Biologic Therapies for Giant Cell Arteritis

Figures & data

Figure 1 Current understanding of GCA pathogenesis.

Box 1 Summary of GiACTA Results

Better than 1 in 2 chance of remission at 1 year with tocilizumab + prednisolone taper

Less than 1 in 5 chance of remission at 1 year with prednisolone alone

The rates of adverse events did not differ across trial groups, with the exception of neutropenia Placebo group received approx. twice the cumulative glucocorticoid dose

Table 1 GiACTA Trial Results: Sustained Remission Rates and Flares

Group	Sustained Remission at 52 Weeks	Flares	HR for Flare vs Placebo + 26 Week Steroid Taper
Tocilizumab weekly + 26 week steroid taper	56%	23%	0.23 (p<0.001)
Tocilizumab every 2 weeks + 26 week steroid taper	53%	26%	0.28 (p<0.001)
Placebo + 26 week steroid taper	14%	68%	N/A
Placebo + 52 week steroid taper	18%	49%	N/A

Figure 2 JAK/STAT pathways and implicated cytokines in GCA.

Table 2 Overview of Biologics in GCA

Biologic	Target	Level of Evidence	Study Results	Study Limitations
Tocilizumab	IL-6	2 RCTs	Villiger et al (2016)^Citation52 30 patients 77% new onset Relapse-free week 52 85% tocilizumab + GC 20% GC alone GiACTA - Stone et al (2017)^Citation13 251 patients 47% new onset Remission week 52 Tocilizumab weekly + 26weeks GC 56% Tocilizumab every 2weeks + 26weeks GC 53% 26weeks GC alone 14% 52weeks GC alone 18%	Villiger et al (2016)^Citation52 Singe centre and small numbers Not blinded to CRP results GC stopped after 6 months No discontinuation data Limited imaging GIACTA- Stone et al (2017)^Citation13 No discontinuation data Lack of imaging data Short duration of follow-up Concern that vascular disease may progress despite clinical remission
Sirukumab	IL-6	RCT	Schmidt et al (2020)^Citation54 Numerically lower rate of flares in sirukumab group	Terminated early
Sarilumab	IL-6	RCT	Commenced but suspended (NCT03600805)
Abatacept	T-cell	RCT	Langford et al (2017)^Citation62 41 patients 56% new onset Abatacept induction for all randomised at month 3 to abatacept + GC versus GC alone Relapse-free week 52 Abatacept + GC 48% GC alone 31%	Modest effect All received abatacept Abatacept ineffective in Takayasu’s arteritis
Ustekinumab	IL-12/IL-23	Open Label	Conway et al (2016, 2018)^Citation17,Citation57 25 patients All refractory GCA Median GC dose decreased from 20mg to 5mg at week 52 No relapses on ustekinumab Imaging evidence of improvement Matza et al 13 patients 39% new onset 23% remission free at week 52	Conway et al(2016, 2018)^Citation17,Citation57 Unblinded No control group Small numbers Single centre Matza et al Unblinded No control group Small numbers Single centre
Secukinumab	IL-17	Case reports	Rotar et al (2018)^Citation74 Sammut et al (2018)^Citation75 Effective in 2 cases	Case report data only
Adalimumab	TNF-α	RCT	Seror et al (2014)^Citation60 70 patients All new onset Remission week 26 GC + adalimumab 59% GC alone 50%	New-onset patients only Excluded ischaemic manifestations
Infliximab	TNF-α	RCT	Hoffmann et al (2007)^Citation59 44 patients All new onset Relapse-free 52 weeks Infliximab + GC 43% GC alone 50%	Small numbers New-onset patients only Study terminated early
Etanercept	TNF-α	RCT	Martinez-Taboada et al (2008)^Citation61 17 patients All in remission on GC with GC-related adverse events GC remission week 52 Etanercept + GC 50% GC alone 22%	Small numbers High discontinuation rate – 11/19 patients
Anakinra	IL-1β	Case series Ongoing RCT	Ly et al (2014)^Citation70 3 refractory GCA patients; remission in all 3 GiAnT (NCT02902731)	Case report data only at present
Gevokizumab	IL-1β	RCT	Commenced but cancelled
Rituximab	B-cells	Case reports	Bhatia et al (2005)^Citation68 Mayrbaeurl et al (2007)^Citation69 Effective in 2 refractory cases	Case report data only
Baricitinib	JAK	Open-label study ongoing	(NCT03026504)
Upadacitinib	JAK	RCT ongoing	SELECT-GCA (NCT03725202)
Tofacitinib	JAK	Laboratory data only
Mavrilimumab	GM-CSF	RCT ongoing	Cid et al (2020)^Citation73 Sustained remission at week 26 in 83% with mavrilimumab compared to 50% with placebo (NCT03827018)	Preliminary data, presented, not published

Figure 3 Proposed GCA treatment algorithm.

Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:1921–1927. doi:10.1016/S0140-6736(16)00560-2

 PubMed Web of Science ®Google Scholar

Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant cell arteritis. N Engl J Med. 2017;377:317–328. doi:10.1056/NEJMoa1613849

 PubMed Web of Science ®Google Scholar

Schmidt WA, Dasgupta B, Luqmani R, et al. A multicentre, randomised, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of sirukumab in the treatment of giant cell arteritis. Rheumatology and Therapy. 2020;7(4):793–810. doi:10.1007/s40744-020-00227-2

 PubMed Web of Science ®Google Scholar

Langford CA, Cuthbertson D, Ytterberg SR, et al. A randomized, double-blind trial of abatacept (CTLA-4Ig) for the treatment of giant cell arteritis. Arthritis Rheumatol. 2017;69:837–845. doi:10.1002/art.40044

 PubMed Web of Science ®Google Scholar

Conway R, O’Neill L, Gallagher P, et al. Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis. 2016;75(8):1578–1579.

 Google Scholar

Conway R, O’Neill L, Gallagher P, et al. Ustekinumab for refractory giant cell arteritis: a prospective 52-week trial. Semin Arthritis Rheum. 2018;48(3):523–528. doi:10.1016/j.semarthrit.2018.04.004

 PubMed Web of Science ®Google Scholar

Rotar Ž, Tomšic M, Hocevar A. Secukinumab for the maintenance of glucocorticoid-free remission in a patient with giant cell arteritis and psoriatic arthritis. Rheumatology. 2018;57:934–936. doi:10.1093/rheumatology/kex507

 PubMed Web of Science ®Google Scholar

Sammut L, Litwic A, Smith R, et al. 002 Biopsy proven giant cell arteritis in a patient with psoriatic arthritis on TNF-alpha inhibitor treated with high dose prednisolone and a switch to secukinumab (anti IL-17). Rheumatology. 2018;57(suppl_3):key075.226. doi:10.1093/rheumatology/key075.226

 Google Scholar

Seror R, Baron G, Hachulla E, et al. Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis. 2014;73(12):2074–2081. doi:10.1136/annrheumdis-2013-203586

 PubMed Web of Science ®Google Scholar

Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med. 2007;146:621–630. doi:10.7326/0003-4819-146-9-200705010-00004

 PubMed Web of Science ®Google Scholar

Martinez-Taboada VM, Rodriguez-Valverde V, Carreno L, et al. A double-blind placebo-controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis. 2008;67:625–630. doi:10.1136/ard.2007.082115

 PubMed Web of Science ®Google Scholar

Ly KH, Stirnemann J, Liozon E, Michel M, Fain O, Fauchais AL. Interleukin-1 blockade in refractory giant cell arteritis. Joint Bone Spine. 2014;81:76–78. doi:10.1016/j.jbspin.2013.06.004

 PubMed Web of Science ®Google Scholar

Bhatia A, Ell PJ, Edwards JC. Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann Rheum Dis. 2005;64:1099–1100. doi:10.1136/ard.2005.036533

 PubMed Web of Science ®Google Scholar

Mayrbaeurl B, Hinterreiter M, Burgstaller S, et al. The first case of a patient with neutropenia and giant-cell arteritis treated with rituximab. Clin Rheumatol. 2007;26(9):1597–1598. doi:10.1007/s10067-007-0684-0

 PubMed Web of Science ®Google Scholar

Cid M, Unizony S, Pupim L, et al. Mavrilimumab (anti GM-CSF receptor α monoclonal antibody) reduces time to flare and increases sustained remission in a phase 2 trial of patients with giant cell arteritis [abstract]. Arthritis Rheumatol. 2020;72(suppl 10).

 Google Scholar