Polymyalgia rheumatic
To address this, larger studies would be required, but supportive evidence from comparable populations may be considered as best surrogate. Even the four-arm GiACTA trial trial studying 250 people within four groups was unable to demonstrate a reduction of glucocorticoid associated adverse events despite the impressive glucocorticoid sparing. Data from registries and other studies involving a large number of subjects are required to confirm what we can only speculate from current tocilizumab trials in giant cell arteritis and polymyalgia rheumatica, namely that treatment of these patients with tocilizumab will ultimately reduce the burden from glucocorticoid-related adverse events. Safety in the elderly was also studied in patients with rheumatoid arthritis. 29 30 Interestingly during the trial musculoskeletal adverse events were reported only in the placebo group. Would one consider all these events were unrecognised flares of polymyalgia rheumatica, then the observed differences between placebo and tocilizumab would be even more pronounced in favour of tocilizumab. PMR-SPARE did not address the sustainability of tocilizumab treatment beyond 8 weeks after its application. Therefore, it is difficult to conclude whether tocilizumab has disease-modifying properties or might even be curative in some individuals, or if it is simply symptom controlling. The sustained glucocorticoid-free remission over the 8 weeks after their last application of tocili- zumab in the trial may indicate that effects of the compound go beyond mere symptom control. In addition no difference was observed at week 24 for CRP and ESR levels between tocili- zumab and placebo treated patients, which might be due to higher rates of glucocorticoid use in the latter. Whether drug- free remission could be maintained for longer or symptoms recur in a proportion of patients as in the long-term follow-up of the GiACTA trial trial (~40% flared at 6 months after stop- ping tocilizumab) is of great interest and has to be clarified by future research. Third, remission and relapse had to be defined purely clinically, as inhibition of the IL-6 receptor was expected to normalise acute phase reactants and may have therefore indi- rectly unblinded patients’ treatment allocation or have biased investigators towards a more frequent adjudication of remission in the tocilizumab group. It is possible that blinding towards ESR and CRP may have increased the uncertainty to define a relapse in both groups, given that activated degenerative shoulder prob- lems may not easily be distinguished from a PMR flare without knowing acute phase reactants. In summary, the double-blind, randomised, controlled PMR- SPARE study shows the superiority of tocilizumab over placebo, in combination with an 11-week course of glucocorticoids, in achieving glucocorticoid-free remission at week 16, and thus allowing one to spare glucocorticoids in the initial treatment of polymyalgia rheumatica. Effects of tocilizumab were maintained for at least 8 weeks after completion of tocilizumab therapy. Further studies are warranted to evaluate tocilizumab for its long-term sustainment of effects, its optimal duration of therapy, its safety and its use in refractory polymyalgia rheumatica. Acknowledgements We thank the teams of trial investigators and subinvestigators, in particular Angelika Lackner (BSc, MSc), Klaus Machold (MD), Christoph Porpaczy (MD), Thomas Karonitsch (MD), Peter Mandl (MD) Daniel Mrak (DM) as well as all the patients who participated in the trial. Contributors DA, JSS and CD were responsible for the study design. HR and AK were responsible for data analysis. MB, DA, JSS, HR and CD were responsible for writing of the manuscript. MD, JS, RH, MB, AK, DM, PM and DA were responsible for recruitment and clinical care of patients. HR, AK, MD, MB and DA accessed and verified the data. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors reviewed and approved the final version of the manuscript. DA accepts full responsibility for the work and/or the conduct of the study, had access to the data and controlled the decision to publish.
Funding The study was sponsored by the Medical University Vienna who received an unrestricted grant from Roche, the manufacturer of tocilizumab, who provided study drug and matching placebo. The funder reviewed and approved the study protocol, but had subsequently no role in conduct of the study including data collection, data analysis, data interpretation or writing of the report. Competing interests AK reports about contracts and personal fees from AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Merck Sharp and Dohme. RH reports about personal fees from MSD, AbbVie, Pfizer, Lilly, Bristol Myers Squibb, Celgene and Novartis. MB reports about personal fees from Eli Lilly. PM reports speaker fees from AbbVie, Janssen and Novartis and research grants from AbbVie, BMS, Novartis, Janssen, MSD and UCB. MB reports about personal fees from Eli Lilly. DA reports about financial support from Roche to perform this study for the Department of Rheumatology. DA received grants and consulting fees from AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche and Sandoz. CD received grants, consulting and personal fees from Celgene, Roche, Sanofi, AbbVie, Janssen, Roche, Novartis and Pfizer. JS reports about grants, consulting and personal fees from AbbVie, AstraZeneca, Lilly, Novartis, Amgen, Astro, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB. All other authors declare no competing interests. DA and JS declare that they currently have active roles as editorial board members of the journal. Patient consent for publication Consent obtained directly from patient(s). Ethics approval The study protocol was approved by the local ethical committee of the Medical University of Vienna (EK:2263/2016; EudraCT: 2016/004990/42). Participants gave informed consent to participate in the study before taking part. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Anonymous participant data are available under specific conditions. Proposals will be reviewed and approved by the sponsor, scientific committee and staff on the basis of scientific merit and absence of competing interests. Once the proposal has been approved, data can be transferred through a secure online platform after the signing of a data access agreement and a confidentiality agreement. Not applicable. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. ORCID iDs Michael Bonelli http://orcid.org/0000-0002-6122-7482 Andreas Kerschbaumer http://orcid.org/0000-0002-6685-8873 REFERENCES 1 Raheel S, Shbeeb I, Crowson CS, et al . Epidemiology of polymyalgia rheumatica 2000- 2014 and examination of incidence and survival trends over 45 years: a population- based study. Arthritis Care Res 2017;69:1282–5. 2 Buttgereit F, Dejaco C, Matteson EL, et al . Polymyalgia rheumatica and giant cell arteritis: a systematic review. JAMA 2016;315:2442–58. 3 Camellino D, Giusti A, Girasole G, et al . Pathogenesis, diagnosis and management of polymyalgia rheumatica. 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