INTRODUCTION — Giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis) is the most common systemic vasculitis in North America and Europe [1,2]. GCA affects only older adults, with a peak incidence between ages 70 and 79 [3]. Many of the clinical features of the disease result from vascular inflammation of the small extracranial branches of the carotid arteries. The disease can be generalized, however, and involve the aorta, leading to aneurysms of the thoracic and abdominal aorta, and large arteries, resulting in ischemic symptoms of the extremities.

The treatment and prognosis of GCA are reviewed here. The clinical manifestations and diagnosis of this disorder are discussed separately. (See "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell arteritis".)

MANAGEMENT

Overall approach

Patients with positive biopsy or imaging — High-dose systemic glucocorticoids are the mainstay of therapy and should be instituted promptly once the diagnosis of giant cell arteritis (GCA) is strongly suspected, especially in patients with recent or threatened visual loss. A temporal artery biopsy or other diagnostic procedure should be obtained as soon as possible, but treatment should not be withheld while awaiting the performance or results (see "Diagnosis of giant cell arteritis"). In patients who have developed or are at high risk for adverse effects of prednisone, glucocorticoid-sparing strategies include the addition of tocilizumab (TCZ) or methotrexate (MTX). (See 'Glucocorticoid-sparing agents' below.)

Patients with negative biopsy and imaging — In cases where the clinical scenario for GCA is compelling but the diagnostic workup is negative, the diagnosis of GCA may be arrived at on clinical grounds. Workup should have included negative temporal artery biopsy or biopsies and/or color-coded duplex ultrasonography, and, as indicated, imaging studies for large vessel involvement. Alternative diagnoses (eg, malignancy and infection) should have been excluded. If both biopsy and extensive imaging tests are negative, a diagnosis of GCA is not likely, and the decision to retain this diagnosis in the face of such a workup should be carefully considered.

Patients with a clinical but unproven diagnosis of GCA are generally treated the same as patients with documented GCA. In patients with only a clinical diagnosis of GCA, the management of recurring headache, constitutional symptoms, or elevations of the acute phase reactants during the course of a glucocorticoid taper can be problematic.

Systemic glucocorticoids

Efficacy — Though never studied in a placebo-controlled manner, the effectiveness of glucocorticoids for the management of GCA has been well established by decades of clinical experience. Glucocorticoids produce prompt improvement in systemic symptoms and signs and, if expeditiously administered, can prevent the most sinister potential complication of GCA, that of sight loss.

The efficacy of glucocorticoid therapy for the prevention of visual loss was shown in a retrospective study of 245 patients with biopsy-proven GCA, all treated with glucocorticoids [4]. Permanent visual loss was found in 34 patients (14 percent), which had occurred in 32 of the 34 patients before initiation of glucocorticoids. Of the two cases of de novo visual loss that developed after glucocorticoids were started, one occurred eight days into treatment, and the other occurred three years after glucocorticoids were first administered and one year after their discontinuation when the erythrocyte sedimentation rate (ESR) was normal, and was therefore unlikely related to GCA. In another study of 144 patients with biopsy-proven GCA described in the ophthalmologic literature, none of the 53 patients with normal vision at presentation lost vision after initiation of glucocorticoids [5]. Of the 91 patients with sight loss at presentation, nine experienced further visual loss after beginning glucocorticoids, all within five days of the start of treatment. Thus, if vision is intact at the time of the diagnosis of GCA, treatment with glucocorticoids effectively reduces the risk of sight loss to less than 1 percent.

Treatment of GCA requires daily glucocorticoid administration. The importance of daily dosing was demonstrated in the course of a study on the use of MTX for the management of GCA in which a rapid glucocorticoid taper to an alternate-day dose was associated with new sight loss in 8 of 98 patients [6]. In another study of regimens for glucocorticoid dosing, daily doses were more effective than alternate-day doses for symptomatic management [7].

Initial dose — Though the efficacy of glucocorticoids for the treatment of GCA is indisputable, an optimal regimen for a starting dose and subsequent taper (one that would prevent visual loss and minimize glucocorticoid-related side effects) has not been formally evaluated. Published recommendations in this regard are consensus-based [8-10].

●Without visual loss at diagnosis – If there are no symptoms or signs of ischemic organ damage (eg, visual loss), we suggest initial treatment with the equivalent of prednisone 1 mg/kg (maximum 60 mg/day) administered in a single daily dose. A population-based study with 120 patients with GCA found that all patients responded rapidly to a median initial dose of 60 mg of prednisone daily [11]. Earlier studies found doses in the range of 20 to 30 mg of prednisone per day to be effective [12,13]. In a retrospective study including 230 patients with either polymyalgia rheumatica (PMR) or GCA, a subgroup analysis of patients with GCA stratified by three different prednisone dose ranges (10 to 20 mg daily, over 20 and under 60 mg daily, and 60 to 90 mg daily) found no differences in terms of the number of remission, relapse rates, and progression of visual complications once treatment was started [12]. Ophthalmologists have tended to recommend higher doses, in the range of 80 mg/day [14]. If potentially reversible symptoms persist or worsen, the dose can be increased until symptomatic control is achieved.

There is insufficient evidence to justify the upfront use of intravenous pulse glucocorticoids in patients with GCA, although they may be used in patients with visual loss at presentation. A randomized trial with 164 patients with GCA (without ocular involvement at presentation) found no differences in the cumulative glucocorticoid doses or the number of GCA complications when comparing three different glucocorticoid protocols, two of which consisted of different pulse glucocorticoid regimens on a background of oral prednisone (240 mg intravenous pulse of methylprednisolone followed by 0.7 mg/kg/day oral prednisone or 240 mg intravenous pulse methylprednisolone followed by 0.5 mg/kg/day) and the other of which consisted of only oral prednisone (0.7 mg/kg/day) [15]. Another small randomized study of 27 patients without ocular involvement found that adding initial pulse glucocorticoid therapy resulted in a reduced total exposure to glucocorticoids and a lower relapse rate [16]. Neither of these randomized trials, however, was designed to assess the outcome of ocular complications.

Patients usually report dramatic improvements of many GCA-related symptoms (eg, headache, fever, malaise) within 24 to 48 hours of glucocorticoid administration. Laboratory measures of disease activity such as the ESR and C-reactive protein (CRP) usually improve substantially within a few days of the institution of therapy, as well; the CRP declines much more rapidly than the ESR. The diagnosis of GCA should be reevaluated in patients who are resistant to adequate glucocorticoid therapy, especially in situations where temporal artery biopsy and imaging studies have been negative.

●Threatened or established visual loss at diagnosis – If there is a strong suspicion of GCA as the cause of visual symptoms or signs, we suggest the use of intravenous "pulses" of methylprednisolone, customarily administered as 500 to 1000 mg intravenously each day for three days, followed by oral therapy with prednisone 1 mg/kg/day (maximum of 60 mg/day), as recommended above for uncomplicated GCA. Patients with presumed or proven GCA and incident diplopia should also be treated with an initial intravenous pulse of high-dose glucocorticoids.

Though not validated in rigorous studies, this approach is used because of the crucial importance of preventing visual impairment due to GCA, which, once established, is rarely reversible [16]. The stark reality of such visual loss is that patients seldom recover useful vision in an affected eye. In a retrospective review of 84 patients (114 eyes) with variable degrees of GCA-associated visual loss (due to anterior ischemic optic neuropathy [AION] in over 90 percent of patients), there were no differences in improvement in visual acuity when comparing patients who received intravenous glucocorticoids followed by oral therapy (41 patients) with patients who received only oral glucocorticoids (43 patients). Improvement in visual acuity was only observed in 4 percent of eyes (three patients treated with intravenous glucocorticoids and two with oral glucocorticoids), as judged by improvement in both visual acuity and central visual field (by kinetic perimetry and Amsler grid) [17]. Numerous other studies testify to this poor outcome [18,19]. Of note, improvement perceived by patients and noted on visual acuity tests may not reflect true recovery of retinal or optic nerve function but rather eccentric compensation for acquired, permanent visual deficits.

Preexisting sight loss can progress, despite initiation of glucocorticoid therapy, in approximately 10 percent of patients, usually within the first week of treatment [5].

Glucocorticoid tapering

Approach to dose reduction — We maintain the starting dose of high-dose prednisone for at least two, but not more than four, weeks. Although symptoms are typically controlled promptly by therapy, disease flares are the rule if the glucocorticoids are tapered too quickly. If the initial dose of prednisone is 60 mg/day, it can generally be reduced to 50 mg/day after two weeks and to 40 mg/day at the end of four weeks, assuming symptoms and signs have receded and the ESR and CRP have declined to normal or near-normal ranges. Subsequently, the dose can gradually be reduced by 5 mg every two weeks to 20 mg/day and then by 2.5 mg every two weeks to 10 mg/day if there are no flares of disease activity. After achieving a daily dose of 10 mg, the prednisone taper should be slowed, such that patients remain on progressively decreasing doses over the ensuing 6 to 12 months. Tapering by 1 mg decrements each month once the daily dose is less than 10 mg can be considered.

Relapses of disease are unusual at doses higher than 20 mg/day but become more frequent at doses below that level. (See 'Relapse' below.)

Monitoring disease activity — One of the most challenging aspects of GCA treatment is the accurate identification of relapses in the setting of the glucocorticoid taper. Acute phase reactants such as the ESR and CRP can be useful adjuncts to clinical decision making. Especially during initial treatment, measurements of the ESR and CRP prior to each decrease in glucocorticoid dose are ideal.

If elevations of the ESR or CRP are not accompanied by symptoms or findings suggestive of recrudescent GCA, reflexive changes in the glucocorticoid dose based upon the test results alone can prolong the period of glucocorticoid therapy unnecessarily, increase the cumulative glucocorticoid dose, and heighten the likelihood of treatment-related adverse effects.

Both the ESR and CRP are imperfect biomarkers in GCA. The ESR usually rises with age (a value of 40 mm/hour may be normal for an 80-year-old), and, in some patients, abnormalities of serum proteins unrelated to GCA can spuriously elevate the ESR. Examples include monoclonal gammopathies and hypergammaglobulinemia secondary to liver disease. Though the ESR and CRP have not been directly compared for the assessment of disease activity in GCA, clinical experience argues strongly that the CRP is more useful. (See "Clinical manifestations of giant cell arteritis", section on 'Erythrocyte sedimentation rate and C-reactive protein' and "Acute phase reactants", section on 'Clinical use'.)

Relapse — Relapse of GCA should be suspected when patients have a return of symptoms that recall their original presentations, when new symptoms compatible with the diagnosis of GCA or PMR occur, or when there is a striking elevation of acute phase reactants. Elevations of the ESR or CRP do not always indicate a disease flare, but their occurrence should trigger close clinical follow-up and questioning of patients about symptoms of recurring disease.

For relapses of disease activity, an increase in the glucocorticoid dose should be appropriate to the nature of the relapse. For visual symptoms attributable to GCA (generally occurring within the first weeks of the initial diagnosis of disease), an increase of the prednisone dose to 30 to 60 mg/day and even pulse doses may be needed. Much smaller increments in the daily dose of prednisone, between 5 to 7.5 mg/day, are appropriate for PMR symptoms.

Reports on the incidence of relapses in GCA, all assembled from tertiary care centers, vary widely, from 34 to 74 percent [20-24]. This range is due in part to a lack of consensus regarding the definition of what constitutes a relapse. In some analyses, asymptomatic rises in the acute phase reactants were counted as a flare of GCA, and, in others, a recrudescence of symptoms only, unaccompanied by rises in the acute phase reactants, was included. All studies construed the appearance of PMR as a relapse of GCA.

Notwithstanding the heterogeneity of the data collection, there is agreement on several clinical points. The majority of relapses in GCA occur at doses of prednisone below 20 mg/day and are most prevalent during the first year of treatment. Headache and PMR are the most common symptomatic expressions of relapse. Other symptoms include jaw claudication, the development of ischemic limb symptoms, and the recurrence of constitutional symptoms. Persisting elevations of the acute phase reactants in the absence of alternative explanations and especially if accompanied by constitutional symptoms should prompt consideration of underlying large vessel vasculitis and advanced diagnostic imaging. Finally, and importantly, the occurrence of sight loss after an initial course of high-dose glucocorticoid treatment, administered daily, is exceptional. (See 'Efficacy' above.)

An initially intense acute phase response, as manifested by anemia and significant elevations of the ESR and CRP [21,22], has been associated with an increased risk of relapse.

Late relapses (and recurrences) of GCA are described, leading to protracted glucocorticoid treatment. In one study, one-half of patients were still on treatment after five years [23]. Other estimates of the total duration of glucocorticoid treatment are in the range of one to two years [25,26], which is more consonant with clinical practice.

Risks of glucocorticoid therapy — The risks of high-dose and of chronic glucocorticoid therapy are well known. A population-based study of 120 GCA patients diagnosed between 1950 and 1991 found that 86 percent experienced at least one adverse event, which included posterior subcapsular cataracts, fractures, infections, hypertension, diabetes mellitus, and osteonecrosis [11]. The median duration of treatment to reach a prednisone dose of 7.5 mg/day was six months. Adverse events correlated with increased age and cumulative glucocorticoid dose but not with a higher initial dose. Other side effects of glucocorticoids, less frequently enumerated but of no less concern, or even explicit morbidity for the patient, include weight gain, hair loss, and capillary fragility. The latter can be especially problematic in older adults on antiplatelet or anticoagulant therapies. (See "Major side effects of systemic glucocorticoids".)

It is the potential toxicities of glucocorticoids, despite their unquestionable value in the treatment of GCA, particularly for the prevention of sight loss, that has led to the search for glucocorticoid-sparing strategies.

GLUCOCORTICOID-SPARING AGENTS — Adjunctive treatment for giant cell arteritis (GCA) may be used in situations where glucocorticoid-related toxicities have ensued or are anticipated. Options include tocilizumab (TCZ) or methotrexate (MTX).

Indications — Indications for the addition of a glucocorticoid-sparing agent include:

●The presence of significant premorbid diseases

●The emergence of significant glucocorticoid-related side effects during the course of treatment

●A relapsing course necessitating protracted glucocorticoid use

Preexisting diabetes mellitus on treatment, osteoporosis, and significant obesity should prompt consideration for the early implementation of a concurrent glucocorticoid-sparing strategy.

Symptoms such as recurring headache that require only lesser adjustments in the glucocorticoid dose or a minor slowing of the glucocorticoid taper are not grounds for adjunctive treatment. The same is true for the emergence of polymyalgia rheumatica (PMR), which needs only low-dose glucocorticoids for treatment. Recurring symptoms should be clearly attributable to GCA and other diagnoses excluded before adding a glucocorticoid-sparing agent.

Choice of agent and practical considerations — TCZ or MTX are options for use as glucocorticoid-sparing agents. On the basis of published data and clinical experience, we favor TCZ as a glucocorticoid-sparing agent if there are no contraindications. (See 'Tocilizumab' below.)

A pragmatic concern with the use of TCZ in the management of GCA pertains to its effects on the acute phase reactants. Interleukin (IL)-6 is a major driver of the acute phase response through its induction of hepatic synthesis of acute phase proteins (see "Acute phase reactants"). Blockade of IL-6 usually completely normalizes the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), with the result that the assessment of GCA in a patient on TCZ must rely on clinical evaluation and, in the case of large vessel involvement, periodic imaging studies. There continues to be an unfulfilled need for a reliable marker for active disease in GCA.

Whether TCZ should be deployed for the routine care of all patients with GCA (that is, at the start of treatment, simultaneous with glucocorticoids) is an evolving issue [27]. Though in the randomized controlled study of TCZ, the drug was initiated at the start of treatment, additional studies are needed to fully define the drug's long-term safety and efficacy (see 'Tocilizumab' below). At this time, we reserve TCZ for the management of individual patients who are at high risk for glucocorticoid toxicity, who incur glucocorticoid-related side effects during the course of treatment, or who experience relapsing disease.

Though MTX is of but modest efficacy, its use can be supported in the individual patient. Concurrent use of MTX and higher glucocorticoid doses warrants use of prophylaxis for Pneumocystis jirovecii pneumonia (PCP) (see 'Prevention of opportunistic infections' below). The routine addition of MTX to glucocorticoid therapy for GCA is not recommended.

Treatment options

Tocilizumab — The use of TCZ, an IL-6 receptor antagonist, for the treatment of GCA was suggested by evidence that IL-6 is important in disease pathogenesis. TCZ can be administered using the same dosing regimen as that for rheumatoid arthritis (see "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy'). The optimal timing and duration of therapy are as yet unknown.

The beneficial effects of TCZ as a glucocorticoid-sparing intervention have been demonstrated in two randomized trials [28,29]. In an industry-sponsored trial, 251 patients with GCA were randomly assigned to receive either weekly or every-other-week subcutaneous TCZ injections, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks [29]. Patients with evidence of critical optic ischemia were not enrolled in the study. Sustained remission at 52 weeks occurred in 56 percent of the weekly TCZ group and in 53 percent of the every-other-week TCZ group, compared with 14 percent of the placebo group who tapered over 26 weeks and 18 percent of the placebo (prednisone-only) group who tapered over 52 weeks. The cumulative median prednisone dose over the 52-week period in each TCZ group was 1862 mg, as compared with 3296 mg in the placebo group on the 26-week taper and 3818 mg in the placebo group on the 52-week taper. Serious adverse events were more common in the placebo groups, most of which were related to infection. One patient in the group receiving TCZ every other week had an episode of anterior ischemic optic neuropathy (AION) that resolved with glucocorticoid treatment.

The optimal duration of therapy with TCZ is unknown, and information about long term effects of TCZ treatment on the disease course are limited [28,29]. A small prospective observational study followed 17 of the patients from the TCZ arm of the phase 2 trial who were in remission after the 52-week treatment [28,30]. Approximately half of the patients relapsed (8 of 17) after a mean of 6 months, while the other patients stayed in remission during the mean follow-up of 28 months. Magnetic resonance angiography (MRA) was performed in all patients, and wall enhancement of the descending aorta persisted in all patients at follow-up.

It remains to be seen whether TCZ has a fundamental, rather than suppressive, effect on the underlying pathophysiology of GCA. In a case report, a patient with GCA in apparent remission on TCZ died of a postoperative myocardial infarction and was found on postmortem examination to have active arteritis of the aorta, subclavian arteries, and right superficial temporal artery [31].

TCZ carries a black box warning about the risk of opportunistic infection.

Methotrexate — Three randomized trials comparing MTX with placebo in patients with GCA treated with glucocorticoids reached divergent conclusions [6,32,33]. Of note, the doses of MTX used in the trials were low by contemporary standards, only 10 mg to 15 mg per week. A meta-analysis of the individual patient-level data of 161 patients from these three trials suggested that the add-on use of MTX resulted in a statistically significant reduction in the cumulative dose of glucocorticoids over the 48 weeks following randomization (cumulative dose reduction of prednisone or equivalent of 842 mg), a decreased rate of first and second relapse, and a higher probability of achieving a glucocorticoid-free remission [34]. There were no differences in adverse effects between the two treatment groups. The superiority of MTX over placebo appeared only after 24 to 36 weeks. A systematic review of the methodology of the three studies concluded that it was the trial of highest quality that reported benefit for adjunctive MTX [35].

These results are consistent with clinical experience, and suggest that MTX, at best, is only moderately effective for the management of GCA.

Other agents — Several other glucocorticoid-sparing agents have been reported as having efficacy as adjunctive treatment for GCA, but their use cannot be endorsed because of small effect, potential toxicity, lack of controls, or small numbers of patients studied.

●Abatacept – A trial of abatacept, a blocker of T-cell costimulation, was proposed on the basis of the presence of activated CD4+ T cells in the typical inflammatory infiltrate of the temporal artery in GCA [36] (see "Pathogenesis of giant cell arteritis"). In a phase 2 randomized, double-blind study of patients with newly diagnosed or relapsing GCA, 49 patients were enrolled and treated with prednisone and intravenous abatacept, administered on days 1, 15, 29, and 56. At week 12, 41 patients were in remission and were randomized to continue treatment with monthly abatacept or placebo. Prednisone was tapered by a standardized schedule and discontinued by week 28. The rate of sustained remission at 12 months in patients treated with abatacept compared with placebo was of borderline significance, 48 versus 31 percent (p = 0.049). There was no difference in adverse events, including infection, between the two groups.

Further study is needed to determine a possible role for abatacept as adjunctive treatment for GCA.

●Azathioprine – In a study from a single center of 31 patients with GCA, PMR, or both, a double-blind randomized controlled study of azathioprine, 150 mg/day, versus placebo showed a small but statistically significant reduction in mean prednisolone dose at 52 weeks (1.9 mg/day ± 0.84 versus 4.2 mg/day ± 0.58) [37]. Only 20 patients completed the study.

●Ustekinumab – T helper (Th)1 and Th17 cells are believed to play key roles in the pathogenesis of GCA [38] (see "Pathogenesis of giant cell arteritis"). Ustekinumab blocks IL-12, a Th1-promoting cytokine, and IL-23, a Th17-promoting cytokine, providing a theoretical basis for its use in the treatment of GCA. In an open-label study of ustekinumab in 14 patients with refractory GCA, the prednisolone dose was decreased from a median of 20 mg/day to 5 mg/day; four patients discontinued glucocorticoid therapy entirely [39].

●Cyclophosphamide – Cyclophosphamide has been widely used in the treatment of systemic vasculitis. A few small, uncontrolled studies have suggested that it may be useful in GCA in patients at high risk of glucocorticoid-related adverse effects who have not responded adequately to other immunosuppressive or immunomodulatory glucocorticoid-sparing treatments [40-42]. A systematic review identified 103 published cases for analysis [42]. The major indications for cyclophosphamide, administered either orally or intravenously, included glucocorticoid-dependency or relapsing disease. Most of the reported patients (86 percent) responded, but 22 percent relapsed despite maintenance immunosuppressive therapy. Adverse effects were described in one-third of the patients, and 12.5 percent discontinued the therapy because of infections and cytopenias. One death due to hepatitis was reported.

●Others – Small, uncontrolled, retrospective series have proposed benefit for dapsone [43], leflunomide [44], and IL-1 blockade [45] for the management of GCA.

Lack of benefit of anti-TNF therapy — Because GCA is characterized by granulomatous inflammation, tumor necrosis factor (TNF) inhibition would appear to be an appropriate approach to treatment. However, several small randomized trials of TNF inhibition have found that infliximab, etanercept, and adalimumab are ineffective in patients with GCA [46-48]. As an example, 44 patients were studied in a multicenter, randomized, placebo-controlled trial of infliximab for the maintenance of remission [46]. After prednisone-induced remission, patients were randomly assigned in a 2:1 ratio to infliximab 5 mg/kg or placebo. An interim analysis at week 22 demonstrated that infliximab did not reduce the proportion of patients with relapses (43 versus 50 percent on placebo). In addition, infliximab did not increase the proportion of patients whose prednisone dose could be tapered to 10 mg/day without relapse (61 versus 75 percent). Consequently, the trial was stopped early. Through the follow-up period, no differences between the treatment groups were observed in the proportion of relapse-free patients, the cumulative dose of prednisone, or the incidence of adverse events.

GENERAL MEASURES IN ALL PATIENTS — Additional monitoring and interventions to prevent complications of disease and therapy should be implemented at the beginning of treatment. Screening tests for tuberculosis and immunizations against influenza and pneumococcal pneumonia must be up to date.

Routine follow-up — Monthly follow-up visits for the first six months of treatment are desirable, though their frequency will be subject to the exigencies of logistical issues. Laboratory data, which can be tracked even if the patient resides a long distance from the clinician, should be monitored at least as frequently. Subsequent follow-up visits can be spaced out to every three months. Ultimately, all matters of follow-up (the interval between clinician visits, the frequency of laboratory monitoring, and the speed of the glucocorticoid taper) are governed by the clinical course of the given patient and must be individualized accordingly. Patients should be counseled to be watchful for symptoms of polymyalgia rheumatica (PMR) or giant cell arteritis (GCA) and should be encouraged to seek medical attention immediately if any symptoms are noted. At each visit, patients should routinely be asked about cranial symptoms (eg, headache, visual symptoms, jaw claudication) as well as any new or worsening symptoms of large vessel involvement (eg, limb claudication).

Patients should also be monitored for glucocorticoid-related adverse effects including osteoporosis, infection, diabetes, and ocular complications such as posterior subcapsular cataracts and glaucoma [11]. (See "Major side effects of systemic glucocorticoids".)

Antiplatelet therapy — In view of the conflicting observational data, the use of low-dose aspirin in patients with newly diagnosed GCA should be guided by current recommendations for the management of atherosclerosis [9]. If low-dose aspirin is used, a proton pump inhibitor should also be administered as aspirin, age, and high-dose glucocorticoids are all risk factors for gastrointestinal bleeding. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Proton pump inhibitors'.)

Retrospective analyses disagree on the value of low-dose aspirin in the management of GCA. In two cohorts, the odds ratios of so-called cranial ischemic events (sight loss and stroke) were reduced in GCA patients on antiplatelet therapy or anticoagulants, mainly the former, compared with patients on no such treatment [49,50]. In these studies, the majority of the aspirin-treated patients had been taking low-dose aspirin for the management of preexisting cardiovascular or cerebrovascular disease prior to the diagnosis of GCA and initiation of glucocorticoid therapy. Three other studies found no effect of established platelet inhibition on the occurrence of visual loss or stroke in newly diagnosed GCA [50-52]. None of the reports found an increased risk of gastrointestinal bleeding in the aspirin-treated patients.

Osteoporosis prevention — Because of the length of the course of glucocorticoid treatment for GCA, osteoporosis prevention should be aggressively pursued at the start of therapy. Adequate dietary calcium and vitamin D intake should be encouraged. Determination of bone mineral density near the time that treatment is begun is essential for guiding management of bone loss. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Prevention of opportunistic infections — Among the familiar risks of high-dose glucocorticoid use is infection. A study using administrative data found that patients with GCA, compared with a matched historical cohort, had increased rates of lower respiratory tract infections, urinary tract infections, and serious infections (defined as pneumonias, upper urinary tract infections, and sepsis) [53]. As would be expected, the increased rate of infections was highest during the first six months after the diagnosis of GCA, during the period of greatest glucocorticoid exposure.

There are rare reports of P. jirovecii pneumonia (PCP) in GCA. In a 32-year study from a tertiary care center, seven GCA patients with PCP were identified, two of whom had received concurrent treatment with methotrexate (MTX) [54]. In another report from a single center, 4 of 62 patients with GCA developed PCP, all of whom were under treatment with concurrent glucocorticoids and MTX [55]. Numerous clinical trials of treatments for GCA have contained no reported cases of PCP.

As opportunistic infection with P. jirovecii in GCA patients receiving only glucocorticoid therapy is exceptional, we do not recommend routine PCP prophylaxis in this situation. If MTX is used concurrently with high-dose glucocorticoids, then PCP prophylaxis should be deployed.

When to refer to a rheumatologist — Because of the potential toxicities inherent in the use of high-dose glucocorticoid therapy in older adults, formal rheumatologic consultation can be considered at the start of treatment for patients with newly diagnosed GCA, especially if the clinician lacks experience with the disease. Rheumatology consultation must be obtained if the initial workup for GCA is negative and a diagnosis of biopsy-negative disease is contemplated, if the glucocorticoid taper is marked by recurring symptoms or glucocorticoid-related side effects, or if there is consideration for implementing a glucocorticoid-sparing strategy.

LARGE VESSEL GCA

Overall approach — Large vessel giant cell arteritis (GCA) refers to involvement of the aorta and the great vessels, most commonly the subclavian arteries and distally to the axillary and brachial arteries. We initially manage patients with large vessel GCA with glucocorticoid therapy in a manner similar to those with cranial GCA, and likewise utilize glucocorticoid-sparing agents (ie, for patients with an initial high risk of glucocorticoid toxicity, the emergence of glucocorticoid-induced side effects, or relapsing disease).

Whether large vessel involvement may require more protracted or intensive treatment is unclear. One retrospective cohort study compared 120 patients with large vessel GCA, as defined by evidence of subclavian involvement on imaging, with 240 patients with cranial GCA. The patients with large vessel GCA had a higher cumulative glucocorticoid dose after one year of treatment, relapsed more frequently, and received more adjunctive immunosuppressant therapies [56].

Imaging studies have shown that large vessel involvement in GCA is common in patients with cranial arteritis and can be demonstrated in 30 to 80 percent of patients, depending on methodology [57-61]. The finding of such involvement, if asymptomatic or uncomplicated, is not a priori grounds for escalation of treatment. (See "Diagnosis of giant cell arteritis", section on 'Imaging modalities' and "Clinical manifestations of giant cell arteritis", section on 'Large vessel involvement'.)

Specific manifestations

Aortic aneurysms — Clinical studies that would inform the management of aortic aneurysms in GCA are lacking.

Prospective imaging studies have shown evidence for aortitis in 45 to 65 percent of GCA patients [57,62]. The development of aneurysms, especially of the thoracic aorta, is less common, of which a small number dissect or rupture [63-65]. Risk factors for the development and progression of aortic aneurysms in GCA, however, have not been clarified. Additionally, the effects of glucocorticoid therapy and glucocorticoid-sparing therapies have not been retrospectively or prospectively studied, so whether treatment affects the two critical clinical outcomes of aortic aneurysm (progression and dissection or rupture) remains undefined. Management of aortic aneurysms in GCA thus remains problematic.

For aortic aneurysms between 3 and 5 cm in diameter that are enlarging and whose presence is associated with increased acute phase reactants, resumption or an increase in glucocorticoid therapy should be considered. Additional medical management of thoracic aortic aneurysm and dissections are discussed in detail separately. (See "Management of thoracic aortic aneurysm in adults" and "Management of acute type B aortic dissection".)

Ischemic limb symptoms — Most ischemic limb symptoms improve or stabilize with medical management in GCA. Vasculitic narrowing of large arteries, such as the subclavian artery, is usually gradual and accompanied by the development of an extensive web of collateral vessels (image 1). With treatment of the underlying inflammatory process, the collateral circulation is commonly adequate to maintain the viability of distal tissues, even though there is some incident limb ischemia or diminished or absent peripheral arterial pulsations (brachial, radial, and ulnar). In one report of 53 treated patients with subclavian involvement due to GCA, symptoms and signs of ischemia resolved in 15 (27 percent), improved in 30 (55 percent), and were unchanged in 8 (15 percent) [66].

Revascularization of arteries to the extremities (eg, angioplasty, stent placement, or bypass surgery) is seldom required. If indicated, stenting or angioplasty should be undertaken when clinical evidence for inflammation has been suppressed with treatment. Restenosis is not infrequent [66].

Monitoring disease activity of large vessel GCA — As markers of disease activity for large vessel GCA, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have the same utilitarian value and are accompanied by the same caveats as they do for the cranial phenotype. Repeat imaging of a newly discovered or enlarging aortic aneurysm should be considered at six months of follow-up; if stable, the interval between imaging studies can be lengthened to an annual basis. The choice of an imaging modality will vary by institution and individual patient (see "Diagnosis of giant cell arteritis", section on 'Imaging modalities'). Assessment of disease activity by any of the different imaging modalities (computed tomography [CT], CT angiography [CTA], magnetic resonance imaging [MRI], MR angiogram [MRA], and positron emission tomography [PET] with CT) requires careful consultation between the clinician and the radiologist.

Role of screening for large vessel disease — The role of screening for large vessel involvement in patients who present with cranial GCA is unsettled. Examples of such screening could involve a PET CT scan or chest CT scan at the time of initial diagnosis or serial CT examinations following diagnosis to assess for the development of aortic aneurysm. Because of the uncertainties regarding the prognosis of aortic aneurysm in GCA and the lack of evidence with respect to the effects of treatment, a program of routine screening for large vessel involvement in all GCA patients is not currently endorsed (see "Diagnosis of giant cell arteritis", section on 'Postdiagnostic imaging evaluation in patients with cranial arteritis'). Patients should be evaluated for screening on a case-by-case basis. As the incidence of aortic aneurysm in GCA increases over time, clinical vigilance should be maintained [67].

Patients with an incidental diagnosis of aortitis — Aortitis of the ascending aorta can come unexpectedly to clinical attention following surgery for an aneurysm of the ascending aorta (see "Clinical manifestations of giant cell arteritis", section on 'Large vessel involvement'). The histopathology of resected aneurysm is similar to that of GCA, including the presence of giant cells.

A diagnostic workup requires a careful history and physical examination and laboratory evaluation as indicated for underlying disease. Measurement of the acute phase reactants immediately postoperation is useless, as the ESR and CRP are certain to be significantly elevated. The vascular tree should be completely imaged for evidence of involvement of other segments of the aorta and of other large arteries. Temporal artery biopsy or ultrasonography of the temporal arteries can be considered. In approximately 20 percent of cases, systemic rheumatic disease can be identified (classic GCA, spondyloarthropathy, Behçet syndrome, and others), for which treatment is then pursued as appropriate [68,69].

In some patients, however, there will be no evidence for associated disease or for other vascular involvement, and a diagnosis of idiopathic ascending noninfectious aortitis will remain. Whether this entity lies along the spectrum of classic GCA remains unclear. In these situations, it can be appropriate to withhold treatment (ie, glucocorticoids) as some patients will not manifest subsequent disease activity, but attentive clinical follow-up and repeat imaging studies are essential.

OVERALL PROGNOSIS — Giant cell arteritis (GCA) is a disease of variable duration. In some, it may have a course of one to two years, while in others the disease is more chronic. The glucocorticoid dose can eventually be reduced and discontinued in the majority of patients, although some patients require low doses of prednisone for a number of years to control symptoms.

GCA does not adversely affect overall survival, excepting the subset of patients with aortic involvement and dissection [67,70,71].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Giant cell arteritis and polymyalgia rheumatica".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Polymyalgia rheumatica and giant cell arteritis (The Basics)")

●Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)" and "Patient education: Polymyalgia rheumatica and giant cell arteritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Glucocorticoid treatment is central to the management of giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis). If vision is intact at the time appropriate glucocorticoid treatment is initiated, the risk of sight loss is reduced to less than 1 percent. (See 'Systemic glucocorticoids' above.)

●For all patients with GCA, we recommend initial treatment with high-dose systemic glucocorticoids to preserve vision (Grade 1C) as well as to treat other clinical symptoms associated with GCA (Grade 2B). Treatment should be initiated promptly once the diagnosis is confirmed or there is a high index of suspicion for GCA. Our practice for initial dosing glucocorticoids is as follows (see 'Initial dose' above):

•For patients without visual loss at presentation: prednisone 1 mg/kg or equivalent, not to exceed 60 mg, given in a single daily dose

•For patients with threatened or established visual loss at presentation: methylprednisolone 500 to 1000 mg intravenous daily, for three days

●Symptoms and signs of GCA usually respond quickly, permitting a taper of the prednisone dose to 50 mg/day after two weeks and to 40 mg/day after another two weeks. The dose can subsequently be reduced by 5 mg decrements every two weeks to 20 mg/day, at which point the speed of the glucocorticoid taper is slowed. It is axiomatic that glucocorticoid dosing be tailored to the individual patient's clinical course. (See 'Glucocorticoid tapering' above.)

●Relapses of disease activity are most common at prednisone doses less than 20 mg/day and are treated with increases in the glucocorticoid dose appropriate to the nature of the relapse. Relapses usually do not result in major adverse events such as visual loss. (See 'Approach to dose reduction' above.)

●Monitoring of disease activity requires careful clinical follow-up and regular tracking of the acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]). Minor fluctuations of the ESR and CRP are common during the course of the glucocorticoid taper and do not of themselves mandate increases in the glucocorticoid dose. Significant increases in the ESR and CRP warrant close clinical follow-up and consideration for a reduction in the speed of the taper. (See 'Monitoring disease activity' above.)

●Patients should be regularly assessed for the presence of glucocorticoid-related side effects. Measures to maintain bone health should be implemented in all patients. Low-dose aspirin should be administered as indicated by current guidelines for management of atherosclerosis. Routine prophylaxis against Pneumocystis jirovecii pneumonia (PCP) is not advised. (See 'General measures in all patients' above.)

●Whether a glucocorticoid-sparing should be used for the routine care of all patients with GCA is an evolving issue. We use an individualized approach for patients who may benefit from a glucocorticoid-sparing agent. For patients with relapsing disease requiring a protracted course of glucocorticoids, we suggest the addition of tocilizumab (TCZ) rather than continuing monotherapy with glucocorticoids (Grade 2B). We also use TCZ for patients who are at higher risk for severe glucocorticoid toxicity (eg, preexisting diabetes mellitus or osteoporosis) or who develop significant glucocorticoid-related toxicities during treatment. The dosing of TCZ is the same as is used for rheumatoid arthritis. Methotrexate (MTX) is an alternative glucocorticoid-sparing agent for patients unable to take TCZ, but limited available data and clinical experience suggest it is less effective. (See 'Glucocorticoid-sparing agents' above.)

●The treatment strategies for large vessel GCA are similar to those used for cranial GCA. (See 'Large vessel GCA' above.)

●The management of aortic aneurysm identified during the course of GCA is hampered by uncertainty as to the impact of treatment on progressive dilatation and dissection or rupture. Owing to this uncertainty, screening for aortic aneurysms is not routinely recommended but can be considered on a case-by-case basis. (See 'Role of screening for large vessel disease' above.)

●Patients in whom a clinical diagnosis of GCA is posited after negative workup are treated similar to those with proven GCA. (See 'Patients with negative biopsy and imaging' above.)

●GCA is a disease of variable duration. Length of treatment may extend from one to multiple years. Glucocorticoid treatment can eventually be discontinued in the majority of patients. (See 'Overall prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gene G Hunder, MD, who contributed to an earlier version of this topic review.