The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
RESEARCH ARTICLE

Steroid-Sparing Agents in Giant Cell Arteritis



Amol Sagdeo1, Ayman Askari1, Josh Dixey1, Hana Morrissey2, *, Patrick A. Ball2
1 The Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, SY10 7AG, UK
2 University of Wolverhampton, School of Pharmacy, WV1 1LY, UK

Abstract

Background:

Giant cell arteritis is the commonest form of medium-to-large vessel vasculitis, requiring long-term corticosteroid therapy. The short- and long-term side effects of corticosteroids are many, including weight gain, psychological effects, osteoporosis, cardiometabolic complications, and infections.

Materials and Methods:

Various agents used in place of or in combination with corticosteroids to reduce corticosteroid-related side effects were reviewed. However, considerable variation in practice was identified giving unclear guidance. This review included the most recent evidence on methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, abatacept, and tocilizumab

Results and Discussion:

Also discussed are encouraging results with tocilizumab in GCA patients. Amongst the agents available for steroid-sparing effects, tocilizumab demonstrated the most robust data and is consequently recommended as the agent of choice for steroid-sparing, for remission induction, remission maintenance, and treating relapsing and refractory cases of GCA.

Keyword: Corticosteroids, Tocilizumab, Giant cell arteritis, Vasculitis, Steroid-sparing, EULAR, Epidemiology.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 61
Last Page: 71
Publisher Id: TORJ-13-61
DOI: 10.2174/1874312901913010061

Article History:

Received Date: 17/04/2019
Revision Received Date: 12/06/2019
Acceptance Date: 08/07/2019
Electronic publication date: 31/07/2019
Collection year: 2019

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© 2019 Sagdeo et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the University of Wolverhampton, School of Pharmacy, WV1 1LY, UK; Email: hana.morrissey@wlv.ac.uk; ORCID: https://orcid.org/0000-0001-9752-537X




1. INTRODUCTION

Giant Cell (temporal) Arteritis (GCA) is a chronic, systemic vasculitis, with a distinct tropism for large and medium-sized arteries with well-developed elastic membranes. The epidemiology of GCA suggests striking differences in disease risk among ethnic groups, with the highest incidence rates found in Scandinavian and other people of Northern European descent, irrespective of their place of residence [1Fauchald P, Rygvold O, Øystese B. Temporal arteritis and polymyalgia rheumatica. Clinical and biopsy findings. Ann Intern Med 1972; 77(6): 845-52.[http://dx.doi.org/10.7326/0003-4819-77-6-845] [PMID: 4644163] -5Gran JT, Myklebust G. The incidence of polymyalgia rheumatica and temporal arteritis in the county of Aust Agder, south Norway: A prospective study 1987-94. J Rheumatol 1997; 24(9): 1739-43.[PMID: 9292797] ]. Globally, the incidence of GCA is around 27 per 100,000 in persons over 50 years of age [6Su Z, Menon V, Gliklich R, Brecht T. Treatment patterns in Large vessel vasculitis (Giant cell arteritis and Temporal arteritis): Findings from a large contemporaneous real world cohort in US Arthritis and Rheumatology 2017; 69(suppl 10)]. Corticosteroids are the mainstay of therapy. Prompt diagnosis and initiation of therapy is critical to prevent complications such as partial visual loss or blindness and other vascular complications [7Gonzalez-Gay MA, Martinez-Dubois C, Agudo M, Pompei O, Blanco R, Llorca J. Giant cell arteritis: Epidemiology, diagnosis, and management. Curr Rheumatol Rep 2010; 12(6): 436-42.[http://dx.doi.org/10.1007/s11926-010-0135-9] [PMID: 20857242] -11Dasgupta B, Borg AF, Hassan N, et al. on behalf of the BSR and BHPR Standards, Guidelines and Audit Working Group, BSR and BHPR guidelines for the management of polymyalgia rheumatic. Rheumatology 2010; 49: 1594-7.[http://dx.doi.org/10.1093/rheumatology/keq039a] [PMID: 20371504] ]. The average duration of corticosteroid therapy in GCA is 2-3 years, although lifelong treatment may be required in some patients [8Matteson EL, Buttgereit F, Dejaco C, Dasgupta B. Glucocorticoids for management of polymyalgia rheumatica and giant cell arteritis. Rheum Dis Clin North Am 2016; 42(1): 75-90, viii.[http://dx.doi.org/10.1016/j.rdc.2015.08.009] [PMID: 26611552] , 12Muratore F, Pipitone N, Hunder GG, Salvarani C. Discontinuation of therapies in polymyalgia rheumatica and giant cell arteritis. Clin Exp Rheumatol 2013; 31(4)(Suppl. 78): S86-92.[PMID: 24129145] -15Strehl C, Bijlsma JW, de Wit M, et al. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis 2016; 75(6): 952-7.[http://dx.doi.org/10.1136/annrheumdis-2015-208916] [PMID: 26933146] ]. Long-term corticosteroid use (3-6 months or more) is potentially associated with treatment-related Adverse Events (AEs), however, the incidence and severity are commonly dependent on a combination of the daily dose and regimen cumulative dose [15Strehl C, Bijlsma JW, de Wit M, et al. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis 2016; 75(6): 952-7.[http://dx.doi.org/10.1136/annrheumdis-2015-208916] [PMID: 26933146] -18Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum 2006; 55(3): 420-6.[http://dx.doi.org/10.1002/art.21984] [PMID: 16739208] ]. These AEs include skin, gastrointestinal, ophthalmological, skeletal, adrenal, cardiometabolic, and neuropsychiatric complications [13Proven A, Gabriel SE, Orces C, O’Fallon WM, Hunder GG. Glucocorticoid therapy in giant cell arteritis: Duration and adverse outcomes. Arthritis Rheum 2003; 49(5): 703-8.[http://dx.doi.org/10.1002/art.11388] [PMID: 14558057] , 17Harris E, Tiganescu A, Tubeuf S, Mackie SL. The prediction and monitoring of toxicity associated with long-term systemic glucocorticoid therapy. Curr Rheumatol Rep 2015; 17(6): 513.[http://dx.doi.org/10.1007/s11926-015-0513-4] [PMID: 25903665] , 19van der Goes MC, Jacobs JW, Boers M, et al. Patient and rheumatologist perspectives on glucocorticoids: An exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2010; 69(6): 1015-21.[http://dx.doi.org/10.1136/ard.2009.114579] [PMID: 19762359] ]. The corticosteroid-related AEs patients and rheumatologists consider the most worrisome include weight gain, psychological effects, osteoporosis, and infections [20McDonough AK, Curtis JR, Saag KG. The epidemiology of glucocorticoid-associated adverse events. Curr Opin Rheumatol 2008; 20(2): 131-7.[http://dx.doi.org/10.1097/BOR.0b013e3282f51031] [PMID: 18349741] ].

Given the substantial morbidity associated with long-term corticosteroid therapy, guidelines (e.g., from the European league against rheumatism [EULAR] and British Society for Rheumatology) recommend that steroid-sparing agents should be used [21Langford CA, Cuthbertson D, Ytterberg SR, et al. Vasculitis Clinical Research Consortium. A randomized double-blind trial of abatacept (CTLA-4Ig) for the treatment of giant cell arteritis. Arthritis Rheumatol 2017; 69(4): 837-45.[http://dx.doi.org/10.1002/art.40044] [PMID: 28133925] ], but as evidence is limited, there are variations in the treatment strategy and no specific guidance available about the agent choice for this diverse group of patients.

This critical review of the literature examines evidence on agents that, if used may reduce the required steroid dose or the duration of steroids treatment and decrease the frequency and/or intensity of patient experienced side effects.

2. MATERIALS AND METHODS

The databases searched were; Medline®, Cochrane library and EMBASE® using the keywords <steroid sparing effects>, <methotrexate>, <mycophenolate mofetil>, <cyclophosphamide>, <azathioprine>, <anti-TNF agents>, <abatacept>, <selective T cell co-stimulation modulator> and <tocilizumab> and <Giant Cell Arteritis>. The limits applied were from 2000 onwards and articles in the English language, and adult population. Relevant natural language and controlled vocabulary terms were selected and combined. Where possible, articles were restricted to systematic reviews, RCTs or case series.

3. RESULTS AND DISCUSSION

3.1. Variations in the Optimal Treatment Strategies for GCA

In a large, representative cohort of real-world patients seen in routine clinical practice of rheumatologists across the United States of America, treatment patterns were reviewed using data from electronic medical records and other sources in an ongoing and continuous updating manner. These patients met the definition of at least two GCA-related diagnosis codes within a 1-year period, between 2013 and 2016. Amongst 1567 patients with a mean age of 72+10 years, 78% were Caucasian and 78% were females. The mean follow-up period was 24 months with an average of 12 Rheumatology clinic visits. There were 14% of all patients treated with more than one agent concurrently, and 85% received corticosteroids. This study demonstrated that there was wide variation in treatment practices where 22% of patients treated with methotrexate, 8% with hydroxychloroquine, 5% with aspirin, 5% with tocilizumab, and 3.5% with azathioprine [6Su Z, Menon V, Gliklich R, Brecht T. Treatment patterns in Large vessel vasculitis (Giant cell arteritis and Temporal arteritis): Findings from a large contemporaneous real world cohort in US Arthritis and Rheumatology 2017; 69(suppl 10)]. This also reflects the lack of clarity around the value of additional steroid-sparing agents to avoid [6Su Z, Menon V, Gliklich R, Brecht T. Treatment patterns in Large vessel vasculitis (Giant cell arteritis and Temporal arteritis): Findings from a large contemporaneous real world cohort in US Arthritis and Rheumatology 2017; 69(suppl 10)] corticosteroids.

3.2. Relapsing and Refractory GCA

The traditional view of GCA as a corticosteroid-responsive disease is not always accurate or predictable; a spectrum of severity and extent exists. In observational cohort studies, relapses were reported in 34-62% of patients, with 15-20% achieving long-term sustained remission with corticosteroids alone [22Dejaco C, Brouwer E, Mason JC, Buttgereit F, Matteson EL, Dasgupta B. Giant cell arteritis and polymyalgia rheumatica: Current challenges and opportunities. Nat Rev Rheumatol 2017; 13(10): 578-92.[http://dx.doi.org/10.1038/nrrheum.2017.142] [PMID: 28905861] ]. Based on treatment response, GCA patients can be divided into four subgroups; in-remission, relapsed, refractory, and corticosteroid intolerant [3Nordborg E, Bengtsson BA. Epidemiology of biopsy-proven Giant Cell Arteritis (GCA). J Intern Med 1990; 227(4): 233-6.[http://dx.doi.org/10.1111/j.1365-2796.1990.tb00150.x] [PMID: 2324677] ]. The last three groups exhibit the greatest unmet need for adjunctive therapy [22Dejaco C, Brouwer E, Mason JC, Buttgereit F, Matteson EL, Dasgupta B. Giant cell arteritis and polymyalgia rheumatica: Current challenges and opportunities. Nat Rev Rheumatol 2017; 13(10): 578-92.[http://dx.doi.org/10.1038/nrrheum.2017.142] [PMID: 28905861] ]. A critical review of the literature published in Clinical and Experimental Rheumatology [23Kötter I, Henes JC, Wagner AD, Loock J, Gross WL. Does glucocorticosteroid-resistant large-vessel vasculitis (giant cell arteritis and Takayasu arteritis) exist and how can remission be achieved? A critical review of the literature. Clin Exp Rheumatol 2012; 30(1)(Suppl. 70): S114-29.[PMID: 22640655] ] revealed five case series with large cohorts. These suggested that 40-48% of GCA patients require additional immunosuppressive agents to achieve remission and to taper their corticosteroid intake.

3.3. Methotrexate and Steroid-Sparing Effect

Methotrexate (MTX) efficacy and safety was evaluated in patients with GCA enrolled in three randomized clinical trials. These reported inconsistent efficacy, but reductions in relapse rate and in overall corticosteroids exposure [24Hoffman GS, Cid MC, Hellmann DB, et al. International Network for the Study of Systemic Vasculitides. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002; 46(5): 1309-18.[http://dx.doi.org/10.1002/art.10262] [PMID: 12115238] -26Spiera RF, Mitnick HJ, Kupersmith M, et al. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of Giant Cell Arteritis (GCA). Clin Exp Rheumatol 2001; 19(5): 495-501.[PMID: 11579707] ]. In a meta-analysis of individual patient data from these trials, it was found that adjunctive low-dose MTX reduced both relapse risk and corticosteroids exposure, though the frequency and severity of AEs were not reduced [27Muratore F, Kermani TA, Crowson CS, et al. Large-vessel giant cell arteritis: a cohort study. Rheumatology (Oxford) 2015; 54(3): 463-70.[http://dx.doi.org/10.1093/rheumatology/keu329] [PMID: 25193809] , 28Mahr AD, Jover JA, Spiera RF, et al. Adjunctive methotrexate for treatment of giant cell arteritis: An individual patient data meta-analysis. Arthritis Rheum 2007; 56(8): 2789-97.[http://dx.doi.org/10.1002/art.22754] [PMID: 17665429] ]. Adjunctive MTX may reduce cumulative corticosteroids doses by 20% [25Jover JA, Hernández-García C, Morado IC, Vargas E, Bañares A, Fernández-Gutiérrez B. Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 134(2): 106-14.[http://dx.doi.org/10.7326/0003-4819-134-2-200101160-00010] [PMID: 11177313] ] and relapses by 35% (28) in GCA. Similar beneficial effects were observed to reduce corticosteroids dose and a reduction in relapses [23Kötter I, Henes JC, Wagner AD, Loock J, Gross WL. Does glucocorticosteroid-resistant large-vessel vasculitis (giant cell arteritis and Takayasu arteritis) exist and how can remission be achieved? A critical review of the literature. Clin Exp Rheumatol 2012; 30(1)(Suppl. 70): S114-29.[PMID: 22640655] ]. Based on a systematic analysis of clinical trial data, the use of MTX as a steroid-sparing strategy may be considered for patients at high risk for corticosteroid-induced AEs at disease outset. It may also be useful for patients whose disease course is protracted and who are at risk for recurrent relapses and corticosteroid-induced AEs [29Buttgereit F, Dejaco C, Matteson EL, Dasgupta B. Polymyalgia rheumatica and giant cell arteritis: A systematic review. JAMA 2016; 315(22): 2442-58.[http://dx.doi.org/10.1001/jama.2016.5444] [PMID: 27299619] , 30Salvarani C, Pipitone N, Versari A, Hunder GG. Clinical features of polymyalgia rheumatica and giant cell arteritis Nature reviews - Rheumatology 2012; 8: 509-21.[http://dx.doi.org/10.1038/nrrheum.2012.97] ].

3.4. Mycophenolate Mofetil

In a retrospective study (n=65 GCA patients), patients were divided into 3 treatment groups; prednisolone alone, prednisolone with methotrexate, and prednisolone with mycophenolate (MMF). No significant difference was shown between the groups. The study concluded that MMF is as effective as MTX and prednisolone alone in the treatment of Large Vessel Vasculitis (LVV). However, the patient group was small which limits the generalisation of this finding. Additionally, there was no randomisation to the treatment group; treatment choice was based on clinician preference. There was potential bias in that patients perceived to be more difficult to treat may have been given MMF or MTX in addition to prednisolone, and there were a higher proportion of patients with LVV compared to GCA in the MMF and MTX treated groups [31Buttgereit F, Matteson EL, Dejaco C, Dasgupta B. Prevention of glucocorticoid morbidity in giant cell arteritis Rheumatology 2018; 57: 11-21.[http://dx.doi.org/10.1093/rheumatology/kex459] -34Sciascia S, Piras D, Baldovino S, et al. Mycophenolate mofetil as steroid-sparing treatment for elderly patients with giant cell arteritis: report of three cases. Aging Clin Exp Res 2012; 24(3): 273-7.[http://dx.doi.org/10.1007/BF03325257] [PMID: 23114555] ].

3.5. Azathioprine

A two-centre retrospective study was designed to describe the use of azathioprine in GCA and to evaluate its steroid-sparing effect. Of the 28 patients included, 21 responded to the combination of azathioprine and prednisolone [35Boureau AS, de Faucal P, Espitia O, De Decker L, Agard C. Place of azathioprine in the treatment of giant cell arteritis. Rev Med Interne 2016; 37(11): 723-9.[http://dx.doi.org/10.1016/j.revmed.2016.03.007] [PMID: 27260788] ]. At 1 year of follow-up from the initiation of azathioprine and a daily dose of prednisone, 18 patients (64%) were still in sustained response, asymptomatic, and showed no increase in acute phase response laboratory markers. Three patients (11%) experienced a relapse during azathioprine treatment. The mean daily dose of prednisone was 25.4 mg at the time of initiation of azathioprine, and 4.7 mg at 1 year of treatment, suggesting a good steroid-sparing effect [35Boureau AS, de Faucal P, Espitia O, De Decker L, Agard C. Place of azathioprine in the treatment of giant cell arteritis. Rev Med Interne 2016; 37(11): 723-9.[http://dx.doi.org/10.1016/j.revmed.2016.03.007] [PMID: 27260788] ]. Treatment cessation was required in 7 out of 10 patients who experienced azathioprine-related serious side effects. It was concluded that azathioprine may be an alternative treatment for patients with GCA requiring prolonged high dose corticosteroids therapy or developing severe corticosteroid related side effects [35Boureau AS, de Faucal P, Espitia O, De Decker L, Agard C. Place of azathioprine in the treatment of giant cell arteritis. Rev Med Interne 2016; 37(11): 723-9.[http://dx.doi.org/10.1016/j.revmed.2016.03.007] [PMID: 27260788] ].

3.6. Cyclophosphamide

Data from 19 patients treated with cyclophosphamide (CYC) were retrospectively analysed. In 15 of the 19 patients, CYC had been administered after the failure of high doses of corticosteroids, or experiencing a relapse during medium to high dose corticosteroids therapy, with or without MTX [36Quartuccio L, Maset M. Role of oral cyclophosphamide in the treatment of giant cell arteritis Rheumatology 2012; 51(9): 1677-86.]. CYC was used as the initial treatment in corticosteroid naive patients (4 of the 19 patients). All of the participants were also diagnosed with type 2 diabetes. During the 6-12 months follow-up, 15 of the 19 patients remained in remission. Corticosteroids were suspended in 6 of the 15 patients, and a dose of 5 mg/day of prednisone was continued in 9 patients. Relapse occurred in 4 of the 15 patients who sustained remission, usually 12 months after CYC was ceased. The cessation or reduction of their corticosteroid daily dose or reduction to 5 mg/day of prednisone took place within the first 6 months of follow-up after the initiation of CYC in 10 of the 15 patients. Ten adverse events were registered in nine patients, with recovery soon after the suspension of CYC or dose reduction [36Quartuccio L, Maset M. Role of oral cyclophosphamide in the treatment of giant cell arteritis Rheumatology 2012; 51(9): 1677-86.]. However, one death occurred due to acute hepatitis. The disappearance of inflammatory infiltrate was demonstrated in one patient when temporal artery biopsy was repeated 3 months after CYC therapy. This study concluded that CYC could represent a useful option for patients requiring prolonged medium- to high-dose of corticosteroid therapy and at high risk of corticosteroids-related side effects (36).

3.7. Anti-TNF Agents and their Steroid-Sparing Effect in GCA

A systematic review [37Silva-Fernández L, Loza E, Martínez-Taboada VM, et al. Systemic autoimmune diseases study group of the spanish society for rheumatology (EAS-SER). Biological therapy for systemic vasculitis: A systematic review. Semin Arthritis Rheum 2014; 43(4): 542-57.[http://dx.doi.org/10.1016/j.semarthrit.2013.07.010] [PMID: 23978781] ] was conducted to evaluate the efficacy and safety of infliximab and etanercept in LVV. This review concluded that infliximab was not more effective than corticosteroids in inducing remission in GCA patients, but it was effective in inducing remission and in steroid-sparing in corticosteroid refractory Takayasu’s arteritis. The review concluded that etanercept has a role as a steroid-sparing agent in GCA with corticosteroid related sever`1`e adverse effects and is effective in inducing remission in corticosteroid refractory GCA [37Silva-Fernández L, Loza E, Martínez-Taboada VM, et al. Systemic autoimmune diseases study group of the spanish society for rheumatology (EAS-SER). Biological therapy for systemic vasculitis: A systematic review. Semin Arthritis Rheum 2014; 43(4): 542-57.[http://dx.doi.org/10.1016/j.semarthrit.2013.07.010] [PMID: 23978781] ].

3.8. Abatacept (Selective T cell Co-Stimulation Modulator) and Steroid-Sparing in GCA

Abatacept, a selective T cell co-stimulation modulator [38Chitale S, Moots R. Abatacept: The first T lymphocyte co-stimulation modulator, for the treatment of rheumatoid arthritis. Expert Opin Biol Ther 2008; 8(1): 115-22.[http://dx.doi.org/10.1517/14712598.8.1.115] [PMID: 18081541] ], was recently evaluated in a multicentre, randomized, double-blind (phase 2) trial of 49 patients with GCA who received a standardized prednisone tapering regimen [20McDonough AK, Curtis JR, Saag KG. The epidemiology of glucocorticoid-associated adverse events. Curr Opin Rheumatol 2008; 20(2): 131-7.[http://dx.doi.org/10.1097/BOR.0b013e3282f51031] [PMID: 18349741] ]. Patients’ selection criteria were temporal artery abnormality, a biopsy demonstrating vasculitis, and characteristic changes of large-vessel stenosis or aneurysm on arteriography. Additionally, those with large-vessel involvement underwent MRI of the aorta and branches initially and at 6-month intervals. At 12 months, the relapse-free rate was significantly higher in the abatacept group than in the placebo group (48 vs 31%; P = 0.049), and a longer median duration of remission was achieved with abatacept (9.9 vs 3.9 months; P = 0.023). Despite the small number of patients with large-vessel involvement in this study population, the findings suggest that abatacept may be an efficacious treatment option for reducing relapse in patients with GCA, but comparative studies will be required to determine its place in therapy.

3.9. IL-6R Antagonist (Tocilizumab) and Steroid-Sparing Effect in GCA

Interleukin (IL)-6 contributes to the pathogenesis of GCA and represents a possible target for therapy. A retrospective study of 12 patients, with relapsing GCA history, were treated with monthly infusions of the IL-6 receptor (IL-6R) antagonist tocilizumab (TCZ). The average daily prednisone dose decreased from 24 mg (95% CI 15-33.5) at the time of TCZ initiation to 7.3 mg (95% CI 0.7-14) by the time of last evaluation (P = 0.01) [39Unizony SH, Keroack B, Stone JH. Tocilizumab for the treatment of giant cell arteritis: Extended follow-up. Presse Med 2013; 42: 727.[http://dx.doi.org/10.1016/j.lpm.2013.02.178] ]. The mean follow-up of this cohort since diagnosis was 37 months. Out of all the patients who received TCZ, 7 patients were in disease remission until the end of follow-up for a mean time of 17.5 months (range 8-26), and 5 patients experienced a flared after an average of 11 months of therapy (range 2-25). It was concluded that TCZ led to a significant decrease in the flare rate and requirement for corticosteroid use in the study sample. These findings supported that TCZ is a steroid-sparing agent during treatment and in GCA remission [39Unizony SH, Keroack B, Stone JH. Tocilizumab for the treatment of giant cell arteritis: Extended follow-up. Presse Med 2013; 42: 727.[http://dx.doi.org/10.1016/j.lpm.2013.02.178] , 40Collinson N, Tuckwell K, Habeck F, et al. Development and implementation of a double-blind corticosteroid-tapering regimen for a clinical trial Int J Rheumatol ID: 589841 2015.[http://dx.doi.org/10.1155/2015/589841] ]. GiACTA, a randomized, double-blind, placebo-controlled trial, evaluated TCZ effectiveness in achieving sustained, corticosteroid -free remission. This was the first trial to employ a blinded, variable-dose corticosteroid-tapering regimen [38Chitale S, Moots R. Abatacept: The first T lymphocyte co-stimulation modulator, for the treatment of rheumatoid arthritis. Expert Opin Biol Ther 2008; 8(1): 115-22.[http://dx.doi.org/10.1517/14712598.8.1.115] [PMID: 18081541] ]. The study concluded that TCZ was not only highly effective in maintaining disease remission induced by the combination of TCZ and prednisone, but also that IL-6R blockade has a pronounced steroid-sparing effect for patients [41Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med 2017; 377(4): 317-28.[http://dx.doi.org/10.1056/NEJMoa1613849] [PMID: 28745999] ]. The trial had 4 arms: 1) TCZ SC 162 mg weekly plus 6-month prednisone taper; 2) TCZ SC 162 mg every other week plus 6-month prednisone taper; 3) prednisone only at 6-month taper; and 4) prednisone only at 12-month taper. Remission was sustained in 56% of the patients treated with TCZ for 52 weeks in the weekly group and in 53% in the ‘every other week’ groups, as compared with 14% in the 6 months prednisone taper group and 18% in the 12 months prednisone taper group (P<0.001 for the comparisons of either TCZ treatment with prednisone only groups). Serious adverse events occurred in 15% of the patients in the group that received TCZ weekly, 14% of those in the group that received TCZ every other week, 22% in the prednisone 6-moth taper group, and 25% in the 12 months prednisone taper group. Anterior ischemic optic neuropathy developed in one patient in the group that received TCZ every other week [31Buttgereit F, Matteson EL, Dejaco C, Dasgupta B. Prevention of glucocorticoid morbidity in giant cell arteritis Rheumatology 2018; 57: 11-21.[http://dx.doi.org/10.1093/rheumatology/kex459] ].

Table 1 summarizes all agents used for steroid-sparing and the type of evidence available and recommendation for steroid-sparing in GCA.

Table 1
Agents used for steroid-sparing in GCA treatments.


CONCLUSION AND RECOMMENDATION

At the time of writing, there was no British Society for Rheumatology guidance although this may be revised soon. We analysed 13 studies (Table 2). There were two studies that did not support the additive value of the use of steroid-sparing agents. Five studies concluded that due to their small sample size, they recommend conducting further larger studies and 11 studies concluded that there was significant value to the use of steroid-sparing agents in side-effect reduction and clinical outcomes improvement.

Considering all the evidence available for choosing the most appropriate steroid-sparing agent in GCA, a large number of studies favoured TCZ. There is good evidence that it can safely be used for:

  • Steroid-sparing
  • Induction of remission
  • Maintenance of remission
  • Less frequent flare-ups

The next best agent for steroid-sparing effect appears to be MTX. There is good quality evidence that supports the use of MTX to reduce flares in relapsing GCA and help in reducing the corticosteroid dose and adverse effects.

Amongst anti-TNF agents, use of etanercept can be an option in corticosteroid refractory GCA to induce remission. Abatacept, a selective T cell co-stimulation modulator had shown promise in reducing relapse in GCA in RCTs involving a small number of GCA patients.

Immunosuppressants like azathioprine, mycophenolate, and cyclophosphamide may be used in refractory GCA or large vessel vasculitis patients as third-line agents.

Table 2
List of studies included in the systematic review.


ETHICAL APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

Not applicable.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICTS OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Decleared none.

REFERENCES

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