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Objectives We investigated the effect of a two-dose messenger ribonucleic acid (mRNA) vaccine on antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient behaviour and shielding concerning fear of coronavirus disease 2019 (COVID-19) in patients with systemic lupus erythematosus or rheumatoid arthritis. Methods Three hundred and three patients and 44 blood donors were included. All patients received two doses of an mRNA vaccine and had total antibodies against SARS-CoV-2 measured before vaccination and 2 and 9 weeks after the second vaccination. Further, patients answered an electronic questionnaire before and after vaccination concerning behaviour, anxiety, and symptoms of depression (Patient Health Questionnaire-9). Results Significantly fewer patients (90%) had measurable antibodies against SARS-CoV-2 compared to blood donors (100%) after the second vaccination (P Conclusion We find a very high seroconversion rate among rheumatic patients and reduced self-imposed isolation and shielding after COVID-19 vaccination.

Objective.We aimed to investigate (1) whether patients with rheumatic disease (RD) treated with rituximab (RTX) raise a serological response toward the coronavirus disease 2019 (COVID-19) mRNA vaccines, and (2) to elucidate the influence of time since the last RTX dose before vaccination on this response.Methods.We identified and included 201 patients with RDs followed at the outpatient clinic at the Department of Rheumatology, Aarhus University Hospital, who had been treated with RTX in the period 2017–2021 and who had completed their 2-dose vaccination series with a COVID-19 mRNA vaccine. Total antibodies against the SARS-CoV-2 spike protein were measured on all patients and 44 blood donors as reference.Results.We observed a time-dependent increase in antibody response as the interval from the last RTX treatment to vaccination increased. Only 17.3% of patients developed a detectable antibody response after receiving their vaccination ≤ 6 months after their previous RTX treatment. Positive antibody response increased to 66.7% in patients who had RTX 9–12 months before vaccination. All blood donors (100%) had detectable antibodies after vaccination.Conclusion.Patients with RDs treated with RTX have a severely impaired serological response toward COVID-19 mRNA vaccines. Our data suggest that the current recommendations of a 6-month interval between RTX treatment and vaccination should be reevaluated.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were launched in December 2020. Vaccination of patients with rheumatic diseases is recommended, as they are considered at higher risk of severe COVID-19 than the general population. Patients with rheumatic disease have largely been excluded from vaccine phase 3 trials. This study explores the safety and reactogenicity of BNT162b2 among patients with rheumatic diseases. Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), median age 58.8 years, 285 subjects in total, were vaccinated twice with the BNT162b2 (Pfizer/BioNTech). Questionnaires on reactogenicity matching the original phase 3 study were answered seven days after completed vaccination. The majority of SLE and RA patients experienced either local (78.0%) or systemic reactions (80.1%). Only 1.8% experienced a grade-4 reaction. Compared to the original study, we found more frequent fatigue [Odds ratio (OR) 2.2 (1.7-2.8)], headache [OR 1.7 (1.3-2.2)], muscle pain [OR 1.8 (1.4-2.3)], and joint pain [OR 2.3 (1.7-3.0)] in patients. In contrast, the use of antipyretics was less frequent [OR 0.5 (0.3-0.6)]. Patients with SLE and RA experience reactogenicity to the Pfizer-BioNTech BNT162b2 COVID-19 vaccine. Reactogenicity was more frequent in patients, however, not more severe compared with healthy controls.

Objective: Patients with chronic rheumatic diseases (CRDs), such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), require special attention during the COVID-19 pandemic as they are considered at risk of severe infections. Our objective was to assess the seroprevalence of SARS–CoV-2 in patients with SLE and RA and to assess patient behavior, disease-related symptoms, and mental health. Methods: More than 900 participants were included: 405 patients with RA or SLE (CRD patients) and 513 blood donors. All participants had blood SARS–CoV-2 total antibodies measured (sensitivity 96.7%, specificity 99.5%) and answered a questionnaire concerning behavior, anxiety, and symptoms of depression (Patient Health Questionnaire 9). The CRD patients were further asked about physical activity, adherence to medication, and disease-related symptoms. Results: CRD patients had a significantly lower seroprevalence of SARS–CoV-2 antibodies (n = 1 of 365, 0.3%) compared to blood donors (n = 10 of 513, 1.9%; P = 0.03). Almost 60% of patients were unable to exercise as usual, and increased pain and disease activity was experienced by 34% and 24% of patients, respectively. Almost 10% of patients reduced or discontinued their immunosuppressive treatments at their own initiative. Symptoms of moderate depression were present in 19% of patients compared to 6.8% of blood donors (P < 0.001). Conclusion: Low seroprevalence in patients with CRDs indicates successful mitigation of exposure to SARS–CoV-2. However, this mitigation appears to occur at the expense of physical activity, experience of increased pain, disease activity, and symptoms of depression. There is a need for care providers to be aware of these negative side effects and for further studies to investigate the possible long-term consequences.

This review aims to make clinicians aware of the newly described syndrome, VEXAS. VEXAS should become an obvious differential diagnosis in cases of unexplained inflammation, anemia, and rheumatological and/or hematological manifestations. Patients with VEXAS are typically male agedgt; 60, with inflammation, and macrocytic anaemia. On suspicion of cancer or infections patients have frequently been exposed to extensive diagnostic procedures and hospital admissions. In this review, we summarise the current knowledge of VEXAS regarding pathogenesis, symptoms, diagnosis, and treatment.

Background and Aims: There is an unmet need for new biomarkers to improve diagnostics and prognostics in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Inter-α-inhibitor heavy chain 4 (ITIH4) is an abundant, liver-produced protein, and its synthesis may be altered in liver diseases. We investigated whether ITIH4 plasma concentrations were affected in PBC and PSC patients.Methods: We developed an immunoassay specific for ITIH4 and determined ITIH4 plasma concentrations in 66 PBC, 126 PSC, 92 autoimmune hepatitis (AIH), 67 chronic hepatitis C (CHC), 33 alcoholic hepatitis (AH) patients and 138 healthy controls (HCs). Hepatic ITIH4 expression was investigated by immunohistochemistry in PBC.Results: The mean plasma concentration of ITIH4 was almost doubled in PBC [409 µg/mL (95% CI: 388-431)] and 35% higher in PSC [308 µg/mL, (95% CI: 296-319)] compared with HCs [226 µg/mL (95% CI: 221-231); pConclusions: The plasma concentration of ITIH4 was highly elevated in patients with PBC and PSC, suggesting that ITIH4 should be further investigated as a biomarker in cholestatic liver disease.

This review aims to make clinicians aware of the newly described syndrome, VEXAS. VEXAS should become an obvious differential diagnosis in cases of unexplained inflammation, anemia, and rheumatological and/or hematological manifestations. Patients with VEXAS are typically male aged > 60, with inflammation, and macrocytic anaemia. On suspicion of cancer or infections patients have frequently been exposed to extensive diagnostic procedures and hospital admissions. In this review, we summarise the current knowledge of VEXAS regarding pathogenesis, symptoms, diagnosis, and treatment.

Objectives Over the past decades new international guidelines recommend that pregnant Systemic lupus erythematosus (SLE) patients are monitored closely in a multi-professional team throughout pregnancy. The importance of low disease activity before pregnancy and continued treatment during pregnancy has been established. However, there is still a high risk of adverse pregnancy outcome (APO). The APO in a Danish SLE cohort was evaluated and compared with the results in a previous study cohort from the same centre and referral area. Methods This retrospective cohort study used the local patient registry to identify pregnancies in SLE patients followed at the Department of Rheumatology, Aarhus University Hospital, Denmark, from January 2010 to October 2020. In total, 66 pregnancies were registered in 41 women. Data were compared with a previous retrospective study (1990–2010) from the same hospital. Results Adverse pregnancy outcome occurred in 65% of pregnancies. Forty-seven pregnancies resulted in a live birth, while 15 ended in miscarriages. Compared to the 1990–2010 cohort, a numerical reduction in preterm deliveries (7.58% vs. 17.9%) and emergent caesarean (6.1% vs. 15.5%) was observed, although not reaching statistical significance ( p = .07 in both cases). Further, a higher average birth weight (3045 g vs. 2870 g) as well as a higher number of pregnancies and live births per year were observed. Gestational hypertension was significantly reduced from 23.8% to 13.6% ( p = .05). Significantly more patients were treated with prednisolone (66.7% vs 35.7%, p = .0002), hydroxychloroquine (6% vs. 73.4%, p < .0001) and acetylsalicylic acid (39.3% vs. 73.1%, p = .0001) in 2010–2020 compared to the 1990–2010. Conclusion We observed significant improvements in the frequency of some APOs in the recent 2010–2020 cohort compared with the previous cohort followed from 1990 to 2010. However, even though a specialized multi-professional team closely follows SLE patients through their pregnancies, pregnancy in SLE still carries a high risk of APO.

The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0–3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from “no disease activity” (0) to the “most severe disease activity” (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.

STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit. STING ER exit is the rate-limiting step in STING signaling, but the mechanism that drives this process is not understood. Paludan and colleagues identify CxORF56, called STEEP here, as a positive regulator of STING signaling.

© Copyright Clinical and Experimental Rheumatology 2022, Objectives: The purpose of this study was to review the frequency and clinical presentation of the rarest clinical manifestations of systemic lupus erythematosus (SLE). Methods: A list of 6 rare SLE manifestations were defined: gastrointestinal, liver, pulmonary, cardiac, ocular and neurological manifestations. Each topic was assigned to a pair of authors to perform a literature search and article review. Results: In total, 149 articles were included in the literature review: 37 for gastrointestinal manifestations, 6 for liver manifestations, 27 for pulmonary manifestations, 50 for cardiac manifestations, 16 for ocular manifestations, 13 for neurological manifestations. Gastrointestinal disorders included several clinical presentations with variable frequency (from 0.5% to 10.7% of the cases); liver involvement included lupus-related hepatitis (9.3%) and autoimmune hepatitis (2.3%). The rarest pulmonary manifestations identified were shrinking lung syndrome, described in 1.5% of patients, while interstitial lung disease and lupus pneumonia were reported in 4% and 3% of patients respectively. Myocarditis and pulmonary hypertension were also rarely described in SLE patients although ranging from 0.4-16% and 1-14% respectively, depending on the methodology used for its identification. Ocular manifestations in SLE included some rare manifestations (reported in less than 5% of patients) and lupus retinopathy that is described in 1.2-28.8% of patients depending on methods of ascertainment. Aseptic meningitis and chorea were also confirmed as very rare manifestations being reported in less than 1% and in 0.3-2.4% of cases respectively. Conclusions: The results of this literature review provide the basis for a better understanding of some less-known manifestations of SLE and for stressing the need for a higher awareness in diagnostic and therapeutic protocols regarding these rare disease aspects.

Proteases play a central role in regulating renal pathophysiology and are increasingly evaluated as actionable drug targets. Here, we review the role of proteolytic systems in inflammatory kidney disease. Inflammatory kidney diseases are associated with broad dysregulations of extracellular and intracellular proteolysis. As an example of a proteolytic system, the complement system plays a significant role in glomerular inflammatory kidney disease and is currently under clinical investigation. Based on two glomerular kidney diseases, lupus nephritis, and membranous nephropathy, we portrait two proteolytic pathomechanisms and the role of the complement system. We discuss how profiling proteolytic activity in patient samples could be used to stratify patients for more targeted interventions in inflammatory kidney diseases. We also describe novel comprehensive, quantitative tools to investigate the entirety of proteolytic processes in a tissue sample. Emphasis is placed on mass spectrometric approaches that enable the comprehensive analysis of the complement system, as well as protease activities and regulation in general.

Protease inhibitors influence a range of innate immunity and inflammatory pathways. We quantified plasma concentrations of key anti-inflammatory protease inhibitors in chronic haemodialysis patients with coronavirus disease 2019 (COVID-19). The samples were collected early in the disease course to determine whether plasma protease inhibitor levels associated with the presence and severity of COVID-19. We used antibody-based immunoassays to measure plasma concentrations of C1 esterase inhibitor, alpha2-macroglobulin, antithrombin and inter-alpha-inhibitor heavy chain 4 (ITIH4) in 100 serial samples from 27 haemodialysis patients with COVID-19. ITIH4 was tested in two assays, one measuring intact ITIH4 and another also detecting any fragmented ITIH4 (total ITIH4). Control cohorts were 32 haemodialysis patients without COVID-19 and 32 healthy controls. We compared protease inhibitor concentration based on current and future COVID-19 severity and with C-reactive protein. Results were adjusted for repeated measures and multiple comparisons. Analysis of all available samples demonstrated lower plasma C1 esterase inhibitor and α2M and higher total ITIH4 in COVID-19 compared with dialysis controls. These differences were also seen in the first sample collected after COVID-19 diagnosis, a median of 4 days from diagnostic swab. Plasma ITIH4 levels were higher in severe than the non-severe COVID-19. Serum C-reactive protein correlated positively with plasma levels of antithrombin, intact ITIH4 and total ITIH4. In conclusion, plasma protease inhibitor concentrations are altered in COVID-19.

Purpose: Ficolin-3 deficiency is caused by a mutation (+1637delC) in the FCN3 gene. It is a rare condition and has been associated with both infection and autoimmune disease including systemic lupus erythematosus (SLE). Here we investigated if ficolin-3 deficiency is more frequent in patients than in controls and tried to identify a common phenotype among ficolin-3 deficient individuals. Since a significant part of patients identified with ficolin-3 deficiency was diagnosed with SLE, we explored whether the heterozygous state of the FCN3+1637delC variant represents a risk factor in the development of SLE. Further, we examined other possible causes of ficolin-3 deficiency when the FCN3+1637delC is not present. Methods: A systematic literature search for studies measuring ficolin-3 was carried out. We examined 362 SLE patients and 596 controls for the presence of the variant FCN3+1637delC. We established assays for measurements of ficolin-3 and of auto-antibodies against ficolin-3. We sequenced the coding and non-coding regions of the FCN3 gene in an SLE patient with ficolin-3 deficiency not carrying the +1637delC. Results: Ficolin-3 deficiency leads to an 8-time increased odds of having a disease (p < 0.05). Three out of nine patients with deficiency had SLE. The heterozygous state of the deficiency variant is not associated with increased risk of developing SLE (p = 0.18). Conclusion: By systematically reviewing the literature for the described cases of ficolin-3 deficiency, an autoimmune phenotype is emerging. Thirty-three percent of the ficolin-3 deficient patients had SLE. Heterozygosity for the FCN3 gene deletion causing the deficiency does not seem to be associated with the development of SLE.

Detection of complement activation products can be carried out in a number of ways, and different methods are used in different laboratories. No international standard for measuring complement activation in the clinical setting has been agreed upon.Here we describe a modified assay for measuring C3dg. The assay is simple, inexpensive and stable. The estimation of C3dg directly reflects complement turnover independently of activation pathway.

ObjectivesSLE displays large clinical heterogeneity that beyond genetic factors may be determined by environmental exposures. In this Danish nationwide study, we aimed to determine if clinical subsets of SLE were associated with smoking history.MethodsAt each of six participating centres, incident or prevalent inpatients and outpatients with SLE were consecutively included. Manifestations forming the basis of SLE classification were registered in an electronic chart system. Patients also provided questionnaire-based data on environmental exposures, including smoking history. Hierarchical cluster analysis was conducted to determine and characterise subsets of patients with similar traits of disease manifestations. Levels of smoking exposure by pack-years were correlated to the identified SLE subsets, as well as discrete SLE manifestations.ResultsThe cohort consisted of 485 patients (88% women and 92% Caucasian) with SLE of which 51% were ever smokers. Common disease manifestations comprised non-erosive arthritis (81%), malar rash (57%), lymphopenia (55%), photosensitivity (50%) and persistent proteinuria (41%). We identified three distinct phenotypic clusters characterised by their preponderance of (A) neurological, serosal and mucosal involvement; (B) renal, haematological and immunological disorders; and (C) acute and chronic skin manifestations. Cluster B was the youngest and had the lowest level of smoking exposure. Age-adjusted regression analyses showed that compared with never smokers a smoking history of >20 pack-years was associated with neurological disorder (OR=3.16), discoid rash (OR=2.22), photosensitivity (OR=2.19) and inversely with haematological disorder (OR=0.40), renal disorder (OR=0.40) and non-erosive arthritis (OR=0.45), pConclusionsOur findings support that SLE presents in varying clinical phenotypes and suggest that they may have differentiated associations with smoking history.

Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA-protein nanoparticulates in the pathobiology of autoimmune diseases.

Detection of complement activation products can be carried out in a number of ways, and different methods are used in different laboratories. No international standard for measuring complement activation in the clinical setting has been agreed upon.Here we describe a modified assay for measuring C3dg. The assay is simple, inexpensive and stable. The estimation of C3dg directly reflects complement turnover independently of activation pathway.

BACKGROUND: Nucleic acids are potent stimulators of type I interferon (IFN-I) and antiviral defense, but may also promote pathological inflammation. A range of diseases are characterized by elevated IFN-I, including systemic lupus erythematosus (lupus). The DNA-activated cGAS-STING pathway is a major IFN-I-inducing pathway, and activation of signaling is dependent on trafficking of STING from the ER to the Golgi.METHODS: Here we used cell culture systems, a mouse lupus model, and material from lupus patients, to explore the mode of action of a STING antagonistic peptide, and its ability to modulate disease processes.FINDINGS: We report that the peptide ISD017 selectively inhibits all known down-stream activities of STING, including IFN-I, inflammatory cytokines, autophagy, and apoptosis. ISD017 blocks the essential trafficking of STING from the ER to Golgi through a mechanism dependent on the STING ER retention factor STIM1. Importantly, ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. Finally, ISD017 treatment blocks pathological cytokine responses in cells from lupus patients with elevated IFN-I levels.INTERPRETATION: These data hold promise for beneficial use of STING-targeting therapy in lupus.FUNDING: The Novo Nordisk Foundation, The European Research Council, The Lundbeck Foundation, European Union under the Horizon 2020 Research, Deutsche Forschungsgemeinschaft, Chulalongkorn University.

ObjectiveTo investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations.MethodsPatients with SLE (ndiscovery cohort=776, nreplication cohort=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p−8) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n=45).ResultsIn the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)).Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively).The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063).Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively).ConclusionsSmoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12−STAT4 pathway in SLE-cardiovascular morbidity.

Aim: Activation of the complement system is known to be a potent inducer of systemic inflammation, which is an important component of post-cardiac arrest syndrome. Mannan-binding-lectin associated protein of 19 kDa (MAp19) is suggested to be a regulatory component of the lectin pathway of complement activation. The aims of this study were to describe serial levels of MAp19 protein in comatose survivors of out-of-hospital cardiac arrest (OHCA), to evaluate the effect of two different regimes of targeted temperature management and to investigate the possible association between levels of MAp19 and mortality. Methods: In this post-hoc study, we analysed data from two large randomized controlled studies: ‘Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest’ (TTM) and ‘Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest’ (TTH). We measured serial levels of MAp19 in 240 patients within 72 h after OHCA and in 82 healthy controls. The effect of targeted temperature management on MAp19 levels was analysed according to temperature allocation in main trials. Results: MAp19 levels were significantly lower in OHCA patients within 48 h after OHCA (p-values Conclusion: Survivors after OHCA have lower levels of MAp19 protein compared with healthy controls. A targeted temperature management at 33°C compared with 36°C was associated with significantly lower MAp19 levels, whereas target temperature at 33°C for 48 h compared with 24 h did not influence MAp19 protein levels. Low MAp19 levels at admission were independently associated with increased mortality.

In human autoimmune diseases, low plasma levels of complement factors C3 and C4 are commonly used as a proxy for complement activation. The measurements of C3 and C4 concentrations (the result of synthesis and consumption) however, show low sensitivity in patient follow-up. We find that the estimation of the C3dg fragment released during complement activation is a better parameter for complement activation. Available techniques for measuring the activation fragment C3dg, e.g. immune-electrophoresis or involving PEG-precipitation, are time-consuming and difficult to standardize. Here we examine the specificity and use of an antibody with mono-specificity for a neoepitope at the N-terminus of C3dg, which is only exposed after cleavage of C3. We present a stable, reproducible, and easy-to-use, time-resolved immunoassay with specificity for C3dg that can be used to directly evaluate ongoing complement activation. We demonstrate that the assay can be applied to clinical samples with a high specificity (95%) and a positive likelihood ratio of 10. It can also differentiate the complement related disease Systemic Lupus Erythematosus from controls and other immune-mediatedimmune mediated diseases like Rheumatoid Arthritis (86% specificity) and Spondyloarthritis (91% specificity).. Further, we establish how the assay may also be used for experimental research in in vivo mouse models.

Hydroxychloroquine (HCQ) is used in the treatment of rheumatologic diseases including systemic lupus erythematosus, rheumatoid arthritis and other conditions. Besides reducing joint and skin inflammation, growing evidence shows other beneficial effects of HCQ, e.g. a positive effect on cardiovascular risk, pregnancy outcome, and flare reduction. In this review, we wish to emphasise "best practice" in the use of HCQ based on the present literature, to show the typical eye damage, which may occur, and to highlight which precautions should be made, so that retinal injury does not occur.

Hydroxychloroquine (HCQ) is used in the treatment of rheumatologic diseases including systemic lupus erythematosus, rheumatoid arthritis and other conditions. Besides reducing joint and skin inflammation, growing evidence shows other beneficial effects of HCQ, e.g. a positive effect on cardiovascular risk, pregnancy outcome, and flare reduction. In this review, we wish to emphasise "best practice" in the use of HCQ based on the present literature, to show the typical eye damage, which may occur, and to highlight which precautions should be made, so that retinal injury does not occur.

Background A subarachnoid hemorrhage (SAH) is a debilitating stroke. Activation of the lectin pathway (LP) of the complement system in SAH patients could worsen the prognosis; however, conflicting results have been reported. This potentially reflects that pathological changes at the site of injury are not reflected in peripheral blood. Aims of the study To measure the concentration of LP proteins in blood from the site of brain injury compared with peripheral blood in SAH patients, and to determine the concentration of LP proteins in cerebrospinal fluid (CSF). Methods We included 11 SAH patients undergoing aneurysm clipping or external ventricular drainage. Blood was collected from the site of injury and from a peripheral artery and/or CSF simultaneously. LP proteins were measured using time‐resolved immunofluorometric assays. Results In all patients, the cerebral blood concentration of mannan‐binding lectin, collectin liver‐1 and collectin kidney‐1, and mannan‐associated serine proteases 1 and 2 were lower than in peripheral blood. The LP proteins were almost undetectable in CSF. Conclusion Lectin pathway protein concentrations measured in peripheral blood do not always reflect changes at the site of injury. For some proteins, more information could be obtained in blood from the site of injury when investigating pathogenic mechanisms., A subarachnoid hemorrhage is a debilitating stroke and activation of the lectin pathway could partially explain the poor prognosis. Conflicting results have been reported regarding the activation of the lectin pathway, which potentially reflects that changes at the site of injury are not reflected in peripheral blood. We found that the concentrations of lectin pathway proteins in peripheral blood do not always reflect changes at the site of injury.

Background Patients with SLE have increased morbidity and mortality due to cardiovascular disease. Here, we construct and validate a polygenic risk score (PRS) for myocardial infarction (MI) in SLE. Methods Patients with SLE (European decent, ≥4 ACR-criteria) were genotyped using a 200K Immunochip SNP array (discovery cohort, Sweden, n=776) and custom MassARRAY assays (replication cohort, Norway/Denmark, n=890). In the discovery cohort, 57 SNPs with previously established association with SLE development (p Results Four SLE-risk genes were found to be associated with a decreased time until the first MI; PTPN22 (OR 1.61, p=0.041), NCF2 (OR 2.47, p=2.1×10-3), STAT4 (OR 1.66, p=5.2×10-3) and IL12A (OR 1.45, p=0.047) and were included in a PRS. The PRS was associated with a higher cumulative prevalence of MI in both the discovery cohort (p=1.1×10-5, fig 1A) and replication cohort (p=7.7×10-3, fig 1B). Exploring the PRS further in the replication cohort, patients in the high, compared to the low, PRS-quartile were more often male (p=1.3×10-3), and displayed higher prevalence of the ACR-1982 nephritis and immunological criteria (p=4.1×10-4 and p=0.036) (fig1C). Analyzing combinations of the identified SNPs, we found the prevalence of MI to be further increased in patients homozygous for both NCF2+STAT4 (pdiscovery=1.6×10-3, preplication=0.015) or STAT4+IL12A (pdiscovery=3.0×10-5, preplication=0.036) (fig1D). Conclusion A high polygenic risk score for MI in SLE is associated with an increased prevalence of myocardial infarction. If confirmed in prospective studies, our results suggest that genetic profiling may be useful for predicting MI in patients with SLE.

Background Lupus Nephritis (LN) is a cause of significant morbidity in SLE. While the genetic background to SLE has been well characterized, less is known about genes predisposing to LN. Methods The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN and LN-negative patients. SNPs with a p-value Results In the discovery cohort, strong association to LN was found with several highly linked SNPs in BANK1, with the top signal in the intronic SNP rs4699261 (p=9.9×10-5, OR 0.66). The association was also present in replication cohort 1 (p=9.5×10-4). In a meta-analysis of the discovery and replication cohort 1, a total of 20 SNPs in BANK1 were associated to LN with the highest signal in rs4699261 (p=3.3×10-7). There was a tendency towards association in replication cohort 2 (p=0.05) and in a meta-analysis of all cohorts, the association with BANK1 was strengthened (p=1.7×10-7). Conclusion BANK1 variations are associated with LN in patients with SLE. Upregulated BANK1 expression in renal biopsies from LN patients has previously been shown, however the exact role of BANK1 in LN pathogenesis remains to be elucidated.

Previous research indicates that the complement system is activated after occurrence of intracerebral hemorrhage (ICH) and spontaneous subarachnoid hemorrhage (SAH). The role of the lectin pathway (LP) of the complement system in this activation has only scarcely been investigated. The aim of this study was to determine the plasma concentration of the LP proteins in patients with ICH or SAH at admission compared to healthy individuals. Secondly, ICH and SAH patients were followed during the initial 24 h of disease, to investigate changes in LP protein concentrations during the critical acute phase. This prospective, observational study included 30 ICH and 33 SAH patients. EDTA plasma samples were collected at admission, 6 and 24 h after symptom onset. Time-resolved immuno-flourometric assays (TRIFMA) were used to measure all proteins of the LP in patient samples and in samples from age- and gender-matched healthy individuals. Compared to healthy individuals, ICH and SAH patients had increased levels of H-ficolin (p = 0.04, p = 0.03), M-ficolin (both p

BACKGROUND: Lectin pathway proteases activate coagulation and may theoretically play a role in the increased thrombosis risk in cancer, which is especially high during surgery.AIMS: To investigate lectin pathway proteins during lung cancer surgery, the influence of low molecular weight heparin (LMWH) on lectin pathway proteins, and correlations between lectin pathway proteins and coagulation.METHODS: Fifty lung cancer patients undergoing video-assisted thoracoscopic surgery lobectomy were randomised to LMWH, n = 26, or no anticoagulant (control), n = 24. Pre-, intra- and postoperative lectin pathway protein concentrations (mannose-binding lectin (MBL), H- and M-ficolin, collectin liver-1, MBL-associated serine protease (MASP)-1, -2 and -3, MBL-associated proteins MAp44 and MAp19) were assessed using a time-resolved immunofluorometric assay, and fibrinogen, fibrin d-dimer, and thrombin generation were analysed.RESULTS: For all proteins except MASP-1, concentrations decreased during surgery in both groups; most markedly M-ficolin which decreased 49% (median: 2836 [quartiles:2297-3505] to 1424 [1187-2199] ng/ml) (LMWH group) and 43% (2974 [2539-3510] to 1685 [1391-2076] ng/ml) (control group), while MBL decreased 12% (1936 [823-2801] to 1702 [676-2830] ng/ml) (LMWH) and 23% (1526 [250-2412] to 1175 [229-1947]) (controls). No differences in postoperative change were observed between groups except for MAp19 (p = 0.03) which decreased 9% (401 [337-467] to 364 [288-416] ng/ml) (LMWH) vs 28% (370 [272-468] to 268 [212-379] ng/ml) (controls). No correlation was found between lectin pathway proteins and coagulation (r = -0.23-0.28, p > 0.06) except for M-ficolin and fibrinogen (r = 0.29-0.36, p = 0.01-0.04).CONCLUSION: Lectin pathway proteins were influenced by surgery but not by LMWH. No consistent correlation was found between lectin pathway proteins and coagulation.

Introduction: IgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.Methods: To elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.Results: M-ficolin, L-ficolin, mannan-binding lectin (MBL)-associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H-related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.Conclusion: Our data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.

Objective Human endogenous retroviruses (HERVs) are remnants of past retroviral infections in the human genome and have been implicated in different aspects of human biology. The aim of this study was to identify HERVs that are associated with the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE). Methods The study subjects included 45 female patients with SLE and 50 healthy controls matched for geographic area, age, and sex. Real-time reverse transcription-polymerase chain reaction analysis was used to examine the transcription levels of 11 genes with coding capacity for complete envelope (Env) protein in these individuals. In this way, 1 HERV locus was identified as a potential modulator of autoimmunity. The env gene encoded by this HERV locus was cloned and examined for the ability to express a functional protein with immunosuppressive potential. Results Expression of the env59 gene was negatively correlated with pathogenetic factors of human autoimmune rheumatic diseases, including such factors as the levels of interleukin-6 (IL-6) and Toll-like receptor 7. This gene was capable of encoding a fully functional Env glycoprotein that was found to contain a domain, the immunosuppressive (ISU) domain, that, when evaluated ex vivo in patients with SLE and those with rheumatoid arthritis as well as in animal models, showed strong antiinflammatory activity, including the ability to lower IL-6 levels. Conclusion The env59 gene has been adapted by the immune system as a control mechanism in autoimmunity. The peptides derived from the ISU domain contained in the Env59 protein may be useful as potentially new biologic treatments in rheumatic diseases such as SLE.

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