Table 2: List of studies included in the systematic review.

Citation Sample Type Results (Direct Quotation) Disagree with the value adding of steroid sparing agents Agree with the value adding of steroid sparing agents More research required
Z. Su, V. Menon, R. Gliklich, T. Brecht, “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, vol 69, (suppl 10), 2017. n=1,567 patient records Medical records audit The cohort included 1,567 patients with a mean age of 72 + 10 years, three quarters were Caucasian (78%) and female (76%). Median follow up time was 24 months with a mean of 12 rheumatology ambulatory encounters. Nearly a third of the cohort had a concomitant diagnosis of polymyalgia rheumatica (33%) and 17% had rheumatoid arthritis. A majority of the patients had at least one erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) measurement. Median ESR at baseline was 21mm/hr (IQR: 8, 48) and median CRP was 1mg/L (0.3, 4.0). Only 6% of patients had a documented temporal artery biopsy. Patient reported pain scores were available in 26% of the patients with a median duration of 6 months between first and last assessment. The majority of patients received glucocorticoids (85%), 22% were treated with methotrexate, 8% with hydroxychloroquine, 5% with aspirin, 5% with tocilizumab and 3.5% with azathioprine; 14% were treated with more than one drug concurrently.
I. Kötter, J. C. Henes, A. D. Wagner, J. Loock, W. L. Gross, “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”, Clinical and Experimental Rheumatology, vol 30 issue 1, Suppl 70, pp 114-129, 2012. n=64 publications Systematic review Sixty-four publications were found. Five case series described large cohorts of patients with GCA (n=2) or TA (n=3) showing that 40.8% to 48% of GCA patients and 46% to 84% of TA patients require additional immunosuppressive agents to achieve remission and taper GC. Most were on biologic agents (mainly infliximab, 24 publications/123 patients), followed by methotrexate (MTX) (14/113), cyclophosphamide (CYC) (9/27), azathioprine (AZA) (8/51), cyclosporine A (CSA) (6/47), mycophenolate mofetil (MMF) (3/32), leflunomide (LEF) (2/2), chlorambucil (1/1) and antimalarials (1/36). There were also 2 case reports on autologous stem cell transplantation. The distribution of the two entities TA and GCA was as follows: MTX: 98% GCA, 2% TA; IFX: 26.8% GCA, 73.2% TA; CYC: 70.4% GCA, 29.6% TA; AZA: 100% GCA; LEF: 100% TA; MMF: 100% TA; antimalarials: 100% GCA, autologous stem cell transplantation: 100% TA. A distinction between GC-resistant and GC-dependent cases could not be made from the data available. However, 50 (79%) of the publications described GC-resistant cases. Whereas almost all case reports and retrospective case series (with the exception of CSA) revealed steroid-sparing effects, the 3 prospective randomised trials and 2 open prospective controlled trials on MTX gave conflicting results. However, a recent meta-analysis which recalculated the original data resulted in superiority of MTX after 24 months, there were less relapses and lower GC doses in the MTX group. The prospective controlled IFX trial where IFX was randomised against placebo after GC-induced remission of GCA did not show advantages for IFX over GC alone for maintenance of remission. The prospective controlled ETA trial, which comprised 17 GCA patients, showed small, non-significant advantages but was too small to draw definite conclusions.
G. S. Hoffman, M. C. Cid, D. B. Hellmann, 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 and Rheumatology, vol 46, pp 1309-1318, 2002. n=98 patients RCT Ninety‐eight patients were enrolled. No significant differences between treatment groups were noted with regard to age, frequency of positive findings on temporal artery biopsy (placebo 87%, MTX 79%), or comorbidities at the time of enrollment. The median dosage of MTX was 15 mg/week. The incidence of treatment failure was comparable between groups after 12 months: 57.5% in the MTX group failed treatment (95% confidence interval [95% CI] 41.6–73.4%) compared with 77.3% in the placebo group (95% CI 61.9–92.8%) (P = 0.26). In a Cox regression analysis, MTX was not associated with a reduced risk of treatment failure (relative risk 0.72; 95% CI 0.41–1.28). There were no significant differences between groups with regard to abnormal elevations of the erythrocyte sedimentation rate following initial remissions, serious morbidity due to GCA, cumulative CS dose, or treatment toxicity. In the MTX group, there were fewer cases of GCA relapse heralded by symptoms of isolated polymyalgia rheumatica (1 case versus 5 in the placebo group; P = 0.05).
J. A. Jover, C. Hernandez-Garcia, I. C. Morado, et al., “Combined treatment of giant-cell arteritis with methotrexate and prednisone. A randomized, double-blind, placebo-controlled trial”, Annals of Internal Medicine, vol 134, pp 106-114, 2001. n+21 patients RCT Twenty-one patients received prednisone and methotrexate and 21 received prednisone and placebo. The 2 groups were similar at baseline, with a mean age of 78 years, a mean erythrocyte sedimentation rate of 91 and 100 mm/h respectively, and a polymyalgia rheumatica prevalence of 57% and 52% respectively. One patient in the methotrexate group and 2 in the placebo group were lost to follow-up. All patients responded to initial treatment. Disease relapse occurred in 9 patients (45%) in the methotrexate group, compared with 16 patients (84%) in the placebo group (p = 0.018). Moreover, fewer relapses involving cranial symptoms occurred among patients in the methotrexate group than among the control subjects (2 v. 7 patients, p = 0.06). The median duration of prednisone treatment was significantly shorter in the methotrexate group than in the placebo group (29 v. 94 weeks, p = 0.0016), resulting in a lower mean cumulative dose of prednisone (4187 v. 5489 mg, p = 0.009). There was a trend toward a lower incidence of diabetes mellitus (3 v. 7 patients), arterial hypertension (12 v. 16 patients) and cushingoid appearance (3 v. 6 patients) in the methotrexate group. Three patients receiving methotrexate experienced myelosuppression or mucositis that necessitated withdrawal of the drug. Of these, 1 patient was not taking folic acid supplementation and 2 had mild renal impairment
R. F. Spiera, H. J. Mitnick, M. Kupersmith, et al., “A prospective, double-blind, randomized, placebo-controlled trial of methotrexate in the treatment of giant cell arteritis (GCA)”, Clinical and Experimental Rheumatology, vol 19, pp 495-501, 2001. n=21 patients RCT Twenty-one patients were enrolled, 12 randomized to methotrexate, 9 to placebo. Baseline characteristics (age, height, weight, sedimentation rate, bone mineral density, total corticosteroid dose prior to randomization, and quality of life as measured by SF-36 and function as measured by AIMS) were comparable between groups.
At completion, there was no significant difference between methotrexate-and placebo-treated patients with regard to the cumulative corticosteroid dose (6469 mg and 5908 mg respectively, p=0.6), number of weeks to completion of steroids (68 and 60 respectively, p=0.5), time (weeks) to taper prednisone to less than 10 mg prednisone/day (23 and 25 respectively, p=0.5), bone mineral density in lumbar spine (p=0.2) or hip (p=0.4) at one year, or functional status as measured by AIMS and quality of life as measured by SF36. There was no late vision loss in either group, and only one major treatment-responsive relapse in a methotrexate-treated patient. There were few major corticosteroid-related side effects and these did not significantly differ between groups.
A. D. Mahr, J. A. Jover, R. F. Spiera, et al., “Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis”, Arthritis and Rheumatology, vol 56, pp2789-27, 2007. n=161 patient records Medical records audit The combined data set comprised 161 patients, of whom 84 received MTX and 77 received placebo. The mean duration of follow-up was 54.7 weeks (SD 39.2 weeks). Hazard ratios (HRs) for a first and second relapse of GCA were 0.65 (P = 0.04) and 0.49 (P = 0.02), respectively, in patients receiving MTX as compared with patients receiving placebo. Accordingly, a predicted 3.6 individuals (95% confidence interval [95% CI] 2.2–56.8) and 4.7 individuals (95% CI 3.3–21.9) need to be treated with MTX to prevent the occurrence of one first or one second relapse, respectively, up to 48 weeks. Use of MTX resulted in a reduction in the corticosteroid cumulative dose by 842 mg within 48 weeks (P < 0.001). Moreover, MTX treatment was associated with a higher probability of achieving sustained discontinuation of corticosteroids for ≥24 weeks (HR 2.84, P = 0.001). Dropout rates and occurrence of adverse events did not differ between treatment groups.
F. Buttgereit, C. Dejaco, E. L. Matteson, B. Dasgupta, “Polymyalgia rheumatica and giant cell arteritis: a systematic review”. Journal of American Medical Association, vol 315, pp 2442-2458, 2016. n=20 RCT (therapy, n = 1016 patients) and n=30 (imaging, n = 2080 patients) Systematic review Twenty randomized clinical trials for therapy (n = 1016 participants) and 30 imaging studies for diagnosis and/or assessing response to therapy (n = 2080 participants) were included. The diagnosis of PMR is based on clinical features such as new-onset bilateral shoulder pain, including subdeltoid bursitis, muscle or joint stiffness, and functional impairment. Headache and visual disturbances including loss of vision are characteristic of GCA. Constitutional symptoms and elevated inflammatory markers (>90%) are common in both diseases. Ultrasound imaging enables detection of bilateral subdeltoid bursitis in 69%of PMR patients. In GCA, temporal artery biopsy remains the standard for definitive diagnosis. Ultrasound and magnetic resonance imaging (MRI) of large vessels revealing inflammation-induced wall thickening support the diagnosis of GCA (specificity 78%-100% for ultrasound and 73%-97%for MRI). Glucocorticoids remain the primary treatment, but the optimal initial dose and tapering treatment regimens are unknown. According to consensus-based recommendations, initial therapy for PMR is prednisone, 12.5 to 25mg/day or equivalent, and 40 to 60mg/day for GCA, followed by individualized tapering regimens in both diseases.
Adjunctive methotrexate may reduce cumulative glucocorticoid dosage by 20%to 44%and relapses by 36%to 54%in both PMR and GCA. Use of tocilizumab as additional treatment with prednisone showed a 2-to 4-fold increase in remission rates of GCA in a randomized clinical trial (N = 30).
R. Smith, K. P. Kuet, R. Kilding, M. Akil, J.Maxwell., “A comparison of the effectiveness of mycophenolate mofetil or methotrexate in combination with prednisolone versus prednisolone alone in the treatment of large vessel vasculitis”, Annals of the Rheumatic Diseases, vol 77, pp 1490, 2017. n=65 patients Cohort comparative study 65 patients were included in the study, 41 with GCA and 24 LVV. 49 were female and 16 male. Mean age at diagnosis was 68; range 21 to 87. 37 patients were treated with prednisolone alone; 35 had GCA and 2 LVV. 20 were treated with MMF and prednisolone; 4 with GCA and 16 LVV. 8 were treated with MTX and prednisolone; 2 had GCA and 6 LVV. The AOC for prednisolone and CRP were not normally distributed across the cohort, and non-parametric methods were therefore used for comparisons. Median AOC prednisolone dose for the prednisolone only group was 68.0, (interquartile range (IQR) 17.7, n=37), for the MMF treated group 70.8 (IQR 28.7, n=20) and for the MTX treated group 67.8 (IQR 20.4 n=8). Median AOC CRP was highest in the group treated with prednisolone alone (58.9, IQR 34.5) compared to MMF (43.8, IQR 26.5) and MTX (49.3 IQR 67.5) but there were no statistical differences between median AOC prednisolone dose or CRP in either the unadjusted or regression models.
S. Sciascia, D. Piras, S Baldovino, et al.,, “Mycophenolate mofetil as steroid sparing treatment for elderly patients with giant cell arteritis: Report of three cases”, Aging Clinical and Experimental Research, vol 24, issue 3, pp 273-277, 2012. n=3 patients Case presentation All three patients showed clinical benefit, and were also able to taper steroid use to a more rapid regimen compared with the recently suggested steroid reduction approach. MMF was well tolerated, and no signs of toxicity were observed in a mean of 21.6 months (12-29) of follow- up
A. S. Boureau, P. de Faucal, O. Espitia, L. De Decker, C. Agard, “Place of azathioprine in the treatment of giant cell arteritis”, Revue de Medecine Interne, vol 37, issue 11, pp 723-729, 2016. n=28 patient medical records Medical records audit Of the 28 patients included, 21 responded to azathioprine. At 1 year of follow-up after the initiation of azathioprine, 18 patients (64%) were still in sustained response, asymptomatic, without increase in acute phase response laboratory markers, and with a daily dose of prednisone<10 mg. Three patients (11%) experienced a relapse during azathioprine treatment. Mean daily dose of prednisone were 25.4 mg at the time of initiation of azathioprine, and 4.7 mg at 1 year of treatment, suggesting a corticosteroid-sparing effect (P<0.001). Ten patients experienced azathioprine serious side effects, leading to discontinuation of treatment in seven cases.
L. Quartuccio, M. Maset, G. De maglio, et al., “Role of oral cyclophosphamide in the treatment of giant cell arteritis”, Rheumatology, vol 51, issue 9, pp 1677-1686, 2012. n=19 patient medical records Medical records audit The efficacy of CYC was observed in 15 of the 19 patients, and remission was still present 6-12 months after CYC suspension in 12 of the 13 patients. GCs were suspended in 6 of the 15 patients, and they were continued at a dose ≤ 5 mg/day of prednisone in all the remaining responders. Relapse occurred in 4 of the 15 patients, usually >12 months after CYC suspension. Suspension of GC daily dose or reduction to ≤ 5 mg/day of prednisone occurred within the first 6 months of follow-up after the beginning of CYC in 10 of the 15 patients. Ten adverse events were registered in nine patients, with recovery usually soon after the suspension of CYC or dose reduction.
However, one death occurred due to acute hepatitis. Disappearance of the inflammatory infiltrate could be demonstrated when temporal artery biopsy was repeated 3 months after CYC in one patient.
L. Silva, E. Loza, V. M. Martínez-Taboada, et al., “Biological therapy for large vessel vasculitis: A systematic review”, Seminars in Arthritis and Rheumatism, vol 43, issue 4, pp 542-557, 2014. n= 90 studies Systematic review Of 3447 citations, abstracts, and hand-searched studies screened, 90 were included. Most of the studies included ANCA-associated vasculitis (AAV) patients and only a few included large vessel vasculitis (LVV) patients. Rituximab was the most used agent, having demonstrated efficacy for remission induction in patients with AAV. A number of studies used different anti-TNFα agents with contrasting results. A few uncontrolled studies on the use of abatacept, alemtuzumab, mepolizumab, and tocilizumab were found.
S. H. Unizony, B. Keroack, J. H. Stone, “Tocilizumab for the treatment of giant cell arteritis: Extended follow-up”, Presse Medicale, vol 42, pp 727, 2013. n=12 patients Case presentation The mean follow-up of this cohort since diagnosis was 37 months (range 17–70). Eight subjects had failed at least one immunosuppressant (methotrexate, azathioprine, cyclophosphamide, infliximab, adalimumab and etanercept), and four had contraindications for the use of GC. TCZ (4mg/kg, n =3 and 8mg/kg, n =9) was given for a mean period of 16 months (range 6–27). Before and during IL-6R blockade, the patients experienced an average of 2.7 (95% CI 2–3.5) and 0.6 (95% CI 0–1.2) disease exacerbations per year, respectively (P =0.0006). The mean daily prednisone dose of the cohort decreased from 24mg (95% CI 15–33.5) at the time of TCZ initiation to 7.3mg (95% CI 0.7–14) by the time of last evaluation (P =0.01). On TCZ, 7 subjects maintained disease remission until the end of follow-up for a mean time of 17.5 months (range 8–26), and 5 patients flared after an average of 11 months of therapy (range 2–25). The mean prednisone dose at the time of disease flare in these 5 patients was 4.5mg/day. One subject relapsed after TCZ discontinuation. Currently, 5 patients take 5mg/day of prednisone or less, and 3 patients are off GC. Adverse effects attributable in part to TCZ in this series included leucopenia (n =5), transaminitis (n =8), and pneumonia (n =1). Autopsy on one patient who died from an unrelated cause revealed persistent vasculitis.
J. H. Stone, K. Tuckwell, S. Dimonaco S et al., “Trial of tocilizumab in giant-cell arteritis”, The New England Journal of Medicine, vol 377, pp 317–328, 2017. n=251 patients RCT Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group
that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week.

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