Clinical manifestations

Presentation and course

Diagnostic criteria. According to the American College of Rheumatology 2022 criteria, patients with giant cell arteritis must be aged 50 years or older at diagnosis and have a cumulative score of 6 or more points across the following 10 items (66):

Non-ophthalmic manifestations. Giant cell arteritis can affect both the head (more medium-sized) vessels as well as the trunk (larger) vessels and manifest with various respective symptoms.

Headache has been reported in up to 70% to 80% of patients (79), reinforcing the fact that the absence of headache does not preclude this diagnosis. Momentary stabbing or ice pick headache accompanying new-onset persistent headache in an elderly person may also be an indicator of giant cell arteritis (73).

Diffuse tenderness and ulceration of the scalp, face, or oral mucosa results from ischemia secondary to widespread arteritic involvement of extracranial vessels. In elderly patients, these signs strongly suggest giant cell arteritis. Patients should be asked if they are experiencing new tenderness when they comb their hair, or if a hat or the temple portion of their glasses is causing new sensitivity to touch there. Scalp ulceration and necrosis may also result from external carotid artery ischemia but is often misdiagnosed as a herpes zoster infection. Lingual ischemia and necrosis from arteritis of the lingual artery, the first branch of the external carotid artery, have also been associated with giant cell arteritis (12) but are often misdiagnosed as glossitis.

Abnormalities of the temporal artery include prominence, irregular contour, tenderness, and a diminished or absent pulse (51).

Jaw claudication is virtually pathognomonic of giant cell arteritis. Because of collateral flow, both internal and external carotid artery systems must be affected to produce this symptom. It must be distinguished from other causes of pain in the lower face and oral cavity. The pain of jaw claudication builds progressively with chewing, owing to ischemia in the domain of the maxillary artery, which supplies the masseter muscles. In contrast, dental pain can occur even with the first bite and with any jaw movement, secondary to pathology in the temporomandibular joint. One proposed method of evaluating for jaw claudication is the “chewing gum test.” Patients are asked to chew gum for several minutes at a rate of one chew per second. A delay in the onset of jaw pain of 2 minutes suggests claudication (47). As with claudication elsewhere, the pain is relieved with rest and usually requires several seconds to dissipate after chewing ceases.

Other non-ophthalmic manifestations of giant cell arteritis include recent-onset fever, leukocytosis, anemia, depression, fatigue, and weight loss. These nonspecific constitutional symptoms are often dismissed by patients and their caregivers as natural consequences of aging. Lower back pain can be the presenting symptom of abdominal aortic arteritis, a finding identifiable on FDG-PET scan (22; 45).

Ophthalmic manifestations. According to a large review, vision loss occurs in one third to one half of patients with giant cell arteritis (25). It is usually monocular at outset and often preceded by non-ophthalmic symptoms by weeks to months. Multiple attacks of transient monocular vision loss typically occur ahead of persistent vision loss. Transient or constant diplopia, a sign of ischemia of oculomotor nerves or extraocular muscles, may occur as an isolated manifestation or precede vision loss (09). Up to 20% of patients can present with vision loss without any other systemic symptoms (“occult giant cell arteritis”) (11).

Vision loss in the initially unaffected eye typically develops within days to weeks of the first eye’s involvement. The goal of timely therapy is to prevent vision loss in that eye and to minimize the extent of vision loss in the initially affected eye.

The most common cause of vision loss in giant cell arteritis is ischemic optic neuropathy. Ophthalmoscopic examination of the affected eye reveals optic disc swelling, often pallid because of extreme infarction. The ischemia derives from reduced perfusion in the posterior ciliary arteries. Very rarely, the optic disc may appear normal on ophthalmoscopy.

An alternative cause of vision loss in giant cell arteritis is central retinal artery or cilioretinal artery occlusion. In central retinal artery occlusion, ophthalmoscopy will disclose a “cherry red spot,’’ or retinal whitening around the fovea with central preservation of its reddish color. The simultaneous occurrence of ischemic optic neuropathy and central retinal artery occlusion in the same eye or in the fellow eye is held to be pathognomonic of giant cell arteritis (31; 37). Cilioretinal artery occlusion will appear as a patch of retinal whitening extending from the optic disc toward the fovea. In such cases, visual acuity may be preserved, but the visual field will be abnormal.

Polymyalgia rheumatica. Polymyalgia rheumatica, like giant cell arteritis, almost exclusively affects individuals over the age of 50 years. Common presenting symptoms include pain and stiffness in the shoulder or pelvic girdles. Pain and limited motion of the axial skeleton, including the cervical and thoracic spine, are also common. Pain and stiffness are often worse on rising in the morning, with some improvement in mobility as the day proceeds. Onset may be insidious or acute. Severity of symptoms can be asymmetric, but the disorder is invariably bilateral. There may be mild swelling of the shoulders and distal joints in the extremities, but there are no visible articular deformities. Polymyalgia rheumatica may have a range of atypical presentations, including peripheral synovitis, mild weakness, and a normal sedimentation rate. The duration of polymyalgia rheumatica symptoms has ranged from 6 months to as long as 14 years in patients who have developed the clinical manifestations of giant cell arteritis.

Prognosis and complications

Visual loss is irreversible. Relapses in non-ophthalmic manifestations are more frequent than relapses in ophthalmic manifestations. They are said to occur in half of treated patients, most often within the first 2 years of diagnosis. The rate of relapse is more often related to an abbreviated duration of steroid therapy than to the initial dose (34; 54). In patients with relapses, the time required to achieve maintenance prednisone dosages was significantly longer, and the cumulative prednisone dose required during the first treatment year was significantly higher in comparison to those without relapse (01; 03).

There is no consistently documented decrease in life expectancy in giant cell arteritis compared to age-matched controls (56; 07; 06). The exceptions are patients who have developed aortic dissection, which markedly increases mortality (62). Death attributed to complications of giant cell arteritis is rare but has been reported from vertebral artery occlusion and myocardial infarction (80). In one study, prophylactic statin treatment reduced the incidence of cardiovascular hospitalizations (69).

The incidence of aortic aneurysm is dramatically increased in giant cell arteritis. Hypertension and polymyalgia rheumatica with a marked inflammatory response at the time of diagnosis were the most predictive characteristics for later development of aortic disease (24). Surgical repair of arteritic aortic aneurysms can be carried out successfully (04; 86).

Clinical vignette

A 78-year-old woman presented with a 2-month history of malaise, poor appetite, and unintentional weight loss. During the previous few weeks, she experienced frequent severe vertex headaches that awoke her from sleep. She experienced scalp pain when combing her hair.

A dentist who was consulted for jaw pain found no dental cause. On further questioning, she specified that the pain in her jaw would start around 1 minute after she began to chew solid food and grow in severity over the following minute to the point that she would have to stop chewing. When she stopped chewing, the jaw pain would subside after 15 to 20 seconds. She reported pain in her hips and stiffness of her legs that made walking difficult.

On the day of her office visit, she recalled a recent 1-minute episode of seeing a “shade pulled down over my left eye.”

Examination revealed a frail-looking elderly woman in mild distress. There was evidence of recent weight loss, and she had difficulty rising from the waiting room chair. Blood pressure was 180/95 in the right arm and 140/80 in the left arm. There was a loud left subclavian bruit. An ulcer was noted in the buccal mucosa next to the left lower teeth. There were no localizing findings on neurologic examination. Her gait appeared painful and stiff, and she held her head rigidly in the straight-ahead position as she walked. When attempting to bend her neck forward to either side, she winced with pain. The examiner was able to move her head and neck in all directions passively, but it required slow and steady movement to minimize pain. Active and passive flexion of either leg caused pain in the hips and upper thighs.

Visual acuity was 20/20. There was no subjective red desaturation with either eye on viewing a red bottle cap. Visual fields were full on confrontation testing. The eyes had normal excursions and were aligned. Pupils were normal in size and reactivity. Ophthalmoscopy was normal.

Complete blood count revealed moderate normochromic, normocytic anemia, and the Westergren erythrocyte sedimentation rate was 89 mm/hr. Carotid duplex blood flow examination showed insignificant stenosis on either side, but ocular pneumoplethysmography showed reduced pulse amplitude in both eyes. Based on a presumptive diagnosis of giant cell arteritis, intravenous methylprednisolone 1 gram daily was initiated for 3 days.

Temporal artery biopsy revealed areas of intimal proliferation and fragmentation of the internal elastic lamina. Adjacent to disrupted segments of the elastic lamina, the media was infiltrated with lymphocytes, plasma cells, epithelioid cells, and multinucleated giant cells. These findings were interpreted as consistent with active giant cell arteritis.

The patient was discharged on prednisone 1 mg/kg/day. Within 48 hours of treatment initiation, she was free of pain, and within 2 weeks her body weight and strength had nearly recovered to premorbid status. After 1 month of steroid therapy, the prednisone dosage was slowly tapered in decrements of 5 mg each month.

During follow-up of 2 years, the steroid dose was eventually tapered off without clinical consequences. The potentially dire consequences of giant cell arteritis were averted by early diagnosis and treatment.

Biological basis

Etiology and pathogenesis

The pathogenesis of giant cell arteritis is believed to be autoimmune. The cellular infiltrate is dominated by mononuclear cells and multinucleated giant cells (49). Monocyte to macrophage differentiation plays an important role (20). Two pathogenetic mechanisms are postulated (92; 18). One mechanism is mediated by Th17 T-cells that produce interleukin 17, which leads to systemic inflammation manifest as steroid-responsive fever, malaise, anorexia, and headache. The other mechanism is mediated by Th1 T-cells that produce interferon-gamma and steroid-resistant vascular wall inflammation.

Varicella zoster virus antigen and DNA have been found in localized patches of arteries that were called “skip areas” in pathologically negative temporal artery specimens examined in patients clinically diagnosed with giant cell arteritis. Re-examination of those virus-positive segments demonstrated pathologic findings typical of giant cell arteritis (59). Later reports have cast doubt on the methodology of these studies (64; 74).

Epidemiology

Analysis of epidemiologic studies in giant cell arteritis is hindered by the variability of diagnostic criteria and differences in population bases. Incidence is higher in the United States, Scandinavia, and northern Europe than in southern Europe (78). Women account for 70% of cases (39). Genetic factors may be important in view of a predilection for Caucasians and an association with the HLA-DR4 genotype.

In an Olmsted County population-based study, the age-adjusted and sex-adjusted annual incidence of vision loss from giant cell arteritis among persons at least 50 years old was 1.3 per 100,000 population (11). The authors postulated that this high incidence reflected that 90.3% of the patients were Caucasian. In that study, 80% of patients with permanent vision loss were women, in accord with other reports. The highest incidence figures of 29.0 per 100,000 (39.9 in women and 16.3 in men) come from South Norway (26).

Prevention

Although vision loss cannot be reversed, it can often be prevented with high-dose corticosteroid treatment. Confronted with vision loss in one eye, clinicians may be able to forestall visual damage in the other eye. Once the diagnosis of giant cell arteritis is secured, the disease must be managed by prolonged treatment with steroid or steroid-sparing agents to prevent further infarction.

Differential diagnosis

Confusing conditions

In older patients with transient vision loss, giant cell arteritis should be in the differential diagnosis. Once persistent vision loss has occurred from ischemic optic neuropathy or retinopathy, the differential diagnosis includes non-arteritic ischemic optic neuropathy (NAION), infection, cancerous infiltration, compression by mass lesions, and alternative inflammatory conditions, such as myelin oligodendrocyte glycoprotein antibody disorder and neuromyelitis optica spectrum disorder.

The principal challenge is to distinguish giant cell arteritis from NAION. NAION typically occurs in patients over the age of 40 with an arteriosclerotic profile that predisposes to small vessel disease. Patients with NAION lack the non-ophthalmic manifestations of giant cell arteritis and polymyalgia rheumatica. Visual loss is less profound than in giant cell arteritis and is not usually preceded by transient vision loss episodes. Optic disc swelling is less pallid, and the optic discs usually have a small cup-to-disc ratio. There should be no evidence of retinal ischemia. MRI will disclose no abnormalities of the optic nerves except enhancement of the affected optic disc and sometimes ischemic cerebral white matter focal signal abnormalities. NAION is usually unprovoked but may also occur after an episode of systemic hypotension, middle fossa irradiation, neurosurgery, cardiac surgery, or prone position spine surgery.

Associated or underlying disorders

Giant cell arteritis may occasionally be part of a panuveitis (70) or an orbital inflammatory syndrome that presents with diplopia, mildly reduced ocular excursions, and periocular pain (15). It has been documented as the most common cause of fever of unknown origin in the elderly (84). Large artery giant cell arteritis may present with ascending aortic aneurysm (27) or as subclavian artery stenosis (76).

Diagnostic workup

The most frequently used tests in the diagnostic workup of giant cell arteritis include Westergren erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complete blood count, and temporal artery biopsy. Mild anemia is common, as are various degrees of leukocytosis, sometimes with a left shift, as well as thrombocytosis.

Marked elevation of ESR is the most common laboratory abnormality, but it is nonspecific. In one study, the laboratory criteria most strongly suggestive of giant cell arteritis were CRP above 2.45 mg/dl and ESR of 47 mm/hr or more. CRP was more sensitive (100%) than ESR (92%) for detection of giant cell arteritis. The combination of ESR and CRP above the cutoff values gave the best specificity (97%) (32). However, a normal ESR or CRP does not rule out giant cell arteritis when other features are highly suggestive.

The ESR in giant cell arteritis and polymyalgia rheumatica is often greater than 100 mm/hr. Other rheumatologic disorders, stroke, coronary artery disease, renal disease, and cancer may also elevate ESR to that degree. Accordingly, studies have sought to identify more distinct biological markers of clinical activity and to differentiate giant cell arteritis from other rheumatological disorders. Elevation of anticardiolipin antibodies was found in approximately 50% of patients with giant cell arteritis and polymyalgia rheumatica. There was no significant correlation between the presence of antiphospholipid antibody and ischemic events (21).

Biopsy remains the gold standard in the diagnosis of giant cell arteritis. The pathology consists of a granulomatous inflammatory reaction concentrated at the innermost part of the vascular media near zones of fragmented and reduplicated internal elastic lamina with adjacent intimal proliferation, at times leading to complete occlusion of the lumen. Giant cells are, however, not necessary for the diagnosis.

There are many cases of active giant cell arteritis in which an entire temporal artery or segments of the artery are not involved—so-called “skip lesions” (43). To compensate for the patchy nature of the pathologic process, both the American College of Rheumatology and British Society for Rheumatology suggest a “long-segment biopsy” of at least 1 cm (52; 57). Although it has been standard practice, the pathologic examination of a temporal artery specimen at multiple levels does not increase the diagnostic yield of the test. The authors recommend that such examination be reserved for cases with high clinical suspicion if initial inspection is negative (10).

The issue of whether to biopsy one or both temporal arteries remains controversial. In a large 2010 survey of U.S. ophthalmologic subspecialists, 61% favored initial unilateral temporal artery biopsy; 18% favored bilateral biopsy; and 16% favored bilateral biopsy only if one biopsy was negative but clinical suspicion was high (77). Rheumatologists were 4.5 times more likely to favor initial bilateral biopsy than ophthalmologists. Most respondents believed that biopsy results would have high diagnostic accuracy if performed within 2 weeks of starting corticosteroid treatment.

The consensus opinion is that each physician must contextualize negative biopsy results based on the degree of clinical suspicion, the adequacy of the specimen, and the degree to which the biopsy material is pathologically examined. Most authorities also agree that if clinical suspicion is high enough, patients should be treated even in the face of a negative biopsy in one temporal artery or both.

Because there is also the possibility of false negatives with temporal artery biopsies and this testing requires a surgical procedure, alternatives have been explored. A low score on a giant cell arteritis risk calculator, or multivariate prediction model, is proposed as a way to decrease the need for a biopsy (40; 41). This model has been validated for the following variables: age, gender, new-onset headache, clinical temporal artery abnormality, jaw claudication, ischemic vision loss, diplopia, CRP, and platelet count.

Temporal and axillary artery ultrasound, MRI, MR angiography (MRA), and PETCT are frequently used in place of biopsy or as adjuncts to it (29). The diagnostic sonographic sign of giant cell arteritis is a noncompressible hyperechoic wall signal (“halo sign”) secondary to thickening of the intima-media complex of the superficial temporal or axillary arteries (42; 67). The European League Against Rheumatism (EULAR) includes temporal artery and axillary artery ultrasound as a diagnostic guideline (16). However, ultrasound results continue to show a sensitivity range between 9% and 100% and a specificity range from 66% to 100%, perhaps reflecting differences in case selection and sonographic skill and technique (13; 33; 60).

MRI and FDG-PET are alternative diagnostic tools. Vascular wall inflammation causes increased vessel wall thickness and mural enhancement (08). Temporal artery MRI and FDG-PET have been gradually adopted in clinical practices and included in the European League Against Rheumatism (EULAR) guideline as an alternative in cases in which ultrasound is not available or is inconclusive (17; 16; 68). The diagnostic accuracy of 3D T1-weighted (“black-blood”) MRI was deemed adequate in the diagnosis of giant cell arteritis (72; 90). A European multicenter prospective study found contrast-enhanced MRI of superficial temporal arteries to be 78.4% sensitive and 90.4% specific in diagnosing giant cell arteritis. Diagnostic accuracy declined after 5 days of steroid treatment (44). A meta-analysis reported a pooled sensitivity of 73% and a specificity of 88% for MRI diagnosis of giant cell arteritis (19). Another study found high-resolution MRI and color-coded duplex ultrasonography of the temporal arteries to be more sensitive than temporal artery biopsy in diagnosing giant cell arteritis and that sensitivity rapidly declined during the first few days after initiation of steroid treatment (30).

Large vessel involvement is present in up to 80% of patients with giant cell arteritis (46). Because of the predominantly large-vessel involvement, patients may present with a negative temporal artery biopsy. CT or MR angiography (MRA) is the diagnostic procedure of choice for suspected large vessel arteritis in giant cell arteritis. MRA of large vessel walls normalized in only one third of the patients who had sustained clinical and laboratory remission (71).

A prospective double-blind, cross-sectional study evaluated the diagnostic accuracy of positron emission tomography/computed tomography (PET/CT) of the head, neck, and chest for determining a diagnosis of giant cell arteritis (75). Compared to temporal artery biopsy, the sensitivity of PET/CT was 92% and specificity was 85%. The negative predictive value was 98%. Compared to clinical diagnosis, PET/CT had a sensitivity of 71% and specificity of 91%. The authors suggested that the high diagnostic accuracy of a PET/CT protocol would support its use as a first-line test for giant cell arteritis. They also concluded that PET/CT had benefit over temporal artery biopsy in detecting aortitis as well as imitators of vasculitis.

Algorithms incorporating multiple imaging modalities may achieve higher sensitivity and specificity for the diagnosis of giant cell arteritis. MRI, MRA, FDG-PET, and PET/CT for both large vessel and cranial artery evaluation can be performed based on availability and cost. In cases of visual loss or diplopia, fluorescein angiography can demonstrate involvement of multiple vascular territories in support of a diagnosis of giant cell arteritis. Other techniques to evaluate choroidal blood flow noninvasively, including optical coherence tomographic angiography, are in development (53).

Management

The standard recommendation for initial treatment of patients without ophthalmic signs is to initiate prednisone at a dosage of 40 to 80 mg/day. This dose is usually maintained for 3 to 4 weeks and then gradually reduced over months, together with monitoring for reemergence of headache, jaw claudication, and other less specific symptoms, or rising levels of ESR and CRP. Sometimes side effects require that the dose be reduced earlier. For polymyalgia rheumatica without signs of giant cell arteritis, patients can be safely managed with prednisone 15 mg/day or less from the outset. They seem to be at low risk for ischemic complications (14).

For patients with vision loss or diplopia attributable to giant cell arteritis, intravenous pulse methylprednisolone therapy is often initiated at 1 gm/day. This is supported by the results of a randomized placebo-controlled study that demonstrated sustained remissions and a lower median daily dose of prednisone at 78 weeks after treatment onset among patients who received intravenous methylprednisolone at 15 mg/kg of ideal body weight per day (58).

Based on clinical manifestations, giant cell arteritis may remain active for at least 1 year after diagnosis and even for an average of 3 to 4 years (48). Therefore, tapering prednisone too early commonly results in recurrence of headache and other symptoms that herald possible ischemic complications. Oftentimes it requires multidisciplinary input to best determine if vague symptoms reflect a recurrence as well. Once confirmed as a recurrence, symptoms can usually be managed by reestablishing the original high dose of steroid therapy, followed by another tapering interval, with close monitoring. This approach is, however, cumbersome and does not provide guaranteed protection from ischemic complications. It is, therefore, preferable to taper slowly and maintain a low corticosteroid or steroid-sparing dose for more than 1 year to avoid reactivation of the disease. Alternate-day steroid therapy is not sufficiently protective.

Long-term steroid therapy is not without significant side effects. One of the most serious complications is osteoporosis. Various authors have recommended prophylactic treatment for osteoporosis with calcium and phosphate compounds, but there has been little proof of their effectiveness. In one report, the risks of diabetes mellitus and bone fracture were two to five times greater among patients treated for polymyalgia rheumatica than among untreated age-matched subjects (23). Proportional hazards modeling showed that the following three factors independently increased the number of adverse events: (1) advanced age at diagnosis, (2) cumulative dose of prednisone at least 1800 mg, and (3) female sex. Treatment should include antibiotic prophylaxis against Pneumocystis jirovecii pneumonia (PCP).

There has been interest in adding immunomodulatory drugs to the treatment regimen to reduce steroid dose requirements. The beneficial effects of tocilizumab, an IL-6 inhibitor, as a corticosteroid-sparing intervention was first demonstrated in 2016 (89; 83). A subsequent prospective trial studied the efficacy of tocilizumab as an adjuvant treatment to systemic corticosteroids in 251 patients with newly diagnosed or relapsing giant cell arteritis (83). The tocilizumab groups had lower cumulative median prednisone doses relative to the placebo group. Serious adverse events were also less common in the tocilizumab groups. A contraindication to starting tocilizumab therapy is a history of diverticulitis, which would predispose to intestinal perforation. In 2017, tocilizumab became the first FDA-approved medication to treat giant cell arteritis (83). A retrospective, single-center analysis found that tocilizumab improved clinical symptoms, including vision loss, in patients with giant cell arteritis and polymyalgia rheumatica (87; 88). The adverse events attributed to corticosteroids were comparable before and after tocilizumab treatment.

The combination of tocilizumab and a prednisone taper was effective in maintaining clinical remission in the Giant Cell Arteritis Actemra (GiACTA) trial (81). In an open-label extension phase of the GiACTA trial, 42% of patients remained in remission without need for tocilizumab or corticosteroids 2 years after tocilizumab cessation (82). However, the study also concluded that for patients who experience relapse, it is important to include prednisone in treatment to prevent further vision loss. The long-term effect of adding tocilizumab in the treatment of giant cell arteritis remains under study (02).

Other immunomodulatory agents have not emerged as useful in the treatment of giant cell arteritis. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate for the treatment of giant cell arteritis did not demonstrate benefit (35). Cyclophosphamide and azathioprine, studied in small cohorts of patients for their effectiveness as steroid-sparing agents, have been of uncertain benefit (50). Etanercept, a tissue necrosis factor inhibitor, reduced the cumulative dose of corticosteroid required to keep giant cell arteritis in clinical remission over the course of a 1-year period, but the contribution of etanercept did not reach statistical significance (55).

In giant cell arteritis involving large arteries, new therapeutic approaches are being sought for the steroid-resistant inflammatory process, possibly involving manipulation of specific inflammatory cytokines and other inflammatory mediators. A prospective study of 25 patients with biopsy-proven giant cell arteritis demonstrated plasma interleukin-6 (IL-6) to be a much more sensitive measure of disease activity than ESR (91).

Outcomes

See prognosis and complications.

Special considerations

Pregnancy

All of the patients are beyond their childbearing years.

Anesthesia

There is no indication of interaction between giant cell arteritis and anesthetic agents.