**4.3 Imaging techniques**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

GCA is characterized histopathologically by mononuclear infiltrates in all layers of the arterial wall. Macrophages and T cells are present in granuloma formation, and multinucleated giant cells are localized close to the fragmented internal elastic lamina. Neutrophils, eosinophils, and plasma cells are rare. Proliferation of the intima results in occlusive vasculopathy. Neoangiogenesis is frequent and at times prominent, and fibrinoid necrosis is typically absent (**Figures 1** and **2**) [13].

The positivity of TAB declines after glucocorticoid treatment is started, and the biopsy should ideally be performed within 2 weeks from the onset of the therapy.

*Histopathological analysis of a patient from the Rheumatology Division of the University of Sao Paulo showing a transmural lymphomonocytary infiltrate and important narrowing of the vessel lumen. HE 100×. Image gently provided by the Pathological Anatomy Division of the University of Sao Paulo, School of Medicine.*

*Histopathological analysis of a patient from the Rheumatology Division of the University of Sao Paulo showing a transmural lymphomonocytary infiltrate and the presence of a granuloma. HE 100×. Image gently provided* 

*by the Pathological Anatomy Division of the University of Sao Paulo, School of Medicine.*

**98**

**Figure 2.**

**Figure 1.**

In 2018, the European League Against Rheumatism (EULAR) published recommendations about the use of imaging techniques in large-vessel vasculitis (LVV), which included GCA and Takayasu's arteritis. According to these recommendations, in patients with suspected GCA, an early imaging test is recommended to complement the clinical criteria for diagnosing GCA, assuming high expertise and prompt availability of the imaging technique [15]. However, imaging should not delay initiation of treatment. The choice of the individual imaging method depends on the predominant clinical symptoms and local settings. In settings where imaging modalities are not readily available or expertise with imaging in GCA is questionable, a biopsy should still be favored in first place. Besides, if positive histology is already available, additional imaging may not be needed for the diagnosis. In centers, however, where imaging (and TAB) is readily available and performed with high quality, the task force recommends that imaging should be preferred as the first test because of low invasiveness, ready availability of imaging results, and assessment of a larger extent of potentially inflamed arteries at the same examination, therefore contributing to a lower number of false-negative results. Imaging should be performed before or as early as possible after initiation of therapy, best within 1 week, because treatment with glucocorticoids rapidly reduces the sensitivity of imaging [15].

#### **Figure 3.**

*Temporal artery duplex scan of a patient from the Rheumatology Division of the University of Sao Paulo, School of Medicine with GCA showing thickness in the vascular wall and the noncompressible "halo" sign.*

**Figure 4.**

*PET-CT of a patient from the Rheumatology Division of the University of Sao Paulo, School of Medicine with GCA showing inflammation in the vascular wall of the aorta and subclavian, common carotid, iliac, femoral, popliteal, and tibial arteries.*

In patients in whom there is a high clinical suspicion of GCA and a positive imaging test, the diagnosis of GCA may be made without an additional test (biopsy or further imaging). In patients with a low clinical probability and a negative imaging result, the diagnosis of GCA can be considered unlikely [15].

Ultrasound of temporal ± axillary arteries is recommended as the first imaging modality in patients with suspected predominantly cranial GCA. A noncompressible "halo" sign is the ultrasound finding most suggestive of GCA (**Figure 3**). Highresolution MRI of cranial arteries to investigate mural inflammation may be used as an alternative for GCA diagnosis if ultrasound is not available or inconclusive. Ultrasound, PET, MRI, and/or CT may be used for the detection of mural inflammation and/or luminal changes in extracranial arteries to support the diagnosis of large-vessel GCA (**Figure 4**). Ultrasound is of limited value for the assessment of aortitis [15].

In patients with a suspected flare, imaging might be helpful to confirm or exclude it. Imaging is not routinely recommended for patients in clinical and biochemical remission. In patients with large-vessel vasculitis, MRA, CTA, and/or ultrasound may be used for long-term monitoring of structural damage, particularly to detect stenosis, occlusion, dilatation, and/or aneurysms [15].

### **5. Treatment**

Treatment with oral glucocorticoid (GC) effectively induces remission and reduces the evolution to visual loss, and it should be started as early as possible

**101**

*Giant Cell Arteritis: Current Advances in Pathogenesis and Treatment*

oral prednisone regimen has not been proven in clinical trials.

when there is a clinical suspicion of GCA. The GC therapy cannot be postponed to after confirmation of the diagnosis, because once the visual loss is installed, it is

Oral prednisone in a daily single dose of 40–60 mg usually resolves the symptoms and normalizes acute inflammation reactants within the first 2–4 weeks of the treatment. When premonitory visual signs are present (amaurosis fugax) or when visual loss is installed, pulse therapy with daily intravenous methylprednisolone (500–1000 mg) for 3 days can be tried, even though its superiority compared to the

Glucocorticoids are effective in inducing clinical remission, but the side effects of its chronical use are undesirable, especially in elderly individuals. Therefore, synthetic or biological immunosuppressants have been used as GC-sparing adjuvants to reduce the cumulative GC dose and to maintain remission after the prednisone withdrawal [17]. There is no consensus on the timing of initiating GC-sparing therapy, but indications to start it early in the disease course include the presence of significant premorbid diseases (diabetes mellitus, osteoporosis, obesity), the emergence of significant glucocorticoid-related side effects, and a relapsing course necessitating protracted CS use. After clinical remission is achieved (symptoms resolved and laboratory inflammation markers normalized), the GC taper can be started. It has to be slow, especially with lower doses. The dose can gradually be reduced by 5 mg every 2 weeks to 20 mg/day and then by 2.5 mg every 2 weeks to 10 mg/day if there are no flares of disease activity. After achieving a daily dose of 10 mg, the prednisone taper should be slowed, such that patients remain on progressively decreasing doses over the ensuing 6–12 months. Tapering by 1 mg decrements each month once the daily dose is less than 10 mg can be considered. Disease relapses are more frequent in this final phase of the GC tapering regimen [18].

**Methotrexate** (MTX) is the conventional immunosuppressive drug most commonly used for the management of refractory GCA. However, the efficacy of this drug in GCA is modest. The trials yielded a role of MTX (10–15 mg/week) to reduce the frequency of relapses (by 35% of a first relapse and by 51% of a second relapse) and decrease the cumulative prednisone dose. However, the optimum efficacy of

**Leflunomide** may also be an effective and well-tolerated glucocorticoid-sparing agent in GCA, but there are no randomized controlled trials to confirm it yet. In one prospective observational study with 76 newly diagnosed GCA patients, 10 mg daily leflunomide was compared with glucocorticoid only in a follow-up period of at least 48 weeks. During the follow-up 13.3% patients in the leflunomide group flared versus 39.1% in the GC-only group (p = 0.02). Furthermore, 56.7% patients in the leflunomide were able to stop GC at week 48 but none in the GC-only group [20]. **Tocilizumab** is a humanized monoclonal antibody that binds to the soluble and membrane-bound forms of the IL-6 receptor (IL-6R). IL-6 has a key role in the pathogenesis of GCA, and elevated levels of IL-6 are present and correlate with disease activity. Efficacy of tocilizumab in GCA has been proved in a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with 251 patients (119 newly diagnosed and 132 with relapsing disease). The patients were randomized to receive subcutaneous tocilizumab (162 mg) weekly or every other week combined with a 26-week prednisone taper or placebo, combined with a prednisone taper over a period of either 26 or 52 weeks. Both groups of patients treated with tocilizumab achieved sustained remission more commonly than those placebo-treated at week 52. Patients who underwent tocilizumab therapy had fewer relapses of disease than

*DOI: http://dx.doi.org/10.5772/intechopen.91018*

**5.1 Glucocorticoid-sparing therapy**

MTX becomes manifest only after 24–36 weeks [19].

rarely reversible [16].

#### *Giant Cell Arteritis: Current Advances in Pathogenesis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.91018*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

In patients in whom there is a high clinical suspicion of GCA and a positive imaging test, the diagnosis of GCA may be made without an additional test (biopsy or further imaging). In patients with a low clinical probability and a negative imag-

*PET-CT of a patient from the Rheumatology Division of the University of Sao Paulo, School of Medicine with GCA showing inflammation in the vascular wall of the aorta and subclavian, common carotid, iliac, femoral,* 

Ultrasound of temporal ± axillary arteries is recommended as the first imaging modality in patients with suspected predominantly cranial GCA. A noncompressible "halo" sign is the ultrasound finding most suggestive of GCA (**Figure 3**). Highresolution MRI of cranial arteries to investigate mural inflammation may be used as an alternative for GCA diagnosis if ultrasound is not available or inconclusive. Ultrasound, PET, MRI, and/or CT may be used for the detection of mural inflammation and/or luminal changes in extracranial arteries to support the diagnosis of large-vessel GCA (**Figure 4**). Ultrasound is of limited value for the assessment of

In patients with a suspected flare, imaging might be helpful to confirm or exclude it. Imaging is not routinely recommended for patients in clinical and biochemical remission. In patients with large-vessel vasculitis, MRA, CTA, and/or ultrasound may be used for long-term monitoring of structural damage, particu-

Treatment with oral glucocorticoid (GC) effectively induces remission and reduces the evolution to visual loss, and it should be started as early as possible

larly to detect stenosis, occlusion, dilatation, and/or aneurysms [15].

ing result, the diagnosis of GCA can be considered unlikely [15].

**100**

aortitis [15].

**Figure 4.**

*popliteal, and tibial arteries.*

**5. Treatment**

when there is a clinical suspicion of GCA. The GC therapy cannot be postponed to after confirmation of the diagnosis, because once the visual loss is installed, it is rarely reversible [16].

Oral prednisone in a daily single dose of 40–60 mg usually resolves the symptoms and normalizes acute inflammation reactants within the first 2–4 weeks of the treatment. When premonitory visual signs are present (amaurosis fugax) or when visual loss is installed, pulse therapy with daily intravenous methylprednisolone (500–1000 mg) for 3 days can be tried, even though its superiority compared to the oral prednisone regimen has not been proven in clinical trials.

Glucocorticoids are effective in inducing clinical remission, but the side effects of its chronical use are undesirable, especially in elderly individuals. Therefore, synthetic or biological immunosuppressants have been used as GC-sparing adjuvants to reduce the cumulative GC dose and to maintain remission after the prednisone withdrawal [17]. There is no consensus on the timing of initiating GC-sparing therapy, but indications to start it early in the disease course include the presence of significant premorbid diseases (diabetes mellitus, osteoporosis, obesity), the emergence of significant glucocorticoid-related side effects, and a relapsing course necessitating protracted CS use. After clinical remission is achieved (symptoms resolved and laboratory inflammation markers normalized), the GC taper can be started. It has to be slow, especially with lower doses. The dose can gradually be reduced by 5 mg every 2 weeks to 20 mg/day and then by 2.5 mg every 2 weeks to 10 mg/day if there are no flares of disease activity. After achieving a daily dose of 10 mg, the prednisone taper should be slowed, such that patients remain on progressively decreasing doses over the ensuing 6–12 months. Tapering by 1 mg decrements each month once the daily dose is less than 10 mg can be considered. Disease relapses are more frequent in this final phase of the GC tapering regimen [18].

### **5.1 Glucocorticoid-sparing therapy**

**Methotrexate** (MTX) is the conventional immunosuppressive drug most commonly used for the management of refractory GCA. However, the efficacy of this drug in GCA is modest. The trials yielded a role of MTX (10–15 mg/week) to reduce the frequency of relapses (by 35% of a first relapse and by 51% of a second relapse) and decrease the cumulative prednisone dose. However, the optimum efficacy of MTX becomes manifest only after 24–36 weeks [19].

**Leflunomide** may also be an effective and well-tolerated glucocorticoid-sparing agent in GCA, but there are no randomized controlled trials to confirm it yet. In one prospective observational study with 76 newly diagnosed GCA patients, 10 mg daily leflunomide was compared with glucocorticoid only in a follow-up period of at least 48 weeks. During the follow-up 13.3% patients in the leflunomide group flared versus 39.1% in the GC-only group (p = 0.02). Furthermore, 56.7% patients in the leflunomide were able to stop GC at week 48 but none in the GC-only group [20].

**Tocilizumab** is a humanized monoclonal antibody that binds to the soluble and membrane-bound forms of the IL-6 receptor (IL-6R). IL-6 has a key role in the pathogenesis of GCA, and elevated levels of IL-6 are present and correlate with disease activity. Efficacy of tocilizumab in GCA has been proved in a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with 251 patients (119 newly diagnosed and 132 with relapsing disease). The patients were randomized to receive subcutaneous tocilizumab (162 mg) weekly or every other week combined with a 26-week prednisone taper or placebo, combined with a prednisone taper over a period of either 26 or 52 weeks. Both groups of patients treated with tocilizumab achieved sustained remission more commonly than those placebo-treated at week 52. Patients who underwent tocilizumab therapy had fewer relapses of disease than

those in the placebo arms [21]. Tocilizumab use was associated with a powerful glucocorticoid-sparing effect, and this effect was stronger in those patients who had experienced relapses before randomization. Tocilizumab in a subcutaneous weekly dose of 162 mg was approved by the US FDA and the European Commission for the treatment of GCA. However, there is concern about the characterization of a relapse in patients that are under tocilizumab therapy, because tocilizumab is very effective in normalizing CRP and ESR and some patients can be oligo-symptomatic during a flare. Periodic imaging in these patients is recommended for accessing vascular activity or progression of the vascular damage during the treatment.

**Ustekinumab** is a human monoclonal antibody that binds to the p40 subunit of both IL-12 and IL-23 preventing their binding to their shared cell surface receptor chain, IL-12β. The inhibition of IL-12 signaling abrogates Th1 response with reduction in TNF-, IFN-, and IL-12 production. The inhibition of IL-23 signaling abrogates Th17 response with the reduction on IL-6, IL-17, IL-21, IL-22, and TNF production. Th1 and Th17 responses both have important roles in the pathogenesis of GCA. A prospective open-label 52-week trial with 25 patients with relapsing GCA showed that ustekinumab may be effective for the treatment of GCA: at week 52 the median daily dose of prednisolone decreased from 20 to 5 mg (p < 0.0001), and no patient experienced a relapse of GCA while receiving ustekinumab [22]. No randomized controlled trial with ustekinumab in GCA patients has been performed yet.

**Abatacept** is a fully human fusion protein that binds to CD80/CD86 on antigenpresenting cells preventing these molecules from binding to their ligand, CD28, on T cells, and is moderately effective in the treatment of GCA. In a multicenter, randomized, double-blind trial, 49 patients with GCA were treated with 10 mg/kg intravenous abatacept on days 1, 4, and 29 and week 8 and monthly after that. The relapse-free survival rate at 12 months, the primary endpoint, was 48% for those receiving abatacept and 31% for those receiving placebo (p = 0.049) [23]. Further studies encompassing larger number of patients are needed to confirm the utility of abatacept as adjunctive therapy in GCA.

Anti-TNF agents have been tested and yielded disappointing results, showing no efficacy in reducing GC dose or relapse rates in GCA. There are other promising target therapies being tested, such as the JAK/STAT inhibitors, but the results are not available, and there is no data to support their use in clinical practice yet.

#### **5.2 Preventing complications**

Patients with GCA are elderly and frequently have multiple comorbid conditions that can be worsened by the use of GC and immunosuppressants. Therefore, the levels of vitamin D must be higher than 30 ng/mL for all patients, and the dietary intake of calcium must be stimulated (or supplementation, if the dietary intake is insufficient) for bone protection, as well as the use of bisphosphonates if indicated.

Low-dose aspirin (80–100 mg/day) should be prescribed for prevention of cardiovascular events, which represent the main cause of death in this population.

#### **6. Prognosis**

The most frequent causes of death in GCA patients are cardiovascular diseases followed by cancer. Combined, these conditions account for approximately two thirds of all deaths. A Norwegian cohort of 881 patients with GCA and 2577 population controls found no significant difference in the overall cumulative survival or survival at any specific time after diagnosis. In this study the mean age of death was

**103**

**Author details**

Marília A. Dagostin and Rosa M.R. Pereira\*

provided the original work is properly cited.

Universidade de Sao Paulo, Sao Paulo, SP, Brazil

\*Address all correspondence to: rosamariarp@yahoo.com

Rheumatology Division, Hospital das Clínicas HCFMUSP, Faculdade de Medicina,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Giant Cell Arteritis: Current Advances in Pathogenesis and Treatment*

83.6 (SD 7.5) years for GCA patients, and survival was more than 80% in 5 years and approximately 50% in 10 years [24]. The same study found that even though the overall mortality was not reduced in GCA, these patients have an increased risk of death due to circulatory diseases and infections but a decreased risk of death due to cancer over time. The increased risk of death by circulatory diseases may be related to aneurysms and dissections, which are recognized as large-vessel complications of GCA. Therefore, it is extremely important in the management of these patients to

identify and to treat other contributing risk factors for circulatory disease.

*DOI: http://dx.doi.org/10.5772/intechopen.91018*

### *Giant Cell Arteritis: Current Advances in Pathogenesis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.91018*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

those in the placebo arms [21]. Tocilizumab use was associated with a powerful glucocorticoid-sparing effect, and this effect was stronger in those patients who had experienced relapses before randomization. Tocilizumab in a subcutaneous weekly dose of 162 mg was approved by the US FDA and the European Commission for the treatment of GCA. However, there is concern about the characterization of a relapse in patients that are under tocilizumab therapy, because tocilizumab is very effective in normalizing CRP and ESR and some patients can be oligo-symptomatic during a flare. Periodic imaging in these patients is recommended for accessing vascular

**Ustekinumab** is a human monoclonal antibody that binds to the p40 subunit of both IL-12 and IL-23 preventing their binding to their shared cell surface receptor chain, IL-12β. The inhibition of IL-12 signaling abrogates Th1 response with reduction in TNF-, IFN-, and IL-12 production. The inhibition of IL-23 signaling abrogates Th17 response with the reduction on IL-6, IL-17, IL-21, IL-22, and TNF production. Th1 and Th17 responses both have important roles in the pathogenesis of GCA. A prospective open-label 52-week trial with 25 patients with relapsing GCA showed that ustekinumab may be effective for the treatment of GCA: at week 52 the median daily dose of prednisolone decreased from 20 to 5 mg (p < 0.0001), and no patient experienced a relapse of GCA while receiving ustekinumab [22]. No randomized controlled trial with ustekinumab in GCA patients has been

**Abatacept** is a fully human fusion protein that binds to CD80/CD86 on antigenpresenting cells preventing these molecules from binding to their ligand, CD28, on T cells, and is moderately effective in the treatment of GCA. In a multicenter, randomized, double-blind trial, 49 patients with GCA were treated with 10 mg/kg intravenous abatacept on days 1, 4, and 29 and week 8 and monthly after that. The relapse-free survival rate at 12 months, the primary endpoint, was 48% for those receiving abatacept and 31% for those receiving placebo (p = 0.049) [23]. Further studies encompassing larger number of patients are needed to confirm the utility of

Anti-TNF agents have been tested and yielded disappointing results, showing no efficacy in reducing GC dose or relapse rates in GCA. There are other promising target therapies being tested, such as the JAK/STAT inhibitors, but the results are not available, and there is no data to support their use in clinical practice yet.

Patients with GCA are elderly and frequently have multiple comorbid conditions that can be worsened by the use of GC and immunosuppressants. Therefore, the levels of vitamin D must be higher than 30 ng/mL for all patients, and the dietary intake of calcium must be stimulated (or supplementation, if the dietary intake is insufficient) for bone protection, as well as the use of bisphosphonates if indicated. Low-dose aspirin (80–100 mg/day) should be prescribed for prevention of cardiovascular events, which represent the main cause of death in this population.

The most frequent causes of death in GCA patients are cardiovascular diseases followed by cancer. Combined, these conditions account for approximately two thirds of all deaths. A Norwegian cohort of 881 patients with GCA and 2577 population controls found no significant difference in the overall cumulative survival or survival at any specific time after diagnosis. In this study the mean age of death was

activity or progression of the vascular damage during the treatment.

**102**

**6. Prognosis**

performed yet.

abatacept as adjunctive therapy in GCA.

**5.2 Preventing complications**

83.6 (SD 7.5) years for GCA patients, and survival was more than 80% in 5 years and approximately 50% in 10 years [24]. The same study found that even though the overall mortality was not reduced in GCA, these patients have an increased risk of death due to circulatory diseases and infections but a decreased risk of death due to cancer over time. The increased risk of death by circulatory diseases may be related to aneurysms and dissections, which are recognized as large-vessel complications of GCA. Therefore, it is extremely important in the management of these patients to identify and to treat other contributing risk factors for circulatory disease.
