Besides treating acute flares, the management of SLE should aim at preventing organ damage accrual and drug-associated harms, improving health-related quality of life and prolonging survival. At ...present, therapy is based on combinations of antimalarials (mainly HCQ), considered the backbone of SLE treatment, glucocorticoids and immunosuppressive drugs. However, these regimens are not universally effective and a substantial degree of damage can be caused by exposure to glucocorticoids. In this review we provide a critical appraisal of the efficacy and safety of available treatments as well as a brief discussion of potentially novel compounds in patients with SLE. We emphasize the use of methylprednisolone pulses for moderate-severe flares, followed by low-moderate doses of oral prednisone with quick tapering to maintenance doses of ≤5 mg/day, as well as the prompt institution of immunosuppressive drugs in the setting of severe disease but also as steroid-sparing agents. Indications for the use of biologic agents, namely belimumab and rituximab, in refractory or organ-threatening disease are also presented. We conclude by proposing evidence- and experience-based treatment strategies tailored to the clinical scenario and prevailing organ involvement that can aid clinicians in managing this complex disease.
Several cytokines and growth factors, as well as their downstream signalling pathways, are implicated in the pathogenesis of haematological and immune-mediated diseases. These mediators act through ...binding to their cognate receptor and activation of one or more of the four Janus family tyrosine kinases (JAKs). Gene knock-out studies together with evidence from patients carrying activating mutant forms of JAKs (eg, JAK2 V617F in myeloproliferative disorders) provided strong rationale for the development of JAK inhibitors. Based on encouraging preclinical data showing the capacity of JAK inhibitors to suppress the signalling from multiple cytokines, an extensive drug development program was set out, with the initial successful introduction of tofacitinib, baricitinib and ruxolitinib in various chronic rheumatic and myeloproliferative diseases, respectively. Importantly, advancements with the design of next-generation, hyper-selective JAK inhibitors hold promise for the better control of inflammation, while reducing the risk for harms, in an expanding spectrum of medical disorders.
Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review ...(01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
Obtaining an updated view of the epidemiology, risk factors, and prognosis of systemic lupus erythematosus (SLE) is pivotal to our understanding of the disease burden. Recent community-based studies ...with comprehensive methodology provided more accurate disease occurrence estimates and suggested that SLE may be more frequent than previously thought. Gender, race, and socioeconomic status are important disease determinants, and there is increasing appreciation of the contribution of family history and environmental exposures in SLE susceptibility. Owing to its systemic nature, assessment of disease activity is challenging, also pertaining to efforts to improve trial endpoints for better discrimination between active drug and placebo. Notably, emerging evidence supports that remission or low disease activity states and prevention of flares are realistic targets in the management of SLE associated with improved prognosis. For the future, we anticipate that high-throughput analyses in patient cohorts will enhance the identification of robust biomarkers for diagnosis, risk stratification, and personalized treatment.
Diagnostic reasoning in systemic lupus erythematosus (SLE) is a complex process reflecting the probability of disease at a given timepoint against competing diagnoses. We applied machine learning in ...well-characterised patient data sets to develop an algorithm that can aid SLE diagnosis.
From a discovery cohort of randomly selected 802 adults with SLE or control rheumatologic diseases, clinically selected panels of deconvoluted classification criteria and non-criteria features were analysed. Feature selection and model construction were done with Random Forests and Least Absolute Shrinkage and Selection Operator-logistic regression (LASSO-LR). The best model in 10-fold cross-validation was tested in a validation cohort (512 SLE, 143 disease controls).
A novel LASSO-LR model had the best performance and included 14 variably weighed features with thrombocytopenia/haemolytic anaemia, malar/maculopapular rash, proteinuria, low C3 and C4, antinuclear antibodies (ANA) and immunologic disorder being the strongest SLE predictors. Our model produced SLE risk probabilities (depending on the combination of features) correlating positively with disease severity and organ damage, and allowing the unbiased classification of a validation cohort into diagnostic certainty levels (unlikely, possible, likely, definitive SLE) based on the likelihood of SLE against other diagnoses. Operating the model as binary (lupus/not-lupus), we noted excellent accuracy (94.8%) for identifying SLE, and high sensitivity for early disease (93.8%), nephritis (97.9%), neuropsychiatric (91.8%) and severe lupus requiring immunosuppressives/biologics (96.4%). This was converted into a scoring system, whereby a score >7 has 94.2% accuracy.
We have developed and validated an accurate, clinician-friendly algorithm based on classical disease features for early SLE diagnosis and treatment to improve patient outcomes.
The release of neutrophil extracellular traps (NETs) represents a novel neutrophil effector function in systemic lupus erythematosus (SLE) pathogenesis. However, the molecular mechanism underlying ...NET release and how NETs mediate end-organ injury in SLE remain elusive.
NET formation and NET-related proteins were assessed in the peripheral blood and biopsies from discoid lupus and proliferative nephritis, using immunofluorescence, immunoblotting, quantitative PCR and ELISA. Autophagy was assessed by immunofluorescence and immunoblotting. The functional effects of NETs in vitro were assessed in a primary fibroblast culture.
Neutrophils from patients with active SLE exhibited increased basal autophagy levels leading to enhanced NET release, which was inhibited in vitro by hydroxychloroquine. NETosis in SLE neutrophils correlated with increased expression of the stress-response protein REDD1. Endothelin-1 (ET-1) and hypoxia-inducible factor-1α (HIF-1α) were key mediators of REDD1-driven NETs as demonstrated by their inhibition with bosentan and L-ascorbic acid, respectively. SLE NETs were decorated with tissue factor (TF) and interleukin-17A (IL-17A), which promoted thrombin generation and the fibrotic potential of cultured skin fibroblasts. Notably, TF-bearing and IL-17A-bearing NETs were abundant in discoid skin lesions and in the glomerular and tubulointerstitial compartment of proliferative nephritis biopsy specimens.
Our data suggest the involvement of REDD1/autophagy/NET axis in end-organ injury and fibrosis in SLE, a likely candidate for repositioning of existing drugs for SLE therapy. Autophagy-mediated release of TF-bearing and IL-17A-bearing NETs provides a link between thromboinflammation and fibrosis in SLE and may account for the salutary effects of hydroxychloroquine.
Neuropsychiatric events are common in patients with systemic lupus erythematosus (SLE), but less than one-third of these events can be directly attributed to SLE. Increased generalized SLE disease ...activity or damage, previous or concurrent major neuropsychiatric SLE (NPSLE) events, and persistently positive moderate-to-high antiphospholipid antibody titers are established risk factors, and their presence could facilitate proper attribution to the disease itself. Diagnostic evaluation is guided by the presenting manifestation; MRI is used to visualize brain or spinal pathologies. For neuropsychiatric events believed to reflect an immune or inflammatory process, or when these events occur in the context of active generalized disease, evidence (primarily from uncontrolled studies) supports the use of glucocorticoids alone or in combination with immunosuppressive therapy. Antiplatelet and/or anticoagulation therapy is recommended for NPSLE manifestations related to antiphospholipid antibodies, especially for thrombotic cerebrovascular disease. For the future, we anticipate that novel biomarkers and advanced neuroimaging tests will better define the underlying pathologic mechanisms of SLE-related neuropsychiatric disease, and help guide therapeutic decisions.
In chronic inflammatory diseases such as rheumatoid arthritis, attainment of a specific cut-off of low (or even absent) disease activity has been associated with favourable long-term disease ...outcomes. Systemic lupus erythematosus (SLE) is a complex, systemic disease where prognosis is determined by a variety of factors including disease activity and exposure to potentially toxic drugs particularly glucocorticoids. To this end, both increased activity (either persistent or exacerbations following a period of inactivity) and continuous intake of prednisone at doses above 5–7.5 mg/day have been correlated with accrual of irreversible dysfunction or damage in a variety of organs.Delineation of the optimal therapeutic goal in SLE is challenging, which is in part due to the inherent limitations of the available clinical instruments for monitoring the disease. Nonetheless, through an evidence- and consensus-based approach, an international expert panel has recently introduced various definitions of remission in SLE 1 namely: (a) complete remission (with normal serological markers); (b) clinical remission (irrespective of serological markers); (c) complete remission on-treatment (allowing intake of stable maintenance immunosuppressives and/or ≤5 mg/day of prednisone); and (d) clinical remission on-treatment. In the aforementioned definitions, remission is established by combination of absent disease activity (typically, SLEDAI=0 and physician-rated global disease activity physician global assessment-PhGA ≤0.5). In addition, an Asia-Pacific collaborative group has proposed lupus low disease activity state (LLDAS) 2 as minimally acceptable disease activity (including serological markers and allowing intake of stable maintenance immunosuppressives and/or ≤7.5 mg/day of prednisone) in patients with SLE. A SLEDAI cut-off of ≤4 with PhGA of ≤1 are included in this definition. Accordingly, a number of observational studies have shown that attainment of either remission or LLDAS is associated with improved patient outcomes such as prevention of flares and organ damage accrual.3 4 However, a number of issues pertaining to the definition of therapeutic target in SLE require clarification. First, although PhGA is useful in monitoring the disease by acting as a ‘safety net’ against the drawbacks of SLEDAI, it is still subject to inter-rater variability.5 Second, existing definitions of remission and LLDAS comprise of a combination of features such as an objective activity index, physician-rated activity and dose of glucocorticoids. The extent to which all these components are prognostically important is not clear and recent studies suggest that SLEDAI=0 alone may suffice for the definition of remission in SLE.6 Finally, it has been a matter of debate whether serology (serum C3/C4, anti-dsDNA) should be included in the definition of treatment targets (remission, LLDAS) or whether the latter should be based on the clinical parameters of SLE activity. This is due to the lack of absolute concordance between clinical and serological activity and the fact, that most patients with stable abnormal serology have favourable long-term prognosis. Further studies in large, well-characterised patient registries will be required to address the abovementioned issues, thus defining the optimal treatment goal in the disease.Learning ObjectivesIdentify factors with an adverse impact on organ damage accrual in patients with SLEDemonstrate understanding of the existing definitions of remission and low disease activity state in SLEDiscuss unresolved issues related to the definitions of remission and low disease activity and their implementations in clinical practiceReferencesvan Vollenhoven R, Voskuyl A, Bertsias G, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis 2017;76(3):554–61.Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis 2016;75(9):1615–21.Petri M, Magder LS. Comparison of Remission and Lupus Low Disease Activity State in Damage Prevention in a United States Systemic Lupus Erythematosus Cohort. Arthritis Rheumatol 2018;70(11):1790–95.Zen M, Iaccarino L, Gatto M, et al. Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission. Ann Rheum Dis 2018;77(1):104–10.Chessa E, Piga M, Arnaud L. Physician global assessment in systemic lupus erythematosus: can we rely on its reliability?Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217632Saccon F, Zen M, Gatto M, et al. Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort. Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217070 published Online First: 2020/04/24.
Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated atherosclerosis and cardiovascular (CV) events including coronary heart disease, cerebrovascular and peripheral ...artery disease. CV events occur both early and late during the disease course, with younger patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert antiatherogenic properties. To date, there is a paucity of randomized studies regarding the effectiveness of preventative strategies and pharmacological interventions specifically in patients with SLE. Nevertheless, both the European League Against Rheumatism recommendations and extrapolated evidence from the general population emphasize that SLE patients should undergo regular monitoring for atherosclerotic risk factors and calculation of the 10-year CV risk. Risk stratification should include diseaserelated factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, minimization of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate. Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assessment and of risk-lowering strategies tailored to SLE.
PDF
