Clinical signs and symptoms of GCA

The classic presentation of GCA is a combination of vascular insufficiency and systemic inflammation (Table 3). Almost all patients have evidence of a systemic inflammatory syndrome, which is associated with an intense acute phase response (42). Signs and symptoms of vascular disease may be less obvious and physicians need to actively search for them. Since vascular stenosis/occlusions can lead to irreversible tissue ischemia, such as blindness or stroke, prompt diagnosis and management is an absolute requirement and the level of suspicion to not miss GCA must be high.

Extravascular GCA

The most frequently encountered extravascular manifestation is polymyalgia rheumatica (PMR), a condition of muscle pain and stiffness affecting the neck, the shoulder girdle, the pelvic girdle and, only occasionally, the trunk. About 40% of patients with GCA will develop PMR along the course of the disease. It may precede, coincide or follow the diagnosis of arteritis. Typically, the forearms, hands and peripheral lower extremities are spared. Myalgias are associated with pronounced stiffness, especially in the morning hours. Patients report difficulties in getting out of bed, brushing their teeth and rising from the toilet seat. PMR frequently appears in treated patients in whom corticosteroids are lowered and is a useful clinical sign to estimate disease activity.

PMR occurs in patients with no signs of active arteritis and such isolated PMR is about tenfold higher in incidence than GCA. However, a subset of patients with PMR has findings of arteritis on histologic evaluation. Careful examination and monitoring of such patients is necessary to not miss GCA. The risk of evolving arteritis appears higher when immunosuppressive therapy is discontinued.

Constitutional symptoms caused by GCA include anorexia, malaise, weight loss and occasionally fever (43). Fever of unknown origin is a frequent reason for referral to a vasculitis specialist. Such patients typically have completed a work-up for an occult malignancy. Clinical findings suggestive of GCA may be minimal and temporal biopsy should be pursued even

when the appear normal on physical examination. Some evidence suggests that GCA is

dominated by systemic inflammation, and constitutional symptoms are pathogenic subsets of

disease. Granulomatous inflammation of the vessel wall may be less severe. Possibly, this

translates into lower risk of emerging ischemic complications but this remains a subject of

further research. Biopsy should be pursued as inflammatory manifestations may be subtle and

microscopic examination of arterial tissue has a central place in establishing the diagnosis.

Laboratory signs indicative of acute phase reaction, including a marked elevation of the

sedimentation rate and CRP, are helpful in distinguishing patients with inflammatory activity

from those with noninflammatory conditions. Such laboratory abnormalities may be the

indication for a search for vasculitis and remain important when screening for arteritis.

Medium and large vessel GCA

Depending on the primary vascular territory affected by the granulomatous arteritis, two categories of GCA have been identified: 1) cranial arteritis characterized by involvement along

the distribution of the , typically manifesting in the 2nd-5th branches, and 2)

large-vessel GCA targeting the aorta, the , the axillary artery and the vertebral

artery. Occasionally, more peripheral upper extremity arteries have arteritic lesions, and,

infrequently, GCA manifests in the lower extremity vessels.

Arteritic stenosis or occlusions of carotid branches dominate the clinical picture. Typically,

patients present with headache, scalp tenderness, and prominent temple vessels. The

occasional patient has involvement of the . Patients describe the headaches as different from all other headaches they have had previously, more intense, with only partial relief when taking analgesics. Inability to rest the head on the pillow, difficulties combing the hair or wearing glasses are useful clues. The patient may have noticed tenderness, swelling and nodularity of their temporal vessels. While headaches are a nonspecific sign, pain in the masseter muscles when chewing or talking (jaw claudication) is virtually pathognomic. Jaw claudication results from restriction of blood flow to the masseter muscles. Limited blood supply can also lead to painful dysphagia and pharyngeal soreness. A nonproductive cough, occasionally the sole referral reason for a vasculitis work-up, has been interpreted as a manifestation of insufficient blood flow to branches of the pulmonary artery.

Neuro-Ophthalmic manifestations of GCA

Because several of the arteries supplying the eye, optic nerve and brain can be affected, GCA is associated with a broad spectrum of neuro-ophthalmic manifestations (Table 4) (44).

Ischemic damage of the optic nerve or other structures of the orbit, classically dependent on blood supply from the , dominate ocular GCA. GCA-induced occlusion of the short posterior ciliary artery leads to anterior ischemic optic neuropathy, which is characterized by optic nerve head ischemia, edema, and splinter hemorrhage (45). Cotton-wool spots, fluffy, white patches in the retinal nerve fiber layer due to ischemia-induced axoplasmic stasis, can be a presenting sign of GCA (46). The posterior ciliary arteries also supply the and, if affected, may lead to cilio-retinal artery occlusion. Anterior ischemic optic neuropathy associated with significant choroidal ischemia or cilioretinal artery occlusion is presumed to be due to GCA until proven otherwise. Localized involvement of the submacular choroid has been reported to cause isolated, bilateral maculopathy and central scotomas (47,

48). Hypoperfusion or, less commonly, emboli, involving the can cause central scotoma from central retinal artery occlusion. Ischemia in the territory can cause vision loss and ocular ischemia syndrome. Posterior ischemic optic neuropathy occurs from involvement of the ophthalmic and orbital arteries, although at a much lower frequency. Inflammatory lesions in the orbita or arteritis at neuroanatomic sites along the visual axis may be a consequence of GCA. The typical GCA patient comes to attention with sudden onset of painless vision loss, which is partial or complete. Awaking in the morning with sight impairment is not unusual. A stuttering course of transient visual obscuration or amaurosis fugax precedes severe vision loss in about one third of cases (49). Most patients present with unilateral involvement, but there is a high risk of progression and involvement of the second

eye, necessitating swift diagnostic and therapeutic decisions. GCA can cause diplopia from

extraocular muscle ischemia, cranial nerve palsies, or brainstem involvement. GCA needs to be on the list of differential diagnoses in at-risk individuals presenting with diplopia and ophthalmoplegia. Homonymous visual field loss results from arteritis-induced ischemia of the brain, such as infarction of the occipital lobe from involvement of the posterior circulation.

Brainstem ischemia from vertebral and basilar vasculitis can be associated with hemiplegia, diplopia, dizziness and other neurologic issues. Notably, the vertebral and basilar arteries are extracranial. Intracranial vessels are typically unaffected by GCA and different types of vasculitic syndromes need to be considered in patients with intracranial vasculitis.

Large vessel GCA

GCA of the aorta and its primary branches displays many similarities with Takayasu’s arteritis

except that the age at disease onset is strikingly different (50, 51). Preferred target regions for

GCA are the ascending and descending aorta as well as the arch while the abdominal aorta is rarely affected. Lesions in the subclavian and axillary arteries result in aortic arch syndrome, pulselessness and asymmetry of pulses and blood pressure measurements. This may be an

incidental finding or the patients come to attention because of upper extremity ischemic

symptoms. Inability to hold up the arms for extended periods, difficulties playing the piano or

cutting vegetables are typical complaints. Gangrenous tissue damage is the exception. Lower

extremity GCA is difficult to distinguish from atherosclerotic peripheral vascular disease. Even

imaging studies may not be able to unequivocally separate an atherosclerotic and vasculitic

pathogenesis. A similar problem complicates the diagnosis of GCA aortitis. Here, the primary

source of information often comes from tissue examination of the aortic wall following the

surgical repair of aortic aneurysm in otherwise asymptomatic patients. While granulomatous

inflammation of medium-sized arteries predictably leads to luminal occlusion, the complications of aortic wall inflammation are those of vessel wall destruction, aneurysm formation, dissection, rupture and aortic insufficiency. The risk of individuals with a diagnosis of GCA to develop aortic

aneurysm, dissection or rupture is much higher than in the general population and patients need

to be actively screened for evidence of large vessel involvement.

Atypical GCA

Since the stakes of unrecognized and untreated GCA are high, physicians need to be alert to the possibility of encountering this vasculitis. Typical presentation with temporal headaches, abnormal temporal arteries and ischemic complications is not always the case.

Ophthalmologists need to be familiar with the atypical features of GCA as they may see patients prior to permanent vision loss.

Diagnosis

Tissue diagnosis

A definite diagnosis of GCA is made through tissue biopsy, usually from the temporal artery. If clinically indicated, the occipital artery can be biopsied. Histologic diagnosis of GCA may also be made from resected aortic wall. Classical findings are mononuclear cell infiltrates in the wall of the affected vessel. Granulomatous formations are often described. About 50% of biopsied tissues contain multinucleated giant cells. The intimal layer is expanded and the lumen may be completely occluded. In some cases, cellular infiltrates are confined to the adventitial layer.

Given the critical role of the adventitia as the port of entry and the location of vasDC, such infiltrates, in general, signal a developing arteritis. Thinning of the media results from loss of

VSMC. Fragmentation of the internal elastic lamina is considered a typical finding.

Multinucleated giant cells have a tendency to accumulate at the media-intima border.

Neoangiogenesis supports the outgrowth of new microvessels in the hyperplastic intima.

Classically, such newly formed vessels are arranged in a circular formation.

Temporal artery biopsy is offered as an outpatient procedure. Ideally, 2-3 cm of the

temporal artery are harvested. The arterial specimen is cut into sections to allow for multiple sampling sites and the identification of so-called “skipped lesions.” The diagnostic yield of a

technically adequate biopsy exceeds 90% (52).

Frozen sections are useful for a preliminary diagnosis. If the diagnosis remains ambiguous, a second-side biopsy can be performed. However, sampling of the second-side is helpful in only a small subset of patients and it may be worthwhile to spare the opposite side for cases in which clinical symptoms continue and worsen or for patients who present with clinical evidence for recurrent disease many years after initial diagnosis.

Clinically, the most challenging patients are those with a negative biopsy (Table 5).

Guided by the fear of missing GCA, many physicians make the diagnosis of GCA when clinical symptoms are suspicious and treat with high-dose corticosteroids. Persistence of nonspecific clinical features, such as headaches, myalgia or elevated inflammatory markers, may prompt

long-term treatment in the absence of a tissue diagnosis. Given the considerable risk of side

effects, establishing a definite diagnosis is essential. Similarly, omitting the tissue biopsy in

patients that appear to be “classical” can complicate an unambiguous diagnosis. If such patients

present with an unusual course, have symptoms suspicious for flaring disease or are treatment-

resistant, chances of obtaining a positive temporal artery biopsy are considerably diminished

after long-term steroid therapy.

A subset of patients has a negative temporal artery biopsy, yet have GCA. In a cohort of cases diagnosed with large vessel involvement based on angiography, only 50% of patients had a positive temporal artery biopsy (27). Temporal artery biopsy may aid diagnosis in other

vasculitides, including polyarteritis nodosa, ANCA-associated vasculitides and amyloidosis.

Non-GCA arteritides often have atypical histomorphological features, such as fibrinoid necrosis

prompting the search for alternative diagnoses.

As observed in the sequential temporal artery study (4), treatment with systemic steroids

up to one year may not be sufficient to eliminate the vascular infiltrates. Biopsy as a high-yield

diagnostic procedure should be encouraged in all patients coming to clinical attention with possible GCA even after initiation of therapy. The rate of false negative biopsies can be expected to be higher in treated patients and tissue should be harvested as early as possible, ideally in the untreated patient.

Laboratory diagnosis

Laboratory testing offers rapid, easily obtainable information relevant to diagnose and treat

GCA. Frequent findings are those of a highly activated acute phase response (53), a hypochromic/normochromic anemia, thrombocytosis and abnormal liver function (elevated alkaline phosphatase). All of these abnormalities are compatible with excess production of the proinflammatory cytokine IL-6 (54).

In GCA, IL-6 is released by circulating macrophages and innate cells in the vascular infiltrates (32). IL-6 sustains the acute phase response by stimulating hepatocytes which release

C-reactive protein and other acute phase proteins, including fibrinogen, alpha-macroglobulin, and serum amyloid protein. CRP is of clinical utility as it is a robust indicator of how active the acute phase response is. In general, it correlates closely with production of IL-6.

Serum biomarkers of acute-phase reactivity are nonspecific but have diagnostic value in monitoring individual patients and contribute information about therapeutic responsiveness and requirements for immunosuppression. Elevated ESR and CRP should not be the sole findings upon which a diagnosis of GCA is being made and therapy is initiated. A subset of patients has normal measurements for CRP and ESR despite findings of active vasculitis on biopsy.

No disease-specific autoantibodies have been identified that aid in the diagnosis of GCA but negative autoantibody results can be helpful in excluding other autoimmune syndromes that have overlapping clinical features and could be mistaken as GCA. Autoantibody panels are useful in adding to the diagnosis of ANCA-associated vasculitis, rheumatoid arthritis or systemic lupus erythematosus. The constitutional symptoms of GCA can occur in malignancy, lymphoproliferative disease and systemic infections

Imaging-based diagnostic tools In the majority of patients with large vessel vasculitis, the diagnosis relies on imaging, collecting

information about the vessel lumen and vascular flow. Imaging modalities offer an easy and fast

way to map the vascular involvement pattern and monitor for dynamic changes. Computed

tomography angiography (CTA) allows for high-resolution evaluation of affected vascular

territories with relatively short examination times. However, there is radiation exposure and patients are exposed to potentially nephrotoxic contrast media. Magnetic resonance imaging

(MRI) and MR angiography (MRA) are considered to be superior in analyzing flow conditions in the small capillaries of the vasa vasorum, potentially providing insights into the inflammatory burden. Attempts to develop MR-based monitoring tools to quantify disease activity have been relatively disappointing. While highly sensitive, this method may not permit distinction between

chronic remodeling of the vessel wall versus fresh inflammatory activity. Great effort is currently

invested into developing the means to measure metabolic activity in situ. Positron emission

tomography (PET) detects inflammation through the uptake of fluorodeoxyglucose (FDG) into

inflammatory cells. Improved technology to combine metabolic analysis with high-resolution

structural analysis will be needed to improve the clinical application of these methods in patients

with both newly diagnosed and chronic GCA.

Being a noninvasive, easily accessible technique without radiation exposure, high- resolution ultrasound (US) has attracted considerable attention as a diagnostic tool. This method should be the first choice for screening and follow-up of patients undergoing reconstructive vascular surgery. Utilizing US to assess the temporal artery, at least to seek out areas with a higher probability of inflammatory wall lesions, seems straightforward. However, comparative studies evaluating the sensitivity and specificity of US versus biopsy have revealed considerably low sensitivity (75%) as well as insufficient specificity (83%) (55). Age-related changes in normal arteries may make it more challenging to detect inflammation-associated alterations, further limiting the diagnostic utility of US. With further development of imaging modalities, it may eventually be possible to reach the molecular level and detect vessel wall invasion by inflammatory cells sufficient to initiate and sustain vasculitis. Currently, no method has as high a yield as temporal artery biopsy. Given the risks of treatment-related side effects, imaging tools remain inferior in establishing a diagnosis of temporal arteritis but are instrumental in diagnosing GCA aortitis.

Treatment

Corticosteroids are highly effective in treating GCA and provide prompt and impressive relief of headaches, constitutional symptoms and PMR. Patients report dramatic improvement often within 24-48 hours of initiating therapy. While acute management is straightforward, considerable uncertainty centers on chronic therapy and how to deal with emergencies, such as vision loss or CNS ischemia (Table 6). All extravascular manifestations are explicitly responsive to steroid-mediated immunosuppression. Adaptive immune responses appear to be less steroid- responsive with persistent IFN-γ production, sustaining smoldering inflammation in the vessel wall. Whether suppression of such persistent immunity is required and beneficial for the patient is currently not known. Considering the age of the affected patients retaining TH1 immunity may actually be advantageous for protection from infectious complications. The standard therapeutic regimen begins with oral prednisone given at 0.5-1 mg/kg (30-60 mg total) and should be

continued until clinical and laboratory response is achieved. Patients require close monitoring

during early therapy to assess for treatment responsiveness. If tolerated, steroids are

subsequently tapered by 10% every 2 weeks. Most patients are able to switch to doses below

20 mg per day after 3-5 months and over the subsequent year the majority of patients can slowly continue tapering and discontinue immunosuppression. Laboratory monitoring is helpful in monitoring the acute phase response and clinical follow-up should focus on assessing involved organ systems to detect disease recurrence or involvement of other organ systems.

Recent vision loss or evidence of progressive ischemia is often managed with pulse steroid induction therapy, followed by oral corticosteroids. Pulse steroid therapy has been compared with oral standard dosing (56). The overall flare rate was lower in the patients that received high-dose treatment early in the disease course. Also, patients in the pulse therapy arm were able to discontinue steroids earlier in the clinical course.

The most frequent clinical manifestation of flaring disease is recurrence of PMR. This is usually managed with a minor increase in the steroid dose. While the majority of patients are able to come off steroids after 1.5-2 years, a subset of patients requires long-term therapy but usually only very small doses of prednisone (< 5 mg/day) are required.

Patients should be informed about sign/symptoms of disease reactivation and should be familiar with steroid side effects. Monitoring of blood pressure and blood glucose is mandatory during the high-dose period. Visual loss is infrequent in treated patients but should be addressed with pulse steroid therapy to revert or minimize ischemic tissue damage.

Acetylsalicylic acid (aspirin) should be added to the therapeutic regime unless contraindicated.

Benefits may derive from both improved blood flow due to anti-platelet activity as well as anti- inflammatory effect (29).

Adjuvant therapy should address bone-sparing management, including monitoring of bone mineral density, calcium supplementation, optimization of Vitamin D levels, and bisphosphonates as indicated. Adjusting the diet and maintaining physical activity should be an integral part of the therapeutic management plan.

A major therapeutic challenge derives from the fear of missing the diagnosis of GCA and the intent to “be on the safe side” which encourages overutilization of corticosteroids. Benefits and risks need to be carefully weighed.

Steroid-sparing immunosuppressants

Not infrequently, the question is raised whether patients should receive a steroid-sparing agent.

Also, a failure to normalize the sedimentation rate is sometimes considered a sign of steroid resistance and alternative treatments are sought. Methotrexate (MTX) and anti-TNFα antibodies

(Infliximab) have been tested in placebo-controlled trials and failed to demonstrate a beneficial effect (57, 58). Adjunct MTX therapy for duration of 48 months has a small, clinically questionable effect in females less than 75 years of age. Information about other immunosuppressants derives from uncontrolled trials and, currently, no convincing evidence for a steroid-sparing effect has been presented. Guided by preliminary reports, clinical studies exploring blockade of the IL-6 axis are underway (59). Also, inhibitors of costimulatory pathways applied in other autoimmune diseases are currently being tested in patients with GCA.

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2011; 141:w13156. Table 3. Typical Clinical Features of GCA Cranium Headache, scalp tenderness, jaw claudication Eye Vision loss; painless, sudden, partial or complete Diplopia Ophthalmoplegia Systemic Fever, malaise, anorexia, depression, weight loss, night sweats Musculoskeletal Polymyalgia rheumatica CNS Stroke, dizziness, vertebrobasilar insufficiency Central vision loss Extremities Upper extremity claudication Pulselessness Asymmetric blood pressure Aorta Aortic insufficiency Aortic aneurysm, dissection, rupture

Table 4. Neuro-Ophthalmic Manifestations of Giant Cell Arteritis Anterior ischemic Most common. Can be bilateral. From hypoperfusion or occlusion of the short optic neuropathy posterior ciliary arteries. May be associated with cilioretinal artery or choroidal ischemia. Retinal vascular Hypoperfusion or occlusion of the central retinal or ophthalmic artery. Rarely, involvement can present as branch retinal artery occlusion. Associated with cotton wool spots. Posterior ischemic Hypoperfusion of the ophthalmic and orbital arteries which supply the optic neuropathy posterior part of the optic nerve. Amaurosis fugax Transient hypoperfusion. Signifies impending vision loss. Present in about 1/3 of patients. Acute submacular Hypoperfusion in the lateral posterior ciliary artery. Macula is a watershed choroidal ischemia zone. Can be bilateral. Ocular ischemic Conjunctival injection, dilated episcleral vessels, corneal edema, iris syndrome (anterior) neovascularization, iris ischemia, anterior chamber cell and flare, decreased intraocular pressure. Ocular ischemic Dilated retinal vessels, microaneurysms, hemorrhages, cotton wool spots, syndrome (posterior) retinal neovascularization. Diplopia Extraocular muscle ischemia from occlusion of muscular arteries or ischemic damage of cranial nerves 3, 4, 6 or brainstem ischemia.

Table 5. Diagnostic Challenges in GCA Biopsy-negative If technically adequate, temporal artery biopsy has a very high GCA probability for obtaining the correct diagnosis. GCA without temporal artery involvement can occur, but is rare. The threshold for diagnosing Bx negative GCA should be high. Non-vasculitic Clinical features of GCA are often nonspecific (headaches, malaise, elevated ESR) and occur much more frequently in nonvasculitic syndromes. Seeking tissue confirmation is mandatory. Large vessel GCA Patients with GCA aortitis and GCA of primary branches of external carotid artery may not have temporal involvement. Often, Dx is based on vascular imaging. Distinction between atherosclerotic and vasculitis disease can be difficult. Lack of disease- Current biomarkers (ESR, CRP, IL-6) all reflect acute phase specific biomarker response and are nonspecific. Novel biomarkers related to the immune pathogenesis of GCA are in development.

Table 6. Therapeutic Challenges in GCA Management of It has not been formally tested whether pulse acute ischemic corticosteroids are superior to standard therapy. events (vision loss) Management of PMR responds to minimal increases in steroids. disease flares Headaches may not respond and may not indicate flare. Management of Treat the patient; do not treat the laboratory. elevated ESR and Rule out alternative cause of acute phase response. CRP Management of In the absence of clinical findings, indicating disease chronic GCA reactivation, complete suppression of ESR and CRP may not be necessary. Lack of disease Few disease flares present with objective findings of specific biomarkers disease reactivation; recurrence of nonspecific symptoms (e.g., headaches) is frequent. Fear of irreversible vision loss encourages overutilization of steroids.