Anifrolumab reduces flare rates in patients with moderate to severe systemic lupus erythematosus

Background Systemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab’s effect on flares, including those arising with glucocorticoid taper. Methods TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). For patients receiving baseline glucocorticoid ≥10 mg/day, attempted taper to ≤7.5 mg/day prednisone or equivalent from Weeks 8–40 was required and defined as sustained reduction when maintained through Week 52. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores versus the previous visit. Flare assessments were compared for patients receiving anifrolumab versus placebo. Results Compared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates (rate ratio 0.75, 95% confidence interval [CI] 0.60–0.95), prolonged time to first flare (hazard ratio 0.70, 95% CI 0.55–0.89), and fewer patients with ≥1 flare (difference −9.3%, 95% CI −16.3 to −2.3), as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had ≥1 flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from ≥10 mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185). Conclusions Analyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE. ClinicalTrials.gov identifiers TULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912); TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).

Employing a latent variable framework to improve efficiency in composite endpoint analysis

Composite endpoints that combine multiple outcomes on different scales are common in clinical trials, particularly in chronic conditions. In many of these cases, patients will have to cross a predefined responder threshold in each of the outcomes to be classed as a responder overall. One instance of this occurs in systemic lupus erythematosus, where the responder endpoint combines two continuous, one ordinal and one binary measure. The overall binary responder endpoint is typically analysed using logistic regression, resulting in a substantial loss of information. We propose a latent variable model for the systemic lupus erythematosus endpoint, which assumes that the discrete outcomes are manifestations of latent continuous measures and can proceed to jointly model the components of the composite. We perform a simulation study and find that the method offers large efficiency gains over the standard analysis, the magnitude of which is highly dependent on the components driving response. Bias is introduced when joint normality assumptions are not satisfied, which we correct for using a bootstrap procedure. The method is applied to the Phase IIb MUSE trial in patients with moderate to severe systemic lupus erythematosus. We show that it estimates the treatment effect 2.5 times more precisely, offering a 60% reduction in required sample size.

AB1249 ASSESSMENT OF FATIGUE IN ADULTS WITH MODERATE-TO-SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): A QUALITATIVE STUDY TO EXPLORE WHAT PATIENTS FEEL SHOULD BE MEASURED IN CLINICAL TRIALS

Background:Fatigue is one of the most common symptoms reported by patients with systemic lupus erythematosus (SLE)—it is responsible for considerable loss of work time and greatly impaired quality of life. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) has been used to assess fatigue in SLE clinical trials1; however, assessment of the content validity of the FACIT-F in adults with SLE suggested that closer evaluation may be warranted.2Objectives:This qualitative study aimed to understand SLE patients’ experience of fatigue and assess the content validity of the FACIT-F.Methods:The evaluation was informed by literature and guided by a project steering committee (PSC; patient advocate, clinical expert, outcomes measure expert). The institutional review board-approved study involved focus groups (Round 1) and cognitive interviews (Round 2) with adults with moderate-to-severely active SLE. All participants provided written informed consent. Round 1 included three focus groups to understand the disease and fatigue-related concepts that were most important to patients; participants also provided high-level feedback on the FACIT-F. Round 2 included 13 one-on-one cognitive interviews on the relevance of content, clarity, and comprehensiveness of the FACIT-F. Interviews were audio-recorded and transcribed and a content analysis was completed. The PSC reviewed results and contributed to decision-making. Specific focus was on determining patient understanding of the FACIT-F, comprehensiveness, and any gaps in concept coverage to evaluate fatigue in the context of a clinical trial.Results:Twenty-eight patients with moderate-to-severely active SLE participated; they were mostly female (n=27), had a mean age of 45.5 ± 12.1 years (range: 18–75), and 23 (82%) had moderate and five (18%) severely active SLE. All participants were receiving SLE treatment, and most (n=23, 82%) reported fatigue among their top three most important SLE-related symptoms. Fatigue was described as having a profound impact on daily life, including ability to perform chores and work-related activities, maintain personal hygiene, exercise, and participate in hobbies. Study participants reported the FACIT-F covered concepts most relevant to their fatigue experience. Participants were able to understand the FACIT-F instructions, items, and response options and felt the recall period of seven days was appropriate.Conclusion:Fatigue was one of the most important symptoms, having a significant impact on adults with moderate-to-severely active SLE, limiting their ability to perform necessary or desired activities. The FACIT-F was found to be an appropriate measure for the assessment of fatigue in this sample.3Evidence of the content validity of the FACIT-F in adults with SLE was confirmed for use to support endpoints in the Cenerimod Assessing S1P1Receptor Modulation in SLE (CARE) clinical trial.References:[1]Izadi Z, Gandrup J, Katz PP, Yazdany J. Patient-reported outcome measures for use in clinical trials of SLE: a review. Lupus Sci Med. 2018;5(1):e000279.[2]Kosinski M, Gajria K, Fernandes A, Cella D. Qualitative validation of the FACIT-Fatigue scale in systemic lupus erythematosus. Lupus. 2013;22(5):422-430.[3]Mannix S, Beyer A, Strand V, Hanrahan L, Abel C, Flamion B, Hareendran A. Assessment of Fatigue in Adults with Moderate to Severe Systemic Lupus Erythematosus (SLE): A Qualitative Study to Explore What Patients Feel Should Be Measured in Clinical Trials [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10).Acknowledgments:We thank Dr. David Cella, developer of the FACIT-F, for his time discussing the measure, interim findings, and PSC feedback; the site staff for patient recruitment; Andrea Schulz and Rodolfo Matos, who conducted interviews.Disclosure of Interests:Sally Mannix Employee of: Evidera, Andrea Beyer Employee of: Idorsia Pharmaceuticals, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Leslie Hanrahan: None declared, Cristina Abél Employee of: Evidera, Bruno Flamion Shareholder of: Idorsia Pharmaceuticals, Employee of: Idorsia Pharmaceuticals, Asha Hareendran Employee of: Evidera

Case of using mycophenolate in combination with steroids for concurrent macrophage activation syndrome and lupus flare

This report highlights the importance of tailored treatment strategies in severe systemic lupus erythematosus (SLE) flares driving the life-threatening condition, macrophage activation syndrome (MAS). We report the case of a 42-year-old woman with active systemic lupus erythematosus (SLE) who was diagnosed with MAS within 3 days of onset of lethargy, rash, joint pain and significant cytopenias. This early diagnosis meant that her condition was managed with less intensive immunosuppression with only modest doses of steroids and mycophenolate mofetil.