The Patient Experience of Fatigue in Systemic Lupus Erythematosus: A Conceptual Model.

INTRODUCTION: Fatigue is frequently experienced in systemic lupus erythematosus (SLE) and is a key outcome in clinical research trials. However, SLE fatigue is complex and poorly understood, and challenging to measure. We aimed to characterise fatigue from the patients' perspective and develop a conceptual model of fatigue based on qualitative interviews. METHODS: We conducted semi-structured qualitative interviews exploring fatigue in patients with SLE recruited from a social network (n = 29) and a phase 2 clinical study (n = 43). Transcripts were coded thematically, and codes were inductively categorised into a conceptual model. RESULTS: Fatigue was the most commonly reported symptom in the interviews and generated a wide range of codes. From these, our concept-driven approach revealed three overarching domains of the fatigue experienced in SLE: (i) physical manifestation of physical and bodily symptoms (including physical energy, stamina and impact on movement); (ii) mental and cognitive manifestation (including mental energy, motivation, and cognitive functioning symptoms); and (iii) susceptibility to fatigue or how easily 'fatigable' patients are, meaning how easily they become fatigued and how easily their fatigue is alleviated (including the rapid, disproportionate, and/or unpredictable onset of fatigue, non-restorative sleep, and need for more sleep/rest breaks). Within each of these, participants described the severity, variation and impact of fatigue on everyday life. Participants also described how the SLE fatigue experience differed from 'everyday tiredness'. CONCLUSIONS: The findings of this research indicate that comprehensive measurement of fatigue in SLE will require consideration and quantification of the three domains described in our conceptual model. Future research will explore whether this conceptual model can form the basis of a valid and reliable measurement of fatigue in SLE.

The FATIGUE-PRO: a new patient-reported outcome instrument to quantify fatigue in patients affected by systemic lupus erythematosus.

OBJECTIVES: This study aimed to implement a patient-centred and evidence-based approach to develop a novel patient-reported outcome (PRO) instrument to measure fatigue in patients with SLE. METHODS: A three-step mixed methods psychometric (MMP) approach was followed. Steps comprised first draft item generation and review using interview data; evaluation and refinement of second draft items using mixed methods data, including interview and quantitative data from a phase 2 clinical study in SLE analysed using Rasch Measurement Theory (RMT) analysis; and evaluation of the final FATIGUE-PRO items using RMT and complementary Classical Test Theory (CTT) analyses. Guided by MMP criteria, a team of clinicians and outcome-measurement experts assessed evidence to inform instrument development. RESULTS: Step 1 culminated in 55 items (n = 39 patients interviewed). Their refinement in step 2 using mixed methods evidence led to the final FATIGUE-PRO instrument comprising 31 items across three scales of fatigue: physical fatigue (9 items), mental and cognitive fatigue (11 items) and susceptibility to fatigue (11 items). Qualitative (n = 43 patients) and quantitative (n = 106 patients) evidence strongly supported the scales' content comprehensiveness and targeting, item quality and fit, conceptual uniqueness and appropriateness of the response scale. The FATIGUE-PRO further benefited from excellent reliability (RMT: 0.92-0.94 and CTT: 0.95-0.96) and supportive evidence of construct validity from assessments against other PROs. CONCLUSION: The conceptual advances, comprehensive coverage and strong psychometric properties of the FATIGUE-PRO will significantly advance the measurement and management of fatigue in SLE, both in clinical trials and routine practice. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT02804763.

Phase 2, randomized, placebo-controlled trial of dapirolizumab pegol in patients with moderate-to-severe active systemic lupus erythematosus.

OBJECTIVE: To evaluate the dose-response, efficacy and safety of dapirolizumab pegol (DZP) in patients with SLE. METHODS: Adults with moderately to severely active SLE (SLEDAI-2K score ≥6 and ≥1 BILAG A or ≥2 BILAG B domain scores), receiving stable CS (≤40 mg/day prednisone-equivalent), antimalarial or immunosuppressant drugs were included. Patients with stable LN (proteinuria ≤2 g/day) not receiving high-dose CS or CYC were permitted entry. Randomized patients received placebo or i.v. DZP (6/24/45 mg/kg) and standard-of-care (SOC) treatment every 4 weeks to week 24, after which patients received only SOC to week 48. The primary objective was to establish a dose-response relationship based on week 24 BILAG-Based Composite Lupus Assessment (BICLA) responder rates. RESULTS: All DZP groups exhibited improvements in clinical and immunological outcomes vs placebo at week 24; however, BICLA responder rates did not fit pre-specified dose-response models [best-fitting model (Emax): P = 0.07]. Incidences of serious treatment-emergent adverse events across DZP groups were low and similar to placebo. Following DZP withdrawal, SLEDAI-2K, physician's global assessment (PGA), BILAG, and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores stabilized; BICLA and SLE Responder Index (SRI-4) responder rates declined (likely due to interventions with disallowed escape medications), BILAG flares increased, and immunologic parameters returned towards baseline. CONCLUSIONS: Although the primary objective was not met, DZP appeared to be well tolerated, and patients exhibited improvements across multiple clinical and immunological measures of disease activity after 24 weeks relative to placebo. The potential clinical benefit of DZP warrants further investigation.

First-in-human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL-17A and IL-17F, in mild psoriasis.

AIMS: To assess safety, pharmacokinetics (PK) and clinical efficacy of bimekizumab (formerly UCB4940), a novel humanized monoclonal antibody and dual inhibitor of interleukin (IL)-17A and IL-17F, in subjects with mild plaque psoriasis. METHODS: Randomized, double-blind, first-in-human study of bimekizumab in 39 subjects who received single-dose intravenous bimekizumab (8-640 mg) or placebo (NCT02529956). RESULTS: Bimekizumab demonstrated dose-proportional linear PK and was tolerated across the dose range assessed. No subject discontinued due to treatment-emergent adverse events and no severe adverse events were reported. Bimekizumab demonstrated fast onset of clinically-meaningful effects on skin of patients with mild psoriasis as early as Week 2. Maximal improvements (100% or near 100% reductions from baseline) in all measures of disease activity were observed between Weeks 8-12 in subjects receiving 160-640 mg bimekizumab. The duration of effect at doses ≥160 mg was evident up to Weeks 12-20 after a single intravenous dose, dependent on endpoint. CONCLUSIONS: This is the first study to demonstrate the safety, tolerability and clinical efficacy of a dual IL-17A and IL-17F inhibitor, in subjects with mild psoriasis. Bimekizumab showed fast onset of clinically-meaningful efficacy by Week 2, with a maximal or near-maximal magnitude of response that was maintained up to study Weeks 12-20. These findings support the continued clinical development of bimekizumab for diseases mediated by both IL-17A and IL-17F, including psoriasis.