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Background Anti-drug antibodies (ADAs) can impact on the efficacy and safety of biologicals, today used to treat several chronic inflammatory conditions. Specific patient groups may be more prone to develop ADAs. Rituximab is routinely used for ANCA-associated vasculitis (AAV) and as off-label therapy for systemic lupus erythematosus (SLE), but data on occurrence and predisposing factors to ADAs in these diseases is limited. Objectives To elucidate the rate of occurrence, and risk factors for ADAs against rituximab in SLE and AAV. Methods ADAs were detected using a bridging electrochemiluminescent (ECL) immunoassay in sera from rituximab-naïve (AAV; n  = 41 and SLE; n  = 62) and rituximab-treated (AAV; n  = 22 and SLE; n  = 66) patients. Clinical data was retrieved from medical records. Disease activity was estimated by the SLE Disease Activity Index-2000 (SLEDAI-2 K) and the Birmingham Vasculitis Activity Score (BVAS). Results After first rituximab cycle, no AAV patients were ADA-positive compared to 37.8% of the SLE patients. Samples were obtained at a median (IQR) time of 5.5 (3.7–7.0) months (AAV), and 6.0 (5.0–7.0) months (SLE). ADA-positive SLE individuals were younger (34.0 (25.9–40.8) vs 44.3 (32.7–56.3) years, p  = 0.002) and with more active disease (SLEDAI-2 K 14.0 (10.0–18.5) vs. 8.0 (6.0–14), p  = 0.0017) and shorter disease duration (4.14 (1.18–10.08) vs 9.19 (5.71–16.93), p  = 0.0097) compared to ADA-negative SLE. ADAs primarily occurred in nephritis patients, were associated with anti-dsDNA positivity but were not influenced by concomitant use of corticosteroids, cyclophosphamide or previous treatments. Despite overall reduction of SLEDAI-2 K (12.0 (7.0–16) to 4.0 (2.0–6.7), p  < 0.0001), ADA-positive individuals still had higher SLEDAI-2 K (6.0 (4.0–9.0) vs 4.0 (2.0–6.0), p  = 0.004) and their B cell count at 6 months follow-up was higher (CD19 + % 4.0 (0.5–10.0) vs 0.5 (0.4–1.0), p  = 0.002). At retreatment, two ADA-positive SLE patients developed serum sickness (16.7%), and three had infusion reactions (25%) in contrast with one (5.2%) serum sickness in the ADA-negative group. Conclusions In contrast to AAV, ADAs were highly prevalent among rituximab-treated SLE patients already after the first course of treatment and were found to effect on both clinical and immunological responses. The high frequency in SLE may warrant implementations of ADA screening before retreatment and survey of immediate and late-onset infusion reactions.

B cell abnormalities are common in systemic lupus erythematosus (SLE), and include expansion of double negative (DN) and age-associated-like B cells (ABC-like). We aimed to investigate rituximab (RTX) effects on DN and ABC-like B-cell subsets and, when possible, also secondary effects on T cells. Fifteen SLE patients, fulfilling the ACR 1982 criteria, starting RTX and followed longitudinally up to two years, were analyzed for B- and T- lymphocyte subsets using multicolor flow cytometry. DN were defined as IgD-CD27- and ABC-like as CD11c+CD21- within the DN gate. Additional phenotyping was performed adding CXCR5 in the B-cell panel. Cellular changes were further analyzed in the context of the generation of anti-drug antibodies (ADA) against RTX and clinical information. The SLE patients were mainly females (86.6%), of median age 36.7 (29.8-49.4) years and disease duration of 6.1 (1.6-11.8) years. Within the DN subset, ABC-like (IgD-CD27-CD11c+CD21-) B cell frequency reduced from baseline median level of 20.4% to 11.3% (p=0.03), at early follow-up. The DN B cells were further subdivided based on CXCR5 expression. Significant shifts were observed at the early follow-up in the DN2 sub-cluster (CD11c+CXCR5-), which reduced significantly (-15.4 percentage points, p=0.02) and in the recently described DN3 (CD11c-CXCR5-) which increased (+13 percentage points, p=0.03). SLE patients treated with RTX are at high risk of developing ADA. In our cohort, the presence of ADA at 6 months was associated with lower frequencies of DN cells and to a more pronounced expansion of plasmablasts at early follow-up. The frequency of follicular helper T cells (T FH , CD4+PD-1+CXCR5+) and of peripheral helper T cells (T PH , CD4+PD-1+CXCR5-) did not change after RTX. A sub-cluster of PD-1 high CD4+ T cells showed a significant decrease at later follow-up compared to early follow-up (p=0.0039). It is well appreciated that RTX transiently influences B cells. Here, we extend these observations to cell phenotypes which are believed to directly contribute to autoimmunity in SLE. We show early transient effects of RTX on ABC-like memory B cells, later effects on PD-1 high CD4+ cells, and possible implications for RTX immunogenicity. Further insight in such effects and their monitoring may be of clinical relevance.

Background Comprehensive simultaneous quantification of bone erosion and enthesiophytes in the joints of patients with psoriatic arthritis (PsA) has not been performed. Herein, we aimed to compare the extent of bone erosion and enthesiophytes in patients with PsA, psoriasis (PSO) and healthy controls, assess the influence of age and disease duration on the development of erosions and enthesiophytes and define their impact on physical function. Methods Patients with PsA or with PSO and controls were analysed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The extent of bone erosions and enthesiophytes was assessed and plotted according to different categories of age, duration of PSO and duration of PsA, respectively. In addition, demographic and disease-specific data, including physical function (health assessment questionnaire) were collected. Results A total of 203 patients were analysed; 101 had PsA, 55 had PSO and 47 were healthy individuals. Patients with PsA had significantly more and larger erosions ( p  = 0.002/ p  = 0.003) and enthesiophytes ( p  < 0.001) compared to patients with PSO and healthy controls. Patients with PSO and healthy controls did not differ in erosions, while enthesiophytes were more frequent in patients with PSO than in healthy controls. Bone erosions, but not enthesiophytes, showed strong age-dependency in all three groups. In contrast, enthesiophytes were mostly influenced by the duration of PSO and PsA and, in contrast to bone erosions, were associated with poorer physical function. Conclusions Bone erosions are age-dependent, enhanced in PsA and increase with disease duration. Enthesiophytes are less age-dependent, are enhanced in both PSO and PsA and strongly influenced by disease duration. Enthesiophytes impact physical function in PsA suggesting the need for early therapeutic interventions to prevent damage.

ObjectivesTo examine the association between social determinants of health (SDH) and outcomes in systemic lupus erythematosus (SLE), in a European setting.MethodsWe conducted a nationwide, register-based cohort study in Sweden including 2434 individuals aged 23–59 years with newly diagnosed SLE, 2005–2021. SDH were assessed at diagnosis and included education, income, marital status, work ability, unemployment and immigration status. Outcomes were organ damage (measured using the Lupus Register-Based Organ Damage Index) and all-cause mortality. Cox proportional hazards models estimated HRs, adjusting for age, sex and morbidity. Sensitivity analyses included SDH measured 2 years prior to diagnosis.ResultsDuring follow-up, a total of 1044 (42.4%) newly diagnosed patients with SLE developed organ damage and 140 (6%) died. There was an increased risk of organ damage associated with sick leave or disability (HR: 1.44; 95% CI 1.27 to 1.64), lower income (HR: 1.33; 95% CI 1.09 to 1.63), being divorced or widowed (HR: 1.30; 95% CI 1.10 to 1.54) at diagnosis. The same SDH were also associated with mortality, as was lower education level (HR: 1.67; 95% CI 1.05 to 2.66). Immigration status and unemployment did not associate with organ damage or mortality. Results were similar when examining SDH measured 2 years prior to diagnosis.ConclusionsIn this population-based SLE cohort, lower education, lower income, being divorced, widowed or single and reduced work ability were independently associated with increased risk of organ damage and mortality. These findings support integrating SDH into risk stratification models and equity-focused interventions to improve SLE care and outcomes.

Patients with chronic inflammatory diseases are often treated with immunosuppressants and therefore are of particular concern during the SARS-CoV-2 pandemic. Serological tests will improve our understanding of the infection and immunity in this population, unless they tests give false positive results. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays using samples from patients with chronic inflammatory diseases collected prior to April 2019, thus defined as negative. Samples from patients with multiple sclerosis (MS, n=10), rheumatoid arthritis (RA, n=47) with or without rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibodies (anti-CCP2) and systemic lupus erythematosus (SLE, n=10) with or without RF, were analyzed for SARS-CoV-2 antibodies using 17 commercially available lateral flow assays (LFA), two ELISA kits and one in-house developed IgG multiplex bead-based assay. Six LFA and the in-house validated IgG assay correctly produced negative results for all samples. However, the majority of assays (n=13), gave false positive signal for samples from patients with RA and SLE. This was most notable in samples from RF positive RA patients. No false positive samples were detected in any assay using samples from patients with MS. Poor specificity of commercial serological assays could possibly be, at least partly, due to interfering antibodies in samples from patients with chronic inflammatory diseases. For these patients, the risk of false positivity should be considered when interpreting results of the SARS-CoV-2 serological assays.

ObjectiveRenal involvement in SLE is most commonly characterized by immunocomplex-mediated glomerulonephritis denoted lupus nephritis (LN). Renal thrombotic microangiopathy (TMA) occurs in a minority and constitutes a diagnostic and therapeutic challenge.IL-16 was recently described as a promising urinary biomarker of active proliferative lupus nephritis by us and others, and detected in kidney biopsies of LN patients. IL-16 expression in other types of renal disease remains unexplored, while necessary to further characterize the biomarker potential of IL-16 in LN.MethodsIL-16 expression was studied by immunohistochemistry in kidney biopsies from 2 patients with SLE, triple-positive antiphospholipid syndrome (APS) and renal TMA, and in 4 patients with renal IgA vasculitis (IgAV). One TMA patient had history of biopsy-proven LN. Half of the patients in both groups had no ongoing treatment. All had albuminuria, erythrocyturia and/or reduced estimated glomerular filtration rate.ResultsHistopathological diagnosis of TMA or IgAV was confirmed by renal pathologist, in parallel with lack of signs of active LN. Renal IL-16 was detected in both TMA patients, localized in the rich chronic interstitial inflammatory infiltrate observed in both cases (figure 1a-b). No glomerular or vascular staining was noted in either case. Furthermore, interstitial staining of varying intensity was seen in all 4 IgAV patients (figure 1c-d). In two cases, strong staining was observed in interstitial inflammatory infiltrate in parallel with glomerular staining. Both IgAV patients who expressed glomerular IL-16 had necrotic glomerular lesions.ConclusionsIL-16 can be detected in renal interstitial infiltrate in SLE- and APS-associated renal TMA and in IgAV, similarly to our previous descriptions of IL-16 expression in membranous and active proliferative LN. Furthermore, glomerular IL-16 may be observed in IgAV, which appears to occur in parallel with glomerular necrosis. This indicates potential diversity of IL-16 expression in kidney disease beyond LN.Next, besides renal expression, urinary IL-16 levels should be investigated in other types of renal disease than LN to further characterize the biomarker properties of IL-16. This is an ongoing process.AcknowledgementsThis work is funded by the Stig and Gunborg Westman Foundation.Abstract P10 Figure 1Immunohistochemical stainings for IL-16.

ObjectiveTo explore the long-term outcomes of patients with chronic kidney disease (CKD) due to Lupus Nephritis (LN), as compared to CKD of other etiologies.MethodsUsing data extracted from the Swedish Renal Registry (2006–2021), we compared clinical outcomes between: 1) CKD related to LN (LN-CKD); 2) CKD related to primary glomerular diseases [PGD-CKD, i.e. IgA nephropathy, focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN)]; 3) CKD related to other causes (Other-CKD, mostly diabetes and nephrosclerosis). Cox proportional hazard models were used to estimate adjusted hazard ratios of mortality, major cardiovascular events (MACE) and kidney replacement therapy (KRT).ResultsAt baseline, LN-CKD (N=317, 61 years, 76% females, mean eGFR 38.7 mL/min per 1.73 m2) and PGD-CKD (N=2296, 57 years, 69% males, mean eGFR 36.5 mL/min per 1.73 m2) had a lower prevalence of cardiovascular disease than the Other-CKD (N=34778, 75 years, 64% males, mean eGFR 26.5 mL/min per 1.73 m2).Over a median follow-up of 6.2 [3.3;9.8] years, 19029 deaths (51%), 15768 (42%) MACE and 8390 (22%) KRT events occurred. The unadjusted 5-year- absolute risks of death and MACE were high both in LN-CKD (27% and 25%) and Other-CKD (50% and 44%), but lower in PGD-CKD (16% and 14%), whereas the 5-year- risk for KRT was higher in PGD (PGD-CKD: 37%, LN-CKD: 23%, Other-CKD: 23%).In the multivariable analyses, as compared to PGD-CKD, the risks of death and MACE were higher in patients with LN-CKD (HR: 1.63 [95%CI: 1.32–2.02] for death, HR: 1.65 [1.31–2.08] for MACE) and Other-CKD (HR: 1.67 [1.52–1.84] for death, HR: 1.76 [1.58–1.96] for MACE). In contrast, the risk for KRT was lower both in patients with LN-CKD (HR: 0.81 [0.64–1.02] although 95%CI slightly overlaps) and in the Other-CKD group (HR: 0.84 [0.78–0.91]) (figure 1).Abstract O44 Figure 1ConclusionWhile LN-CKD had a lower risk for KRT than PGD-CKD, exhibited higher risk for MACE and death, reaching the risk magnitude of older patients with high cardiovascular burden (Other-CKD). This highlights the need for cardiovascular prevention in LN, especially in moderate to advanced CKD.

The PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data. A total of 396 RA cases and 477 controls, all of Italic ancestry, were genotyped for PTPN22 rs2476601 polymorphism. Patients were tested for autoantibodies positivity. The meta-analysis was performed on 23 selected studies. The PTPN22 T1858 allele was significantly more frequent in RA patients compared to controls (5.7% vs. 3.7%, p = 0.045). No clear relationship arose with the autoantibodies tested. The 1858T allele frequency in Italian RA patients was lower than the one described in northern European populations and similar to the frequency found in Spain, Turkey, Greece, Tunisia. A clear-cut North-South gradient arose from the analysis. The PTPN22 T1858 allele is associated with RA in the Italian population. A North-South gradient of the allele frequency seems to exist in Europe, with a lower prevalence of the mutation in the Mediterranean area.

Objective Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes. Methods We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis. Results ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm3) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%). Discussion Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with RA.