are the mainstay of treatment, but at high doses and for prolonged periods of time are associated with substantial side effects. In April 2019, the National Institute for Health and Care Excellence (NICE) licensed tocilizumab for patients with refractory or relapsing disease.2 This article provides a practical update for non-specialists with particular emphasis on making a diagnosis and initial management. It also discusses the new NICE guideline on tocilizumab and its likely impact.
Who gets it?
GCA is relatively rare in a non-specialist setting, with an incidence of 7-29/100 000 population aged >50 in Europe.3 It is more prevalent in people of northern European ancestry.3 Frequency increases with age, being very rare in those under 50, with a mean age of onset of 70.4 As with many other autoimmune diseases, it is more common in women than men (2-6 times more likely).4
What causes it?
Inflammation in the affected blood vessel wall, for example in the carotid artery and its branches, is characterised by the presence of macrophages (which may fuse to form the characteristic giant cells) and CD4+ T lymphocytes.5 This leads to thickening of the intima, and results in reduced blood flow and ischaemia, which is the main cause of pain in the areas that are supplied by the affected vessel (eg, temporal artery involvement can lead to headache). The release of cytokines leads to systemic symptoms.
Why does it matter?
Early diagnosis and treatment of GCA can prevent development of serious complications, such as visual loss. Even when treated, visual loss can occur and be permanent. Before corticosteroid treatment was used to treat GCA, visual loss was noted in 30-60% of patients.6 If left untreated, up to half of individuals with GCA could sustain unilateral visual loss within days to weeks of symptoms.7
How do patients present?
Symptoms and signs (table 1) frequently occur because of the involvement of arteries arising from the cranial branches of the aortic arch, particularly the extracranial branches of the carotid arteries (fig 1).
Symptoms and signs of GCA and arterial involvement
Assessing a patient: history and examination
Ask about
Headache—this is the most common symptom, but it isn’t always present. When present it is usually a severe temporal headache although GCA can present with occipital or parietal pain.8 It is quite often insidious in onset but can also be acute. The pain is described as dull in nature but this varies.
Visual symptoms—ask about visual symptoms in anyone presenting with a headache. Is there partial or complete loss of vision or diplopia? Ask specifically about both eyes. If a patient has unilateral eye involvement, the likelihood of the other eye being affected at the same time is 20-50%.9
Scalp tenderness – is there scalp tenderness when brushing hair?
Constitutional symptoms—fatigue, weight loss, anorexia, and sweats or fevers are frequently present. However, differential diagnoses, such as infection and malignancy, should also be considered.
Pain in the jaw on chewing (jaw claudication)—this is the most common ischaemic complication. Usually pain happens after minutes of chewing over the masseter muscle, due to its ischaemia.10 Tongue claudication is very rarely the presenting symptom and is present in about 2-4% of patients.11 Jaw (or tongue) claudication is associated with a high risk of ischaemic complications.12
Proximal muscle pain and stiffness—patients with coexisting polymyalgia rheumatica (PMR) may report muscle pain, particularly in the proximal arms and legs, and early morning stiffness usually lasting several hours. They often find it difficult to get out of bed in the morning.
Examine
Temporal arteries—palpate the temporal artery to look for tenderness, beading that feels like small hard lumps, and/or decreased or absent pulsation, for example by comparing it with the other site.
Vascular examination—look for large vessel vasculitis features such as bruits (for example carotid or subclavian artery), decreased arterial pulsation, or a blood pressure differential between arms.
Eyes—check visual acuity and visual fields, looking for anterior ischaemic optic neuropathy secondary to GCA, which may present as monocular loss of vision (over hours to days). Some patients report altitudinal vision loss (either lower or upper half of the visual field is selectively affected) or scotoma. Check pupillary reflexes for a relative afferent defect secondary to optic nerve ischaemia, and perform fundoscopy. Fundoscopy findings are not specific to GCA and may include cotton wool patches, oedema, pale discs, or even haemorrhage.
Scalp—feel for tenderness over the scalp; do not limit your examination only to the skin overlying the temporal artery as arteries supplying the scalp can also be involved.
Perform a thorough general examination, including (but not limited to) cardiovascular, respiratory, and abdominal systems to exclude other differential diagnoses (table 2).
Investigations
Recommended investigations are presented in table 3.
Investigations to consider
Classification
When classifying patients with vasculitis, the American College of Rheumatology criteria (box 1) may be helpful, but these are not diagnostic criteria, and should not be used as such. However, the criteria are straightforward to use and may help to start early treatment and trigger specialist referral.
The American College of Rheumatology classification criteria15
At least three of five criteria must be present—sensitivity 93.5%, specificity 91.2%
Age at onset >50
New onset headache
High erythrocyte sedimentation rate (>50 mm/hour by the Westergren method)
Abnormal temporal artery on palpation
Changes consistent with GCA on biopsy
Referral
Refer all patients with suspected GCA urgently to secondary care. If there is visual involvement refer immediately for ophthalmology review. Refer other cases urgently for rheumatology outpatient review to be seen as soon as possible, usually within two weeks. Commence glucocorticosteroids in primary care as soon as the diagnosis is suspected. Many specialist centres have a fast track GCA pathway (fig 2), which is likely to include prompt review, temporal artery biopsy, with or without ultrasound. Be aware of your local arrangements and discuss atypical cases early with your local specialist.
Example of local referral pathway for suspected GCA
Temporal artery biopsy is currently the gold standard for diagnosis in all patients with suspected GCA. According to the 2010 British Society of Rheumatology guidelines for the management of GCA, a unilateral biopsy of at least 1 cm should be done in an experienced surgical unit. The procedure is usually carried out under local anaesthesia. A positive result means that inflammatory changes are confirmed. According to American College of Rheumatology 1990 criteria for classification of GCA, the specificity of temporal artery biopsy is 73.1% and sensitivity is 92.9%. Do not delay steroid treatment waiting for the results as the diagnosis of GCA is mainly based on clinical judgement, and even with a negative biopsy a patient can still have GCA. Biopsy remains positive for 2-6 weeks after commencing steroids, although the sooner the biopsy is preformed the greater the chance of it being positive.16 One of the biggest challenges is the high false negative rate due in part to the presence of skip lesions.
Ultrasound is increasingly being introduced as part of the assessment of patients with suspected GCA, to visualise temporal and axillary arteries. Typical findings include a halo suggestive of vessel wall oedema. Monti et al17 found that ultrasound had a sensitivity of 63% and specificity of 100% in routine clinical practice. Introduction of this technique in their centre led to a decrease in their biopsy rate from 42% to 24%. Other techniques, such as F‐18 FDG‐PET/CT, are particularly useful in cases where there are systemic but no localising features.
Management
Glucocorticosteroids are the mainstay of treatment in GCA. Symptoms usually reduce substantially within a week. Consider alternative diagnoses if there is no notable response within this timescale. Steroid regimes vary and evidence is inconsistent.7 Current British Society of Rheumatology guidelines suggest 40-60 mg of prednisolone daily for at least three or four weeks and until resolution of all the symptoms in uncomplicated GCA (with no visual symptoms or jaw claudication). Subsequently taper the prednisolone by 10 mg every two weeks to 20 mg then by 2.5 mg every 2-4 weeks to 10 mg. Finally, reduce by 1 mg every 1-2 months until stopped. Dosage and tapering regimes vary but the key principle is to adjust the dose according to response to treatment.
If the patient presents with any visual complications they will require intravenous methylprednisolone 500 mg to 1 g for three days before starting oral steroids.
Studies have not shown any statistically significant long term benefit for high dose intravenous steroids in uncomplicated GCA.18 Consider offering aspirin 75 mg to all patients with GCA19 (it has been shown to reduce the incidence of neurovascular complications). Offer gastro-protection with a proton pump inhibitor, bone density scanning, and bone protection to those who require long term steroids.
How to monitor patients with GCA and what to watch out for
Routine follow-up of patients is recommended in weeks 0, 1, 3, and 6, and three monthly thereafter in the first year. After the third month the follow-up could be on a shared care basis, involving primary care.3 At each review, ask about clinical symptoms, vascular complications, and steroid induced complications such as diabetes mellitus and osteoporosis. Consider simple interventions to improve the patient’s quality of life, for example considering low dose nocturnal amitriptyline to help with sleep disturbance. GCA can be life changing as it is a chronic medical condition and the patient will need to follow steroid treatment for at least 18 months. It is important to offer patient education and access to support networks (box 2). In particular, encouraging patients to keep physically active is important for their wellbeing and health.
Patient education resources
Polymyalgia Rheumatica and Giant Cell Arteritis charity provides advice and information about GCA, including access to support groups, web forums, and results from research studies. They will post out an information pack on request: http://www.pmrgca.co.uk/content/home-page
Versus Arthritis has some patient information leaflets on GCA, steroid tablets, and managing symptoms such as pain: https://www.versusarthritis.org/
RETURN TO TEXTThe British Society of Rheumatology recommends checking full blood count, inflammatory markers, urea and electrolytes, and glucose at every visit. High inflammatory markers with clinical symptoms are indicative of a flare of the disease. Offer chest radiograph to all patients with diagnosed GCA to monitor for aortic aneurysm two yearly. If there is any suspicion of aortic aneurysm, request an echocardiogram.
What happens if the patient has a flare-up?
Relapses of GCA activity are common, with 43% of patients suffering at least one relapse in population based studies.20 Consider relapse in patients who have new onset of ischaemic complications, polymyalgia rheumatica, or recurrence of the GCA headache. Note that inflammatory markers could be normal at that point. The British Society of Rheumatology recommends increasing the steroid dosage to the previously effective higher doses of prednisolone with recurrence of the headache. If patients develop new jaw claudication, they advise increasing the steroids back to 60 mg daily. New or recurring eye symptoms require high doses of steroids—usually 60 mg daily and/or consideration of intravenous methylprednisolone infusion. There are no studies that confirm the superiority of one over the other.21 There is not enough evidence to suggest a standardised dosage of steroids and therefore all the recommendations are based on consensus. A randomised controlled trial by Chavalet et al showed no difference in complications or cumulative dosage in patients with GCA (excluding those with ocular complications) using different protocols, including intravenous methylprednisolone.18
Steroid related side effects are common in patients with GCA. The British Society of Rheumatology recommends introduction of a disease modifying antirheumatic drug, such as methotrexate, as a steroid sparing agent if a patient experiences a third relapse of GCA.3 Research is ongoing as to whether azathioprine or leflunomide may also provide benefit as a steroid sparing agent.
Complications
The most feared long term complication of GCA is permanent visual loss, therefore it is very important to recognise the symptoms promptly and treat patients with suspected GCA. Between 10% and 20% of patients have been described as developing aortic aneurysm.22 Aortic dissection and stroke have also been described but are less common.22
What’s new?
In April 2018, NICE published guideline 158 in the UK, which allows the treatment of GCA with tocilizumab (a humanised monoclonal antibody against the interleukin-6 receptor) for refractory or relapsing disease provided certain circumstances are met. This decision was made following the publication of studies2324 showing that treatment with tocilizumab plus tapered glucocorticosteroids was superior to placebo in achieving sustained remission in GCA. Tocilizumab can be used with glucocorticosteroids or after they are tapered down by itself (however not for flares of GCA). It must be stopped after one year of uninterrupted treatment. To be eligible for tocilizumab the patient needs to have a diagnosis confirmed by biopsy and/or imaging, which only applies to a proportion of patients. Patients taking tocilizumab are at increased risk of serious infections, gastric perforation, laboratory abnormalities (thrombocytopenia, neutropenia, elevated liver tests and lipids), and other less common side effects. Therefore, liver function tests, platelets, and neutrophils have to be checked four to eight weeks after starting the therapy and 3 monthly thereafter. Lipids should be checked four to eight weeks after and 24 weekly thereafter.
Education into practice
Would you consider GCA as a diagnosis in a patient who didn’t present with a headache?
Would you start glucocorticoid treatment before referral?
Think about the last time you reviewed someone with GCA. Did you discuss potential steroid side effects and ways of minimising their impact? How might you do this more next time?
Patient commentary
I had been on holiday in the Arctic and within days of being home I began to have very severe headaches. I said nothing for a couple of days, not wanting to be accused of having Man Flu, but the headaches persisted. They did not seem like normal headaches, but were centred mainly on my scalp. It was almost as if something was pressing against it. They became so bad that even taking a shower was painful. The headaches would wake me during the night and I would take paracetamol and go back to sleep. By this time I had convinced myself that there was something seriously wrong. I thought I had a brain tumour. I was lucky that my GP immediately recognised the possible diagnosis of GCA and did a blood test straight away. She rang me later that evening and I returned and started prednisolone that day.
The treatment, at least from my point of view, seemed straightforward. The headaches disappeared almost immediately. I did experience some reaction to the steroids in that I felt a bit on edge sometimes and although I am normally very calm when driving I could sometimes feel myself becoming quite angry.
How patients were involved in the creation of this article
We have discussed living with GCA with several of our patients, one of whom was kind enough to contribute the patient commentary. Our patients highlighted many important issues, including difficulty obtaining a diagnosis, and were extremely keen that we familiarise more doctors with the condition. They were unanimous about the need to improve diagnosis (such as by using ultrasound) and the side effect burden that is associated with long term glucocorticoid use. We have used this to inform the writing of our article.
Footnotes
Competing interestsThe BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.
Further details of The BMJ policy on financial interests is here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests
Provenance and peer review: commissioned, based on an idea from the author; externally peer reviewed.