To Örebro University

Background: Belimumab (BEL) is a human IgG1λ monoclonal antibody that selectively binds to soluble BLyS and is approved for systemic lupus erythematosus (SLE) and lupus nephritis. In an integrated post hoc analysis of five Phase 3 trials (publications ranging years 2011–2022) in adults with active SLE, BEL plus standard therapy (ST) showed greater benefit than placebo (PBO) plus ST in attaining Definition of Remission in SLE (DORIS) remission (8% vs 6%) and Lupus Low Disease Activity State (LLDAS; 17% vs 10%) at Week 52. The DORIS remission and LLDAS definitions include SLE Disease Activity Index 2000 (SLEDAI-2K), Physician's Global Assessment (PGA) and glucocorticoid (GC) dose components. As the five included trials were conducted before GC tapering recommendations were introduced, GC tapering was not mandated, resulting in prolonged GC courses in a substantial proportion of patients, with a major impact on the attainability of DORIS remission and LLDAS in these trials.

Objectives: To assess attainment of DORIS remission and LLDAS with BEL versus PBO based on DORIS and LLDAS definitions excluding the GC requirement (non-GC-DORIS and non-GC-LLDAS), in the pooled population of five Phase 3 trials.

Methods: This post hoc analysis pooled data for adults with active, seropositive SLE (antinuclear antibodies and/or anti-dsDNA antibodies) from five trials (BLISS-76 [GSK Study 110751, NCT00410384], BLISS-52 [GSK Study 110752, NCT00424476], North East Asia [GSK Study 113750, NCT01345253], BLISS-SC [GSK Study 112341, NCT01484496] and EMBRACE [GSK Study 115471, NCT01632241]), receiving BEL (10 mg/kg/month intravenous or 200 mg/week subcutaneous) or PBO, plus ST. Non-GC-DORIS remission and non-GC-LLDAS attainment rates were calculated based on SLEDAI-2K and PGA scores, allowing for GC doses above the DORIS and LLDAS criteria thresholds (see Figure 1 for full definitions). Proportions of attainers were calculated and comparisons between BEL and PBO were conducted every 4 weeks to Week 52, using modified Poisson regression adjusted for trial variance, in all patients and in subgroups based on the following baseline/patient characteristics: SLEDAI-2K score, anti-dsDNA positivity, complement levels, GC dose, antimalarial use, and patient race.

Results: Data for 1869 BEL and 1217 PBO patients were analysed. At Week 52, non-GC-DORIS remission and non-GC-LLDAS attainment were higher with BEL versus PBO (non-GC-DORIS remission: 18.0% vs 12.8%, risk ratio, RR [95% confidence interval, CI]: 1.44 [1.20, 1.71], p<0.001; non-GC-LLDAS: 32.2% vs 21.4%, RR [95% CI]: 1.50 [1.32, 1.71], p<0.001). Statistical significance that was maintained to Week 52 was reached by Weeks 20 and 24 for non-GC-DORIS remission and non-GC-LLDAS, respectively (Figure 1). At Week 52, significantly greater proportions of patients treated with BEL versus PBO were in non-GC-DORIS remission and non-GC-LLDAS across most patient subgroups defined by baseline characteristics (Figure 2). In patients with a baseline SLEDAI-2K score ≥10, significantly greater proportions achieved maintained non-GC-DORIS remission and non-GC-LLDAS with BEL versus PBO as early as Week 16 (non-GC-DORIS remission: RR [95% CI]: 1.95 [1.20, 3.16], p=0.009; non-GC-LLDAS: RR [95% CI]: 1.54 [1.17, 2.02], p=0.003). At Week 52, the proportions of non-GC-DORIS remission and non-GC-LLDAS attainment were higher with BEL versus PBO for Asian (BEL n=698, PBO n=405; non-GC-DORIS remission: 14.6% vs 9.6%, RR [95% CI]: 1.60 [1.13, 2.27], p=0.013; non-GC-LLDAS: 28.9% vs 18.0%, RR [95% CI]: 1.59 [1.25, 2.02], p=0.001) and White patients (BEL n=596, PBO n=436; non-GC-DORIS remission: 20.6% vs 12.2%, RR [95% CI]: 1.66 [1.23, 2.25], p=0.002; non-GC-LLDAS: 35.9% vs 20.2%, RR [95% CI] 1.76 [1.42, 2.19], p<0.001), but a numerical difference only was seen for patients of Black African ancestry (BEL n=403, PBO n=229; non-GC-DORIS remission: 15.6% vs 13.5%, RR [95% CI]: 1.13 [0.76, 1.69], p=0.577; non-GC-LLDAS: 27.3% vs 23.6%, RR [95% CI]: 1.14 [0.86, 1.51]; p=0.438) or Indigenous American patients (BEL n=172, PBO n=147; non-GC-DORIS remission: 27.9% vs 22.4%, RR [95% CI]: 1.17 [0.80, 1.71], p=0.496; non-GC-LLDAS: 43.6% vs 30.6%, RR [95% CI]: 1.35 [1.00, 1.82], p=0.117).

Conclusion: When analysing data from past trials, it is key to consider their context and timing, and the effect of confounding factors, an example being current guidelines for GC. Importantly, GC taper was not mandated in the BEL trial protocols and it was not a part of the assessment of BEL benefit. In this post hoc analysis of five Phase 3 BEL trials using DORIS remission and LLDAS criteria excluding the GC component, BEL plus ST was associated with higher attainment of both outcomes compared with PBO plus ST in the overall population and across most analysed patient subgroups. Attainment rates with the exclusion of the GC component from the DORIS and LLDAS criteria were ~2-fold higher than those previously reported with the full definitions. This analysis corroborates the benefit of BEL plus ST over PBO plus ST in inducing remission and low disease activity in patients with SLE.

Background: The Anifrolumab Study of Treatment Effectiveness in the Real World (ASTER; NCT05637112), is a multi-national, prospective, observational study assessing the effectiveness of anifrolumab in patients with systemic lupus erythematosus (SLE) in routine clinical practice. Post-hoc analyses of the phase 3 TULIP-1/-2 and long-term extension (LTE) trials showed that, compared with placebo, remission according to the Definition of Remission in SLE (DORIS) and Lupus Low Disease Activity State (LLDAS), is more attainable and sustainable with anifrolumab treatment in addition to standard therapy in patients with SLE, with shorter time to first attainment and longer cumulative time in these states.[1,2] Here, we describe an interim analysis of DORIS remission and LLDAS attainment rates after 6 months of anifrolumab treatment in patients who participated in ASTER.

Objectives: To evaluate the effects of anifrolumab treatment on DORIS remission and LLDAS attainment in patients with SLE from the first 6 months of the ASTER study.

Methods: Eligible adults with SLE were enrolled at routine clinical visits before the first anifrolumab infusion date (index) and started anifrolumab treatment per the approved country-specific label at study sites. Baseline disease characteristics were collected retrospectively for 1 year prior to index. Data are reported as mean (standard deviation, SD) for time from SLE diagnosis, SLE Disease Activity Index 2000 (SLEDAI-2K), Physician Global Assessment (PGA), and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores, and oral corticosteroid (OCS) daily dosage. Proportions of patients in DORIS remission, LLDAS, and the individual components of each were evaluated during the observed period at baseline and every 3 months up to 6 months in patients with ≥1 anifrolumab infusion; only patients with no missing individual components were included at each timepoint. The observed period was the time from the first anifrolumab infusion to study discontinuation or loss to follow-up. DORIS remission was defined by clinical SLEDAI-2K=0, PGA <0.5, OCS ≤5 mg/day prednisone or equivalent, and standard maintenance immunosuppressant or biologic dosing, if any. LLDAS was defined by all of the following criteria: SLEDAI-2K ≤4 with no activity in major organ systems, no new lupus disease activity compared with the previous assessment, PGA ≤1, OCS ≤7.5 mg/day prednisone or equivalent, and standard maintenance immunosuppressant or biologic dosing, if any.

Results: Among the 266 patients in the interim ASTER cohort, mean (SD) time from SLE diagnosis to index was 12.3 (9.6) years. At baseline, mean (SD) scores were SLEDAI-2K=7.4 (4.1), PGA=1.5 (0.6), CLASI activity=6.4 (7.2), and CLASI damage=3.3 (6.4). Among patients with available SDI data, about half (53.0%, n/N=133/251) had a baseline SDI score ≥1. Of the 260 patients with available SLEDAI-2K data, most patients (74.2%, 193/260) had a baseline SLEDAI-2K score <10. Overall, mean (SD) OCS dosage at baseline was 5.7 (8.6) mg/day (>5 mg/day: 28.9%, 77/266; >7.5 mg/day: 23.7%, 63/266); among patients with baseline OCS dosage >0 mg/day (n=144), mean dosage was 10.5 (9.2) mg/day. At baseline, 23.3% of patients (62/266) had prior use of a biologic, 13.2% (35/266) an immunosuppressant, and 30.8% (82/266) received at least one of these medications. Among the patients with no missing data for any DORIS remission components, rates of DORIS remission increased from 1.2% (3/256) at baseline to 10.5% (18/171) at 3 months and 19.0% (15/79) at 6 months after the first anifrolumab infusion (Table 1). Similarly, rates of LLDAS attainment increased from 10.5% (27/256) at baseline to 35.7% (61/171) at 3 months and 36.7% (29/79) at 6 months after the first anifrolumab infusion. Over 6 months of follow-up, the greatest increase in the proportion of patients achieving an individual DORIS component was in the clinical SLEDAI-2K=0 component (baseline: 6.3%, 16/256; 3 months: 36.8%, 63/171; and 6 months: 49.4%, 39/79); the greatest increase among LLDAS components was in the PGA ≤1 component (baseline: 28.5%, 73/256; 3 months: 66.7%, 114/171; and 6 months: 75.9%, 60/79) (Table 1).

Conclusion: In ASTER at baseline, rates of DORIS remission and LLDAS were low among patients receiving routine SLE care. Within 6 months of the first anifrolumab infusion, attainment rates for both states substantially increased. Though follow-up data beyond 6 months are needed to determine if these effects can be sustained, these findings suggest that both targets are achievable with anifrolumab treatment in a real-world setting.

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.

OBJECTIVE: Lupus nephritis (LN) is characterized by a variable disease course, necessitating continuous monitoring. There is an urgent need to identify non-invasive biomarkers. By reviewing and critically assessing the quality of existing studies on LN biomarkers correlating with histopathology, we here explore the challenges in promoting their use in clinical practice and identify promising candidates for future validation.

METHODS: A systematic literature search was conducted, including studies on adult patients with biopsy-proven LN, published between 2012 and 2024. The search focused on studies demonstrating correlations between biomarkers and histological findings, particularly the National Institutes of Health activity and chronicity indices, the International Society of Nephrology/Renal Pathology Society histological classes, and specific active and chronic lesions. The quality of selected articles was assessed by a multidisciplinary panel of experts utilizing a standardized scoring system.

RESULTS: Ninety-three articles investigating the potential utility of over 100 biomarkers were selected. In quality assessment, 68% of the articles were weak or very weak (score<5, scale 2-9). From the remaining articles (adequate or robust) we identified five biomarkers with a potential for implementation in clinical practice: TGF-β1, PTX3, (s)CD163, CD11b, and IL-16.

CONCLUSION: The methodological heterogeneity across studies and the overall moderate score of the quality of the articles represent obstacles to the implementation of new biomarkers into clinical practice. The LN working group advocates further research on selected biomarkers that demonstrated good capacity to reflect specific histopathological features outperforming traditional tests. At present, the choice of biomarkers that perform to these standards is very limited.

Background and Aims: Systemic lupus erythematosus (SLE) is characterized by a complex and variable disease course, necessitating continuous clinical and laboratory assessments to monitor organ involvement and disease progression. Lupus nephritis (LN), thmost common organ-threatening manifestation of SLE, is commonly monitored using kidney biopsies, alongside blood and urine parameters. While kidney biopsy remains the gold standard for diagnosis, it is an invasive procedure and provides only a snapshot in time. Therefore, there is growing interest in non-invasive biomarkers that could improve clinical management of LN, aiding in diagnosis, prognostic assessment, and treatment decisions. By critically assessing the quality of existing studies on potential biomarkers—urinary, serum-based, or others—correlating with histological findings, we here explore the challenges in implementing these biomarkers in clinical practice and identify promising candidates for future validation.

Method: A systematic literature search on LN biomarkers was conducted, extending a previous review by Palazzo et al. [1]. Studies in English, published between 2012 and 2024, and involving adult patients with biopsy-proven LN were included. The search focused on studies demonstrating significant correlations between biomarkers and histological findings, particularly the National Institutes of Health (NIH) activity index (AI) and chronicity index (CI), the International Society of Nephrology/Renal Pathology Society (ISN/RPS) histological classes, and specific active or chronic lesions. From this search, 96 articles were selected, investigating the potential utility of over 100 biomarkers, which were categorized into groups. The quality of each article was assessed by a multidisciplinary panel of experts utilizing the scoring system by Guyatt et al. [2].

Results: The 96 publications were stratified into various biomarker categories: autoantibodies (n = 6), complement factors (n = 4), cytokines, chemokines, growth factors (n = 26), cell adhesion and surface molecules (n = 8), immune cells (n = 8), markers of kidney damage (n ≈ 20), micro-RNA (n ≈ 10), others (n ≈ 30). The biomarkers were tested against various lesions, both individual and combined, as well as measurements such as NIH AI and CI, and ISN/RPS classes. In quality assessment, over 50% of the articles were weak, 17% were very weak (score <5), and only 1 was deemed robust (score >8). Considering the scores of the respective articles, transforming growth factor beta 1 (TGF-β1) emerged as the biomarker deriving from the most robust study, followed by pentraxin 3 (PTX3), CD163, CD11b, hemopexin, and interleukin 16 (IL-16) (Figure 1).

Conclusion: Our findings highlight the challenges in translating biomarker research into clinical practice for LN. Methodological heterogeneity across studies is a limitation to the interpretation of results. Furthermore, by focusing on selected markers, many studies oversimplify the intricate landscape of histological findings in a kidney biopsy. All clinical trials in LN should store samples for biomarker assessment and validation, prioritizing their ability to accurately reflect specific histological features, evolve with biopsy parameters over time, and demonstrate predictive value for long-term outcomes. Until substantial progress is made in the development of new biomarkers for LN, their clinical applicability will remain limited

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.