Objectives Ncf1 polymorphisms leading to low production of reactive oxygen species (ROS) are strongly associated with autoimmune diseases in animal models. The human NCF1 gene is very complex with both functional and non-functional gene copies and genotyping requires assays specific for functional NCF1 genes. We aimed at investigating association and function of the missense single nucleotide polymorphism (SNP), rs201802880 (here denoted NCF1-339) in NCF1 with systemic lupus erythematosus (SLE). Methods We genotyped the NCF1-339 SNP in 973 Swedish patients with SLE and 1301 controls, using nested PCR and pyrosequencing. ROS production and gene expression of type 1 interferon-regulated genes were measured in isolated cells from subjects with different NCF1-339 genotypes. Results We found an increased frequency of the NCF1-339 T allele in patients with SLE, 11% compared with 4% in controls, OR 3.0, 95% CI 2.4 to 3.9, p=7.0×10⁻²⁰. The NCF1-339 T allele reduced extracellular ROS production in neutrophils (p=0.004) and led to an increase expression of type 1 interferon-regulated genes. In addition, the NCF1-339 T allele was associated with a younger age at diagnosis of SLE; mean age 30.3 compared with 35.9, p=2.0×1⁻⁶. Conclusions These results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.

Objective: C‐reactive protein (CRP) is synthesized by hepatocytes in response to interleukin‐6 (IL‐6) during inflammation. Despite raised IL‐6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon‐α (IFNα), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP.Methods: The interference of all 12 IFNα subtypes with CRP promoter activity induced by IL‐6 and IL‐1β was studied in a CRP promoter– and luciferase reporter–transfected human hepatoma cell line, Hep‐G2. CRP secretion by primary human hepatocytes was analyzed by enzyme‐linked immunosorbent assay.Results: CRP promoter activity was inhibited by all single IFNα subtypes, as well as by 2 different mixtures of biologically relevant IFNα subtypes. The most prominent effect was seen using a leukocyte‐produced mixture of IFNα (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFNα was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep‐G2 proliferation/viability were not affected by IFNα.Conclusion: The current study demonstrates that IFNα is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up‐regulated IFNα and a muted CRP response during SLE disease flares. Given the fundamental role of both IFNα and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.

C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjögren’s syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.

Objective.: Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables.Methods.: Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjögren syndrome (n = 54) served as controls.Results.: CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fisher’s exact test revealed striking differences between methods regarding associations with certain disease phenotypes.Conclusion.: CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.

Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disease, characterized by episodes of disease flares and remissions over time, which may restrain affected patients’ ability to perform daily activities. The purpose of the present study was to characterize variation in activity limitations among well-defined SLE patients, and to describe disease phenotypes, acquired organ damage and their relations to activity limitation and self-reported health, respectively. The disease phenotypes were organized into 4 different clinical groups and logistic regression analyses were used to identify how an elevated health assessment questionnaire (HAQ) score was related to disease variables such as phenotypes, disease activity and damage accrual. Correlation and multiple linear regression analyses were used to examine the association between each group of variables – background variables, disease variables and self-reported measurements – and the degree of elevated HAQ. We found a higher proportion of activity limitation in patients with skin and joint involvement compared to others. The presence of activity limitation, as detected by the HAQ instrument, was significantly associated with quality of life (EuroQol–5D) and accrual of organ damage using the Systemic Lupus International Collaborative Clinics/ACR damage index. The findings highlight the differing requirements of the multi-professional rehabilitation interventions for the various SLE phenotypes in order to optimize the clinical care of the patients.