Background: Systemic lupus erythematosus (SLE) is characterized by increased type I interferon (IFN) activity and elevated levels of peripheral blood plasmablasts (PB), both serving as established biomarkers for disease activity and severity. However, although being linked in immune dysregulation, these biomarkers have rarely been evaluated in combination for their prognostic value. Objectives: Here, we aimed to investigate the role of elevated IFN and peripheral blood PB levels in correlation to clinical disease measures, and to evaluate the prognostic value of these markers in SLE. Methods: SLE patients were investigated cross-sectionally by flow cytometry for the analysis of SIGLEC-1 on monocytes (as surrogate maker for IFN-I activity) and frequencies of circulating CD19posCD20negCD27++HLA-DR+ PB from freshly isolated PBMCs between January 2015 and September 2019. In addition, these patients were prospectively followed for a median of 4.5 years (range 0.8 - 6.6 years), and investigated for the development of flares according to the SELENA-SLEDAI flare index (SFI). The study was approved by the local ethical committee (EA1/124/09). Results: 121 patients were included (89% female, median age 45.0 years), which could be separated into groups of SIGLEClowPBlow (43.8%), SIGLEChighPBlow (35.5%), SIGLEClowPBhigh (7.4%) and SIGLEChighPBhigh (13.2%). Compared to SIGLEChighPBlow, patients with SIGLEChighPBhigh had a significantly higher disease activity (median SLEDAI of 8 vs. 4, p=0.001), lower rates of LLDAS (25.0% vs. 58.5%, p= 0.038), higher serum anti-dsDNA antibodies (26.9 vs. 200 IU/L, p< 0.001), lower serum C3 levels (760 vs. 910mg/dl, p=0.018), and more frequent renal involvement (56.3% vs. 27.9%, p= 0.046). Throughout the observational period, a total of 385 flares occurred, comprising 337 mild/moderate and 48 severe flares. When standardized to flares per 10 observed years, the flare rate was significantly higher in the SIGLEChighPBhigh group (10.0 vs. 4.8, p=0.027), most pronounced for mild/moderate flares (8.4 vs. 3.9, p=0.013). This was associated with a higher cumulative glucocorticoid dosage (2181.6 vs. 1430.2 mg/year, p=0.043). Interestingly, there was no difference in the flare development in patients from the group of SIGLEChighPBlow vs. SIGLEClowPBlow. Conclusion: Our data indicate that SLE patients with a combination of IFN and humoral activity have a higher disease burden and poorer outcomes compared to patients with isolated IFN activity, which may have future implications in personalized therapeutic approaches. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

Background: Autoantibody production by long-lived plasma cells (PCs) have been implicated in the pathogenesis of systemic lupus erythematosus (SLE) but targeting them remains a therapeutic challenge. Objectives: We aimed to investigate the safety and efficacy of the anti-CD38 monoclonal antibody daratumumab in moderate to severe SLE. This reagent depletes PCs and is approved for the treatment of multiple myeloma. Methods: A single-center, phase 2, open-label investigator-initiated study was conducted in 10 patients with SLE receiving background standard therapy. Eligible patients were adults meeting the 2019 EULAR/ACR classification criteria, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6, were positive for anti-double-stranded (ds)DNA antibodies and had failed or did not tolerate at least 2 previous state-of-the-art immunosuppressive drugs. Patients received 8 subcutaneous injections once weekly of 1800mg daratumumab and were followed-up for 36 weeks. Primary endpoint was the reduction of anti-dsDNA antibody levels at week 12. Secondary endpoints included safety and tolerability, reductions in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and Clinical Disease Activity Index (CDAI), SRI-4 responses, pharmacokinetics and immunological changes. This trial was supported by Janssen-Cilag and registered at www.clinicaltrials.gov (NCT04810754). Results: Between August 2021 and January 2023, 10 patients were enrolled and received at least six doses of daratumumab. Anti-dsDNA antibodies decreased from a median 166.3 at baseline to 61.1 U/ml at week 12 (p=0.002), accompanied by significant clinical improvements, reflected in median reductions of SLEDAI-2K from 12 to 4 (p=0.002), CLASI-A from 6 to 0 (p=0.002) and CDAI from 11.5 to 0 (p=0.004), resulting in an SRI-4 response of 100%. Serum IgG levels decreased from 12.1 to 6.9 g/L, and serum complement C3 increased from 875 to 955 mg/L (p=0.002). During follow-up, two patients developed flares at week 16 and 24, respectively. At the final visit, SRI-4 response rate was 70%, despite reductions of daily prednisolone dosages from 6.25 at baseline to 5.0mg (p=0.016). No severe adverse events (SAEs) occurred. Treatment emergent AEs were mild-moderate, including hypogammaglobulinemia (5/10), nausea (4/10), headache (4/10), injection site reactions (3/10), COVID-19 (3/10) and herpes zoster (2/10). Pharmacodynamic analysis showed transient reductions of natural killer cells and plasmacytoid dendritic cells, while peripheral blood B and T cell numbers remained stable. Conclusion: Daratumumab induced a therapeutically relevant reduction of pathogenic anti-dsDNA antibodies in SLE with a favorable safety profile. Clinical responses were rapid and durable, even in refractory cases, with efficacy in all major organ sites. These data justify the further development of CD38-targeting antibodies in the treatment of moderate-severe SLE. REFERENCES: NIL. Acknowledgements: This study was supported by Janssen-Cilag. Disclosure of Interests: Tobias Alexander This study was supported by Janssen-Cilag, Lennard Ostendorf: None declared, Jan Zernicke: None declared, Jens Klotsche: None declared, Udo Schneider: None declared, Robert Biesen: None declared, Robin Kempkens: None declared, Qingyu Cheng: None declared, Laleh Khodadadi: None declared, Frederik Heinrich: None declared, Pawel Durek: None declared, Gerd R. Burmester: None declared, Mir-Farzin Mashreghi: None declared, Gerhard Krönke: None declared, Falk Hiepe: None declared.Figure 1Clinical and serologic responses of 8 weekly daratumumab injections in 10 SLE patients. Change from baseline of A) anti-dsDNA antibodies, B) serum IgG levels, C) complement factor C3, D) SLEDAI-2K, E) CLASI-A and F) CDAI score.

Background: Individuals with inflammatory rheumatic and musculoskeletal diseases (iRMDs) face a significantly higher risk of adverse COVID-19 outcomes, with increased rates of hospitalization, intensive care unit (ICU) admission, and mortality, compared to the general population [1]. However, individual factors influencing the specific outcomes for iRMD patients in ICUs are incompletely understood. Objectives: This study aims to identify factors associated with adverse outcomes in iRMD patients with COVID-19 admitted to the ICU. Methods: We conducted a retrospective study at a large tertiary university hospital, analyzing patients admitted from March 2020 to December 2021. The study involved a total of 1562 critically ill patients with COVID-19, including 98 iRMD patients and 1464 non-iRMD patients. Multivariable Cox proportional regression analysis was used to evaluate factors associated with mortality in the iRMD group. We also examined factors linked to prolonged ICU stays (>30 days) among survivors. Furthermore, we compared the differences between factors associated with mortality between the iRMD and the general cohort. Results: Mean age in the iRMD group was 48.1 ± 14.5 years with an average disease duration of 16.3 ± 9.9 years, of which 51% were female. Rheumatoid arthritis was the most frequent diagnosis among iRMD patients (58%), followed by vasculitides (13%) and connective tissue diseases (7%). Within the iRMD cohort 81% required mechanical ventilation, 33% died, and 24% of the survivors experienced prolonged ICU stays. Multivariable analysis based on pre-selected factors (age, body mass index (BMI), sex, presence of chronic kidney disease, diabetes mellitus, vaccination status, virus variant, peak Interleukin (IL)-6 levels, latest glucocorticoid dose and use of csDMARDs) identified BMI (HR 1.11, CI 1.01-1.21, p=0.030), male sex (HR 14.47, CI 1.27-165.26, p=0.031), peak IL-6 levels (HR 1.05, CI 1.02-1.09, p=0.001) as significant factors associated with mortality. Factors such as vaccination status or iRMD specific treatment did not independently affect mortality risk. Prolonged ICU stay was associated with high IL-6 (by 1000, HR 1.37, CI 1.02-1.87, p=0.004), and general ICU complications such as delirium (HR 7, CI 1.89-25.97, p=0.004), pulmonary embolism (HR 6.6, CI 1.55-28.16, p=0.011), and major cardiac events (HR 11.67, CI 2.50-54.54, p=0.002) in univariable regression analysis. Compared with the general ICU cohort, mortality in the iRMD group was more likely to be associated with three or more COVID-19 vaccinations (HR 6.31, CI 1.32-29.65, p=0.020) and peak IL-6 levels (HR 1.03, CI 1.06-25.97, p=0.041), otherwise the factors influencing mortality were similar. Conclusion: In iRMD patients, higher BMI, male sex, and elevated IL-6 levels are key indicators of a poorer prognosis in the ICU setting for COVID-19. Apart from IL-6, these factors and the outcomes for iRMD patients do not significantly differ from the general ICU population, highlighting the impact of hyperinflammation. REFERENCES: [1] Conway R, Grimshaw AA, Konig MF, Putman M, Duarte-García A, Tseng LY, Cabrera DM, Chock YPE, Degirmenci HB, Duff E, Egeli BH, Graef ER, Gupta A, Harkins P, Hoyer BF, Jayatilleke A, Jin S, Kasia C, Khilnani A, Kilian A, Kim AHJ, Lin CMA, Low C, Proulx L, Sattui SE, Singh N, Sparks JA, Tam H, Ugarte-Gil MF, Ung N, Wang K, Wise LM, Yang Z, Young KJ, Liew JW, Grainger R, Wallace ZS, Hsieh E; COVID-19 Global Rheumatology Alliance. SARS-CoV-2 Infection and COVID-19 Outcomes in Rheumatic Diseases: A Systematic Literature Review and Meta-Analysis. Arthritis Rheumatol. 2022 May;74(5):766-775. doi: 10.1002/art.42030. Epub 2022 Mar 28. PMID: 34807517; PMCID: PMC9011807. Acknowledgements: NIL. Disclosure of Interests: Edgar Wiebe honoraria from Novartis, Frédéric Münch: None declared, Nadège Léprêtre: None declared, Jens Klotsche: None declared, Jan-Hendrik Bernhard Hardenberg: None declared, Kerstin Rubarth: None declared, Mirja Mittermaier: None declared, Felix Balzer: None declared, Robert Biesen: None declared, Gerhard Krönke: None declared, Kai-Uwe Eckardt: None declared.

Background Given their contribution to the chronicity of autoimmune response, long-lived plasma cells (PCs) resemble an attractive treatment target in systemic lupus erythematosus (SLE) and other autoantibody-mediated diseases. We have recently reported the successful treatment of daratumumab, a CD38-targeting human monoclonal antibody, in two refractory patients with SLE [1], demonstrating a clinically relevant depletion of long-lived plasma cells with marked reduction of anti-double-stranded DNA (dsDNA) antibodies and marked clinical improvement in both cases over a follow-up period of 12 months. Objectives Here, we describe the long-term clinical and serologic responses of daratumumab treatment in one patient with SLE with a follow-up of 36 months. Methods A 51-year-old woman, who suffered from active lupus nephritis WHO class-III/V with nephrotic syndrome, pericarditis, arthritis and skin rash despite treatment with mycophenolate mofetil (MMF), cyclosporine A (CsA), hydroxychloroquine (HCQ) and glucocorticoids (GC), had received 4 weekly intravenous doses of 16mg/kg daratumumab as add on to background medication, which was complemented by subcutaneous 200mg belimumab weekly, starting 4 months after the initiation of daratumumab. Autoantibodies were investigated with ELISA and type-I interferon (IFN-I) activity investigated by measuring SIGLEC-I expression on monocytes with flow cytometry. Results During follow-up, the patients´ Urinary Protein/Creatinine Ratio (UPCR) declined from 1197 mg/g at 12 months to 467mg/g Creatinine at the last follow-up, while serum creatinine remained within normal levels (Figure 1A). No flares or novel disease manifestations occurred during the 3-year observation period, although the dosage of MMF was tapered to 1g daily at 21 months and prednisolone discontinued at 33 months, respectively, after the first daratumumab administration. Serologically, serum anti-dsDNA antibodies further decreased from 254 IE/ml at the 12 months follow-up to 38 IE/ml at 36 months (Figure 1B), and complement levels for C3 were consistently within the normal range (Figure 1C). Serum IgG levels remained stable after previous substitution with two doses of 30g intravenous immunoglobulins (Figure 1D). In addition, her initially increased type-I interferon activity, determined by the flow cytometric assessment of SIGLEC-1 on freshly isolated monocytes, completely normalized during follow-up, an effect most strongly observed during the first weeks following daratumumab that further substantiated under belimumab therapy (Figure 1E). At the last follow-up, she was in complete clinical remission, with a SLEDAI-2K of 2 due to slightly elevated dsDNA antibodies (Figure 1F). No severe adverse events occurred during follow-up, and no hospitalization was required for the management of SLE, infections or comorbidities. Conclusion Our data demonstrate that the administration of daratumumab as induction therapy for refractory and serologically active SLE may provide sustained clinical responses, when combined with immunosuppression and/or belimumab as maintenance therapy to prevent recurrence of autoreactive PCs. Apparently, depletion of long-lived PCs resulted in a therapeutically relevant reduction of autoantibodies and IFN-I activity, indicating a profound disease modification with resetting the chronic autoreactive immune system into an earlier stage of development, regaining responsiveness to standard therapies. These data suggest further studies to investigate the safety and efficacy of daratumumab in SLE and other autoantibody-mediated autoimmune diseases. Reference [1]Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, Enghard P, Richter U, Biesen R, Schneider U, Knebel F, Burmester G, Radbruch A, Mei HE, Mashreghi MF, Hiepe F, Alexander T. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149-1155. Acknowledgements: NIL. Disclosure of Interests Tobias Alexander Grant/research support from: Janssen, Lennard Ostendorf: None declared, Robert Biesen: None declared, Andreas Radbruch: None declared, Gerd Rüdiger Burmester: None declared, Falk Hiepe: None declared.Figure 1Clinical and serologic responses to daratumumab in one patient with SLE.

Background: Commercially available ELISA-based antibody tests are used to approximate vaccination success against SARS-CoV-2 in at-risk patients, but it is unclear whether they correlate with neutralization of the Omicron variant.Methods: 269 serum samples of a cohort of 44 non-immunosuppressed participants and 65 MTX-treated rheumatic patients taken before and after COVID-19 booster vaccinations were measured using COVID-19 antibody testing systems with wild-type and Omicron BA.1 antigens developed by three different manufacturers (surrogate virus neutralization test cPass, and binding antibody tests QuantiVac and SeraSpot), as well as with a pseudovirus neutralization test (pVNT). The pVNT was considered the gold standard for determining the presence and level of anti-SARS-CoV-2 antibodies.Results: All three wild-type ELISAs showed excellent test performance compared with wild-type neutralization in pVNT. However, out of 56 samples without Omicron BA.1 neutralization in pVNT, 71.4% showed positive results in at least one and 28.6% in all three wild-type ELISAs at the manufacturer-defined cut-offs. Omicron ELISAs showed either decreased specificity (57.1% and 55.4% for binding ELISAs) or sensitivity (51.2% in cPass) compared to Omicron neutralization in pVNT. The proportion of any false positive results among all samples decreased from 26.5% before to 3.2% after booster vaccination, however binding antibody test specificities remained below 70%.Conclusions: We found a poorer test performance of new Omicron antibody test systems compared to wild-type tests in detecting neutralizing antibodies against the corresponding SARS-CoV-2 variants. Decisions for booster vaccination or passive immunization of at-risk patients should not be based solely on antibody test results.

Background The introduction of novel targeted biologic therapies has dramatically improved the treatment landscape for autoimmune diseases (AD). However, although providing more specificity, such therapies routinely depend on continuous or repeated administration, with a cumulative risk of long-term side effects, and are not curative. In contrast, immunoablation followed by hematopoietic stem cell transplantation (HSCT) has emerged as a promising on-off therapy over the past decades, to provide long-term remissions even in patients with severe courses of their disease, through the restoration of immunologic self-tolerance [1]. Objectives Here, we summarize the outcomes of AD patients receiving HSCT at the Charité – University Medicine between February 1998 and October 2015. Methods In this retrospective study, the clinical outcome of 22 patients was analyzed, who received a CD34+-selected autologous HSCT after immunoablation with 200mg/kg cyclophosphamide and 90mg/kg rabbit antithymocyte globulin (ATG) for autoimmune diseases. Indication for transplant were systemic lupus erythematosus (SLE, n=10), systemic sclerosis (SSc, n=4), vasculitis (n=3), multiple sclerosis (MS, n=2), polychondritis (n=1), chronic inflammatory demyelinating polyneuropathy (CIDP, n=1) and autoimmune hemolytic anaemia (AIHA, n=1). The median age at transplant was 29 years (range 16-48), and 82% of patients were female. Multiparamter flow cytometry was applied to characterize peripheral blood lymphocytes subsets, assessment of SIGLEC-1 expression on monocytes as surrogate for type-I interferon (IFN-I) activity in SLE. Results With a median follow-up of 78 months (range 0.1-300), the overall survival was 76.4% and progression-free survival 58.2%, respectively. 3 deaths were regarded treatment related (2 infections in SLE and 1 cardiac failure in SSc). One patient had persisting disease (AIHA) and 4 relapses occurred in SLE patients at 18, 36, 81 and 83 months, respectively. Remaining patients are in stable clinical remission for up to 25 years post-transplant, despite discontinuation of immunosuppressive therapy in most cases. HSCT was associated with significant reduction or normalization of autoantibody levels and a profound reconfiguration of the adaptive immune system, the latter characterised by a re-emergence of naïve T cells with markers of recent thymic emigrants, including Foxp3+ Tregs and regeneration of naïve B cells. In SLE patients, SIGLEC-1 expression on monocytes completely normalized suggesting an abrogation of type I interferon signalling in responding patients. Conclusion Our data provide the `proof-of-concept` that a chronic autoimmune system can be reset into a naïve and self-tolerant state by immunoablation and HSCT, providing a potential curative treatment option. Although initially applied as salvage therapy in severely affected patients with poor outcomes, transplantation related mortality has gradually improved over the past years, due to accumulating centre experience, better patient selection and improved supportive care. Therefore, HSCT still resembles a promising treatment option, especially in those patients with insufficient response to standard-of-care, with poor prognosis and live-threatening disease, in which the risk:benefit ratio of HSCT seems acceptable. Reference [1]Alexander T, Greco R. Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2022 Jul;57(7):1055-1062. Acknowledgements: NIL. Disclosure of Interests Tobias Alexander Grant/research support from: Amgen, Miltenyi, Janssen, Robert Biesen: None declared, Gerd Rüdiger Burmester: None declared, Andreas Radbruch: None declared, Renate Arnold: None declared, Falk Hiepe: None declared.

Objective: To evaluate the safety and effects of irinotecan, an inhibitor of topoisomerase I, on refractory lupus nephritis. Method: A patient with refractory lupus nephritis under medication with mycophenolic acid, prednisolone, and hydroxychloroquine was treated with add-on low-dose irinotecan. Irinotecan was applied every fourth week at a dose of 50 mg/m(2) for four cycles followed by 100 mg/m(2) for another eight cycles. Renal function and anti-double-stranded DNA antibodies as well as blood count for evaluation of side effects were assessed during the treatment with irinotecan. Results: Before starting the treatment with irinotecan, a urine protein/creatinine ratio of 1298 mg/g was determined. This declined to 613 mg/g after four cycles with 50 mg/m(2) irinotecan and was further reduced to 198 mg/g when using the higher dose of irinotecan. Kidney function remained stable, with creatinine levels of 1.66 mg/dL at the beginning and 1.76 mg/dL at the end of treatment with irinotecan. Importantly, no side effects, such as diarrhoea or neutropenia, were observed during the entire course of treatment. Conclusion: Administration of low-dose irinotecan as add-on medication for the treatment of refractory lupus nephritis was shown to be safe. Clinical trials are needed to determine whether irinotecan can improve kidney function and the outcome of patients with refractory lupus nephritis.

Background:While there have been advances in the therapy of systemic lupus erythematosus (SLE) in recent years, there have been no major new findings in SLE biomarkers [1, 2]. Type I interferon (IFN) plays a pivotal role in the pathogenesis of SLE [3]. In 2008, we first described CD169 / SIGLEC-1 (sialic acid-binding immunoglobulin-like lectin-1), an interferon-induced adhesion molecule on monocytes in SLE patients [4]. For over five years SIGLEC-1 has been routinely assessed in our clinic.Objectives:To evaluate and compare the diagnostic utility of the type I IFN induced SIGLEC-1 with established biomarkers in the initial diagnosis of the disease.Methods:We analyzed retrospectively 232 patients who were on suspicion of SLE at Charité University Hospital Berlin between October 2015 and September 2020. Patients underwent full clinical characterization, and biomarkers were determined in the routine laboratory. Based on the final diagnosis, we divided patients into two groups: A) initial diagnosis of SLE and B) Non-SLE mimicking condition.Results:In 76 patients (32.3 %) SLE was confirmed by fulfilling the EULAR / ACR 2019 classification criteria [5]. SIGLEC-1 was dramatically increased in patients with an initial diagnosis of SLE compared to patients without SLE (p<0.0001). For a threshold of 2500 molecule per monocyte, a sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 %, and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC-1. Adjusted to the prevalence of SLE in Germany (36.7 per 100,000 inhabitants [6]) NPV and PPV turned out to > 99.9 % and 0.2 %. We further aimed to compare not only the performance of the tests at a given cutoff but also across all possible measured values. Therefore, we conducted ROC curves analyses (see figure 1). The area under the curve (AUC) of SIGLEC-1 test was significantly higher than that of ANA test (AUC=0.88, p=0.031), C3 (AUC = 0.83, p=0.001), C4 (AUC=0.83, p=0.002), but not than that of the Anti-dsDNA ELISA (AUC=0.90, p=0.163).Conclusion:Our study shows that IFN activity is a hallmark at the onset of the disease and that the interferon biomarker SIGLEC-1 is valuable to rule out SLE in suspected cases.References:[1]Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, Enghard P, Richter U, Biesen R, Schneider U et al: Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med 2020, 383(12):1149-1155.[2]Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, Amoura Z, Yu X, Mok CC, Santiago MB et al: Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med 2020, 383(12):1117-1128.[3]Ronnblom L, Leonard D: Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med 2019, 6(1):e000270.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, Haupl T, Rudwaleit M, Riemekasten G, Radbruch A et al: Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum 2008, 58(4):1136-1145.[5]Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, Smolen JS, Wofsy D, Boumpas DT, Kamen DL et al: 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Annals of the Rheumatic Diseases 2019, 78(9):1151-1159.[6]Brinks R, Fischer-Betz R, Sander O, Richter JG, Chehab G, Schneider M: Age-specific prevalence of diagnosed systemic lupus erythematosus in Germany 2002 and projection to 2030. Lupus 2014, 23(13):1407-1411.Disclosure of Interests:None declared

The interferon (IFN) pathway is a complex system with multiple proteins and diverse downstream effects on gene and protein expression. IFNs have been implicated in multiple RMDs. Despite significant potential, IFN assays have not progressed into clinical practice.To perform a SLR on IFN assays in RMDs and propose a consensus terminology.OvidMedline, Embase and Web of Science were searched for reports of IFN and RMDs up to October 2019. Information about the properties of assays measuring type I IFN and measures of truth were extracted and summarised. Terminology was agreed through an interactive consensus process with reference to the existing evidence.10037 abstracts were identified. 275 fulfilled eligibility criteria, and were used for data extraction. Some used more than one technique to measure IFN-I pathway activation. Hence, 275 papers generated data on 393 methods. There was great heterogeneity in the methods used and presentation of results. IFN-I pathway activation was measured using: qPCR (n=121), immunoassays (n=101), microarray (n=69), reporter cell assay (n=38), DNA methylation (n=14), flow cytometry (n=14), cytopathic effect assay (n=11), RNA sequencing (n=9), Plaque reduction assay (n=8), Nanostring (n=5), bisulphite sequencing (n=3). All papers fulfilled Face Validity. Due to lack of gold standard for IFN-I pathway activation, evidence of criterion validity was variable. Concurrent validity was presented for n=150 assays. The terminology used to describe aspects of type I IFN pathway activation was not consistent, so a consensus terminology for IFN research (Table 1) was proposed by the taskforce.Table 1.Consensus terminologyTermAbbreviationDefinitionInterferonIFNProteins with anti-viral activity; IFNs are mediators of an anti-viral response. They belong to the Type I, Type II and Type III IFN families.Type I interferonIFN-IThe IFNs alpha, beta, omega, kappa, epsilon, secreted by any nucleated cell, and binding to the IFNAR, which is expressed on any nucleated cell.Type II interferonIFN-IIIFN gamma, mostly secreted by T cells, binding to the IFNGR, which is expressed on most leucocytes.Type III interferonIFN-IIIIFN lambda, which are structurally more similar to IL-10 but share downstream signalling and gene expression with IFN-I.Interferon-stimulated genesISGsGenes whose expression is known to be upregulated by any kind of IFN. Individual ISGs may not exclusively represent Type I IFN pathway activation.Type I Interferon pathway activationAny evidence for function of the components of the Type I IFN pathway. This includes: secretion of a Type I IFN protein, binding to the IFNAR, initiation of JAK/STAT signalling pathways, expression of IFN-stimulated genes, expression of IFN-stimulated proteins.Type I interferon pathway assayAn assay measuring one or more components of the Type I IFN pathway at a molecular or functional level.Interferon stimulated gene expression signatureA qualitative description of coordinated expression of a set of ISGs that is indicative of Type I IFN pathway activation.Interferon stimulated gene expression scoreA quantitative variable derived from expression of a defined set of ISGs that is indicative of Type I IFN pathway activation.Interferon stimulated protein scoreA variable derived from expression of a defined set of soluble biomarkers known to be upregulated by IFN, although not specific for Type I IFN.InterferonopathyMonogenic diseases in which there is constitutive Type I IFN pathway activation with a causal role in pathology. The clinical picture may resemble rheumatic musculoskeletal diseases. However, most diseases with IFN pathway activation are not Interferonopathies.Diverse methods have been reported as IFN assays and these differ in what elements of type IFN-I pathway activation they measure. The taskforce consensus terminology on type I IFN reporting should be considered for research and clinical applications.Agata Burska: None declared, Javier Rodriguez Carrio: None declared, Philip G Conaghan: None declared, Willem A Dik: None declared, Robert Biesen: None declared, Maija-leena Eloranta: None declared, Giulio Cavalli: None declared, Marianne Visser: None declared, Dimitrios Boumpas: None declared, George Bertsias: None declared, Marie Wahren-Herlenius: None declared, Jan Rehwinkel: None declared, Marie-Louise Frémond: None declared, Mary K. Crow Consultant of: AstraZeneca, Bristol Meyers Squibb, Lilly, Shannon Pharmaceuticals, Grant/research support from: Gilead, Lars Ronnblom Consultant of: AstraZeneca, Edward Vital Speakers bureau: GSK, Consultant of: AURINIA, SANDOZ, GSK, AstraZeneca, Roche, Modus, Grant/research support from: AstraZeneca, Marjan Versnel: None declared

Background: Idiopathic inflammatory myopathies (IIM) are autoimmune diseases that mainly affect skeletal muscle, lung, skin and joints. IIM can be separated into dermatomyositis (DM), inclusion body myositis (IBM), antisynthetase syndrome (AS) and immune-mediated necrotizing myopathy (IMNM). Type I interferons (IFN) are known to play a crucial role in the etiopathogenesis of some of these entities such as DM.[1] Sialic acid binding Ig-like lectin 1 (SIGLEC1, CD169) is part of the type I IFN signature found in SLE and DM and is expressed on the cell surface of monocytes. Thus, analysis of SIGLEC1 expression by flow cytometry enables a straightforward assessment of the type I IFN signature. Its utility has been shown for juvenile and adult SLE and other rheumatic diseases but not in IIM.[2,3] The assessment of the type I IFN system in clinical practice is an unmet need and, in this context, SIGLEC1 might be useful. Objectives: To assess SIGLEC1 expression on monocytes by flow cytometry as a type I IFN biomarker in IIM Methods: Pediatric and adult patients with a clinical diagnosis of DM, AS, IMNM and IBM and at least one measurement of SIGLEC1 who have been treated at the Department of Rheumatology, Charité - Universitätsmedizin Berlin between 2015 and 2020 were included in this retrospective study. Control groups of healthy individuals (n=19) and SLE patients (n=30) were included. Disease activity was assessed by Physician Global Assessment (PGA) and Childhood Myositis Assessment Scale (CMAS). SIGLEC1 expression on monocytes was analyzed by flow cytometry. Cross-sectional analyses (n=74) were performed using Mann Whitney-U test (MWU) and two-level mixed-effects linear regression model was used for longitudinal analyses (n=26, 110 visits). This study was approved by the local ethics committee of the Charité - Universitätsmedizin Berlin. Results: 74 patients (adult/juvenile DM: n=21/n=17; AS: n=19; IMNM: n=8; IBM: n=9) were included. In cross-sectional analysis, SIGLEC1 expression was significantly upregulated in adult and juvenile DM patients with moderate to severe disease activity (PGA≥5) compared with adult/juvenile DM patients with no to moderate disease activity (PGA<5) (both p<0.001). In longitudinal analyses, SIGLEC1 correlated with disease activity in juvenile DM (SIGLEC1 vs. CMAS: betaST=-0.65; p<0.001) and adult DM (SIGLEC1 vs. PGA: betaST=0.52; p<0.001), better than Creatine Kinase (CK) (juvenile DM, CK vs. CMAS: betaST=-0.50; p<0.001; adult DM, CK vs PGA: betaST=0.17; p=0.149). In AS 42,1% of the patients showed elevated SIGLEC1 expression, while it was not upregulated in IMNM and only in two patients with IBM, who were concurrently positive for autoantibodies that affect the type I IFN system (see Figure 1). Conclusion: SIGLEC1 is a useful biomarker to identify an activated type I IFN system in IIM. Flow cytometry is used widely in laboratory medicine, which could facilitate the implementation of SIGLEC1 into clinical routine. References: [1]Gallay L, Mouchiroud G, Chazaud B. Interferon-signature in idiopathic inflammatory myopathies: Current Opinion in Rheumatology 2019; 31 :634–42. doi:10.1097/BOR.0000000000000653 [2]Rose T, Grutzkau A, Hirseland H, et al. IFNalpha and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis 2013; 72 :1639–45. doi:10.1136/annrheumdis-2012-201586 [3]Stuckrad SL von, Klotsche J, Biesen R, et al. SIGLEC1 (CD169) is a sensitive biomarker for the deterioration of the clinical course in childhood systemic lupus erythematosus. Lupus 2020;:961203320965699. doi:10.1177/0961203320965699 Figure 1. SIGLEC1 expression on monocytes in IIM subgroups and control groups; in IIM subgroups, patients with low disease activity (PGA<5) are marked in blue, patients with high disease activity (PGA≥5) are marked in red; mAb/cell, monoclonal antibodies bound per cell Disclosure of Interests: None declared

Background: Rheumatoid arthritis (RA) is associated with increased systemic bone loss, leading to a high risk for fragility fractures. Especially anti-citrullinated protein antibody (ACPA) positivity is considered a risk factor for local bone erosions and systemic bone loss1. Objectives: The purpose of this study was to compare ACPA positive versus ACPA negative RA patients in terms of the prevalence of osteoporosis and fragility fractures and to identify differences in underlying risk factors that influence bone health. Methods: Rh-GIOP is an ongoing prospective observational study collecting and analyzing disease- and bone-related data from patients with chronic rheumatic diseases or psoriasis treated with glucocorticoids (GC). In this cross-sectional analysis, we performed a matched-pair analysis, matching 114 ACPA positive to 114 ACPA negative RA patients according to age (5-year-steps), sex, and body mass index (BMI, 2-unit-steps). Descriptive analyses were performed, with values displayed as mean ± standard deviation for continuous variables. Non-parametric tests were used at a two-sided significance level of 5% to compare differences in underlying and potential risk factors without adjustment for multiple testing. Results: At same mean age (63.9 ±10.2 years) and BMI (27.9 ±5.6kg/m2), the matched groups had a female proportion of 82.5%. APCA positive patients had a significantly longer mean disease duration (13.9 vs 9.9 years, p Conclusion: In a cross-sectional analysis of our cohort, the prevalence of osteoporosis and fragility fractures was similar between ACPA positive and ACPA negative RA patients, despite longer disease duration and GC-treatment in ACPA positive patients. This is remarkable since it implies that ACPA negative patients are at a similar risk for osteoporosis and associated fractures. Optimal management of disease activity with or without GCs may represent a mainstay in preventing disease-related comorbidities such as osteoporosis. References: [1]Steffen, U., Schett, G., & Bozec, A. (2019). How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis. Frontiers in immunology, 10, 1483. doi:10.3389/fimmu.2019.01483 Disclosure of Interests: Edgar Wiebe: None declared, Desiree Freier: None declared, Dorte Huscher: None declared, gloria dallagiacoma: None declared, Robert Biesen: None declared, Sandra Hermann: None declared, Gerd Rudiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).

Background: Clinicians rely on the elicitation of features of inflammatory back pain (IBP) for diagnosis of axial spondyloarthritis (axSpA) but the utility of IBP criteria in patients presenting with extra-articular features of axSpA remains unclear. Assessment of utility should include not only rheumatologist diagnosis as benchmark but imaging to address the circularity between elicitation of IBP and clinical diagnosis. Objectives: To assess the diagnostic utility of all criteria for IBP in patients with psoriasis, iritis, or colitis and undiagnosed back pain using the rheumatologist diagnosis and imaging as benchmarks. Methods: Consecutive patients (n=246) with undiagnosed back pain ≤45 years of age, ≥3 months, with any one of psoriasis (n=46), acute anterior uveitis (AAU)(n=73), or colitis (n=127) had diagnostic evaluation by a rheumatologist. Majority central reader assessment of MRI indicative of axSpA and diagnosis by the rheumatologist were external standards for testing the utility of these IBP criteria: ASAS, Berlin, Calin, rheumatologist global for IBP >5 (0-10 scale). Results: AxSpA was diagnosed in 44.4%, 61.6%, and 41.8% of patients with psoriasis, iritis, and IBD, respectively. Diagnostic utility for all IBP criteria was comparably poor (Table 1). MRI was indicative of axSpA in 21.2%, 43.5%, and 19.7% of patients with psoriasis, iritis, and IBD. The utility of the IBP criteria was even worse using MRI as the external reference (Table 2), especially in patients with psoriasis. Only 14% of psoriasis patients with a positive MRI reported “improvement with exercise but not rest” as compared to 70% and 62% of patients with iritis and IBD, respectively. Conclusion: All IBP criteria have poor diagnostic utility for diagnosis of axSpA, especially in patients with psoriasis. This reinforces the desirability of less subjective assessment tools, especially imaging. Disclosure of Interests: Georg Krober: None declared, Ulrich Weber: None declared, Raj Carmona: None declared, James Yeung: None declared, Jon Chan: None declared, Sibel Aydin: None declared, Liam Martin: None declared, Ariel Masetto: None declared, Stephanie Keeling: None declared, Olga Ziouzina: None declared, Sherry Rohekar: None declared, Rana Dadashova: None declared, Joel Paschke: None declared, Amanda Carapellucci: None declared, Robert G Lambert: None declared, Walter P. Maksymowych Grant/research support from: AbbVie, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Employee of: Chief Medical Officer of CARE Arthritis Limited, Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, and UCB