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Systemic lupus erythematosus (SLE) flares elicit progressive organ damage, leading to disability and early mortality. This study evaluated clinical and immunologic factors associated with impending flare in the Biomarkers of Lupus Disease study. Autoantibodies and 32 soluble mediators were measured by multiplex assays, immune pathway activation by gene expression module scores, and immune cell subset frequencies and activation states by flow cytometry. After providing baseline samples, participants received transient steroids to suppress disease and were followed until flare. Flare occurred early (within 60 days of baseline) in 21 participants and late (90–165 days) in 13. At baseline, compared to the late flare group, the early flare group had differential gene expression in monocyte, T cell, interferon, and inflammation modules, as well as significantly higher frequencies of activated (aCD11b+) neutrophils and monocytes, and activated (CD86hi) naïve B cells. Random forest models showed three subgroups of early flare patients, distinguished by greater baseline frequencies of aCD11b+ monocytes, or CD86hi naïve B cells, or both. Increases in these cell populations were the most accurate biomarkers for early flare in this study. These results suggest that SLE flares may arise from an overlapping spectrum of lymphoid and myeloid mechanisms in different patients.

Background Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. Methods Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb–) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. Findings Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

Objective Incomplete lupus erythematosus (ILE) involves clinical and/or serologic manifestations consistent with but insufficient for systemic lupus erythematosus (SLE) classification. Because the nature of ILE is poorly understood and no treatment recommendations exist, we examined the clinical manifestations, medication history, and immunologic features in a diverse collection of ILE and SLE patients. Methods Medical records of subjects enrolled in the Lupus Family Registry and Repository were reviewed for medication history and American College of Rheumatology (ACR) classification criteria to identify ILE patients (3 ACR criteria; n = 440) and SLE patients (≥4 ACR criteria; n = 3,397). Participants completed the Connective Tissue Disease Screening Questionnaire. Anticardiolipin and plasma B lymphocyte stimulator (BLyS) were measured by enzyme-linked immunosorbent assay, antinuclear antibodies (ANAs) by indirect immunofluorescence, and 13 autoantibodies by bead-based assays. Results On average, ILE patients were older than SLE patients (46.2 years versus 42.0 years; P < 0.0001), and fewer ILE patients were African American (23.9% versus 32.2%; P < 0.001). ILE patients exhibited fewer autoantibody specificities than SLE patients (1.3 versus 2.6; P < 0.0001) and were less likely to have ANA titers ≥1:1,080 (10.5% versus 19.5%; P < 0.0001). BLyS levels were intermediate in ILE patients (controls < ILE; P = 0.016; ILE < SLE; P = 0.008). Pericarditis, renal, or neurologic manifestations occurred in 12.5% of ILE patients and were associated with non–European American race/ethnicity (P = 0.012). Hydroxychloroquine use increased over time, but was less frequent in ILE than SLE patients (65.2% versus 83.1%; P < 0.0001). Conclusion Although usually characterized by milder symptoms, ILE manifestations may require immunomodulatory treatments. Longitudinal studies are necessary to understand how ILE affects organ damage and future SLE risk, and to delineate molecular pathways unique to ILE.

Infections remain a significant source of morbidity and mortality in systemic lupus erythematosus (SLE). Both the underlying disease process and therapeutic immunosuppression can increase susceptibility to a wide variety of pathogens while influencing the clinical course of infections. Because of the atypical presentation of many infections and the varied array of baseline symptoms, distinguishing an acute infection from a lupus flare is a common clinical challenge in treating SLE patients. This challenge is compounded by the need to suppress the immune system enough to prevent autoimmune complications without making patients overly vulnerable to infection. This chapter reviews the impact of infections on lupus morbidity and mortality, risk factors for infection, the clinical spectrum of infections in lupus, proposed mechanisms of infection susceptibility, and biomarkers or other factors that may assist the clinician when differentiating active infection from an SLE disease flare.

Background Systemic lupus erythematosus (SLE) is characterised by remarkable clinical and pathophysiological diversity, hindering diagnosis, treatment and treatment development. Subsetting of patients based upon clinical presentations alone has not identified homogeneous groups of patients best treated with a directed therapeutic. Objectives To cluster SLE patients into more homogeneous subsets with common molecular pathway signatures, and to assess the clinical, therapeutic, and demographic features enriched in each cluster. Methods Serial or single plasma, serum and RNA samples (n=290) were collected from 198 SLE patients who met ACR classification. Disease activity was assessed by modified SELENA-SLEDAI at an average of 17 visits per patient. Transcriptional co-expression signature module scores were calculated from Illumina Beadchip Microarray gene expression data for 29 immune pathway related modules. Plasma soluble mediators (n=23) and 12 antinuclear autoantibodies (anti-dsDNA, chromatin, ribosomal P, Sm, Sm, SmRNP, RNP, Ro/SSA, La/SSB, centromere B, Scl-70 and Jo-1) were assessed by multiplex bead-based assay and ELISA. Spearman correlations were used for univariate and multivariate analysis using R. Patients were clustered on module signature scores and soluble mediators using random forest and tSNE. Results SLEDAI scores strongly correlated with interferon modules and were modestly correlated with plasmablast and select cell cycle signatures in this adult lupus collection. SLEDAI scores also correlated with soluble levels of IFNa, IL21, IL1a, IL17A, IP10 and MIG. Random forest defined seven clusters of SLE patients with unique molecular phenotypes based upon gene co-expression module signatures and soluble mediators. Inflammation and interferon (IFN) signatures were elevated in Clusters 1 (moderately) and 4, with decreased T cell signatures in Cluster 4. The other clusters had lower IFN and inflammation signatures, but differed in their monocyte, plasmablast and T cell signatures. Clusters 1 and 4 had the highest SLEDAI scores, with high rates of anti-dsDNA, low complement, proteinuria and hematuria; these features were also prominent in Cluster 3, which lacked the IFN and inflammation signatures. Cluster 6 had the highest plasmablast module score, highest IL1a levels, and SLEDAI scored rashes, but only moderate IFN and inflammation module scores. Cluster 2 had higher rates of SLEDAI scored alopecia, a slightly elevated inflammation signature, but lower interferon signature and lower soluble mediator levels. Conclusions SLE subsets can be distinguished by a range of molecular profiles encompassing IFN, T cell, neutrophil, plasmablast, and inflammation co-expression signatures, as well as soluble mediators that vary with disease activity. Prospective longitudinal studies of these molecular profiles may inform clinical trial design and personalised disease management. Acknowledgements This work was supported in part by grants from the National Institutes of Health: U19AI082714, U01AI101934, U54GM104938, and P30AR053483. Disclosure of Interest None declared

Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with varied morbidity and mortality. We assessed clinical presentations, autoantibody specificities and therapeutic interventions in Native American (NA) patients with SLE. Methods: Patients with SLE meeting 1997 American College of Rheumatology classification criteria (n=3148) were enrolled between 1992 and 2010 in the multiethnic, cross-sectional Lupus Family Registry and Repository. Clinical, demographic and therapeutic information were extracted from medical records using a standardised form and formalised training. Autoantibodies were assessed by indirect immunofluorescence (antinuclear antibodies (ANA) and antidouble-stranded DNA), precipitin (ENA) and ELISA (IgG and IgM anticardiolipins). Results: NA patients met SLE classification at a younger age (29.89±12.3 years) than European Americans (EA; 32.02±12.87, P=0.0157) and a similar age to African-Americans (AAs) and Hispanics (HIS). More NA patients had concurrent rheumatic diseases or symptoms, such as Raynaud's phenomenon, interstitial lung disease, Sjögren's syndrome and systemic sclerosis. Compared with EAs, NAs were more likely to have high-titre ANA (≥1:3240; P

Objectives Epstein-Barr virus (EBV) is considered an important environmental factor in SLE aetiology, but the relationship between SLE and EBV in the Filipino population is unknown. We tested associations between SLE, lupus-associated autoantibodies and seropositivity for EBV and other herpes viruses in the Filipino population. Methods Sera from Filipino patients with SLE (n=233), unaffected first-degree relatives (FDRs, n=543) and unrelated controls (n=221) were tested for antibodies against EBV, cytomegalovirus (CMV) and herpes simplex viruses (HSV-1 and HSV-2) by standardised ELISAs. Humoral specificity against EBV nuclear antigen (EBNA)-1 was compared by solid-phase epitope mapping. Autoantibodies were detected by a bead-based multiplex assay. Results were analysed by Fisher's exact test, Student's t-test, χ2 test and one-way analysis of variance, as appropriate for the question. Results Filipino patients with SLE had increased seroprevalence and elevated antibody concentrations against EBV viral capsid antigen (EBV-VCA), CMV, HSV-1 and HSV-2 compared with unrelated controls (p

Systemic lupus erythematosus (SLE) etiology likely involves complex interactions between genetic and environmental stimuli that lead to autoantibody production and chronic inflammation. Infections are considered likely environmental triggers of SLE because certain viruses and bacteria can stimulate the innate immune system, incite the production of autoreactive responses, and alter immune cell activation and regulation. Specifically, decades of research point to Epstein–Barr virus (EBV) contributing to lupus pathogenesis. EBV promotes the development of lupus-associated autoantibodies through molecular mimicry and epitope spreading, and EBV proteins can drive aberrant activation of B cells and cytotoxic T cells by mimicking the functional effects of CD40 and interleukin-10. In individuals who are inherently susceptible to immune dysregulation, such microbe-driven changes can enhance the onset or progression of autoimmune disease. Microbiota may also influence autoimmunity. Finally, some infections may protect against autoimmunity in animal models, highlighting the intricacy of the gene–environment interactions that influence SLE pathogenesis.

Systemic lupus erythematosus (SLE) is often preceded by immune dysregulation and clinical manifestations below the threshold for SLE classification. This review discusses current and evolving concepts about the preclassification period of SLE, including clinical and mechanistic observations, and potential avenues for early identification and intervention.Although incomplete lupus erythematosus (ILE) involves fewer clinical manifestations than SLE, ILE patients can suffer organ damage and early mortality. Common clinical features in ILE include antinuclear antibody seropositivity, polyarthritis, immunologic manifestations, and hematological disorders. Despite having lower disease activity and damage scores than SLE patients, ILE patients may develop pulmonary arterial hypertension, or renal, neurological, or peripheral vascular damage. The recently proposed Systemic Lupus International Collaborating Clinics SLE classification criteria could shift the period considered 'preclinical SLE'. Murine studies suggest that the balance of T-helper/T-regulatory cells, peroxisome proliferator-activated receptor γ activity, and plasmacytoid dendritic cell pathways may be valuable targets for early intervention.Advances in our understanding of early SLE, including stages before clinical features are fully developed, will improve our ability to identify individuals at high risk of classification for potential prevention trials, provide necessary information to improve diagnostic testing, and perhaps identify novel targets for directed therapeutics in clinical SLE.

Objective SLE is traditionally classified using the American College of Rheumatology (ACR) criteria. The Systemic Lupus International Collaborating Clinics (SLICC) recently validated an alternative system. This study examined large cohorts of subjects with SLE and incomplete lupus erythematosus (ILE) to compare the impact of ACR and SLICC criteria. Methods Medical records of subjects in the Lupus Family Registry and Repository were reviewed for documentation of 1997 ACR classification criteria, SLICC classification criteria and medication usage. Autoantibodies were assessed by indirect immunofluorescence (ANA, antidouble-stranded DNA), precipitin (Sm) and ELISA (anticardiolipin). Other relevant autoantibodies were detected by precipitin and with a bead-based multiplex assay. Results Of 3575 subjects classified with SLE under at least one system, 3312 (92.6%) were classified as SLE by both systems (SLE both ), 85 only by ACR criteria (SLE ACR-only ) and 178 only by SLICC criteria (SLE SLICC-only ). Of 440 subjects meeting 3 ACR criteria, 33.9% (149/440) were SLE SLICC-only , while 66.1% (n=291, designated ILE) did not meet the SLICC classification criteria. Under the SLICC system, the complement criterion and the individual autoantibody criteria enabled SLE classification of SLE SLICC-only subjects, while SLE ACR-only subjects failed to meet SLICC classification due to the combined acute/subacute cutaneous criterion. The SLICC criteria classified more African-American subjects by the leucopenia/lymphopenia criterion than did ACR criteria. Compared with SLE ACR-only subjects, SLE SLICC-only subjects exhibited similar numbers of affected organ systems, rates of major organ system involvement (∼30%: pulmonary, cardiovascular, renal, neurological) and medication history. Conclusions The SLICC criteria classify more subjects with SLE than ACR criteria; however, individuals with incomplete lupus still exist under SLICC criteria. Subjects who gain SLE classification through SLICC criteria exhibit heterogeneous disease, including potential major organ involvement. These results provide supportive evidence that SLICC criteria may be more inclusive of SLE subjects for clinical studies.