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Temporal arteritis

GtoPdb Disease Summaries

This section gives an overview of the disease, and where available shows the following:

  • Synonyms: Shows known synonyms for the disease.
  • Description: Gives a basic description/definition of the disease.
  • Database Link: External links to the same disease at the Disease Ontology, OMIM or Orphanet sites.
  • Immunopharmacology comments: General comments about the target's role in immunopharmacology, provided by GtoImmuPdb curators.
  • Associated with: Counts are displayed for the total targets the disease is associated with in GtoPdb. The counts of targets and ligands of immunological relevance associated to the disease are also shown.

More information can be found in the help pages.

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Disease ID:1039
Name:Temporal arteritis
Associated with:1 target
4 immuno-relevant ligands
Synonyms
Giant cell arteritis
Description
This is a chronic inflammatory disease of medium-large arteries. Costicosteroids are the primary treatment for GCA, however blockade of the IL-6/IL-6R pathway has proven an effective alternative to costicosteroids. The anti-IL-6Rα monoclonal antibody tocilizumab was approved for GCA by the FDA in 2017. IL-6 production is downstream of GM-CSF and does not address all of the underlying causes of inflammation in GCA, and the GM-CSF pathway itself is now an active therapeutic target for this indication.
Database Links
Disease Ontology: DOID:13375
OMIM: 187360
Orphanet: ORPHA397

Targets

GtoPdb Disease Summaries - Targets

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Where available, information is display on the role of the target in the disease; drugs which target the disease and their therapeutic use and side-effects.

If there is mutation data curated in GtoPdb this is indicated, with a link back to the appropriate section on the target detailed view page

Immuno ligand interactions - If available, a table of immuno-relevant ligands is shown. These ligands have been curated as having an association to the disease and possess interaction data with the target in GtoPdb. The approval status of the ligand is shown, along with curator comments and an indication of whether the target is considered the primary target of the ligand.

More information can be found in the help pages.

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Key to terms and symbols
NLRP1

Ligands

GtoPdb Disease Summaries - Ligands

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  • Approved: If the ligand is an approved drug this is indicated, along with approval bodies.
  • Immuno: Immuno icon indicates the ligand is immuno-relevant

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  • Immuno Disease Comments: Curatorial comments specifically added as part of GtoImmuPdb. They give more information on the association between the ligand and disease in the context of immunopharmacology.
  • Clinical Use: General clinical comments relating to the ligand and may not necessarily be specific to the disease in question. With hyperlink to more details on the ligand summary pages.
  • Bioactivty Comments: Curatorial comments specifically about the compounds biological activity - with hyperlink to more details on the ligand summary pages.

More information can be found in the help pages.

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Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
tocilizumab 19
Immuno Disease Comments: Approved drug for temporal (giant cell) arteritis (May 2017).
Clinical Use: Tocilizumab had been approved in Japan in 2005 as a treament for giant lymph node hyperplasia (Castleman's disease) [10], before being granted EMA and FDA approvals for use as a treatment for rheumatoid arthritis [9,13] and systemic and polyarticular juvenile idiopathic arthritis [21].
In May 2017 tocilizumab became the first FDA approved drug for the treatment of adults with giant cell arteritis.
Phase 3 clinical trials for immune conditions including ankylosing spondylitis, hand osteoarthritis, systemic sclerosis and primary Sjögren's syndrome (pSS) are ongoing. Tocilizumab was initally used off-label to manage severe or life-threatening cytokine release syndrome (CRS), which is a serious, and potentially life-threatening side effect of CAR T-cell therapy. In September 2017, the FDA extended tocilizumab approval to include treatment of CAR T-cell therapy-induced CRS. It was approved particularly to manage CRS in patients ≥2 years of age receiving tisagenlecleucel (Kymriah®,CTL019), the first CAR T-cell therapy approved for relapsed and refractory B-cell ALL.

SARS-CoV-2 and COVID-19: China's National Health Commission authorised tocilizumab as a treatment for serious COVID-19 lung damage early on in the outbreak. The Chinese Clinical Trial Registry has two studies that are designed to evaluate tocilizumab efficacy in patients with severe COVID-19 pneumonia (Registration Numbers ChiCTR2000029765 and ChiCTR2000030442). Results from an observational study, of low-dose tocilizumab in patients with confirmed elevations in inflammatory markers, showed an indication of reduced mortality [1]. This finding was not confirmed by preliminary results from Roche's Phase 3 COVACTA RCT (NCT04320615). The limitations and differences between the studies, and reasoning that might explain the apparently contradictory findings are discussed by Campochiaro and Dagna (2020) [2]. In addition, early results from 20 severe COVID-19 patients treated with tocilizumab have been posted on the preprint server of the Chinese Academy of Sciences (ChinaRix) (url http://www.chinaxiv.org/abs/202003.00026, DOI: 10.12074/202003.00026). Tocilizumab appears to have reduced disease symptoms and aided full recovery in 19/20 patients. In mid-March 2020, the National Cancer Institute in Naples (Italy) began a Phase 2 observational trial of tocilizumab in patients with COVID-19 pneumonia; this study is named TOCIVID-19, and has clinicaltrials.gov registry ID NCT04317092. | View clinical data
Bioactivity Comments: Unfortunately, we have been unable to find publicly available data providing a binding affinity for this antibody at its molecular target. | View biological activity
sirukumab
Immuno Disease Comments: Phase 3 clinical candidate for temporal arteritis (giant cell arteritis)- see NCT02531633
Clinical Use: Phase 3 clinical trials assessing sirukumab for RA have been completed or are still ongoing (Oct 2017). Click here to link to ClinicalTrials.gov's listing of Phase 3 sirukumab trials. Other trials are collecting data in additional inflammatory conditions including lupus nephritis [15], cutaneous lupus erythematosus, systemic lupus erythematosus and giant cell arteritis.
Research is beginning to indicate that the disease pathophysiology of depression may have an immune component [4,7,12], and reviewed in [22]. In particular, IL-6 has been identified as a susceptibility gene for major depressive disorder (MDD), with the promoter polymorphism rs1800797 showing a marginally significant correlation with cortical IL-6 expression [23]. This and other work (including [12]) has led to clinical trial of sirukumab as an adjunct to conventional antidepressant therapy in patients with MDD (see Phase 3 trial NCT02473289). | View clinical data
upadacitinib
Immuno Disease Comments: Phase 3 clinical candidate for temporal arteritis (giant cell arteritis)- see NCT03725202
Clinical Use: Upadacitinib (ABT-494) completed successful Phase 3 clinical evaluation for rheumatoid arthritis (RA) [6,11,17], and was granted FDA approval in August 2019 adn EMA approval in December 2019, as a treatment for patients with moderate-severe active RA that is inadequately controlled by [5]. Evaluation of upadacitinib's potential in additional immune-mediated conditions (psoriatic arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, atopic dermatitis, SLE and temporal arteritis) are ongoing [14,16,18]. Click here to link to ClinicalTrials.gov's list of ABT-494 studies.
Abbvie reported (in a press release) that upadacitinib met its primary and secondary endpoints in Phase 3 evaluation in psoriatic arthritis (October 2019). No new safety risks were detected. Depending on the dose administered, 25-29% of patients achieved minimal disease activity at week 24 of the study. Formal publication of these results will follow. | View clinical data
Bioactivity Comments: In a kinase screening panel, only two other kinases, Rock1 and Rock2 have IC50s below 1000nM [20]. | View biological activity
mavrilimumab
Immuno Disease Comments: Mavrilimumab is a Phase 2 clinical candidate for temporal arteritis (giant cell arteritis).
Clinical Use: A phase 2 clinical trial (NCT01712399) of mavrilimumab in adult rheumatoid arthritis (RA) patients has been completed (May 2017). In these patients mavrilimumab produced a rapid and prolonged reduction in interleukin-6 production which is indicative of suppression of tissue inflammation. Further development in RA has been discontinued, however Kiniksa Pharmaceuticals are actively evaluating mavrilimumab (which they have re-coded as KPL-301) in a Phase 2 trial in patients with giant cell arteritis (GCA) [8]. | View clinical data
Bioactivity Comments: Results presented in patent US8263075 [3] show that mavrilimumab (antibody 6) has potent effects in biological assays, including inhibition of GM-CSF-induced proliferation of TF-1 ( human erythroleukemic) cells and activity in GM-CSF-induced shape change assays using human granulocytes. | View biological activity

References

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1. Biran N, Ip A, Ahn J, Go RC, Wang S, Mathura S, Sinclaire BA, Bednarz U, Marafelias M, Hansen E et al.. (2020) Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study. The Lancet, [Epub ahead of print]. DOI: 10.1016/S2665-9913(20)30277-0

2. Campochiaro C, Dagna L. (2020) The conundrum of interleukin-6 blockade in COVID-19. The Lancet, [Epub ahead of print]. DOI: 10.1016/S2665-9913(20)30287-3

3. Cohen ES, Minter RR, Harrison PR, Sleeman MA, Nash AD, Fabri LJ. (2012) Antibody molecule for human GM-CSF receptor alpha. Patent number: US8263075. Assignee: Medimmune Limited. Priority date: 27/03/2006. Publication date: 11/09/2012.

4. Du Preez A, Leveson J, Zunszain PA, Pariante CM. (2016) Inflammatory insults and mental health consequences: does timing matter when it comes to depression?. Psychol Med, 46 (10): 2041-57. [PMID:27181594]

5. Duggan S, Keam SJ. (2019) Upadacitinib: First Approval. Drugs, 79 (16): 1819-1828. [PMID:31642025]

6. Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, Durez P, Ostor AJ, Li Y, Zhou Y et al.. (2019) Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol, 71 (11): 1788-1800. [PMID:31287230]

7. Hepgul N, Cattaneo A, Agarwal K, Baraldi S, Borsini A, Bufalino C, Forton DM, Mondelli V, Nikkheslat N, Lopizzo N et al.. (2016) Transcriptomics in Interferon-α-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression. Neuropsychopharmacology, 41 (10): 2502-11. [PMID:27067128]

8. Kiniksa Pharmaceuticals. Mavrilimumab. Accessed on 04/03/2020. Modified on 04/03/2020. kiniksa.com, https://www.kiniksa.com/our-pipeline/mavrilimumab/

9. Maini RN, Taylor PC, Szechinski J, Pavelka K, Bröll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J et al.. (2006) Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum, 54 (9): 2817-29. [PMID:16947782]

10. Matsuyama M, Suzuki T, Tsuboi H, Ito S, Mamura M, Goto D, Matsumoto I, Tsutsumi A, Sumida T. (2007) Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease. Intern Med, 46 (11): 771-4. [PMID:17541233]

11. Mohamed MF, Klünder B, Camp HS, Othman AA. (2019) Exposure-Response Analyses of Upadacitinib Efficacy in Phase II Trials in Rheumatoid Arthritis and Basis for Phase III Dose Selection. Clin Pharmacol Ther, 106 (6): 1319-1327. [PMID:31194885]

12. Money KM, Olah Z, Korade Z, Garbett KA, Shelton RC, Mirnics K. (2016) An altered peripheral IL6 response in major depressive disorder. Neurobiol Dis, 89: 46-54. [PMID:26804030]

13. Ohsugi Y, Kishimoto T. (2008) The recombinant humanized anti-IL-6 receptor antibody tocilizumab, an innovative drug for the treatment of rheumatoid arthritis. Expert Opin Biol Ther, 8 (5): 669-81. [PMID:18407769]

14. Pérez-Jeldres T, Tyler CJ, Boyer JD, Karuppuchamy T, Yarur A, Giles DA, Yeasmin S, Lundborg L, Sandborn WJ, Patel DR et al.. (2019) Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists. Front Pharmacol, 10: 212. [PMID:30930775]

15. Rovin BH, van Vollenhoven RF, Aranow C, Wagner C, Gordon R, Zhuang Y, Belkowski S, Hsu B. (2016) A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis. Arthritis Rheumatol, 68 (9): 2174-83. [PMID:27110697]

16. Shukla T, Sands BE. (2019) Novel Non-biologic Targets for Inflammatory Bowel Disease. Curr Gastroenterol Rep, 21 (5): 22. [PMID:31016396]

17. Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, Zhang Y, Damjanov N, Friedman A, Othman AA et al.. (2019) Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet, 393 (10188): 2303-2311. [PMID:31130260]

18. Torgutalp M, Poddubnyy D. (2018) Emerging treatment options for spondyloarthritis. Best Pract Res Clin Rheumatol, 32 (3): 472-484. [PMID:31171316]

19. Unizony S, Kermani TA. (2018) IL-6 Blockade and its Therapeutic Success in Giant Cell Arteritis. J Neuroophthalmol, 38 (4): 551-558. [PMID:30199509]

20. Voss JW, Camp HS, Padley RJ. (2015) Jak1 selective inhibitor and uses thereof. Patent number: WO2015061665. Assignee: Abbvie Inc.. Priority date: 24/10/2013. Publication date: 30/04/2015.

21. Yokota S, Miyamae T, Imagawa T, Katakura S, Kurosawa R, Mori M. (2005) Clinical study of tocilizumab in children with systemic-onset juvenile idiopathic arthritis. Clin Rev Allergy Immunol, 28 (3): 231-8. [PMID:16129907]

22. Young JJ, Bruno D, Pomara N. (2014) A review of the relationship between proinflammatory cytokines and major depressive disorder. J Affect Disord, 169: 15-20. [PMID:25128861]

23. Zhang C, Wu Z, Zhao G, Wang F, Fang Y. (2016) Identification of IL6 as a susceptibility gene for major depressive disorder. Sci Rep, 6: 31264. [PMID:27502736]