**4. Vascular remodeling is the 'unmet need' in GCA treatment-standard therapy and future perspectives**

#### **4.1 Glucocorticosteroids treatment-advantages and disadvantages**

The glucocorticosteroids (GS) remain the drug of choice for the GCA treatment. In presence of the characteristic clinical signs, GCA is diagnosed by using the Westergren method, high erythrocyte precipitate is indicative of this inflammatory condition and the indication is to start the GS therapy without delay and followed up with a biopsy of the temporal artery [29]. GS treatment is started with about 1 mg/ kg/day prednisone and then is tapered at 3, 6, 9 and 12 months-a long taper with intend to withdraw GS around 12–24 months [29]. GCA disease, if treated properly, has an excellent prognosis, but it is difficult for most people to be tapered off prednisone entirely. Most GCA patients must take low dose prednisone daily for months and years. GCA patients are elderly people, a prednisone hit on top of a frail constitution leads to higher disease toll compared to if the disease would occur earlier in life.

About 50% patient relapse after a mean follow up of 7 months at a mean prednisone dose of 4 mg/day [29]. Furthermore, GS are generating side effects, about 90% of patients receiving prednisone for GCA will have at least one GCA-related side effect after 1 year [29].

The question to ask is what we can add or substitute for GS to get tide control of the disease and address the unmet need of vascular luminal changes. GS are easing the symptoms quickly, by blocking inflammatory responses, probably correlated with the rapid decrease in the serum IL 6 and blockage of activation, proliferation, and polarization of the T cells, in particular of Th17 cells. Therefore, GS are still the best available treatment for the induction and remission of GCA, but, unfortunately, they fail to resorb the vessel wall infiltrates or to attenuate the underlying vascular dysfunction pathogenic mechanisms. It is not well known how GS intervene on systemic inflammation's vascular component in GCA, but for instance Cid et al. 2000 reported that GS treatment was not sufficient to completely abrogate the expression of adhesion molecules, [55] in their patients, indicating a persistent exposure of ECs and VSMCs cells to a remaining inflammatory microenvironment despite the rapid symptomatic improvement achieved at follow-up after GS treatment. Moreover, GS have no effect on the restoration of regulatory T cells, and mild effect on TH1 polarization [21, 29]. Another interesting study on 40 patients with TAB+ GCA treated with prednisone, in which they had a randomization for followup TABs at 3, 6,9 and 12 months, has shown that in 50% of cases, positive TAB histopathologic signs were still present after one year of GS treatment, showing GS have little to zero effect on vascular remodeling [21, 92, 93]. Vascular remodeling remains the unmet need of current GCA therapy [43, 93]. Therefore, it is very important to develop new strategies to spare GS in GCA. Some of the drugs proposed in the past are toxic or ineffective [5].

The other drug that is recommended for almost all GCA patients is low dose aspirin (85 mg a day) because it decreases the risk of developing subsequential visual loss or cerebrovascular events in giant cell arteritis [69], and it addresses any thrombogenic tendency in blood vessels supplying the eye and the CNS. Some more recent studies challenge the benefit of using aspirin in GCA treatment [5]. The use of otherconventional anticoagulant therapy for the thromboembolic complications of GCA remains controversial and is not recommended [5, 70].

Up to more recent date, the only GS-saving agent was methotrexate [5]. It was demonstrated in a metanalysis gathering phase III randomized blind controlled trials on 161 patients that methotrexate decreases the risk of GCA relapses and is able of GS-saving effect [43].

*Cellular and Molecular Characteristics of Vascular Damage in Giant Cell Arteritis, the 'Unmet… DOI: http://dx.doi.org/10.5772/intechopen.97933*

#### **4.2 Experimental models of GCA**

In most to-date published studies, the biochemical assays were conducted on cultured human arteries collected by TAB from GCA patients compared with healthy cultured arterial cells, according to protocol from healthy subjects unrelated to GCA and on peripheral blood collected from GCA patients.

Several murine models of large vessel vasculitis are currently available [5, 43]. Some murine models are KO for genes which encode proteins that have crucial roles in GCA pathogenesis. IL1 rn−/− mice are lacking the gene encoding for the IL 1 receptor antagonist and it was found that these mice develop T-cell dependent vasculitis [5, 43]. Others used herpes virus-infected mouse models of vasculitis [10]. Another model involved microsurgery and physical contact of the murine aorta with an elastase to destroy the vascular wall and mice developed aortitis [5, 43].

The most interesting systemic murine model developed by Weyand group [4] uses implant of human temporal artery (allowing dissection of specific GCA pathogenetic mechanisms) or infusion of human peripheral blood monocytes from GCA patients in severely immunodeficient mice [38]. The model of subcutaneous engraftment of human TAB+ GCA arteries in severely immunodeficient mice opened the possibility to test new biologics therapy effects on immune cells and its afferent GCA artery, both cells and GCA artery originating from the specific patient in the murine model of GCA, maybe allowing in future studies collection of predictive data on how a specific GCA patient would react to the administrated drug of choice [4].

#### **4.3 GS-sparing agents for GCA treatment**

#### *4.3.1 Tocilizumab and GiACTA study*

One of the most important therapeutic targets for the treatment of GCA disease is related to IL6.

Tocilizumab is a monoclonal antibody targeted against IL6 receptor α [94]. IL6 is the cytokine that controls the balance between regulatory T cells, Th17 and Th1 which is particularly involved in GCA pathogenesis. Collectively, IL6 published data leaded to the breakthrough Giant cell Arteritis Actemra (GiACTA) study was published in 2017 by Stone et al. [94]. GiACTA is a global, randomized, double blind, double placebo-controlled Phase III trial evaluating efficacy and safety of tocilizumab in active GCA in which there were compared 4 groups: in two groups people where receiving IL6 receptor antagonist tocilizumab every week or every other week in association with prednisone over 6 months or 1 year; in the two placebo groups patients were receiving prednisone either 6 months or 1 year [94]. The primary outcome measurement at one year was the sustained remission (56% of the patients in weekly tocilizumab group and 53% in those receiving every other week tocilizumab group compared to only 14% in the short-course prednisone without tocilizumab group, of a total of 251 patients) [95]. GiACTA results demonstrates the superiority of tocilizumab to placebo non-dependent on the duration of prednisone, sustained remission, excluding CRP concentration normalization [94].

GiACTA lead to the FDA approval of tocilizumab in 2017 as first and only specific therapy to treat GCA in the USA and Europe [30, 95], in combination with protocol-defined dose of GS. Tocilizumab successful clinical trials indicate that blockage of IL-6-dependent inflammatory pathways strongly inhibits systemic inflammation as well as PMR and ocular syndrome in GCA patients [30, 95]. Tocilizumab prescription is particularly useful in corticodependance and severe adverse reactions to GS (osteoporosis, diabetics, HTA) [30, 95].

There were a few reports of what happens after tocilizumab withdrawal. In an effort to optimize the tocilizumab treatment duration, a multicenter prospective open label study investigated the risk of relapse associated with tocilizumab discontinuation after new GCA patients received 4 infusions of tocilizumab at weeks 0, 4, 8 and 12 wks [5, 43]. They observed that this treatment can be very effective, but after tocilizumab termination, at least in some patients (25%), it was seen relapse revival [43]. Same, in a long-term follow-up of the GiACTA study confirmed on larger number of patients, in which the treatment was stopped at one year, the relapse revival decrease was seen and it was more comparable between groups after two years follow-up [43, 93]. Importantly, there is no proof of tocilizumab efficacy on vascular remodeling. One of the molecular effects of IL-6 blockade was reported by Terrades-Garcia et al. who investigated the molecular effects of tocilizumab; for this study temporal arteries from 13 GCA patients and 8 controls were cultured with or without tocilizumab. After 5 days of culture, tocilizumab selectively induced a decrease in CXC 13 chemokine mRNA expression in cultured arteries, and they concluded disruption of B cell homeostasis may partially account for the therapeutic effects of tocilizumab (ACR meeting 2016), with no significant changes in other chemokines [5]. Further studies are needed to identify predictive factors of relapses.

## *4.3.2 Therapeutical targets-updates and controversies*

METOGia is a currently conducted, randomized controlled clinical study comparing administration tocilizumab for one year with one-year treatment of methotrexate in association with protocol-controlled prednisone [43].

A new IL1R antagonist (anakinra) effects in GCA treatment is currently under clinical trial, with promising perspective [43].

Activated T cells could be moderated by inference at immunoinhibitory checkpoints [36]. A potential drug intervention is to control excessive TH cell activation and invasion along arterial wall by using abatacerpt. Abatacept is a recombinant fusion protein made from fragment of human Ig1 fused to a domain of cytotoxic T-lymphocyte-associated antigen 4 (which is usually expressed on stimulated T cells) used in vasculitis with positive results, mild efficacy [96], mild GC-sparing effect [5]. There is an ongoing Phase III clinical trial [93].

Blocking IL-12/23 by binding to their common p40 subunit, with another monoclonal antibody ustekinumab has according to one report a positive influence in relapsing GCA [97]. Ustekinumab administered after rapid decrease in GS dose did not prevent disease relapse in one recent small study [98], it still has an open trial label for comparative multicenter study comparing GS alone treatment to GS and ustekinumab in refractory GCA [43].

Macrophages' activation various pathways (mediated by IFN-ỿ, TNFα, CSF-2/ CSF-2R (CSF-2: colony-stimulating factor 2), IL 6/IL-6 receptor) [2] should be therapeutically targeted in GCA to prevent blood vessel destruction [54, 56] and the faulty vascular reparatory remodeling [2, 38, 54, 57, 62]. For instance, mavrilimumab is another agent under clinical trial for GCA treatment, targeting macrophage CSF-2/CSF-2R [43].

One of the most promising targets are Janus Kinase (JAK) inhibitors which are pursuing to block the signaling pathways of cytokines. JAKs are kinases that are involved in the signaling of different cytokines. The JAK inhibitors would possibly block different cytokines at the same time. It will be interesting to see whether blocking JAKs in GCA artery will block the signaling of both vascular inflammation (IL6 mediated pathway) and vascular remodeling (IFNỿ-mediated pathway) at the same

*Cellular and Molecular Characteristics of Vascular Damage in Giant Cell Arteritis, the 'Unmet… DOI: http://dx.doi.org/10.5772/intechopen.97933*

time. This very interesting concept was first demonstrated by the Weyand research group, by blocking concomitantly vascular inflammation and vascular remodeling, with tofacitinib (an inhibitor of Jak1 and 3) as shown in *ex vivo* studies by Zhang et al. 2017 [36]. SELECT-GCA is an ongoing Phase III clinical trial investigating Upadacitinib, another JAK inhibitor for active GCA, at new onset or relapse [43, 93].

#### *4.3.3 Future therapeutical strategies and developments*

In terms of therapeutic strategy, the question to ask is which targeted therapy has more GS-saving effects, and also which of them reduces vascular dysfunction and vascular remodeling, which is still the "unmet need" in GCA treatment. For these purposes, we could target by blocking different molecules for instance, endothelin 1, PDGF, mTor (rapamycin) [43]. TLR-induced activation of dendritic cells attracts and retain more dendritic cells and promote the activation of TH1 and TH17 cells, one of the putative therapeutic development would be TLR blockage [5]. vWF and its crosstalk with LRP4/integrin αvβ3 axis could also constitute a future target for new therapeutics (monoclonal antibody against VWF to prevent pathological hyperplasia of the GCA arterial wall [58], or as possible future research perspective and therapy objective one could investigate could be using a small molecule to inhibit Weibel-Palade bodies secretion from arterial ECs [82, 99] and therefore control ECs mediators' availability.

The impact of targeted GCA treatment on vascular inflammation and vascular remodeling, associated with vascular complications, needs to be further evaluated [22, 95] for more insight into the vascular inflammation and vascular repair unique features specific to GCA.

#### **5. Discussion and conclusions**

In this review study, we discussed several cellular and molecular pathogenetic mechanisms of vascular damage characteristic to GCA, that might occur during the progress of disease, especially during the active phase of the disease.

The paradigm in terms of GCA physiopathology is that inflammation starts in the adventitial layer with the activation of the vascular DCs which shifts the situation to the point where there are multiple types of immune cells recruited, proliferating, and differentiating in the vessel wall, causing together with inflamed vascular cells an erroneous repair of the arterial wall. It is unlikely that DCs are the one cells driving these processes, given the multitude of cell functions the arterial wall's ECs play in complicated processes of vascular inflammation, hemostasis/ thrombosis, and vascular repair, resulting in a distinct GCA-specific vasculopathy most commonly term used in the field is GCA-related vascular remodeling. There are three ECs populations in GCA artery: arterial luminal ECs, vasa vasorum ECs and capillary ECs formed *de novo* in the intima and media layers (which showed be avascular in a normal arteries) of the diseased artery. These three types of ECs are activated in a sequential manner, probably their activation is subordinated to the invading immune cells, but not to all. For instance, vasa vasorum ECs are activated after vascular DCs are activated but ECs activation most probably precedes the activation of T cells. The invading cells must get in the vessel wall through the vasa vasorum. Activated ECs provide the means for invasion by mobilizing, preformed contents of storage granules WPBs. These secreted ECs mediators are released in a timely manner to fulfill proinflammatory, chemoattractant and neoangiogenic roles, or increased endothelial permeability functions.

Biomarkers have the potential to detect the disease that is missed by TAB/imaging. Several large multi-centers clinical trials being done recently [43, 71, 95, 96] led to the discovery of new potential biomarkers to monitor disease activity and relapses, which is a new critical development in the field. Some of the recently published data imply that testing several blood acute phase reactants can optimize earlier diagnosis and the ability to predict flares and complications [73, 93].

In addition, our study underlines the importance of the candidate targets for novel therapeutics. In the more severe complications of this disease-as blindness or stroke-the underlying GCA-related vascular damage does not respond to GS, as previously reported by several independent studies. A multistep treatment for GCA should be envisioned which involves first line: steroids, especially when people with GCA are particular ill; and secondly, efficient medication to control vascular dysfunction (for instance to lower proinflammatory cytokine levels, to lower the levels of circulating active vWF in parallel). From the variety of GCA treatments that are being investigating a few have the potential to improve outcomes and reduce the need for steroids. The availability of new drug tocilizumab was received with a lot of enthusiasm it is the only FDA approved drug specific for GCA treatment. Tocilizumab is effective to control GCA symptoms, allows rapid GS tapering, and persistent remission with a low dose GS after 6 mo followup, however after tocilizumab discontinuation the relapse-free survival (%) decreases, at least in some patients. Tocilizumab poses certain challenges for clinicians regarding biomarkers follow-up of patients, since tocilizumab is repressing both CRP and ESR; therefore, making careful anamnesis, physical examination, and clinical judgement even more important part of the disease assessment. 20 adverse events were considered directly related to drug; danger with tocilizumab administration was reported in the instance of infection in patients receiving tocilizumab [43, 93], with pneumonia and no CRP and ESR rise, [43] signifying that more careful assessing of the disease activity and infections in the patients treated with tocilizumab is required [43]. Further studies are needed to determine the optimal duration of treatment and maintaining of dosing and to further reduce the risk of relapse [93]. An important note to make is that molecular pathogenic pathways promoting GCA disease are changing with the disease progression under treatment [93]. This situation is frequent in clinical practice and requires adequate follow-up and adapted therapeutic strategies [93].

Hopefully, future research will bring us closer to the goal of identifying new therapy for active and/or refractory GCA, which used in substitution or addition to steroids will provide tide control of the disease, addressing not only vascular inflammation but also vascular remodeling, skewed thrombotic propensity and luminal changes in GCA patients at the brink of having VL, or a stroke or other ischemic event at the initial onset of the arterial disease or in evolution.

*Cellular and Molecular Characteristics of Vascular Damage in Giant Cell Arteritis, the 'Unmet… DOI: http://dx.doi.org/10.5772/intechopen.97933*
