POS1427 EFFECTIVENESS OF INTERLEUKIN-6 RECEPTOR INHIBITORS VERSUS CONVENTIONAL SYNTHETIC IMMUNOMODULATORY THERAPY FOR TREATMENT OF FRAIL PATIENTS WITH POLYMYALGIA RHEUMATICA
Authors: S. E. Sattui, C. Dejaco, K. Ford, S. Fiore, S. Unizony, F. Xie, J. R. Curtis
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Treatment of polymyalgia rheumatica (PMR), a common inflammatory rheumatic disease in older adults, is hindered by a paucity of glucocorticoid (GC)-sparing therapies with proven efficacy. A retrospective study showed treatment with IL-6 receptor inhibitors (IL-6Ri) vs. conventional synthetic immunomodulatory drugs (csIM [methotrexate, leflunomide, and azathioprine]) was associated with greater likelihood of GC discontinuation (HR [95% CI]: 1.32 [1.09–1.58]) at 1 year<sup>1</sup>. Frailty, a syndrome characterized by increased vulnerability to stressors and poor health outcomes is associated with aging and inflammation. Frailty may be accelerated and more prevalent in patients with PMR vs. the general population<sup>2</sup>. Prolonged GC treatment may exacerbate frailty<sup>3</sup>, highlighting the need to reduce GC use in these patients. IL-6 is involved in the pathogenesis of PMR and frailty<sup>2</sup> and thus, patients with both may particularly benefit from IL-6Ri therapy. <h3>Objectives:</h3> To compare effectiveness of IL-6Ri vs. csIM therapy as second (2L) and third (3L) line treatment for frail patients with PMR. <h3>Methods:</h3> A subgroup analysis of patients with frailty from a retrospective cohort study comparing the effectiveness of IL-6Ri to csIM in 2L and 3L treatment of patients with PMR identified from 3/2016–6/2019 using Medicare claims data was conducted. IL-6Ri and csIM PMR patients were direct matched on multiple factors (e.g. baseline GC dose category, and history of giant cell arteritis) and then propensity matched pairs were assessed with a validated claims-based frailty index (CFI)<sup>4</sup>. Although CFI ≥0.2<sup>5</sup> and ≥0.25<sup>4</sup> have been used as thresholds for frailty, due to sample size median CFI was used as the threshold to identify more frail patients. Matched pairs of patients with CFI ≥median, were retained for comparison. The primary outcomes were time-to-GC discontinuation (&gt;60-day gap) and time-to-GC discontinuation or minimal GC dose (≤2 mg/day of prednisone equivalent) using Cox proportional hazards models stratified by 2L or 3L treatment. Patients were censored at 1 year, 60 days prior to the end of enrollment, death, outcome achievement, stopping csIM/IL-6Ri therapy or switching csIM/IL-6Ri therapy. Cumulative GC dose was also compared. <h3>Results:</h3> Of the 187 2L and 228 3L PS matched pairs from the parent cohort, 89 (35 [39.3%] 2L and 54 [60.7%] 3L) had CFI ≥0.2, the median. The most common csIM therapy in 2L and 3L was methotrexate (77.1%) and leflunomide (64.8%), respectively. Patient characteristics were generally balanced <b>(Table 1</b>) though patients with IL-6Ri were less likely to enroll in Medicare due to disability than csIM initiators (19.1% vs. 31.5%) and they had more inpatient days during baseline (Mean [SD] 2.1 [6.2] vs. 0.9 [2.6]) <b>(Table 1</b>). IL-6Ri vs. csIM initiators were significantly more likely to discontinue GC (HR [95% CI] 2.32 [1.35–3.99], P=0.002) and achieve discontinuation of GC or minimal GC dose (HR [95% CI] 2.23 [1.34–3.71], P=0.002), and had a lower cumulative GC dose (Mean [SD], mg; (3017.6 [4327.1] vs. 5764.0 [14690.3], P=0.025)) <b>(Table 2</b>). Results of sensitivity analyses for discontinuation of GC varying the censoring rules by removing censoring for 1 year, stopping or switching csIM or IL-6Ri, and stopping csIM or IL-6Ri resulted in similar findings with HR (95% CI) of 1.88 (1.14–3.10), P=0.013; 2.49 (1.59–3.89), P&lt;0.001 and 2.71 (1.71–4.29), P&lt;0.001, respectively. <h3>Conclusion:</h3> Compared with csIM, IL-6Ri therapy had a greater GC-sparing effect in frail patients with PMR. The effect size seen in patients with frailty appears to be larger than previously reported in a general PMR cohort<sup>1</sup>, suggesting patients with frailty may derive even greater benefit from IL-6Ri therapy compared with csIM therapy. <h3>REFERENCES:</h3> [1] Curtis JR et al. AMCP 2023 Poster No. M18. [2] Sattui SE et al. <i>Rheumatology (Oxford</i>) 2022;61:4455–64. [3] Motta F et al. <i>Front Immunol</i> 2020;11:576134. [4] Kim DH et al. <i>J Gerontol A Biol Sci Med Sci</i> 2019;74:1271–6. [5] Halawa OA et al. <i>Ophthalmology</i> 2023;130:646–54. <h3>Acknowledgements:</h3> The study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Medical writing support for this abstract was provided by Kritika Dhamija, M.S. (Pharm.), of Sanofi. <h3>Disclosure of Interests:</h3> Sebastian E. Sattui Research funding from Bristol Myers Squibb Foundation Robert A. Winn Diversity in Clinical Trials Career Development Award, Research support AstraZeneca and Glaxo Smith Kline (clinical trials), Consulting and advisory boards for Sanofi and Amgen (all funds toward research support), Christian Dejaco Consulting/speaker's fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, Sparrow, Roche, Galapagos, and Sanofi, Editorial board member of ARD, Kerri Ford Employee of Sanofi and may hold stock and/or stock options in the company, Stefano Fiore Employee of Sanofi and may hold stock and/or stock options in the company, Sebastian Unizony Consulting fees from Kiniksa, Janssen, and Sanofi, Research support from Genentech, Fenglong Xie: None declared, Jeffrey R Curtis Consulting, research grants from AstraZeneca, Amgen, AbbVie, Bendcare, Genentech, GSK, Horizon, Janssen, Lilly, Novartis, Pfizer, Sanofi, Scipher Medicine, Setpoint, and UCB.