February 2024
Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicenter service evaluation in England
Quick V et al. Rheumatology (Oxford). 2023 Nov 11: doi:10.1093/rheumatology/kead604
VASAS summary
Interleukin-6 (IL-6) is a critical, pro-inflammatory cytokine in the pathogenesis of giant cell arteritis (GCA).
Early studies from VASAS members demonstrated that blocking IL-6 with the monoclonal antibody tocilizumab (TCZ; marketed as Actemra) is highly effective in GCA (Villiger PM et al. Lancet 2016).
This was confirmed in the GiACTA (Giant-Cell Arteritis Actemra) study, a large randomized-controlled trial (RCT) establishing sustained disease remission in 56% of TCZ treated patients vs. 14% in controls (Stone JH et al. N Engl J Med 2017).
This landmark study revolutionized the treatment of GCA patients.
However, follow-up data from the GiACTA trial showed that after TCZ discontinuation, a substantial proportion of patients experience relapses.
How prevalent relapses after TCZ occur in real-life settings, i.e. outside the selected patients in RCTs, remains to be defined.
A recent, large UK research consortium involving 40 centers addressed this question in >300 GCA patients treated with weekly TCZ.
TCZ was stopped after a median of 12 months (12-17) of treatment.
The 12 months are based on the GiACTA trial data and the NHS coverage of this indication.
The main outcome was relapse rates 6, 12, and 24 months following treatment-stop.
Notably, the patients were still on a median prednisolone dose of 2 (IQR 0-5) mg/day at that time.
The frequency of patients experiencing a relapse 6 months after stopping TCZ was 21.4%.
This proportion increased to 35.4% and 48.6% after 12 and 24 months, respectively.
In this cohort, relapse was treated with an increase in prednisolone in median to 20 mg/day.
Importantly, one-third of the relapses were major relapses (EULAR definition of major relapse: clinical signs of ischemia (ophthalmological damage, jaw claudication, scalp necrosis, stroke, limb ischemia) or aortic damage (stenosis and aortic aneurysms, aortic dissections)).
The authors confirmed risk factors for early relapses, specifically:
(i) having had previous relapses during TCZ therapy;
(ii) absence of remission at the time of TCZ stop, and
(iii) having large-vessel involvement.
These factors can be considered to be very intuitive or have previously been described (large-vessel disease and relapse risk).
Intriguingly, or age (≥65 years old), gender, vision loss, TCZ treatment duration and prednisolone dosing were not associated with time to relapse.
This study corroborates previous findings of high relapse rates after cessation of 12 months of TCZ therapy. Almost half of the patients experienced disease relapses within two years. This data is in line with Swiss studies of VASAS members reporting GCA relapse rates following TCZ discontinuation between 40-60% in cohorts from Basel (Berger CT et al., Ann Rheum Dis. 2019) and Bern (Adler S et al., Rheumatology (Oxford). 2019), as well as from international cohorts (47% in Matza MA et al., RMD Open 2023).
This data argues that despite the great success of TCZ in the treatment of GCA there is still a need for novel GCA therapies targeting the origin of inflammation rather than the inflammation itself.
The study identifies risk groups likely in need of extended treatment durations, which should be prospectively studied.
Author of the abstract:
Prof. Christoph T. Berger, Basel
VASAS summary
Interleukin-6 (IL-6) is a critical proinflammatory cytokine in the pathogenesis of giant cell arteritis (GCA).
Early studies by VASAS members showed that blocking IL-6 with the monoclonal antibody tocilizumab (TCZ; Actemra) is highly effective in RZA (Villiger PM et al. Lancet 2016).
This was seen in the GiACTA (Giant-Cell Arteritis Actemra) study with a sustained disease remission of 56% in TCZ treated patients versus 14% in control subjects (Stone JH et al. N Engl J Med 2017).
This pivotal study revolutionized the treatment of RZA patients.
However, follow-up data from the GiACTA study showed that relapses occur in a significant proportion of patients after discontinuation of TCZ.
How often relapses occur after TCZ in real life, i.e. outside of the selected patients in a randomized controlled trial, has yet to be defined.
A recent large UK research consortium of 40 centers investigated this question in more than 300 RZA patients treated weekly with TCZ.
TCZ was discontinued after a median treatment duration of 12 months (IQR 12-17 months).
The 12 months is based on the GiACTA trial data and NHS coverage for this indication.
The main outcome was relapse rates at 6, 12 and 24 months after the end of treatment.
Of note, patients were still receiving a median prednisone dose of 2 (IQR 0-5) mg/day at this time point.
The frequency of patients who relapsed 6 months after discontinuation of TCZ was 21.4%.
This proportion increased to 35.4 % and 48.6 % after 12 and 24 months, respectively.
In this cohort, relapse was treated by increasing the prednisone dose to a median of 20 mg/day.
Importantly, one third of the relapses were severe relapses (EULAR definition of severe relapse: clinical signs of ischemia (visual disturbance, headache, scalp necrosis, stroke or limb ischemia) or aortic damage (stenosis and aortic aneurysms, aortic dissections).
The authors also confirmed risk factors for early recurrence:
(i) previous relapses during TCZ therapy;
(ii) no remission at the time of TCZ discontinuation; and
(iii) involvement of large vessels.
These factors can be considered highly intuitive or have been previously described (i.e., large vessel disease and risk of relapse).
Interestingly, age (≥ 65 years), gender, vision loss, TCZ treatment duration and prednisone dosage were not associated with time to relapse.
This study confirms earlier findings of high relapse rates after completion of 12 months of TCZ therapy. Almost half of the patients experienced relapses within two years. These data are consistent with Swiss data from VASAS members who observed 40-60% relapses after discontinuation of TCZ (Berger CT et al., Ann Rheum Dis. 2019; Adler S et al, Rheumatology (Oxford). 2019) and international cohort data (47 % in Matza MA et al., RMD Open 2023).
From these data, it can be concluded that despite the great success of TCZ in the treatment of RZA, there is still a need for novel RZA therapies.
Ideally, these should target the origin of the inflammation rather than the inflammation itself.
The UK study further identifies risk groups that are likely to require a longer duration of treatment, which should be investigated prospectively.
