This viewpoint article on a forecast of clinically meaningful changes in the management of systemic lupus erythematosus (SLE) in the next 10 years is based on a review of the current state of the art. The groundwork has been laid by a robust series of classification criteria and treatment recommendations that have all been published since 2019. Building on this strong foundation, SLE management predictably will take significant steps forward. Assessment for lupus arthritis will presumably include musculoskeletal sonography. Large-scale polyomics studies are likely to unravel more of the central immune mechanisms of the disease. Biomarkers predictive of therapeutic success may enter the field; the type I interferon signature, as a companion for use of anifrolumab, an antibody against the common type I interferon receptor, is one serious candidate. Besides anifrolumab for nonrenal SLE and the new calcineurin inhibitor voclosporin in lupus nephritis, both of which are already approved in the United States and likely to become available in the European Union in 2022, several other approaches are in advanced clinical trials. These include advanced B cell depletion, inhibition of costimulation
To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects.The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.
Type I interferons (IFN-Is) are a group of molecules with pleiotropic effects on the immune system forming a crucial link between innate and adaptive immune responses. Apart from their important role in antiviral immunity, IFN-Is are increasingly recognized as key players in autoimmune CTDs such as SLE. Novel therapies that target IFN-I appear effective in SLE in early trials, but effectiveness is related to the presence of IFN-I biomarkers. IFN-I biomarkers may also act as positive or negative predictors of response to other biologics. Despite the high failure rate of clinical trials in SLE, subgroups of patients often respond better. Fully optimizing the potential of these agents is therefore likely to require stratification of patients using IFN-I and other biomarkers. This suggests the unified concept of type I IFN–mediated autoimmune diseases as a grouping including patients with a variety of different traditional diagnoses.
Fatigue is a prevalent and debilitating symptom in SLE and related autoimmune connective tissue diseases (CTDs) which often predates diagnosis or organ manifestations. Its primary immunological mechanisms may be obscured by glucocorticoids, damage, and comorbidity. Anti-nuclear antibody (ANA) positivity is established years in advance of clinical autoimmunity and evolves to overt CTDs in a small subset. We hypothesise that immunological drivers of fatigue in CTDs are established during the prodromal ANA+ subclinical phase and are differentially modulated in established disease states.
Methods
Bulk RNASeq on PBMCs from therapy-naive ANA+ individuals (n=35) lacking diagnostic CTD criteria, was analysed with weighted gene co-expression network analysis (WGCNA) and correlated against symptoms and signs of interest. Consensus networks were constructed to identify modular signatures retained in established CTDs.
Results
Fatigue burden was high in ANA+ subjects (mean VAS 65/100) but did not correlate with physician global assessment visual analogue score (VAS) (R=0.12, p=0.58). A 122-gene module comprising a dense network of interferon stimulated genes (including OAS1, IRF7, IFI44) showed strongest positive correlation with fatigue VAS (R=0.49, p=0.003) and also correlated with subsequent progression status from ANA+ to SLE at 12 months. Strongest negative modular association (358 genes) with fatigue VAS (R=-0.34, p=0.05) enriched for cellular stress and unfolded protein response (included ATF3, JUNB, HSPA1B). This was significantly related to health assessment questionnaire score (p=0.02) but not pain VAS (p=0.2). Both modules were highly retained in SLE and primary Sjogren's syndrome WGCNA networks. Pain and tender joint counts displayed distinct modular associations, unrelated to fatigue and progression.
Conclusions
Novel modular transcriptomic analyses in sub-clinical ANA+ subjects provide potential insights into the immunological basis for the key symptomatology of early SLE and autoimmune CTDs. We are currently evaluating these signatures established CTDs stratified by symptom burden.
Assessment of systemic lupus erythematosus (SLE) activity is important to determine the efficacy of treatment and to decide on further therapy. Russian-language versions of activity indices are needed to meet the needs of Russian-speaking patients and clinicians and to facilitate the use of these tools in clinical practice. An important step in this direction is the adaptation of the EASY-BILAG index, which is used to more accurately assess disease activity and select appropriate therapy in patients with SLE.
Abstract B cell depletion using rituximab is widely used to treat autoimmune diseases, but patient response varies. The efficacy of rituximab is limited by the efficiency of depletion. Strategies to improve response include altering rituximab dosing, switching anti-CD20-mAb, alternative B cell targets, or non-B cell targeted therapies. Implementing an appropriate strategy requires understanding of the mechanism(s) of resistance to depletion and, if this varies between individuals, a means to test for it. Rituximab kills B cells via a variety of Fcγ receptor (FcγR)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), as well as non-FcγR mechanisms. We conducted a longitudinal cohort study in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) using two national registries. Qualitative and quantitative FCGR functional variants were measured using multiplexed ligation-dependent probe amplification, supplemented by novel FCGR2C assays. We provide consistent evidence that FCGR3A, specifically increased number of copies of the FCGR3A- 158V allele, was the major FcγR gene associated with rituximab response, including clinical response in RA and SLE and depth of B cell depletion in the combined cohort. In SLE, we provide preliminary data suggesting increased FCGR2C ORF copies were also associated with improved clinical response. Furthermore, we demonstrated the impact of disease status and concomitant therapies on both natural killer cell FcγRIIIa expression and rituximab-induced ADCC; demonstrating increased FcγRIIIa expression and FCGR3A genotype were independently associated with clinical response and B cell depletion. Our findings highlight the importance of enhancing FcγR-effector functions, may help stratify patients, and support ongoing development of next-generation CD20 depleting therapeutics. One Sentence Summary The high affinity FcγRIIIa allotype on NK cells explains depth of B cell depletion and clinical response in rituximab therapy for autoimmune disease
We read with interest the report by Jesus et al on the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS).1 We agree that the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) in its original form has limitations as a disease activity tool. Since each organ manifestation can only be graded as present or absent, it is unable to differentiate between mild, moderate or severe disease activity, nor partial response in any feature.
Our group is researching outcome measures in musculoskeletal SLE. We published a previous study of responsiveness of various musculoskeletal outcome measures in patients treated with glucocorticoids.2 As expected, the musculoskeletal component of the SLEDAI-2K was less responsive than the physician visual …
Background: Systemic Lupus Erythematosus (SLE) is clinically and immunologically heterogeneous with a variable response to treatment. MASTERPLANS is an MRC-funded consortium that seeks to identify immunophenotypic subgroups of patients that predict response to therapy. Autoantibody profiles can differentiate subgroups of patients and have potential to predict response to treatment. Objectives: To determine whether known and novel autoantibodies are associated with response to rituximab (RTX), and analyse the association between these antibodies and disease involvement in various organ systems. Methods: Serum was obtained from 224 SLE patients in the BILAG Biologics Registry who received rituximab according to NHS England criteria (2). Patients were recruited if they were starting a first cycle of rituximab for active SLE (BILAG A or 2xBILAG B) despite previous cyclophosphamide or mycophenolate mofetil. Evidence of any single organ system involvement previous or current was taken as having a BILAG score of A-D but not E. Disease activity was measured using BILAG-2004. Clinical response was defined as improvement by >=1 grade in active BILAG-2004 systems with no worsening in other systems. Autoantibodies were measured by immunoprecipitation of proteins by sera from 35 S-labelled K562 cell lines, followed by SDS-PAGE separation and autoradiography. Autoantibodies not able to be detected by this technique (anti-Ro52, anti-dsDNA and aCL) were measured by ELISA. Autoantibody data was analysed in IBM SPSS and GraphPad Prism v8.2. Association between autoantibodies and RTX response was analysed using binary logistic interaction terms and Pearson’s Chi-Square test. Results: Of the 224 patients (201 female, 23 male, median age 40 years) the most common system involvement from the 9 BILAG domains was musculoskeletal (164 patients) and the least ophthalmic (11 patients). Patients with anti-Ro52 and anti-U1RNP/Sm had more frequent involvement of mucocutaneous ( p <0.036, p <0.012) and musculoskeletal domains ( p <0.015 for U1RNP) respectively. There were 136 patients with sufficient data to define as either responders (n=67) or non-responders (n=69) to RTX at 6 months. RTX responders had a higher frequency of anti-U1RNP/Sm compared to non-responders (Figure 1). Further Pearson’s Chi-Square analysis showed a significant association between presence of anti-U1RNP/Sm and better response to RTX ( p <0.018). Conclusion: Our findings suggest that the presence of U1RNP/Sm autoantibodies in a cohort of patients who have received treatment with RTX is associated with more frequent musculoskeletal and mucocutaneous involvement and predicts a more favourable response to treatment. Acknowledgments : Funded by a grant from the Medical Research Council, grant number MR/M01665X/1. BILAG BR has been funded by unrestricted educational donations from Roche, GSK and LUPUS UK. Part-funded by a grant from LUPUS UK. Disclosure of Interests: : Danyang Li: None declared, Hui Lu: None declared, Juliet Dunphy: None declared, Theresa Smith: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB, Neil McHugh: None declared
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