To Örebro University

OBJECTIVE: Studies supporting therapeutic drug monitoring to biopharmaceuticals in systemic lupus erythematosus (SLE) are scarce. We aimed to assess anti-drug antibody (ADA) occurrence in belimumab-treated SLE patients and associations between belimumab concentrations and clinical response, serological outcomes, and adverse events.

METHODS: We included 100 patients treated with intravenous belimumab. Clinical data and biological samples were collected at baseline and months 3, 6, 12, and 24. Belimumab levels were determined by quantitative sandwich ELISA, and ADA by an acid-dissociation radioimmunoassay. Clinical activity was evaluated with the SLE disease activity index 2000 (SLEDAI-2K), revised SLE activity measure (SLAM-R), and physician's global assessment (PhGA). Serological markers included C3, C4, and anti-dsDNA. We performed cross-sectional Spearman's rank correlation analyses, and longitudinal analyses using generalised estimating equations.

RESULTS: Belimumab concentrations varied widely (median: 25.8; IQR: 20.9-43.5 μg/ml) but were stable over time at the group level. Pre-existing ADA were detected in 2 patients, but no patient developed ADA during follow-up. Belimumab levels moderately correlated with SLEDAI-2K (ρ: -0.37; p= 0.003) and PhGA (ρ: -0.41; p= 0.005) at month 6, while longitudinal analysis revealed a very weak association with SLEDAI-2K (β: -0.10; SE: 0.05; p= 0.031) and a weak association with SLAM-R (β: -0.32; SE: 0.13; p= 0.014). Despite moderate correlations between belimumab levels and serological markers at month 6, there were no associations in longitudinal analysis. There was no relationship between belimumab levels and adverse events.

CONCLUSION: Belimumab yielded no immunogenicity. Belimumab levels were modestly associated with clinical activity but not with serological activity or adverse events.

OBJECTIVE: To determine the efficacy of belimumab on mucocutaneous manifestations of systemic lupus erythematosus (SLE) in a large integrative analysis.

METHODS: Using data from five phase III clinical trials (BLISS-52; BLISS-76; BLISS-NEA; EMBRACE; BLISS-SC; N = 3086), we investigated the effect of belimumab vs placebo on top of standard therapy on inducing improvement in mucocutaneous British Isles Lupus Assessment Group (mcBILAG) and mucocutaneous SLE Disease Activity Index 2000 (mcSLEDAI-2K), and on preventing mcBILAG flares. We employed logistic and Cox regression analysis, adjusting for trial variance.

RESULTS: Belimumab was superior to placebo in inducing mcBILAG (week-52 OR: 1.29; 95% CI: 1.07-1.57; p = 0.008) and mcSLEDAI-2K (week-52 OR: 1.37; 95% CI: 1.16-1.62; p < 0.001) improvement, as well as in inducing sustained (≥2 visits, maintained through week 52) mcBILAG (HR: 1.23; 95% CI: 1.07-1.41; p = 0.003) and mcSLEDAI-2K (HR: 1.24; 95% CI: 1.17-1.31; p < 0.001) improvement. These associations held true for patients with SLEDAI-2K ≥10 and positive anti-dsDNA levels at baseline, but not their counter groups. Belimumab prevented mcBILAG flares to a greater extent than placebo in patients with positive anti-dsDNA levels (HR: 0.70; 95% CI: 0.50-0.98; p = 0.035) and with a near-significant separation in patients with baseline SLEDAI-2K ≥10 (HR: 0.71; 95% CI: 0.51-1.00; p = 0.050), whereas no difference was seen in their counter groups.

CONCLUSION: Belimumab is superior to placebo in inducing improvement and in preventing flares in the mucocutaneous domain of SLE, especially in patients with high disease activity and in serologically active patients.

OBJECTIVES: To explore prevalence, characteristics and risk factors of COVID-19 breakthrough infections (BIs) in idiopathic inflammatory myopathies (IIM) using data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study.

METHODS: A validated patient self-reporting e-survey was circulated by the COVAD study group to collect data on COVID-19 infection and vaccination in 2022. BIs were defined as COVID-19 occurring ≥14 days after 2 vaccine doses. We compared BIs characteristics and severity among IIMs, other autoimmune rheumatic and non-rheumatic diseases (AIRD, nrAID), and healthy controls (HC). Multivariable Cox regression models assessed the risk factors for BI, severe BI and hospitalisations among IIMs.

RESULTS: Among 9449 included response, BIs occurred in 1447 (15.3%) respondents, median age 44 years (IQR 21), 77.4% female, and 182 BIs (12.9%) occurred among 1406 IIMs. Multivariable Cox regression among IIMs showed age as a protective factor for BIs [Hazard Ratio (HR)=0.98, 95%CI = 0.97-0.99], hydroxychloroquine and sulfasalazine use were risk factors (HR = 1.81, 95%CI = 1.24-2.64, and HR = 3.79, 95%CI = 1.69-8.42, respectively). Glucocorticoid use was a risk factor for severe BI (HR = 3.61, 95%CI = 1.09-11.8). Non-White ethnicity (HR = 2.61, 95%CI = 1.03-6.59) was a risk factor for hospitalisation. Compared with other groups, patients with IIMs required more supplemental oxygen therapy (IIM = 6.0% vs AIRD = 1.8%, nrAID = 2.2%, and HC = 0.9%), intensive care unit admission (IIM = 2.2% vs AIRD = 0.6%, nrAID, and HC = 0%), advanced treatment with antiviral or monoclonal antibodies (IIM = 34.1% vs AIRD = 25.8%, nrAID = 14.6%, and HC = 12.8%), and had more hospitalisation (IIM = 7.7% vs AIRD = 4.6%, nrAID = 1.1%, and HC = 1.5%).

CONCLUSION: Patients with IIMs are susceptible to severe COVID-19 BI. Age and immunosuppressive treatments were related to the risk of BIs.

OBJECTIVES: To investigate the prevalence of psoriasis in SLE using a Swedish regional cohort and a nationwide cohort from the National Patient Register (NPR). Furthermore, we compared clinical features between patients with and without comorbid psoriasis.

METHODS: In total, 351 patients diagnosed with SLE based on the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics criteria from Linköping University Hospital were evaluated. We obtained patient-reported and relevant clinical data extracted in 2024. Individuals with coexisting psoriasis were identified via the International Classification of Diseases code L40 and subsequent confirmation through chart review in the regional cohort. In the NPR, 7490 subjects with SLE living in Sweden in 2022 were identified, as well as therapies obtained from the Prescribed Drug Register.

RESULTS: We identified 12 subjects with SLE and coexisting psoriasis (3.4%) in the regional cohort and 367 patients (4.9%) in the nationwide cohort. Men were proportionally more common in the group with comorbid psoriasis in both cohorts. Patients with psoriasis reported more pain on a visual analogue scale (median 45.5/100 mm, IQR 23.3-58.3) compared with those without coexisting psoriasis (median 27.0/100 mm, IQR 7.0-50.5, p<0.04). We observed no differences in damage accrual or clinical phenotypes between the two groups. Subjects with psoriasis were more frequently prescribed methotrexate in the nationwide cohort.

CONCLUSION: The prevalence of coexisting psoriasis in patients with SLE in Sweden was estimated to be 3.4-4.9%. Individuals with comorbid psoriasis reported more pain and were more likely to be prescribed methotrexate than those without psoriasis.

OBJECTIVES: Physical function in RA is largely influenced by multiple clinical factors, however, there is a growing body of evidence that psychological state and other comorbidities also play an essential role. Using data obtained in the COVID-19 Vaccination in Autoimmune Diseases study, an international self-reported e-survey, we aimed to explore the predictive ability of sociodemographic and clinical variables on Patient-Reported Outcomes Measurement Information System Physical Function Short Form 10a (PROMIS PF-10a) in RA and to investigate variation in disease activity and functional outcomes based on country-level socio-economic parameters.

METHODS: Patient demographics, disease characteristics including current symptom status, functional status and treatment variables, as well as income level of the country of residence, were extracted from survey responses. PROMIS PF-10a scores were compared across country income levels. The influence of extracted variables on reversed PROMIS PF-10a scores were investigated using negative binomial univariable- and multivariable regression. RESULTS: A total of 1342 RA patients were included in this analysis. In the optimised parsimonious predictive model for reversed PROMIS PF-10a, older age, female gender, disease duration, fatigue and pain levels were independently associated with worse physical function, whereas Asian ethnicity, higher overall physical health ratings, ability to carry out everyday activities and residing in a country with an upper-middle or high-income level were independently associated with better physical function.

CONCLUSION: Our study highlights that clinical factors remain strong predictors of physical function in RA, irrespective of individual and country-level socio-economic differences. Interestingly, high country-level income was associated with better physical function, irrespective of individual sociodemographic and clinical factors.

OBJECTIVE: To develop a Register-Based Organ Damage Index (RBODI) in SLE, and evaluate its accuracy in estimating Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) scores. Additionally, to describe organ damage accrual and associations with mortality in a Swedish population-based nationwide cohort.

METHODS: SDI items were translated into diagnosis, treatment and procedural codes retrieved from Swedish health registers. RBODI was calculated using the same rules as the SDI and its accuracy was evaluated using SDI data from the Clinical Lupus Register in North-Eastern Gothia cohort as the gold standard. Among newly diagnosed patients with SLE from Sweden (2005-2021), we estimated 5-year risks of organ damage, and adjusted HRs of first RBODI-based organ damage accrual associated with patient characteristics. Lastly, we estimated the association between RBODI-based organ damage within 5 years of diagnosis and mortality.

RESULTS: The evaluation cohort included 271 prevalent cases (65.3% developed organ damage). RBODI had a positive predictive value of 90%, sensitivity 80% and specificity 83%. Among 4441 newly diagnosed patients with SLE, 40% developed organ damage within 5 years. Males had a 30% higher risk of developing damage compared with females (HR 1.3) and older individuals (>45 years old compared with younger) had more than threefold higher risk (HR 3.3). Early development of organ damage was associated with a 2.1-fold higher risk of mortality.

CONCLUSION: Our novel RBODI accurately estimates SDI scores and describes long-term trends in damage accrual in the largest cohort of incident SLE to date. The strong association between early damage accrual and mortality highlights the need for efficient prevention strategies.

OBJECTIVES: The management of neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging because of clinical heterogeneity and the complexity of pathophysiologic mechanisms involved. We sought to determine the molecular signature of NPSLE and its endotypes towards novel biomarkers and targeted therapies.

METHODS: Whole-blood RNA sequencing from 308 patients with systemic lupus erythematosus (119 with NPSLE, 189 non-NPSLE) and 72-matched healthy controls (HCs) were performed. Supervised pathway enrichment analysis and unsupervised weighted gene coexpression network analysis were applied to distinguish clinically and molecularly defined NPSLE endotypes.

RESULTS: Compared with HCs, patients with NPSLE demonstrated dysregulation of adaptive immune responses along with upregulation of interleukin (IL)-1, IL-6, IL-17, and IL-12/IL-23 signalling pathways. The comparison between NPSLE and non-NPSLE groups revealed a robust upregulation of complement cascade, DNA damage response, adaptive immunity, and IL-1 and IL-6 signalling. Furthermore, active NPSLE exhibited a strong autophagy signature. The B cell and complement cascade signatures exhibited a gradual upregulation across the non-NPSLE, inactive NPSLE, and active NPSLE subgroups. Within NPSLE, diffuse syndromes correlated positively with the oxidative phosphorylation module, while antiphospholipid antibody-positive NPSLE was not associated with specific signatures by unsupervised analysis. NPSLE endotypes such as cognitive dysfunction, seizures, psychosis, and optic neuritis were associated with distinct transcriptomic signatures namely IL-6 signalling and leukocyte migration, DNA damage response, inflammation, and type-I interferon, respectively.

CONCLUSIONS: The clinical heterogeneity of NPSLE appears to be associated with molecular diversity, with certain endotypes or syndromes exhibiting distinct gene signatures. Upregulation of adaptive immune response and complement cascade suggests that complement inhibitors and B cell-targeted therapies could be further explored in NPSLE.

Implementation of Treat-to-Target (T2T) in routine clinical practice remains low in systemic lupus erythematosus (SLE). Real-world data reveal excessive use of glucocorticoids (GCs) and frequently inadequate disease control. Here, an international task force convened to develop a consensus framework for implementing T2T in routine clinical care of adult patients with SLE. This T2T task force comprised an international panel of 22 physicians involved in the care of SLE and 3 lupus patient research partners. Following a scoping review and online discussions, during which definitions and instruments available for T2T in SLE were examined, the panel developed potential framework statements for implementing T2T in SLE, which were extensively discussed before being agreed upon by Delphi consensus. Additionally, the current challenges of implementing T2T in SLE and how future research may address these issues were analyzed. The framework comprises 5 overarching principles and 11 statements. Despite the absence of formal evidence that T2T offers superiority to conventional SLE management, T2T in SLE has been recommended for over a decade. This task force offers a framework for effectively implementing T2T in SLE from a real-life perspective, informing a wide range of physicians, including those outside the limited circle of lupus specialists.

Despite advancements in the management of systemic lupus erythematosus (SLE), patients experience poor health-related quality of life (hrQoL) and premature death due to disease severity and treatment side effects. Achieving remission offers substantial benefits, including improved hrQoL and reduced mortality, yet the complexity of SLE, with its diverse underlying immune mechanisms and clinical manifestations, hampers progress. Involvement of the central nervous system with symptoms like fatigue, pain and brain fog often goes unaddressed due to limited evidence-based guidance and measurement tools. This neglect reflects gaps in training, discomfort in addressing untreatable symptoms and an overemphasis on evidence-based medicine, compromising holistic care. Recognising patient-reported outcomes has shifted SLE care towards a more patient-centred model, addressing hrQoL and aligning treatment goals. Embracing this approach and prioritising symptom management, even when a definitive cure is lacking, ensures compassionate, comprehensive care that improves adherence, satisfaction and the overall lived experience of patients with SLE.

Background: Systemic lupus erythematosus (SLE) is characterised by the production of a multitude of autoantibodies (Abs), yet the antigen specificities remain elusive for most of these Abs. The diagnosis of SLE is supported by the presence of certain Abs; however, SLE-specific Abs currently used for diagnosis or surveillance, e.g., anti-dsDNA and anti-Smith, lack sensitivity.

Objectives: To perform a broad explorative screen of IgG and IgA antibodies against autoantigen specificities in patients with SLE vs healthy controls (HC) to gain insight into disease pathogenesis and identify novel Abs that could potentially serve as diagnostic biomarkers.

Methods: We analysed plasma samples from 289 patients with SLE and 196 age- and sex-matched HC from the European PRECISESADS project (NTC02890121). Samples were screened for IgG and IgA seroreactivity against a panel of >1,600 protein autoantigens using KREX-based i-Ome arrays (Sengenics). Differential expression analysis was performed with the limma R package adjusting for e.g., polyspecific antibody reactivity. The level of significance for differentially expressed Abs (DEAbs) was set at p<0.05 and |fold change (FC)| >1.5. Machine learning (ML) was applied to identify the ten most discriminative Abs. ROC analysis was carried out for each individual DEAb and for the combined top ten ML-selected DEAb model, producing discriminative performance metrics including sensitivity, specificity, area under the curve (AUC), and accuracy. Functional analysis was performed with gene ontology (GO) enrichment and signalling pathway impact analysis using the corresponding antigens of the DEAbs (p<0.1; |FC| >1.1).

Results: DEAb analysis revealed 14 IgG and 2 IgA upregulated DEAbs in patients with SLE vs HC. Of IgG DEAbs, anti-LIN28A (sen=0.77, spe=0.69, AUC=0.80), anti-HBGB2 (sen=0.65, spe=0.81, AUC=0.79), anti-HMG20B (sen=0.75, spe=0.71, AUC=0.70), and anti-NRF1 (sen=0.63, spe=0.80, AUC=0.77) demonstrated the best discriminative capacity. ML identified the top ten IgG Abs distinguishing SLE from HC (SSB, TROVE2, LIN28A, TFCP2, HNRNPA2B1, KLF12, RAD51, CCNB1, EEF1D, PSMD4) with a good whole-panel performance (sen=0.84, spe=0.72, AUC=0.78). Functional analysis of IgG DEAbs revealed 2 GO-term enrichments at the cellular component level: extracellular region and cell surface, suggesting that autoantigens eliciting IgG in SLE are accessible at the cell surface or released by cell lysis and may be altered in an immunogenic manner by SLE-associated pathophysiological processes. Of IgA DEAbs, anti-LIN28A (sen=0.65, spe=0.83, AUC=0.80) and anti-SSB (sen=0.64, spe=0.82, AUC=0.78) demonstrated the best discriminative capacity. ML identified the top ten IgA Abs discriminating SLE from HC (APOBEC3G, SUB1, LIN28A, SSB, TROVE2, PCBP2, TFCP2, PRKRA, ZMAT3, UBE2I) with reasonable whole-panel performance (sen=0.84, spe=0.69, AUC=0.76). Functional analysis of IgA DEAbs revealed 17 GO-term enrichments related to DNA-binding transcription repressor activity, chromatin binding, transcription factor binding, and regulation of transcription by RNA polymerase II, suggesting that autoantigens eliciting IgA in SLE are enriched for nucleic acid binding.

Conclusion: This study corroborated both classical IgG Ab specificities (e.g., anti-SSB, anti-TROVE2) and previously reported specificities (anti-LIN28A, anti-HBGB2, anti-HMG20B, anti-HNRNPA2B1)1 and identified novel IgG (anti-NRF1, anti-PCBP2, anti-TGIF2, HMGN5, anti-SUB1, anti-PSIP1, anti-CCNB1) and novel IgA (anti-LIN28A) Abs described for the first time in SLE, with robust accuracy in distinguishing SLE from HC. Importantly, these novel Abs outperformed the accuracy of currently used Abs, e.g., anti-dsDNA (sen=0.36, spe=0.95, AUC=0.61)1. ML further enhanced the diagnostic accuracy, heralding promise for the early diagnosis of SLE. Functional analysis revealed distinct mechanisms with suggested differential roles in the production of IgG and IgA Abs in SLE.