Arthritis Care & Research | 2021
Reply
Abstract
the results of our study demonstrated that UST was not as effective as originally hoped. We agree with Conway and Molloy that other studies can be designed to better define whether there is a role for UST in the treatment of GCA. Limiting enrollment to relapsing patients, using longer prednisone tapers, or leaving patients on a low prednisone maintenance dose are some possibilities. Ultimately, we agree that to rigorously test the efficacy and safety of UST for GCA, an adequately powered randomized, placebocontrolled trial is required. Our trial may be insightful in understanding that a steroid taper of 6 months may indeed be too short when used with UST. Although shorter than tapers commonly used in clinical practice, the 6month taper employed in our trial (Supplementary Table 1 of our article, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24200/abstract) is in accordance with those used in most GCA clinical trials (1– 4) (ClinicalTrials.gov identifiers: NCT03827018, NCT03600805, NCT02531633, NCT03725202). Such tapers have had the objective of assessing whether an intervention offers unequivocal glucocorticoidsparing potential, which was one of the main drivers of our investigation. Furthermore, when planning the prednisone regimen used in our study, we considered that between 8 and 12 weeks are required for UST to exert its immunomodulatory effects (5). To ensure enough prednisone treatment until the onset of action of UST, the duration of the taper was 6 months in all cases, leading to prednisone doses of 12.5 mg/day, 10 mg/ day, and 6 mg/day at week 12 for patients starting the taper at 60 mg, 40 mg, and 20 mg, respectively. In addition, we opted for a higher UST dose (90 mg at baseline, week 4, and every 8 weeks) than the one used in the prior study (6) to achieve higher serum concentrations and increase the cumulative exposure to this agent. As was discussed in our prior response to the letter by Samson and Bonnotte, a posteriori analysis of the flares occurring in our study (Supplementary Table 2 of our article, available at http://onlinelibrary.wiley.com/doi/10.1002/acr.24200/abstract) further suggests, in our opinion, that the prednisone taper chosen was adequate if indeed UST was to be effective. All disease flares occurred at or after week 16 following an adequate duration of UST treatment. In addition, the individual prednisone doses at week 12 were 10 mg/day or greater for all except 1 patient, who experienced a flare, indicating that the great majority of the patients with flares received a daily prednisone dose commonly associated with remission maintenance (7–9) by the onset of action of UST. Nevertheless, we also believe it is important to understand how UST would fare as a glucocorticoidsparing agent with a slightly longer taper or when patients remain on low, nontoxic glucocorticoid doses. The relapse rate seen in our study is within the range reported in some cohort studies of patients with GCA treated only with glucocorticoids (7,10–12), clinical trials of drugs proven to be ineffective, and placebo arms of clinical trials of drugs 1. Matza MA, Fernandes AD, Stone JH, Unizony SH. Ustekinumab for the treatment of giant cell arteritis. Arthritis Care Res (Hoboken) 2021;73:893– 7. 2. Conway R, O’Neill L, McCarthy GM, Murphy CC, Fabre A, Kennedy S, et al. Interleukin 12 and interleukin 23 play key pathogenic roles in inflammatory and proliferative pathways in giant cell arteritis. Ann Rheum Dis 2018;77:1815– 24. 3. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, et al. Trial of tocilizumab in giantcell arteritis. N Engl J Med 2017;377:317– 28. 4. Mainbourg S, Addario A, Samson M, Puéchal X, François M, Durupt S, et al. Prevalence of giant cell arteritis relapse in patients treated with glucocorticoids: a metaanalysis. Arthritis Care Res (Hoboken) 2020;72:838– 49. 5. Proven A, Gabriel SE, Orces C, O’Fallon WM, Hunder GG. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum 2003;49:703– 8. 6. Jamilloux Y, Liozon E, Pugnet G, Nadalon S, Heang Ly K, Dumonteil S, et al. Recovery of adrenal function after longterm glucocorticoid therapy for giant cell arteritis: a cohort study. PLoS One 2013;8:e68713. 7. Kroon FP, Kortekaas MC, Boonen A, Böhringer S, Reijnierse M, Rosendaal FR, et al. Results of a 6week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a doubleblind, randomised, placebocontrolled trial. Lancet 2019;394:1993– 2001. 8. Conway R, O’Neill L, Gallagher P, McCarthy GM, Murphy CC, Veale DJ, et al. Ustekinumab for refractory giant cell arteritis: a prospective 52week trial. Semin Arthritis Rheum 2018;48:523– 8. 9. Conway R, O’Neill L, O’Flynn E, Gallagher P, McCarthy GM, Murphy CC, et al. Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis 2016;75:1578– 9.