# The pipeline of immunomodulatory therapies in polymyalgia rheumatica and giant cell arteritis: A systematic review of clinical trials

Lou Kawka, Baptiste Chevet, Laurent Arnaud, Guillaume Becker, Guillermo

Carvajal Alegria, Renaud Felten

► To cite this version:

Lou Kawka, Baptiste Chevet, Laurent Arnaud, Guillaume Becker, Guillermo Carvajal Alegria, et al. The pipeline of immunomodulatory therapies in polymyalgia rheumatica and giant cell arteritis: A systematic review of clinical trials. Autoimmunity Reviews, 2024, 23, 10.1016/j.autrev.2024.103590. hal-05233354

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## Review

# The pipeline of immunomodulatory therapies in polymyalgia rheumatica and giant cell arteritis: A systematic review of clinical trials

<figure><img src="image_3.png" /></figure>

Lou Kawka<sup>a</sup>, Baptiste Chevet<sup>b,c</sup>, Laurent Arnaud<sup>a</sup>, Guillaume Becker<sup>d,e</sup>, Guillermo Carvajal Alegria<sup>f</sup>, Renaud Felten<sup>a,e,g,*</sup>

## ARTICLE INFO

**Keywords:**

Giant cell arteritis

Polymyalgia rheumatica

Disease-modifying antirheumatic drugs,

DMARDs

Clinical trials

## ABSTRACT

**Introduction:** The objective of this systematic review was to provide an overview of current developments and potentially available therapeutic options for polymyalgia rheumatic (PMR) and giant cell arteritis (GCA), in the coming years.

**Methods:** We conducted a systematic review of 17 national and international clinical trial databases for all disease-modifying anti-rheumatic drugs (DMARDs) for PMR and GCA that are already marketed, in clinical development or withdrawn. The search was performed on January 2024, with the keywords "polymyalgia rheumatica" and "giant cell arteritis". For each molecule, we only considered the study at the most advanced stage of clinical development.

**Results:** For PMR, a total of 15 DMARDs were identified: 2 conventional synthetic DMARDs (csDMARDs), 11 biologic DMARDs (bDMARDs) and 2 targeted synthetic DMARDs (tsDMARDs). For GCA, 18 DMARDs were identified: 2 csDMARDs, 14 bDMARDs and 2 tsDMARDs. Currently, there are only 2 approved corticosteroid-sparing therapies in these diseases, which both target the IL-6 signaling pathway, namely tocilizumab in GCA and sarilumab in PMR. Most of the molecules in current development are repurposed from other conditions and clinical research in PMR/GCA seems to be mostly driven by the potential to repurpose existing treatments rather than by translational research.

**Conclusion:** This systematic review identified 23 DMARDs evaluated for PMR and GCA: 3 csDMARDs, 17 bDMARDs and 3 tsDMARDs. Several promising treatments are likely to be marketed in the coming years.

## 1. Introduction

Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) are inflammatory rheumatic diseases primarily affecting individuals in the aging population, and often presenting with clinical challenges for healthcare providers. GCA is characterized by inflammation of large-sized arteries, particularly the temporal arteries which can lead to severe complications, such as blindness and stroke if left untreated [1]. PMR is recognized for its articular and periarticular involvement [2],

leading to pain and stiffness in the shoulders and hips. The clinical course of PMR can significantly impact the quality of life for affected individuals, often requiring long-term treatment with corticosteroids [3]. PMR and GCA often coexist, sharing clinical features and immunopathogenic mechanisms, which justifies a closer examination of therapeutic strategies for modulating the immune response.

While corticosteroids remain the mainstay of treatment, the prolonged use of these agents is associated with significant side effects (including osteoporosis, diabetes, and cardiovascular complications),

<footnote><sup>a</sup> Service de Rhumatologie, Centre National de Référence des Maladies Auto-immunes et Systémiques Rares (RESO), Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France</footnote>

<footnote><sup>b</sup> UMR 1227 Lymphocytes B et auto-immunité, université de Brest, Inserm, CHU de Brest, Brest, France</footnote>

<footnote><sup>c</sup> Service de Rhumatologie, Hôpital de la Cavale Blanche, CHU de Brest, Bd Tanguy-Prigent, 29200 Brest, France</footnote>

<footnote><sup>d</sup> Pole Pharmacie-Pharmacologie, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France</footnote>

<footnote><sup>e</sup> Département Universitaire de Pharmacologie, Addictologie, Toxicologie et Thérapeutique (DUPATT), Université de Strasbourg, Strasbourg, France</footnote>

<footnote><sup>f</sup> Université de Tours, CHRU de Tours, Service de Rhumatologie, Tours, France</footnote>

<footnote><sup>g</sup> Center for Clinical Investigation, INSERM U1434, Strasbourg, France</footnote>

<footnote>* Corresponding author at: Service de Rhumatologie, Centre National de Référence des Maladies Autoimmunes et Systémiques Rares, Hôpital de Hautepierre, 1 Avenue Molière BP 83049, 67098 Strasbourg Cedex, France.</footnote>

<footnote>E-mail address: renaud.felten@chru-strasbourg.fr (R. Felten).</footnote>
emphasizing the need for alternative therapeutic strategies. The management of PMR and GCA is therefore based on a therapeutic strategy designed to minimize the adverse effects of corticosteroids while controlling the underlying inflammation. In this context, cortisone-sparing treatments have recently emerged as promising therapeutic options.

Despite considerable progress in understanding the pathophysiology of GCA [4] and PMR [2], there is a need for alternative immunomodulatory therapies that provide effective disease control while minimizing the risks associated with corticosteroid use by a corticosteroid-sparing effect.

This systematic review of clinical trials investigating immunomodulatory therapies aims to synthesize existing evidence and market authorizations, identify trends, and offer insights into the future directions of therapeutic strategies in PMR and GCA.

## 2. Methods

A systematic review of all Disease-Modifying Anti-Rheumatic Drugs (DMARDs) for GCA and PMR was conducted. We identified DMARDs that are already available, in current development or withdrawn using 17 national and international clinical trial databases listed in the World Health Organization (WHO) registry network (Table 1), using the methodology that we published before for lupus, Sjögren's syndrome, rheumatoid arthritis and spondyloarthritis [5-8]. Additional clinical trials, not found within these databases, were included based on expert recommendations.

The search was conducted in January 2024 in each database, with the keywords "polymyalgia rheumatica" and "giant cell arteritis". First, we ruled out duplicates, interventional non-therapeutic or non-interventional trials and trials that did not pertain to GCA or PMR or their activity measurement. Next, we also ruled out corticosteroids regimen, cell therapies and non-immunological treatments. Lastly, we examined only the immunosuppressive and immunomodulating agents and considered for each remaining molecule the most advanced stage of clinical development (according to the current definitions for phases I, II, III and IV). One author (L.K.) sorted the trials, with arbitration by consensus with 2 other authors (G.B. and R.F.). Then, the molecules were classified according to conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs) in the same way, following the 2013 Smolen's DMARDs nomenclature [9].

<caption>**Table 1**</caption>

List of international and national databases of clinical trials used for this systematic review.

<table><thead><tr><td>Databases</td><td>URL Internet</td></tr></thead><tbody><tr><td>ClinicalTrials.gov</td><td>https://clinicaltrials.gov</td></tr><tr><td>EU Clinical Trials Register</td><td>https://www.clinicaltrialsre<br>gister.eu</td></tr><tr><td>Australian New Zealand Clinical Trials Registry</td><td>https://www.australianclinical<br>trials.gov.au</td></tr><tr><td>Japan Primary Registries Network</td><td>http://www.umin.ac.jp/ctr/</td></tr><tr><td>ISRCTN (International Standard Randomized<br>Controlled Trial Number)</td><td>https://www.isrctn.com</td></tr><tr><td>Chinese Clinical Trial Registry</td><td>http://www.chictr.org.cn</td></tr><tr><td>Cuban Public Registry of Clinical</td><td>http://registroclinico.sld.cu</td></tr><tr><td>Peruvian Clinical Trials Registry</td><td>http://www.ensayosclinicos-rep<br>ec.ins.gob.pe</td></tr><tr><td>Clinical Trials Registry - India</td><td>http://ctri.nic.in</td></tr><tr><td>German Clinical Trials Register</td><td>https://www.drks.de</td></tr><tr><td>The Netherlands National Trial Register</td><td>http://www.trialregister.nl</td></tr><tr><td>Brazilian Clinical Trials Registry (ReBec)</td><td>http://www.ensaiosclinicos.<br>gov.br</td></tr><tr><td>Clinical Research Information Service - Republic<br>of Korea</td><td>https://cris.nih.go.kr</td></tr><tr><td>Pan african Clinical Trial Registry</td><td>http://www.pactr.org</td></tr><tr><td>Sri Lanka Clinical Trials Registry</td><td>http://slctr.lk</td></tr><tr><td>Thai Clinical Trials Register</td><td>http://www.clinicaltrials.in.th</td></tr><tr><td>Iranian Registry of Clinical Trials (IRCT)</td><td>http://www.irct.ir</td></tr></tbody></table>

Molecules were classified into the 3 categories "marketed", "in development" and "withdrawn" based on the information collected in the databases and by cross-referencing internet searches. A treatment was considered "marketed" if it had at least a marketing authorization from the Food & Drug Administration (FDA) and/or the European Medicines Agency (EMA) for PMR or GCA. A treatment was considered "in development" if at least one trial was still ongoing at the time of our search and "withdrawn" if we had no information of clinical development after a negative trial of information from its pharmaceutical that the molecule will not be developed despite a positive trial. For the molecules which were evaluated in several studies, we have also described the design of each study.

## 3. Results

### 3.1. Polymyalgia rheumatica

Using the keywords « polymyalgia rheumatica », a total of 230 trials were retrieved across the clinical trial databases listed in Table 1. Four additional clinical trials, not found within these databases, was included based on expert recommendation. Among these trials, 37 were therapeutic studies, comprising 29 on DMARDs, 7 on glucocorticoids and 1 on SPI-62, which is an inhibitor of the 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) that aims to reduce intracellular cortisol levels and mitigate its numerous adverse effects. The DMARDs trials encompassed 15 distinct molecules, including 2 csDMARDs, 11 bDMARDs, and 2 tsDMARDs (Fig. 1, 2A and Table 2).

Polymyalgia Rheumatica Activity Score (PMR-AS) is now often used as a composite endpoint to assess disease activity in PMR. It is a clinical tool used to assess the disease activity in patients with PMR [10]. This score incorporates several parameters, including the following components: CRP level reported in mg/dL; Patient Global Assessment (PGA) measured on a visual analog scale (VAS) ranging from 0 to 10; Physician Global Assessment (PhGA) also measured on a VAS from 0 to 10; Morning Stiffness Duration reported by the patient in minutes; elevation of the upper limb (EUL) (3 = none, 2 = below shoulder girdle, 1 = up to shoulder girdle, 0 = above shoulder girdle). Each component contributes to the total score. A higher PMR-AS indicates higher disease activity. The PMR-AS is calculated using the following formula: CRP (mg/dl) + PGA (0-10) + PhGA (0-10) + Morning stiffness (minutes x 0.1) + EUL (3-0) [10].

#### 3.1.1. Conventional synthetic DMARDs

Two csDMARDs are currently in clinical development in PMR: methotrexate and leflunomide (Fig. 2A and Table 2).

Methotrexate has been investigated in two randomized, double-blind, placebo-controlled studies with contradictory outcomes, justifying the need for further research. The first study involved 72 patients newly diagnosed with PMR, treated with either 10 mg of oral methotrexate or a placebo, in addition to prednisone starting at 25 mg/day (prednisone equivalent) and tapered to 0 mg/day over 24 weeks, with adjustments for flare-ups [11]. This study found that methotrexate was significantly associated with corticoid sparing (at 76 weeks, median prednisone dose was 2.1 g in the methotrexate group and 2.97 g in the placebo group, *p* = 0.03). The second study examined 40 patients with PMR, including six who also had GCA, who received either 7.5 mg of oral methotrexate or a placebo, along with a tapering course of corticosteroids starting at 20 mg/day (prednisone equivalent) [12]. This study did not find a significant corticosteroid-sparing effect of methotrexate.

Methotrexate and leflunomide are both undergoing investigation in phase III randomized, double-blind, placebo-controlled trials in patients newly diagnosed with PMR: the PMR MODE study for methotrexate [13], which has been completed but has not yet been published, and the PMRLEFRCT study for leflunomide, which is still active. The PMR MODE study is a randomized, placebo-controlled superiority trial to assess the
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Study flow chart. csDMARDs: conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs); bDMARDs: biologic DMARDs; tsDMARDs: targeted synthetic DMARDs;</figcaption></figure>

efficacy of oral methotrexate 25 mg/week versus placebo in a 1:1 ratio in 100 recently diagnosed PMR patients according to the 2012 EULAR/ ACR criteria. Patients allocated to the treatment arm will start with oral MTX 15 mg per week, which will be increased to 25 mg per week after 4 weeks if no clinically relevant MTX-related side effects occur [13]. Methotrexate and leflunomide are also being examined in the STERLING-PMR study, targeting patients with PMR who have experienced at least one relapse (ISRCTN17828080). This phase III trial is an open-labelled, randomized controlled study, planning to include up to 200 patients, that compares standard care versus standard care plus methotrexate or leflunomide if methotrexate is not tolerated. Methotrexate will be started at 15 mg weekly and progressively increased to 25 mg or reduced to 10 mg weekly if not tolerated. If 10 mg weekly methotrexate is not tolerated, or not effective, it may be switched to leflunomide starting at 10 mg daily and then increased to 20 mg daily if tolerated, or reduced to 10 mg every 2 days if not tolerated.

### 3.1.2. Biologic DMARDs

In PMR, 11 bDMARDs have been investigated. Of these, 1 is already marketed, 5 are in various stages of development, and 5 were withdrawn (Fig. 2A and Table 2).

#### 3.1.2.1. IL-6 signaling inhibition.
Sarilumab, an IL6R inhibitor, is the only bDMARD currently marketed for PMR. Tocilizumab, another IL6R inhibitor, is considered under development because of the lack of marketing authorization for PMR, while the only study that was examining sirukumab, an IL6 inhibitor, has been withdrawn.

Sarilumab was evaluated in the SAPHYR study, published in 2023 [14]. This phase III, randomized, double-blind, placebo-controlled trial involved 118 patients who were either treated with sarilumab 200 mg every two weeks for 52 weeks in addition to glucocorticoids for the first 14 weeks, or given a placebo plus glucocorticoids for 52 weeks. Significantly more patients receiving sarilumab completed a sustained

remission at 52 weeks in the sarilumab group compared to the patients in the placebo group (28% vs 10%, *p* = 0.02). Furthermore, the cumulative glucocorticoids dose was significantly lower in the sarilumab group than in the placebo group (777 mg vs 2044 mg, *p* < 0.001).

Tocilizumab has been examined across 3 phase II studies [15–17], 1 phase II/III study [18], and 1 phase III study [19]. All these studies reported positive outcomes. Notably, the SEMAPHORE study, a phase III double-blind, parallel-group, placebo-controlled randomized trial, enrolled 101 patients with glucocorticoid-dependent PMR who continued to show disease activity despite being on glucocorticoid therapy with a dose of 10 mg/day or higher [19]. Participants were treated with either intravenous tocilizumab at a dosage of 8 mg/kg or a placebo, in addition to a tapering course of glucocorticoids. Low disease activity (PMR-AS<10) with glucocorticoid independence (≤5 mg absolute value or decrease ≥10 mg from week 0 to week 24 [prednisone equivalent]) at week 24 was significantly more frequently in the tocilizumab group than in the placebo group (67.3% vs 31.4%, *p* < 0.001).

Sirukumab was evaluated in a phase III study, which was prematurely withdrawn due to a pharmaceutical company's decision (NCT02899026).

#### 3.1.2.2. TNF alpha inhibitors.
Two bDMARDs targeting TNF-α were explored for PMR treatment. Of these, infliximab is still under investigation and etanercept has been withdrawn.

Etanercept has been investigated in a phase III trial involving 20 newly diagnosed PMR patients who were glucocorticoids-free [20]. They were randomized to receive either etanercept 25 mg subcutaneously biweekly or a placebo. After 14 days, the PMR-AS score decreased by 24% from the baseline (*p* = 0.011) in the etanercept-treated patients, whereas it remained unchanged in the placebo group (*p* > 0.05).

Infliximab was investigated in a phase III trial involving 51 patients newly diagnosed with PMR. These patients were randomized to receive infusions of either infliximab or a placebo, in combination with a
A

<figure><img src="image_5.png" /></figure>

B

<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Currently marketed and in-development disease-modifying anti-rheumatic drugs (DMARDs), their mechanisms of action and development phase.</figcaption></figure>

Molecules in bold: with positive results, strikethrough molecules: withdrawn.
A. in PMR B. in GCA.

tapering course of corticosteroids that concluded at 16 weeks. At 52 weeks, there was no significant difference in relapse rates between the two groups [21]. It is currently still under investigation in another phase III trial for patients with corticosteroid-dependent PMR (NCT01423591).

3.1.2.3. **IL-17 inhibitor.** Secukinumab, an anti-IL-17 A therapy, is currently under investigation in PMR. A phase II study, conducted as a proof of concept study, randomized trial, explored the efficacy of 3 mg/ kg secukinumab and canakinumab in treating PMR (NCT01364389). The main outcome was the decrease of PMR-AS after a single dose, two weeks after the infusion. The trial was early terminated because data did not show that the two biologic treatments impacted PMR disease activity to the same degree as steroid treatment within a 2-week treatment period. The REPLENISH study, a phase III randomized, double-blind, placebo-controlled trial, is actively recruiting participants (NCT05767034). Its objective is to evaluate secukinumab at doses of 150 mg or 300 mg every 4 weeks, in combination with a tapering glucocorticoid regimen, in patients experiencing a relapse of glucocorticoid-dependent PMR.

3.1.2.4. **Other targets.** Rituximab, a CD20 antigen inhibitor, is in development in PMR. It was evaluated in the phase II BRIDGE-PMR

study, which involved 47 patients randomized to receive either a single IV dose of rituximab 1000 mg or a placebo, alongside glucocorticoids for 17 weeks. At 52 weeks, significantly more rituximab-treated patients achieved glucocorticoid-free remission compared to those receiving placebo (52% vs 21%, *p* = 0.04) [22]. Two Phase III trials, REDUCE-PMR-1 and REDUCE-PMR-2, are ongoing, evaluating rituximab in new-onset and relapsing PMR patients, respectively, in randomized double-blind placebo-controlled settings (NCT05533125, NCT05533164).

**Abatacept** is a fusion protein of the extracellular domain of the human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc of human immunoglobulin 1 (IgG1) that modulated the T-cell co-stimulatory signal. It was evaluated in early-onset PMR in the ALORS study, a phase III multicenter, double-blinded, randomized, placebo-controlled, proof of concept study to evaluate whether abatacept allows low disease activity without glucocorticoids [23]. The low disease activity (CRP PMR-AS ≤10) at week 12 without glucocorticoids and without rescue treatment was reached in 8 (50%) of 16 patients in the abatacept group and 4 of 18 patients in the placebo group (22%, *p* = 0.070). This study suggested that the efficacy of abatacept as a unique treatment is not superior enough compared to glucocorticoids to be given alone in early PMR [23].

**ABBV-154** is an innovative antibody-drug conjugate (iADC), designed as an anti-TNF Glucocorticoid Receptor Modulator. It uniquely combines a glucocorticoid receptor modulator with an anti-TNF antibody, aiming to specifically modulate the TNF-mediated pathway. This mechanism allows for the direct delivery of glucocorticoids into immune cells expressing membrane-bound TNF-α, offering a targeted approach to treating inflammatory conditions. It has been evaluated in a phase II trial involving PMR patients who experienced at least two flares but was prematurely terminated due to the pharmaceutics' decision (NCT04972968).

**Interleukin 2**, administered at low doses for 12 weeks, is being examined in a phase II single-center, open-label trial involving PMR patients (NCT04062006).

**Canakinumab**, an IL-1β inhibitor, was explored, along with secukinumab, in a prematurely terminated phase II study because data did not show that the two biologic treatments impacted PMR disease activity to the same degree as steroid treatment within a 2-week treatment period (NCT01364389).

### 3.1.3. Targeted synthetic DMARDs

JAK/STAT inhibitors are intracellular kinases that are blocking the Janus kinase-signal transducer and activator of transcription pathway, thereby reducing inflammation and modulating immune responses.

Two tsDMARDs, **baricitinib** and **tofacitinib**, are in development for PMR treatment (Fig. 2A and Table 2).

**Baricitinib**, a JAK1-2 inhibitor, was explored in the BACHELOR study, a phase II multicenter, double-blind, randomized placebo-controlled trial, targeting early PMR with a glucocorticoid-free regimen. The study evaluated baricitinib at 4 mg per day for 12 weeks, followed by 2 mg per day for another 12 weeks if PMR-AS≤10 was achieved at week 12 (NCT04027101) in patients with no oral or parenteral glucocorticoids during the past 2 weeks. From week 4 to week 12, glucocorticoids were proposed as a rescue for both arms at investigators' discretion and according to PMR-AS. Although completed, results have not been published yet. A phase III trial, the JAK-SPARE1 study, is currently recruiting. It measures the proportion of newly diagnosed PMR patients treated by baricitinib treatment that achieve glucocorticoids-free remission after 16 weeks (2020-005081-34).

**Tofacitinib**, a JAK1-3 inhibitor, was studied in two phase II trials with positive results. The first one involved 14 patients with highly active PMR treated by tofacitinib 10 mg/day alongside corticosteroids [24]. By week 20, 12 of the 14 patients achieved remission, defined as a low PMR-AS <7 and a corticosteroid dose ≤2.5 mg/day (prednisone equivalent). The second one, the EAST PMR study, randomized 76
<table><caption>**Table 2**
DMARDs studied in therapeutic trials in PMR.</caption><thead><tr><th>Therapeutic class</th><th>Molecule</th><th>Current development stage</th><th>NCT or reference number of trial</th><th>Reference</th><th>Development phase</th><th>Current status of the latest trial</th></tr></thead><tbody><tr><td rowspan="5">csDMARDs</td><td rowspan="2">Methotrexate</td><td rowspan="2">In development</td><td>NL8366 / (PMR MODE)</td><td>[12]</td><td>II</td><td>Completed</td></tr><tr><td>ISRCTN17828080 (STERLING PMR)</td><td>[13]</td><td>III</td><td>Completed</td></tr><tr><td>Leflunomide</td><td>In development</td><td>ISRCTN17828080 (STERLING PMR)</td><td>[11]</td><td>III</td><td>Completed</td></tr><tr><td rowspan="3">Sarilumab</td><td rowspan="3">Marketed</td><td>NCT03576794 (PMRLEFRCT)</td><td></td><td>III</td><td>Recruiting</td></tr><tr><td>NCT03600818 (SAPHYR)</td><td>[14]</td><td>III</td><td>Unknown</td></tr><tr><td>NCT01396317</td><td>[15]</td><td>II</td><td>Completed</td></tr><tr><td rowspan="10">IL-6 signaling inhibitors</td><td rowspan="3">Tocilizumab</td><td rowspan="3">In development</td><td>NCT01713842 (TENOR)</td><td>[16]</td><td>II</td><td>Completed</td></tr><tr><td>NCT03263715 (PMR-SPARE)</td><td>[17]</td><td>II</td><td>Completed</td></tr><tr><td>NCT02908217 (SEMAPHORE)</td><td>[18]</td><td>II/III</td><td>Completed</td></tr><tr><td>Sirukumab</td><td>Withdrawn</td><td>NCT02899026</td><td>[19]</td><td>III</td><td>Completed</td></tr><tr><td>Etanercept</td><td>Withdrawn</td><td>NCT00524381</td><td>[20]</td><td>III</td><td>Withdrawn</td></tr><tr><td rowspan="3">TNF alpha inhibitors</td><td rowspan="3">Infliximab</td><td rowspan="3">In development</td><td>ACTRN012606000205538</td><td>[21]</td><td>II</td><td>Completed</td></tr><tr><td>NCT01423591</td><td></td><td>III</td><td>Unknown</td></tr><tr><td>NCT06130540</td><td></td><td>I</td><td>Recruiting</td></tr><tr><td rowspan="2">IL-17 inhibitor</td><td rowspan="2">Secukinumab</td><td rowspan="2">In development</td><td>NCT01364389</td><td></td><td>II</td><td>Terminated</td></tr><tr><td>NCT05767034 (REPLENISH)</td><td></td><td>III</td><td>Recruiting</td></tr><tr><td rowspan="3">CD20 inhibitor</td><td rowspan="3">Rituximab</td><td rowspan="3">In development</td><td>2018-002641-11 (BRIDGE-PMR)</td><td>[22]</td><td>II</td><td>Completed</td></tr><tr><td>NCT05533125 (REDUCE-PMR-1)</td><td></td><td>III</td><td>Recruiting</td></tr><tr><td>NCT05533164 (REDUCE-PMR-2)</td><td></td><td>III</td><td>Recruiting</td></tr><tr><td>CTLA4-Ig</td><td>Abatacept</td><td>Withdrawn</td><td>NCT03632187 (ALORS)</td><td>[23]</td><td>III</td><td>Completed</td></tr><tr><td>Anti-TNF Glucocorticoid Receptor Modulator</td><td>ABBV-154</td><td>Withdrawn</td><td>NCT04972968 (AIM-PMR)</td><td></td><td>II</td><td>Terminated</td></tr><tr><td>Interleukin 2</td><td>Interleukin 2</td><td>In development</td><td>NCT04062006</td><td></td><td>II</td><td>Unknown</td></tr><tr><td rowspan="2">IL-1 inhibitor</td><td>Canakinumab</td><td>Withdrawn</td><td>NCT01364389</td><td></td><td>II</td><td>Terminated</td></tr><tr><td>Baricitinib</td><td>In development</td><td>NCT04027101 (BACHELOR) 2020-005081-34 (JAK SPARE 1)</td><td></td><td>II</td><td>Completed</td></tr><tr><td rowspan="2">JAK/STAT inhibitors</td><td rowspan="2">Tofacitinib</td><td rowspan="2">In development</td><td>NCT04799262</td><td>[24]</td><td>II</td><td>Active</td></tr><tr><td>ChiCTR2000038253 (EAST-PMR)</td><td>[25]</td><td>II</td><td>Completed</td></tr><tr><td></td><td></td><td></td><td>NCT06172361 (ITTGPMR)</td><td></td><td>III</td><td>Not yet recruiting</td></tr></tbody></table>

newly-diagnosed PMR patients to receive either tofacitinib 5 mg/day or corticosteroids 15 mg/day gradually tapered. At weeks 12 and 24, all patients in both groups had PMR-AS <10 [25]. A phase III randomized open-label trial, the ITTGPMR study, is currently ongoing. It compares the proportion of patients achieving PMR-AS<10 at week 52 between two groups: one treated with a tapering dose of tofacitinib over 11 months in combination with decreasing doses of glucocorticoids for 4 weeks, and a control group receiving only glucocorticoids (NCT06172361).

## 3.2. Giant cell arteritis

Using the keywords « giant cell arteritis », a total of 276 trials were retrieved across 17 national and international clinical trial databases listed by the WHO (Table 1). Three additional clinical trials, not found within these databases, were included based on expert recommendation. Among these trials, 45 were therapeutic studies, comprising 3 on glucocorticoids, 1 on stem cell transplantation, 2 on non-immunomodulatory molecules (bosentan and naltrexone), while 39 focused on DMARDs. The DMARDs trials encompassed 18 distinct molecules, including 2 csDMARDs, 14 bDMARDs, and 2 tsDMARDs (Fig. 1, Fig. 2B and Table 3).

### 3.2.1. Conventional synthetic DMARDs

Two csDMARDs were evaluated in GCA: **methotrexate** and **hydroxychloroquine** (Fig. 2B and Table 3).

**Methotrexate**, whose mechanism of action is to inhibit purine and pyrimidine synthesis, is currently still evaluated in GCA. Three completed phase II trials have investigated methotrexate in combination with gradually decreasing doses of glucocorticoids in GCA, yielding contradictory results. Only one study showed positive results [26]. It

was a randomized, double-blind, placebo-controlled trial involving 42 patients with new-onset GCA, comparing oral methotrexate at the dose of 10 mg per week to a placebo, both in conjunction with a glucocorticoid tapering protocol. This trial found that, compared to placebo, patients treated by methotrexate experienced significantly fewer relapses (45% vs. 84.2%; *P* = 0.02) and had a lower cumulative dose of glucocorticoid therapy. Additionally, there was no difference in the rate and severity of side effects between the two groups. The other two studies, which were double-blind, placebo-controlled trials, did not demonstrate a significant benefit of methotrexate in GCA. The first one, analyzing 21 patients, found no reduction in the cumulative glucocorticoid dose or in the number of weeks to completion of steroid treatment in patients treated by methotrexate [27]. The second one, analyzing 98 patients, found no reduction in treatment failure, defined as two distinct relapses or persistence of disease activity after the first relapse, in patients treated by methotrexate and a 6-month glucocorticoid therapy [28].

Two addition trials investigating methotrexate in GCA are currently ongoing. A phase II trial is assessing methotrexate's efficacy in maintaining remission induced by a tocilizumab-glucocorticoid regimen (NCT05623592). A phase III multicenter randomized controlled trial is comparing methotrexate to tocilizumab, both associated to glucocorticoid regimen (NCT03892785).

**Hydroxychloroquine**, whose main mechanism of action is to inhibit lysosomal activity in immune cells, was studied in a phase III trial as a glucocorticoid sparing therapy in uncomplicated GCA (NCT00430807). The primary end point defined by being in remission with 5 mg prednisone or less for at least 3 months at 96 weeks was not reached. Seventy four patients were randomized to receive placebo (n = 38) or hydroxychloroquine (n = 36). Among them, 10 were excluded before beginning the study drug (7 for cancellation of earlier approval, 1 for a severe GC-induced psychosis, 2 due to a major deviation). Among the 64 remaining
<table><caption>**Table 3**
DMARDs studied in therapeutic trials in GCA.</caption><thead><tr><th>Therapeutic class</th><th>Molecule</th><th>Current development stage</th><th>Trial</th><th>Reference</th><th>Development phase</th><th>Current status of the latest trial</th></tr></thead><tbody><tr><td rowspan="10">csDMARDs</td><td rowspan="2">Methotrexate</td><td rowspan="2">In development</td><td>NCT00004686</td><td rowspan="2">[28]</td><td>II</td><td>Completed</td></tr><tr><td>NCT05623592 (MTXinGCA)</td><td>II</td><td>Recruiting</td></tr><tr><td rowspan="8">Hydroxychloroquine</td><td rowspan="8">Withdrawn</td><td>NCT03892785 (METOGIA)</td><td rowspan="8">[29]</td><td>II</td><td>Completed</td></tr><tr><td>NCT00430807</td><td>II</td><td>Completed</td></tr><tr><td>NCT03923738</td><td>III</td><td>Recruiting</td></tr><tr><td>NCT03745586 (GUSTO)</td><td>I</td><td>Completed</td></tr><tr><td>NCT01450137</td><td>I/II</td><td>Completed</td></tr><tr><td>NCT01910038 / (HORTOCI)</td><td>II</td><td>Completed</td></tr><tr><td>NCT04239196 (TOCIAION)</td><td>II</td><td>Recruiting</td></tr><tr><td rowspan="12">IL-6 signaling inhibitors</td><td rowspan="12">Tocilizumab</td><td rowspan="12">Marketed</td><td>NCT05168475 (BIOVAS)</td><td rowspan="12">[30]</td><td>II</td><td>Active, not recruiting</td></tr><tr><td>NCT03202368</td><td>II</td><td>Completed</td></tr><tr><td>NCT01791153 (GiACTA)</td><td rowspan="3">[33]</td><td>III</td><td>Completed</td></tr><tr><td>NCT04888221 (TOGIAC)</td><td>III</td><td>Recruiting</td></tr><tr><td>NCT06037460 (MAGICA)</td><td>III</td><td>Not yet recruiting</td></tr><tr><td>NCT03726749</td><td rowspan="4">[34]</td><td>IV</td><td>Completed</td></tr><tr><td>CTRI/2020/11/028814</td><td>IV</td><td>Recruiting</td></tr><tr><td>NCT03244709</td><td>IV</td><td>Unknown</td></tr><tr><td>NCT03600805</td><td>III</td><td>Terminated</td></tr><tr><td>Sarilumab</td><td>Withdrawn</td><td>NCT02531633</td><td>[35]</td><td>Terminated</td><td>Unknown</td></tr><tr><td>Sirukumab</td><td>Withdrawn</td><td>NCT00076726</td><td>II</td><td>Terminated</td><td>Unknown</td></tr><tr><td>Infliximab</td><td>In development</td><td>NCT05168475 (BIOVAS)</td><td>II</td><td>Active, not recruiting</td></tr><tr><td rowspan="5">TNF alpha inhibitors</td><td>Adalimumab</td><td>Withdrawn</td><td>NCT00305539 (HECTHOR)</td><td>[38]</td><td>III</td><td>Completed</td></tr><tr><td rowspan="2">Etanercept</td><td rowspan="2">Withdrawn</td><td>NCT06130540</td><td rowspan="2">[39]</td><td>I, II</td><td>Terminated</td></tr><tr><td>NCT03765788 (TitAIN)</td><td>I</td><td>Recruiting</td></tr><tr><td>Secukinumab</td><td>In development</td><td>NCT04930094 (GCAptAIN)</td><td>[40]</td><td>II</td><td>Completed</td></tr><tr><td rowspan="10">IL-17 inhibitor</td><td rowspan="10">Ustekinumab</td><td rowspan="10">In development</td><td>NCT05380453 (GigAINt)</td><td rowspan="10">[41]</td><td>III</td><td>Recruiting</td></tr><tr><td>NCT02955147 (UGCA)</td><td>III</td><td>Recruiting</td></tr><tr><td>NCT03711448 (ULTRA)</td><td>I, II</td><td>Terminated</td></tr><tr><td>NCT04633447 (THEIA)</td><td>II</td><td>Recruiting</td></tr><tr><td>NCT02902731 (GiAnT)</td><td>II</td><td>Active, not recruiting</td></tr><tr><td>2013–002778-38</td><td>III</td><td>Unknown</td></tr><tr><td>NCT00556439</td><td>II</td><td>Terminated</td></tr><tr><td>NCT03192969</td><td>III</td><td>Completed</td></tr><tr><td>NCT04474847</td><td>III</td><td>Terminated</td></tr><tr><td>NCT03827018</td><td>[43]</td><td>II</td><td>Active, not recruiting</td></tr><tr><td>GM-CSF-R inhibitor</td><td>Mavrilimumab</td><td>Withdrawn</td><td>NCT05168475 (BIOVAS)</td><td>[43]</td><td>II</td><td>Completed</td></tr><tr><td rowspan="2">CD20 inhibitor</td><td>Rituximab</td><td>In development</td><td>NCT03026504</td><td>[44]</td><td>II</td><td>Active, not recruiting</td></tr><tr><td>Baricitinib</td><td>In development</td><td>NCT03725202 (SELECT-GCA)</td><td>[44]</td><td>III</td><td>Completed</td></tr><tr><td>JAK/STAT inhibitors</td><td>Upadacitinib</td><td>In development</td><td>NCT03725202 (SELECT-GCA)</td><td>[44]</td><td>III</td><td>Active, not recruiting</td></tr></tbody></table>

patients, 32 received the placebo and 32 hydroxychloroquine. Fourteen out of 32 hydroxychloroquine-treated patients and 21 out of 32 placebo patients reached the primary endpoint (log-rank test: *p* = 0.22). [29]

### 3.2.2. Biologic DMARDs

Among the 14 bDMARDs studied in GCA, 1 is already marketed, 7 are in development and 6 are currently withdrawn (Fig. 2B and Table 3).

#### 3.2.2.1. IL-6 signaling inhibition.
Tocilizumab, which is an IL-6 receptor (IL-6R) inhibitor, is marketed in GCA, while sarilumab, another IL-6R inhibitor, and Sirukumab, an anti-IL-6 monoclonal antibody, are currently withdrawn.

Tocilizumab is being studied in 13 GCA trials. Three completed phase II trials [30–32], one completed phase III trial [33] and one completed phase IV trial [34] have demonstrated the efficacy to obtain remission, glucocorticoid-sparing effect and safety of tocilizumab in GCA. The GIACTA study, a phase III multicenter, randomized, double-blind, placebo-controlled trial published in 2017, analyzed 251 patients that were treated either with subcutaneous tocilizumab at a dose of 162 mg per week or every other week, combined with tapering glucocorticoids over 26 weeks, or with a placebo, combined with tapering

glucocorticoids over 26 or 52 weeks. After one year of treatment, the study showed that sustained remission with no glucocorticoids was significantly more frequently achieved in the tocilizumab groups than in the placebo group (56% for tocilizumab weekly, 53% for tocilizumab every two weeks, 18% for placebo and glucocorticoids over 52 weeks, and 14% for placebo and glucocorticoids alone over 26 weeks, *p* < 0.001). Furthermore, the cumulative dose of glucocorticoids was significantly lower in the tocilizumab group (1862 mg in both tocilizumab groups, 3296 mg in the 26-week glucocorticoid group, 3818 mg in the 52-week glucocorticoid group [prednisone equivalent], *p* < 0.001). The percentages of patients experiencing adverse events were similar across groups [33]. Notably, the GUSTO trial, a phase II proof-of-concept study, enrolled 18 patients recently diagnosed with GCA [32]. These patients received an initial treatment of 500 mg of methylprednisolone intravenously for three consecutive days, followed by tocilizumab therapy (one 8 mg/kg intravenous infusion followed by 162 mg subcutaneous injections for 52 weeks). The study demonstrated sustained remission with tocilizumab since 14 out of 18 patients achieved remission within 24 weeks, and 13 maintained remission with no relapses up to 52 weeks.

Two ongoing trials are specifically focused on the efficacy of
tocilizumab in specific manifestations associated with GCA. The TOCIAION phase II study is investigating the efficacy of subcutaneous tocilizumab in combination with intravenous glucocorticoid pulses versus intravenous glucocorticoid pulses alone in treating Acute Anterior Ischemic Optic Neuropathy (AAION) associated with GCA (NCT04239196). The TOGIAC study, a phase III trial, is evaluating the efficacy of subcutaneous tocilizumab in preventing the recurrence of ischemic stroke in GCA patients with neurovascular involvement (NCT04888221). Two trials are assessing the risk of relapse post-tocilizumab discontinuation, investigating different tapering protocols. The MAGICA study, a phase III trial, is comparing relapse-free survival between the gradual discontinuation of subcutaneous tocilizumab (one injection every 2 weeks from Week 0 to Week 12, then one injection every 4 weeks until Week 24) versus the immediate discontinuation of tocilizumab (NCT06037460). A phase IV study is analyzing the maintenance of clinical remission after a gradual interruption of tocilizumab (intravenous 8 mg/Kg monthly for 12 weeks, followed by subcutaneous tocilizumab 162 mg weekly for 12 weeks, then tapering every 8 weeks, until week 48) (NCT03244709).

**Sarilumab**, combined with a tapered glucocorticoid regimen, was investigated in a phase III randomized, double-blind, placebo-controlled trial involving patients with GCA [35]. The recruitment process was significantly slowed by the COVID-19 pandemic, leading to the study's early termination before reaching the planned recruitment target. A numerically higher proportion of patients achieved sustained remission at week 52 in the group treated by sarilumab compared to those receiving placebo (46% with sarilumab 200 mg and 26-weeks glucocorticoids, 43% with sarilumab 150 mg and 26-weeks glucocorticoids, 30% with placebo and 52-weeks glucocorticoids, 0% with placebo and 26-weeks glucocorticoids) but the small sample size resulted in insufficient data to draw precise conclusions.

**Sirukumab** was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study for the treatment of GCA [36]. Due to a decision of the pharmaceutical company, the study was prematurely terminated, and the number of participants included was insufficient to clearly interpret the results (161 patients). However, treatment with sirukumab resulted in a numerically lower proportion of patients experiencing flares by week 52 compared to those receiving a placebo (18.4% with sirukumab 100 mg and 6-months glucocorticoids, 28.2% with sirukumab 100 mg and 3-months glucocorticoids, 30.8% with sirukumab 50 mg and 6-months glucocorticoids, 40.0% with placebo and 6-months glucocorticoids, 37.0% with placebo and 12-months glucocorticoids).

### 3.2.2.2. TNF alpha inhibitors.
Among the three anti-TNF alpha inhibitor evaluated in GCA, one, **infliximab**, is still in development, while two, **adalimumab** and **etanercept**, were withdrawn.

**Infliximab** was investigated in a phase II trial which was prematurely terminated due to a lack of efficacy in interim analyses [37]. This study included 44 patients with newly diagnosed giant cell arteritis, who were treated either with infliximab plus glucocorticoids or with placebo plus glucocorticoids. At week 22, the proportion of patients without relapse was not lower in the infliximab group (43% with infliximab, 50% with placebo, *p* = 0.65), and the incidence of infections was numerically higher in the infliximab group (71% with Infliximab, 56% with placebo). Infliximab is currently investigated for the treatment of refractory vasculitis, including GCA, in a phase II trial, the BIOVAS study (NCT05168475).

**Adalimumab** was tested in the HECTHOR study, a phase III, multicenter, double-blind, randomized trial [38]. In this trial involving 70 patients with newly-diagnosed GCA, treatment with adalimumab in addition to glucocorticoid therapy did not result in an increased number of patients in remission on <0.1 mg/kg of prednisone at week 26 (58.9% with adalimumab, 50.0% with placebo, *p* = 0.46).

**Etanercept** was evaluated in a phase II trial that failed to

demonstrate effectiveness in achieving remission at 12 months [39]. Only 17 patients were enrolled due to early termination prompted by difficulties in enrollment.

#### 3.2.2.3. IL-17 inhibitor. Secukinumab, a fully human monoclonal antibody targeting IL-17 A, is in clinical development in GCA. A phase II trial, the TitAIN study, a randomized, parallel-group, double-blind, placebo-controlled, multi-center study, enrolled 64 patients with new-onset or relapsing GCA. Sustained remission until week 28 was significantly more frequent in patients treated with secukinumab plus glucocorticoids than patients treated with placebo and glucocorticoids (median proportion of 70% vs 20%) [40]. Two phase III trials are currently ongoing. The GCAptAIN study is investigating the efficacy and safety of subcutaneous secukinumab 300 mg or 150 mg in combination with a glucocorticoid taper regimen in patients with new-onset or relapsing GCA (NCT04930094) and the GigAINt study is evaluating secukinumab 300 mg in patients with new-onset GCA in clinical remission possibly after a short glucocorticoid treatment. (NCT05380453).

#### 3.2.2.4. IL-12/23 and IL-23 inhibitors. Ustekinumab, a human monoclonal antibody IL-12 and IL-23 antagonist that binds to their p40 subunit, and guselkumab, a monoclonal antibody IL-23p19 inhibitor, are currently being assessed in phase II trials. Ustekinumab has already been studied in a phase I/II prospective open-label trial that enrolled 13 patients with active new-onset or relapsing GCA and was prematurely terminated due to lack of efficacy [41]. Only 3 (23.0%) participants achieved prednisone-free remission through week 52. The ULTRA study is a randomized, open-label trial that evaluates ustekinumab efficacy for the treatment of relapse of refractory GCA (NCT03711448). The THEIA study is a double-blind, randomized trial that evaluates the efficacy of guselkumab compared to placebo, in combination with a 26-week glucocorticoid taper regimen, in patients with new-onset or relapsing GCA (NCT04633447).

#### 3.2.2.5. IL-1 inhibitors. Anakinra, a recombinant molecule of IL-1RA specifically blocking the IL-1α/β, is being evaluated in one phase III trial, the GiAnT study. This phase III, randomized, placebo-controlled, double-blind trial evaluates anakinra in add-on therapy with glucocorticoids for 16 weeks in GCA patients newly diagnosed or on relapse (NCT02902731).

**Gevokizumab**, an anti-interleukin 1β monoclonal antibody, has been studied in phase II trial which has been prematurely terminated by sponsor decision for strategic reasons that were unrelated to safety issue (2013–002778-38).

#### 3.2.2.6. Other targets. Abatacept is currently evaluated in GCA and has demonstrated its efficacy in reducing the risk of relapse in a phase II trial [42]. This multicenter, randomized, double-blind trial enrolled 49 patients which were all treated with glucocorticoids for 28 weeks and abatacept for 8 weeks. At week 12, 41 patients achieved remission and underwent randomization to continue to receive abatacept monthly or switch to placebo. The relapse-free survival rate at 12 months was significantly higher in the abatacept arm (48% with abatacept, 31% with placebo, *p* = 0.049). Abatacept is currently evaluated in newly diagnosed or relapsing GCA patients in the ABAGART study, an academic, phase III, randomized, double-blind, placebo-controlled trial, reported as active but not recruiting (NCT04474847). The phase III trial that was conducted by the pharmaceutical company has been withdrawn due to changes in business objectives (NCT03192969).

**Mavrilimumab** (KPL-301) is a high-affinity human monoclonal IgG4 that inhibits human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R). It was studied in a phase II double-blind trial in which 70 patients were randomized to receive either mavrilimumab or placebo, both in conjunction with a 26-week glucocorticoids
taper. The median time to flare was significantly lower in the mavrilimumab arm (not reached within the 26-week follow-up period with mavrilimumab, compared to 25.1 weeks in the placebo group, HR 0.38; 95% CI 0.15 to 0.92; *p* = 0.026) [43].

**Rituximab**, an anti-CD20 chimeric monoclonal antibody, is being assessed in the BIOVAS study, a phase II trial evaluating rituximab, infliximab and tocilizumab in refractory vasculitis, reported as active but not recruiting (NCT05168475).

### 3.2.3. Targeted synthetic DMARDs

Two JAK/STAT inhibitors are currently in clinical development in GCA: **baricitinib** and **upadacitinib** (Fig. 2B and Table 3).

Baricitinib selectively inhibits JAK1 and JAK2 and has a suppressive effect on both the Th17 (IL-6, IL-23) and Th1 (IL-12, IFN-γ) pathways. It was investigated in an open-label phase II study in which 15 patients with relapsing GCA were treated with baricitinib at the dose of 4 mg/day in combination with glucocorticoid therapy [44]. One patient had to discontinue treatment due to side effects, one relapsed, and the remaining 13 were able to stop corticosteroid therapy and maintain remission for 52 weeks.

Upadacitinib, a preferentially JAK1 inhibitor, is currently being evaluated in the SELECT-GCA study, a phase III multicenter, randomized, double-blind, placebo-controlled study, including patients with active GCA, either new onset or relapsing (NCT03725202). The recruitment has been completed, however, the study is still ongoing and results have not yet been published.

## 4. Discussion

We performed a systematic review of trials to describe and analyze the full pipeline of corticosteroid-sparing agents evaluated in PMR and GCA. Our search identified a total of 505 trials (209 in PMR and 276 in GCA) ultimately yielding a total of 23 DMARDs: 3 csDMARDs, 16 bDMARDs and 3 tsDMARDs. By comparison, we identified a total of 4652 trials and 243 molecules for rheumatoid arthritis [7] and 3574 trials of 63 DMARDs for spondyloarthritis [8] in our previous studies using the same methodology.

Of note, the majority of molecules in current development in PMR and GCA are coming from drug repurposing from other conditions [45]. Clinical research into these 2 diseases therefore seems to be driven by the potential to repurpose existing treatments rather than by fundamental or translational research. Only 2 treatments were specifically developed for PMR and GCA, ABBV-154 and mavrilumab respectively. The concept behind ABBV-154 was to target the corticosteroid receptor at sites of inflammation by binding to TNF. However, the trial was prematurely terminated (business decision). Mavrilumab, an anti GM-CSF receptor, was based on histological findings as GM-CSF transcripts were detected in temporal arteries from patients with GCA, GM-CSF protein has been shown to be produced and secreted by peripheral blood mononuclear cells from patients with active GCA [46], detected in GCA-involved temporal arteries by immunohistochemistry [47], and expression of GM-CSF and its receptor was demonstrated in GCA lesions [48]. Nevertheless, despite interesting results in phase II, its development is currently withdrawn by the pharmaceutical company mainly due to market considerations, as it was unable to demonstrate sufficient efficacy in rheumatoid arthritis.

Currently, very few corticosteroid-sparing treatments are marketed or recommended by medical societies in GCA or PMR. Methotrexate is used off-label in GCA (lowering the risk of relapses) as reported in an individual patient data meta-analysis of 3 randomized placebo-controlled trials in patients with newly diagnosed GCA [49]. Its role in PMR is more controversial and still under evaluation, but it is recommended in recent French guidelines as an alternative to IL6R inhibitors in corticosteroid-dependent PMR [50]. With regard to biologics, only IL-6 receptor inhibitors have obtained marketing authorization: tocilizumab in GCA (EMA and FDA market authorizations) and sarilumab in

PMR (FDA market authorization only). For patients with newly diagnosed GCA, the American College of Rheumatology/Vasculitis Foundation recommends the use of tocilizumab with oral corticosteroids over oral corticosteroids alone [51]. For EULAR, the first-line treatment remains corticosteroid therapy alone, starting at 40 to 60 mg per day (prednisone equivalent). In the event of relapse, the initiation of sparing therapy is recommended, with tocilizumab as first-line therapy rather than methotrexate [52]. The use of tocilizumab in PMR is still off-label, but it is recommended [50], after a collegial discussion, due to its positive results as a corticosteroid-sparing therapy in the SEMAPHORE [19] or TENOR [16] studies. No other treatment has marketing authorization for PMR or GCA, but this should change rapidly in the coming years, given the promising results and phase III trials currently underway.

Among the most advanced and promising compounds is secukinumab which is currently evaluated in phase III trials both in GCA and PMR. There is robust evidence for the involvement of the IL-17 pathway in the pathogenesis of GCA such as Th17 cell populations expansion in active GCA and abundant IL-17-producing cells in temporal artery specimens [53]. The first case report of the use of secukinumab in GCA [54] (already approved for psoriasis and spondyloarthritis), followed by the promising phase II results of the TiTAIN study, point to the possibility of marketing authorization in the coming years. Its position in the therapeutic strategy and in relation to tocilizumab should then be assessed and clarified.

JAK inhibitors also appear to be promising treatments. Cytokine signaling dependent on JAK3 and JAK1 have been showed to be important in GCA [55]. Transcriptomic analysis in inflamed aortas from GCA patients compared to non-inflammatory control aorta showed enrichment for JAK/STAT signaling pathway [56]. Of note, IL-6, type I IFNs, and GM-CSF are well known to be involved in the pathogenesis of GCA, all of which use the JAK-STAT pathway, making it likely that JAK inhibitors should be effective in this indication [57]. Regarding PMR, a future in which patients could be treated without glucocorticoids is getting closer as this type of management has been explored, with baricitinib (NCT04027101) and tofacitinib [25]. However, they will need to demonstrate a favorable safety profile in elderly patients at higher cardiovascular risk, given the recent warning about their use in these at-risk populations in rheumatoid arthritis.

While the majority of patients respond to initial corticosteroid therapy, the purpose of finding new treatments for GCA and PMR is essentially corticosteroid-sparing, or even discontinuing corticosteroids. These strategies will then need to be evaluated on a medico-economic basis so that the authorities can approve these costly treatments. We will also probably need biomarkers that will enable us to choose between blocking IL-6, IL-17 or the JAK-STAT pathway in a given patient.

This study has some limitations as it relies on development pipeline updates, which are time-dependent. In addition, it depends on updates provided by manufacturers, leading to potential changes in the status and progress of clinical trials. Nevertheless, the process of bringing a molecule to market is a long one, which makes it possible to anticipate potential molecules in phases I and II over the coming years. The main strength of this study lies in the systematic review of all clinical trials in 17 international databases, as well as the in-depth analysis and summary of the data available for each investigational agent.

## 5. Conclusions

This systematic review identified 22 DMARDs evaluated for PMR and GCA. Of those, 3 are csDMARDs, 17 are bDMARDs and 3 are tsDMARDs. Currently, there are only 2 approved corticosteroid-sparing therapies in these diseases, which both target IL-6 signaling pathway, namely tocilizumab in GCA and sarilumab in PMR. Ongoing studies will soon enable us to refine the positioning of methotrexate in these two diseases, while several promising treatments are likely to be marketed in the coming years.
## Funding

No funding source.

## Ethical approval information

Not applicable.

## Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting, or dissemination plans of this study.

## Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Renaud FELTEN reports a relationship with AbbVie France that includes: board membership, consulting or advisory, and non-financial support. Renaud FELTEN reports a relationship with Amgen SAS that includes: speaking and lecture fees. Renaud FELTEN reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and speaking and lecture fees. Renaud FELTEN reports a relationship with Celltrion, Inc. that includes: consulting or advisory. Renaud FELTEN reports a relationship with Fresenius Kabi France LLC that includes: consulting or advisory. Renaud FELTEN reports a relationship with Galapagos that includes: consulting or advisory. Renaud FELTEN reports a relationship with GSK that includes: consulting or advisory. Renaud FELTEN reports a relationship with Janssen-Cilag SAS that includes: consulting or advisory, non-financial support, speaking and lecture fees, and travel reimbursement. Renaud FELTEN reports a relationship with Eli Lilly and Company that includes: speaking and lecture fees and travel reimbursement. Renaud FELTEN reports a relationship with MEDAC that includes: speaking and lecture fees and travel reimbursement. Renaud FELTEN reports a relationship with MSD France SAS that includes: travel reimbursement. Renaud FELTEN reports a relationship with Nordic Group that includes: travel reimbursement. Renaud FELTEN reports a relationship with Novartis Pharma SAS that includes: board membership, consulting or advisory, employment, speaking and lecture fees, and travel reimbursement. Renaud FELTEN reports a relationship with Pfizer France that includes: speaking and lecture fees. Renaud FELTEN reports a relationship with Sanofi-Aventis France SA that includes: non-financial support and travel reimbursement. Renaud FELTEN reports a relationship with UCB Inc. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Laurent ARNAUD reports a relationship with AstraZeneca that includes: consulting or advisory. Laurent ARNAUD reports a relationship with AbbVie Inc. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Alpine Institute for Drug Discovery SA that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Biogen that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Boehringer Ingelheim Ltd. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Chugai Pharmaceutical Co Ltd. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with GSK that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Grifols Inc. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Janssen Pharmaceuticals Inc. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Kezar Life Sciences Inc. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with LFB Biopharmaceuticals Ltd. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Eli Lilly and Company that includes: consulting or advisory. Laurent ARNAUD reports a relationship with MEDAC that includes: consulting or advisory. Laurent ARNAUD

reports a relationship with Merck & Co Inc. that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Novartis that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Pfizer that includes: consulting or advisory. Laurent ARNAUD reports a relationship with Roche that includes: consulting or advisory. Laurent ARNAUD reports a relationship with UCB that includes: consulting or advisory. Guillermo CARVAJAL ALEGRIA reports a relationship with AbbVie France that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with Biogen that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with BMS that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with Chugai that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with Fresenius-Kabi that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with Galapagos that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with Lilly that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with MSD that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with Novartis that includes: speaking and lecture fees. Guillermo CARVAJAL ALEGRIA reports a relationship with Pfizer that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

## Acknowledgements

None.

## Appendix A. Supplementary data: PRISMA 2020 checklist

Supplementary data to this article can be found online at https://doi.org/10.1016/j.autrev.2024.103590.

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