7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment of giant cell arteritis : Carlo Salvarani, MD, Francesco Muratore, MD : Jonathan Trobe, MD, Kenneth J Warrington, MD : Philip Seo, MD, MHS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 01, 2023. 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. One of the most concerning potential complications of GCA is that of sight loss, which serves as the rationale for prompt initiation of glucocorticoids as soon as the diagnosis is suspected. The disease can be generalized, however, and involve the aorta, leading to aneurysms of the thoracic aorta, and may cause stenoses in the 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".) INITIAL MANAGEMENT No visual loss at diagnosis Glucocorticoids For all patients with giant cell arteritis (GCA), we recommend initial treatment with high-dose glucocorticoids rather than a moderate dose of glucocorticoids. The specific dose and route of administration of glucocorticoids for newly diagnosed GCA varies https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 1/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate depending on whether the patient presents with or without threatened or established visual loss at diagnosis. (See 'Threatened or established visual loss at diagnosis' below.) For patients without signs of ischemic organ damage (eg, visual loss), we initiate glucocorticoid therapy with prednisone 40 to 60 mg/day (or equivalent) administered in a single daily dose, with the goal of relieving symptoms and preventing visual loss. In selected cases in which reversible symptoms persist or worsen, the dose can be increased until symptomatic control is achieved (up to a maximum of prednisone 80 mg or equivalent). We do not use lower doses of glucocorticoids (ie, prednisone <40 mg/day) as initial therapy in any patients with newly diagnosed GCA. In patients at high risk of developing glucocorticoid toxicity, we also use high doses of glucocorticoids and add a glucocorticoid-sparing agent. The approach to using a glucocorticoid-sparing agent and glucocorticoid tapering is discussed in detail below. (See 'Glucocorticoid-sparing agent in selected patients' below and 'Glucocorticoid tapering' below.) Patients usually report dramatic improvements of many GCA-related symptoms (eg, headache, fever, malaise) within 24 to 48 hours of glucocorticoid administration. 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. (See "Diagnosis of giant cell arteritis", section on 'Diagnosis'.) Efficacy Though never studied in a randomized trial, the role of glucocorticoids for the prevention of visual loss is supported by observational data and decades of clinical experience [4-6]. In a retrospective study of 245 patients with biopsy-proven GCA, all of whom were treated with glucocorticoids, permanent visual loss was found in 34 patients (14 percent) [5]. However, vision loss occurred in 32 of the 34 patients before the 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 [6]. Of the 91 patients with sight loss at presentation, 9 experienced further visual loss after beginning glucocorticoids, all within 5 days of the start of treatment. Thus, if vision is intact at the time of the diagnosis of GCA, treatment with glucocorticoids appears to reduce the risk of sight loss to less than 1 percent. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 2/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Data regarding initial dose There are no clinical trials comparing different initial oral glucocorticoid doses for newly diagnosed GCA; however, clinical experience and observational data suggest that almost all patients with GCA respond symptomatically within 1 to 7 days to a 40 to 60 mg of oral prednisone (or equivalent) [4,7-10]. As an example, 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 [7]. Our approach to the initial glucocorticoid dose is consistent with the European Alliance of Associations for Rheumatology (EULAR; formerly European League Against Rheumatism) guidelines, which recommend a fixed starting dose of prednisone 40 to 60 mg daily (or equivalent) [11]. By contrast, the American College of Rheumatology (ACR) guidelines recommend a starting dose of 1 mg/kg of prednisone or equivalent, up to a maximum of 80 mg daily [12,13]. Our preference is based on the fact that the majority of clinical trials have used fixed starting doses of prednisone 60 mg daily, and that additional high-quality data on the optimal starting dose of glucocorticoids in GCA are lacking. We do not use starting doses of <40 mg/day, as the use of such doses have not been systematically studied. There is insufficient evidence to justify the upfront use of intravenous pulse glucocorticoids in all patients with GCA, although they are recommended in patients with visual loss at presentation (see 'Threatened or established visual loss at diagnosis' below). 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) [14]. 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 [15]. Neither of these randomized trials, however, was designed to assess the outcome of ocular complications. No role for alternate-day dosing Treatment of GCA requires daily glucocorticoid administration. The importance of daily dosing was demonstrated in the course of a study on the use of methotrexate 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 [16]. In another study of regimens for glucocorticoid dosing, daily doses were more effective than alternate-day doses for symptomatic management [17]. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 3/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate The risks of high-dose and of chronic glucocorticoid therapy are well known and include cataracts, fractures, infections, hypertension, diabetes, osteoporosis, and osteonecrosis [7]. Other side effects of glucocorticoids include weight gain; hair loss; and capillary fragility, which can be especially problematic in older adults on antiplatelet or anticoagulant therapies. (See "Major side effects of systemic glucocorticoids".) Glucocorticoid-sparing agent in selected patients Indications and rationale For patients with newly diagnosed GCA with increased risk of glucocorticoid-related adverse effects, we suggest the addition of tocilizumab to glucocorticoids. Patients who are at increased risk of developing glucocorticoid-related side effects or complications include those with osteoporosis, diabetes, hypertension, or glaucoma. We also add tocilizumab at first disease relapse, which is discussed further below. (See 'Tocilizumab' below and 'Management' below.) Methotrexate may be used as an alternative glucocorticoid-sparing agent for patients who are unable to use tocilizumab due to factors such as availability, cost, recurrent infections, or a history of gastrointestinal perforations or diverticulitis. (See 'Methotrexate' below.) Our approach to the use of a glucocorticoid-sparing agent is consistent with the EULAR guidelines [11] but differs from those of the ACR [12,13], in which tocilizumab use is recommended for all newly diagnosed patients with GCA. Despite the glucocorticoid-sparing effects of tocilizumab and its beneficial effects of remission rates, our caution with the use of tocilizumab is based on the lack of definitive data confirming the safety of long-term exposure of tocilizumab in an older adult population with multiple comorbidities. Furthermore, there are no definitive data showing that tocilizumab is able to reduce glucocorticoid-related side effects or definitively alter the inflammation in patients with large vessel disease. (See 'Tocilizumab' below.) Tocilizumab Tocilizumab is administered as a 162 mg subcutaneous weekly injection or as a monthly intravenous infusion in combination with glucocorticoids. When tocilizumab is administered intravenously, we typically dose it at 8 mg/kg once every four weeks (with a maximum of 800 mg/infusion). The dose more commonly used in the United States is 6 mg/kg based on regulatory approval. Tocilizumab may be administered as monotherapy following discontinuation of glucocorticoids. In patients who develop an adverse event (eg, cytopenias or abnormal liver function tests) with the standard initial dose, the tocilizumab dose should be adjusted and injections can be administered every other week or the intravenous dose can be reduced to 4 mg/kg. The risks of tocilizumab include opportunistic infection, neutropenia, abnormal liver function tests, increased serum cholesterol, diverticulitis, and gastrointestinal perforation. Additional https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 4/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate information regarding dose adjustments and adverse effects are described separately as well as in the Lexicomp drug information topic within UpToDate. (See "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects", section on 'Adverse effects'.) The optimal duration of therapy with tocilizumab is unknown. We generally continue treatment for 12 to 18 months. If clinical remission is maintained, and glucocorticoids are successfully tapered off, we attempt complete discontinuation of tocilizumab. In some patients with relapsing disease who achieve sustained remission with tocilizumab, we try spacing out the tocilizumab injections to every other week (or reduce the dose of the intravenous infusion) for a period of 6 to 12 months before complete discontinuation. A pragmatic concern with the use of tocilizumab 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 activity completely normalizes the ESR and C-reactive protein (CRP), with the result that the assessment of GCA in a patient on tocilizumab 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 of active disease in GCA. (See 'Routine monitoring of disease activity' below and 'Imaging surveillance for patients with large vessel involvement' below.) The beneficial effects of tocilizumab as a glucocorticoid-sparing intervention have been demonstrated in two randomized trials [18,19]. In an industry-sponsored Giant Cell Arteritis Actemra (GiACTA) trial, 251 patients with newly diagnosed or relapsing GCA were randomly assigned to receive either weekly or every-other-week subcutaneous tocilizumab injections, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 or 52 weeks [19]. 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 tocilizumab group and in 53 percent of the every-other-week tocilizumab 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. When normalization of the CRP concentration was excluded from the definition, sustained remission at 52 weeks occurred in 59 percent of the weekly tocilizumab group and in 55 percent of the every-other-week tocilizumab group, compared with 20 percent of the placebo group, who tapered over 26 weeks, and 33 percent of the placebo (prednisone-only) group, who tapered over 52 weeks. The cumulative median prednisone dose over the 52-week period in each tocilizumab 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 tocilizumab every https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 5/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate other week had an episode of anterior ischemic optic neuropathy (AION) that resolved with glucocorticoid treatment. Information about long-term effects of tocilizumab treatment on the disease course are limited [18,19]. In the two-year extension study of the GiACTA trial, after tocilizumab discontinuation, relapses were common, occurring in over half of patients enrolled [20]. Restarting tocilizumab (with or without glucocorticoids) was effective in restoring clinical remission in most patients. The glucocorticoid-sparing effect of tocilizumab demonstrated in the initial trial was maintained through year 3. Cumulative glucocorticoid doses over three years were significantly lower in patients originally randomized to tocilizumab compared with those originally randomized to placebo (median cumulative prednisone dose 2647 mg for tocilizumab once a week, 3948 mg for tocilizumab every other week, 5277 mg for placebo with a 26-week prednisone taper, and 5323 mg for placebo with a 52-week prednisone taper). No new or unexpected safety findings were reported over the full three years of the study. It remains to be seen whether tocilizumab definitively resolves vessel inflammation and consequently prevents the long-term development of aortic aneurysm and supra-aortic vessels stenosis. In a case report, a patient with GCA in apparent remission on tocilizumab 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 [21]. Methotrexate When used, methotrexate is typically initiated at a dose of 10 to 15 mg/week, with increases in dose every two to eight weeks of 5 mg/week up to 25 mg/week. We use the same regimen and approach to titration as that used in rheumatoid arthritis. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.) Limited data suggest that methotrexate is, at best, only moderately effective for reducing cumulative glucocorticoid dose and the rate of relapses [22]. Three randomized trials comparing methotrexate with placebo in patients with GCA treated with glucocorticoids reached divergent conclusions [16,23,24]. Of note, the doses of methotrexate used in the trials were low by contemporary standards, only 10 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 methotrexate 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 [25]. Adverse effects between the two treatment groups were similar. The superiority of methotrexate over placebo appeared only after 24 to 36 weeks. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 6/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate There are no randomized trials comparing methotrexate with tocilizumab in GCA. In an observational study on patients with new-onset, active, large vessel GCA starting treatment with either glucocorticoid monotherapy or combination with methotrexate or tocilizumab, all three treatment regimens controlled the clinical and biochemical signs of GCA and vascular inflammation evaluated by the positron emission tomography/computed tomography (PET/CT) [26]. Mean cumulative prednisone doses, however, were higher with glucocorticoid monotherapy (5637 mg), intermediate with methotrexate (4478 mg), and significantly lower with tocilizumab (2984 mg). Threatened or established visual loss at diagnosis Patients who present with visual manifestations (amaurosis fugax or unilateral visual loss) or with cerebrovascular events (eg, stroke or transient ischemic attack) potentially attributed to GCA require a higher initial dose of glucocorticoids, which should be administered promptly. We use either 500 to 1000 mg/day of intravenous methylprednisolone daily for three days (followed by 40 to 60 mg/day of oral prednisone) or 1 mg/kg/day of oral prednisone (if intravenous pulse cannot be rapidly initiated). While the association between diplopia and visual loss in patients with GCA has not been confirmed in all studies, we treat patients with GCA who present with diplopia with an initial course of intravenous glucocorticoids [27]. 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 [15]. The stark reality of such visual loss is that patients seldom recover useful vision in an affected eye [28-30]. In a retrospective review of 84 patients (114 eyes) with variable degrees of GCA-associated visual loss (due to 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) [28]. 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. Limited data suggest that the timing of glucocorticoid therapy may be more important than the route of administration for the prevention of future severe ischemic events [31]. A retrospective multicenter study of 29 patients with GCA with permanent visual loss is the only study that used a cut-off interval time of 24 hours from diagnosis to treatment onset to define early treatment. Early treatment was the only significant predictor of improvement of visual acuity (odds ratio https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 7/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate [OR] 17.7); the therapeutic regimen (intravenous pulse versus oral prednisone) did not influence visual outcome [32]. Preexisting sight loss can progress, despite initiation of glucocorticoid therapy, in approximately 10 percent of patients, usually within the first week of treatment [6]. If untreated, the second eye is likely to become affected in up to 30 percent of patients, and more than half of these patients develop bilateral loss of vision within the first two weeks [33]. Patients with large vessel involvement Large vessel GCA refers to involvement of the aorta and the great vessels, most commonly the subclavian arteries and distally to the axillary and brachial arteries. Patients with large vessel GCA are managed in a manner similar to those without large vessel involvement. It remains uncertain whether large vessel involvement may require more protracted or intensive treatment. In one retrospective cohort study comparing 120 patients with large vessel GCA 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 [34]. Additional information regarding the clinical features of large vessel involvement is presented separately. (See "Clinical manifestations of giant cell arteritis", section on 'Large vessel involvement'.) Additional management considerations for patients with large vessel include the following: Antiplatelet therapy for selected patients For patients who have critical or flow-limiting involvement of the cerebral or carotid arteries, we add low-dose aspirin to glucocorticoid and glucocorticoid-sparing therapy. 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'). The rationale for low-dose aspirin use in this setting is for prevention of ischemic events in patients with vascular narrowing resulting in decreased cerebral flow. Otherwise, there are limited data supporting the role of antiplatelet therapy for the prevention of ischemic events in patients with GCA [35-39]. Vascular complications For patients with vascular complications such as aortic aneurysms or stenosis resulting in limb or organ ischemia, management decisions regarding potential surgical intervention should involve collaboration of the vascular surgeon and the rheumatologist. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 8/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate For patients with GCA who require vascular surgical intervention and have clinical evidence of active disease, we typically use high-dose glucocorticoids in the periprocedural period. Clinical studies that would inform the management of complications such as limb ischemia or aortic aneurysms in GCA are lacking, and the approach to management is largely based on clinical experience and extrapolated from experience with Takayasu arteritis. Additional considerations regarding specific vascular complications include: Ischemic limb symptoms Most ischemic limb symptoms from stenosis improve or stabilize with medical management in GCA, and revascularization of arteries to the extremities (eg, angioplasty, stent placement, or bypass surgery) is seldom required. 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 1 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) [40]. If indicated, stenting or angioplasty should be undertaken when clinical evidence for inflammation has been suppressed with treatment. Restenosis is not infrequent [40]. Aortic aneurysms Patients with aortic aneurysms related to GCA should be carefully evaluated for the presence of ongoing active vascular inflammation with laboratory (ESR, CRP) and imaging studies (magnetic resonance angiography [MRA], PET). Patients with active disease are treated with resumption or an increase in glucocorticoid therapy. If patients are not taking a glucocorticoid-sparing agent, this could be added. Additional information regarding medical and surgical management of thoracic aortic aneurysm and dissections is presented separately. (See "Management of thoracic aortic aneurysm in adults" and "Management of acute type B aortic dissection".) SUBSEQUENT MANAGEMENT Glucocorticoid tapering Symptoms and signs of giant cell arteritis (GCA) usually respond quickly to glucocorticoids, permitting a taper after two to four weeks. The approach to glucocorticoid tapering generally depends on whether patients are also receiving tocilizumab. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 9/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Patients on glucocorticoid monotherapy For patients who are not on tocilizumab, we use a more standard, slower tapering regimen similar to that used in the Giant Cell Arteritis Actemra (GiACTA) trial ( table 1). The initial dose of prednisone 60 mg/day 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 erythrocyte sedimentation rate (ESR) and C-reactive protein (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, particularly in patients with concomitant polymyalgia rheumatica (PMR). In selected patients with significant risk for severe glucocorticoid toxicity and contraindications to tocilizumab and methotrexate, we use an accelerated taper regimen consistent with the taper used for patients on tocilizumab. Patients on glucocorticoids plus tocilizumab For most patients with GCA receiving glucocorticoids in combination with tocilizumab, we use an accelerated glucocorticoid- tapering regimen. We use the accelerated tapering regimen used in the trial demonstrating the glucocorticoid-sparing effect of tocilizumab (GiACTA) [19]. Patients are initiated on prednisone 60 mg daily and tapered off over 26 weeks as indicated in the table ( table 2). The details of this study presented above. (See 'Tocilizumab' above.) Routine monitoring of disease activity Monthly follow-up visits for the first six months of treatment are ideal, though their frequency will be subject to the exigencies of logistical issues. In stable patients, 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. The goal of these visits is to evaluate the patient's response to therapy and assess for toxicity of the treatment regimen. Patients should be counseled to be watchful for symptoms of PMR or GCA and should be encouraged to seek medical attention immediately if any symptoms are noted. The following data are obtained during follow-up visits: History and physical examination At each visit, patients should routinely be asked about cranial symptoms (eg, headache, visual symptoms, jaw claudication) and PMR https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 10/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate symptoms (eg, proximal musculoskeletal symptoms and/or signs), as well as any new or worsening symptoms and signs of large vessel involvement (eg, limb claudication, aortic murmur, peripheral loss of pulses). Patients should also be monitored for adverse effects from glucocorticoids (eg, osteoporosis, infection, diabetes, cataracts, and glaucoma) [7] and tocilizumab. (See "Major side effects of systemic glucocorticoids" and "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects", section on 'Adverse effects'.) ESR and CRP For patients who are not on tocilizumab, the ESR and CRP can be useful adjuncts to clinical decision making. Blockade of interleukin (IL) 6 activity with tocilizumab completely normalizes the ESR and CRP levels, with the result that these inflammatory makers are not useful for monitoring disease activity. Unfortunately, there are no useful alternative markers for monitoring disease activity in patients on tocilizumab, and clinicians must rely on clinical evaluation and, in the case of large vessel involvement, periodic imaging studies. For most patients on glucocorticoid monotherapy, the ESR and CRP usually improve substantially within a few days of the institution of therapy; the CRP declines much more rapidly than the ESR. Elevations of the ESR and CRP should be accompanied by other clinical findings suggestive of recrudescent GCA if changes in glucocorticoid doses are to be made. As markers of disease activity for large vessel GCA, the ESR and CRP have the same value and are accompanied by the same caveats as they do for the cranial phenotype. Both the ESR and CRP, however, 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 suggests 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'.) Imaging surveillance for patients with large vessel involvement Different imaging modalities (CT, CT angiography [CTA], magnetic resonance imaging [MRI], MR angiography [MRA], and ultrasound) may be used for long-term monitoring of structural damage, particularly to detect stenosis, occlusion, dilatation, and/or aneurysms. The frequency of surveillance, as well as the imaging method applied, should be decided on an individual basis. Repeat imaging of a https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 11/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 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'). There are not enough data to recommend the routine use of any of the different imaging modalities for monitoring disease activity during follow-up of patients with large vessel GCA. As an example, in a large retrospective cohort study of patients diagnosed with large vessel GCA, positron emission tomography (PET)/CT grading showed moderate accuracy in distinguishing between clinically active and inactive disease, with a sensitivity of 51 and specificity of 83 percent [41]. Furthermore, PET/CT was not able to predict subsequent relapse. However, in selected cases in which a flare is suspected, imaging might be helpful to confirm or exclude it. Prevention of treatment-associated toxicity Immunosuppressive therapy with high-dose glucocorticoids with or without a glucocorticoid-sparing agent has both infectious and noninfectious toxicities that warrant additional prophylactic measures. The specific regimens are discussed in detail separately: Prevention of opportunistic infections Reports of Pneumocystis jirovecii pneumonia (PCP) in GCA are rare [42,43]. In a retrospective cohort study of 1168 patients with GCA, no cases of PCP were identified over 547 patient-years of follow-up [44]. However, prednisone use at 16 mg daily or more for eight weeks has been shown to be associated with an increased risk of PCP [45], and to date, the risk of PCP in patients on prednisone and tocilizumab is unknown. While the absolute risk of PCP in GCA is small, some experts recommend PCP prophylaxis for patients with GCA given the risk of morbidity and mortality associated with PCP pneumonia. Ultimately, the decision to prescribe PCP prophylaxis should be individualized based on patient risk factors and preference and following a careful discussion of risks and benefit. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.) 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".) Age-appropriate vaccinations Age-appropriate vaccinations should be up to date in immunosuppressed patients. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".) https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 12/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Screening for latent tuberculosis Screening tests of latent tuberculosis should be performed at the start of therapy. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".) DISEASE RELAPSE Incidence and clinical features Reports on the incidence of relapses in giant cell arteritis (GCA) vary widely, from 34 to 74 percent [46-50]. 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 polymyalgia rheumatica (PMR) as a relapse of GCA. 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 [49]. Other estimates of the total duration of glucocorticoid treatment are in the range of one to two years [51,52], which is more consonant with clinical practice. 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. Elevations of the erythrocyte sedimentation rate (ESR) or C-reactive protein (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. In addition, if elevations in ESR and CRP are accompanied by constitutional symptoms, diagnostic imaging for underlying large vessel vasculitis may be considered. The occurrence of sight loss after an initial course of high-dose glucocorticoid treatment, administered daily, is exceptional. Management Increase glucocorticoid dose For patients who experience a relapse of GCA, we increase the glucocorticoid dose 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 40 to 60 mg/day and even pulse doses may be needed. For other symptoms, an increase of the daily dose of glucocorticoids to the last effective dose or 5 to 15 mg above this dose is appropriate. Smaller increments in the daily dose of prednisone, between 5 to 7.5 mg/day, are usually appropriate for PMR symptoms. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 13/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Addition of a glucocorticoid-sparing agent For patients who are not already on a glucocorticoid-sparing agent at the time of relapse, a glucocorticoid-sparing agent, preferably tocilizumab, should be added. The rationale for this approach is based on data from the clinical trials of tocilizumab for GCA that included patients with relapsing disease. These trials are discussed in detail above. (See 'Tocilizumab' above.) For patients with relapsing disease while already on tocilizumab, in addition to increasing the glucocorticoid dose, some experts may modify the tocilizumab dose or route of administration when possible. This approach is based on clinical experience, as there are no data to support this approach. As an example, if a patient relapses while on tocilizumab subcutaneous injections every other week, the dosing frequency may be increased to weekly injections. As another example, if a patient relapses while receiving tocilizumab 6 mg/kg intravenously once every four weeks, they may have their dose increased to 8 mg/kg once every four weeks. Additionally, switching from subcutaneous administration to intravenous administration may be attempted. Entry into an investigational trial may also be an option at some institutions for patients with relapsing disease while already on tocilizumab. UNPROVEN OR INEFFECTIVE AGENTS