Systemic lupus erythematosus : biomarkers and biologics

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, predominantly affecting women of childbearing age. The pathogenesis of SLE is multifactorial, and the clinical phenotype and course vary considerably within the SLE population. Multiple organs can be involved, lupus nephritis (LN) being one of the most severe manifestations. Immunologic abnormalities constitute a hallmark of SLE, and hyperactivity of the B cell lineage plays an important role in the pathogenesis, resulting in a prominent production of autoantibodies to nuclear components and immune complex depositions. The heterogeneity of SLE makes its management and the development of new therapies challenging. Belimumab is a monoclonal antibody targeting the B cell activating cytokine BAFF, also known as BLyS, approved for the treatment of SLE. In the studies included in this thesis, we focused on biomarkers in lupus nephritis and effects of belimumab treatment in SLE. For the purpose of the first part, immune components that have been implied to be important in lupus nephritis were evaluated as biomarkers of activity, response to treatment and long-term prognosis. In the second part, we investigated the clinical and immunologic effects of belimumab in a prospective, real-life clinical setting. We identified an association of antiphospholipid antibodies with short-term renal function impairment during LN flares, but we found no association with the long-term renal prognosis. In contrast, soluble TNF receptor 2 was predictive of kidney tissue damage and long-term renal function deterioration. Soluble TNF receptor 2 was shown to predict treatment response in patients with membranous nephritis, whereas a role of APRIL, a plasma cell survival cytokine, was implicated in proliferative glomerulonephritis. Finally, low baseline serum concentrations of BLyS were predictive of response to induction treatment for LN. We demonstrated decreased disease activity and corticosteroid usage, and no significant damage progression in patients with SLE during belimumab treatment. We observed rapid effects on naïve B cells and B cells of earlier developmental stages, whereas later stage B cells showed delayed or no changes. High baseline disease activity and steroid dose were associated with beneficial treatment outcomes, whereas smoking and established organ damage predicted reduced treatment efficacy. While high BLyS levels predicted clinical improvements, high B cell counts predicted unfavourable outcomes, implying that patients with a high B cell activity and, therefore, suppressed BLyS activity may benefit from B cell depletion preceding BLyS inhibition. Based on our results from the studies of belimumab, smokers who qualify for treatment with this biologic agent should actively be encouraged to quit smoking. An important implication for the use of belimumab is that early treatment evaluation might underestimate delayed clinical improvements occurring as a consequence of late therapy-associated B cell changes

COVID-19 vaccination in autoimmune diseases (COVAD) Study: vaccine safety and tolerance in rheumatoid arthritis

OBJECTIVES: The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in rheumatoid arthritis (RA) patients. METHODS: An online self-reported questionnaire (March-December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. RESULTS: Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA who had a mean (standard deviation) age of 50.7 (13.7) years, and 74.2% were women, and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both OR = 0.7; 95%CI = 0.5-0.9), and injection site pain (OR = 0.6; 95%CI = 0.5-0.8) with similar major AE and hospitalization frequencies. CONCLUSION: Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs providing reassurance to the safety of COVID-19 vaccination in them

Evolving Concepts in Treat-to-Target Strategies for Systemic Lupus Erythematosus

Funding Information: IP has received grants from the Swedish Rheumatism Association (R-969696), King Gustaf V\u2019s 80-year Foundation (FAI-2020-0741), Swedish Society of Medicine (SLS-974449), Nyckelfonden (OLL-974804), Professor Nanna Svartz Foundation (2021-00436), Ulla and Roland Gustafsson Foundation (2021-26), Region Stockholm (FoUI-955483), and Karolinska Institutet. DN has received grants from Ulla o Roland Gustafssons Donationsfond (2024-49), Ulla och Gustaf af Ugglas stiftelse (2023-025029) and Reumatikerf\u00F6rbundet (2024 R-995557). Publisher Copyright: © 2024 The Author(s).Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterised by a wide range of symptoms and a risk for irreversible organ damage, leading to increased morbidity and mortality. To improve long-term outcomes, innovative therapeutic goals have been explored, including attainment and maintenance of remission or low disease activity, with minimal use of glucocorticoids. Other goals encompass early diagnosis, potent yet less toxic therapies, appropriate glucocorticoid tapering, and better quality of life for the patients. Implementing a treat-to-target (T2T) approach involves treatment adjustments to achieve predefined objectives. Evidence from other chronic diseases, like hypertension and diabetes, supports the success of target-based approaches. In rheumatic diseases, the multitude of clinical features adds complexity to T2T strategies, but in rheumatoid arthritis, T2T has yielded improved outcomes. The application of T2T in SLE requires realistic therapeutic goals and practical tools for their measurement. International task forces have developed T2T recommendations for SLE, focusing on limiting disease activity, preventing organ damage, and minimising glucocorticoid use, while considering patients’ quality of life. Advancements in defining clinically meaningful remission and low disease activity states, coupled with promising novel therapies, have spurred progress in the management of SLE.publishersversionpublishe

Cardiovascular risk evaluation in psoriatic arthritis by aortic stiffness and the Systemic Coronary Risk Evaluation (SCORE): results of the prospective PSOCARD cohort study

Introduction Psoriatic arthritis (PsA) is associated with increased cardiovascular (CV) risk and mortality. Aortic stiffness measured by carotid-femoral pulse wave velocity (cfPWV) has been shown to predict CV risk in the general population. The present study aimed to examine cfPWV values of patients with PsA compared to healthy controls and to evaluate associations of cfPWV with patient- and disease-associated characteristics, as well as with an established traditional CV prediction score of the European Society of Cardiology (Systemic Coronary Risk Evaluation; SCORE), for the first time. Methods cfPWV and SCORE were evaluated in patients with PsA and healthy controls, along with clinical and laboratory disease parameters. Differences in cfPWV measurements between the two groups and associations of cfPWV with patient- and disease-associated characteristics were statistically evaluated. Results A total of 150 patients with PsA (PSOCARD cohort) and 88 control subjects were recruited. cfPWV was significantly higher in the PsA group compared to controls, even after adjustment for confounders (padj = 0.034). Moreover, cfPWV was independently associated with disease duration (r = 0.304, p = 0.001), age (rho = 0.688, p < 0.001), systolic arterial pressure (rho = 0.351, p < 0.001), glomerular filtration rate (inverse: rho = − 0.264, p = 0.001), and red cell distribution width, a marker of major adverse CV events (MACE) (rho = 0.190, p = 0.02). SCORE revealed an elevated CV risk in 8.73% of the patients, whereas cfPWV showed increased aortic stiffness and end-organ disease in 16.00% of the same cohort. Conclusions In the largest cfPWV/PsA cohort examined to date, patients with PsA exhibited increased aortic stiffness compared to healthy controls. PsA duration was the most important independent disease-associated predictor of increased aortic stiffness, next to traditional CV risk factors. cfPWV measurements may help identify subclinical end-organ disease and abnormal aortic stiffness and thus assist CV risk classification in PsA

Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs). Methods: Serum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays. Results: Of the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak. Discussion: Our findings suggest that, upon validation, CCL8, CXCL13, and IL- 1RA could serve as promising serum biomarkers of activity in SLE.Swedish Rheumatism Association (R- 969696)King Gustaf V’s 80-year Foundation (FAI-2020-0741)Swedish Society of Medicine (SLS-974449)Nyckelfonden (OLL- 974804)Professor Nanna Svartz Foundation (2021-00436)Ulla and Roland Gustafsson Foundation (2021-26)Region Stockholm (FoUI- 955483)Karolinska InstitutetInnovativeMedicines Initiative (IMI) Joint Undertaking (JU) for the PRECISESADS project (grant number 115565)IMI 2 JU for the 3TR project (grant number 831434)EU Horizon 2020 research and innovation programme and EFPI

Disentangling the riddle of systemic lupus erythematosus with antiphospholipid syndrome:blood transcriptome analysis reveals a less-pronounced IFN-signature and distinct molecular profiles in venous versus arterial events

Introduction: Systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS) represents a challenging SLE endotype whose molecular basis remains unknown. Methods: We analysed whole-blood RNA-sequencing data from 299 patients with SLE (108 SLE-antiphospholipid antibodies (aPL)-positive, including 67 SLE-APS; 191 SLE-aPL-negative) and 72 matched healthy controls (HC). Pathway enrichment analysis, unsupervised weighted gene coexpression network analysis and machine learning were applied to distinguish disease endotypes. Results: Patients with SLE-APS demonstrated upregulated type I and II interferon (IFN) pathways compared with HC. Using a 100-gene random forests model, we achieved a cross-validated accuracy of 75.6% in distinguishing these two states. Additionally, the comparison between SLE-APS and SLE-aPL-negative revealed 227 differentially expressed genes, indicating downregulation of IFN-α and IFN-γsignatures, coupled with dysregulation of the complement cascade, B-cell activation and neutrophil degranulation. Unsupervised analysis of SLE transcriptome identified 21 gene modules, with SLE-APS strongly linked to upregulation of the 'neutrophilic/myeloid' module. Within SLE-APS, venous thromboses positively correlated with 'neutrophilic/myeloid' and 'B cell' modules, while arterial thromboses were associated with dysregulation of 'DNA damage response (DDR)' and 'metabolism' modules. Anticardiolipin and anti-β2GPI positivity - irrespective of APS status - were associated with the 'neutrophilic/myeloid' and 'protein-binding' module, respectively. Conclusions: There is a hierarchical upregulation and - likely - dependence on IFN in SLE with the highest IFN signature observed in SLE-aPL-negative patients. Venous thrombotic events are associated with neutrophils and B cells while arterial events with DDR and impaired metabolism. This may account for their differential requirements for anticoagulation and provide rationale for the potential use of mTOR inhibitors such as sirolimus and the direct fIIa inhibitor dabigatran in SLE-APS.</p

Developing a European longitudinal and interprofessional curriculum for clinical reasoning

Clinical reasoning is a complex and crucial ability health professions students need to acquire during their education. Despite its importance, explicit clinical reasoning teaching is not yet implemented in most health professions educational programs. Therefore, we carried out an international and interprofessional project to plan and develop a clinical reasoning curriculum with a train-the-trainer course to support educators in teaching this curriculum to students. We developed a framework and curricular blueprint. Then we created 25 student and 7 train-the-trainer learning units and we piloted 11 of these learning units at our institutions. Learners and faculty reported high satisfaction and they also provided helpful suggestions for improvements. One of the main challenges we faced was the heterogeneous understanding of clinical reasoning within and across professions. However, we learned from each other while discussing these different views and perspectives on clinical reasoning and were able to come to a shared understanding as the basis for developing the curriculum. Our curriculum fills an important gap in the availability of explicit clinical reasoning educational materials both for students and faculty and is unique with having specialists from different countries, schools, and professions. Faculty time and time for teaching clinical reasoning in existing curricula remain important barriers for implementation of clinical reasoning teaching

Type 1 diabetes, COVID-19 vaccines and short-term safety: Subgroup analysis from the global COVAD study

AIMS/INTRODUCTION Coronavirus disease 2019 (COVID-19) vaccinations have been proven to be generally safe in healthy populations. However, the data on vaccine safety in patients with type 1 diabetes are scarce. This study aimed to evaluate the frequency and severity of short-term (<7-day) adverse vaccination events (AEs) and their risk factors among type 1 diabetes patients. MATERIALS AND METHODS This study analyzed data from the COVID-19 vaccination in Autoimmune Diseases (COVAD) survey database (May to December 2021; 110 collaborators, 94 countries), comparing <7-day COVID-19 vaccine AE among type 1 diabetes patients and healthy controls (HCs). Descriptive statistics; propensity score matching (1:4) using the variables age, sex and ethnicity; and multivariate analyses were carried out. RESULTS This study analyzed 5,480 completed survey responses. Of all responses, 5,408 were HCs, 72 were type 1 diabetes patients (43 females, 48.0% white European ancestry) and Pfizer was the most administered vaccine (39%). A total of 4,052 (73.9%) respondents had received two vaccine doses. Patients with type 1 diabetes had a comparable risk of injection site pain, minor and major vaccine AEs, as well as associated hospitalizations to HCs. However, type 1 diabetes patients had a higher risk of severe rashes (3% vs 0.4%, OR 8.0, 95% confidence interval 1.7-36), P = 0.007), although reassuringly, these were rare (n = 2 among type 1 diabetes patients). CONCLUSIONS COVID-19 vaccination was safe and well tolerated in patients with type 1 diabetes with similar AE profiles compared with HCs, although severe rashes were more common in type 1 diabetes patients