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Newer Therapies for Giant Cell Arteritis
Advances in Ophthalmology and Optometry 2 (2017) 321–338
ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY
Newer Therapies for Giant Cell Arteritis Imran Jivraj, MD*, M.A. Tamhankar, MD Scheie Eye Institute, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA
Keywords
Giant cell arteritis Temporal arteritis Ischemic optic neuropathy Temporal artery biopsy Treatment
Key points
Giant cell arteritis (GCA) is the most common systemic vasculitic disease within the elderly population and is associated with typical symptoms of headache, scalp tenderness, jaw claudication, visual symptoms, and polymyalgia rheumatica in most patients.
Inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein, are elevated in most patients with GCA. Anemia and thrombocytosis may also be identified.
Treatment of GCA with high doses of corticosteroids must be initiated urgently to preserve vision, even when diagnostic studies are pending.
Relapse of inflammation is common in GCA and is identified by worsening of typical symptoms of GCA, elevations in inflammatory markers, or both. Recurrences of inflammation necessitate an escalation of corticosteroid dosage.
Emerging evidence for adjunctive therapy with tocilizumab, methotrexate, aspirin, angiotensin receptor blockers, and statins is encouraging and may lead to a more mainstream role for these therapies among patients with GCA.
INTRODUCTION Giant cell arteritis (GCA) is the most common systemic vasculitic disease among the elderly population and affects medium- to large-sized arteries. GCA classically presents in patients older than 50 years of age and is more common among women and Caucasians [1]. Typical symptoms of GCA
The authors have nothing to disclose.
*Corresponding author. E-mail address: [email protected] http://dx.doi.org/10.1016/j.yaoo.2017.03.014 2452-1760/17/ª 2017 Elsevier Inc. All rights reserved.
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include new-onset headache (60%–90%), temporal artery tenderness (40%– 70%), jaw claudication (30%–70%), constitutional symptoms such as fever (20%–50%), symptoms of polymyalgia rheumatica (PMR) (30%–50%), including aching and stiffness involving the neck, shoulder, or pelvic girdle, visual symptoms (14%–70%), and limb claudication (5%–15%) [1,2]. A history of transient episodes of visual loss should be elicited because these are described in 44% of patients who later suffer permanent visual loss from GCA [3]. In 20% of patients, the disease is clinically occult [4,5]. The most common ophthalmic manifestation of GCA is arteritic anterior ischemic optic neuropathy (A-AION), which is thought to result from vasculitic occlusion of the posterior ciliary vessels causing ischemia of the optic nerve head. A-AION typically presents with acute and often severe monocular vision loss in association with dyschromatopsia, an afferent pupillary defect, and pallid swelling of the optic nerve head. This entity must be differentiated from non–arteritic ischemic optic neuropathy (NA-AION) [6,7]. GCA may be associated with other forms of ophthalmic ischemia, such as posterior ischemic optic neuropathy, central retinal artery occlusion, branch retinal artery occlusion, cilioretinal artery occlusion, ophthalmic artery occlusion, and orbital ischemic syndrome. Cerebral ischemia may occur, most commonly in the vertebrobasilar distribution. Potentially lethal systemic complications of GCA include aortitis and large vessel vasculitis. INVESTIGATIONS When GCA is suspected, diagnostic investigations should include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count, including platelet count. What constitutes an elevated ESR level has been the subject of debate. The American College of Rheumatology (ACR) criteria defines an ESR greater than 50 mm/h to be elevated [8]. Miller and colleagues [9] devised a formula that is widely used by clinicians; the ESR is considered to be elevated if it exceeds half the patient’s age for men, whereas for women, the ESR must exceed the (patient age þ 10)/2. Hayreh and colleagues [10] proposed another formula to define an elevated ESR level. CRP is considered to be elevated if it exceeds 0.5 mg/dL [11]. One or both of these inflammatory markers are elevated in 90% to 95% of patients with GCA [6,12]. A complete blood count may reveal anemia and/or thrombocytosis (platelets >400,000/lL) [11]. In one study, the most common abnormal laboratory investigations associated with a positive temporal artery biopsy were thrombocytosis, followed by an elevated CRP [11]. Various diagnostic algorithms have scored the likelihood of GCA based on symptoms and levels of inflammatory markers [11,12]. TEMPORAL ARTERY BIOPSY A temporal artery biopsy is considered the gold standard for confirming the diagnosis of GCA. The ACR published a 5-point scoring system for diagnosing GCA within the research setting that ascribes one point for each of the following criteria: age greater than 50, newly acquired headache, painful and pulseless
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temporal artery, ESR >50 mm/h, and positive temporal artery biopsy. A score of 3 or greater had 93.5% sensitivity and 91.2% specificity for GCA [8,13,14]. Using ACR criteria, it is possible to make the diagnosis of GCA without obtaining a temporal artery biopsy, but empiric steroid treatment is almost never recommended and histologic confirmation is sought by most clinicians because of discordance between the ACR criteria and biopsy results [11,15,16]. A temporal artery biopsy is performed in all cases of suspected GCA at the authors’ center. A temporal artery biopsy is 100% specific for GCA, but the sensitivity of a single temporal artery biopsy has been reported to be 87.1% to 91.4% [11,17,18]. Biopsies of at least 2 cm in length have been recommended to reduce the risk of false negative results from skip lesions, although one retrospective study found no correlation between length of biopsy and histologic findings in specimens of at least 4 mm in length [19]. In most cases, a unilateral temporal artery biopsy is sufficient in suspected cases of GCA [20,21]. However, discordant results in cases in which bilateral temporal artery biopsies have been performed have been reported at a rate of 2% in one study and 13% in another, leading some clinicians to obtain bilateral temporal artery biopsies in all patients [22–25]. In situations where very high clinical suspicion for GCA exists despite a negative unilateral temporal artery biopsy, a contralateral biopsy is performed at the authors’ center. Biopsy of the temporal artery should be obtained soon after diagnosis is suspected, because the results may be altered if corticosteroid therapy has been instituted for more than 1 week; however, steroid treatment should not be delayed. Some literature suggests that a biopsy performed more than 2 weeks after corticosteroid therapy is initiated may still have diagnostic value [26]. In one study, which included patients with chronic PMR, temporal artery biopsy remained positive in 88% of patients despite the use of low-dose daily corticosteroids [26]. Typical histopathologic features seen on superficial temporal artery biopsy include mononuclear cell infiltrates most prominent within the adventitia and media, lymphocytes, macrophages, dendritic cells, and multinucleated giant cells associated with breakdown of the elastic lamina, and mural hyperplasia with luminal narrowing [1,27]. Complications of temporal artery biopsy are rare in experienced hands but include hematoma, wound dehiscence, brow ptosis, and facial nerve paresis [28]. OTHER ANCILLARY TESTS Intravenous fluorescein angiography may be useful in distinguishing cases of A-AION from those with NA-AION. In A-AION, fluorescein angiography may demonstrate delayed and patchy choroidal filling due to choroidal ischemia [7,29]. However, other clinical parameters, such as the patient’s age, presence of typical symptoms, past medical history, severity of vision loss, appearance and distribution of optic nerve swelling, optic nerve head configuration in the contralateral eye, and levels of inflammatory markers, may be useful in distinguishing the 2 conditions. Color Doppler ultrasonography (CDU) of the superficial temporal artery has been described as a noninvasive diagnostic test for GCA. CDU is
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performed using B-mode ultrasound and a suitable linear array transducer of 10 to 15 MHz to delineate vascular anatomy and may be combined with pulsed-wave Doppler to assess blood flow. In GCA, the ‘‘halo sign’’ has been described, which appears as a distinct hypoechogenic perivascular structure that is thought to represent perifocal arterial wall edema from inflammation. Other features of GCA that may be observed with ultrasonography include stenosis and complete occlusion of the vessel. CDU offers the advantage of assessment of the entire length of the temporal artery and can be performed bilaterally but requires expertise and may suffer from interoperator variability. Various meta-analyses have concluded that the halo sign is an accurate diagnostic test for GCA with a sensitivity of 69% to 75% and specificity of 82% to 98% compared with temporal artery biopsy; a bilaterally positive halo sign had 100% specificity for GCA [28,30–32]. Thus, in cases with a high clinical suspicion for GCA, the positive halo sign as assessed by an experienced ultrasonography operator may be a useful specific test to rule in the diagnosis when a biopsy cannot be performed; however, temporal artery biopsy still remains the gold standard for diagnosing GCA [28]. MRI of the temporal artery is being investigated as ancillary diagnostic tests for GCA. Postcontrast T1-weighted spin-echo MRI of the scalp arteries may demonstrate wall thickening and late contrast enhancement in GCA, although this may be identified in other conditions as well. In one prospective study, MRI was shown to have a sensitivity of 93.6% and a specificity of 77.9% when compared with the results of temporal artery biopsy, suggesting a possible role for MRI as a screening test in GCA [33]. The utility of MRI in the diagnosis of GCA is the subject of current research. TREATMENT: THE ROLE OF CORTICOSTEROIDS Unanimity exists about the necessity for immediate administration of high-dose steroids in the treatment of ophthalmic GCA. Before the era of corticosteroids, vision loss occurred in 30% to 60% of patients with GCA [34]. Moreover, up to 50% of patients presenting with vision loss from GCA will experience vision loss in the fellow eye within days to weeks if left untreated [3]. There may be a visual benefit to the affected eye with rapid initiation of corticosteroids as well. In patients who received corticosteroid therapy within 24 hours of visual symptoms, symptomatic improvement occurred in 58%; in contrast, only 6% had visual improvement after delayed steroid initiation [35]. The urgent administration of corticosteroid therapy is paramount to improving the chances of visual recovery in the affected eye, but more importantly, to protect vision in the fellow eye and minimize complications from systemic vasculitis (Table 1). INITIAL DOSE OF CORTICOSTEROIDS The initial dose of corticosteroids varies widely in the rheumatologic and neuro-ophthalmic literature and should be guided by the presence of ophthalmic involvement. Higher starting dosage of corticosteroids is required in patients who have impending or permanent vision loss and are discussed
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Table 1 Summary of treatment recommendations for giant cell arteritis Acute management of GCA Ophthalmic GCA Urgent intravenous methylprednisolone 15 mg/kg/d for 3–5 d, then 1–1.5 mg/kg/d prednisone Consider inpatient admission while receiving intravenous corticosteroids Nonophthalmic GCA Urgent oral prednisone 1 mg/kg/d Polymyalgia rheumatica Low-dose oral prednisone All patients Proton pump inhibitor or histamine H2 blocker Consider low-dose aspirin if there are no contraindications CTA or MRA to detect aortic aneurysm and large vessel vasculitis Consultation with primary care provider or internist for monitoring and prevention of steroid-related complications (hypertension, diabetes mellitus, osteoporosis, infectious prophylaxis) Encourage smoking cessation
Tapering of corticosteroids
Relapse
Follow-up examinations ESR/CRP must be normal and clinical symptoms absent before tapering prednisone Follow-up visits should be arranged every 2–4 wk until a daily dose of 40 mg is reached, then visit intervals may be increased to 4–6 wk Follow-up should be maintained for at least 1 year and longer if there are relapses
Tapering Schedule for ophthalmic GCA Taper by 10 mg/mo until a daily dose of 40 mg is reached Taper by 5 mg/mo until a daily dose of 20 mg is reached Taper by 2.5 mg/mo until a daily dose of 10 mg is reached Taper by 1–2 mg/mo until a maintenance dose is achieved or corticosteroids can be discontinued
Suspect relapse when clinical symptoms of GCA recur or when ESR/CRP levels increase without explanation, even if they remain within the normal range If ophthalmic involvement is suspected, consider administering intravenous corticosteroids for 3–5 d and initiating high-dose prednisone (see section ‘‘Acute Management’’) When nonophthalmic involvement is suspected, escalate oral prednisone dose to the last effective dose Consider immunosuppressive therapy with relapses, dependence on high doses of corticosteroids or high risk of complications from corticosteroids; partnership with an internist is strongly encouraged
later. Patients with GCA who do not have ophthalmic or cerebral manifestations may benefit from 40 to 60 mg of prednisone daily, and PMR classically responds rapidly to 20 mg of prednisone daily or less [1]. EVIDENCE FOR INTRAVENOUS VERSUS ORAL CORTICOSTEROIDS IN OPHTHALMIC GIANT CELL ARTERITIS The role of intravenous corticosteroid therapy in GCA is debatable and no class 1 studies have been done to prove its efficacy over oral corticosteroids. A study by Chevalet and colleagues [36] showed no benefit of a single dose of 240 mg of
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intravenous methylprednisolone in the treatment of systemic GCA without ocular or cerebral involvement. Another study reported similar results with the rate of visual deterioration in patients with GCA being no different among patients receiving high-dose intravenous versus oral corticosteroids alone [37]. Other studies have reported a benefit from intravenous corticosteroids, especially in those with ophthalmic involvement from GCA [38]. One study reported sustained remissions after initial therapy with intravenous methylprednisolone at a dose of 15 mg/kg/d for 3 days when compared with patients receiving intravenous saline followed by prednisone with identical tapering schedules. Moreover, patients who received intravenous corticosteroids had a lower median daily dose of steroids at 78 weeks, and a lower cumulative steroid dose [39]. A retrospective study reviewing the records of 100 consecutive patients with visual loss in GCA from AION found an increased likelihood of improved vision in the group that received high-dose intravenous corticosteroid for 3 days compared with patients who received oral corticosteroids alone [40]. The authors’ practice is to administer initial intravenous corticosteroids in those with vision loss, a recommendation supported by guidelines published by the European League against Rheumatism and the British Society for Rheumatology [41,42]. At the authors’ center, suitable patients are admitted for intravenous methylprednisolone at a dose of 15 mg/kg daily for 3 to 5 consecutive days followed by oral prednisone at a dose of 1 to 1.5 mg/kg. Alternatively, clinicians may choose to use initial therapy with oral prednisone. Labarca and colleagues [43] retrospectively evaluated 286 patients with biopsy-proven GCA and found that patients who received an initial oral dose of prednisone greater than 40 mg daily were able to reach a dose of less than 5 mg/d and discontinue corticosteroids sooner than patients receiving less than or equal to 40 mg/d without an increase in glucocorticoid-associated adverse events. Prednisone at a dose of 1 to 1.5 mg/kg/d (80–100 mg/d) is reasonable as initial therapy for ophthalmic GCA. IMPROVEMENT WITH STEROID Following initial therapy with corticosteroids, the vast majority of patients with systemic symptoms from GCA will notice rapid and dramatic improvement over hours to days [44]. Levels of ESR and CRP generally normalize within 2 to 4 weeks of steroid therapy [45]. Unfortunately, only 4% to 34% of patients experience improvement in vision loss despite corticosteroid treatment [46]. Sequential visual loss or further deterioration of vision in the affected eye may occur despite high-dose corticosteroids, often within the first 5 days of treatment [46]. DURATION AND TAPERING OF CORTICOSTEROID TREATMENT Corticosteroid treatment of ophthalmic GCA must be continued for months to years. Prednisone at an initial daily dose of 1 to 1.5 mg/kg should be maintained for a few weeks to suppress inflammation, after which the dose may
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be gradually tapered as long as ESR and CRP values remain within the normal range with tapering. It is reasonable to taper the dose of corticosteroids by 10 mg each month until a daily dose of 40 mg is reached and then taper the dose by 5 mg each month until a daily dose of 10 mg has been reached. The dose can then be reduced by 1 to 2.5 mg/mo until a daily maintenance dose is achieved or corticosteroids can be discontinued. Follow-up visits should occur every 2 to 4 weeks initially but may be extended to every 4 to 6 weeks after the corticosteroid dose is less than 40 mg daily. After discontinuation of corticosteroids, patients should be monitored for further relapses for at least 1 year [3,46]. IDENTIFICATION AND MANAGEMENT OF RELAPSE Relapse is suspected if a patient develops new symptoms concerning for GCA or if ESR and CRP levels increase without explanation, even in the absence of new symptoms. A small increase in ESR and CRP within the normal range should be followed carefully and repeated and should be correlated with other systemic medical issues in seeking an alternative explanation such as infection or malignancy [46]. Relapses are usually accompanied by increased ESR and CRP levels that may not exceed those at disease onset and, in one study, occurred at a mean corticosteroid dose of 5.3 mg/d [47]. The ESR and CRP were both within the normal range in 21% of relapses in another study [48]. When relapse is suspected, an escalation of the steroid dose is recommended. If ophthalmic involvement is suspected, intravenous or high-dose oral corticosteroids may be necessary. For systemic GCA symptoms, escalation to the last effective corticosteroid dose is appropriate. Treatment should be continued for at least 1 year, because a relapse rate as high as 77% was observed among patients who discontinued corticosteroid therapy within 1 year [47]. Late recurrences without new symptoms or elevations in inflammatory markers occurring 13 months after presentation have been reported [49]. SYSTEMIC MANIFESTATIONS OF GIANT CELL ARTERITIS Screening for aortic aneurysm and large vessel occlusive disease is recommended at disease presentation and every 2 to 5 years for those patients who would benefit from intervention [50,51]. Computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) imaging of the thoracic aorta and branch vessels are appropriate initial diagnostic tests. 18F-FluorodeoxyglucosePET is another imaging modality that has been used to detect large-vessel vasculitis in GCA [1,52,53]. CORTICOSTEROID SIDE EFFECTS Intravenous corticosteroids carry significant risk for adverse events. Worsening of cardiovascular disease, cardiac arrhythmias, myocardial infarction, hypertensive crises, psychosis, hyperosmolar hyperglycemia, hepatotoxicity, and sudden death have been reported rarely in patients receiving intravenous corticosteroids [54]. Clinicians should consider hospital admission for patients who
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are frail or have cardiovascular risk factors so that they may be monitored while receiving intravenous corticosteroid treatment. Proven and colleagues [55] reported that 86% of patients treated with corticosteroids for GCA experienced side effects, including posterior subcapsular cataracts (41%), bone fractures (38%), infections (31%), hypertension (22%), diabetes mellitus (9%), gastrointestinal bleeding (4%), and avascular necrosis of the hip (2.5%). Evaluation and follow-up with a physician who is experienced in longterm corticosteroid management are recommended for patients with GCA. The ACR recommends that all patients on long-term corticosteroids receive calcium supplementation (1200 mg/d) and vitamin D (800 IU/d) as well as bisphosphonate therapy if osteoporosis is seen on baseline bone mineral density. Weight-bearing exercise, smoking cessation, and reduction of alcohol intake should be encouraged. Dyspepsia and peptic ulcer disease may be managed with proton pump inhibitors or H2-receptor antagonists. Antimicrobial prophylaxis may be necessary because of the increased likelihood of opportunistic infection. Hypertension and diabetes may worsen with steroid treatment and should be managed aggressively [56]. IMMUNOSUPPRESSIVE AGENTS Although steroids alone may be used successfully in most patients with GCA, additional immunosuppression may be desirable when the disease is resistant to corticosteroid monotherapy, when a relapse of inflammation occurs at high doses of corticosteroid therapy, if a patient has experienced complications from corticosteroids, or if is thought to be at high risk of developing them [57]. The current role of immunosuppression is to permit lower cumulative corticosteroid doses and reduce adverse events without incurring further toxicity. However, the role of immunosuppressive therapy is evolving and monotherapy may be considered in the near future. TOCILIZUMAB Tocilizumab (Tocilizumab), a humanized anti-interleukin-6 (IL-6) receptor antibody, has been used with success in conditions such as rheumatoid arthritis and Crohn disease [58]. IL-6 is a pivotal proinflammatory cytokine that participates in the synthesis of acute phase proteins, promotes the passage of acute to chronic inflammation, and is essential for the development of adaptive immunity. Levels of IL-6 are elevated in the histologic specimens of temporal arteries in patients with GCA, and serum levels correlate with the extent of disease activity [58–60]. The efficacy of tocilizumab, when used in combination with corticosteroids or as an exclusive therapy for GCA, was demonstrated in small series and case reports [58,61–64]. The clinician should be aware that reduced inflammatory markers are not reliable indicators of GCA control in tocilizumab therapy [58]. A recent retrospective multicenter open-label study assessed the efficacy of tocilizumab in 22 patients with GCA who had refractory disease or unacceptable side effects from corticosteroids [65]. In this study, 86.4% of patients achieved rapid and maintained clinical improvement and reduction in clinical
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markers of inflammation and were able to taper steroids following tocilizumab therapy. However, tocilizumab had to be stopped in 3 patients because of severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, one patient died after the second infusion of tocilizumab because of a stroke in the setting of infectious endocarditis. Similar results were reported in another multicenter retrospective study involving 34 patients with GCA; tocilizumab was effective in 82.4%, but one patient died and 3 patients experienced serious adverse effects necessitating treatment cessation [66]. These studies demonstrated that tocilizumab leads to rapid and maintained improvement in patients with refractory GCA, but reaffirmed its association with an increased risk of serious infection, especially when used in concert with steroids and other immunosuppressant medications. The first phase 2 randomized, double-blind, placebo controlled trial of tocilizumab studied its efficacy in the induction and maintenance of remission in GCA. Thirty patients with new onset or relapsing disease were randomized to receive either tocilizumab or placebo infusions intravenously while receiving oral prednisone dosed according to a standardized taper schedule. In this study, 85% of patients receiving tocilizumab and 40% of patients receiving placebo achieved remission by week 12. Relapse-free survival was achieved in 85% of tocilizumab patients and 20% of placebo patients by 52 weeks. This study demonstrated the efficacy of tocilizumab in the induction and maintenance of remission in patients with GCA for the first time in a randomized trial setting [67]. Two other trials investigating IL-6–targeted therapies in larger numbers of patients with GCA involving tocilizumab and sirukinumab, another fully human anti-IL-6 antibody, are underway. It is conceivable that, with additional evidence from multiple randomized controlled trials, tocilizumab combined with corticosteroids may be considered a first-line treatment of GCA. Moreover, the role of tocilizumab as monotherapy for patients with GCA who are at unacceptably high risk from corticosteroid therapy may be explored [68]. METHOTREXATE The efficacy of methotrexate in newly diagnosed GCA was assessed in 3 prospective, randomized, double-blind controlled trials from 2001 to 2002 that yielded discordant conclusions. Two studies found no difference in the cumulative corticosteroid dose or duration of treatment in patients with GCA who were randomized to receive methotrexate or placebo during a corticosteroid taper [69,70]. A third study found that patients newly diagnosed with GCA who were randomized to receive methotrexate in addition to high-dose corticosteroids experienced fewer relapses, required a smaller cumulative corticosteroid dose and a shorter duration of treatment, but found no difference in the rate or severity of adverse events [71]. In a pooled meta-analysis from these trials, a reduction in the risk of relapse and a higher probability of achieving sustained discontinuation of steroids at 24 weeks was observed when methotrexate was administered at doses of 7.5 to 15 mg per week. However, there was no change in the rate of adverse
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events [72]. Methotrexate appears to be effective in GCA but appears to have a delayed corticosteroid-sparing effect. The available studies lacked long-term follow-up and did not use higher doses of methotrexate, which may demonstrate increased efficacy in GCA. IMMUNOSUPPRESSIVE AGENTS The efficacy of cyclophosphamide has been studied in retrospective reviews and case reports; cyclophosphamide was associated with a reduction in steroid requirements, but patients experienced a significant number of relapses as well as potentially life-threatening adverse events requiring suspension of treatment [73–75]. One study demonstrated a complete or partial response to leflunomide among 23 patients with PMR with or without GCA who were not adequately controlled on steroids or methotrexate [76]. Dapsone was associated with fewer relapses in patients with GCA who were concurrently receiving steroids, but there is currently insufficient evidence for its role in GCA [77]. A few studies support the use of azathioprine as an adjunctive agent in GCA, but its mild steroid-sparing effect must be balanced with the potential for serious adverse events [78–80]. Cyclosporine was studied in a multicenter prospective randomized, controlled open study and was shown to have a statistically significant reduction in the corticosteroid dosage and improvement in clinical parameters, but a high rate of adverse events [81,82]. Mycophenolate mofetil has been studied exclusively in case reports [83]. BIOLOGIC THERAPY Infliximab was initially thought to be a potential therapeutic agent in GCA, because of the elevated levels of tumor necrosis factor-alpha found in inflamed arteritis in GCA [84]; however, a randomized controlled trial was stopped prematurely due to lack of efficacy and concern about adverse events [85]. Currently, there is no evidence to suggest a role for infliximab in GCA. Etanercept was studied in a small double-blind placebo controlled trial in patients who had biopsy-proven GCA and had suffered adverse events from corticosteroids. A higher percentage of patients receiving etanercept was able to control the disease without corticosteroids, although this was not statistically significant, suggesting a possible steroid-sparing benefit [86]. Adalimumab is not currently considered to be efficacious in the management of GCA [87]. Rituximab has not been sufficiently studied in GCA [88]. Anakinra’s IL-1 blocking effect may be a potential therapeutic for GCA in light of elevated circulating levels of IL-1 in patients with GCA [89,90]. A case series of 3 patients suggested a beneficial effect in GCA, which warrants further study [91]. ANGIOTENSIN-CONVERTING-ENZYME INHIBITORS AND ANGIOTENSIN 2 RECEPTOR BLOCKERS IN GIANT CELL ARTERITIS Angiotensin 2 (AT2) is an important component of the renin-angiotensin system and is thought to be responsible for proinflammatory effects in
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hypertension. Angiotensin-converting-enzyme inhibitors (ACEi) and AT2 receptor blockers (ARB) suppress AT2-signaling, and several studies have addressed potential anti-inflammatory effects in autoimmune inflammation of the central nervous system [92]. Alba and colleagues [93] found that patients with GCA who were being treated with ARB had a significantly longer relapse-free survival and required a lower prednisone dose than those who were being treated with ACEi or patients receiving neither. The potential anti-inflammatory role of ARBs is encouraging and should be further explored. STATINS IN GIANT CELL ARTERITIS Statins possess anti-inflammatory and immunomodulatory properties [94], and there have been conflicting results about their role in GCA [95,96]. In a recent study, statin exposure was not associated with the development of GCA, but exposure to statins was associated with more rapid tapering of corticosteroids in patients who developed GCA [97]. These results suggest a possible protective role of statin therapy in GCA that merits further study. Clinicians should be aware that statins and nonsteroidal anti-inflammatory drugs may impact the levels of inflammatory markers [98]. ASPIRIN Aspirin’s action as an antiplatelet agent has been shown to prevent ischemic complications, such as stroke and myocardial infarction, in patients with atherosclerotic cardiovascular disease. The risk of cranial ischemic complications is higher among patients with GCA, particularly within the vertebrobasilar circulation. Various studies have sought to study the effect of aspirin on cranial ischemic complications among patients with GCA with mixed results [99–103]. The impact of a patient’s preexisting vascular risk factors has been difficult to separate from a therapeutic effect of aspirin, but one study supported the idea that atherosclerotic risk factors increased the risk of developing severe ischemic complications in GCA [104]. A meta-analysis concluded that there was no effect of antiplatelet or anticoagulant therapy instituted before the diagnosis of GCA on preventing severe ischemic complications. However, antiplatelet or anticoagulant therapy prevented the development of severe ischemic complications after the diagnosis of GCA without increasing the risk of bleeding [105]. A Cochrane Review concluded that there was insufficient evidence to recommend the use of aspirin as an adjunct treatment of GCA because no randomized controlled trials exist in the current literature [106]. The use of low-dose aspirin in patients with GCA is supported by European guidelines [41,42]. Clinicians who are considering the use of low-dose aspirin as an adjunctive treatment in GCA must recognize the established hemorrhagic risks associated with aspirin, especially in the context of concurrent treatment with corticosteroids, and its impact on renal physiology in the elderly [107,108]. There is a clear need for randomized controlled trials to establish the role of aspirin in the prevention of ischemic complications from GCA.
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OTHER FORMS OF ANTICOAGULATION It has been postulated that systemic anticoagulation may be beneficial during the initial phase of steroid treatment. In a prospective study, patients with GCA who presented with thrombocytosis were likely to experience ischemic visual symptoms, and that the finding of thrombocytosis should emphasize the need for urgent treatment, with consideration of inhibitors of platelet aggregation or anticoagulation therapy. There are no published prospective trials that have studied efficacy of anticoagulation in GCA, but 2 prior case reports have described improvement in vision with intravenous heparin [109,110]. Thus, the evidence, indications, and risks of anticoagulation in GCA have not been studied. ANTIVIRAL THERAPY A role of antiviral therapy has been proposed based on evidence that varicella zoster virus (VZV) may trigger the immunopathology of GCA. Virological analyses of temporal artery biopsy specimens demonstrated the presence of VZV in most GCA-positive temporal artery biopsies but VZV was also found in 20% of temporal artery biopsies from non-GCA postmortem controls [111]. Case reports have suggested some clinical benefit from treatment with intravenous acyclovir [106,112]. Currently, there is insufficient evidence for the use of antiviral therapy in GCA. SUMMARY Making the diagnosis of GCA is critical to preserving sight, but requires a thoughtful approach to the clinical history, presentation, and use of ancillary investigations. Typical symptoms are present in most patients, although a substantial number may have an occult presentation. Elevated inflammatory markers, such as ESR, CRP, anemia, and thrombocytosis, may support the diagnosis, although they are not specific to GCA. A temporal artery biopsy remains the gold standard diagnostic test. There is debate about the need for bilateral temporal artery biopsies and the role of other ancillary tests, including CDU and contrast-enhanced MRI of the temporal arteries, which are less invasive. The management of GCA poses a complex clinical challenge: on the one hand, failure to control inflammation may lead to devastating visual loss or systemic complications; on the other hand, therapeutic options are wrought with complications and morbidity. Corticosteroid therapy remains the cornerstone of immunosuppressive therapy in GCA and is initiated urgently at high doses, either intravenously or orally, when ophthalmic involvement of GCA is suspected. Over the course of at least 1 year, corticosteroids may be gradually tapered as the vigilant clinician monitors for symptoms and levels of inflammatory markers to identify relapse of inflammation. Prevention, screening, and management of corticosteroid-induced complications are essential. Failure to respond to steroids, relapses occurring with steroid taper, and development of steroid-related adverse effects are indications to consider immunosuppression. Methotrexate continues
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to be the most widely used agent, although it seems to have a modest effect. The evidence for tocilizumab is mounting as an effective adjunctive therapy in GCA. Mainstream use of other immunosuppressive agents is limited by a lack of proven efficacy beyond small case reports, evidence suggesting limited efficacy, or a high burden of toxicity. Initiation of low-dose aspirin may be beneficial in preventing severe ischemic complications at the time of diagnosis, while bearing in mind potential hemorrhagic complications when used in tandem with corticosteroids. The role for AT2 receptor blockers and statins is intriguing and merits further study. References [1] Hoffman GS. Giant cell arteritis. Ann Intern Med 2016;165(9):ITC65–80. [2] Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. Ann Intern Med 2003;139(6):505–15. [3] Almarzouqi SJ, Morgan ML, Lee AG. Treatment of giant cell arteritis. Curr Opin Ophthalmol 2015;26(6):469–75. [4] Simmons RJ, Cogan DG. Occult temporal arteritis. Arch Ophthalmol 1962;68:8–18. [5] Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 1998;125(4):521–6. [6] Buttgereit F, Dejaco C, Matteson EL, et al. Polymyalgia rheumatica and giant cell arteritis: a systematic review. JAMA 2016;315(22):2442–58. [7] Hayreh SS. Anterior ischaemic optic neuropathy. Differentiation of arteritic from nonarteritic type and its management. Eye (Lond) 1990;4(Pt 1):25–41. [8] Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33(8):1122–8. [9] Miller A, Green M, Robinson D. Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed) 1983;286(6361):266. [10] Hayreh SS, Podhajsky PA, Raman R, et al. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997;123(3):285–96. [11] El-Dairi MA, Chang L, Proia AD, et al. Diagnostic algorithm for patients with suspected giant cell arteritis. J Neuroophthalmol 2015;35(3):246–53. [12] Kermani TA, Schmidt J, Crowson CS, et al. Utility of erythrocyte sedimentation rate and C-reactive protein for the diagnosis of giant cell arteritis. Semin Arthritis Rheum 2012;41(6):866–71. [13] Rao JK, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis. Ann Intern Med 1998;129(5):345–52. [14] Davies C, Frost B, Eshan O, et al. Temporal artery biopsy.who needs one? Postgrad Med J 2006;82(969):476–8. [15] Drehmer TJ, Khanna D, Markert RJ, et al. Diagnostic and management trends of giant cell arteritis: a physician survey. J Rheumatol 2005;32(7):1283–9. [16] Murchison AP, Gilbert ME, Bilyk JR, et al. Validity of the American College of Rheumatology criteria for the diagnosis of giant cell arteritis. Am J Ophthalmol 2012;154(4): 722–9. [17] Niederkohr RD, Levin LA. A Bayesian analysis of the true sensitivity of a temporal artery biopsy. Invest Ophthalmol Vis Sci 2007;48(2):675–80. [18] Bhatti MT, Tabandeh H. Giant cell arteritis: diagnosis and management. Curr Opin Ophthalmol 2001;12(6):393–9. [19] Chambers WA, Bernardino B. Specimen length in temporal artery biopsies. J Clin Neuroophthalmol 1988;8(2):121–5. [20] Boyev LR, Miller NR, Green WR. Efficacy of unilateral versus bilateral temporal artery biopsies for the diagnosis of giant cell arteritis. Am J Ophthalmol 1999;128(2):211–5.
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[21] Hall JK, Volpe NJ, Galetta SL, et al. The role of unilateral temporal artery biopsy. Ophthalmology 2003;110(3):543–8 [discussion: 548]. [22] Huston KA, Hunder GG, Lie JT, et al. Temporal arteritis: a 25-year epidemiologic, clinical, and pathologic study. Ann Intern Med 1978;88(2):162–7. [23] Pless M, Rizzo JF 3rd, Lamkin JC, et al. Concordance of bilateral temporal artery biopsy in giant cell arteritis. J Neuroophthalmol 2000;20(3):216–8. [24] Danesh-Meyer HV, Savino PJ, Eagle RC Jr, et al. Low diagnostic yield with second biopsies in suspected giant cell arteritis. J Neuroophthalmol 2000;20(3):213–5. [25] Niederkohr RD, Levin LA. Management of the patient with suspected temporal arteritis a decision-analytic approach. Ophthalmology 2005;112(5):744–56. [26] Bury D, Joseph J, Dawson TP. Does preoperative steroid treatment affect the histology in giant cell (cranial) arteritis? J Clin Pathol 2012;65(12):1138–40. [27] Roberts WC, Zafar S, Ko JM. Morphological features of temporal arteritis. Proc (Bayl Univ Med Cent) 2013;26(2):109–15. [28] Landau K, Savino PJ, Gruber P. Diagnosing giant cell arteritis: is ultrasound enough? J Neuroophthalmol 2013;33(4):394–400. [29] Siatkowski RM, Gass JD, Glaser JS, et al. Fluorescein angiography in the diagnosis of giant cell arteritis. Am J Ophthalmol 1993;115(1):57–63. [30] Karassa FB, Matsagas MI, Schmidt WA, et al. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med 2005;142(5):359–69. [31] Ball EL, Walsh SR, Tang TY, et al. Role of ultrasonography in the diagnosis of temporal arteritis. Br J Surg 2010;97(12):1765–71. [32] Arida A, Kyprianou M, Kanakis M, et al. The diagnostic value of ultrasonography-derived edema of the temporal artery wall in giant cell arteritis: a second meta-analysis. BMC Musculoskelet Disord 2010;11:44. [33] Rheaume M, Rebello R, Pagnoux C, et al. High-resolution magnetic resonance imaging of scalp arteries for the diagnosis of giant cell arteritis: results of a prospective cohort study. Arthritis Rheumatol 2017;69(1):161–8. [34] Gonzalez-Gay MA, Blanco R, Rodriguez-Valverde V, et al. Permanent visual loss and cerebrovascular accidents in giant cell arteritis: predictors and response to treatment. Arthritis Rheum 1998;41(8):1497–504. [35] Eberhardt RT, Dhadly M. Giant cell arteritis: diagnosis, management, and cardiovascular implications. Cardiol Rev 2007;15(2):55–61. [36] Chevalet P, Barrier JH, Pottier P, et al. A randomized, multicenter, controlled trial using intravenous pulses of methylprednisolone in the initial treatment of simple forms of giant cell arteritis: a one year followup study of 164 patients. J Rheumatol 2000;27(6):1484–91. [37] Hayreh SS, Zimmerman B. Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy. Ophthalmology 2003;110(6):1204–15. [38] Liu GT, Glaser JS, Schatz NJ, et al. Visual morbidity in giant cell arteritis. Clinical characteristics and prognosis for vision. Ophthalmology 1994;101(11):1779–85. [39] Mazlumzadeh M, Hunder GG, Easley KA, et al. Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial. Arthritis Rheum 2006;54(10):3310–8. [40] Chan CC, Paine M, O’Day J. Steroid management in giant cell arteritis. Br J Ophthalmol 2001;85(9):1061–4. [41] Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009;68(3):318–23. [42] Dasgupta B, Giant Cell Arteritis Guideline Development Group. Concise guidance: diagnosis and management of giant cell arteritis. Clin Med (Lond) 2010;10(4):381–6. [43] Labarca C, Koster MJ, Crowson CS, et al. Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study. Rheumatology (Oxford) 2016;55(2):347–56.
NEWER THERAPIES FOR GIANT CELL ARTERITIS
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[44] Salvarani C, Cantini F, Boiardi L, et al. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002;347(4):261–71. [45] Gonzalez-Gay MA, Pina T. Giant cell arteritis and polymyalgia rheumatica: an update. Curr Rheumatol Rep 2015;17(2):6. [46] Fraser JA, Weyand CM, Newman NJ, et al. The treatment of giant cell arteritis. Rev Neurol Dis 2008;5(3):140–52. [47] Alba MA, Garcia-Martinez A, Prieto-Gonzalez S, et al. Relapses in patients with giant cell arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients. Medicine (Baltimore) 2014;93(5):194–201. [48] Kermani TA, Warrington KJ, Cuthbertson D, et al. Disease relapses among patients with giant cell arteritis: a prospective, longitudinal cohort study. J Rheumatol 2015;42(7): 1213–7. [49] Kim N, Trobe JD, Flint A, et al. Late ipsilateral recurrence of ischemic optic neuropathy in giant cell arteritis. J Neuroophthalmol 2003;23(2):122–6. [50] Mackie SL, Hensor EM, Morgan AW, et al. Should I send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A systematic literature review and meta-analysis. Ann Rheum Dis 2014;73(1):143–8. [51] Bienvenu B, Ly KH, Lambert M, et al. Management of giant cell arteritis: recommendations of the French Study Group for Large Vessel Vasculitis (GEFA). Rev Med Interne 2016;37(3): 154–65. [52] Houthuizen P, Polak PE, Edelbroek MA, et al. Giant cell arteritis as a cardiovascular entity. Neth Heart J 2009;17(7–8):281–3. [53] Nayar AK, Casciello M, Slim JN, et al. Fatal aortic dissection in a patient with giant cell arteritis: a case report and review of the literature. Case Rep Vasc Med 2013;2013: 590721. [54] Gutkowski K, Chwist A, Hartleb M. Liver injury induced by high-dose methylprednisolone therapy: a case report and brief review of the literature. Hepat Mon 2011;11(8):656–61. [55] Proven A, Gabriel SE, Orces C, et al. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum 2003;49(5):703–8. [56] Briot K, Cortet B, Roux C, et al. 2014 update of recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis. Joint Bone Spine 2014;81(6): 493–501. [57] Spies CM, Burmester GR, Buttgereit F. Methotrexate treatment in large vessel vasculitis and polymyalgia rheumatica. Clin Exp Rheumatol 2010;28(5 Suppl 61):S172–7. [58] Unizony S, Arias-Urdaneta L, Miloslavsky E, et al. Tocilizumab for the treatment of largevessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken) 2012;64(11):1720–9. [59] Roche NE, Fulbright JW, Wagner AD, et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993;36(9):1286–94. [60] Emilie D, Liozon E, Crevon MC, et al. Production of interleukin 6 by granulomas of giant cell arteritis. Hum Immunol 1994;39(1):17–24. [61] Beyer C, Axmann R, Sahinbegovic E, et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis 2011;70(10):1874–5. [62] Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156. [63] Pazzola G, Padovano I, Boiardi L, et al. Tocilizumab in glucocorticoid-naive large-vessel vasculitis. Clin Exp Rheumatol 2013;31(1 Suppl 75):S59–61. [64] Evans J, Steel L, Borg F, et al. Long-term efficacy and safety of tocilizumab in giant cell arteritis and large vessel vasculitis. RMD Open 2016;2(1):e000137. [65] Loricera J, Blanco R, Hernandez JL, et al. Tocilizumab in giant cell arteritis: multicenter open-label study of 22 patients. Semin Arthritis Rheum 2015;44(6):717–23.
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[66] Regent A, Redeker S, Deroux A, et al. Tocilizumab in giant cell arteritis: a multicenter retrospective study of 34 patients. J Rheumatol 2016;43(8):1547–52. [67] Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016;387(10031):1921–7. [68] Devauchelle-Pensec V. Has the time come for biotherapies in giant cell arteritis and polymyalgia rheumatica? Joint Bone Spine 2016;83(5):471–2. [69] Spiera RF, Mitnick HJ, Kupersmith M, et al. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol 2001;19(5):495–501. [70] Hoffman GS, Cid MC, Hellmann DB, et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46(5):1309–18. [71] Jover JA, Hernandez-Garcia C, Morado IC, et al. Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134(2):106–14. [72] Mahr AD, Jover JA, Spiera RF, et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum 2007;56(8):2789–97. [73] Quartuccio L, Maset M, De Maglio G, et al. Role of oral cyclophosphamide in the treatment of giant cell arteritis. Rheumatology (Oxford) 2012;51(9):1677–86. [74] Loock J, Henes J, Kotter I, et al. Treatment of refractory giant cell arteritis with cyclophosphamide:a retrospective analysis of 35 patients from three centres. Clin Exp Rheumatol 2012;30(1 Suppl 70):S70–6. [75] de Boysson H, Boutemy J, Creveuil C, et al. Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review. Semin Arthritis Rheum 2013;43(1):105–12. [76] Adizie T, Christidis D, Dharmapaliah C, et al. Efficacy and tolerability of leflunomide in difficult-to-treat polymyalgia rheumatica and giant cell arteritis: a case series. Int J Clin Pract 2012;66(9):906–9. [77] Liozon F, Vidal E, Barrier J. Does dapsone have a role in the treatment of temporal arteritis with regard to efficacy and toxicity? Clin Exp Rheumatol 1993;11(6):694–5. [78] De Silva M, Hazleman BL. Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis 1986;45(2):136–8. [79] Boureau AS, de Faucal P, Espitia O, et al. Place of azathioprine in the treatment of giant cell arteritis. Rev Med Interne 2016;37(11):723–9 [in French]. [80] Nuenninghoff DM, Matteson EL. The role of disease-modifying antirheumatic drugs in the treatment of giant cell arteritis. Clin Exp Rheumatol 2003;21(6 Suppl 32):S29–34. [81] Schaufelberger C, Andersson R, Nordborg E. No additive effect of cyclosporin A compared with glucocorticoid treatment alone in giant cell arteritis: results of an open, controlled, randomized study. Br J Rheumatol 1998;37(4):464–5. [82] Schaufelberger C, Mollby H, Uddhammar A, et al. No additional steroid-sparing effect of cyclosporine A in giant cell arteritis. Scand J Rheumatol 2006;35(4):327–9. [83] Sciascia S, Piras D, Baldovino S, et al. Mycophenolate mofetil as steroid-sparing treatment for elderly patients with giant cell arteritis: report of three cases. Aging Clin Exp Res 2012;24(3):273–7. [84] Ahmed MM, Mubashir E, Hayat S, et al. Treatment of refractory temporal arteritis with adalimumab. Clin Rheumatol 2007;26(8):1353–5. [85] Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007;146(9):621–30. [86] Martinez-Taboada VM, Rodriguez-Valverde V, Carreno L, et al. A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis 2008;67(5):625–30.
NEWER THERAPIES FOR GIANT CELL ARTERITIS
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[87] Seror R, Baron G, Hachulla E, et al. Adalimumab for steroid sparing in patients with giantcell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis 2014;73(12):2074–81. [88] Bhatia A, Ell PJ, Edwards JC. Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann Rheum Dis 2005;64(7):1099–100. [89] Pountain G, Hazleman B, Cawston TE. Circulating levels of IL-1beta, IL-6 and soluble IL-2 receptor in polymyalgia rheumatica and giant cell arteritis and rheumatoid arthritis. Br J Rheumatol 1998;37(7):797–8. [90] Hernandez-Rodriguez J, Segarra M, Vilardell C, et al. Tissue production of proinflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology (Oxford) 2004;43(3):294–301. [91] Ly KH, Stirnemann J, Liozon E, et al. Interleukin-1 blockade in refractory giant cell arteritis. Joint Bone Spine 2014;81(1):76–8. [92] Stegbauer J, Lee DH, Seubert S, et al. Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system. Proc Natl Acad Sci U S A 2009;106(35): 14942–7. [93] Alba MA, Garcia-Martinez A, Prieto-Gonzalez S, et al. Treatment with angiotensin II receptor blockers is associated with prolonged relapse-free survival, lower relapse rate, and corticosteroid-sparing effect in patients with giant cell arteritis. Semin Arthritis Rheum 2014;43(6):772–7. [94] Montecucco F, Mach F. Update on statin-mediated anti-inflammatory activities in atherosclerosis. Semin Immunopathol 2009;31(1):127–42. [95] Garcia-Martinez A, Hernandez-Rodriguez J, Grau JM, et al. Treatment with statins does not exhibit a clinically relevant corticosteroid-sparing effect in patients with giant cell arteritis. Arthritis Rheum 2004;51(4):674–8. [96] Schmidt J, Kermani TA, Muratore F, et al. Statin use in giant cell arteritis: a retrospective study. J Rheumatol 2013;40(6):910–5. [97] Pugnet G, Sailler L, Bourrel R, et al. Is statin exposure associated with occurrence or better outcome in giant cell arteritis? Results from a French population-based study. J Rheumatol 2015;42(2):316–22. [98] Hegg R, Lee AG, Tagg NT, et al. Statin or nonsteroidal anti-inflammatory drug use is associated with lower erythrocyte sedimentation rate in patients with giant cell arteritis. J Neuroophthalmol 2011;31(2):135–8. [99] Nesher G, Berkun Y, Mates M, et al. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 2004;50(4):1332–7. [100] Lee MS, Smith SD, Galor A, et al. Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum 2006;54(10):3306–9. [101] Narvaez J, Bernad B, Gomez-Vaquero C, et al. Impact of antiplatelet therapy in the development of severe ischemic complications and in the outcome of patients with giant cell arteritis. Clin Exp Rheumatol 2008;26(3 Suppl 49):S57–62. [102] Salvarani C, Della Bella C, Cimino L, et al. Risk factors for severe cranial ischaemic events in an Italian population-based cohort of patients with giant cell arteritis. Rheumatology (Oxford) 2009;48(3):250–3. [103] Berger CT, Wolbers M, Meyer P, et al. High incidence of severe ischaemic complications in patients with giant cell arteritis irrespective of platelet count and size, and platelet inhibition. Rheumatology (Oxford) 2009;48(3):258–61. [104] Gonzalez-Gay MA, Pineiro A, Gomez-Gigirey A, et al. Influence of traditional risk factors of atherosclerosis in the development of severe ischemic complications in giant cell arteritis. Medicine (Baltimore) 2004;83(6):342–7. [105] Martinez-Taboada VM, Lopez-Hoyos M, Narvaez J, et al. Effect of antiplatelet/anticoagulant therapy on severe ischemic complications in patients with giant cell arteritis: a cumulative meta-analysis. Autoimmun Rev 2014;13(8):788–94.
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[106] Mollan SP, Sharrack N, Burdon MA, et al. Aspirin as adjunctive treatment for giant cell arteritis. Cochrane Database Syst Rev 2014;(8):CD010453. [107] Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002;162(19):2197–202. [108] Caspi D, Lubart E, Graff E, et al. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum 2000;43(1):103–8. [109] Buono LM, Foroozan R, de Virgiliis M, et al. Heparin therapy in giant cell arteritis. Br J Ophthalmol 2004;88(2):298–301. [110] Staunton H, Stafford F, Leader M, et al. Deterioration of giant cell arteritis with corticosteroid therapy. Arch Neurol 2000;57(4):581–4. [111] Gilden D, Nagel MA. Varicella zoster virus triggers the immunopathology of giant cell arteritis. Curr Opin Rheumatol 2016;28(4):376–82. [112] Gilden D, White T, Khmeleva N, et al. Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology 2015;84(19):1948–55.
ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY
Newer Therapies for Giant Cell Arteritis Imran Jivraj, MD*, M.A. Tamhankar, MD Scheie Eye Institute, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA
Keywords
Giant cell arteritis Temporal arteritis Ischemic optic neuropathy Temporal artery biopsy Treatment
Key points
Giant cell arteritis (GCA) is the most common systemic vasculitic disease within the elderly population and is associated with typical symptoms of headache, scalp tenderness, jaw claudication, visual symptoms, and polymyalgia rheumatica in most patients.
Inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein, are elevated in most patients with GCA. Anemia and thrombocytosis may also be identified.
Treatment of GCA with high doses of corticosteroids must be initiated urgently to preserve vision, even when diagnostic studies are pending.
Relapse of inflammation is common in GCA and is identified by worsening of typical symptoms of GCA, elevations in inflammatory markers, or both. Recurrences of inflammation necessitate an escalation of corticosteroid dosage.
Emerging evidence for adjunctive therapy with tocilizumab, methotrexate, aspirin, angiotensin receptor blockers, and statins is encouraging and may lead to a more mainstream role for these therapies among patients with GCA.
INTRODUCTION Giant cell arteritis (GCA) is the most common systemic vasculitic disease among the elderly population and affects medium- to large-sized arteries. GCA classically presents in patients older than 50 years of age and is more common among women and Caucasians [1]. Typical symptoms of GCA
The authors have nothing to disclose.
*Corresponding author. E-mail address: [email protected] http://dx.doi.org/10.1016/j.yaoo.2017.03.014 2452-1760/17/ª 2017 Elsevier Inc. All rights reserved.
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include new-onset headache (60%–90%), temporal artery tenderness (40%– 70%), jaw claudication (30%–70%), constitutional symptoms such as fever (20%–50%), symptoms of polymyalgia rheumatica (PMR) (30%–50%), including aching and stiffness involving the neck, shoulder, or pelvic girdle, visual symptoms (14%–70%), and limb claudication (5%–15%) [1,2]. A history of transient episodes of visual loss should be elicited because these are described in 44% of patients who later suffer permanent visual loss from GCA [3]. In 20% of patients, the disease is clinically occult [4,5]. The most common ophthalmic manifestation of GCA is arteritic anterior ischemic optic neuropathy (A-AION), which is thought to result from vasculitic occlusion of the posterior ciliary vessels causing ischemia of the optic nerve head. A-AION typically presents with acute and often severe monocular vision loss in association with dyschromatopsia, an afferent pupillary defect, and pallid swelling of the optic nerve head. This entity must be differentiated from non–arteritic ischemic optic neuropathy (NA-AION) [6,7]. GCA may be associated with other forms of ophthalmic ischemia, such as posterior ischemic optic neuropathy, central retinal artery occlusion, branch retinal artery occlusion, cilioretinal artery occlusion, ophthalmic artery occlusion, and orbital ischemic syndrome. Cerebral ischemia may occur, most commonly in the vertebrobasilar distribution. Potentially lethal systemic complications of GCA include aortitis and large vessel vasculitis. INVESTIGATIONS When GCA is suspected, diagnostic investigations should include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count, including platelet count. What constitutes an elevated ESR level has been the subject of debate. The American College of Rheumatology (ACR) criteria defines an ESR greater than 50 mm/h to be elevated [8]. Miller and colleagues [9] devised a formula that is widely used by clinicians; the ESR is considered to be elevated if it exceeds half the patient’s age for men, whereas for women, the ESR must exceed the (patient age þ 10)/2. Hayreh and colleagues [10] proposed another formula to define an elevated ESR level. CRP is considered to be elevated if it exceeds 0.5 mg/dL [11]. One or both of these inflammatory markers are elevated in 90% to 95% of patients with GCA [6,12]. A complete blood count may reveal anemia and/or thrombocytosis (platelets >400,000/lL) [11]. In one study, the most common abnormal laboratory investigations associated with a positive temporal artery biopsy were thrombocytosis, followed by an elevated CRP [11]. Various diagnostic algorithms have scored the likelihood of GCA based on symptoms and levels of inflammatory markers [11,12]. TEMPORAL ARTERY BIOPSY A temporal artery biopsy is considered the gold standard for confirming the diagnosis of GCA. The ACR published a 5-point scoring system for diagnosing GCA within the research setting that ascribes one point for each of the following criteria: age greater than 50, newly acquired headache, painful and pulseless
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temporal artery, ESR >50 mm/h, and positive temporal artery biopsy. A score of 3 or greater had 93.5% sensitivity and 91.2% specificity for GCA [8,13,14]. Using ACR criteria, it is possible to make the diagnosis of GCA without obtaining a temporal artery biopsy, but empiric steroid treatment is almost never recommended and histologic confirmation is sought by most clinicians because of discordance between the ACR criteria and biopsy results [11,15,16]. A temporal artery biopsy is performed in all cases of suspected GCA at the authors’ center. A temporal artery biopsy is 100% specific for GCA, but the sensitivity of a single temporal artery biopsy has been reported to be 87.1% to 91.4% [11,17,18]. Biopsies of at least 2 cm in length have been recommended to reduce the risk of false negative results from skip lesions, although one retrospective study found no correlation between length of biopsy and histologic findings in specimens of at least 4 mm in length [19]. In most cases, a unilateral temporal artery biopsy is sufficient in suspected cases of GCA [20,21]. However, discordant results in cases in which bilateral temporal artery biopsies have been performed have been reported at a rate of 2% in one study and 13% in another, leading some clinicians to obtain bilateral temporal artery biopsies in all patients [22–25]. In situations where very high clinical suspicion for GCA exists despite a negative unilateral temporal artery biopsy, a contralateral biopsy is performed at the authors’ center. Biopsy of the temporal artery should be obtained soon after diagnosis is suspected, because the results may be altered if corticosteroid therapy has been instituted for more than 1 week; however, steroid treatment should not be delayed. Some literature suggests that a biopsy performed more than 2 weeks after corticosteroid therapy is initiated may still have diagnostic value [26]. In one study, which included patients with chronic PMR, temporal artery biopsy remained positive in 88% of patients despite the use of low-dose daily corticosteroids [26]. Typical histopathologic features seen on superficial temporal artery biopsy include mononuclear cell infiltrates most prominent within the adventitia and media, lymphocytes, macrophages, dendritic cells, and multinucleated giant cells associated with breakdown of the elastic lamina, and mural hyperplasia with luminal narrowing [1,27]. Complications of temporal artery biopsy are rare in experienced hands but include hematoma, wound dehiscence, brow ptosis, and facial nerve paresis [28]. OTHER ANCILLARY TESTS Intravenous fluorescein angiography may be useful in distinguishing cases of A-AION from those with NA-AION. In A-AION, fluorescein angiography may demonstrate delayed and patchy choroidal filling due to choroidal ischemia [7,29]. However, other clinical parameters, such as the patient’s age, presence of typical symptoms, past medical history, severity of vision loss, appearance and distribution of optic nerve swelling, optic nerve head configuration in the contralateral eye, and levels of inflammatory markers, may be useful in distinguishing the 2 conditions. Color Doppler ultrasonography (CDU) of the superficial temporal artery has been described as a noninvasive diagnostic test for GCA. CDU is
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performed using B-mode ultrasound and a suitable linear array transducer of 10 to 15 MHz to delineate vascular anatomy and may be combined with pulsed-wave Doppler to assess blood flow. In GCA, the ‘‘halo sign’’ has been described, which appears as a distinct hypoechogenic perivascular structure that is thought to represent perifocal arterial wall edema from inflammation. Other features of GCA that may be observed with ultrasonography include stenosis and complete occlusion of the vessel. CDU offers the advantage of assessment of the entire length of the temporal artery and can be performed bilaterally but requires expertise and may suffer from interoperator variability. Various meta-analyses have concluded that the halo sign is an accurate diagnostic test for GCA with a sensitivity of 69% to 75% and specificity of 82% to 98% compared with temporal artery biopsy; a bilaterally positive halo sign had 100% specificity for GCA [28,30–32]. Thus, in cases with a high clinical suspicion for GCA, the positive halo sign as assessed by an experienced ultrasonography operator may be a useful specific test to rule in the diagnosis when a biopsy cannot be performed; however, temporal artery biopsy still remains the gold standard for diagnosing GCA [28]. MRI of the temporal artery is being investigated as ancillary diagnostic tests for GCA. Postcontrast T1-weighted spin-echo MRI of the scalp arteries may demonstrate wall thickening and late contrast enhancement in GCA, although this may be identified in other conditions as well. In one prospective study, MRI was shown to have a sensitivity of 93.6% and a specificity of 77.9% when compared with the results of temporal artery biopsy, suggesting a possible role for MRI as a screening test in GCA [33]. The utility of MRI in the diagnosis of GCA is the subject of current research. TREATMENT: THE ROLE OF CORTICOSTEROIDS Unanimity exists about the necessity for immediate administration of high-dose steroids in the treatment of ophthalmic GCA. Before the era of corticosteroids, vision loss occurred in 30% to 60% of patients with GCA [34]. Moreover, up to 50% of patients presenting with vision loss from GCA will experience vision loss in the fellow eye within days to weeks if left untreated [3]. There may be a visual benefit to the affected eye with rapid initiation of corticosteroids as well. In patients who received corticosteroid therapy within 24 hours of visual symptoms, symptomatic improvement occurred in 58%; in contrast, only 6% had visual improvement after delayed steroid initiation [35]. The urgent administration of corticosteroid therapy is paramount to improving the chances of visual recovery in the affected eye, but more importantly, to protect vision in the fellow eye and minimize complications from systemic vasculitis (Table 1). INITIAL DOSE OF CORTICOSTEROIDS The initial dose of corticosteroids varies widely in the rheumatologic and neuro-ophthalmic literature and should be guided by the presence of ophthalmic involvement. Higher starting dosage of corticosteroids is required in patients who have impending or permanent vision loss and are discussed
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Table 1 Summary of treatment recommendations for giant cell arteritis Acute management of GCA Ophthalmic GCA Urgent intravenous methylprednisolone 15 mg/kg/d for 3–5 d, then 1–1.5 mg/kg/d prednisone Consider inpatient admission while receiving intravenous corticosteroids Nonophthalmic GCA Urgent oral prednisone 1 mg/kg/d Polymyalgia rheumatica Low-dose oral prednisone All patients Proton pump inhibitor or histamine H2 blocker Consider low-dose aspirin if there are no contraindications CTA or MRA to detect aortic aneurysm and large vessel vasculitis Consultation with primary care provider or internist for monitoring and prevention of steroid-related complications (hypertension, diabetes mellitus, osteoporosis, infectious prophylaxis) Encourage smoking cessation
Tapering of corticosteroids
Relapse
Follow-up examinations ESR/CRP must be normal and clinical symptoms absent before tapering prednisone Follow-up visits should be arranged every 2–4 wk until a daily dose of 40 mg is reached, then visit intervals may be increased to 4–6 wk Follow-up should be maintained for at least 1 year and longer if there are relapses
Tapering Schedule for ophthalmic GCA Taper by 10 mg/mo until a daily dose of 40 mg is reached Taper by 5 mg/mo until a daily dose of 20 mg is reached Taper by 2.5 mg/mo until a daily dose of 10 mg is reached Taper by 1–2 mg/mo until a maintenance dose is achieved or corticosteroids can be discontinued
Suspect relapse when clinical symptoms of GCA recur or when ESR/CRP levels increase without explanation, even if they remain within the normal range If ophthalmic involvement is suspected, consider administering intravenous corticosteroids for 3–5 d and initiating high-dose prednisone (see section ‘‘Acute Management’’) When nonophthalmic involvement is suspected, escalate oral prednisone dose to the last effective dose Consider immunosuppressive therapy with relapses, dependence on high doses of corticosteroids or high risk of complications from corticosteroids; partnership with an internist is strongly encouraged
later. Patients with GCA who do not have ophthalmic or cerebral manifestations may benefit from 40 to 60 mg of prednisone daily, and PMR classically responds rapidly to 20 mg of prednisone daily or less [1]. EVIDENCE FOR INTRAVENOUS VERSUS ORAL CORTICOSTEROIDS IN OPHTHALMIC GIANT CELL ARTERITIS The role of intravenous corticosteroid therapy in GCA is debatable and no class 1 studies have been done to prove its efficacy over oral corticosteroids. A study by Chevalet and colleagues [36] showed no benefit of a single dose of 240 mg of
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intravenous methylprednisolone in the treatment of systemic GCA without ocular or cerebral involvement. Another study reported similar results with the rate of visual deterioration in patients with GCA being no different among patients receiving high-dose intravenous versus oral corticosteroids alone [37]. Other studies have reported a benefit from intravenous corticosteroids, especially in those with ophthalmic involvement from GCA [38]. One study reported sustained remissions after initial therapy with intravenous methylprednisolone at a dose of 15 mg/kg/d for 3 days when compared with patients receiving intravenous saline followed by prednisone with identical tapering schedules. Moreover, patients who received intravenous corticosteroids had a lower median daily dose of steroids at 78 weeks, and a lower cumulative steroid dose [39]. A retrospective study reviewing the records of 100 consecutive patients with visual loss in GCA from AION found an increased likelihood of improved vision in the group that received high-dose intravenous corticosteroid for 3 days compared with patients who received oral corticosteroids alone [40]. The authors’ practice is to administer initial intravenous corticosteroids in those with vision loss, a recommendation supported by guidelines published by the European League against Rheumatism and the British Society for Rheumatology [41,42]. At the authors’ center, suitable patients are admitted for intravenous methylprednisolone at a dose of 15 mg/kg daily for 3 to 5 consecutive days followed by oral prednisone at a dose of 1 to 1.5 mg/kg. Alternatively, clinicians may choose to use initial therapy with oral prednisone. Labarca and colleagues [43] retrospectively evaluated 286 patients with biopsy-proven GCA and found that patients who received an initial oral dose of prednisone greater than 40 mg daily were able to reach a dose of less than 5 mg/d and discontinue corticosteroids sooner than patients receiving less than or equal to 40 mg/d without an increase in glucocorticoid-associated adverse events. Prednisone at a dose of 1 to 1.5 mg/kg/d (80–100 mg/d) is reasonable as initial therapy for ophthalmic GCA. IMPROVEMENT WITH STEROID Following initial therapy with corticosteroids, the vast majority of patients with systemic symptoms from GCA will notice rapid and dramatic improvement over hours to days [44]. Levels of ESR and CRP generally normalize within 2 to 4 weeks of steroid therapy [45]. Unfortunately, only 4% to 34% of patients experience improvement in vision loss despite corticosteroid treatment [46]. Sequential visual loss or further deterioration of vision in the affected eye may occur despite high-dose corticosteroids, often within the first 5 days of treatment [46]. DURATION AND TAPERING OF CORTICOSTEROID TREATMENT Corticosteroid treatment of ophthalmic GCA must be continued for months to years. Prednisone at an initial daily dose of 1 to 1.5 mg/kg should be maintained for a few weeks to suppress inflammation, after which the dose may
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be gradually tapered as long as ESR and CRP values remain within the normal range with tapering. It is reasonable to taper the dose of corticosteroids by 10 mg each month until a daily dose of 40 mg is reached and then taper the dose by 5 mg each month until a daily dose of 10 mg has been reached. The dose can then be reduced by 1 to 2.5 mg/mo until a daily maintenance dose is achieved or corticosteroids can be discontinued. Follow-up visits should occur every 2 to 4 weeks initially but may be extended to every 4 to 6 weeks after the corticosteroid dose is less than 40 mg daily. After discontinuation of corticosteroids, patients should be monitored for further relapses for at least 1 year [3,46]. IDENTIFICATION AND MANAGEMENT OF RELAPSE Relapse is suspected if a patient develops new symptoms concerning for GCA or if ESR and CRP levels increase without explanation, even in the absence of new symptoms. A small increase in ESR and CRP within the normal range should be followed carefully and repeated and should be correlated with other systemic medical issues in seeking an alternative explanation such as infection or malignancy [46]. Relapses are usually accompanied by increased ESR and CRP levels that may not exceed those at disease onset and, in one study, occurred at a mean corticosteroid dose of 5.3 mg/d [47]. The ESR and CRP were both within the normal range in 21% of relapses in another study [48]. When relapse is suspected, an escalation of the steroid dose is recommended. If ophthalmic involvement is suspected, intravenous or high-dose oral corticosteroids may be necessary. For systemic GCA symptoms, escalation to the last effective corticosteroid dose is appropriate. Treatment should be continued for at least 1 year, because a relapse rate as high as 77% was observed among patients who discontinued corticosteroid therapy within 1 year [47]. Late recurrences without new symptoms or elevations in inflammatory markers occurring 13 months after presentation have been reported [49]. SYSTEMIC MANIFESTATIONS OF GIANT CELL ARTERITIS Screening for aortic aneurysm and large vessel occlusive disease is recommended at disease presentation and every 2 to 5 years for those patients who would benefit from intervention [50,51]. Computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) imaging of the thoracic aorta and branch vessels are appropriate initial diagnostic tests. 18F-FluorodeoxyglucosePET is another imaging modality that has been used to detect large-vessel vasculitis in GCA [1,52,53]. CORTICOSTEROID SIDE EFFECTS Intravenous corticosteroids carry significant risk for adverse events. Worsening of cardiovascular disease, cardiac arrhythmias, myocardial infarction, hypertensive crises, psychosis, hyperosmolar hyperglycemia, hepatotoxicity, and sudden death have been reported rarely in patients receiving intravenous corticosteroids [54]. Clinicians should consider hospital admission for patients who
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are frail or have cardiovascular risk factors so that they may be monitored while receiving intravenous corticosteroid treatment. Proven and colleagues [55] reported that 86% of patients treated with corticosteroids for GCA experienced side effects, including posterior subcapsular cataracts (41%), bone fractures (38%), infections (31%), hypertension (22%), diabetes mellitus (9%), gastrointestinal bleeding (4%), and avascular necrosis of the hip (2.5%). Evaluation and follow-up with a physician who is experienced in longterm corticosteroid management are recommended for patients with GCA. The ACR recommends that all patients on long-term corticosteroids receive calcium supplementation (1200 mg/d) and vitamin D (800 IU/d) as well as bisphosphonate therapy if osteoporosis is seen on baseline bone mineral density. Weight-bearing exercise, smoking cessation, and reduction of alcohol intake should be encouraged. Dyspepsia and peptic ulcer disease may be managed with proton pump inhibitors or H2-receptor antagonists. Antimicrobial prophylaxis may be necessary because of the increased likelihood of opportunistic infection. Hypertension and diabetes may worsen with steroid treatment and should be managed aggressively [56]. IMMUNOSUPPRESSIVE AGENTS Although steroids alone may be used successfully in most patients with GCA, additional immunosuppression may be desirable when the disease is resistant to corticosteroid monotherapy, when a relapse of inflammation occurs at high doses of corticosteroid therapy, if a patient has experienced complications from corticosteroids, or if is thought to be at high risk of developing them [57]. The current role of immunosuppression is to permit lower cumulative corticosteroid doses and reduce adverse events without incurring further toxicity. However, the role of immunosuppressive therapy is evolving and monotherapy may be considered in the near future. TOCILIZUMAB Tocilizumab (Tocilizumab), a humanized anti-interleukin-6 (IL-6) receptor antibody, has been used with success in conditions such as rheumatoid arthritis and Crohn disease [58]. IL-6 is a pivotal proinflammatory cytokine that participates in the synthesis of acute phase proteins, promotes the passage of acute to chronic inflammation, and is essential for the development of adaptive immunity. Levels of IL-6 are elevated in the histologic specimens of temporal arteries in patients with GCA, and serum levels correlate with the extent of disease activity [58–60]. The efficacy of tocilizumab, when used in combination with corticosteroids or as an exclusive therapy for GCA, was demonstrated in small series and case reports [58,61–64]. The clinician should be aware that reduced inflammatory markers are not reliable indicators of GCA control in tocilizumab therapy [58]. A recent retrospective multicenter open-label study assessed the efficacy of tocilizumab in 22 patients with GCA who had refractory disease or unacceptable side effects from corticosteroids [65]. In this study, 86.4% of patients achieved rapid and maintained clinical improvement and reduction in clinical
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markers of inflammation and were able to taper steroids following tocilizumab therapy. However, tocilizumab had to be stopped in 3 patients because of severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, one patient died after the second infusion of tocilizumab because of a stroke in the setting of infectious endocarditis. Similar results were reported in another multicenter retrospective study involving 34 patients with GCA; tocilizumab was effective in 82.4%, but one patient died and 3 patients experienced serious adverse effects necessitating treatment cessation [66]. These studies demonstrated that tocilizumab leads to rapid and maintained improvement in patients with refractory GCA, but reaffirmed its association with an increased risk of serious infection, especially when used in concert with steroids and other immunosuppressant medications. The first phase 2 randomized, double-blind, placebo controlled trial of tocilizumab studied its efficacy in the induction and maintenance of remission in GCA. Thirty patients with new onset or relapsing disease were randomized to receive either tocilizumab or placebo infusions intravenously while receiving oral prednisone dosed according to a standardized taper schedule. In this study, 85% of patients receiving tocilizumab and 40% of patients receiving placebo achieved remission by week 12. Relapse-free survival was achieved in 85% of tocilizumab patients and 20% of placebo patients by 52 weeks. This study demonstrated the efficacy of tocilizumab in the induction and maintenance of remission in patients with GCA for the first time in a randomized trial setting [67]. Two other trials investigating IL-6–targeted therapies in larger numbers of patients with GCA involving tocilizumab and sirukinumab, another fully human anti-IL-6 antibody, are underway. It is conceivable that, with additional evidence from multiple randomized controlled trials, tocilizumab combined with corticosteroids may be considered a first-line treatment of GCA. Moreover, the role of tocilizumab as monotherapy for patients with GCA who are at unacceptably high risk from corticosteroid therapy may be explored [68]. METHOTREXATE The efficacy of methotrexate in newly diagnosed GCA was assessed in 3 prospective, randomized, double-blind controlled trials from 2001 to 2002 that yielded discordant conclusions. Two studies found no difference in the cumulative corticosteroid dose or duration of treatment in patients with GCA who were randomized to receive methotrexate or placebo during a corticosteroid taper [69,70]. A third study found that patients newly diagnosed with GCA who were randomized to receive methotrexate in addition to high-dose corticosteroids experienced fewer relapses, required a smaller cumulative corticosteroid dose and a shorter duration of treatment, but found no difference in the rate or severity of adverse events [71]. In a pooled meta-analysis from these trials, a reduction in the risk of relapse and a higher probability of achieving sustained discontinuation of steroids at 24 weeks was observed when methotrexate was administered at doses of 7.5 to 15 mg per week. However, there was no change in the rate of adverse
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events [72]. Methotrexate appears to be effective in GCA but appears to have a delayed corticosteroid-sparing effect. The available studies lacked long-term follow-up and did not use higher doses of methotrexate, which may demonstrate increased efficacy in GCA. IMMUNOSUPPRESSIVE AGENTS The efficacy of cyclophosphamide has been studied in retrospective reviews and case reports; cyclophosphamide was associated with a reduction in steroid requirements, but patients experienced a significant number of relapses as well as potentially life-threatening adverse events requiring suspension of treatment [73–75]. One study demonstrated a complete or partial response to leflunomide among 23 patients with PMR with or without GCA who were not adequately controlled on steroids or methotrexate [76]. Dapsone was associated with fewer relapses in patients with GCA who were concurrently receiving steroids, but there is currently insufficient evidence for its role in GCA [77]. A few studies support the use of azathioprine as an adjunctive agent in GCA, but its mild steroid-sparing effect must be balanced with the potential for serious adverse events [78–80]. Cyclosporine was studied in a multicenter prospective randomized, controlled open study and was shown to have a statistically significant reduction in the corticosteroid dosage and improvement in clinical parameters, but a high rate of adverse events [81,82]. Mycophenolate mofetil has been studied exclusively in case reports [83]. BIOLOGIC THERAPY Infliximab was initially thought to be a potential therapeutic agent in GCA, because of the elevated levels of tumor necrosis factor-alpha found in inflamed arteritis in GCA [84]; however, a randomized controlled trial was stopped prematurely due to lack of efficacy and concern about adverse events [85]. Currently, there is no evidence to suggest a role for infliximab in GCA. Etanercept was studied in a small double-blind placebo controlled trial in patients who had biopsy-proven GCA and had suffered adverse events from corticosteroids. A higher percentage of patients receiving etanercept was able to control the disease without corticosteroids, although this was not statistically significant, suggesting a possible steroid-sparing benefit [86]. Adalimumab is not currently considered to be efficacious in the management of GCA [87]. Rituximab has not been sufficiently studied in GCA [88]. Anakinra’s IL-1 blocking effect may be a potential therapeutic for GCA in light of elevated circulating levels of IL-1 in patients with GCA [89,90]. A case series of 3 patients suggested a beneficial effect in GCA, which warrants further study [91]. ANGIOTENSIN-CONVERTING-ENZYME INHIBITORS AND ANGIOTENSIN 2 RECEPTOR BLOCKERS IN GIANT CELL ARTERITIS Angiotensin 2 (AT2) is an important component of the renin-angiotensin system and is thought to be responsible for proinflammatory effects in
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hypertension. Angiotensin-converting-enzyme inhibitors (ACEi) and AT2 receptor blockers (ARB) suppress AT2-signaling, and several studies have addressed potential anti-inflammatory effects in autoimmune inflammation of the central nervous system [92]. Alba and colleagues [93] found that patients with GCA who were being treated with ARB had a significantly longer relapse-free survival and required a lower prednisone dose than those who were being treated with ACEi or patients receiving neither. The potential anti-inflammatory role of ARBs is encouraging and should be further explored. STATINS IN GIANT CELL ARTERITIS Statins possess anti-inflammatory and immunomodulatory properties [94], and there have been conflicting results about their role in GCA [95,96]. In a recent study, statin exposure was not associated with the development of GCA, but exposure to statins was associated with more rapid tapering of corticosteroids in patients who developed GCA [97]. These results suggest a possible protective role of statin therapy in GCA that merits further study. Clinicians should be aware that statins and nonsteroidal anti-inflammatory drugs may impact the levels of inflammatory markers [98]. ASPIRIN Aspirin’s action as an antiplatelet agent has been shown to prevent ischemic complications, such as stroke and myocardial infarction, in patients with atherosclerotic cardiovascular disease. The risk of cranial ischemic complications is higher among patients with GCA, particularly within the vertebrobasilar circulation. Various studies have sought to study the effect of aspirin on cranial ischemic complications among patients with GCA with mixed results [99–103]. The impact of a patient’s preexisting vascular risk factors has been difficult to separate from a therapeutic effect of aspirin, but one study supported the idea that atherosclerotic risk factors increased the risk of developing severe ischemic complications in GCA [104]. A meta-analysis concluded that there was no effect of antiplatelet or anticoagulant therapy instituted before the diagnosis of GCA on preventing severe ischemic complications. However, antiplatelet or anticoagulant therapy prevented the development of severe ischemic complications after the diagnosis of GCA without increasing the risk of bleeding [105]. A Cochrane Review concluded that there was insufficient evidence to recommend the use of aspirin as an adjunct treatment of GCA because no randomized controlled trials exist in the current literature [106]. The use of low-dose aspirin in patients with GCA is supported by European guidelines [41,42]. Clinicians who are considering the use of low-dose aspirin as an adjunctive treatment in GCA must recognize the established hemorrhagic risks associated with aspirin, especially in the context of concurrent treatment with corticosteroids, and its impact on renal physiology in the elderly [107,108]. There is a clear need for randomized controlled trials to establish the role of aspirin in the prevention of ischemic complications from GCA.
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OTHER FORMS OF ANTICOAGULATION It has been postulated that systemic anticoagulation may be beneficial during the initial phase of steroid treatment. In a prospective study, patients with GCA who presented with thrombocytosis were likely to experience ischemic visual symptoms, and that the finding of thrombocytosis should emphasize the need for urgent treatment, with consideration of inhibitors of platelet aggregation or anticoagulation therapy. There are no published prospective trials that have studied efficacy of anticoagulation in GCA, but 2 prior case reports have described improvement in vision with intravenous heparin [109,110]. Thus, the evidence, indications, and risks of anticoagulation in GCA have not been studied. ANTIVIRAL THERAPY A role of antiviral therapy has been proposed based on evidence that varicella zoster virus (VZV) may trigger the immunopathology of GCA. Virological analyses of temporal artery biopsy specimens demonstrated the presence of VZV in most GCA-positive temporal artery biopsies but VZV was also found in 20% of temporal artery biopsies from non-GCA postmortem controls [111]. Case reports have suggested some clinical benefit from treatment with intravenous acyclovir [106,112]. Currently, there is insufficient evidence for the use of antiviral therapy in GCA. SUMMARY Making the diagnosis of GCA is critical to preserving sight, but requires a thoughtful approach to the clinical history, presentation, and use of ancillary investigations. Typical symptoms are present in most patients, although a substantial number may have an occult presentation. Elevated inflammatory markers, such as ESR, CRP, anemia, and thrombocytosis, may support the diagnosis, although they are not specific to GCA. A temporal artery biopsy remains the gold standard diagnostic test. There is debate about the need for bilateral temporal artery biopsies and the role of other ancillary tests, including CDU and contrast-enhanced MRI of the temporal arteries, which are less invasive. The management of GCA poses a complex clinical challenge: on the one hand, failure to control inflammation may lead to devastating visual loss or systemic complications; on the other hand, therapeutic options are wrought with complications and morbidity. Corticosteroid therapy remains the cornerstone of immunosuppressive therapy in GCA and is initiated urgently at high doses, either intravenously or orally, when ophthalmic involvement of GCA is suspected. Over the course of at least 1 year, corticosteroids may be gradually tapered as the vigilant clinician monitors for symptoms and levels of inflammatory markers to identify relapse of inflammation. Prevention, screening, and management of corticosteroid-induced complications are essential. Failure to respond to steroids, relapses occurring with steroid taper, and development of steroid-related adverse effects are indications to consider immunosuppression. Methotrexate continues
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to be the most widely used agent, although it seems to have a modest effect. The evidence for tocilizumab is mounting as an effective adjunctive therapy in GCA. Mainstream use of other immunosuppressive agents is limited by a lack of proven efficacy beyond small case reports, evidence suggesting limited efficacy, or a high burden of toxicity. Initiation of low-dose aspirin may be beneficial in preventing severe ischemic complications at the time of diagnosis, while bearing in mind potential hemorrhagic complications when used in tandem with corticosteroids. The role for AT2 receptor blockers and statins is intriguing and merits further study. References [1] Hoffman GS. Giant cell arteritis. Ann Intern Med 2016;165(9):ITC65–80. [2] Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. Ann Intern Med 2003;139(6):505–15. [3] Almarzouqi SJ, Morgan ML, Lee AG. Treatment of giant cell arteritis. Curr Opin Ophthalmol 2015;26(6):469–75. [4] Simmons RJ, Cogan DG. Occult temporal arteritis. Arch Ophthalmol 1962;68:8–18. [5] Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 1998;125(4):521–6. [6] Buttgereit F, Dejaco C, Matteson EL, et al. Polymyalgia rheumatica and giant cell arteritis: a systematic review. JAMA 2016;315(22):2442–58. [7] Hayreh SS. Anterior ischaemic optic neuropathy. Differentiation of arteritic from nonarteritic type and its management. Eye (Lond) 1990;4(Pt 1):25–41. [8] Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33(8):1122–8. [9] Miller A, Green M, Robinson D. Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed) 1983;286(6361):266. [10] Hayreh SS, Podhajsky PA, Raman R, et al. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997;123(3):285–96. [11] El-Dairi MA, Chang L, Proia AD, et al. Diagnostic algorithm for patients with suspected giant cell arteritis. J Neuroophthalmol 2015;35(3):246–53. [12] Kermani TA, Schmidt J, Crowson CS, et al. Utility of erythrocyte sedimentation rate and C-reactive protein for the diagnosis of giant cell arteritis. Semin Arthritis Rheum 2012;41(6):866–71. [13] Rao JK, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis. Ann Intern Med 1998;129(5):345–52. [14] Davies C, Frost B, Eshan O, et al. Temporal artery biopsy.who needs one? Postgrad Med J 2006;82(969):476–8. [15] Drehmer TJ, Khanna D, Markert RJ, et al. Diagnostic and management trends of giant cell arteritis: a physician survey. J Rheumatol 2005;32(7):1283–9. [16] Murchison AP, Gilbert ME, Bilyk JR, et al. Validity of the American College of Rheumatology criteria for the diagnosis of giant cell arteritis. Am J Ophthalmol 2012;154(4): 722–9. [17] Niederkohr RD, Levin LA. A Bayesian analysis of the true sensitivity of a temporal artery biopsy. Invest Ophthalmol Vis Sci 2007;48(2):675–80. [18] Bhatti MT, Tabandeh H. Giant cell arteritis: diagnosis and management. Curr Opin Ophthalmol 2001;12(6):393–9. [19] Chambers WA, Bernardino B. Specimen length in temporal artery biopsies. J Clin Neuroophthalmol 1988;8(2):121–5. [20] Boyev LR, Miller NR, Green WR. Efficacy of unilateral versus bilateral temporal artery biopsies for the diagnosis of giant cell arteritis. Am J Ophthalmol 1999;128(2):211–5.
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[21] Hall JK, Volpe NJ, Galetta SL, et al. The role of unilateral temporal artery biopsy. Ophthalmology 2003;110(3):543–8 [discussion: 548]. [22] Huston KA, Hunder GG, Lie JT, et al. Temporal arteritis: a 25-year epidemiologic, clinical, and pathologic study. Ann Intern Med 1978;88(2):162–7. [23] Pless M, Rizzo JF 3rd, Lamkin JC, et al. Concordance of bilateral temporal artery biopsy in giant cell arteritis. J Neuroophthalmol 2000;20(3):216–8. [24] Danesh-Meyer HV, Savino PJ, Eagle RC Jr, et al. Low diagnostic yield with second biopsies in suspected giant cell arteritis. J Neuroophthalmol 2000;20(3):213–5. [25] Niederkohr RD, Levin LA. Management of the patient with suspected temporal arteritis a decision-analytic approach. Ophthalmology 2005;112(5):744–56. [26] Bury D, Joseph J, Dawson TP. Does preoperative steroid treatment affect the histology in giant cell (cranial) arteritis? J Clin Pathol 2012;65(12):1138–40. [27] Roberts WC, Zafar S, Ko JM. Morphological features of temporal arteritis. Proc (Bayl Univ Med Cent) 2013;26(2):109–15. [28] Landau K, Savino PJ, Gruber P. Diagnosing giant cell arteritis: is ultrasound enough? J Neuroophthalmol 2013;33(4):394–400. [29] Siatkowski RM, Gass JD, Glaser JS, et al. Fluorescein angiography in the diagnosis of giant cell arteritis. Am J Ophthalmol 1993;115(1):57–63. [30] Karassa FB, Matsagas MI, Schmidt WA, et al. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med 2005;142(5):359–69. [31] Ball EL, Walsh SR, Tang TY, et al. Role of ultrasonography in the diagnosis of temporal arteritis. Br J Surg 2010;97(12):1765–71. [32] Arida A, Kyprianou M, Kanakis M, et al. The diagnostic value of ultrasonography-derived edema of the temporal artery wall in giant cell arteritis: a second meta-analysis. BMC Musculoskelet Disord 2010;11:44. [33] Rheaume M, Rebello R, Pagnoux C, et al. High-resolution magnetic resonance imaging of scalp arteries for the diagnosis of giant cell arteritis: results of a prospective cohort study. Arthritis Rheumatol 2017;69(1):161–8. [34] Gonzalez-Gay MA, Blanco R, Rodriguez-Valverde V, et al. Permanent visual loss and cerebrovascular accidents in giant cell arteritis: predictors and response to treatment. Arthritis Rheum 1998;41(8):1497–504. [35] Eberhardt RT, Dhadly M. Giant cell arteritis: diagnosis, management, and cardiovascular implications. Cardiol Rev 2007;15(2):55–61. [36] Chevalet P, Barrier JH, Pottier P, et al. A randomized, multicenter, controlled trial using intravenous pulses of methylprednisolone in the initial treatment of simple forms of giant cell arteritis: a one year followup study of 164 patients. J Rheumatol 2000;27(6):1484–91. [37] Hayreh SS, Zimmerman B. Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy. Ophthalmology 2003;110(6):1204–15. [38] Liu GT, Glaser JS, Schatz NJ, et al. Visual morbidity in giant cell arteritis. Clinical characteristics and prognosis for vision. Ophthalmology 1994;101(11):1779–85. [39] Mazlumzadeh M, Hunder GG, Easley KA, et al. Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial. Arthritis Rheum 2006;54(10):3310–8. [40] Chan CC, Paine M, O’Day J. Steroid management in giant cell arteritis. Br J Ophthalmol 2001;85(9):1061–4. [41] Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009;68(3):318–23. [42] Dasgupta B, Giant Cell Arteritis Guideline Development Group. Concise guidance: diagnosis and management of giant cell arteritis. Clin Med (Lond) 2010;10(4):381–6. [43] Labarca C, Koster MJ, Crowson CS, et al. Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study. Rheumatology (Oxford) 2016;55(2):347–56.
NEWER THERAPIES FOR GIANT CELL ARTERITIS
335
[44] Salvarani C, Cantini F, Boiardi L, et al. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002;347(4):261–71. [45] Gonzalez-Gay MA, Pina T. Giant cell arteritis and polymyalgia rheumatica: an update. Curr Rheumatol Rep 2015;17(2):6. [46] Fraser JA, Weyand CM, Newman NJ, et al. The treatment of giant cell arteritis. Rev Neurol Dis 2008;5(3):140–52. [47] Alba MA, Garcia-Martinez A, Prieto-Gonzalez S, et al. Relapses in patients with giant cell arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients. Medicine (Baltimore) 2014;93(5):194–201. [48] Kermani TA, Warrington KJ, Cuthbertson D, et al. Disease relapses among patients with giant cell arteritis: a prospective, longitudinal cohort study. J Rheumatol 2015;42(7): 1213–7. [49] Kim N, Trobe JD, Flint A, et al. Late ipsilateral recurrence of ischemic optic neuropathy in giant cell arteritis. J Neuroophthalmol 2003;23(2):122–6. [50] Mackie SL, Hensor EM, Morgan AW, et al. Should I send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A systematic literature review and meta-analysis. Ann Rheum Dis 2014;73(1):143–8. [51] Bienvenu B, Ly KH, Lambert M, et al. Management of giant cell arteritis: recommendations of the French Study Group for Large Vessel Vasculitis (GEFA). Rev Med Interne 2016;37(3): 154–65. [52] Houthuizen P, Polak PE, Edelbroek MA, et al. Giant cell arteritis as a cardiovascular entity. Neth Heart J 2009;17(7–8):281–3. [53] Nayar AK, Casciello M, Slim JN, et al. Fatal aortic dissection in a patient with giant cell arteritis: a case report and review of the literature. Case Rep Vasc Med 2013;2013: 590721. [54] Gutkowski K, Chwist A, Hartleb M. Liver injury induced by high-dose methylprednisolone therapy: a case report and brief review of the literature. Hepat Mon 2011;11(8):656–61. [55] Proven A, Gabriel SE, Orces C, et al. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum 2003;49(5):703–8. [56] Briot K, Cortet B, Roux C, et al. 2014 update of recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis. Joint Bone Spine 2014;81(6): 493–501. [57] Spies CM, Burmester GR, Buttgereit F. Methotrexate treatment in large vessel vasculitis and polymyalgia rheumatica. Clin Exp Rheumatol 2010;28(5 Suppl 61):S172–7. [58] Unizony S, Arias-Urdaneta L, Miloslavsky E, et al. Tocilizumab for the treatment of largevessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken) 2012;64(11):1720–9. [59] Roche NE, Fulbright JW, Wagner AD, et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993;36(9):1286–94. [60] Emilie D, Liozon E, Crevon MC, et al. Production of interleukin 6 by granulomas of giant cell arteritis. Hum Immunol 1994;39(1):17–24. [61] Beyer C, Axmann R, Sahinbegovic E, et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis 2011;70(10):1874–5. [62] Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156. [63] Pazzola G, Padovano I, Boiardi L, et al. Tocilizumab in glucocorticoid-naive large-vessel vasculitis. Clin Exp Rheumatol 2013;31(1 Suppl 75):S59–61. [64] Evans J, Steel L, Borg F, et al. Long-term efficacy and safety of tocilizumab in giant cell arteritis and large vessel vasculitis. RMD Open 2016;2(1):e000137. [65] Loricera J, Blanco R, Hernandez JL, et al. Tocilizumab in giant cell arteritis: multicenter open-label study of 22 patients. Semin Arthritis Rheum 2015;44(6):717–23.
336
JIVRAJ & TAMHANKAR
[66] Regent A, Redeker S, Deroux A, et al. Tocilizumab in giant cell arteritis: a multicenter retrospective study of 34 patients. J Rheumatol 2016;43(8):1547–52. [67] Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016;387(10031):1921–7. [68] Devauchelle-Pensec V. Has the time come for biotherapies in giant cell arteritis and polymyalgia rheumatica? Joint Bone Spine 2016;83(5):471–2. [69] Spiera RF, Mitnick HJ, Kupersmith M, et al. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol 2001;19(5):495–501. [70] Hoffman GS, Cid MC, Hellmann DB, et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46(5):1309–18. [71] Jover JA, Hernandez-Garcia C, Morado IC, et al. Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134(2):106–14. [72] Mahr AD, Jover JA, Spiera RF, et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum 2007;56(8):2789–97. [73] Quartuccio L, Maset M, De Maglio G, et al. Role of oral cyclophosphamide in the treatment of giant cell arteritis. Rheumatology (Oxford) 2012;51(9):1677–86. [74] Loock J, Henes J, Kotter I, et al. Treatment of refractory giant cell arteritis with cyclophosphamide:a retrospective analysis of 35 patients from three centres. Clin Exp Rheumatol 2012;30(1 Suppl 70):S70–6. [75] de Boysson H, Boutemy J, Creveuil C, et al. Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review. Semin Arthritis Rheum 2013;43(1):105–12. [76] Adizie T, Christidis D, Dharmapaliah C, et al. Efficacy and tolerability of leflunomide in difficult-to-treat polymyalgia rheumatica and giant cell arteritis: a case series. Int J Clin Pract 2012;66(9):906–9. [77] Liozon F, Vidal E, Barrier J. Does dapsone have a role in the treatment of temporal arteritis with regard to efficacy and toxicity? Clin Exp Rheumatol 1993;11(6):694–5. [78] De Silva M, Hazleman BL. Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis 1986;45(2):136–8. [79] Boureau AS, de Faucal P, Espitia O, et al. Place of azathioprine in the treatment of giant cell arteritis. Rev Med Interne 2016;37(11):723–9 [in French]. [80] Nuenninghoff DM, Matteson EL. The role of disease-modifying antirheumatic drugs in the treatment of giant cell arteritis. Clin Exp Rheumatol 2003;21(6 Suppl 32):S29–34. [81] Schaufelberger C, Andersson R, Nordborg E. No additive effect of cyclosporin A compared with glucocorticoid treatment alone in giant cell arteritis: results of an open, controlled, randomized study. Br J Rheumatol 1998;37(4):464–5. [82] Schaufelberger C, Mollby H, Uddhammar A, et al. No additional steroid-sparing effect of cyclosporine A in giant cell arteritis. Scand J Rheumatol 2006;35(4):327–9. [83] Sciascia S, Piras D, Baldovino S, et al. Mycophenolate mofetil as steroid-sparing treatment for elderly patients with giant cell arteritis: report of three cases. Aging Clin Exp Res 2012;24(3):273–7. [84] Ahmed MM, Mubashir E, Hayat S, et al. Treatment of refractory temporal arteritis with adalimumab. Clin Rheumatol 2007;26(8):1353–5. [85] Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007;146(9):621–30. [86] Martinez-Taboada VM, Rodriguez-Valverde V, Carreno L, et al. A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis 2008;67(5):625–30.
NEWER THERAPIES FOR GIANT CELL ARTERITIS
337
[87] Seror R, Baron G, Hachulla E, et al. Adalimumab for steroid sparing in patients with giantcell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis 2014;73(12):2074–81. [88] Bhatia A, Ell PJ, Edwards JC. Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann Rheum Dis 2005;64(7):1099–100. [89] Pountain G, Hazleman B, Cawston TE. Circulating levels of IL-1beta, IL-6 and soluble IL-2 receptor in polymyalgia rheumatica and giant cell arteritis and rheumatoid arthritis. Br J Rheumatol 1998;37(7):797–8. [90] Hernandez-Rodriguez J, Segarra M, Vilardell C, et al. Tissue production of proinflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology (Oxford) 2004;43(3):294–301. [91] Ly KH, Stirnemann J, Liozon E, et al. Interleukin-1 blockade in refractory giant cell arteritis. Joint Bone Spine 2014;81(1):76–8. [92] Stegbauer J, Lee DH, Seubert S, et al. Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system. Proc Natl Acad Sci U S A 2009;106(35): 14942–7. [93] Alba MA, Garcia-Martinez A, Prieto-Gonzalez S, et al. Treatment with angiotensin II receptor blockers is associated with prolonged relapse-free survival, lower relapse rate, and corticosteroid-sparing effect in patients with giant cell arteritis. Semin Arthritis Rheum 2014;43(6):772–7. [94] Montecucco F, Mach F. Update on statin-mediated anti-inflammatory activities in atherosclerosis. Semin Immunopathol 2009;31(1):127–42. [95] Garcia-Martinez A, Hernandez-Rodriguez J, Grau JM, et al. Treatment with statins does not exhibit a clinically relevant corticosteroid-sparing effect in patients with giant cell arteritis. Arthritis Rheum 2004;51(4):674–8. [96] Schmidt J, Kermani TA, Muratore F, et al. Statin use in giant cell arteritis: a retrospective study. J Rheumatol 2013;40(6):910–5. [97] Pugnet G, Sailler L, Bourrel R, et al. Is statin exposure associated with occurrence or better outcome in giant cell arteritis? Results from a French population-based study. J Rheumatol 2015;42(2):316–22. [98] Hegg R, Lee AG, Tagg NT, et al. Statin or nonsteroidal anti-inflammatory drug use is associated with lower erythrocyte sedimentation rate in patients with giant cell arteritis. J Neuroophthalmol 2011;31(2):135–8. [99] Nesher G, Berkun Y, Mates M, et al. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 2004;50(4):1332–7. [100] Lee MS, Smith SD, Galor A, et al. Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum 2006;54(10):3306–9. [101] Narvaez J, Bernad B, Gomez-Vaquero C, et al. Impact of antiplatelet therapy in the development of severe ischemic complications and in the outcome of patients with giant cell arteritis. Clin Exp Rheumatol 2008;26(3 Suppl 49):S57–62. [102] Salvarani C, Della Bella C, Cimino L, et al. Risk factors for severe cranial ischaemic events in an Italian population-based cohort of patients with giant cell arteritis. Rheumatology (Oxford) 2009;48(3):250–3. [103] Berger CT, Wolbers M, Meyer P, et al. High incidence of severe ischaemic complications in patients with giant cell arteritis irrespective of platelet count and size, and platelet inhibition. Rheumatology (Oxford) 2009;48(3):258–61. [104] Gonzalez-Gay MA, Pineiro A, Gomez-Gigirey A, et al. Influence of traditional risk factors of atherosclerosis in the development of severe ischemic complications in giant cell arteritis. Medicine (Baltimore) 2004;83(6):342–7. [105] Martinez-Taboada VM, Lopez-Hoyos M, Narvaez J, et al. Effect of antiplatelet/anticoagulant therapy on severe ischemic complications in patients with giant cell arteritis: a cumulative meta-analysis. Autoimmun Rev 2014;13(8):788–94.
338
JIVRAJ & TAMHANKAR
[106] Mollan SP, Sharrack N, Burdon MA, et al. Aspirin as adjunctive treatment for giant cell arteritis. Cochrane Database Syst Rev 2014;(8):CD010453. [107] Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002;162(19):2197–202. [108] Caspi D, Lubart E, Graff E, et al. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum 2000;43(1):103–8. [109] Buono LM, Foroozan R, de Virgiliis M, et al. Heparin therapy in giant cell arteritis. Br J Ophthalmol 2004;88(2):298–301. [110] Staunton H, Stafford F, Leader M, et al. Deterioration of giant cell arteritis with corticosteroid therapy. Arch Neurol 2000;57(4):581–4. [111] Gilden D, Nagel MA. Varicella zoster virus triggers the immunopathology of giant cell arteritis. Curr Opin Rheumatol 2016;28(4):376–82. [112] Gilden D, White T, Khmeleva N, et al. Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology 2015;84(19):1948–55.