GIANT CELL ARTERITIS (GCA) ; SYSTEMIC VASCULITIS

GIANT CELL ARTERITIS (GCA)

Giant cell arteritis is common form of systemic vasculitis that occurs mostly in the age of 50 and above and become more common with age progression (1). GCA can affect any medium or large artery and particularly hits aorta and its extra cranial branches. Most common features of this condition are polymyalgia and head ache. It may cause vision loss or stroke in 25 percent and aortic aneurysm in 18 percent of affected people. In terms of pathology, it is characterized by granulomatous inflammatory infiltrate (2). Pathogenic mechanism involves TH1- and TH17 mediated inflammatory cascades (3). Clinical features of GCA are depicted in table 1

GIANT CELL ARTERITIS (GCA) ; SYSTEMIC VASCULITIS

Figure 1. Giant cell arteritis (4)

Table 1: Clinical features of GCA (5)

Common clinical features	Frequent clinical features	Uncommon
Ocular symptoms	Anemia	High fever
Weight loss	Headache	Limb claudication
Malaise	Scalp tenderness	Myocardial infarction

 

PATHOGENESIS

Exact mechanism of GCA is yet to establish due to complexity of molecular mechanisms. Many studies indicated that GCA is triggered by unknown external factors in the persons with genetic predisposition. GCA mostly targets medium and large sizes vessels leading to vascular inflammation. This inflammation causes occlusion of arteries lumen and destruction of vessels wall. Vascular damage results in vascular complications such as ischemia (6). Most studies supported the role of genetics in occurrence of GCA. This is due to presence of strong association between human leukocyte antigen (HLA) region and GCA (7). Aging is main factor itself in the pathogenesis of disease because epigenetic modification keep on occurring with progressive age.Changes also induces biochemical modifications in the matrix proteins of the arteries wall further triggering development of GCA. Differences in the methylation level in different genes also reported in patients of GCA as compared to non GCA population (8).

Inflammation spread causes production of pro-inflammatory cytokines such as IL-1, IL-6 and activation of T cells and CD4+T lymphocytes (9). Activated CD4+T lymphocytes are polarized towards Th1 and Th17 cells. Th1 cells are generated in presence of IL- 12 and IL 18 and produces IFN- γ and Th17 are produced in presence of IL-6, IL-1C and IL-23 and produces IL-17 (9). Th1 and Th17 infiltrated into arterial wall cells cause production of IFN-γ and IL-17 respectively. IFN-γ is responsible for production of several chemokine by vascular smooth cells particularly CCL2, CXCL9, CXCL10 and CXCL11. CCL leads to recruitment and merging of monocytes and forms multinucleated Giant cells that are hallmark of GCA (10).

TREATMENT

If the blindness occurs due to GCA then chances of visual recovery are very low, therefore treatment must not be delayed if person is suspect of GCA (11). Following is the brief overview of the classical management as well as new interventions in treatment of GCA

1. CORNER STONE THERAPY: GLUCOCORTICOIDS

Glucocorticoids are gold standard therapy to reduce risks and to improve symptoms of GCA. Initial doses of prednisone/prednisolone for GCA is 40/60mg per day for 3 to 4 week therapy (12). After the onset of glucocorticoid therapy, there is improvement of cranial symptoms such as jaw claudication, facial pain and scalp tenderness with in first 24 to 72 hours. Most studies recommend 40mg /day initial dose of prednisone in patients of GCA without severe ischemic complications (13). For severe ischemic complications, most clinicians recommend use of an initial prednisone/prednisolone dose of 60mg/ day (14). Within 2 to 4 weeks after initiation of glucocorticoid therapy, acute phase reactants such as CPR and ESR become normal in patients and after that, dose can be gradually tapered. (12) Along with the above mentioned benefits, one major concern is chronic relapse and side effects related to glucocorticoids. This concern emphasize to use glucocorticoids sparing agents in patients with GCA. Glucocorticoid sparing agents help to reduce duration of therapy as well as reduction in side effects due to long term therapy of glucocorticoid therapy (14).

 2. IMMUNOSUPPRESSANTS: METHOTREAXATE

Immunosuppressant agents are used for reduction in relapse and side effects of glucocorticoid therapy. Most commonly used agent is methotrexate (MTX) (15) Reported scientific evidence of use of any other immunosuppressive agent is not adequate hence not supported (11)

 3. BIOLOGICAL AGENTS

Biological agents are another suitable treatment option for the patients with GCA. The most important agents belonging to this category that are used for GCA are

 3a. Tumor necrosis factor alpha inhibitors

These are first of the biological agents used for GCA treatment. In GCA, there is high level of tissue necrosis factor alpha (TNF-α so it is speculated that anti (TNF- α) may be effective for the treatment of GCA (16).

 3b. Tocilizumab

There are reports of increase level of interleukins in inflamed arteries and in serum of patients of GCA. Due to this reason, this has emerged as attractive option for GCA. Tocilizumab is monoclonal antibody and inhibitor of interleukin 6 (16).

 3c. Abatacept

Abatacept is modulator of T cells, modulation is achieved by binding of this agent to CD₈₀/CD₈₆ molecule and subsequent inhibition of signal required for T-cell activation. In recent studies, Abatacept when used in combination with glucocorticoids is helpful in relapse free survival of 12 months as compared to monotherapy of Glucocorticoid (17).

 3d. Ustekinumab

Two important immune responses in CGA are Th1 mediated by IL-12 and Th17 mediated by IL-23. Ustekinumab is a monoclonal antibody that act on both IL-12 and IL-23 mediated Th1 and TH17 responses. Recommended dose of three Ustekinumab is three injections of 45 mg given at weeks 0, 4 and 16. This significantly reduces Th1 and th17 cells and cytotoxic lymphocytes in peripheral blood (17)

 To test the safety and efficacy of Ustekiumab in GCA patients, an open label study is underway. This study was estimated to be completed till end of March, 2020 (18)

 4. LATEST INTERVENTIONS

• Gevokizumab is a recombinant humanized anti-IL-1β antibody that is also being investigated as a potential agent for the management of GCA. (European Clinical Trials Database Identifier 2013–002778–38).
• Another agent under investigation is Anakinra that is interleukin-1β blockade agent, use is reported in three patients of GCA (19)
• Rituximab (anti-CD20 agent) efficacy in GCA has been reported in two case reports (20)
• New treatment approach Algothrim is suggested for patients’ of GCA in 2018 by Candice Low and Richard Conway as shown in Figure 3

Figure 2. Suggested algorithm in GCA treatment (21)

References

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4.         Giant cell arteritis occurs at similar rate in blacks, whites [Internet]. Baltimore: Johns Hopkins Wilmer Eye Institute; p. 1. (JAMA Ophthalmology). Available from: https://medicalxpress.com/news/2019-08-giant-cell-arteritis-similar-blacks.html

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7.         Gonzalez-Gay MA. The diagnosis and management of patients with giant cell arteritis. J Rheumatol. 2005 Jul; 32(7):1186–8.

8.         Coit P, De Lott LB, Nan B, Elner VM, Sawalha AH. DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis. Ann Rheum Dis. 2016 Jun; 75(6):1196–202.

9.         Samson M, Corbera-Bellalta M, Audia S, Planas-Rigol E, Martin L, Cid MC, et al. Recent advances in our understanding of giant cell arteritis pathogenesis. Autoimmunity Reviews. 2017 Aug; 16(8):833–44.

10.       Corbera-Bellalta M, Planas-Rigol E, Lozano E, Terrades-García N, Alba MA, Prieto-González S, et al. Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis. Ann Rheum Dis. 2016 Jun; 75(6):1177–86.

11.       Gonzalez-Gay MA, Castañeda S, Llorca J. Giant Cell Arteritis: Visual Loss Is Our Major Concern. J Rheumatol. 2016 Aug; 43(8):1458–61.

12.       González-Gay MA, Pina T. Giant Cell Arteritis and Polymyalgia Rheumatica: an Update. Curr Rheumatol Rep. 2015 Feb; 17(2):6.

13.       González-Gay MA, Pina T, Prieto-Peña D, Calderon-Goercke M, Blanco R, Castañeda S. Current and emerging diagnosis tools and therapeutics for giant cell arteritis. Expert Review of Clinical Immunology. 2018 Jul 3; 14(7):593–605.

14.       Martínez-Rodríguez I, Jiménez-Alonso M, Quirce R, Jiménez-Bonilla J, Martínez-Amador N, De Arcocha-Torres M, et al. 18 F-FDG PET/CT in the follow-up of large-vessel vasculitis: A study of 37 consecutive patients. Seminars in Arthritis and Rheumatism. 2018 Feb; 47(4):530–7.

15.       Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009 Mar; 68(3):310–7.

16.       Hernandez-Rodriguez J. Tissue production of pro-inflammatory cytokines (IL-1, TNF and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology. 2003 Dec 16; 43(3):294–301.

17.       Langford CA, Cuthbertson D, Ytterberg SR, Khalidi N, Monach PA, Carette S, et al. A Randomized, Double‐Blind Trial of Abatacept (CTLA‐4Ig) for the Treatment of Giant Cell Arteritis. Arthritis & Rheumatology. 2017 Apr; 69(4):837–45.

18.       González-Gay MÁ, Pina T, Prieto-Peña D, Calderon-Goercke M, Gualillo O, Castañeda S. Treatment of giant cell arteritis. Biochemical Pharmacology. 2019 Jul; 165:230–9.

19.       Ly K-H, Stirnemann J, Liozon E, Michel M, Fain O, Fauchais A-L. Interleukin-1 blockade in refractory giant cell arteritis. Joint Bone Spine. 2014 Jan; 81(1):76–8.

20.       Ciccia F, Rizzo A, Maugeri R, Alessandro R, Croci S, Guggino G, et al. Ectopic expression of CXCL13, BAFF, APRIL and LT-β is associated with artery tertiary lymphoid organs in giant cell arteritis. Ann Rheum Dis. 2017 Jan; 76(1):235–43.

21.       Low C, Conway R. Current advances in the treatment of giant cell arteritis: the role of biologics. Ther Adv Musculoskelet Dis. 2019; 11:1759720X19827222.