Giant Cell Arteritis and Polymyalgia Rheumatica

Giant Cell Arteritis and
Polymyalgia Rheumatica
Treatment Approaches and New Targets
Desh Nepal, MDa,*, Michael Putman, a

MD, MS ,
Sebastian Unizony, MDb
KEYWORDS
Giant cell arteritis Polymyalgia rheumatica Tocilizumab Glucocorticoids
Mavrilimumab Secukinumab Abatacept Guselkumab
KEY POINTS
Treatment with tocilizumab has substantially reduced glucocorticoid toxicity for patients
with giant cell arteritis (GCA) and has become the standard of care.
Many patients with GCA still relapse despite this approach, and additional therapies are
being studied, including mavrilimumab, secukinumab, guselkumab, abatacept, and
upadacitinib.
Fewer options have been studied for patients with polymyalgia rheumatica, but trials of
tocilizumab, sarilumab, and rituximab have recently been completed or are underway.
INTRODUCTION
Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are systemic inflamma-
tory conditions that affect people aged 50 years and older.1 GCA is a granulomatous
large-vessel vasculitis involving the aorta and its major branches.2 It often presents
with constitutional symptoms (fever, fatigue, weight loss), jaw pain upon mastication
(ie, jaw claudication), new-onset headache,3 scalp tenderness, and visual symptoms
(eg, diplopia, amaurosis fugax, and transient blurred vision).4 Permanent vision loss,
most commonly due to anterior ischemic optic neuropathy (AION), is the most feared
complication and occurs in 15% to 20% of patients.4 Approximately half of the pa-
tients with GCA report PMR symptoms defined as pain and stiffness involving the
shoulder and hip girdles that develop after periods of immobilization (eg, early morn-
ing) and improve with activities. PMR can also be seen in the absence of other GCA
a
Department of Medicine, Division of Rheumatology, Hub for Collaborative Medicine, Medical
College of Wisconsin, 8701 Watertown Plank Road, Rheumatology, 6th Floor, Milwaukee, WI
53226, USA; b Massachusetts General Hospital, Vasculitis and Glomerulonephritis Center, Har-
vard Medical School, 55 Fruit Street, Yawkey 4B, Boston, MA 02114, USA
* Corresponding author.
E-mail address: [email protected]
Rheum Dis Clin N Am 49 (2023) 505–521

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506 Nepal et al
manifestations in a condition called primary PMR, which is 3 times more frequent

than GCA.3–7
The vascular inflammation in GCA is predominantly composed of CD41 T cells and
macrophages. The classic pathology finding of multinucleated giant cells can also be
seen in roughly half of temporal artery biopsy specimens and likely reflect the highly
inflammatory nature of the vascular infiltrate.8 Studies suggest that the inflammatory
process is driven by T helper (Th)17 and Th1 CD41 cells and that regulatory T cells
demonstrate an inflammatory phenotype and have an impaired suppressive func-
tion.9–14 Substantial progress has been made in the treatment of patients affected
by GCA, but many individuals receiving standard of care treatment continue to
demonstrate residual arterial inflammation, have vascular imaging changes raising
the concern for possible ongoing disease activity (vs vascular wall remodeling), and
develop clinical relapses.13,15
In this review, we elaborate on the established and novel treatment approaches for
GCA and PMR and discuss future therapeutic perspectives for these disorders.
CURRENT TREATMENT APPROACHES FOR GIANT CELL ARTERITIS AND

POLYMYALGIA RHEUMATICA
Glucocorticoids for Giant Cell Arteritis
Glucocorticoids (eg, prednisone) have been the mainstay of treatment for GCA for de-
cades and continue to be required upfront to establish disease control (ie, induction of
remission) and prevent irreversible sight loss. Glucocorticoids affect both the innate
and the adaptive immune systems, which include suppression of Th17 cells and mac-
rophages. However, reports suggest that these agents may incompletely suppress the
Th1 pathway,16 which could explain the high relapse rate of GCA patients receiving
glucocorticoid monotherapy.17–19
High-quality evidence to inform recommendations for glucocorticoid administration
and initial dosing is not available, but observational studies have described better vi-
sual outcomes with the early use of glucocorticoids.20–22 Based on lower-quality ev-
idence and consensus of expert opinions, the 2021 American College of
Rheumatology (ACR)/Vasculitis Foundation (VF)23 and the 2018 European Alliance
of Associations for Rheumatology (EULAR)24 GCA guidelines recommend high-dose
oral glucocorticoids when GCA is diagnosed or suspected. While the ACR/VF recom-
mends an initial dose of 1 mg/kg/d (up to 80 mg) of prednisone or equivalent, EULAR
recommends a dose of 40 to 60 mg/d.24
The efficacy of intravenous (IV) pulse glucocorticoids for the treatment or prevention
of visual ischemia has not been formally tested in randomized controlled trials (RCTs),
and low-quality evidence has shown conflicting results regarding the value of initial
treatment with IV pulse glucocorticoids versus oral glucocorticoids in terms of visual
recovery in GCA patients presenting with visual impairment. That said, given the cata-
strophic consequences of ocular ischemia in GCA, both ACR/VF and EULAR recom-
mend IV pulse glucocorticoids for those patients with threatened (eg, amaurosis fugax
and episodic blurred vision) or new-onset vision loss (ACR/VF: methylprednisolone
0.5–1 g for 3–5 days; EULAR: methylprednisolone 0.25–1 g for up to 3 days).
The duration of the glucocorticoid therapy in GCA can be variable depending on the
occurrence of relapse, the presence of comorbidities, and whether a glucocorticoid-
sparing medication is concomitantly used. In the absence of relapse, glucocorticoids
are generally tapered within 12 to 24 months when they are used in monotherapy and
approximately within 6 months when they are administered in combination with a
glucocorticoid-sparing medication. When used in monotherapy, approximately 65%
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Treatment Approaches and New Targets 507
of the patients relapse when relapse is defined as the reoccurrence of characteristic

GCA clinical manifestations regardless of the level of inflammatory markers.17 Re-
lapses mostly occur when the daily doses of prednisone fall below 10 mg.25 A phase
3 open-label RCT to directly compare a 28-week versus a 52-week prednisone taper
(CORTODOSE) is underway (ClinicalTrials.gov identifier: NCT04012905).
Glucocorticoids for Polymyalgia Rheumatica

Similar to GCA, no high-quality evidence exists to guide the glucocorticoid therapy for
patients with primary PMR. A systematic review of studies comparing various predni-
sone starting doses concluded that the dose of 15 mg/d is effective in the great ma-
jority of the cases, with less than 1% of patients requiring an increase of the initial dose
to control the PMR symptoms.26 Similar rates of remission were observed among pa-
tients randomized to receive oral prednisone at 15 mg/d versus intramuscular (IM)
methylprednisolone given at a dose of 120 mg every 3 weeks for 12 weeks27 although
the use of IM methylprednisolone has not been widely adopted in cases of PMR. In a
more recent open-label study, 78% of patients starting prednisone 12.5 mg/d reported
symptomatic improvement.28 Current expert recommendations propose an initial
daily dose between 12.5 mg and 25 mg of prednisone or equivalent.3,29 The optimal
duration of glucocorticoid taper in PMR has not been well defined, but experts recom-
mend slow dose reductions over 12 to 18 months. A common practice is to taper the
initial dose by 2.5 mg every 2 to 4 weeks until the dose of 10 mg daily is reached and
then further decrease the daily dose by 1 mg every 2 to 4 weeks until discontinuation.
Slower tapers have been proposed by some authors.26 Regardless of the specific
glucocorticoid reduction strategy, over half of patients with primary PMR may ulti-
mately require glucocorticoid therapy for 2 years or more,26 and over 50% of them
relapse at some point during the prednisone taper.30
Glucocorticoid Toxicity
The toxicity burden of glucocorticoid exposure, especially among patients with GCA,
can be high. Observational studies have observed mean cumulative doses of nearly
10 g.31 Substantial morbidity is associated with such glucocorticoid exposure, which
is compounded by the older age and comorbidities of patients with GCA. Short-term
side effects can include anxiety, sleeplessness, infection, and hyperglycemia. Longer-
term side effects can be devastating and include diabetes, hypertension, cardiovas-
cular disease, osteoporosis, fractures, and cataracts. The rate of these adverse events
is as high as 86% in patients with GCA, including fractures (38%), infections (31%),
hypertension (22%), diabetes (9%), and cataract formation (41%).31
Accurately defining glucocorticoid toxicity as an outcome measure has historically
been difficult.32 Recently a validated measure of glucocorticoid toxicity, the Glucocor-
ticoid Toxicity Index (GTI), has been developed.33 The GTI has two components, the
composite GTI and specific list. The composite GTI measures potential glucocorticoid
toxicity in nine domains (body mass Index, glucose tolerance, blood pressure, lipids,
bone density, steroid myopathy, skin toxicity, neuropsychiatric toxicity, infections),
which when measured at study initiation and at 3-month intervals can be used to
calculate a total score and a domain-specific score.33 Important and often severe
glucocorticoid-related toxicities (eg, hypertensive emergency, severe steroid-
induced myopathy, severe skin toxicity, bowel perforation, adrenal insufficiency,
etc.) that are not scored as a part of the composite GTI are included in a specific
list, which assesses eleven domains and 23 individual items. It is hoped that the use
of the GTI will improve reporting of glucocorticoid toxicity in clinical trials and provide
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508 Nepal et al
clinicians with a more effective means to balance the risks and benefits of glucocor-
ticoid therapy.
Interleukin-6 Blockade Therapy

Tocilizumab for giant cell arteritis
Substantial progress in reducing glucocorticoid exposure has been made in the last
decade, during which interleukin (IL)-6 receptor blockade therapy with tocilizumab
has become the standard of care for most patients with GCA in developed countries.
The clinical utility of IL-6 inhibition for GCA was confirmed in a phase 3 RCT known as
Giant Cell Arteritis Actemra trial (GiACTA).34 In GiACTA, 251 patients were randomized
into groups that received tocilizumab (weekly or every other week) plus a 26-week
prednisone taper or a prednisone taper over 26 or 52 weeks in combination with pla-
cebo. The trial met its primary outcome measure, which was the rate of sustained
glucocorticoid-free remission at week 52. Patients were significantly more likely to
be in remission if randomized to tocilizumab (53%–56%) than to placebo (14%–
18%). The study also showed that tocilizumab was overall well tolerated, led to
reduced cumulative prednisone exposure, and improved health-related quality-of-
life measures.35 Considering these data, the US Food and Drug Administration
(FDA) and the European Medicines Agency approved its use in GCA. The ACR/VF
guidelines23 recommend tocilizumab for all patients with newly diagnosed disease
and for most patients with disease relapse, while the EULAR guidelines24 recommend
tocilizumab for patients with relapse or patients with new-onset disease if there is
occurrence or increased risk of glucocorticoid-related adverse events.
Despite the progress made with the introduction of tocilizumab for the treatment of
GCA, multiple important management questions remain unanswered. First, the
optimal duration of treatment with tocilizumab has not been defined, and long-term
outcome data after treatment discontinuation are scarce.36 Second, the effects of
tocilizumab on vascular inflammation and risk of long-term arterial complications
(eg, aortic thoracic aneurysm) are largely unknown.37 This gap in the current knowl-
edge is especially important given that similar to glucocorticoids, IL-6 signaling
blockade may preferentially target the Th17 pathway,10 possibly leaving residual
Th1 immune response activity that could manifest in the long term as slowly progres-
sive structural arterial damage. Third, very few patients in the GiACTA studies experi-
enced vision loss, which is likely due to selection bias from the patients enrolled into
the trial. Therefore, the efficacy of tocilizumab in patients with ocular ischemia is un-
clear. Uncontrolled observational studies, however, have reported low rates of vision
loss.38 Finally, and perhaps most importantly, roughly 30% of patients fail treatment
with tocilizumab due to refractory disease or disease relapse, and 5% to 10% of sub-
jects must discontinue therapy due to adverse events.34,38,39 Thus, even though IL-6
inhibition represents a substantial advancement in the treatment of GCA, more treat-
ment options are needed.
IL-6 blockade therapy for polymyalgia rheumatica

A phase 2/3 RCT demonstrated efficacy of tocilizumab for primary PMR. In this study,
36 subjects were randomized to receive 11 weeks of prednisone in combination with
tocilizumab or placebo. The patients assigned to tocilizumab demonstrated better
remission rates at 16 weeks (63% vs 12% placebo; P < .05) and 24 weeks (58% vs
18% placebo; P < .05) and required less prednisone than the patients assigned to pla-
cebo.40 A phase 3 study (SAPHYR, ClinicalTrials.gov identifier: NCT03600818)
compared sarilumab, a fully human anti-IL-6 receptor monoclonal antibody, plus
14 weeks of glucocorticoids with placebo plus 52 weeks of glucocorticoids. The study
reservados.
terminated early for reasons not related to efficacy or safety. Nevertheless, the anal-
ysis of the patients that completed treatment showed that patients randomized to sar-
ilumab had better rates of sustained remission at 52 weeks (28% vs 10% placebo;
P 5 .02), lower rate of relapse (17% vs 29%; P 5 .02), and improved health-related
quality of life.41 Based on the results of this study, the FDA recently approved sarilu-
mab for the treatment of adult patients with polymyalgia rheumatica who have had an
inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.
Methotrexate
Methotrexate for Giant Cell Arteritis
The evidence supporting the use of methotrexate for GCA is conflicting. One single-
center RCT of methotrexate (10 mg weekly) versus placebo42 in combination with gluco-
corticoids observed a benefit with regard to relapse. Patients in the methotrexate arm
received a lower cumulative dose of prednisone (4187 1529 mg) than those in the pla-
cebo arm (5489.5 1396 mg). Two other RCTs,43,44 however, observed no significant
improvements in relapse rate or cumulative prednisone dose. A meta-analysis of the
three RCTs including 161 patients suggests that methotrexate may offer modest benefits
in terms of remission maintenance and glucocorticoid-sparing with a number needed to
treat to prevent a first and second relapse of 3.6 and 4.7 patients, respectively.45 Notably,
the methotrexate dose in these trials (7.5 m to 15 mg weekly) was lower than that typically
used in rheumatoid arthritis, which could have limited the efficacy of this agent. Despite
the mixed results, ACR/VF and EULAR both recommend the use of the methotrexate as
an alternative to tocilizumab for those in need for glucocorticoid-sparing agents who
have contraindication, intolerance, or limited access to tocilizumab.23,24 A phase 3
head-to-head RCT comparing methotrexate to tocilizumab for patients with GCA is
currently underway (METOGiA, ClinicalTrials.gov identifier: NCT03892785).
Methotrexate for Polymyalgia Rheumatica
Studies with varying designs (eg, different methotrexate dosing, treatment duration,
and prednisone tapers) have evaluated the efficacy and safety of methotrexate for
PMR with mixed results.46–49 In two RCTs of methotrexate dosed at 10 mg weekly,
higher rates of remission and decreased cumulative prednisone dose were
observed.46,48 Other studies found no benefit from adding methotrexate to conven-
tional glucocorticoid regimens.47,49 Practice guidelines conditionally recommend
methotrexate for those patients who relapse or develop glucocorticoid-related
adverse events or are at a high risk of glucocorticoid toxicity.3,29
NEW TARGETS FOR GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA
Even within these successful trials, relapses occurred in over 40% of patients, a figure
that has been corroborated by recent meta-analyses.50 Major relapses, defined by
clinical features of ischemia or active aortic inflammation, occurred less frequently
but still affected 1 in 30 patients with GCA.51 Hence, there is a need for additional
disease-modifying agents with glucocorticoid sparing effects for these patient popu-
lations. Following significant advances in the knowledge of the pathophysiology of
GCA and PMR, numerous newer agents are under investigation and discussed below.
CD41 T-Cell Costimulation Blockade
Abatacept is a fusion protein composed of the Fc region of the immunoglobulin IgG1
and the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-
4). The CTLA-4 domain binds to CD80 and CD86 expressed on dendritic cells and
blocks the interaction between these costimulatory molecules and CD28 expressed
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510 Nepal et al
by CD41 T cells, an important step in the activation of autoreactive lymphocytes

(Fig. 1). Abatacept was studied in a phase 2 treatment-withdrawal RCT.52 In this study,
41 GCA patients in remission after receiving 4 doses of IV abatacept (10 mg/kg on days
1, 15, 29, and week 8) and a prednisone taper from 40 to 60 mg/d to 20 mg/d were ran-
domized to receive monthly abatacept infusions or a placebo along with the continua-
tion of the prednisone taper completed by week 28. Compared to placebo, patients
receiving abatacept had a lower rate of relapse-free survival at 12 months (48% vs
31%, P 5 .049) and a longer median time of remission duration (9.9 months vs
3.9 months, P 5 .023). Abatacept was relatively well tolerated. In light of these findings,
the ACR/VF recommends the use of abatacept as an alternative agent when tocilizumab
would be indicated but cannot be used or is not effective.23 EULAR noted the data at the
moment are limited, precluding a specific recommendation.24 Studies comparing aba-
tacept and tocilizumab have been limited but include a prospective study involving 33
GCA patients,53 which observed a better clinical response among those who received
tocilizumab (100% vs 62%). Additional data are necessary, but no such head-to-head
RCTs are currently registered. Abatacept is also currently being evaluated for use in
PMR (ClinicalTrials.gov identifier: NCT03632187).
IL-12/IL-23 Signaling Inhibition

Ustekinumab is a human IgG1 kappa monoclonal antibody against the shared P40
subunit of IL-12 and IL-23 (see Fig. 1). These cytokines are secreted by dendritic cells
and participate in the differentiation of Th1 (IL-12) and Th17 (IL-23) CD41 cells. Two
prospective, open-label, uncontrolled studies with different study designs evaluated
ustekinumab in GCA and had mixed results.54,55 One of these studies evaluated uste-
kinumab in refractory GCA patients who had relapsed while tapering glucocorti-
coids.54 With ustekinumab, the median dose of prednisolone decreased to 5 mg at
week 52 from 15 mg at baseline. No disease relapses were reported while patients
were on ustekinumab. However, 75% of the patients were still receiving glucocorti-
coids by the time the efficacy outcomes were evaluated at week 52.54 In contrast, a
second study involving 13 new-onset or relapsing GCA patients was stopped prema-
turely after 7 of the initial 10 patients enrolled relapsed.55 The mean time to relapse
was 23 weeks, and the mean daily prednisone dose at relapse was 3 mg. Unlike in
the prior ustekinumab study, in the second study, all patients followed a rigorous pred-
nisone taper regimen aiming for prednisone discontinuation at 6 months. Therefore, it
is possible that the better response seen in the first ustekinumab study54 was due to
the effects of glucocorticoids instead of ustekinumab. Adequately powered RCTs are
necessary to properly evaluate the efficacy of ustekinumab in GCA. A phase 2 RCT of
ustekinumab versus placebo is currently underway, but additional phase 3 studies
may be needed (ClinicalTrials.gov identifier: NCT03711448). No studies to date
have evaluated the role of IL-12/IL-23 inhibitors in PMR.
IL-17 Signaling Inhibition

Secukinumab is a fully human IgG1 kappa monoclonal antibody that selectively in-
hibits IL-17A (see Fig. 1). IL-17 A produced by Th17 CD41 cells and CD81 T cells
acts on macrophages, endothelial cells, and vascular smooth muscle cells, leading
to inflammation, vascular injury, and remodeling. IL-17 inhibition may offer a
steroid-sparing opportunity as glucocorticoids primarily act on the Th17 pathway in
GCA. A phase 2 study evaluated secukinumab in 52 new or relapsing GCA patients
(TitAIN trial; ClinicalTrials.gov identifier: NCT03765788). Participants were randomized
to receive secukinumab (300 mg weekly for 4 weeks, then every 4 weeks) or pla-
cebo.56 All patients received a 26-week prednisone taper. Results showed that the
reservados.
Fig. 1. GCA immuno-pathophysiology and sites of interventions of approved and investiga-

tional targeted biologic therapy. DC in the adventitia layer activated by unknown triggers
secrete chemokines and cytokines that recruit and activate CD41 T cells toward the Th1
or Th17 pathway. IL-12 and IL-18 lead to the Th1 pathway, and IL-23, IL-1b, IL-6, and IL-21
transform and maintain CD41 T cells toward the Th17 pathway. In the next stage, chemo-
kines and cytokines (IFN-g, IL-1b, IL-6, IL-21) from Th1 cells help recruit monocytes and
CD81 T cells. These in turn activate VSMCs. VSMC and CD81 T cells help amplify the mono-
cytic recruitment and inflammation in GCA. Monocytes then transform into macrophages
and merge to form multinucleated giant cells. IL-6, IL-1b, and TNF-a released by macro-
phages lead to the local inflammation and the systemic constitutional symptoms of GCA.
In the final stage of the GCA pathogenesis, vascular injury and remodeling occur. VSMC pro-
duces MMP-2 and undergoes apoptosis. Macrophages and giant cells (in the media) produce
additional mediators (ROS, NO, MMP-9) of vascular injury. In addition, macrophages and
injured VSMC produce VEGF, PDGF that facilitates neoangiogenesis (in media and intima)
and vascular remodeling, a process that includes myofibroblast differentiation of VSMC.
These myofibroblasts then migrate to the intima and lead to intimal hyperplasia. The
Th17 pathway (maintained by IL-23) secretes IL-17, which acts on cells including macro-
phages, endothelial cells, and VSMC, thus playing a vital role in further vascular remodeling
and intimal proliferation of GCA. Additionally, GM-CSF plays a vital role in multiple crucial
steps of GCA including DC activation, monocytic recruitment, and activation. Finally, various
cells and cytokines implicated in the GCA pathogenesis use JAK-STAT signaling. DC, dendritic
cells; GCA, giant cell arteritis; GM-CSF, granulocyte-macrophage colony-stimulating factor;
IFN, interferon; IL, interleukin; JAK-STAT, Janus kinase–signal transduction and activator
of transcription; MMP, metalloproteinase; NO, nitric oxide; PDGF, platelet-derived growth
factor; ROS, reactive oxygen species; Th, T helper cells; VEGF, vascular endothelial growth
factor; VSMC, vascular smooth muscle cells. (Created with BioRender.com.)
secukinumab treatment group had higher sustained remission rates at 28 weeks

(70.1% vs 20.3%) and 52 weeks (59.3% vs 8.0%).57 A phase 3 RCT is currently
ongoing (ClinicalTrials.gov identifier: NCT04930094). No studies to date have evalu-
ated the role of IL-17 inhibitors in PMR.
reservados.
512 Nepal et al
Granulocyte-Macrophage Colony-Stimulating Factor Signaling Inhibition

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a multifunctional cyto-
kine that modulates the biology of dendritic cells, CD41 T cells, and macrophages,58 is
implicated in the pathogenesis of GCA. GM-CSF, its receptor, and downstream
signaling molecules are expressed by immune and endothelial cells in temporal ar-
teries from patients, and GM-CSF receptor blockade in cultured arterial biopsies leads
to decreased expression of dendritic cell, CD41 T cell, and macrophage markers
along with downregulation in transcription of Th1- and Th17-related genes (eg, inter-
feron [IFN]-g and IL-6).59 Furthermore, GM-CSF seems to be crucial for macrophage-
induced tissue destruction and remodeling,60,61 and the blockade of this pathway in
animal models was associated with reduced arterial inflammation, neovascularization,
and intimal hyperplasia.62
Mavrilimumab is a fully human immunoglobulin G4 monoclonal antibody that inhibits
GM-CSF activity by binding to its receptor alpha subunit. A recent phase 2 RCT was
successful in demonstrating the efficacy of blocking GM-CSF for maintaining disease
remission in GCA. In this study, 42 patients were randomized (3:2) to receive either
mavrilimumab 150 mg or placebo. Both groups received a 26-week prednisone taper.
Mavrilimumab was associated with longer time to relapse (hazard ratio 0.38, 95% con-
fidence interval 0.15–0.92), and significantly more patients receiving this agent were in
remission by week 26 (83% vs 50% for placebo, P 5 .004).63 No studies to date have
evaluated the role of GM-CSF in PMR.
Janus Kinase Signaling Inhibition

Various immune cells (eg, dendritic cells, CD41 T cells) implicated in the pathogenesis
of GCA respond to cytokines (eg, IL-2, IL-6, IL-12, IL-21, IL-22, IL-23, IFN-g, GM-CSF)
that signal through the Janus kinase–signal transduction and activator of transcription
(JAK-STAT) pathway.64 JAK inhibitors (JAKi) affect JAK-STAT signaling, potentially
impacting the Th1 (IL-12, IFN-g, GM-CSF) and Th17 pathways (IL-23, IL-6, GM-
CSF) and dendritic cell activity (GM-CSF). Theoretically this strategy may overcome
the limitations of other treatments, where vascular inflammation mediated by addi-
tional cytokines may go unchecked. Currently, baricitinib and upadacitinib are being
studied in GCA. Baricitinib, which inhibits JAK1/JAK2, was investigated in an uncon-
trolled, open-label pilot study involving 15 relapsing GCA patients.65 Patients received
baricitinib (4 mg/d) and a glucocorticoid taper over 15 to 22 weeks. Overall, 13 patients
were able to discontinue glucocorticoids and remained in clinical remission through
week 52. These findings require confirmation in an RCT. Upadacitinib, which more
selectively inhibits JAK1, is currently being studied in a phase 3 RCT (SELECT-
GCA; ClinicalTrials.gov identifier: NCT03725202). The role of JAKi in PMR is currently
being assessed in phase 2 studies using baricitinib (ClinicalTrials.gov identifier:
NCT04027101) and tofacitinib (selective for JAK1/JAK3) (ClinicalTrials.gov identifier:
NCT04799262).
It should be noted that ongoing and future studies of JAKi will require careful safety
assessments in view of the recently published oral surveillance study. This large ran-
domized FDA-mandated safety study of the JAKi tofacitinib identified an increased
incidence of cardiovascular events and malignancy among patients with rheumatoid
arthritis older than 50 years and with at least 1 cardiovascular risk factor.66
B-Cell-Depleting Therapies
Decreased number of circulating B cells has been noted in GCA and PMR,67 and dys-
regulation of B-cell function has been observed in GCA.68 Although B cells can
reservados.
modulate CD41 T-cell responses via the production of IL-6,69 a clear role for B cells in
the pathogenesis of GCA and PMR has not been established. In fact, biopsies of GCA
patients do not exhibit significant amounts of B-cell infiltrates. That said, rituximab, an
anti-CD20 B-cell-depleting monoclonal antibody, was tested in PMR.70 In this RCT
(BRIDGE-PMR), a single infusion of 1000 mg of rituximab was compared to placebo
on a background of 17 weeks of glucocorticoids. Patients receiving rituximab had a
higher rate of glucocorticoid-free remission at 21 weeks than those receiving placebo
(48% vs 21%; P 5 0.049). Further studies to clarify the role of rituximab in GCA and
PMR are needed.
IL-23 Signaling Inhibition
Guselkumab is a monoclonal antibody that selectively inhibits IL-23 by binding to its P19
subunit (see Fig. 1). IL-23 is secreted by dendritic cells and promotes Th17 CD41 cell
differentiation and survival.64 A phase 2 RTC is currently underway to assess the safety
and efficacy of IL-23 inhibition with guselkumab in GCA (ClinicalTrials.gov identifier:
NCT04633447). No studies to date have evaluated the role of IL-23 inhibitors in PMR.
IL-1b Signaling Inhibition
Anakinra is a recombinant IL-1 receptor antagonist (IL-1ra). IL-1b is produced by mac-
rophages and leads to inflammation by binding to IL-1 receptors. IL-1b is believed to
contribute to GCA’s systemic symptoms and stimulate the production of other cyto-
kines, including IL-6 and TNF-a. Along with other cytokines (eg, IL-6 and IL-23), IL-
1b may help maintain the Th-17 pathway.64 Anakinra is currently under investigation
in a phase 3 RCT in GCA (ClinicalTrials.gov identifier: NCT02902731). No studies to
date have evaluated the role of IL-1ra in PMR.
Endothelin-1 Signaling Inhibition
Endothelin-1, a potent vasoconstrictor, may be implicated in the vascular remodeling
occurring in GCA.71 In GCA patients, tissue endothelin-1 levels do not decrease early
on despite the use of glucocorticoids.72 Bosentan, an endothelin-1 receptor antago-
nist, inhibits the action of endothelin-1 and might help prevent vision loss. The role
of bosentan in preventing blindness is currently being studied in a phase 3 RCT for
GCA (ClinicalTrials.gov identifier: NCT03841734).
Fig. 1 summarizes the pathogenesis of GCA including established and speculated
therapeutic targets. Table 1 summarizes prior and ongoing pharmacologic studies
including drug mechanism of action.
Glucocorticoid Tapers Lasting Less than 6 Months
In the wake of the GiACTA study, current and planned phase 3 clinical trials in GCA
typically evaluate patients against a background of a 26-week steroid taper. While
this represents a substantial reduction in glucocorticoid exposure as compared to pre-
vious tapering regimens, glucocorticoid-related adverse events may still occur, and
additional lowering would be of benefit. The uncontrolled, open-label, proof-of-
concept GUSTO (GCA treatment with ultra-short glucocorticoids and tocilizumab)
study evaluated an ultra-short glucocorticoid regimen in combination with tocilizumab
for new-onset GCA patients.73 In this study, 18 patients received 500 mg of IV meth-
ylprednisolone for 3 days and 1 dose of IV tocilizumab (8 mg/kg body weight) followed
by weekly subcutaneous tocilizumab injections (162 mg) until week 52. No additional
glucocorticoids were provided unless patients experienced a relapse. The primary
outcome of remission achieved by day 31 and maintained through week 24 was
achieved only by 25% of the patients. In contrast, the secondary outcome of
reservados.
514
Nepal et al
Table 1
Therapeutic targets in GCA based on pathogenesis
Pathogenic Mechanism Targeted or Potentially

Agent Targeted Stage of Development

Methotrexate Several cell types are involved in the Phase 242–44
pathogenesis of GCA including CD41 T cells,
CD81 T cells, and macrophages. Methotrexate
is a nontargeted immunosuppressant that
inhibits AICAR formyl transferase that
ultimately leads to increase in adenosine.
Increased adenosine in turn leads to increased
intracellular cAMP that causes
immunosuppression.75
Abatacept Abatacept interferes with the costimulation Phase 2 (completed)52
reservados.
provided by DCs to CD41 T cells, which

prevents CD41 T-cell activation.
Guselkumab IL-23 is involved in the differentiation of CD41 Phase 2 (ongoing) (ClinicalTrials.gov identifier:
T cells toward the Th17 phenotype. NCT04633447)
Guselkumab inhibits the signaling of IL-23.
Secukinumab IL-17 acts on macrophages, endothelial cells, and Phase 2 (completed)
VSMC causing vascular injury and remodeling (TitAIN) trial (ClinicalTrials.gov identifier:
by affecting VSMC apoptosis and monocytic NCT03765788)
recruitment. Secukinumab inhibits IL-17A. Phase 3 (ongoing)
(ClinicalTrials.gov identifier: NCT04930094)
Tocilizumab, Sirukumab IL-6 secreted by DC, Th17 cells, macrophages, Tocilizumab: phase 3 (completed)34; FDA
and giant cells leads to local inflammation and approved
systemic symptoms of GCA; it also affects Treg Sirukumab: phase 3 (withdrawn)
cells leading to Th17 pathway. Tocilizumab (an (ClinicalTrials.gov identifier: NCT02531633)76
IL-6 receptor antagonist) and sirukumab (an
IL-6 inhibitor) affect IL-6-mediated changes in
GCA.
Mavrilimumab GM-CSF is implicated in multiple steps in GCA Phase 2 (completed)63
including DC activation, monocytic
recruitment, and activation. Mavrilimumab is
a GM-CSF inhibitor
Ustekinumab The Th1 pathway is maintained by IL-12, and the Open label (completed)54
Phase 1 open label (terminated)55

Th17 pathway by IL-23. IL-12 and IL-23 both

have a common subunit P40. Ustekinumab Phase 2 (ongoing) (ClinicalTrials.gov identifier:

binds to P40 and inhibits Th1 and Th17 NCT03711448)
pathways.
Adalimumab, etanercept, infliximab Macrophage and giant cells secrete TNF along No benefit seen77–79
with IL-1b and IL-6, which leads to local
inflammation and systemic symptoms of GCA.
Adalimumab, etanercept, and infliximab are
TNF inhibitors.
Baricitinib, upadacitinib JAK-STAT signaling is integral to multiple cells Phase 2 open-label study65
(DC, T cells, monocytes) and various cytokines Phase 3 (ongoing) (SELECT-GCA, (ClinicalTrials.
(IL-6, IL-12, IL-23, IL-2, IFN-g) implicated in GCA gov identifier: NCT03725202)
reservados.
pathogenesis. Baricitinib and upadacitinib are
Treatment Approaches and New Targets

JAK inhibitors with varying selectivity to JAK
subtypes.
Anakinra IL-1b secreted by DC, Th17 cells, macrophage, Phase 3 (ClinicalTrials.gov identifier:
and giant cells leads to local inflammation and NCT02902731)
systemic symptoms of GCA. Anakinra, IL-1
receptor inhibitor, affects IL-1b-mediated
changes in GCA.
Bosentan Endothelin-1 causes vascular remodeling in GCA. Phase 3 (ongoing) (ClinicalTrials.gov identifier:
Bosentan, an endothelin-1 receptor NCT03841734)
antagonist, blocks the effect of endothelin-1.
Abbreviations: AICAR, amino-imidazolecarboxamidoribonucleotide; cAMP, cyclic adenosine monophosphate; DC, dendritic cell; FDA, Food and Drug Administra-
tion; GCA, giant cell arteritis; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; JAK-STAT, Janus kinase–signal transduction and activator
of transcription; Th, T helper cells; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cells.
515
516 Nepal et al
relapse-free remission at week 52 was achieved by 72% of the participants. Of note, 1

patient developed AION on day 17.
A second uncontrolled, open-label, proof-of-concept study evaluated the efficacy
of weekly tocilizumab injections in combination with 8 weeks of prednisone for new-
onset and relapsing GCA patients.74 The primary endpoint, sustained remission,
was defined as the absence of relapse from induction of remission up to week 52 while
adhering to the prednisone taper. The initial prednisone dose was 60 mg (n 5 7), 50 mg
(n 5 1), 40 mg (n 5 7), 30 mg (n 5 6), and 20 mg (n 5 9). All patients entered remission
within 4 weeks of baseline. The primary endpoint was achieved by 23 (77%) patients.
The mean (standard deviation) cumulative prednisone dose in these 23 responder pa-
tients was 1052 (390) mg. No cases of permanent vision loss occurred during the
study. Confirmation of these findings in an RCT trial is required.
Nonimmunosuppressive Adjunctive Therapy

A number of nonimmunosuppressive measures are recommended for patients with
GCA and PMR. These include agents to treat or prevent glucocorticoid-induced oste-
oporosis, vaccines according to age and the use of nonglucocorticoid immunosup-
pressive medications, and aspirin for certain type of patients. The ACR/VF
guidelines currently recommend against the use of statins to treat GCA23 while condi-
tionally recommending aspirin in cases of hemodynamically significant extra-cranial
vessel involvement.23 The EULAR guidelines24 recommend against such use of anti-
platelet agents or anticoagulation unless indicated for other reasons. Both profes-
sional societies recommend surgical or endovascular revascularization in cases of
clinically significant ischemia not responding to medical therapy.23,24 However,
high-quality studies to guide revascularization in GCA are lacking. In nonemergent
cases, vascular interventions should be done when GCA is in remission.23
SUMMARY
After several decades with prolonged glucocorticoid tapers as the cornerstone for the
treatment of GCA and primary PMR, the therapeutic landscape for these disorders is
rapidly changing. IL-6 signaling blockade in combination with shorter glucocorticoid
tapers has shown efficacy in terms of remission maintenance, glucocorticoid-
sparing effects, and improvement of health-related quality of life in both GCA and
PMR patients. Phase 2 RCTs with the GM-CSF antagonist mavrilimumab and the
IL-17A inhibitor secukinumab recently met their respective primary efficacy outcomes
in patients with GCA. Phase 2 and 3 RCTs with tocilizumab and sarilumab have also
shown positive results in patients with primary PMR. Tocilizumab might facilitate even
further reduction in glucocorticoid use for patients with GCA, but confirmatory RCTs
are needed before shorter glucocorticoid tapers can be recommended. Lastly, several
phase 2 and 3 RCTs are currently underway with medications including guselkumab,
abatacept, upadacitinib, and secukinumab. In view of the robust research agenda in
both GCA and primary PMR, the therapeutic armamentarium against these conditions
will hopefully continue to expand in the coming years.
CLINICS CARE POINTS
Early initiation of glucocorticoids remains a key aspect of GCA and PMR management.
Glucocorticoid route, dose, duration and taper are affected by clinical presentations and
co-morbid conditions.
reservados.
GCA and PMR patients are at risk of significant glucocorticoid-related toxicities. Initiating
glucocorticoid-sparing agents should be considered to minimize toxicities when indicated.
New options for GCA and PMR are under development and may be available in the coming
years.
DISCLOSURE
M. Putman participates in clinical trials funded by Abbvie, United States (SELECT-

GCA) and AstraZeneca (MANDARA) and receives consulting payments from Novartis.
S. Unizony receives consulting payments from Kiniksa and Janssen and research sup-
port from Genentech, United States. D. Nepal has nothing to disclose.
FUNDING
Supported in part by a Scientist Development Grant from the Rheumatology Research

Foundation, United States.
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Giant Cell Arteritis and

Desh Nepal, MDa,*, Michael Putman, a

Rheum Dis Clin N Am 49 (2023) 505–521

manifestations in a condition called primary PMR, which is 3 times more frequent

CURRENT TREATMENT APPROACHES FOR GIANT CELL ARTERITIS AND

of the patients relapse when relapse is defined as the reoccurrence of characteristic

Glucocorticoids for Polymyalgia Rheumatica

Interleukin-6 Blockade Therapy

IL-6 blockade therapy for polymyalgia rheumatica

NEW TARGETS FOR GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA

by CD41 T cells, an important step in the activation of autoreactive lymphocytes

IL-12/IL-23 Signaling Inhibition

IL-17 Signaling Inhibition

Fig. 1. GCA immuno-pathophysiology and sites of interventions of approved and investiga-

secukinumab treatment group had higher sustained remission rates at 28 weeks

Granulocyte-Macrophage Colony-Stimulating Factor Signaling Inhibition

Janus Kinase Signaling Inhibition

Pathogenic Mechanism Targeted or Potentially

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de

Agent Targeted Stage of Development

provided by DCs to CD41 T cells, which

Phase 1 open label (terminated)55

Th17 pathway by IL-23. IL-12 and IL-23 both

have a common subunit P40. Ustekinumab Phase 2 (ongoing) (ClinicalTrials.gov identifier:

pathogenesis. Baricitinib and upadacitinib are

Treatment Approaches and New Targets

relapse-free remission at week 52 was achieved by 72% of the participants. Of note, 1

Nonimmunosuppressive Adjunctive Therapy

CLINICS CARE POINTS

M. Putman participates in clinical trials funded by Abbvie, United States (SELECT-

Supported in part by a Scientist Development Grant from the Rheumatology Research

1. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology

50. Mainbourg S, Addario A, Samson M, et al. Prevalence of Giant Cell Arteritis

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de

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