Table 2.
Role of non-tocilizumab biologic disease-modifying antirheumatic drugs in giant cell arteritis.
| Author, Year [Ref.] | Type of Study | n | Sex F (%) |
Population/Median Follow-Up | Therapeutic Protocol | Prior DMARD n (%) | Main Efficacy Outcomes | Serious Adverse Events |
|---|---|---|---|---|---|---|---|---|
| TNF-α Antagonists | ||||||||
| Hoffman et al., 2007 [80] | Multicenter, randomized, DB, PBO-controlled trial | 44 (IFX 28, PBO 16) 2:1 ratio |
IFX 24 (86) PBO 11 (69) |
Newly diagnosed GCA in GC-induced remission. FU: 54 weeks (early termination after interim analysis at week 22) |
i.v. IFX 5mg/kg vs. PBO | Prior DMARD not allowed | Differences in relapse-free patients (43% IFX vs. 50% PBO) and % of patients with GC tapering without relapse (61% IFX vs. 75% PBO) at 22w between groups were NS | 29% IFX vs. 25% PBO, NS Serious infections 11% IFX vs. 6% PBO, NS |
| Martinez-Taboada et al., 2008 [82] | Multicenter, randomized, DB, PBO-controlled trial | 17 (ETN 8, PBO 9) 1:1 ratio |
ETN 6 (75) PBO 8 (88.9) |
Clinically asymptomatic biopsy-proven GCA with GC-related comorbidity. FU: 52 weeks |
s.c. ETN 25 mg twice weekly vs. PBO | Prior DMARD not allowed | Clinical disease control without GC at 52 w: 50% ETN vs. 22.2% PBO (NS). ETN cumulative GC dose was significantly lower (p = 0.03) |
12.5% ETN vs. 11.1% PBO, NS |
| Seror et al., 2018 [81] | Multicenter, randomized, DB, PBO-controlled trial (HECTHOR trial) |
70 (ADA 34, PBO 36) |
ADA 24 (71) PBO 28 (78) |
Newly diagnosed GCA (GCA-related visual symptoms were an exclusion criteria). FU: 10 weeks |
s.c. ADA 45 mg q2w vs. PBO | Prior DMARD not allowed | Remission on less than 0.1 mg/kg of prednisone at week 26: 59% ADA vs. 50% PBO (NS). NS differences in prednisone dose reduction or % of relapse-free patients |
14.5% ADA vs. 47.2% PBO. Serious infections: 3 ADA vs. 5 PBO. Deaths: 1 ADA (pneumonia) vs. 2 PBO (septic shock and cancer) |
| Ustekinumab | ||||||||
| Conway et al., 2016 [29] | Single center, prospective open-label registry | 14 | 11 (79) | Refractory GCA (inability to taper GC to <10 mg/d due to symptoms of active GCA with a minimum of two relapses). FU: 13.5 months |
s.c. UST 90 mg every 3 months | 12 (86) | No relapses. Significant reduction of GC dose (p = 0.001). 29% stopped GC and 92% stopped other DMARD. Image improvement in LVV (n = 5), without new stenoses or aneurysm |
3 Discontinuations due to AE |
| Conway et al., 2018 [86] | Multicenter, open-label prospective registry | 25 | 20 (80) | Refractory GCA (inability to taper GC due to recurrence of symptoms consistent with active GCA, after an initial treatment response to high-dose GC). FU: 52 weeks |
s.c. UST 90 mg every 3 months | 17 (68) | No relapses. Significant reduction of GC dose (p < 0.001) and CRP decrease (p = 0.006). 24% stopped GC and 76% stopped other DMARD. Image improvement in LVV (n = 8), without new stenoses or aneurysm |
3 Discontinuations due to AE: 1 recurrent respiratory tract infections, 1 alopecia and 1 non-dermatomal limb paresthesia |
| Matza et al., 2021 [87] |
Single center, single-arm prospective open-label trial | 13 | 11 (85) | Active new-onset (39%) or relapsing GCA. FU: 52 weeks (enrollment closed prematurely due to relapse of 7/10 initial patients) |
s.c. UST 90 mg every 3 months | 2 (15) | 23% achieved prednisone-free remission (absence of relapse through week 52 and normalization of ESR and CRP). 7 Patients relapsed after a mean period of 23 w |
1 SAE: mild diverticulitis that required hospitalization |
| Abatacept | ||||||||
| Langford et al., 2017 [90] | Multicenter, randomized DB, PBO-controlled study |
41 (20 ABA, 21 PBO) 1:1 ratio |
ABA 16 (80) PBO 21 (100) |
Newly-diagnosed or relapsing GCA with active disease within the prior 2 m. FU: 12 months |
Initially (n = 49): i.v. ABA 10 mg/kg/m At 12 w (n = 41): DB randomization to ABA vs. PBO of cases in remission |
NR Prior bDMARD was not allowed within established time schedule |
Relapse-free survival at 12 m: 48% ABA vs. 31% PBO (p = 0.049). Longer duration of remission with ABA (9.9 m) vs. PBO (3.9 m), p = 0.023 |
23 SAE in 15 patients. NS difference in frequency or severity of AE between treatment arms, including the rate of infection or SAE. No deaths |
| Rossi et al., 2021 [91] |
Single center, two-arm prospective open-label study | 33 (17 TCZ, 16 ABA) 1:1 ratio |
21 (63.6) | Consecutive biopsy-proven newly diagnosed or relapsing GCA. FU: 12 months |
TCZ: i.v. 8mg/kg/m (n = 8), s.c. 162 mg/w (n = 9) ABA: s.c. 125 mg/w Combination with other DMARD was not allowed |
22 (66.6) | i.v. TCZ, s.c. TCZ and ABA clinical response was complete in 57%, 67% and 31%, and partial in 43%, 16% and 31%, respectively 100% TCZ group and 43% ABA group reduced prednisone to ≤ 7.5 mg/d at 12 m, p = 0.0003. Switch due to inefficacy more frequent with ABA (0.0445) |
No significant side effects |
| Sirukumab | ||||||||
| Schmidt et al., 2020 [79] | Multicenter, randomized DB, PBO-controlled parallel-group study + open-label extension |
161 (SIR 107, PBO 54) | 124 (77) | Newly diagnosed or relapsing GCA. FU of DB phase: 52 weeks FU of OL phase: 104 weeks (early termination by sponsor decision) |
DB phase: s.c. SIR 100 mg q2w + 6 m or 3 m of GC taper; s.c. SIR 50 mg q4w + 6 m GC taper;PBO q2w + 6 m or 12 m GC taper OL phase: SIR 100 mg q2w at investigator discretion |
Prior cs- and bDMARD was not allowed within established time schedule | At 52 w: Sustained remission not achieved by 82.4–88.9% patients in SIR arms and 100% in PBO arms; Lower % of flares with SIR than PBO (18.4–30.8% vs. 37–40%); Highest % of flares (23.1%) and withdrawals (61.5%) with SIR 100 mg q2w + 3 m GC taper. OL phase: 60% maintained remission at 4w without SIR administration; No flares |
At 52 w: 19.3% SAE; NS differences across arms; No deaths. OL phase: No SAE; No deaths |
| Meta-analysis | ||||||||
| Berti et al., 2018 [75] | 10 RCT (9 phase 2 and 1 phase 3) |
645 | TCZ, i.v. GC and MTX significantly improved the likelihood of being relapse free with relative risks and 95% CI of 3.54 (2.28, 5.51), 5.11 (1.39, 18.81) and 1.54 (1.02, 2.30) | |||||
| Song et al., 2020 [92] |
6 RCT (2 TCZ, 3 TNF antagonists 1 and ABA) |
260 patients 193 controls |
Remission rate higher for TCZ than PBO (OR 7.009, 95% CI 3.854–12.75, p < 0.001). Relapse rate lower for TCZ than PBO (OR 0.222, 95% CI 0.129–0.381, p < 0.001). NS difference in remission and relapse between groups with TNF antagonists, ABA and PBO |
Number of SAE lower for TCZ than PBO (OR 0.539, 95% CI 0.296–0.982, p = 0.044). NS difference in SAE among patients treated with TNF antagonists, ABA and PBO. Infection rate higher for TNF antagonists than PBO (OR 2.407, 95% CI 1.168-4.960, p = 0.017), but with NS differences between TCZ, ABA and PBO |
||||
Abbreviations: ABA: abatacept; ADA: adalimumab; AE(s): adverse event(s); bDMARD: biologic disease modifying antirheumatic drug; CI: confidence interval; CMV: cytomegalovirus; CRP: C-reactive protein; csDMARD: conventional synthetic disease modifying antirheumatic drug; CV: cardiovascular; d: day; DB: double-blind; DMARD: disease modifying antirheumatic drug; ESR: erythrocyte sedimentation rate; ETN: etanercept; F: female; FU: follow-up; GC: glucocorticoids; GCA: giant cell arteritis; GI: gastrointestinal; i.v.: intravenous; kg: kilogram; m: month; LVV: large vessel vasculitis; mg: milligram; MI: myocardial infarction; MTX: methotrexate; n: number; NS: not significant; OL: open-label; PBO: placebo; qw: every week; q2w: every other week; RCT: randomized controlled trial; RD: risk difference; SAE: serious adverse event; s.c.: subcutaneous; SIR; sirukumab; TBC: tuberculosis; TCZ: tocilizumab; TNF: tumor necrosis factor; vs: versus; w: week.