Update on the management of giant cell arteritis

Abstract

Giant cell arteritis (GCA) is a large vessel vasculitis that may be associated with significant complications such as blindness, stroke, or aortic aneurysm and dissection in a subset of patients. Given the serious side effects associated with prolonged courses of glucocorticoids and frequent relapses experienced when doses are tapered, increased efforts are being dedicated to the discovery of safer and more effective therapies to control this disease. The purpose of this review is to critically evaluate the role of glucocorticoid-sparing agents in the medical management of GCA with a special focus on the most recent evidence regarding the role of biologic agents, including tocilizumab (TCZ), abatacept and ustekinumab, and other novel therapies.

Introduction

Giant cell arteritis (GCA) is the most common primary systemic vasculitis affecting adults over 50 years of age.¹ It classically targets the large vessels,² with a strong propensity for the aorta, its proximal branches and the branches of the external carotid artery, including the temporal arteries. Persistent vessel wall inflammation may lead to vascular damage, resulting in stenoses, occlusions or more rarely, aneurysms, and produces typical symptoms of headache, scalp tenderness, and jaw and limb claudication.³

Without treatment, complications such as visual loss may affect up to 10% of patients.⁴ Large artery complications are also increasingly well recognized.^5,6 Using imaging techniques, large vessel inflammation appears to affect between 70% and 80% of GCA patients at diagnosis,^7,8 and, according to one very thorough post-mortem study, may be identified at the tissue level in all patients.⁹ While studies of mortality in GCA are somewhat conflicting^5,10–12 recent research has shown evidence of increased mortality, primarily due to disease of the cardiovascular system.¹³

The incidence and socioeconomic impacts of GCA are rising in the developed world, as a consequence of an aging population and increased disease awareness.¹⁴ Glucocorticoids, the first-line treatment for GCA, are very effective at high doses, however, relapses occur in up to 50% of patients when doses are tapered,¹⁵ and side effects remain a major concern. The increasing awareness of GCA, its associated morbidity, and relative lack of effective therapeutic options have prompted interest in identifying new treatments with improved safety profiles. This review will summarize the evidence for glucocorticoid-sparing therapies in GCA, including methotrexate and the use of biologics and other novel therapies.

Methotrexate

A role for methotrexate in GCA was initially explored due to the positive experience with its use in Takayasu’s arteritis.¹⁶ Based on favorable outcomes from one of three randomized trials and a subsequent meta-analysis of the combined data, several guideline papers have recommended methotrexate be considered in GCA patients experiencing multiple relapses.^17–19 The results of major studies are summarized briefly below.

Evidence for methotrexate

To date, three randomized controlled trials have evaluated the use of weekly oral methotrexate in patients with GCA.^20–22 One of the initial studies, by Spiera et al., found that in 21 participants with newly diagnosed disease, the addition of low-dose weekly methotrexate to prednisone failed to significantly reduce rates of disease flare, prednisone exposure or side effects after 24 months of follow up.²⁰ The same year, Jover and colleagues performed a larger study with newly diagnosed, biopsy-proven participants, with different results. Fewer relapses (46.6% versus 83.3%; p = 0.06) and glucocorticoid-sparing benefits (mean difference in prednisone exposure 1302 mg between groups, p = 0.009) were noted with the addition of 10 mg weekly methotrexate to the usual prednisone.²¹ The third, and largest multicenter study included 98 newly diagnosed patients with elevated inflammatory markers.²² Patients received 1 mg/kg/day of prednisone (maximum of 60 mg per day) with taper, combined with either oral methotrexate 0.15 mg/kg/week (to a maximum of 15 mg per week) or placebo. At 12 months, no significant difference in relapse, or median dose or duration of glucocorticoid treatment was observed.

Given the conflicting results of the above studies, a meta-analysis using individual patient data from the three studies was performed.²³ In this manner, the addition of methotrexate was found to reduce the risk of first relapse by 35%, [hazard ratio (HR) = 0.65; p = 0.04], and second relapse by 51% (HR = 0.49; p = 0.02). No significant difference in adverse events was noted, however, the benefits of methotrexate did not emerge until after 6 months of treatment.

Taken together, the results of these studies suggest that the addition of methotrexate is safe, and moderately beneficial in GCA. The evidence points towards a relatively modest improvement in disease activity, however, and positive effects may take months to emerge. The observed delay in therapeutic benefit may be due to the drug’s slow onset of action, or may have been influenced by certain aspects of the trials’ designs, including dose (generally ≤15 mg/week) and route of methotrexate used. Methotrexate use is not recommended routinely in all GCA patients, but it may be considered in those patients who experience frequent relapses or have difficulty tapering prednisone.

Role of tumor necrosis factor α in giant cell arteritis

Elevated levels of tumor necrosis factor α (TNFα) have been detected in histopathologically positive temporal arteries of GCA patients, localizing particularly to the intima and media of the vessel where giant cells and macrophages are found.^24,25 Increased levels of TNFα have also been shown to correlate with more resistant disease,²⁶ offering support for its use as a potential target for therapy.

Anti-tumor necrosis factor α studies

Like methotrexate, a role for anti-TNFα therapy in GCA was initially considered due to its success in Takayasu’s arteritis.²⁷ An early case report of four patients with long-standing GCA described sustained glucocorticoid-free remission in three out of four patients with infliximab, also suggesting benefit.²⁸ Three randomized controlled trials of anti-TNFα therapy in GCA have now been conducted, however, with disappointing results.^29–31 The first study of 44 patients in glucocorticoid-induced remission, randomized 28 patients to infliximab and 16 to placebo, and was terminated prematurely at 22 weeks due to a lack of benefit.²⁹ No difference in the proportion of relapses or cumulative glucocorticoid exposure was observed between groups, and a trend towards increased infections was noted with infliximab (71% versus 56% in placebo). One year later, a multicenter double-blind, placebo-controlled trial of etanercept in biopsy-proven GCA was published.³⁰ Despite low numbers (eight patients in the treatment group and nine in placebo) and a high discontinuation rate, a significantly lower cumulative prednisone dose at 1 year was observed in the treatment group (1.5 g with etanercept versus 3 g with placebo; p = 0.03). Although more patients in the etanercept group achieved glucocorticoid-free remission at 12 months (50% versus 22% in the placebo group), this did not reach statistical significance.³⁰ The third trial compared the addition of 10 weeks of adalimumab with placebo, plus prednisone taper in 70 newly diagnosed GCA patients. This trial failed to show any significant benefit of adalimumab, either in glucocorticoid sparing or in the prevention of disease relapse at 26 or 52 weeks.³¹

Although numbers studied are small and follow up relatively limited, there is no convincing evidence that anti-TNFα therapy provides additional benefit above prednisone monotherapy in GCA. Due to a possible increased risk of infection with this medication and lack of clear benefit, the use of anti-TNFs is not recommended.

Role of interleukin-6 and tocilizumab in giant cell arteritis

Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by numerous immune cells, including macrophages, neutrophils, dendritic cells, and CD4 T cells. Its broad-reaching effects on the immune system include activation of neutrophils and macrophages, differentiation of T-helper cells into type 17 T-helper cells (Th17 cells), inhibition of T-regulatory cells, promotion and differentiation of B cells, and stimulation of endothelial cells.^32,33 IL-6 potently stimulates hepatocytes to release the acute-phase markers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP),³⁴ and is believed to play a critical role in promoting the switch from acute to chronic inflammation. Elevated levels of IL-6 have been found in both the inflamed arteries and peripheral circulation of patients with GCA, highlighting this cytokine as a potential target for treatment.^34,35

Tocilizumab studies

Tocilizumab (TCZ), a humanized monoclonal antibody directed against the IL-6 receptor, continues to gain attention as an effective therapeutic agent in GCA. To date, there are 16 full publications describing the use of TCZ in 116 GCA patients, with impressive results. Prior to this year, data supporting the use of TCZ was predominantly observational in nature. In 2016, however, complete results from the first randomized controlled trial of TCZ in GCA were published,³⁶ and the preliminary results of GiACTA, a large, multicenter trial of 251 patients, were recently presented and released in abstract form.³⁷

The first report of TCZ in GCA was published by Seitz et al. in 2011, describing rapid improvement among five GCA patients.³⁸ Since then, several reports and small series have described impressive clinical responses and glucocorticoid-sparing effects with use of TCZ. The major results of these observational studies are summarized in Table 1. Of special interest, in 2012, Unizony and colleagues published a comprehensive description of TCZ use in seven GCA patients refractory to conventional therapies.³⁹ All patients achieved clinical remission and substantially reduced their daily prednisone doses, with few reported side effects. A single death, however, (a postoperative myocardial infarction) occurred in an 82-year-old female following an elective surgery, during a period of perceived clinical remission on TCZ. Despite the clinical impression, post-mortem examination revealed extensive active arteritis involving the thoracic and abdominal aorta, brachiocephalic, subclavian, carotid, vertebral, temporal and femoral arteries. This case represents the only reported example in which tissue has been available for correlation of disease activity in a TCZ-treated GCA patient. The discordance observed raises the possibility that, despite dramatic clinical improvements reported with TCZ, subclinical vasculitis may persist. Indeed, persistence of tissue infiltrates have also occasionally been observed in patients receiving weeks, or sometimes months, of prednisone.^40,41 Further studies evaluating correlation of histopathology with clinical parameters in TCZ-treated patients will be of interest.

Table 1.

Summary of observational studies of tocilizumab in giant cell arteritis.

Author [year]	Patient responses n (%)	Prednisone pre-TCZ (mg)	Prednisone post-TCZ (mg)	F/u (months)	Relapse after TCZ d/c n (%)	Adverse events (n)
Seitz [2011]38	5/5 (100)	11.5	2	4.3	0/2 (0)	Dyslipidemia (2)
Sciascia [2011]45	2/2 (100)	25	5	7	N/A	None
Beyer [2011]46	3/3 (100)	30	7.5	6	N/A	Fracture (1)
Christidis [2011]47	1/1 (100)	20	3.5	5	N/A	Neutropenia
Besada [2012]48	1/1 (100)	20	10	7	1/1 (100)	None
Salavarani [2012]49	1/1 (100)	12.5	2.5	11	1/1 (100)	None
Vinit [2012]50	1/1 (100)	20	5	6	0/1 (0)	None
Unizony [2012]39	7/7 (100)	25.5	2.3	7.9	1/1 (0)	Cytopenias (4) Transaminitis (4) Adrenal (1) Death(1)
Lurati [2012]51	1/1 (100)	12.5	0	10	N/A	None
Isik [2013]52	1/1 (100)	30	30	4	N/A	None
Oliveira [2014]53	4/4 (100)	30	3.75	NS	N/A	None
Loricera [2014]54	7/7 (100)	20.4	3.9	9.4	N/A	Neutropenia (1) Pneumonia (1) Hypotension (1)
Loricera [2015]42	19/22 (86)	18.75	5	9	N/A	Neutropenia (1) CMV(1) Pneumonia (1) death(1)
Evans [2016]44	8/8 (100)	25	4.7	34	2/5 (40)	Neutropenia and empyema(1)
Regent [2016]43	34/34* (100)	26.3	10.3	13	8/23 (35)	Neutropenia (3) TB pericarditis (1) Transaminitis (1) Death (1)
Total	93/96 (97%)	11.5–30	0–30	4–34	13/32 (41%)	See above

^*All 34 patients in the study showed clinical improvement, however 6/34 continued to have minor clinical symptoms. D/c, discontinuation; Adrenal, adrenal insufficiency; TB, tuberculous pericarditis; CMV, cytomegalovirus; F/u, follow up; TCZ, tocilizumab.

In 2015, Loricera et al. described their experience with TCZ in 22 refractory GCA patients. All patients were previously treated with high-dose prednisone, and 19 had previously tried other conventional or biologic immunosuppressive therapies (most often, methotrexate).⁴² With the addition of TCZ, the majority (19/22) of patients had a complete response, however, three severe infections were noted, including disseminated cytomegalovirus, recurrent pneumonia, and bacterial endocarditis resulting in death. More recently, Regent et al. published a retrospective description of 34 TCZ-treated GCA patients, of whom nine received TCZ within the first 3 months of diagnosis.⁴³ All patients experienced rapid clinical improvement within 1–2 months, and ultimately, 23 patients discontinued TCZ. Eight patients (35%) subsequently relapsed, but interestingly, no relapses were observed after TCZ discontinuation among the seven patients who received the drug at an early stage of illness. In contrast, 50% of patients with well established disease subsequently relapsed after TCZ was withdrawn. Whether early introduction of TCZ works to potentially arrest the inflammatory process in GCA will be an interesting area for future study.

The results of the first randomized, double-blind, placebo-controlled trial of TCZ in GCA were recently published by Villiger and colleagues.³⁶ This single-center study enrolled 30 patients with new-onset or relapsing GCA, confirmed with either positive temporal artery biopsy or large vessel imaging, of whom 20 received TCZ 8 mg/kg/month for 52 weeks and 10 received placebo. Both groups also received prednisolone 1 mg/kg/day, with a relatively rapid steroid-tapering protocol, such that relapse-free patients were receiving an average of 7 mg/day of prednisolone by week 12. The majority of patients had new-onset GCA (16/20 patients in TCZ arm, 7/10 in placebo arm), more than half had radiological evidence of large vessel vasculitis (LVV), and all patients were required to have elevated inflammatory markers (ESR, CRP) at inclusion. Patients with concomitant health problems necessitating glucocorticoid use, active infection or previous biologic exposure were excluded. Despite aggressive glucocorticoid tapering, 85% percent of patients in the TCZ group achieved the primary outcome, complete remission by week 12, versus only 40% of the control group, p = 0.03. In addition, both relapse-free survival at 52 weeks (85% TCZ versus 20% placebo; p = 0.001) and cumulative prednisolone exposure at 52 weeks (43 mg/kg versus 110 mg/kg; p = 0.0005) were also significantly better in the TCZ arm. Serious adverse events occurred with equal frequencies between groups, with seven reported in TCZ group. These included three gastrointestinal complications (one perforated ulcer, one hepatopathy, one gastrointestinal bleed), one severe infection [Herpes simplex virus (HSV) and Moraxella ocular infection], one Stevens–Johnson syndrome, one tinnitus and one glucocorticoid-induced psychosis.

Most recently, the highly anticipated results of GiACTA, the largest randomized trial in GCA to date, were presented and published in abstract form.³⁷ In this multicenter, randomized, double-blind, placebo-controlled study, 251 GCA patients were randomized to one of four groups, including: short-course 26-week prednisone taper + placebo (50 patients), long-course 52-week prednisone taper + placebo (51 patients), TCZ 162 mg subcutaneously weekly + 26-week course of prednisone (100 patients), or every-other-week TCZ 162 mg subcutaneously + 26-week course of prednisone (49 patients). Patients with active GCA (new or relapsing) with either a positive temporal artery biopsy or radiographic proof of large vessel disease, with associated elevation in acute phase reactants, were eligible for enrollment. The primary outcome, the proportion of patients achieving sustained remission at 52 weeks while adhering to the prednisone taper, was achieved significantly more frequently in both TCZ arms (56% of weekly TCZ group and 53% of the every-other-week TCZ group) as compared with the short-course prednisone placebo group (14%; p < 0.0001). Patients in both TCZ-treatment groups were also significantly more likely to achieve sustained remission as compared with the more conventional long-course prednisone group (17.6%; p < 0.0002), while being exposed to less prednisone over time (median cumulative dose 1862 mg in each TCZ group versus 3817.5 mg in long-course prednisone patients). Serious adverse events, including infections, occurred in a similar percentage of patients across the groups with no deaths reported.

At present, little information is available regarding the long-term use and safety of TCZ in GCA. The longest available follow-up data thus far comes from a retrospective review by Evans et al., with a mean follow-up period of 34 months in eight treated GCA patients.⁴⁴ Patients received between 5 and 41 infusions of TCZ, and only one serious adverse event (empyema) requiring cessation of therapy was documented. Two of four patients experienced a relapse after cessation of the drug, with good symptom control after reintroduction of TCZ.

Conclusions from tocilizumab studies

In support of the numerous positive observational reports, the recent completion of two randomized control trials have provided evidence that the addition of TCZ (in either intravenous or subcutaneous form) may provide additional benefit to prednisone for both inducing and maintaining remission in GCA patients for up to 52 weeks. TCZ appears to be quick in onset, and helps to minimize glucocorticoid exposure over time. Whether early introduction of TCZ at diagnosis can influence the natural history of disease remains to be investigated. Additional future studies evaluating the longer-term safety outcomes and risk of relapse after drug discontinuation are anticipated.

Other targeted biologic therapies

In addition to anti-IL-6-directed therapies, there are emerging reports describing the use of biologics that inhibit T cells, cytokines IL-1, 12 and 23, and B cells in patients with relapsing disease. The sections below will summarize the available evidence for abatacept, ustekinumab, anakinra and rituximab in GCA.

Abatacept in giant cell arteritis

T cells are key players in the development of both the systemic and vascular manifestations of GCA.⁵⁵ In health, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a molecule expressed on T cells, is believed to serve as an important immune checkpoint by binding to CD80/86 on antigen-presenting cells and effectively preventing the second signal required for T-cell activation.⁵⁶ Recently, a report of two patients treated with ipilimumab, a monoclonal antibody targeting CTLA-4 for malignant melanoma developed drug-induced temporal artery biopsy-proven GCA, reinforcing a possible role for abnormal CTLA-4 in the pathogenesis of this disease.⁵⁷

The results of the first randomized controlled trial of abatacept, a soluble fusion CTLA-4 protein, in GCA were recently published in abstract form. Newly diagnosed or relapsing patients meeting American College of Rheumatology (ACR) 1990 criteria for GCA, received prednisone and abatacept [10 mg/kg intravenously (IV) on day 1, 15, 29 and week 8], followed by double-blind randomization at week 12 to either continued abatacept or placebo.⁵⁸ Prednisone was tapered following a standardized schedule with discontinuation by week 28. Of the 41 patients randomized at week 12, relapse-free survival at 12 months was significantly increased in the abatacept group (48% versus 31% placebo; p = 0.049), and a longer duration of remission was observed (9.9 versus 3.9 months). No significant adverse event signal was noted between the groups. This data suggests that the addition of abatacept to prednisone is safe and may result in a reduced risk of relapse as compared with prednisone alone.

Ustekinumab in giant cell arteritis

There is evidence to support both increased Th1- and Th17-cell activity in the blood and vascular tissues of GCA patients.⁵⁵ While glucocorticoids are very effective at dampening the Th17 signal in affected arteries, they do not appear to suppress Th1 cells, suggesting an unmet need for therapies that target this pathway.⁵⁵ Ustekinumab, an anti-IL-12 and -23 monoclonal antibody, functions by inhibiting both the Th1 and Th17 pathways simultaneously, and has shown promising results in the open-label treatment of 14 patients with relapsing GCA.⁵⁹ In this study, the addition of ustekinumab to current treatment was shown to provide a significant glucocorticoid-sparing benefit, with average prednisone dose decreasing from 20 mg to 5 mg daily, p = 0.001. Side effects occurred in 6 of 14 patients, including three infections (one UTI, one tinea pedis and one dental abscess). After 13.5 months of follow up, two of three patients who stopped ustekinumab experienced relapse. Given promising preliminary results, a larger randomized study would be of interest to more accurately determine the role of this drug in GCA.

Anti-interleukin-1 therapy in giant cell arteritis

Interleukin-1β (IL-1β) has also been consistently detected in GCA-positive temporal artery biopsies. Levels appear to correlate with a greater systemic inflammatory response and increased prednisone requirements in patients.²⁶ In addition, animal studies demonstrate that mice lacking the IL-1-receptor–antagonist gene may develop large vessel vasculitis, suggesting a specific role for this cytokine in disease pathogenesis.⁶⁰

Ly and colleagues previously reported three cases of refractory GCA who experienced favorable responses to anakinra, an IL-1-receptor antagonist.⁶¹ In all three cases, initiation of drug resulted in a rapid improvement in both clinical and biochemical markers of disease activity, significant glucocorticoid-sparing, and resolution of large vessel involvement on repeat imaging. In a single patient, however, follow-up imaging after drug discontinuation revealed recurrence of vessel wall inflammation, suggesting that the effects of anakinra were not sustained long term. Due to very limited experience, no recommendation regarding use of anakinra can be made at this time.

Rituximab in giant cell arteritis

Although cell-mediated autoimmunity has traditionally been the focus of pathogenesis and treatment studies in GCA, recent data also suggest an emerging role for B cells in this disease. The distribution and homeostasis of B cells in active GCA appears disturbed, and potentially contributes to an enhanced IL-6 reponse.⁶² In addition, levels of B-cell-activating factor in GCA patients appear to directly correlate with disease activity.⁶³ Thus far, only two published cases in the literature describe the use of rituximab in refractory GCA patients .^64,65 Improvements in vasculitic manifestations were observed in both cases, but one patient required intensive-care-unit admission shortly postinfusion due to lower respiratory tract infection. In both reported cases, follow up was limited to 6 months or less, therefore, little is known regarding the long-term efficacy, glucocorticoid-sparing effect, or safety profile of rituximab in these patients.

A role for antivirals?

Although generally considered an autoimmune disease of unknown etiology, interest has recently been renewed in the possible role of varicella zoster virus (VZV) in GCA pathogenesis. VZV is a virus of interest because of its ability to lie latent in nerve root ganglions after primary infection, and reactivate many years later. It has been shown to replicate within intracerebral blood vessels, resulting in manifestations such as ischemic stroke, and biopsy of VZV-infected cerebral arteries reveals granulomatous arteritis with similar histopathological findings to those of GCA.⁶⁶

Role of varicella zoster in giant cell arteritis

Initial investigations of the frequency of VZV in GCA in the late 1990s and early 2000s were not able to confirm a definitive role for arterial infection in these patients.^67–70 Results, however, may have been influenced by the small number of tissue sections examined per patient.⁷¹ In the past several years, reports have again emerged highlighting both the clinical and pathological overlap between VZV vasculopathy and GCA .^72–77 In follow up to these observations, Gilden and colleagues examined 86 temporal artery biopsy specimens from patients with histopathologically confirmed GCA for the presence of VZV antigen, and compared with 16 age-matched post-mortem controls.⁷¹ Examining a remarkable 50 sections per artery, VZV antigen was identified in 74% of GCA temporal arteries versus only 8% of controls (p < 0.0001). VZV DNA was also confirmed in 40% of the GCA arteries, despite formalin fixation. An extension of this study analyzed temporal arteries of not only 93 biopsy-positive GCA patients, but 70 clinically diagnosed biopsy-negative GCA patients, and 49 controls from 17 referral centers.⁷⁸ VZV antigen was again identified in 73% of biopsy-positive GCA temporal arteries, as well as 64% of biopsy-negative GCA specimens, as compared with only 22% of controls (p < 0.001), suggesting a possible role for VZV in biopsy-negative GCA, too. In affected arteries, VZV antigen was identified in noncontiguous ‘skip’ lesions, colocalizing with inflammatory changes typical of GCA. In addition to temporal arteries, VZV antigen has also been identified in 11 of 11 samples of granulomatous aortitis as compared with 5 of 18 (28%) control aortic specimens, p = 0.0001, suggesting a possible role in extracranial GCA, as well.⁷⁹ To date, a few case reports describe improvement in symptoms with the addition of IV acyclovir to prednisone,^80–82 prompting some authors to advocate for combined treatment with high-dose glucocorticoids and valacyclovir 1 g t.i.d. in GCA.⁶⁶

Although tremendously interesting, the number of treated cases reported to date is very small, and little is known regarding the optimal route, or duration of antiviral therapy. In addition, shared epitopes between VZV and various muscle proteins have been described, creating potential for nonspecific binding of anti-VZV antibodies in arteries, possibly leading to false-positive staining results.⁸³ In related literature, VZV DNA has also been detected with increased frequency in the synovial fluid of patients with rheumatoid arthritis and ankylosing spondylitis. In these cases, the presence of viral nucleic acids is of unknown significance, perhaps a result of either primary immunological disturbances, or the use of immunosuppressive therapy, or perhaps in some way linked to disease pathogenesis.⁸⁴ While VZV represents an exciting and novel avenue of exploration in GCA, replication of the above studies at different centers using methods to minimize false positives will be needed before the use of antivirals can be broadly recommended in all GCA patients.

Conclusion

Prednisone remains the cornerstone of treatment for GCA, however, the search for safer and more effective long-term therapies remains an active area of research. Of the available literature, TCZ has promising evidence to support its use as a glucocorticoid-sparing agent in the management of GCA. Although generally described for use in relapsing patients, the full results of GiACTA may shed light on its possible use in newly diagnosed patients, as well. Of note, serious infections, both typical and atypical, have occasionally been described with TCZ, and limited information is available regarding outcomes beyond 1 year. With respect to other options, methotrexate has relatively modest evidence of a glucocorticoid-sparing role, with no significant increased infection signal. Positive effects may take up to 6 months to appreciate, however, therefore this drug may be preferred for relapsing patients in whom rapid prednisone tapering is not a high priority, or in those who are deemed to be poor candidates for TCZ, due to perceived risk of infection, gastrointestinal contraindications, or access issues. Other promising options for future consideration include abatacept and ustekinumab. With increasing insight into disease pathogenesis and the triggering events that precipitate GCA, it is our hope that in the near future, additional targets for treatment, and potentially even for cure, will also be recognized.