14 minute read
HPN 2023 November
60 Second Summary
Giant cell arteritis (GCA) is the most common form of systemic vasculitis. Its incidence demonstrates a strong association with aging. GCA will affect 1 in 100 women and 1 in 200 men in Ireland in their lifetime.
Characteristic symptoms include temporal headache, jaw pain, and systemic features.
Devastating irreversible ischaemic complications such as vision loss and stroke may occur at disease onset. In the longer term, complications such as aortic aneurysms may occur. Inflammatory markers (ESR and CRP) are generally elevated, but not always markedly so.
Temporal artery biopsy remains the gold standard for diagnosis but has poor sensitivity. The utility of temporal artery ultrasound and other imaging techniques has progressed in recent years.
Glucocorticoids remain an indispensable part of the treatment algorithm but are associated with a multitude of treatment related adverse events. The biologic agent tocilizumab has emerged as a key part of GCA treatment, facilitating lower cumulative glucocorticoid doses and reducing flare rates.
The majority of people with GCA should now be initiated on combination treatment in order to minimise treatment related complications and improve long term outcomes. Uncertainties remain but significant progress has been made in GCA management in recent years.
Giant Cell Arteritis
Introduction
Giant cell arteritis (GCA) is a systemic inflammatory rheumatic disease. It is the commonest form of systemic vasculitis in Ireland. It has a striking age predilection, virtually never occurring prior to age 50 and becoming more common until a peak in the 70’s with a plateau thereafter. GCA demonstrates a marked geographic preponderance being strikingly more common in Northern European populations than in other parts of the world. This association seems to be genetically based rather than due to physical location with emigrant populations maintaining the risk of their ancestral origin. The lifetime risk of GCA in populations similar to Ireland is 1% in women and 0.5% in men – this is not a rare condition.1 The cause of GCA is unknown; the marked age association suggests a key role for immunosenescence. It is hypothesised that a particular individual’s immune system may be primed, by aging and/or other factors, to develop GCA, and then a subsequent second hit triggers the disease. The nature of this trigger has been elusive, and this may reflect the fact that there is no specific trigger; rather it may be the case that anything that stimulates the immune system can act in this role, this would correlate with the wide variety of infectious agents mooted as triggers, and indeed with the more controversial association with vaccines.
Clinical Presentation
GCA may present with a variety of different clinical phenotypes (Figure 1). In the past the focus has predominantly been on the classic cranial GCA phenotype with limited recognition of other potential presentations. The phenotypes may overlap with patients presenting with features of more than one simultaneously or in succession.
Cranial GCA typically presents with unilateral or bilateral temporal headache. Headache is of course one of the most common clinical presentations and there is a wide differential. Scalp, and more specifically focal temporal artery tenderness is frequently present. The most specific clinical feature of cranial GCA is jaw claudication. Jaw claudication present similarly to intermittent claudication in the legs. There is, at least initially, no pain at rest, pain develops with use (typical chewing), to the extent that it frequently limits eating. Cessation of the provoking chewing activity will lead to symptom resolution and the ability to resume chewing until pain subsequently returns. This process is the basis for the “chewing gum test” in GCA, where the patient is offered gum, the chewing of which can precipitate claudication. Visual complications are the most feared outcome in cranial GCA. Unfortunately they remain common, affecting 20% of patients. Our treatment Polymyalgia rheumatica (PMR) is another rheumatic disease entity characterised by bilateral proximal arm and leg, as well as neck, stiffness with early morning predominance. While it is still debated, PMR and GCA are likely two ends of the spectrum of a single disease process. This is supported by shared pathogenic mechanisms, demographic associations, treatment responses, and particularly by the frequent co-occurrence of the two – 50% of GCA patients have polymyalgic symptoms, while 10-30% of people with PMR will ultimately develop GCA. All patients presenting with PMR should have a clinical assessment for GCA including examination of the temporal arteries and for large vessel arterial bruits. If the history or examination raise concern for GCA, further investigation with imaging and/or temporal artery biopsy should be pursued. There are two main scenarios in which GCA occurs in the context of apparent PMR. The first of these is when de novo GCA develops as a progression of existing PMR disease. The second is when what appears to be PMR was in fact always GCA. This occurs due to the fact that involvement of the subclavian and axillary arteries in GCA can closely mimic PMR shoulder symptoms in particular. The clues to the presence of GCA in this setting can be from arterial bruits (but need to be assessed for prior to glucocorticoid treatment), imaging findings (again need to be prior to glucocorticoids), are a sustained failure of tapering in PMR. Doses of glucocorticoids used to treat PMR are significantly lower than required in GCA and will lead to a temporary symptom amelioration but never fully control disease, leading to frequent relapses on relatively high glucocorticoid doses.
Stroke may also occur as an ischaemic complication in GCA. 1-6% of patients with GCA present with stroke, and the risk of stroke is increased in patients with known GCA with a Hazard Ratio (HR) of 1.28-2.21 The increased risk of stroke in GCA is particularly pronounced at the time of onset and decreases significantly following the institution of treatment but with a small residual increase in risk compared to the general population. In GCA the usual frequency pattern of stroke is reversed with a 3:1 ratio of posterior circulation to anterior circulation stroke. There may be minimal other symptoms of GCA and a high level of clinical suspicion in posterior circulation stroke is warranted, especially in the presence of any atypical features. In such cases, a careful clinical examination is the most useful tool, and may be complemented by checking inflammatory markers or vascular imaging.
The final common GCA phenotype is perhaps the most challenging. This is the patient who presents with exclusively constitutional symptoms. These may represent some combination of fever, weight loss, and anorexia. It may also present exclusively with a “pyrexia of unknown origin” or with raised inflammatory markers of unknown cause. This group of patients frequently have extensive investigatory process prior to their ultimate diagnosis. A thorough clinical assessment may reveal other signs of GCA at initial presentation and it is a diagnosis which should always be considered in such cases. It is not infrequent for cross-sectional imaging, such as CT or PET, to identify vascular inflammation consistent with GCA in previously unsuspected cases.
Clinical Examination
The clinical findings in GCA vary widely both based on the phenotype but also between individual patients. Patients may look extremely unwell with marked cachexia, but at the same time may look entirely healthy. Temporal arteries can be swollen, nodular, apulsatile, and tender –but can also be normal. In more prolonged disease, temporalis muscle wasting may be noted. Occipital arteries are more difficult to palpate but tenderness may be elicited in the occipital notch – this is important to assess as isolated occipital artery involvement may occur. Arterial bruits should be sought by auscultation in the carotid, subclavian, and axillary arteries in particular. Reduced or asymmetric pulses, and blood pressure differences between the limbs may be seen with large vessel disease. Fundoscopic exam should be performed in any patient with visual symptoms searching for anterior ischaemic optic neuropathy. In addition those with diplopia warrant a thorough neurologic eye exam for cranial nerve palsies.
Laboratory Investigations
GCA is a systemic inflammatory rheumatic disease. As such acute phase reactants / inflammatory markers are characteristically but not invariably elevated. Erythrocyte sedimentation rate (ESR) is the traditional diagnostic test in GCA but actually, C-reactive protein (CRP) is the more useful test overall. CRP is elevated in 95% of patients with GCA. ESR can be normal in up to 20% of patients with untreated GCA. An important pitfall to avoid is being misled by the extent of the inflammatory marker elevation. While it sometimes occurs, GCA does not necessarily need to be associated with very high inflammatory markers, lesser elevations are also significant in the appropriate clinical scenario.
Fibrinogen is another potentially useful acute phase reactant and biomarker in GCA, however its widespread utilisation is limited due to cost implications.2 Patients can also have elevated platelets as an acute phase response, as well as reduced haemoglobin and albumin as negative acute phase reactants.
In terms of monitoring, while all of the above acute phase reactants may be elevated, for the individual patient it is likely that one or the other more closely reflects their disease activity. This will most frequently be the CRP, but for some patients ESR, fibrinogen, or even platelets may be more closely related to their symptoms. It is useful to check all available and practical markers at first presentation, and then to choose to monitor the best marker of the patient’s disease longitudinally.
Imaging and Biopsy
Temporal artery biopsy is the traditional gold standard investigation in GCA. It has a very high specificity for vasculitis. However, while most cases of vasculitis affecting the temporal artery will be due to GCA, other vasculitidies including ANCA-associated vasculitis and Takayasu arteritis can involve this artery. Sensitivity is where temporal artery biopsy falls down, being negative in 50-70% of patients who really do have GCA. This is due to a variety of reasons including technical issues, skip lesions, and GCA phenotypes which do not involve the temporal arteries. Temporal artery biopsy can be challenging to obtain due to logistic issues, and is associated with potential complications given the invasive nature of the procedure.
Vascular ultrasound is a more recent innovation, offering a non-invasive way of assessing the temporal artery structure. Procedurally at least the temporal artery, and often other arteries such as the axillary artery, are imaged. Its widespread adoption has not occurred yet, mainly due to issues over training, expertise, resources, and equipment. Ultrasound has a similar sensitivity to biopsy of around 50% but a higher false positive rate of 20-30%. Many other conditions can result in this positivity including atherosclerosis, migraine, and malignancy.
A substantial proportion of patients with GCA have involvement of the aorta and its branches, some of these in the absence of temporal artery involvement. In this setting CT angiogram, MR angiogram, or PET imaging of the large arteries may be diagnostic. The choice between these modalities depends on availability and expertise at individual centres.
Treatment
Glucocorticoids were first used to treat GCA in 1949, and have been the mainstay of treatment since that time. Glucocorticoids rapidly improve symptoms and reduce subsequent ischaemic complications. The glucocorticoid experience in GCA however is marred by troublesome adverse events, and frequent relapses on reducing the dose. Despite the extensive experience with glucocorticoids in GCA, we have little evidence to guide optimum treatment regimens, and physicians adopt different approaches. Given the potentially devastating nature of GCA and likewise the severity of glucocorticoid related adverse events, these patients are best managed in a specialist centre and the following discussion of my personal treatment approach is for information purposes rather than any expectation that non-GCA specialist physicians should undertake this alone, Figure 2. If patients are hospitalised with vision loss or stroke, IV methylprednisolone at daily doses of 500-1000mg is administered for 3 days prior to the oral dosing described below. The majority of GCA patients are managed sufficiently with initial oral glucocorticoids. Patients with ischaemic symptoms (vision loss, stroke, jaw or limb claudication) are typically initiated on prednisolone 60mg daily, with those with no ischaemic symptoms commenced on 40mg daily. Glucocorticoids are weight based drugs and consideration of adjustment of dosing in light of body weight and comorbidities is prudent. The initial treatment dose is generally continued for 1 month following which tapering commences. Those on a 60mg dose are reduced to 40mg initially. From 40mg prednisolone is tapered by 5mg every 2 weeks until 20mg daily, then by 2.5mg every 2 weeks until 10mg daily, and thereafter by 1mg a month. Relapses requiring dose escalation are common in GCA and should be dealt with promptly as delay results in both potential damage and greater difficulty recapturing disease control. Recurrence of ischaemic complications may necessitate a return to the initial high prednisolone doses. Most other relapses will respond to an increase of approximately 20% of the prednisolone dose.
Due to the high doses involved glucocorticoid related adverse events are seen in more than 90% of people with GCA. Many of these are associated with significant morbidity and indeed mortality; fractures, sepsis, hypertension, diabetes mellitus, and cataracts, among others, are commonly seen. Preventable glucocorticoid related complications should be ameliorated with prophylaxis for glucocorticoid induced osteoporosis (generally a bisphosphonate and calcium/ vitamin D) and peptic ulcer disease. It is evident from the associated adverse event rate that glucocorticoid monotherapy is not an ideal approach. The search for glucocorticoid sparing agents in GCA was until recently dominated by disappointment with multiple agents demonstrating no efficacy. Methotrexate was traditionally used in GCA but it is at best beneficial for a limited number of patients.4 The anti-tumour necrosis factor alpha agents which have revolutionised other areas of rheumatology are entirely ineffective in GCA.
This state changed in 2017 when the GiACTA randomised controlled trial demonstrated dramatic efficacy for the interleukin-6 blocking monoclonal antibody tocilizumab. This followed on from an earlier smaller trial also demonstrating efficacy.5,6 The benefit of tocilizumab demonstrated in the GiACTA trial is among the most pronounced seen in any medication intervention trial in rheumatic diseases. While the exact role of tocilizumab in GCA remains to be fully defined, it is likely beneficial for the majority of patients at initial diagnosis, and certainly all relapsing patients, in the absence of contraindications, Figure 3. If tocilizumab is utilised the glucocorticoid reduction can be accelerated in line with the study protocol from the GiACTA trial - this can be approximated by tapering twice as quickly as outlined in Figure 2. Tocilizumab is a biological disease-modifying antirheumatic drug. The main concern with these agents is infectious risk. Tocilizumab has an association with diverticulitis and increase diverticular perforation - however this association is weak.
Glucocorticoids have a more significant impact on both infections overall and diverticulitis, so when the choice is between these two options tocilzumab is generally preferable from an adverse event viewpoint.
Tocilizumab is administered by subcutaneous injection weekly for the first year. After 1 year in remission, some patients will be able to increase their dosing interval to every second week with no relapse. The need for long-term treatment with tocilizumab remains to be clarified, however given that giant cell arteritis is a long-term condition, and our experience with tocilizumab in rheumatoid arthritis, my own current practice is to recommend continuation of tocilizumab long-term. The mode of action of tocilizumab results in normalisation of CRP and ESR, which may be discordant with the clinical state of the patient. The consequence of this is that they will generally remain artificially low even in the presence of GCA relapse, or indeed other intercurrent events such as infections. Therefore considered clinical assessment becomes even mroe essential in tocilizumab treated GCA patients.
Trials of multiple other agents are ongoing with promising early data and it is hoped that our treatment armamentarium will further expand in the near future. The agents being studied include the T-cell modulator abatacept, IL-17 inhibitor secukinumab, IL-23 inhibitor guselkumab, IL-12/23 inhibitor ustekinumab, GM-CSF inhibitor mavrilimumab, and JAK inhibitor upadacitinib.7, 8
Summary
GCA is a relatively common and potentially devastating condition. Prompt diagnosis and treatment can avert the immediate risks of vision loss and stroke. In the longer term, the aim is minimisation of treatment related adverse events while maintaining disease control. Glucocorticoids remain a central pillar of treatment but most patients benefit from initial combination treatment incorporating tocilizumab.
References available on request
