Giant Cell Arteritis and Polymyalgia Rheumatica – current challenges and opportunities

Christian Dejaco1,2, Elisabeth Brouwer3, Justin C Mason4, Frank Buttgereit5, Eric L. Matteson6, Bhaskar Dasgupta7

1Department of Rheumatology and Immunology of the Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria; 2Rheumatology service, South Tyrolean Health Trust, Hospital of Bruneck, Spitalstraße 11, 39031 Bruneck, Italy3Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, The Netherlands4Vascular Science and Rheumatology, Imperial College London, London, UK5Charité University Medicine, Department of Rheumatology and Clinical Immunology, Berlin, Germany6Mayo Clinic College of Medicine and Science, Division of Rheumatology and Division of Epidemiology, Departments of Internal Medicine and Health Sciences Research; Rochester, MN, USA7Southend University Hospital & Anglia Ruskin University, Department of Rheumatology, Southend, UK

Corresponding author:Professor B DasguptaSouthend University HospitalPrittlewell ChaseWestcliff-on-sea, Essex, SS0 0RYBhaskar.dasgupta@southend.nhs.ukPhone No: 0044-170-2385254; Fax Number: 0044-170-2385909

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ABSTRACT

The fields of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) have been rapidly advancing in recent years resulting in a new understanding of the disease concept. Ultrasound and other imaging techniques have been introduced in daily clinical routine and there have been promising reports on the efficacy of biological agents, particularly interleukin-6 antagonists. Along with these intriguing developments, that should improve the outcome of patients with GCA and PMR, new questions and unmet needs have emerged such as which pathogenetic mechanisms contribute to the different phases and clinical phenotypes of GCA, what role imaging plays in the early diagnosis and monitoring, and in which patients and disease phases novel biological drugs should be used. In this review, we discuss the implications of recent developments in GCA and PMR, as well as the unmet needs concerning epidemiology, pathogenesis, imaging and treatment of these diseases.

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Introduction

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are overlapping inflammatory rheumatic disorders of older people 1. Although reports by Horton (1932), Paulley & Hughes (1960) and Hamrin (1972) already recognized the systemic nature of GCA, clinicians have generally viewed GCA as a “headache disease”, a perception perhaps fostered by the 1990 ACR classification criteria of GCA, which have frequently been misused for diagnostic purposes. The ACR criteria mainly focus on cranial symptoms such as headache and swelling and/or tenderness of the temporal artery 2,3. More recently, routine use of vascular imaging studies has demonstrated that large-vessel involvement is more frequent than previously thought, leading to a broader understanding of GCA as a ‘vasculitic’ syndrome that includes large vessel vasculitis and PMR 3. Large vessel GCA (LV-GCA) affects large, particularly supra-aortic arteries, their branches and/or the aorta and is frequently first discovered on vascular imaging studies conducted in patients with difficult to treat polymyalgia and/or constitutional symptoms such as weight loss, night sweats and fever of unknown origin 1,3. LV-GCA related arterial stenosis may result in upper limb claudication. Aortic inflammation is often associated with constitutional symptoms, and may lead to aneurysm formation causing abdominal, thoracic and/or back pain if complicated by intramural haematoma, dissection or rupture 4. PMR is clinically characterized by aching and stiffness in the cervical region, shoulder and pelvic girdles 5.The most feared complication of GCA is irreversible permanent sight loss. Cerebrovascular strokes, infarction of the tongue and scalp necrosis are less common6. Permanent visual loss caused by anterior ischemic optic neuropathy occurs in 15-20% of patients 7,8. Better recognition of the disease and prompt initiation of therapy in recent years has led to a reduction of visual and other ischemic complications 9,10. Glucocorticoids (GC) are the standard treatment for both GCA and PMR; however, GC-related adverse events occur in up to 85% of cases 11. Many patients have pre-existing co-morbidities that may pose relative/absolute contraindications to GC therapy. The prevalence of flares is high, and it is related to the dose and duration of GC therapy. Whereas in cohort studies, flares have been observed in 34-62% of patients 12–14, recent trials with a rapid tapering of GCs suggested that sustained remission is achieved in no more than 15-20% of cases treated with GCs alone 15,16. Methotrexate (MTX) is used in individual cases with GCA and PMR 17–20; however, more effective treatment strategies are needed to lower the burden from long-term GCs. A better understanding of the pathogenesis and clinical phenotypes of GCA will facilitate the identification of new targeted therapies and provide safe, sustained remission and prevent disease relapses (Box 1). In this review we discuss the challenges encountered in studying the epidemiology of GCA subsets, the emergence of novel imaging techniques and their role for diagnosis, monitoring and outcome prediction of GCA and PMR. Further, we present

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a summary of current understanding of the pathogenesis of the disease and the possible role of novel drugs in the treatment of GCA and PMR.

How common is GCA and PMR? Challenges to study the epidemiology

PMR is considered the second most common rheumatic disease in the elderly, and in countries where it is known to occur, GCA is the most frequent primary vasculitis 21,22. The epidemiology of these conditions, however, is challenging to study because of their common clinical and subclinical overlap. Large scale epidemiologic studies of GCA and PMR are lacking in several parts of the world including Latin America, South Asia and Africa. The highest incidence of GCA and PMR is seen among persons of Northern European ancestry, particularly in persons of Scandinavian descent, where incidence of GCA ranges from 18 to 29, and that of PMR from 41 to 113 cases per 100,000 among people aged ≥50 years 22–29. It is likely that the occurrence of GCA will increase due to an aging population. The projected world-wide disease burden of GCA by 2050 is more than 3 million, and about 500,000 people will become visually impaired 30. Features of PMR are observed in 40–60% of patients with GCA at diagnosis, and 16–21% of patients with PMR have GCA 1. Subclinical GCA in patients with PMR may be detected by vascular imaging, which however, is uncommonly performed in patients who appear to have PMR only. Another difficulty is that there are no definite diagnostic tests for PMR, and even for GCA, the gold standard temporal artery biopsy (TAB) is positive in only 39-87% of cases, and in <60% of patients with predominant LV-GCA 31–36. LV-GCA occurs in up to 83% of patients with GCA and with unknown frequency in PMR. The possibility of coexistent GCA arises in PMR patients with incomplete GC response, constitutional symptoms and markedly elevated acute phase reactants37,38. LV-GCA may be present at diagnosis, and may occur at any point during the disease course, and is detected with increasing frequency in GCA patients after 4 to 5 years of disease 39. The definition of LV-GCA is still imprecise, which hampers the performance of proper epidemiological studies. A biopsy of larger arteries is not feasible in routine practice, and LV-GCA diagnosis is thus based on imaging methods such as axillary ultrasound, 18F-fluorodeoxy-glucose positron emission tomography (18F-FDG–PET), computed tomography angiography (CTA) or magnetic resonance imaging (MRI) to assess mural inflammation and changes in the lumen. The new understanding of GCA as a disease complex that is not limited to cranial arteries, along with advanced imaging techniques and international efforts to better define the disease will facilitate future studies on the epidemiology of GCA, permitting better understanding of its incidence, prevalence and disease course.

The role of imaging in GCA and PMR

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Which imaging techniques can we use to diagnose GCA and PMR?

Although imaging in GCA and PMR is evolving quickly, there is still significant controversy about when and which imaging techniques to use.The majority of imaging studies were performed to assess the role of ultrasound for diagnosis of GCA and PMR. In GCA, ultrasonography has not yet replaced temporal artery biopsy (TAB), although several studies report a sensitivity of 55-100% and specificity of 78-100% of the sonographic “halo sign”, which is a non-compressible hypo-echoic ring around the lumen reflecting inflammation of the vessel wall 1,32,40–42. The TABUL study prospectively compared the performance of color Doppler ultrasound (CDUS) and TAB, reporting sensitivities of 54% and 39%, respectively and specificities of 81% and 100%, respectively for the diagnosis of GCA. Because TAB was part of the reference standard, the reported higher specificity of TAB may in part be an artifact of the study methodology 33. PMR is still considered a clinical diagnosis but ultrasonography can improve diagnostic accuracy and has therefore been included in the ACR-EULAR classification criteria 43,44. A characteristic sonographic lesion in PMR is sub-acromial/sub-deltoid bursitis which indicates a diagnosis of PMR with a sensitivity of 79% and a specificity of only 59% 45. This overlap relates to a true overlap between PMR and inflammatory arthritis since ultrasound performed better in distinguishing PMR from non-inflammatory mimics 43,44 The principal role of 18F-FDG–PET in GCA is for establishing a diagnosis in patients presenting with marked systemic symptoms and/or raised inflammatory markers without characteristic features of cranial GCA, as well as to search for alternative diagnoses in patients with unexplained illness and a low probability of GCA 46. 18F-FDG–PET visualizes local glucose metabolism, and as vascular inflammation is associated with increased glucose consumption, enhanced tracer uptake in the vessel wall suggests vasculitis. In patients with PMR, characteristic 18F-FDG–PET findings are shoulder and hip girdle uptake as well as the presence of lumbar and cervical interspinous bursitis 47,48. One study also reported bilateral capsular tracer uptake at the knees in 84% of PMR cases 49. 18F-FDG–PET may reveal underlying LV-GCA in up to 30% of PMR cases, particularly in those with anemia, markedly elevated inflammatory markers and treatment resistant/relapsing disease, while subclinical large vessel inflammation is less common in patients with “pure” PMR. 48,50–52.

CTA and MR angiography (MRA) are alternative or complementary imaging techniques in GCA enabling the detection of soft tissue swelling/cuffing of the wall of large arteries and the aorta, and also provide information about the luminal anatomy and blood flow. These techniques are thus particularly helpful for detecting GCA related vascular stenosis or aneurysms 53,54. The sensitivity and specificity of these techniques for establishing a diagnosis of GCA is still unclear. The role of high resolution MRI for the investigation of cranial arteries in GCA is evolving. A multicenter trial comparing MRI and TAB in suspected GCA

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demonstrated a sensitivity of 88% and a specificity of 75% for cranial vasculitis 55. Exciting preliminary data suggests that new generation 7T MRI is even more sensitive than 3T MRI for detailing involved and uninvolved segments within an affected temporal artery 56. High resolution MRI may also detect inflammation in both the deep temporal arteries and temporalis muscle, a finding particularly useful in patients where GCA is strongly suspected but the superficial temporal arteries appear normal 57. The limited availability of 3T and 7T MRI, however, restricts the clinical utility of this imaging modality in GCA.Another pilot study of 12 patients with GCA or Takayasu arteritis (TAK) observed that 18F-FDG–PET-MRI performed favorably compared to 18F-FDG–PET-CT in both GCA and TAK 58. 18F-FDG–PET-MRI demonstrated improved soft tissue resolution and was optimal for determining disease extent for both diseases. Imaging findings of the aorta and large vessels in GCA and TAK are considered comparable.

Is imaging a reliable outcome parameter and/or tool for monitoring?

The value of sonography for the follow-up of inflammation at temporal arteries seems to be limited because the characteristic “halo sign” disappears after 1-2 weeks upon initiation of GC treatment and re-appears only in case of a major relapse 41,59–61. Whether the extent, persistence or re-appearance of the “halo sign” at this site is of any prognostic value for patients with GCA requires investigation. Ultrasonography of large arteries such as the carotids or the axillary artery might be more useful in this regard because wall swelling in these larger arteries persists longer than in superficial cranial arteries despite therapy 40. Changes of the intima and media thickness during follow-up might reflect alterations of disease activity, but prospective evaluation is still needed to establish the significance of these changes 62. 18F-FDG–PET, typically performed with CT, exposes the patient to a radiation dose of 10-15 mSv, thus precluding its routine use in follow-up. Moreover, there is also uncertainty concerning the relationship between low-grade FDG uptake and arterial wall inflammation. In one prospective study, arterial FDG uptake at diagnosis of GCA decreased significantly following 3 months of treatment, however, no further reduction was seen at 6 months despite clinical remission 37. Residual tracer uptake could reflect persistent arterial wall inflammation, but may also be caused by myofibroblast proliferation, fibrosis or the presence of atheroma, all of which are glucose consuming processes. Longitudinal follow-up studies of MRA and CTA in GCA are scarce. In a prospective study, CTA scans were scheduled in 35 biopsy-proven cases at diagnosis and after 1 year of treatment. While arterial wall thickening was still present in 68% of cases, the number of affected segments, wall thickness and contrast enhancement decreased with therapy. No patients developed worsening of or new aortic dilation, suggesting that aneurysm formation is a delayed complication in most patients 63. This observation is in accordance with previous retrospective studies 39,64,65. Lack of radiation exposure with MR imaging, as well as the possibility to use gadolinium-based contrast agents to distinguish active arterial wall inflammation from fibrosis,

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makes MRA an attractive tool for the follow-up of GCA, particularly in patients with LV-GCA 66. Lower spatial resolution and longer scan times compared to CT, and the infrequent but serious nephrotoxicity of gadolinium are disadvantages of MRA. No consensus exists regarding the screening for stenosis/aneurysms of large arteries and the aorta. It is the practice of the authors to attempt obtaining a baseline imaging of large arteries and the aorta in all patients with GCA, particularly with aforementioned symptoms of LV-GCA, although there are no data proving the cost-effectiveness of this approach. Patients with an aortic diameter outside the sex and age-matched normal range, those known to have active aortitis and those with risk factors for aortic aneurysm development (for example smokers, hypertensives and patients with pre-existing cardiovascular disease) might then be followed-up every 1-2 years with MRA in order to detect possible aortic dilatation while minimising radiation exposure 67,68. In patients without these risk factors, axillary artery ultrasound, chest radiograph, echocardiogram and abdominal sonography every other year might be sufficient, with any change in aortic diameter being further investigated 19.

Emerging developments in the field of imaging in GCA and PMR

The ability to reliably detect low-grade ‘grumbling’ arterial wall inflammation and early disease relapse in those already on treatment is a critical imaging aspiration. New approaches include the search for novel, specific PET ligands. PK11195 binds specifically to translocator protein (TSPO), which is highly expressed on activated neutrophils, monocytes and macrophages. [11C]-PK11195 sensitively identified the 5 cases with active disease amongst 15 patients with GCA and TAK 69. A small study of GCA and TAK study comparing CDUS with microbubble contrast-enhanced US (CEUS) reported that the latter optimises assessment of arterial wall lesions and detects neovascularisation 70. Moreover, initial evidence suggests that CEUS can quantify disease activity and monitor response to treatment in carotid arteritis 71–73. Another important issue is the assessment of ischemia of the optic nerve head, retina and choroid in patients with GCA. Traditionally fluorescein and indo cyanine green angiography have been used but they are invasive procedures with risk of allergic reactions to the dyes. Optical Coherence Tomography (OCT) is a noninvasive interferometric optical imaging modality which may be of particular use in differentiating non-arteritic from GCA related anterior ischemic optic neuropathy (AION) 74. OCT-A uses motion contrast imaging to produce high-resolution volumetric blood flow information that provides visualisation of the distinct retinal, chororetinal and choroidal capillary networks 75,76. In GCA, this technique might be applied to identify patients at risk of visual loss.

Understanding the pathogenesis of GCA to move toward targeted interventions

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The current concept of GCA is that of an immune-mediated disease of large vessels, including cranial arteries as the most frequent target, and/or the aorta and its major branches. Inflammation starts in the adventitia, eventually involving the inner layers of the vessel wall. Patients with isolated PMR or polymyalgic syndrome in association with elderly onset inflammatory rheumatic diseases such as rheumatoid arthritis (RA) are affected by a systemic inflammatory syndrome in conjunction with bursitis and synovitis of shoulders, hips and the spine 3. PMR in association with GCA may be regarded as an early or aborted form of vasculitis where vascular inflammation is often limited to the adventitia and peri-adventitial small vessels 77. The acute phase of GCA is mainly inflammatory, whereas chronic stages are characterized by inflammation, degradation and repair mechanisms collectively leading to structural changes of the vessel wall, ischemic complications and aneurysm development (Figure 1). Table 1 highlights areas of future research based on current understanding of pathogenesis of PMR and GCA including possible biomarkers and treatment targets.

What initiates the disease process of GCA?

The trigger for the inflammatory cascade resulting in GCA is still unclear. The adventitia is an important site of immune surveillance and abounds in toll-like receptor (TLR) expressing resident DCs and tissue resident macrophages 78. In GCA, these cells become aberrantly activated via pathogen-associated molecular patterns (PAMPs) or microorganisms-associated molecular patterns (MAMPs) leading to the production of pro-inflammatory cytokines and activation of T-cells. A low expression of the co-inhibitory ligand programmed death ligand-1 (PD-L1) by DCs in GCA seems to accelerate the recruitment and retention of T cells in the inflamed artery 79. CD8+CCR7+ regulatory T-cells with reduced expression of the NADPH oxidase 2 (NOX2) were detected in the peripheral blood of GCA patients resulting in decreased suppression of CD4+ T-cell responses 80. T-cells, macrophages and other immune cells eventually cause tissue damage and the release of damage-associated molecular patterns (DAMPs). The latter are increased in aged vessels already, and act synergistically with PAMPs to further stimulate the inflammatory process 81.A recent study reported the presence of abundant viral and bacterial DNA in the arterial wall using advanced DNA sequencing techniques 82. Earlier studies recurrently observed various bacterial strains (Chlamydia, Burkholderia) or viruses (ParvoB19, VZV) in temporal arteries collectively supporting the hypothesis that PAMPs/MAMPs are crucial for the outset of GCA. The identification of a specific GCA-causing microorganism that might be targeted by anti-infective agents, however, has never been confirmed 83–85. Treatment strategies directed at silencing DCs and adventitial macrophages at an early stage include IL-1/IL1 inhibition (e.g. by canakinumab or gevokizumab) and blockade of co-stimulatory molecules (e.g. CTLA4 by abatacept). Some of these drugs have already been tested in GCA and/or PMR as detailed below.

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Amplifying inflammation: Feed forward loops

Upon maturation of DCs and resident macrophages, CD4+ T-cells are stimulated to polarize into Th1 and Th17 cells, migrating via chemokines CXCR3 and CCR6, respectively into the vessel wall. Th1 and Th17 cells attract new macrophages via IFN- and IL-17 production, respectively 86. In addition to CD4+ T-cells, a small proportion of CD8+ T-cells also infiltrates into the temporal artery via CXCR3, producing IL-17 and IFN- as well as perforin and granzyme-B. The latter seem to correlate with the extent of vessel wall destruction and disease severity 87. IL-17 and IL-6 also regulate the crosstalk between T-cells and a newly discovered subset of neutrophil granulocytes. In one study, AnxA1hiCD62LloCD11bhi neutrophils were detected early after initiation of GC-therapy suppressing T-cell activity. Following reduction of the GC dose, and paralleled by a rise of IL-17 and IL-6, there was a change in neutrophil phenotype (AnxA1hiCD62LhiCD11bhi) and function with resultant inability to control T-cell responses 88. Cytokine and chemokine gradients orchestrate the migration of tissue destructive monocytes, macrophages and B-cells, and in parallel, neoangiogenesis is stimulated by vascular endothelial growth factor (VEGF) released mainly by macrophages 89,90. Targeting IL-6 receptors with tocilizumab and IL-6 with sirukumab, blockade of IL-17 or IL-12/23 with secukinumab and ustekinumab, respectively, as well as modulation of chemokines or intracellular signaling pathways (e.g. with JAK/STAT inhibitors) might interrupt the feed-forward loops and terminate amplifying inflammation.IL-6 plays a pivotal role in the pathogenesis of the systemic inflammatory response, whereas the recruitment of media infiltrating macrophages, giant cell formation and proliferation of vascular smooth muscle cells in GCA may reflect contribution of other inflammation driving factors such as TNF- and IFN- 86,90–92. The Janus family kinases (Jaks) facilitate signal transduction of different cytokines depending on the formation of homo- or heterodimers 93. IFN- for example signals though JAK1/JAK2 whereas Type II cytokine receptors such as those for IL-6 and IL-1 mainly signal through JAK1 94,95. The JAK inhibitor tofacitinib preferentially blocks signalling by cytokine receptors associated with JAK3 and/or JAK1 96,97. Baracitinib has selectivity for JAK1 and JAK2 dependent receptors thereby targeting both Th17 and Th1 cells in GCA 98. Apremilast, which seems to be effective in psoriatic arthritis and Behçet's syndrome 99,100, binds to the catalytic site of the PDE4 enzyme and blocks degradation of cAMP 101 resulting in a reduction in Th1, Th2, and Th17 immune responses and lower production of IFN-, TNF-, IL-12, IL-17, and IL-23, all of which play an important role in the pathogenesis of GCA 102,103. While possibly promising agents to halt the transmural and/or systemic inflammation in these diseases, there are as yet no reports of JAK-inhibitors or apremilast for treating GCA or PMR. Although it has long been known that B-cells are present in temporal artery tissue of patients with GCA, their specific role in the pathogenesis of GCA/PMR has only recently been explored 104. Circulating B cell levels are decreased in patients with

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newly diagnosed GCA/PMR and recover rapidly once remission is achieved 89. A recent study further described the occurrence of tertiary lymphoid organs in the media layer of temporal arteries in 60% of patients with GCA in close proximity to high endothelial venules 105. It is known that B cells may function as antigen-presenting cells and they could thus provide important costimulatory signals required for CD4+ T-cell clonal expansion 106.

Vessel wall injury, remodeling/repair, intimal hyperplasia and neo-angiogenesis

In GCA, several mediators contribute to intimal hyperplasia and vascular occlusion. PDGF for example, had a high vaso-occlusive potential in an in vitro model of cultured primary human temporal artery derived myointimal cells and also stimulated the production of angiogenic factors (angiogenin) and chemo- attractants (CCL2) 107. In temporal artery specimens from patients with GCA, PDGF-A and PDGF-B producing macrophages were located at the media-intima junction particularly in cases with concentric intimal hyperplasia 91. Neurotrophins are growth factors mediating the differentiation and survival of neurons as well as vascular cells. In GCA, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and the neurotrophin co-receptor sortilin were overexpressed in different histological layers of temporal arteries. In vitro, NGF and BDNF promoted proliferation of VSMC, and BDNF also facilitated the migration of temporal artery VSMCs 108. Endothelin-1 and endothelin-B receptor are also expressed in GCA lesions, particularly on VSMC and multinucleated giant cells109. Although the exact contribution of endothelins to the pathogenesis of GCA remains elusive, they may promote inflammation, increase the sensitivity to vasoconstriction, increase VSMCs proliferation and stimulate migration of VSMCs towards the intimal layer, thus collectively contributing to intimal hyperplasia and vascular occlusion 110–112.

Macrophages and giant cells from patients with GCA release VEGF eventually leading to vasa vasorum formation 90. Whether local hypoxia (potentially explained by high oxygen consumption of inflammatory and stromal cells) or pro-inflammatory cytokines are the major driving forces for VEGF secretion needs to be elucidated 113. Macrophages are a further major source of proteases (MMPs, cathepsins, elastase), which play an important role for the emergence and branching of vasa vasorum 114.

Whether vascular remodeling and intimal hyperplasia can be influenced by immunsuppressive therapies is still unclear. One study, obtaining paired temporal artery biopsies from 4 patients at baseline and after 1 year of therapy reported decrement of tissue mRNA levels from inflammatory cytokines while factors mediating vascular remodeling (MMP-9, TGF-, PDGF-A and PDGF-B) were increased 103. Another study observed that endothelin tissue concentrations were similar in temporal artery specimens of patients with active or inactive (treated) disease 112.

Further research is necessary to better understand the factors contributing to arterial

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remodeling and vascular occlusion in GCA and to identify possible targets for interrupting these processes. Direct inhibitors of proliferative or pro-angiogenetic factors could be promising, but bear the risk of disrupting terminal vascularization such as vessels supplying the optic nerve, potentially worsening ischemic complications.

Unmet needs in therapy: How to improve the benefit-risk ratio of glucocorticoids?

GCs remain the mainstay treatment of both PMR and GCA, but the basis for the use of different GC dosages in different clinical conditions is empiric 1. According to consensus-based recommendations, initial therapy for PMR is prednisone (equivalent) 12.5–25mg/day, and 40–60mg/day for GCA, followed by individualized tapering regimens 17–19,115. The optimization of the benefit-risk ratio of GCs in order to minimize adverse events while achieving sustained remission is an ongoing disease management challenge 116. Improved implementation of current treatment recommendations for the optimal use of GCs is one possible way the burden of GCs could be reduced 17–19. A recent EULAR task force concluded that the risk of GC related harm for the majority of patients taking GCs for a prolonged period (3-6 months or more) is low if doses of ≤5mg/d prednisone equivalent are prescribed, but high if doses >10mg/d are used. At doses between >5 and ≤10 mg/d, patient-specific risk factors determine the probability of harm. The second major approach to increasing the benefit-risk ratio of GCs is the development of innovative GC preparations and/or GC receptor ligands. A novel class of GCs are the dissociated agonists of the GC receptors [DAGR, also called selective GC receptor modulators (SEGRM)] 117. The underlying concept is that DAGRs predominately induce trans-repression of GC target genes mediating anti-inflammatory effects, while trans-activation, which is mainly responsible for adverse effects, is low 118. Liposomal GCs have been designed to deliver conventional GCs to inflamed tissues using very small, nanometresized liposomes 119. This technology may provide strong therapeutic effects with minimum systemic adverse effects. DAGRs and liposomal GCs are both currently being evaluated in RA. Trials in PMR and GCA may follow if results of these RA trials are favorable. Finally, modified-release prednisone (MR prednisone) was recently investigated in PMR. This drug allows optimal chronotherapy with bedtime administration of the drug but release of prednisone at the optimal time for suppression of pro-inflammatory cytokines (~2 a.m.). While MR prednisone yielded clinical superiority over conventional prednisone in RA (CAPRA-1/2) 120,121, the multicentre randomized, phase 3 study in PMR was terminated early due to insufficient recruitment (only 62 of 400 planned patients were included) and barely failed its primary endpoint 122. MR prednisone has also been studied in a small phase 2 trial in 12 patients with new

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onset GCA. At 26 weeks, there were no significant differences between the groups in terms of reduction in inflammatory markers, pain, fatigue and quality of life 123.

Emerging therapies in PMR and GCA

There is a need for GC-sparing agents in the treatment of GCA and PMR. MTX is currently the only conventional disease-modifying anti-rheumatic drug (DMARD) demonstrating even a modest reduction of the cumulative GC dose in systematic reviews and meta-analyses 20,124, although individual trials reported no effect 125–127. Current EULAR recommendations are conditionally in favour of using this drug in a subpopulation of patients with GCA and PMR 18,115. For other conventional DMARDs such as azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine A or dapsone, there are either insufficient data from trials, or they were ineffective or toxic in small, usually low quality clinical studies 1. Case series have shown some potential benefit of leflunomide in patients with refractory GCA 128,129; however, this drug still needs prospective evaluation by randomized controlled trials. Among biological agents, TNF- antagonists were the first agents studied in both GCA and PMR (either as monotherapy in PMR, or in combination with GCs in both PMR and GCA). Initial case reports and case series revealed promising results, however, RCTs of infliximab (GCA and PMR), etanercept (GCA and PMR) and adalimumab (GCA only) were all disappointing (see Table 2 for trials on biological agents in PMR/GCA) 130–134. There is no clear explanation for the failure of these drugs, but it might be possible that there are redundant pathways that may render TNF blockade insufficient. The results from recent trials on tocilizumab (TCZ) in GCA have generated optimism for this approach. A phase II 52-weeks study of 30 patients with GCA suggested that treatment with intravenous TCZ in combination with a short cycle of GCs resulted in higher remission rates, lower cumulative GC doses, and a shorter duration of GC therapy compared to placebo treatment 15. In the phase III GiACTA trial, 119 new and 132 relapsing patients with GCA were randomly assigned (2:1:1:1) to weekly or every-other-week subcutaneous TCZ in combination with a 26-week prednisone taper, or to one of two placebo arms in which prednisone was tapered over 26 or 52 weeks 16. The primary outcome of sustained prednisone-free remission (defined as absence of a disease flare and normal CRP) at week 52, was achieved in 56% in the TCZ weekly and in 53% in the TCZ every other week groups. In contrast, only 14% and 18% achieved the endpoint in the placebo groups, respectively. Because of the direct influence of TCZ on acute phase reactants, a sensitivity analysis was conducted excluding CRP from the definition of sustained remission. This analysis confirmed the primary results. Other outcomes such as proportion of patients with at least one flare or quality of life were also better in the TCZ groups. The cumulative GC dose was ≥40% lower in TCZ than in GCs treated patients and serious adverse events occurred in 14-15% in TCZ compared to 22-26% in placebo groups. Whether the rate of serious adverse events and cumulative GCs were directly related is unclear, since the study was not powered to

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investigate such an association. Longer follow-up of patients treated with TCZ is now required in order to determine the durability of remission and safety of tocilizumab. Based on GiACTA and other trial results, TCZ has recently been approved by FDA for use in GCA16.In PMR, two prospective open-label studies on TCZ (one without and one with accompanying GCs, both without a proper control group) reported achievement of the primary efficacy endpoint, namely a low disease activity at 12 weeks according to a PMR-AS ≤10, or GC-free remission at 6 months, in 100% of patients 135,136. These studies complement the evidence from numerous case reports, case series and small non-randomized studies reporting a benefit of TCZ in PMR and GCA 137–140. The data on PMR, however, are still insufficient to recommend TCZ treatment for this condition outside trials or exceptional cases with GC resistant disease or contraindications to GCs. A phase III study of another IL-6 receptor blocker, sirukumab or placebo plus GCs in GCA, is currently ongoing. Recruitment is expected to be completed in the second half of 2017 and first results may be available by the end of 2018 141.Inhibiting T cell activation and halting subsequent cascades that lead to transmural inflammation by T cells and macrophages may be a key intervention to halt the destruction of the arterial wall in GCA 142,143. Co-stimulatory signal blockade of T-cells with abatacept or placebo plus GCs has recently been studied in a small RCT in GCA 144. A significantly higher rate of relapse free remission was achieved after 12 months in the abatacept compared to the placebo group. The majority of T-cells in the arterial wall of patients with GCA, however, are effector cells lacking co-expression of CD28, whose interaction with B7 molecules is usually targeted by abatacept 81. Interestingly, in TAK, abatacept was not more effective than placebo in regard to maintenance of remission 145.In PMR, a proof of concept study has recently been conducted to study the efficacy of canakinumab, an IL1 inhibitor as well as secukinumab, an IL-17 inhibitor, in comparison to GC therapy 146. This trial also failed its primary endpoint but the observational period of 2 weeks might have been too short to demonstrate any significant effects. A study of the anti-IL-1 antibody gevokizumab in GCA has been terminated early because of the negative outcome of a trial of this agent in Behcet disease 147,148.Ustekinumab, a IL-12/23 blocker has been studied in a small open trial of patients with treatment refractory GCA 149. significant reduction of the GC dose as well as the possibility for discontinuing other immunosuppressive agents was reported 149. The role of this agent for treatment of GCA outside of clinical trials remains to be defined. A few cases of GCA have also been treated successfully with rituximab, suggesting that placebo controlled trials may be warranted to better study this agent for remission maintenance and GC sparing effects 150,151.The role for biologics is emerging, and biologic use in GCA and perhaps PMR can be anticipated in routine clinical care in the not so distant future. Successful use of biologics with subsequent rapid tapering of GCs could markedly reduce the burden of GC related side-effects.

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Future approach to treatment in GCA and PMR Which patients will benefit from biological agents in GCA and PMR?

The current unmet clinical need in GCA and PMR is the treatment of patients with persisting high burden of inflammatory disease, multiple relapses with inability to wean GCs, failure of MTX, co-morbidities and other factors where GC related adverse events are increased, and cases resistant to GC therapy 14,67,152–155. It is anticipated that biological agents, particularly IL-6 inhibitors will first be used in these subpopulations even though clinical trials have focused on patients with new onset or relapsing disease 15,135,136. Biological agents might also be used early in patients at risk for disease complications and/or treatment-related adverse events. Unfortunately, the majority of data on prognostic factors in PMR and GCA are weak or contradictory, impeding the definition and identification of the “at risk” population 124 (Gonzalez-Chiappe S, Dejaco C, Dasgupta B et al, unpublished). A pronounced inflammatory response at disease outset has been associated with a higher probability for relapses in both GCA and PMR 12,13,156. Assuming that IL-6 blockade would be particularly effective in cases with high levels of systemic inflammation, these patients would possibly benefit most from treatment with IL-6 blockers.

How will biologic agents be used in GCA and PMR therapy?

A rapid response to GCs has been considered an important feature of both GCA and PMR for decades. Immediate treatment and a rapid response is also pivotal to prevent blindness in GCA 9,10. Although TCZ yielded impressive results in GCA trials for maintenance of remission, we cannot assume that TCZ therapy without accompanying GCs will prevent vascular complications such as sight loss or aneurysms 15,16. The outcome parameters used in these studies mostly reflected the inflammatory response rather than underlying vessel wall damage. In PMR, TCZ without GCs did not result in a rapid improvement of symptoms as indicated by the study of Devauchelle-Pensec et al.: Although 100% of patients with PMR achieved the primary endpoint, improvement was more gradual than normally seen with GCs 136. A low disease activity as defined by the PMR-AS was achieved by less than 50% after 4 weeks. Response to abatacept might also be more gradual compared to GCs, however due its mode of action the effect may be more lasting with a greater impact on reducing vascular damage 142. Based on these results it is currently unlikely that biologics will be used as monotherapy for remission induction in GCA and PMR in the near future; rather a short course of GCs might be required for a rapid improvement of symptoms, and remission might then be maintained by biologic therapies alone. It is still unclear for how long treatment with biological agents needs to be continued once stable

14

remission has been achieved, or whether they could be changed to MTX or another agent for remission maintenance. Long-term treatment with biologics or other immunosuppressive agents is probably warranted to prevent late vascular complications in patients with LV-GCA, however, this still needs to be demonstrated by proper clinical studies.

What are the treatment targets for GCA and PMR?

One important unmet challenge in the treatment of GCA and PMR is the vague definition of treatment targets. Whereas remission of symptoms or the prevention of blindness are obvious treatment goals, others treatment goals as elicited in in-depth discussions with patients as well as patient surveys are less clear 157,158. For example, patients with PMR complain about disability and fatigue, symptoms which are rated as important as pain. “Coming off steroids” as well as “living with steroids” were highly valuated concepts according to a survey conducted by the GCA/PMR charity group “GCAPMRuk” 159. In addition, remission and relapse have been defined differently in the majority of published studies 160. In most GCA and PMR studies, qualitative criteria of remission and relapse have been used as outcome measures taking into account the history and clinical assessment of GCA and/or PMR features, physician’s global assessment, ESR, CRP, blood count and fibrinogen. Remission was generally defined as the absence of abnormal findings of these parameters whereas a relapse was considered if characteristic signs and symptoms of the disease reappeared 16,125,130,160. The absence of a relapse does not automatically imply remission. The prognostic relevance of low-grade disease activity states which are neither compatible with remission nor with a relapse is currently unclear. Some PMR studies used the composite PMR activity score (PMR-AS) to define remission/low disease activity while others have applied qualitative remission/relapse criteria 131,134,136,161. The PMR-AS combines patient assessment of pain, physician global assessment (both assessed on a visual analogue scale from 0–10), duration of morning stiffness, elevation of the upper limbs (semi-quantitative assessment from 0–3) and the C-reactive protein (CRP) into a quantitative score. Another challenge of outcome criteria for PMR and GCA is the fact that certain agents such as IL-6 (receptor) blockers directly influence acute phase reactants which are integral to currently used remission and relapse criteria 16,125,130,160,162. The inclusion of ESR/CRP in outcome measures of anti-IL6 (receptor) trials might therefore produce a type I error (i.e. incorrect rejection of a true null hypothesis); however, remission/relapse criteria without a laboratory criterion are still not available. Whether imaging or other biomarkers that are independent of the acute phase response would be a possible alternative to ESR/CRP is unclear.Another unanswered question is whether treatment decisions could be based on abnormal imaging with or without laboratory results. It might be tempting to modify treatment in a patient with GCA who has elevated acute phase reactants and positive 18F-FDG–PET despite the absence of symptoms 37. We do not know, however,

15

whether these tests are reliable surrogates of ongoing inflammation or even predictive of future large vessel damage and resultant complication, and whether patients might benefit in the long-term if treatment is changed based on these parameters.

Conclusions

The new understanding of GCA and PMR with overlapping clinical phenotypes, new developments in the field of imaging as well as new treatment options have raised new questions and identified unmet needs: 1) What is the true epidemiology of the disease given the frequent clinical and subclinical overlap of cranial and large vessel disease, and PMR/lGCA overlap, 2) are there different pathophysiological pathways determining the clinical phenotype, prognosis and treatment response, 3) which biomarkers can help to recognize early and predict unfavourable disease outcomes, 4) what is the role of currently available and evolving imaging techniques for diagnosis and monitoring, 5) how to use emerging therapies in GCA and PMR and 6) what treatment targets should be used in future clinical studies? Multinational collaboration is needed in order to conduct studies answering these questions.

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Key points

GCA is best understood as an inflammatory vascular syndrome with features of cranial and/or large vessel vasculitis, systemic inflammation and PMR, which frequently overlap

PMR and GCA are among the most common inflammatory rheumatic diseases in the elderly. The prevalence of these diseases is expected to increase due to an aging population

The role and value of imaging in PMR and GCA is evolving quickly. The pathophysiology of GCA is characterized by phases of initiation, transmural

inflammation and chronic vessel wall injury and repair, each which may be targets for novel drugs.

Glucocorticoids are still the standard-of-care treatment for PMR and GCA; methotrexate is used in individual cases. Anti-IL-6 biologic therapy has demonstrated impressive results in recent trials and will become available soon for treatment of GCA.

Selection of patients for biologic therapy, defining best treatment strategies and development of reliable outcome parameters are challenges in the future management of PMR and GCA

17

Financial and competing interest disclosure

Christian Dejaco reported receiving consultancy fees and honoraria from MSD, Pfizer, UCB, AbbVie, Roche, Novartis, Lilly, Celgene, Merck, Sandoz, clinical trials design advisory board consultancies from GSK, and an unrestricted grant support from Pfizer and MSD.

Elisabeth Brouwer received consultancy fees from Roche and an unrestricted grant (Janssen)

Justin Mason reported receiving consultancy fees and honoraria from Roche and Novartis

Frank Buttgereit reported receiving consultancy fees, honoraria and travel expenses from Horizon Pharma (formerly Nitec Pharma), Mundipharma Int Ltd, Roche and Galapagos, and grant support from Horizon Pharma. He serves as co-principal investigator and site investigator in a Mundipharma sponsored trial in PMR investigating the effects of MR prednisone.

Eric Matteson reported serving as coordinating investigator (Novartis) and consultant (Glaxo-Smith-Kline) in PMR trials, consultant (Glaxo-Smith-Kline, Endocyte) and as site investigator in GCA trials (Bristol Meyer Squibb, Hoffman-LaRoche, Genentech, Glaxo-Smith-Kline), and editor, contributor for PMR/GCA (UpToDate, Paradigm).

Bhaskar Dasgupta reported clinical trials design advisory board consultancies (Roche, Servier, GSK, Mundipharma, Pfizer, Merck, Sobi), and unrestricted grant support from Napp and Roche, and speakers honoraria from UCB and Merck.

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Biography of authors

Christian Dejaco, MD, PhD, MBA is a consultant and Associate Professor in Rheumatology. He is the head of the rheumatology service of the South Tyrolian Health Trust at the Hospital of Bruneck (ITA) and he is a researcher at the Medical University of Graz (A). His major research interest has been in polymyalgia rheumatica and giant cell arteritis, the role of imaging in rheumatic diseases, and the relevance of T-cell aging for inflammatory diseases.

Elisabeth Brouwer, MD, PhD, is an internist and rheumatologistat the UMCG with a research interest in large vessel vasculitis, immune regulation and aging; translational studies, imaging and treatment in GCA and PMR. She is the co-founder of the vasculitis expertise centre Groningen and WP leader of an EU H2020 program called RELENT on checkpoint molecules in AAV and GCA.

Justin Mason is Professor of Vascular Rheumatology at Imperial College London, based at Hammersmith Hospital. His scientific research is focused on understanding the molecular mechanisms involved in vascular endothelial cytoprotection. Clinical research interests include the optimization of clinical assessment and treatment of large vessel vasculitides, and understanding the relationship between chronic endothelial dysfunction and accelerated atherosclerosis.

Frank Buttgereit, MD is a senior consultant and Deputy Head of the Department of Rheumatology and Clinical Immunology, Charité University Medicine (CCM), Berlin. He also directs a liaison research group at the Deutsche Rheumaforschungszentrum. Dr. Buttgereit´s research interests comprise clinical aspects of glucocorticoids in the treatment of rheumatic diseases including chronotherapy, mechanisms of glucocorticoid actions and bioenergetics of immune functions.

Eric L. Matteson, M.D., M.P.H. is consultant and John F. Finn Professor of Medicine in the Division of Rheumatology at Mayo Clinic College of Medicine and Science. He has a joint appointment in the Division of Epidemiology in the Department of Health Sciences Research. Dr. Matteson’s major research concentrations have been through defining the biopathology, epidemiology and opulation burden of rheumatic diseases.

Professor Dasgupta is the Head of the Rheumatology and Clinical Director of Research and Audit at Southend University Hospital and holds a Honorary Professorship at Essex University, Visiting Professorship at Anglia Ruskin University and Honorary Professorship at Queen Marys University London. He founded the patient charity PMRGCAuk and is its Honorary President. He has had a career-long clinical and research interest in polymyalgia rheumatica and giant cell arteritis (GCA) and has published over 150 articles on these topics.

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Box 1. Top three unmet needs of different aspects of polymyalgia rheumatica and giant cell arteritis

Epidemiology1. Epidemiology and extent of overlap between different GCA phenotypes

(cranial GCA, LLV, PMR)2. Prevalence of subclinical GCA in clinically isolated PMR3. Expected increment of GCA and PMR incidence due to aging of the

population

Imaging1. Role of imaging methods as compared to temporal artery biopsy for diagnosis

of GCA; role of imaging for assessing large vessel involvement and for diagnosis of PMR

2. Role of imaging for monitoring of disease activity, prediction of flares and follow-up of damage in both, GCA and PMR

3. Role of evolving imaging techniques such as contrast enhanced ultrasound, PET using novel tracers or Optical Coherence Tomography-Angiography in GCA and/or PMR

Etiopathogenesis1. Identify possible (avoidable or treatable) triggers for GCA and PMR2. Investigate the possibility of different pathways in GCA and PMR leading to

different clinical phenotypes, prognosis and treatment targets3. Interference with amplification and chronicity of inflammation and remodelling

Treatment1. Optimise the use of GC and GC sparing agents (e.g. remission induction –

remission maintenance, treat-to-target)2. To study novel treatment targets in GCA and PMR3. Define outcome parameters and identify prognostic factors for stratification of

treatment

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Table 1. Areas for future research in polymyalgia rheumatica and giant cell arteritis: pathogenic mechanisms with matching clinical phenotypes, imaging modalities, possible biomarkers and possible therapies

Pathogenetic mechanism

Matching clinical symptoms

Imaging findingsPossible

Biomarkers*Possible treatment targets*

Trigger/activation of innate immunity,

DCs,T-cells, B-cells 78

‘flu-like’ symptoms,fever, night sweats

No known imagingtechnique

Acute phase response,

possibly IL-6

anti-infection therapies;immunisation;

blockade of DC activation (anti-IL1 IL-1/IL1 inhibition with canakinumab/ gevokizumab/

leflunomide);costimulatory blockade (abatacept);

IL-6 blockade (tocilizumab, sirukumab)

Arterial Inflammatory

infiltrate88,104,142,143

Headache, scalp pain, thickened arteries, painful

arteries, constitutional

symptoms

Characteristic inflammatory imaging findings such as

‘Halo’ sign (GCA) with sonography,

MRA and/or PET

Acute phase response,

neutrophilia

costimulatory blockade (abatacept);JAK inhibitors (tofacitinib, Baricitinib);

cytokine blockade (IL-6, IFN, TNF, IL-12, IL-17, IL-23)

Vascular smooth muscle cell and

intimal proliferation 90

Jaw claudication, scalp/tongue

necrosis, visual and other ischemic manifestations

Imaging signs of inflammation and damage: ‘Halo’ sign,

occlusion, stenosis;OCT-A changes of retinal and choroidal vessels, as well as

optic nerve head

Vascular biomarkers

anti-VEGF;anti-IFN;

anti-IL-17 (secukinumab)inihibitors of neurotrophins

inihibitors of endothelin

Neo-angiogenesis, possible

haemorrhage of

Jaw claudication, ischemic damage

such as AION, scalp

Increased axillary and carotid thickness of media, occlusion,

stenosis and mural

Angiogenesis markers such aselevated VEGF

anti-VEGF;inhibitors of proteases (MMPs,

cathepsins, elastase)

21

media 90,114 and tongue necrosis;Aortic dissection

enhancement using CEUS

Cytokine production,

interleukin-6 163

Constitutional symptoms,

Polymyalgia

Main imaging findings in polymyalgia rheumatica are subdeltoid bursitis, bicipital

tenosynovitis

Acute phase response

IL-6 blockade (tocilizumab, sirukumab)

Medial thinning 87 Aortic aneurysm CTA, MRAPossible markers

of vascular damage

?

Fibrosis and chronic

intimal-medial hyperplasia 91

(Large vessel) stenosis, ischemic

limb painCTA, MRA

Possible markers of vascular repair

Biologics therapy as aboveSurgery?

Endovascular treatment?

*This table intends to stimulate future research concerning various aspects of polymyalgia rheumatica and giant cell artereitis. It should not be understood as an advice to apply all mentioned biomarkers and therapeutic interventions in clinical practiceAION, Anterior ischemic optic neuropathy; CEUS, contrast-enhanced ultrasound; CTA, Computed tomography angiography; DC, dendritic cell; IFN, interferon; IL, Interleukin; MRA, magnetic resonance imaging; OCT-A, Optical Coherence Tomography Angiography; PET, 18F-fluorodeoxy-glucose positron emission tomography; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor

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Table 2. Clinical trials of biological agents for the treatment of polymyalgia rheumatica and giant cell arteritis

Agent Mechanism of action

Publicat. type

Trial information

Sample size

Study population Durat. Main results Ref.

Polymyalgia rheumatica

Infliximab TNF- blocker Full paperRandomized, multi-centre,

double-blinded51

PMR, new untreated

52 weeks

Did not achieve primary and main secondary endpoints

Salvarani 2007 130

Etanercept TNF- blocker Full paperRandomized, single-centre,

double-blinded22

PMR, new untreated

14 daysDid not achieve primary and main secondary endpoints

Kreiner 2010 134

Tocilizumab IL-6 receptor blocker

Full paperNot randomized,

single-centre open-label

20PMR, new

treated with GCs ≤1 month

15 months

Relapse-free remission off GCs at 6 months: 100% in TCZ vs. 0% in control group

Cumulative GC dose: 1.1g in TCZ vs. 2.6g in control group (p=0.01)

Duration of GC exposure: 3.9 in TCZ vs. 14.1 months in control group (p=0.002)

Lally 2016 135

Tocilizumab IL-6 receptor blockade

Full paperSingle group,multi-centre open-label

20

PMR <12mo, GC-naive or GCs<1mo +

off GCs 7 days

24 weeks

PMR-AS≤10 at 12weeks: 100%, no flares

Cumulative GC dose: 0.8g

Devauchelle-Pensec 2016 136

AIN457 (Secukinumab)ACZ885 (Canakinumab)

IL-17 blockerIL1 blocker

Final report ClinicalTrial

.gov

Single-blind, Randomized, 3-

arm Proof of Concept Study

16 PMR, new 2 weeks Did not achieve primary endpoint

Matteson 2014 146

23

Giant cell arteritisInfliximab TNF- blocker Full paper Randomized,

multi-centre, double-blinded

44 GCA, new (cranial)

54 weeks

Did not achieve primary and main secondary endpoints

Hoffman 2007 130

Etanercept TNF- blocker Full paper Randomized, multi-centre,

double-blinded

17 GCA in remission, stable oral prednisone

15 months

Cumulative GC dose: 1.5g in ETN vs. 3.0g in control group (p=0.03)

other outcomes negative

Martinez-Taboada 2008 133

Adalimumab TNF- blocker Full paper Randomized, multi-centre,

double-blinded

70 GCA, new (cranial)

52 weeks

Did not achieve primary and main secondary endpoints

Seror 2014 132

Tocilizumab IL-6 receptor blockade

Full paper Randomized, single-centre,

double-blinded

30 GCA, new or relapsing

52 weeks

Complete remission at 12/52 weeks: 85%/85% in TCZ vs. 40%/20% in control group (p=0.03/p=0.001)

Time to relapse: 50 weeks in TCZ vs. 25 weeks in control group (p<0.001)

Discontinuation of GCs: 80% in TCZ vs. 20% in control group (p=0.004)

Cumulative GC dose: 43mg/kg in TCZ vs. 110mg/kg in control group (p<0.001)

Villiger 2016 15

Tocilizumab IL-6 receptor blockade

Abstract Randomized, multi-centre,

double-blinded

251 GCA, New or refractory

52 weeks +

52 weeks open label

Sustained remission at 12 months: 56% (weekly injections), 53% (bi-weekly injections) in TCZ vs. 14% in control group (p < 0.0001)

Stone 2016 16

24

extension phase

Cumulative GC dose at 12 months:1.8g in both TCZ groups compared to 3.3g and 3.8g in the 2 placebo groups (one with a short and one with a long GC tapering course)

Sirukumab IL-6 blockerOngoing

study

Randomized, multi-centre,

double-blinded204 GCA, active

52 weeks +

52 weeks open label

Results available by end of 2018

NCT02531633

Abatacept CTLA-4 Ig Full paperRandomized, multi-centre,

double-blinded49

GCA, new or relapsing

12 months

Relapse free remission at 12 months: 48% in abatacept vs. 31% in control group (p=0.049)

Langford 2015 144

Abatacept CTLA-4 IgStudy

completed

Randomized, multi-centre,

double-blinded98

GCA or TAK, active

48 months

Results not yet availableNCT00556

439

Abatacept CTLA-4 Ig RecruitingRandomized, multi-centre,

double-blinded200 GCA, new

52 weeks

Estimated completion by 2021

NCT03192969

ETN, etanercept; Durat., Duration; GC(s), glucocorticoid(s); GCA, giant cell arteritis; IL, interleukin; mo, months; PMR, polymyalgia rheumatica; PMR-AS, polymyalgia rheumatica activity score; Public., Publication; Ref., Reference; TAK, Takayasu arteritis TCZ, tociliumab; TNF, tumor necrosis factor;

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Figure 1. Pathogenetic pathways and treatment targets in giant cell arteritis

The yellow box depicts the initiation phase of giant cell arteritis (GCA) in which dendritic cells (DCs) within the adventitia become activated via pathogen-/ microorganisms-associated molecular patterns (PAMPs/MAMPs) and damage associated molecular patterns (DAMPs), initiating the production of pro-inflammatory cytokines and activation of naïve T-cells via MHC class II molecules (grey) and co-stimulatory molecules (green) which interact with the T-cell receptor complex present on T-cells.

Upon maturation of DCs and resident macrophages, CD4+ T-cells are stimulated to polarize into Th1 and Th17 cells. Th1 and Th17 cells recruit new macrophages via Interferon IFN- and Interleukin IL-17 production, respectively. Chemokines, induced by pro-inflammatory cytokines, play a crucial role in guiding T-cells and macrophages and also B-cells into the vessel wall (depicted in the blue box).

In the chronic phase (depicted in the pink box) local hypoxia together with macrophages and giant cells amplify cell migration of both inflammatory and resident cells. Major players besides cytokines and chemokines in the chronic phase are, angiopoietins, endothelin-1, platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) which activate inflammatory cells, vascular smooth muscle cells (VSMC), stromal cells, pericytes and endothelial cells inducing the formation of new vessels, VSMC migration, fragmentation of the external and internal elastic lamina by metalloproteinases (red dots) and endothelial cell proliferation. Ectopic lymphoid structures are formed within the adventitia in this phase of chronic inflammation and remodeling.

Possible targets for treatment are: prevention of activation of DC’s in the initiation phase by antimicrobials; blocking cytokines, chemokines, co-stimulatory pathways, notch and signaling pathways by biologicals and/or synthetic drugs in both the initiation and amplification phase of GCA, and blocking VEGF and cytokines in the chronic phase of GCA.

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References

1. Buttgereit, F., Dejaco, C., Matteson, E. L. & Dasgupta, B. Polymyalgia rheumatica and giant cell arteritis: a systematic review. JAMA 315, 2442–58 (2016).

2. Hunder, G. G. et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum. 33, 1122–1128 (1990).

3. Dejaco, C., Duftner, C., Buttgereit, F., Matteson, E. L. & Dasgupta, B. The spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of the disease. Rheumatology (Oxford). [Epub ahead of print] (2016). doi:10.1093/rheumatology/kew273

4. Evans, J. M., O’Fallon, W. M. & Hunder, G. G. Increased incidence of aortic aneurysm and dissection in giant cell (temporal) arteritis. A population-based study. Ann. Intern. Med. 122, 502–507 (1995).

5. Salvarani, C., Cantini, F., Boiardi, L. & Hunder, G. G. Polymyalgia rheumatica and giant-cell arteritis. N. Engl. J. Med. 347, 261–271 (2002).

6. Dejaco, C., Duftner, C., Dasgupta, B., Matteson, E. L. & Schirmer, M. Polymyalgia rheumatica and giant cell arteritis: management of two diseases of the elderly. Aging health 7, 633–645 (2011).

7. Nesher, G. et al. Risk factors for cranial ischemic complications in giant cell arteritis. Medicine (Baltimore). 83, 114–22 (2004).

8. Salvarani, C. et al. Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis. Arthritis Rheum. 53, 293–7 (2005).

9. Patil, P. et al. Fast track pathway reduces sight loss in giant cell arteritis: results of a longitudinal observational cohort study. Clin. Exp. Rheumatol. 33, S-103-6 (2015).

10. Diamantopoulos, A. P., Haugeberg, G., Lindland, A. & Myklebust, G. The fast-track ultrasound clinic for early diagnosis of giant cell arteritis significantly reduces permanent visual impairment: towards a more effective strategy to improve clinical outcome in giant cell arteritis? Rheumatology (Oxford). 55, 66–70 (2016).

11. Broder, M. S. et al. Corticosteroid-related adverse events in patients with giant cell arteritis: A claims-based analysis. Semin. Arthritis Rheum. 46, 246–52 (2016).

12. Alba, M. A. 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). 93, 194–201 (2014).

13. Hachulla, E. et al. Prognostic factors and long-term evolution in a cohort of 133 patients with giant cell arteritis. Clin. Exp. Rheumatol. 19, 171–6 (2001).

14. Kermani, T. A. et al. Disease Relapses among Patients with Giant Cell Arteritis: A Prospective, Longitudinal Cohort Study. J. Rheumatol. 42, 1213–7 (2015).

15. Villiger, P. M. et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet (London, England) 387, 1921–7 (2016).

16. Stone, J. et al. Tocilizumab for Sustained Glucocorticoid-Free Remission in Giant Cell Arteritis. N. Engl. J. Med. (in press), (2017).

17. Dejaco, C. et al. 2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann. Rheum. Dis. 74, 1799–807 (2015).

18. Dejaco, C. et al. 2015 Recommendations for the Management of Polymyalgia

27

Rheumatica: A European League Against Rheumatism/American College of Rheumatology Collaborative Initiative. Arthritis Rheumatol. (Hoboken, N.J.) 67, 2569–2580 (2015).

19. Dasgupta, B. et al. BSR and BHPR guidelines for the management of giant cell arteritis. Rheumatology (Oxford). 49, 1594–1597 (2010).

20. Mahr, A. D. et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum. 56, 2789–97 (2007).

21. Lawrence, R. C. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 58, 26–35 (2008).

22. Smeeth, L., Cook, C. & Hall, A. J. Incidence of diagnosed polymyalgia rheumatica and temporal arteritis in the United Kingdom, 1990-2001. Ann. Rheum. Dis. 65, 1093–8 (2006).

23. Gran, J. T. & Myklebust, G. The incidence of polymyalgia rheumatica and temporal arteritis in the county of Aust Agder, south Norway: a prospective study 1987-94. J. Rheumatol. 24, 1739–43 (1997).

24. Doran, M. F., Crowson, C. S., O’Fallon, W. M., Hunder, G. G. & Gabriel, S. E. Trends in the incidence of polymyalgia rheumatica over a 30 year period in Olmsted County, Minnesota, USA. J. Rheumatol. 29, 1694–1697 (2002).

25. Salvarani, C., Gabriel, S. E., O’Fallon, W. M. & Hunder, G. G. The incidence of giant cell arteritis in Olmsted County, Minnesota: apparent fluctuations in a cyclic pattern. Ann. Intern. Med. 123, 192–4 (1995).

26. Chandran, A. K., Udayakumar, P. D., Crowson, C. S., Warrington, K. J. & Matteson, E. L. The incidence of giant cell arteritis in Olmsted County, Minnesota, over a 60-year period 1950-2009. Scand. J. Rheumatol. 44, 215–8 (2015).

27. Ramstead, C. L. & Patel, A. D. Giant cell arteritis in a neuro-ophthalmology clinic in Saskatoon, 1998-2003. Can. J. Ophthalmol. 42, 295–298 (2007).

28. Chaudhry, I. A. et al. Epidemiology of giant-cell arteritis in an Arab population: a 22-year study. Br. J. Ophthalmol. 91, 715–8 (2007).

29. Artal, N. M. et al. Giant cell arteritis in a Hispanic population. Ophthalmology 109, 1757; discussion 1757 (2002).

30. De Smit, E., Palmer, A. J. & Hewitt, A. W. Projected worldwide disease burden from giant cell arteritis by 2050. J. Rheumatol. 42, 119–25 (2015).

31. Brack, A., Martinez-Taboada, V., Stanson, A., Goronzy, J. J. & Weyand, C. M. Disease pattern in cranial and large-vessel giant cell arteritis. Arthritis Rheum. 42, 311–7 (1999).

32. Diamantopoulos, A. P. et al. Diagnostic value of color Doppler ultrasonography of temporal arteries and large vessels in giant cell arteritis: a consecutive case series. Arthritis Care Res. (Hoboken). 66, 113–9 (2014).

33. Luqmani, R. et al. The Role of Ultrasound Compared to Biopsy of Temporal Arteries in the Diagnosis and Treatment of Giant Cell Arteritis (TABUL): a diagnostic accuracy and cost-effectiveness study. Health Technol. Assess. (Rockv). 20, 1–238 (2016).

34. Roth, A. M., Milsow, L. & Keltner, J. L. The ultimate diagnoses of patients undergoing temporal artery biopsies. Arch. Ophthalmol. (Chicago, Ill. 1960) 102, 901–3 (1984).

35. Hall, S. et al. The therapeutic impact of temporal artery biopsy. Lancet (London, England) 2, 1217–20 (1983).

28

36. Allsop, C. J. & Gallagher, P. J. Temporal artery biopsy in giant-cell arteritis. A reappraisal. Am. J. Surg. Pathol. 5, 317–23 (1981).

37. Blockmans, D. et al. Repetitive 18F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients. Arthritis Rheum. 55, 131–137 (2006).

38. Prieto-Gonz?lez, S. et al. Large vessel involvement in biopsy-proven giant cell arteritis: prospective study in 40 newly diagnosed patients using CT angiography. Ann. Rheum. Dis. 71, 1170–6 (2012).

39. Kermani, T. A. et al. Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann. Rheum. Dis. 72, 1989–94 (2013).

40. Aschwanden, M. et al. Vascular involvement in patients with giant cell arteritis determined by duplex sonography of 2x11 arterial regions. Ann. Rheum. Dis. 69, 1356–9 (2010).

41. Karahaliou, M. et al. Colour duplex sonography of temporal arteries before decision for biopsy: a prospective study in 55 patients with suspected giant cell arteritis. Arthritis Res. Ther. 8, R116 (2006).

42. Nesher, G., Shemesh, D., Mates, M., Sonnenblick, M. & Abramowitz, H. B. The predictive value of the halo sign in color Doppler ultrasonography of the temporal arteries for diagnosing giant cell arteritis. J. Rheumatol. 29, 1224–6 (2002).

43. Dasgupta, B. et al. 2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum. 64, 943–954 (2012).

44. Dasgupta, B. et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann. Rheum. Dis. 71, 484–92 (2012).

45. Falsetti, P., Acciai, C., Volpe, A. & Lenzi, L. Ultrasonography in early assessment of elderly patients with polymyalgic symptoms: a role in predicting diagnostic outcome? Scand. J. Rheumatol. 40, 57–63 (2011).

46. de Boysson, H. et al. Giant-cell arteritis without cranial manifestations. Medicine (Baltimore). 95, e3818 (2016).

47. Camellino, D. & Cimmino, M. A. Imaging of polymyalgia rheumatica: indications on its pathogenesis, diagnosis and prognosis. Rheumatology (Oxford). 51, 77–86 (2012).

48. Camellino, D. et al. Interspinous bursitis is common in polymyalgia rheumatica, but is not associated with spinal pain. Arthritis Res. Ther. 16, 492 (2014).

49. Cimmino, M. A. et al. High frequency of capsular knee involvement in polymyalgia rheumatica/giant cell arteritis patients studied by positron emission tomography. Rheumatology 52, 1865–1872 (2013).

50. Blockmans, D. et al. Repetitive 18-fluorodeoxyglucose positron emission tomography in isolated polymyalgia rheumatica: a prospective study in 35 patients. Rheumatology (Oxford). 46, 672–677 (2007).

51. Lavado-Pérez, C. et al. (18)F-FDG PET/CT for the detection of large vessel vasculitis in patients with polymyalgia rheumatica. Rev. Esp. Med. Nucl. Imagen Mol. 34, 275–81

52. Rehak, Z. et al. Various forms of 18F-FDG PET and PET/CT findings in patients with polymyalgia rheumatica. Biomed. Pap. 159, 629–36 (2015).

53. Lariviere, D. et al. Positron emission tomography and computed tomography angiography for the diagnosis of giant cell arteritis: A real-life prospective

29

study. Medicine (Baltimore). 95, e4146 (2016).54. Nakagomi, D. et al. Development of a score for assessment of radiologic

damage in large-vessel vasculitis (Combined Arteritis Damage Score, CARDS). Clin. Exp. Rheumatol. 35 Suppl 103, 139–145

55. Klink, T. et al. Giant Cell Arteritis: Diagnostic Accuracy of MR Imaging of Superficial Cranial Arteries in Initial Diagnosis—Results from a Multicenter Trial. Radiology 273, 844–852 (2014).

56. Goll, C. et al. Feasibility study: 7 T MRI in giant cell arteritis. Graefe’s Arch. Clin. Exp. Ophthalmol. 254, 1111–6 (2016).

57. Veldhoen, S. et al. MRI displays involvement of the temporalis muscle and the deep temporal artery in patients with giant cell arteritis. Eur. Radiol. 24, 2971–9 (2014).

58. Einspieler, I. et al. Imaging large vessel vasculitis with fully integrated PET/MRI: a pilot study. Eur. J. Nucl. Med. Mol. Imaging 42, 1012–24 (2015).

59. Habib, H. M., Essa, A. A. & Hassan, A. A. Color duplex ultrasonography of temporal arteries: role in diagnosis and follow-up of suspected cases of temporal arteritis. Clin. Rheumatol. 31, 231–7 (2012).

60. De Miguel, E. et al. The utility and sensitivity of colour Doppler ultrasound in monitoring changes in giant cell arteritis. Clin. Exp. Rheumatol. 30, S34-8 (2012).

61. Schmidt, W. A., Kraft, H. E., Vorpahl, K., Völker, L. & Gromnica-Ihle, E. J. Color duplex ultrasonography in the diagnosis of temporal arteritis. N. Engl. J. Med. 337, 1336–42 (1997).

62. Czihal, M. et al. Impact of cranial and axillary/subclavian artery involvement by color duplex sonography on response to treatment in giant cell arteritis. J. Vasc. Surg. 61, 1285–91 (2015).

63. Prieto-González, S. et al. Effect of glucocorticoid treatment on computed tomography angiography detected large-vessel inflammation in giant-cell arteritis. A prospective, longitudinal study. Medicine (Baltimore). 94, e486 (2015).

64. Evans, J. M., Bowles, C. A., Bjornsson, J., Mullany, C. J. & Hunder, G. G. Thoracic aortic aneurysm and rupture in giant cell arteritis. A descriptive study of 41 cases. Arthritis Rheum. 37, 1539–47 (1994).

65. Nuenninghoff, D. M., Hunder, G. G., Christianson, T. J. H., McClelland, R. L. & Matteson, E. L. Incidence and predictors of large-artery complication (aortic aneurysm, aortic dissection, and/or large-artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years. Arthritis Rheum. 48, 3522–3531 (2003).

66. Spira, D., Xenitidis, T., Henes, J. & Horger, M. MRI parametric monitoring of biological therapies in primary large vessel vasculitides: a pilot study. Br. J. Radiol. 89, 20150892 (2016).

67. Blockmans, D. et al. Relationship between fluorodeoxyglucose uptake in the large vessels and late aortic diameter in giant cell arteritis. Rheumatology (Oxford). 47, 1179–1184 (2008).

68. Robson, J. C. et al. The relative risk of aortic aneurysm in patients with giant cell arteritis compared with the general population of the UK. Ann. Rheum. Dis. 74, 129–35 (2015).

69. Pugliese, F. et al. Imaging of vascular inflammation with [11C]-PK11195 and positron emission tomography/computed tomography angiography. J. Am. Coll. Cardiol. 56, 653–61 (2010).

30

70. Schinkel, A. F. L., van den Oord, S. C. H., van der Steen, A. F. W., van Laar, J. A. M. & Sijbrands, E. J. G. Utility of contrast-enhanced ultrasound for the assessment of the carotid artery wall in patients with Takayasu or giant cell arteritis. Eur. Heart J. Cardiovasc. Imaging 15, 541–6 (2014).

71. Giordana, P. et al. Contrast-enhanced ultrasound of carotid artery wall in Takayasu disease: first evidence of application in diagnosis and monitoring of response to treatment. Circulation 124, 245–7 (2011).

72. Magnoni, M. et al. Assessment of Takayasu arteritis activity by carotid contrast-enhanced ultrasound. Circ. Cardiovasc. Imaging 4, e1-2 (2011).

73. Germano, G. et al. Contrast-Enhanced Ultrasound of the Carotid Artery in Patients With Large Vessel Vasculitis: Correlation With Positron Emission Tomography Findings. Arthritis Care Res. (Hoboken). 69, 143–149 (2017).

74. Huang, D. et al. Optical coherence tomography. Science 254, 1178–81 (1991).75. Choi, W. et al. Choriocapillaris and choroidal microvasculature imaging with

ultrahigh speed OCT angiography. PLoS One 8, e81499 (2013).76. Ferrara, D., Waheed, N. K. & Duker, J. S. Investigating the choriocapillaris and

choroidal vasculature with new optical coherence tomography technologies. Prog. Retin. Eye Res. 52, 130–55 (2016).

77. Chatelain, D. et al. Small-vessel vasculitis surrounding an uninflamed temporal artery: a new diagnostic criterion for polymyalgia rheumatica? Arthritis Rheum. 58, 2565–73 (2008).

78. Pryshchep, O., Ma-Krupa, W., Younge, B. R., Goronzy, J. J. & Weyand, C. M. Vessel-specific Toll-like receptor profiles in human medium and large arteries. Circulation 118, 1276–84 (2008).

79. Zhang, H. et al. Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc. Natl. Acad. Sci. 114, E970–E979 (2017).

80. Wen, Z. et al. NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs. J. Clin. Invest. 126, 1953–67 (2016).

81. Dejaco, C. et al. NKG2D stimulated T-cell autoreactivity in giant cell arteritis and polymyalgia rheumatica. Ann. Rheum. Dis. 72, 1852–9 (2013).

82. Bhatt, A. S. et al. In search of a candidate pathogen for giant cell arteritis: Sequencing based characterization of the giant cell arteritis microbiome. Arthritis Rheumatol. (Hoboken, N.J.) 66, 1939–44 (2014).

83. Gabriel, S. E. et al. The role of parvovirus B19 in the pathogenesis of giant cell arteritis: a preliminary evaluation. Arthritis Rheum. 42, 1255–8 (1999).

84. Wagner, A. D. et al. Detection of Chlamydia pneumoniae in giant cell vasculitis and correlation with the topographic arrangement of tissue-infiltrating dendritic cells. Arthritis Rheum. 43, 1543–51 (2000).

85. Nagel, M. A. et al. Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis. JAMA Neurol. 72, 1281–7 (2015).

86. Deng, J., Younge, B. R., Olshen, R. A., Goronzy, J. J. & Weyand, C. M. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 121, 906–15 (2010).

87. Samson, M. et al. Involvement and prognosis value of CD8(+) T cells in giant cell arteritis. J. Autoimmun. 72, 73–83 (2016).

88. Nadkarni, S. et al. Investigational analysis reveals a potential role for neutrophils in giant-cell arteritis disease progression. Circ. Res. 114, 242–8 (2014).

89. van der Geest, K. S. M. et al. Disturbed B cell homeostasis in patients with newly-diagnosed giant cell arteritis and polymyalgia rheumatica. Arthritis

31

Rheumatol. (Hoboken, N.J.) 66, 1927–38 (2014).90. Kaiser, M., Younge, B., Björnsson, J., Goronzy, J. J. & Weyand, C. M.

Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. Am. J. Pathol. 155, 765–74 (1999).

91. Kaiser, M., Weyand, C. M., Björnsson, J. & Goronzy, J. J. Platelet-derived growth factor, intimal hyperplasia, and ischemic complications in giant cell arteritis. Arthritis Rheum. 41, 623–33 (1998).

92. Wagner, A. D., Björnsson, J., Bartley, G. B., Goronzy, J. J. & Weyand, C. M. Interferon-gamma-producing T cells in giant cell vasculitis represent a minority of tissue-infiltrating cells and are located distant from the site of pathology. Am. J. Pathol. 148, 1925–33 (1996).

93. Ghoreschi, K., Laurence, A. & O’Shea, J. J. Janus kinases in immune cell signaling. Immunol. Rev. 228, 273–87 (2009).

94. Kohlhuber, F. et al. A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses. Mol. Cell. Biol. 17, 695–706 (1997).

95. Müller, M. et al. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature 366, 129–35 (1993).

96. Lee, E. B. et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 370, 2377–86 (2014).

97. Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367, 495–507 (2012).

98. Genovese, M. C. et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N. Engl. J. Med. 374, 1243–52 (2016).

99. Hatemi, G. et al. Apremilast for Behçet’s Syndrome — A Phase 2, Placebo-Controlled Study. N. Engl. J. Med. 372, 1510–1518 (2015).

100. Kavanaugh, A. et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann. Rheum. Dis. 73, 1020–6 (2014).

101. Man, H.-W. et al. Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor. J. Med. Chem. 52, 1522–4 (2009).

102. Hernández-Rodríguez, J. et al. Tissue production of pro-inflammatory 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). 43, 294–301 (2004).

103. Visvanathan, S. et al. Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis--a prospective longitudinal study. Rheumatology (Oxford). 50, 2061–70 (2011).

104. Cid, M. C. et al. Immunohistochemical analysis of lymphoid and macrophage cell subsets and their immunologic activation markers in temporal arteritis. Influence of corticosteroid treatment. Arthritis Rheum. 32, 884–93 (1989).

105. Ciccia, F. et al. Ectopic expression of CXCL13, BAFF, APRIL and LT-β is associated with artery tertiary lymphoid organs in giant cell arteritis. Ann. Rheum. Dis. (2016). doi:10.1136/annrheumdis-2016-209217

106. Takemura, S., Klimiuk, P. A., Braun, A., Goronzy, J. J. & Weyand, C. M. T cell activation in rheumatoid synovium is B cell dependent. J. Immunol. 167, 4710–8 (2001).

32

107. Lozano, E., Segarra, M., Garcia-Martinez, A., Hernandez-Rodriguez, J. & Cid, M. C. Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis. Ann. Rheum. Dis. 67, 1581–1588 (2008).

108. Ly, K. H. et al. Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling. Arthritis Res. Ther. 16, 487 (2014).

109. Dimitrijevic, I., Andersson, C., Rissler, P. & Edvinsson, L. Increased Tissue Endothelin-1 and Endothelin-B Receptor Expression in Temporal Arteries from Patients with Giant Cell Arteritis. Ophthalmology 117, 628–636 (2010).

110. Kida, T. et al. Chronic treatment with PDGF-BB and endothelin-1 synergistically induces vascular hyperplasia and loss of contractility in organ-cultured rat tail artery. Atherosclerosis 214, 288–294 (2011).

111. Planas-Rigol, E. et al. Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis. Ann. Rheum. Dis. annrheumdis-2016-210792 (2017). doi:10.1136/annrheumdis-2016-210792

112. Lozano, E. et al. Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events. Ann. Rheum. Dis. 69, 434–442 (2010).

113. O’Neill, L. et al. Regulation of Inflammation and Angiogenesis in Giant Cell Arteritis by Acute-Phase Serum Amyloid A. Arthritis Rheumatol. 67, 2447–2456 (2015).

114. Segarra, M. et al. Gelatinase expression and proteolytic activity in giant-cell arteritis. Ann. Rheum. Dis. 66, 1429–35 (2007).

115. Mukhtyar, C. et al. EULAR recommendations for the management of large vessel vasculitis. Ann. Rheum. Dis. 68, 318–323 (2009).

116. Buttgereit, F., Spies, C. M. & Bijlsma, J. W. J. Novel glucocorticoids: where are we now and where do we want to go? Clin. Exp. Rheumatol. 33, S29-33

117. Sundahl, N., Bridelance, J., Libert, C., De Bosscher, K. & Beck, I. M. Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds. Pharmacol. Ther. 152, 28–41 (2015).

118. van Lierop, M.-J. C. et al. Org 214007-0: A Novel Non-Steroidal Selective Glucocorticoid Receptor Modulator with Full Anti-Inflammatory Properties and Improved Therapeutic Index. PLoS One 7, e48385 (2012).

119. Hosseini, S. H., Maleki, A., Eshraghi, H. R. & Hamidi, M. Preparation and in vitro /pharmacokinetic/pharmacodynamic evaluation of a slow-release nano-liposomal form of prednisolone. Drug Deliv. 23, 3008–3016 (2016).

120. Buttgereit, F. et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann. Rheum. Dis. 72, 204–10 (2013).

121. Buttgereit, F. et al. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet (London, England) 371, 205–14 (2008).

122. Cutolo, M., Hopp, M., Liebscher, S., Dasgupta, B. & Buttgereit, F. Modified-release prednisone for polymyalgia rheumatica: a multicentre, randomised, active-controlled, double-blind, parallel-group study. RMD Open 3, e000426 (2017).

123. Raine, C. et al. A 26-week study comparing the efficacy and safety of a

33

modified-release prednisone with immediate-release prednisolone in newly-diagnosed cases of Giant Cell Arteritis. Int. J. Rheum. Dis. (in press), (2017).

124. Dejaco, C. et al. Current evidence for therapeutic interventions and prognostic factors in polymyalgia rheumatica: a systematic literature review informing the 2015 European League Against Rheumatism/American College of Rheumatology recommendations for the management of po. Ann. Rheum. Dis. 74, 1808–17 (2015).

125. Hoffman, G. S. et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 46, 1309–18 (2002).

126. van der Veen, M. J., Dinant, H. J., van Booma-Frankfort, C., van Albada-Kuipers, G. A. & Bijlsma, J. W. Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis?.[Erratum appears in Ann Rheum Dis 1996 Aug;55(8):563]. Ann. Rheum. Dis. 55, 218–223 (1996).

127. Spiera, R. F. et al. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin. Exp. Rheumatol. 19, 495–501

128. Adizie, T., Christidis, D., Dharmapaliah, C., Borg, F. & Dasgupta, B. Efficacy and tolerability of leflunomide in difficult-to-treat polymyalgia rheumatica and giant cell arteritis: a case series. Int. J. Clin. Pract. 66, 906–9 (2012).

129. Diamantopoulos, A. P., Hetland, H. & Myklebust, G. Leflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series. Biomed Res. Int. 2013, 120638 (2013).

130. Hoffman, G. S. et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann. Intern. Med. 146, 621–30 (2007).

131. Salvarani, C. et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann. Intern. Med. 146, 631–639 (2007).

132. Seror, R. et al. Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial. Ann. Rheum. Dis. 73, 2074–81 (2013).

133. Martínez-Taboada, V. M. et al. A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann. Rheum. Dis. 67, 625–30 (2008).

134. Kreiner, F. & Galbo, H. Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial. Arthritis Res. Ther. 12, R176 (2010).

135. Lally, L., Forbess, L., Hatzis, C. & Spiera, R. Efficacy and Safety of Tocilizumab for the Treatment of Polymyalgia Rheumatica. Arthritis Rheumatol. 68, 2550–4 (2016).

136. Devauchelle-Pensec, V. et al. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann. Rheum. Dis. 75, 1506–10 (2016).

137. Macchioni, P. et al. Tocilizumab for polymyalgia rheumatica: report of two cases and review of the literature. Semin. Arthritis Rheum. 43, 113–8 (2013).

138. Unizony, S. et al. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res. (Hoboken). 64, 1720–9 (2012).

139. Toussirot, É., Martin, A., Soubrier, M., Redeker, S. & Régent, A. Rapid and

34

Sustained Response to Tocilizumab in Patients with Polymyalgia Rheumatica Resistant or Intolerant to Glucocorticoids: A Multicenter Open-label Study. J. Rheumatol. 43, 249–51 (2016).

140. Régent, A. et al. Tocilizumab in Giant Cell Arteritis: A Multicenter Retrospective Study of 34 Patients. J. Rheumatol. 43, 1547–52 (2016).

141. Clinicaltrials.gov. Efficacy and Safety Study of Sirukumab in Patients With Giant Cell Arteritis. NCT02531633 at <https://clinicaltrials.gov/ct2/show/NCT02531633?cond=giant+cell+arteritis+sirukumab&rank=1>

142. Brack, A. et al. Giant cell vasculitis is a T cell-dependent disease. Mol. Med. 3, 530–43 (1997).

143. Rittner, H. L. et al. Tissue-destructive macrophages in giant cell arteritis. Circ. Res. 84, 1050–8 (1999).

144. Langford, C. A. et al. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Giant Cell Arteritis. Arthritis Rheumatol. 69, 837–845 (2017).

145. Langford, C. A. et al. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Takayasu Arteritis. Arthritis Rheumatol. (Hoboken, N.J.) 69, 846–853 (2017).

146. Matteson, E. L. et al. A 2-Week Single-Blind, Randomized, 3-Arm Proof of Concept Study of the Effects of Secukinumab (anti-IL17 mAb), Canakinumab (anti IL-1 b mAb), or Corticosteroids on Initial Disease Activity Scores in Patients with PMR, Followed By an Open-Label Extension t. Arthritis Rheumatol. Abstract 885 (2014). at <http://acrabstracts.org/abstract/a-2-week-single-blind-randomized-3->

147. ClinicalTrialsRegister.eu. A randomised, double-blind, placebo-controlled proof-of concept study of the efficacy and safety of gevokizumab in the treatment of patients with giant cell arteritis. EUTRACT No. 2013-002778-38 (2014). at <https://www.clinicaltrialsregister.eu>

148. Clinicaltrials.gov. Efficacy of Gevokizumab in the Treatment of Patients With Behçet’s Disease Uveitis (EYEGUARDTM-B). NCT01965145 (2013). at <https://clinicaltrials.gov/ct2/show/NCT01965145?term=gevokizumab&cond=Behcet+Syndrome&rank=2>

149. Conway, R. et al. Ustekinumab for the treatment of refractory giant cell arteritis. Ann. Rheum. Dis. 75, 1578–9 (2016).

150. Bhatia, A., Ell, P. J. & Edwards, J. C. W. Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann. Rheum. Dis. 64, 1099–100 (2005).

151. Mayrbaeurl, B., Hinterreiter, M., Burgstaller, S., Windpessl, M. & Thaler, J. The first case of a patient with neutropenia and giant-cell arteritis treated with rituximab. Clin. Rheumatol. 26, 1597–8 (2007).

152. Kremers, H. M. et al. Relapse in a population based cohort of patients with polymyalgia rheumatica. J. Rheumatol. 32, 65–73 (2005).

153. Garcia-Martinez, A. et al. Development of aortic aneurysm/dilatation during the followup of patients with giant cell arteritis: a cross-sectional screening of fifty-four prospectively followed patients. Arthritis Rheum. 59, 422–430 (2008).

154. Proven, A., Gabriel, S. E., Orces, C., O’Fallon, W. M. & Hunder, G. G. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum. 49, 703–8 (2003).

155. Gabriel, S. E., Sunku, J., Salvarani, C., O’Fallon, W. M. & Hunder, G. G.

35

Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum. 40, 1873–8 (1997).

156. Nesher, G., Nesher, R., Mates, M., Sonnenblick, M. & Breuer, G. S. Giant cell arteritis: intensity of the initial systemic inflammatory response and the course of the disease. Clin. Exp. Rheumatol. 26, S30-4 (2008).

157. Mackie, S. L. et al. Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: Outcomes of Importance for Patients with PMR. J. Rheumatol. 41, 819–23 (2014).

158. Twohig, H., Mitchell, C., Mallen, C., Adebajo, A. & Mathers, N. ‘I suddenly felt I’d aged’: a qualitative study of patient experiences of polymyalgia rheumatica (PMR). Patient Educ. Couns. 98, 645–50 (2015).

159. Gilbert, K. Polymyalgia Rheumatica and Giant Cell Arteritis: a survival guide. (Amazon Digital Services, 2014). at <http://www.amazon.com/Polymyalgia-Rheumatica-Giant-Cell-Arteritis-ebook/dp/B00IJJBXS2/ref=sr_1_3?ie=UTF8&qid=1397063656&sr=8-3&keywords=gilbert+kate>

160. Dejaco, C. et al. Definition of remission and relapse in polymyalgia rheumatica: data from a literature search compared with a Delphi-based expert consensus. Ann. Rheum. Dis. 70, 447–453 (2011).

161. Leeb, B. F., Rintelen, B., Sautner, J., Fassl, C. & Bird, H. A. The polymyalgia rheumatica activity score in daily use: proposal for a definition of remission. Arthritis Rheum. 57, 810–815 (2007).

162. Castell, J. V et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett. 242, 237–9 (1989).

163. Roche, N. E. et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum. 36, 1286–94 (1993).

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