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Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with systemic lupus erythematosus (SLE) we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
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A bimodal pattern of mortality in systemic lupus erythematosus (SLE) exists. Early-stage deaths are predominantly caused by infection, whereas later-stage deaths are mainly caused by atherosclerotic disease. Further, although SLE-related mortality has reduced considerably in recent years, cardiovascular (CV) events remain one of the leading causes of death in people with SLE. Accelerated atherosclerosis in SLE is attributed to both an increase in traditional CV risk factors and the inflammatory effects of SLE itself. Many of these changes occur within the microenvironment of the vascular-immune interface, the site of atherosclerotic plaque development. Here, an intimate interaction between endothelial cells, vascular smooth muscle cells, and immune cells dictates physiological vs pathological responses to a chronic type 1 interferon environment. Low-density neutrophils (LDNs) have also been implicated in eliciting vasculature-damaging effects at such lesion sites. These changes are thought to be governed by dysfunctional metabolism of immune cells in this niche due at least in part to the chronic induction of type 1 interferons. Understanding these novel pathophysiological mechanisms and metabolic pathways may unveil potential innovative pharmacological targets and therapeutic opportunities for atherosclerosis, as well as shed light on the development of premature atherosclerosis in patients with SLE who develop CV events.
Subject(s)
Atherosclerosis , Lupus Erythematosus, Systemic , Rheumatic Diseases , Humans , Endothelial Cells , Risk Factors , Atherosclerosis/etiology , Lupus Erythematosus, Systemic/drug therapy , Rheumatic Diseases/complicationsABSTRACT
The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology.
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OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.
Subject(s)
Antiphospholipid Syndrome , Rheumatology , Female , Pregnancy , Humans , United States , beta 2-Glycoprotein I , Autoantibodies , Immunoglobulin G , Immunoglobulin MABSTRACT
OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.
Subject(s)
Antiphospholipid Syndrome , Rheumatology , Female , Pregnancy , Humans , Antiphospholipid Syndrome/diagnosis , Autoantibodies , Immunoglobulin G , Immunoglobulin MSubject(s)
Antiphospholipid Syndrome , Lupus Erythematosus, Systemic , Thrombosis , Infant, Newborn , Female , Humans , Mothers , Antibodies, AntiphospholipidABSTRACT
BACKGROUND: Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures. OBJECTIVES: We aimed to investigate somatostatin receptor 2 (SST2) as a novel inflammation-specific molecular imaging target in LVV. METHODS: In a prospective, observational cohort study, in vivo arterial SST2 expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using 68Ga-DOTATATE and 18F-FET-ßAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing. RESULTS: Sixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST2 maximum tissue-to-blood ratio was 61.8% (P < 0.0001) higher in active/grumbling LVV than inactive LVV and 34.6% (P = 0.0002) higher than myocardial infarction, with good diagnostic accuracy (area under the curve: ≥0.86; P < 0.001 for both). Arterial SST2 signal was not elevated in any of the control subjects. SST2 PET/MRI was generally consistent with 18F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST2 maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST2 expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers. CONCLUSIONS: SST2 PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell and Takayasu Arteritis [PITA], NCT04071691; Residual Inflammation and Plaque Progression Long-Term Evaluation [RIPPLE], NCT04073810).
Subject(s)
Atherosclerosis , Giant Cell Arteritis , Myocardial Infarction , Takayasu Arteritis , Humans , Receptors, Somatostatin , Prospective Studies , Fluorodeoxyglucose F18 , Inflammation/diagnostic imaging , Positron-Emission Tomography/methods , Magnetic Resonance Imaging , Coronary Vessels/pathology , Atherosclerosis/diagnostic imaging , Radiopharmaceuticals/pharmacologyABSTRACT
Introduction: Lupus nephritis (LN) class III or IV is strongly related to patient mortality and morbidity. The interobserver agreement of endocapillary hypercellularity by routine light microscopy, one of the most important lesions determining whether class III or IV is present, is moderate. In IgA nephropathy (IgAN), the presence of glomerular CD68+ cells was found to be a good surrogate marker for endocapillary hypercellularity. We investigated whether the presence of glomerular CD68+ cells could serve as a surrogate marker for endocapillary hypercellularity as well in LN. Methods: A total of 92 LN biopsies were scored for the number of glomerular CD68+ cells using CD68 staining, including endocapillary hypercellularity and the activity index (AI). A new AI was calculated in which CD68+ cells replaced endocapillary hypercellularity. Clinical parameters were obtained from time of biopsy, 1 year after, and 2 years after. Results: The number of glomerular CD68+ cells significantly correlated with endocapillary hypercellularity. A cutoff value of 7 for the maximum number of CD68+ cells within 1 glomerulus in a biopsy yielded a sensitivity of 88% and a specificity of 67% for the presence of endocapillary hypercellularity. Both endocapillary hypercellularity and CD68+ cells correlated with renal function during follow-up. The current and the new AI correlated equally well with the clinical outcome. Conclusion: In LN, CD68+ cells can be used as a surrogate marker for endocapillary hypercellularity.
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OBJECTIVES: Low-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE. METHODS: Proteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively. RESULTS: Proteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM. CONCLUSIONS: Modulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy.
Subject(s)
Granulocytes/pathology , Lupus Erythematosus, Systemic/immunology , Membrane Proteins/analysis , Neutrophils/pathology , Proteome/analysis , Case-Control Studies , Genetic Heterogeneity , Granulocytes/physiology , Humans , Interferon Type I/metabolism , Lupus Erythematosus, Systemic/blood , Microvessels/metabolism , Neutrophils/physiology , Phosphorylation , ProteomicsABSTRACT
OBJECTIVES: To assess non-invasive imaging for detection and quantification of gland structure, inflammation and function in patients with primary Sjogren's syndrome (pSS) using PET-CT with 11C-Methionine (11C-MET; radiolabelled amino acid), and 18F-fluorodeoxyglucose (18F-FDG; glucose uptake marker), to assess protein synthesis and inflammation, respectively; multiparametric MRI evaluated salivary gland structural and physiological changes. METHODS: In this imaging/clinical/histology comparative study (GSK study 203818; NCT02899377) patients with pSS and age- and sex-matched healthy volunteers underwent MRI of the salivary glands and 11C-MET PET-CT. Patients also underwent 18F-FDG PET-CT and labial salivary gland biopsies. Clinical and biomarker assessments were performed. Primary endpoints were semi-quantitative parameters of 11C-MET and 18F-FDG uptake in submandibular and parotid salivary glands and quantitative MRI measures of structure and inflammation. Clinical and minor salivary gland histological parameter correlations were explored. RESULTS: Twelve patients with pSS and 13 healthy volunteers were included. Lower 11C-MET uptake in parotid, submandibular and lacrimal glands, lower submandibular gland volume, higher MRI fat fraction, and lower pure diffusion in parotid and submandibular glands were observed in patients vs healthy volunteer, consistent with reduced synthetic function. Disease duration correlated positively with fat fraction and negatively with 11C-MET and 18F-FDG uptake, consistent with impaired function, inflammation and fatty replacement over time. Lacrimal gland 11C-MET uptake positively correlated with tear flow in patients, and parotid gland 18F-FDG uptake positively correlated with salivary gland CD20+ B-cell infiltration. CONCLUSION: Molecular imaging and MRI may be useful tools to non-invasively assess loss of glandular function, increased glandular inflammation and fat accumulation in pSS.
Subject(s)
Salivary Glands/diagnostic imaging , Sjogren's Syndrome/diagnostic imaging , Adult , Aged , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Positron Emission Tomography Computed TomographySubject(s)
Antiphospholipid Syndrome , Lupus Erythematosus, Systemic , Sjogren's Syndrome , Humans , Mass MediaABSTRACT
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that is highly heterogeneous in its presentation. This can pose significant challenges for physicians responsible for the diagnosis and treatment of such patients. SLE arises from a combination of genetic, epigenetic and environmental factors. Pathologically, the disease is primarily driven by loss of immune tolerance and abnormal B- and T-cell function. Major organ involvement may lead to significant morbidity and mortality. Classification criteria for SLE have been developed largely for research purposes; however, these are also widely used in clinical practice. Antinuclear antibodies are the hallmark serological feature, occurring in over 95% of patients with SLE at some point during their disease. The mainstay of treatment is antimalarial drugs such as hydroxychloroquine, combined with corticosteroids and conventional immunosuppressive drugs. An increasing understanding of pathogenesis has facilitated a move towards the development of targeted biologic therapies, with the introduction of rituximab and belimumab into clinical practice.
Subject(s)
Lupus Erythematosus, Systemic , Humans , Immunosuppressive Agents/therapeutic useABSTRACT
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with variable clinical manifestations. While the clearest guidelines for the treatment of SLE exist in the context of lupus nephritis, patients with other lupus manifestations such as neuropsychiatric, hematologic, musculoskeletal, and severe cutaneous lupus frequently require immunosuppression and/or biologic therapy. Conventional immunosuppressive agents such as mycophenolate mofetil, azathioprine, and cyclophosphamide are widely used in the management of SLE with current more rationalized treatment regimens optimizing the use of these agents while minimizing potential toxicity. The advent of biologic therapies has advanced the treatment of SLE particularly in patients with refractory disease. The CD20 monoclonal antibody rituximab and the anti-BLyS agent belimumab are now widely in use in clinical practice. Several other biologic agents are in ongoing clinical trials. While immunosuppressive and biologic agents are the foundation of inflammatory disease control in SLE, the importance of managing comorbidities such as cardiovascular risk factors, bone health, and minimizing susceptibility to infection should not be neglected.
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OBJECTIVE: Antiphospholipid antibodies (aPL) are frequently present in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) patients; however, the prognostic impact of aPL in such patients has not been elucidated. The objective of this study was to determine whether persistent aPL positivity in AAV patients was associated with increased long-term damage accrual. METHODS: Clinical data were retrospectively collected on all AAV patients who attended the vasculitis clinic at our center over a 4-year period. Data collection included presence of lupus anticoagulant (LAC) and IgG and IgM anticardiolipin (aCL) antibody titers, along with concurrent diagnosis of antiphospholipid syndrome (APS). Accumulation of long-term damage was quantified using the Vasculitis Damage Index (VDI). RESULTS: Data from 116 AAV patients were analyzed. A total of 34% (n = 40) had persistently positive aCL or LAC or a concurrent diagnosis of APS and were classified as AAV/aPL. A total of 76 patients (66%) were classified as AAV alone. LAC was present in a statistically higher proportion of AAV/aPL patients than those in the AAV-alone group (P < 0.0001). Mean VDI score was significantly higher in the AAV/aPL group at mean ± SD 3.54 ± 1.36 as compared to 1.96 ± 1.42 in the AAV-alone group (P < 0.0001). Major vascular damage scores were significantly higher in the AAV/aPL group, with mean ± SD 0.32 ± 0.59 as compared to 0.07 ± 0.26 in the AAV-alone group (P < 0.007). CONCLUSION: Persistently positive occurrence of aPL, in particular LAC, is present in a significant proportion of AAV patients and is associated with a higher VDI score. Clinicians should consider screening AAV patients for aPL.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/blood , Antiphospholipid Syndrome/blood , Lupus Coagulation Inhibitor/blood , Adult , Aged , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pathology , Antibodies, Anticardiolipin/blood , Antibodies, Anticardiolipin/immunology , Antibodies, Antineutrophil Cytoplasmic/blood , Antibodies, Antineutrophil Cytoplasmic/immunology , Antibodies, Antiphospholipid/blood , Antibodies, Antiphospholipid/immunology , Antiphospholipid Syndrome/immunology , Blood Vessels/immunology , Blood Vessels/pathology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Lupus Coagulation Inhibitor/immunology , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , TimeABSTRACT
Systemic lupus erythematous (SLE) is a chronic multisystem disease with significant associated morbidity and mortality. A deeper understanding of the pathogenesis of SLE has led to the development of biologic agents, primarily targeting B cells and others inhibiting costimulatory molecules, type I interferons and cytokines such as interleukin-6. Several of these agents have been studied in clinical trials; some have shown promise while others have yielded disappointing results. Economic and regulatory issues continue to hamper the availability of such therapies for SLE patients. With increasing recognition that recurrent flares of disease activity lead to long-term damage accrual, one of the most important recent developments in patient management has been the concept of treat-to-target in SLE while minimizing patient exposure to excessive corticosteroid and other immunosuppressive therapy. This article reviews these key issues in SLE management, outlining recent developments and clinical implications for patients.
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INTRODUCTION: Systemic lupus erythematosus (SLE) is a severe autoimmune disease and a sizeable proportion of patients remain refractory to currently available immunosuppressive agents. The burden of uncontrolled disease is significant as disease flare and persistent inflammation lead to long-term damage accrual and increased morbidity. Belimumab , a humanized monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), is the first drug to be approved by the US FDA for the treatment of SLE in 50 years. AREAS COVERED: In this review, we provide an overview of novel therapeutic agents under development for the treatment of SLE, a description of the pharmacodynamic and pharmacokinetic properties of belimumab, evidence of efficacy of belimumab as demonstrated in clinical trials, safety and tolerability data and a summary of ongoing clinical trials of belimumab in SLE. This information was amassed following a comprehensive MEDLINE and Cochrane library search. Ongoing clinical trial information was obtained from ClinicalTrials.gov. EXPERT OPINION: Two, large Phase III trials have demonstrated the clinical efficacy of belimumab in musculoskeletal, mucocutaneous, haematologic and constitutional features of SLE. Patients with severe disease manifestations such as lupus nephritis and CNS disease were excluded from these trials and hence the role of belimumab in the overall management of SLE has yet to be established. Studies in lupus nephritis are ongoing.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Animals , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/pharmacology , B-Cell Activating Factor/antagonists & inhibitors , Drug Approval , Drug Design , Humans , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/pharmacology , Lupus Erythematosus, Systemic/physiopathologyABSTRACT
In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advances in our understanding of the complexity of SLE immunopathogenesis have led to the testing of several biologic agents in clinical trials. Monoclonal therapies currently emerging or under development include B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anticytokine therapies. Issues remain, however, regarding clinical trial design and outcome measures in SLE which need to be addressed to optimize translation of these promising therapies into clinical practice.
Subject(s)
B-Lymphocytes/immunology , Biological Therapy/trends , Lupus Erythematosus, Systemic/therapy , T-Lymphocytes/immunology , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , B-Cell Activating Factor/antagonists & inhibitors , B-Lymphocytes/drug effects , Cell Survival/drug effects , Clinical Trials as Topic , Humans , Interferon-alpha/therapeutic use , Lupus Erythematosus, Systemic/immunology , Lymphocyte Depletion , Receptor Cross-Talk/drug effects , T-Lymphocytes/drug effects , Translational Research, Biomedical , Tumor Necrosis Factor Ligand Superfamily Member 13/antagonists & inhibitorsABSTRACT
Given their pivotal role in autoantibody production, B-cells have become an attractive therapeutic target in systemic lupus erythematosus (SLE). Belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (BLyS), a B-cell survival factor, was licensed in 2011 for the treatment of autoantibody-positive SLE. The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients compared to placebo with standard therapy. Overall, belimumab has been found to be safe and well tolerated. While the BLISS-52 and BLISS-76 studies are the largest clinical trials in SLE to date, they mainly focused on musculoskeletal, mucocutaneous, hematologic and general constitutional features of the disease. Patients with severe lupus nephritis and severe central nervous system disease were excluded from these trials. Studies of belimumab in lupus nephritis are ongoing that may clarify the role of this agent in the clinical management of SLE.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , B-Cell Activating Factor/antagonists & inhibitors , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , B-Cell Activating Factor/immunology , Clinical Trials, Phase III as Topic , Humans , Lupus Erythematosus, Systemic/immunologyABSTRACT
There have been a number of major advances in the treatment of systemic lupus erythematosus and we are now in the era of biologic therapies for this multisystem autoimmune disorder. There has been a greater awareness of the toxicities of the traditional therapies including the recognition that the doses of corticosteroids used in the past have been excessive, resulting in unacceptable toxicities. Other advances have included the development of lower cumulative doses of cyclophosphamide and the widespread acceptance of mycophenolate mofetil for the treatment of lupus nephritis. This review addresses the current management of severe lupus with corticosteroids and cytotoxic agents.
Subject(s)
Adrenal Cortex Hormones/administration & dosage , Cytotoxins/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Antirheumatic Agents/therapeutic use , Cyclophosphamide/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Induction Chemotherapy/methods , Lupus Nephritis/drug therapy , Maintenance Chemotherapy/methods , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic useABSTRACT
OBJECTIVE: Renal biopsy remains the gold standard investigation for both diagnostic and prognostic purposes in the clinical management of lupus nephritis. However, it is not without potentially significant complications. The objectives of this study were to determine the rate of significant bleeding post-renal biopsy in patients with lupus nephritis and to identify risk factors associated with hemorrhagic complications. METHODS: Clinical data were retrospectively collected on 215 renal biopsies performed over a 13-year period (1999-2012). Patients were categorized into 3 groups: a diagnosis of systemic lupus erythematosus (SLE) alone, SLE with coexisting antiphospholipid syndrome (APS), or a diagnosis of SLE with either positive anticardiolipin antibodies and/or lupus anticoagulant (LAC) without clinical APS manifestations. RESULTS: Major bleeding complications were significantly more common in those with coexisting APS and/or antiphospholipid antibodies (aPL). LAC, presence of thrombotic microangiopathy (TMA) on renal biopsy, older age at the time of the biopsy (age >40 years), and elevated serum creatinine (>400 µmoles/liter) were independent risk factors for increased risk of bleeding. TMA and severe fibrous intimal hyperplasia on renal biopsy were significantly more prevalent in those who developed severe bleeding complications. CONCLUSION: Based on these findings, lupus nephritis patients with coexisting APS, positive LAC, and histologic evidence of TMA and/or fibrous intimal hyperplasia are at increased risk of bleeding post-renal biopsy. aPL should be checked in all lupus nephritis patients before undergoing renal biopsy, as this subset of patients warrants particular caution pre- and postprocedure.