Unravelling treatment efficacy and failure in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organ systems with varying severity and presents with unpredictable patterns over time. In the past fifteen years, the management of SLE has advanced notably through the introduction of three new licensed medications, the adoption of a target-driven treatment paradigm, and an increased focus on minimising treatment toxicities and managing comorbidities. Nevertheless, there remains a need to optimise the implementation of systematic monitoring strategies and holistic management plans that address diverse aspects of SLE through tailored interventions.

Using multiple data sources and study designs, this thesis investigates the effects of therapeutic interventions, with a focus on B-cell therapy, and lifestyle factors on health-related quality of life (HRQoL), disease activity, and organ damage in patients with SLE.

Study I examined the prevalence of poor HRQoL outcomes and severe fatigue amongst individuals classified as treatment responders in two randomised controlled trials of belimumab. Despite significant improvements from baseline, a substantial proportion of these patients continued to experience poor HRQoL, particularly in physical aspects (8-29%), and fatigue (26%). Organ damage contributed to poor physical HRQoL, while belimumab was protective against severe fatigue.

Studies II and III are cross-sectional studies evaluating associations between lifestyle factors and various patient-reported outcomes. In study II we explored associations between BMI and HRQoL and fatigue in all patients enrolled in the same two clinical trials of belimumab, and observed that BMI significantly impacted physical aspects of HRQoL, fatigue and social functioning, independently of disease activity, treatment, and organ damage. There was a gradual decline in HRQoL with increasing BMI. In Study III we expanded to associations of obesity and tobacco smoking with a broader array of patient- reported outcomes in patients from the Östergötland county in Sweden. We confirmed similar patterns of diminished HRQoL and fatigue amongst overweight and obese patients. Compared with non-smokers, current smokers reported reduced HRQoL and higher levels of fatigue and pain, with estimates that were consistently larger than those derived from comparisons with former smokers.

Study IV is a post-hoc analysis of four randomised controlled trials of belimumab where we estimated the effect of belimumab and antimalarial agents on preventing renal flares. Intravenous belimumab, at both 1 mg/kg or 10 mg/kg doses every fourth week, was associated with a lower risk of renal flares. Similarly, the use of antimalarial agents conferred a protective effect. Importantly, the protective effect of belimumab against renal flares was enhanced when it was co- administered with antimalarial agents.

In Study V, we investigated whether belimumab levels in serum were associated with clinical response and safety, as well as the occurrence of anti-drug antibodies against belimumab. In a cohort of 100 belimumab-treated SLE patients followed for up to two years at three Swedish University Hospitals, we found modest associations between belimumab levels and various measures of disease activity, but no clear link with serological activity or safety outcomes. Notably, using a drug-tolerant acid-dissociation radioimmunoassay, we did not detect anti-drug antibody formation following belimumab exposure.

Lastly, in Study VI, we developed a novel tool to measure organ damage using healthcare administrative codes and evaluated its accuracy to estimate SDI scores collected from a well-characterised cohort from Sweden. This new index displayed very high sensitivity, specificity and positive predictive value to detect organ damage. When applied to a nationwide cohort of newly diagnosed SLE patients from Sweden, 40% of them developed organ damage within the first five years of diagnosis. Men and older individuals had a higher risk to develop organ damage compared with their counterparts, while no changes in the risk of organ damage were observed across calendar periods over the last decades. Additionally, there was a strong association between early development of RBODI- based organ damage and long-term mortality, underscoring the need for effective strategies to prevent organ damage.

List of scientific papers

I. Adverse health-related quality of life outcome despite adequate clinical response to treatment in systemic lupus erythematosus. Gomez A, Qiu V, Cederlund A, Borg A, Lindblom J, Emamikia S, Enman Y, Lampa J, Parodis I. Front Med (Lausanne). 2021;8:651249 https://doi.org/10.3389/fmed.2021.651249

II. Impact of overweight and obesity on patient-reported health- related quality of life in systemic lupus erythematosus. Gomez A, Butrus F, Johansson P, Åkerström E, Soukka S, Emamikia S, Enman Y, Pettersson S, Parodis I. Rheumatology (Oxford). 2021;60(3):1260-72. https://doi.org/10.1093/rheumatology/keaa453

III. Obesity and tobacco smoking are independently associated with poor patient-reported outcomes in SLE: a cross-sectional study. Gomez A, Parodis I, Sjöwall C. Rheumatology International. 2024;44(5):851-61. https://doi.org/10.1007/s00296-024-05546-z

IV. Belimumab and antimalarials combined against renal flares in patients treated for extra-renal systemic lupus erythematosus: results from 4 phase III clinical trials. Gomez A, Jägerback S, Sjöwall C, Parodis I. Rheumatology (Oxford). 2024;63(2):338-48. https://doi.org/10.1093/rheumatology/kead253

V. Belimumab concentrations and immunogenicity in relation to drug efficacy and safety in systemic lupus erythematosus. Gomez A, Walhelm T, Loeff F, Jonsen A, Nikolopoulos D, van den Broek B, Bengtsson A, de Vries A, Rispens T, Sjöwall C, Parodis I. [Manuscript]

VI. Development and evaluation of a register-based organ damage index in systemic lupus erythematosus: a nationwide, population-based study from Sweden. Gomez A, Parodis I, Saleh M, Simard JF, Sjöwall C, Arkema EV. [Manuscript]