Managing Giant Cell Arteritis With Tocilizumab: Relapses and Adverse Events

What about GCA relapses in patients taking TCZ?

Relapses are common in patients with GCA. Studies conducted in the prebiologic era showed that relapses and recurrences frequently occur in patients with homogenously treated GCA. One study assessing a series of 174 patients with biopsy-proven GCA followed for at least 1 year after diagnosis found that 71 patients (40.8%) experienced relapses or recurrences of the disease.⁹ In this series of patients, the median dose of prednisone was 5 mg/day, and the median duration of prednisone treatment was 16 months, both at the time of first relapse. Additionally, 32 patients experienced recurrences after discontinuation of prednisone.⁹

In the study by Nagase et al, most relapses occurred following a reduction in the dose of TCZ or after TCZ discontinuation. However, the frequency of relapses was significantly lower than that reported in patients with GCA managed during the prebiologic era.¹ This difference could be attributed to the early introduction of TCZ in Nagase’s study, with a median of 53 days from GCA diagnosis to the initiation of TCZ.¹

The Giant-Cell Arteritis Actemra (GiACTA) trial provided valuable insights into the efficacy of TCZ in achieving sustained, GC-free remission in GCA over a 52-week period.⁵ In this trial, 251 patients were enrolled between July 2013 and April 2015. The participants were randomly assigned to 1 of 4 groups: 100 patients received TCZ weekly, 50 received TCZ every other week, 50 received placebo with a 26-week GC taper, and 51 received placebo with a 52-week GC taper. Interestingly, 56% of patients in the group receiving TCZ weekly and 53% in the group receiving TCZ every other week achieved sustained remission at 52 weeks (the primary outcome), compared to only 14% in the placebo group with the 26-week taper and 18% in the placebo group with the 52-week taper.⁵ Relapse rates were also notably lower in the TCZ groups: 23% in the weekly group and 26% in the every other week group, compared to 68% in the placebo group with the 26-week taper and 49% in the placebo group with the 52-week taper.⁵ Thus, the relapse rate observed in the study by Nagase et al was comparable to, and even slightly lower than, that reported in the GiACTA trial.^1,5

In a subsequent analysis, Stone and the members of the GiACTA trial group evaluated the maintenance of efficacy following discontinuation of TCZ after 1 year, the effectiveness of retreatment with TCZ following a relapse, and GC-sparing effects of TCZ in the long term.¹⁰ The authors found that TCZ effectively maintained long-term remission in patients with GCA, with many participants remaining relapse-free for extended periods. TCZ also significantly reduced GC use, thereby minimizing GC-related side effects while effectively controlling disease activity. Further, patients with GCA who continued TCZ treatment in the open-label extension phase of the GiACTA trial exhibited lower relapse rates compared to historical relapse rates in patients with GCA treated with GCs alone. Relapse rates were particularly low among patients who had achieved remission during the initial trial phase.¹⁰

In another subsequent study, Stone and the members of the GiACTA trial assessed 3-year results from a randomized controlled trial and extension study. They confirmed that TCZ administered weekly delayed the time to relapse and reduced the cumulative GC dose in patients with both relapsing and new-onset GCA.¹¹ Based on these findings, the authors advocated for the use of weekly TCZ as part of first-line therapy for all patients with active GCA.¹¹

Of particular interest is the retrospective analysis of 65 North American patients with GCA treated with TCZ at a single center between 2010 and 2022.¹² In this study, patients were followed for a mean duration of 3.1 (SD 1.6) years, with the mean duration of the initial TCZ course being 1.9 years. Notably, the Kaplan-Meier–estimated relapse rate at 18 months while on TCZ was 15.5%.¹² This relapse rate was remarkably similar to the 16% described in Japanese patients with GCA by Nagase et al.¹ Thus, regardless of geographic location or race, TCZ demonstrates effectiveness, with a notably reduced rate of relapses in GCA.

Nevertheless, in the study by Nagase et al, since 56 (90%) patients received subcutaneous TCZ—12 every other week and 44 weekly¹—it does not answer what might have occurred if the patients receiving treatment every other week had been switched to a weekly schedule or if the subcutaneous administration had been changed to intravenous administration to manage relapses.

Is it possible to optimize TCZ dosage in patients with GCA in disease remission?

To address this question on TCZ dose optimization, Calderón-Goercke et al assessed 231 patients with GCA in prolonged remission on TCZ.¹³ At the onset of TCZ treatment, no significant differences in demographic, clinical, or laboratory data were observed between optimized and nonoptimized patients. The first TCZ optimization occurred after a median follow-up of 12 months. Intravenous TCZ was optimized from 8 mg/kg every 4 weeks to 4 mg/kg every 4 weeks in 44% of patients, whereas subcutaneous TCZ was optimized from 162 mg/week to 162 mg every other week in 65% of cases. At the end of the follow-up period, prolonged remission rates (78.2% vs 84.2%, P = 0.29) and relapse rates (5.6% vs 10.4%, P = 0.18) were similar between optimized and nonoptimized patients with GCA, with fewer serious AEs.¹³ These findings support the potential optimization of TCZ once remission is achieved.

Is TCZ in GCA associated with high rates of AEs?

A study by Gale et al assessed the rates of AEs associated with TCZ therapy in patients with GCA and rheumatoid arthritis (RA).¹⁴ To do this, they analyzed the safety profile of TCZ in both populations, performing a comprehensive analysis of data from multiple clinical trials and real-world postmarketing claims databases. TCZ treatment was associated with a range of AEs in both patients with GCA and RA. The incidence of AEs was comparable between the 2 groups, with some differences in the types of events observed.¹⁴ The most common AEs included infections, such as upper respiratory tract infections, and liver enzyme abnormalities. Infections were a significant concern, with patients receiving TCZ being at increased risk for both mild and serious infections. Liver enzyme abnormalities, such as elevated transaminases, were also observed, though they were generally reversible upon dose adjustment or discontinuation of the drug. Overall, the safety profile of TCZ in patients with GCA was similar to that seen in patients with RA.¹⁴ The study concluded that although TCZ is generally well tolerated in both GCA and RA patient populations, there is a notable risk of infections and liver enzyme abnormalities. These risks should be considered when initiating TCZ therapy, and regular monitoring is recommended, especially with long-term use.¹⁴

Another study compared the clinical characteristics and AEs of patients from the GiACTA trial (n = 251) with those from a multicenter cohort of real-world patients with GCA receiving TCZ therapy (n = 134).¹⁵ The real-world patients were older, had a longer disease duration, higher erythrocyte sedimentation rate values, and were more likely to have received conventional immunosuppressants, particularly methotrexate (MTX), compared to those in the GiACTA trial. Despite these clinical differences, TCZ demonstrated similar effectiveness in both groups.¹⁵ However, serious AEs were observed during the follow-up period in 14.8% of patients from the GiACTA group, compared to 23.9% in the clinical practice series.¹⁵ Infections were the most frequent AE in both cohorts, but were more commonly observed among patients with GCA from clinical practice than those in the GiACTA trial.¹⁵ TCZ had to be discontinued due to AEs in 6% of the patients from the GiACTA trial and in 12.7% of the real-world patients. Deaths were reported in 5 patients from the real-world series.¹⁵

Nagase et al reported 39 AEs in 28 patients (45%), with infections (23%) and hematological abnormalities (19%) being the most common.¹ Interestingly, no deaths occurred during the study, despite 29 (47%) of the 56 patients tested showing large-vessel vasculitis (LVV) involvement on imaging.¹ Eight AEs (13%) led to TCZ discontinuation, including 2 cases each of infections and hematological abnormalities. Four patients discontinued TCZ within the first 6 months, whereas the other 4 discontinued between 6 and 12 months. Patients who continued TCZ for 12 months tolerated the treatment well thereafter.¹ Interestingly, the frequency of AEs leading to TCZ treatment discontinuation in Japanese individuals with GCA was remarkably similar to that reported in real-world patients with GCA from Spain.¹⁵ Therefore, AEs, particularly those leading to TCZ discontinuation, appear to be independent of the genetic background of the population.

Is the combination of TCZ with a nonbiological agent, such as MTX, useful to reduce the frequency of GCA relapses?

In the Japanese study, Nagase et al used concomitant immunosuppressants in some patients: MTX in 17 patients (27%) and mizoribine (an immunosuppressant with a mechanism of action similar to mycophenolate mofetil) in 7 patients (11%).¹ Adjusting combinations of TCZ, GC, and/or MTX managed relapses without serious consequences, and most relapsed patients thereafter achieved low-dose GC regimens (≤ 5 mg/day). This interesting result raises the question of whether TCZ alongside conventional immunosuppressants is more effective than TCZ alone in maintaining prolonged disease remission. To address this question, we took advantage of data from a multicenter study that assessed patients with refractory GCA.¹⁶ In this study, patients with GCA treated with TCZ monotherapy (n = 82) and those treated with TCZ combined with conventional immunosuppressants (n = 52; 48 with MTX) were compared.¹⁶ The main outcomes measured were prolonged remission (defined as normalization of clinical and laboratory variables for ≥ 6 months) and the number of relapses. Patients treated with TCZ combined with conventional immunosuppressants were younger (68.8 vs 71.2 years), had a trend toward a longer GCA duration (18.5 vs 13.0 months), and had higher and more prevalent extracranial LVV features (57% vs 34.1%) compared to the TCZ monotherapy group. Both groups showed rapid and sustained improvement in symptoms. The improvement was similar in both groups at 12 months; however, patients treated with TCZ combined with conventional immunosuppressants had a significantly higher rate of prolonged remission. Rates of relapses and serious AEs were similar in both groups.¹⁶ According to these results, in clinical practice, TCZ, either as monotherapy or in combination with conventional immunosuppressive agents, is effective for treating GCA. However, combining TCZ with immunosuppressive drugs, particularly MTX, appears to enhance the likelihood of prolonged remission, even in patients with longer disease duration, more extracranial LVV involvement, and higher acute-phase reactants.¹⁶

What about other anti–IL-6 receptor antagonists, such as sarilumab?

Sarilumab is another IL-6 receptor antagonist like TCZ. It has also shown potential in treating GCA, with clinical studies suggesting it can reduce disease activity and GC use, similar to TCZ. However, it is not as widely used as TCZ in this context.¹⁷

Other therapies are currently under investigation for the treatment of refractory GCA, showing promising results.¹⁸