Systemic Lupus Erythematosus: Year in Review 2019
Systemic lupus erythematosus (SLE) is a chronic, prototypic autoimmune disorder that can affect almost any organ or system. The disease is characterized by extreme heterogeneity, making its diagnosis and management particularly challenging. Over the years, significant progress has been made in understanding SLE, leading to improved survival rates. For instance, the 10-year survival rate has increased from 63.2% in the 1950s to 95% in the modern era. The year 2019 marked a significant milestone in SLE research, with updates in classification criteria, management recommendations, and the development of new therapeutic agents.
Updated Classification Criteria and Management Recommendations
In 2019, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) jointly released updated classification criteria and management recommendations for SLE. Unlike previous criteria, the EULAR/ACR-2019 criteria introduced a score-based system. This system includes ten hierarchical domains (seven clinical and three immunological) comprising 22 criteria with distinct weights. The entry criterion is the positivity of anti-nuclear antibodies (ANA), and a total score of 10 or higher classifies a patient as having SLE. This new system emphasizes the importance of high-quality ANA testing, as patients with negative ANA are excluded from SLE classification.
The updated management recommendations strongly advocate for minimizing disease activity, with remission or low disease activity as the primary therapeutic goal. This approach aligns with the treat-to-target strategy, which has been shown to reduce damage accrual and improve health-related quality of life in SLE patients. Belimumab, the first biological drug approved for SLE, was newly recommended for patients with extra-renal disease, inadequate control by first-line treatments, and inability to taper glucocorticoids to acceptable levels (e.g., prednisone ≤7.5 mg/d). The recommended dosage of hydroxychloroquine (HCQ) was also discussed, with a focus on the need for further studies to confirm the efficacy of lower doses (≤5 mg/kg daily) compared to the previously recommended 6.5 mg/kg daily. Regular screening for HCQ retinopathy is advised before administration and at intervals during treatment.
Novel Insights into SLE Pathogenesis
The pathogenesis of SLE involves immune dysregulation and aberrant production of autoantibodies. Although the precise mechanisms remain elusive, abnormalities in the activation of both innate and adaptive immune systems are well-recognized. The type I interferon (IFN) family of innate immune cytokines plays a crucial role in the aberrant immune functions observed in SLE. Recent research has highlighted the role of mitochondrial DNA (mtDNA) in autoimmunity. Oxidative stress can cause the release of short mtDNA fragments into the cytosol, where they induce type I IFN production and promote lupus-like disease.
Neutrophils and neutrophil extracellular traps (NETs) have also been implicated in SLE inflammation and autoimmunity. A novel T cell subset, CXCR5−CXCR3+PD1hiCD4+ T peripheral helper cells, was identified in SLE patients. These cells activate B cells in a unique manner, promoting autoantibody development. Additionally, Chinese scientists discovered that reduced levels of circular RNAs (circRNAs) in SLE patients lead to augmented protein kinase phosphorylation, providing a connection between circRNAs and SLE pathogenesis.
The use of immune checkpoint inhibitors (ICIs) in cancer treatment has been associated with immune-related adverse events, including the induction of SLE. Analysis of the FDA Adverse Event Reporting System identified 18 lupus cases related to ICIs, particularly programmed cell death-1/programmed cell death ligand-1 inhibitors. Furthermore, a study identified 118 drugs associated with drug-induced lupus (DIL), 42 of which had not been previously reported, underscoring the need to revisit the spectrum of DIL.
Advances in Clinical Manifestations
Lupus Nephritis (LN)
Lupus nephritis (LN) is a severe complication affecting up to 50% of SLE patients. Despite a decrease in the severity of LN in recent decades, the disease burden remains significant. A French nationwide database study found that 10.1% of SLE patients without chronic kidney disease (CKD) at baseline developed CKD, while 33.15% of those with CKD at baseline progressed to end-stage renal disease (ESRD). Kidney transplantation is a well-established option for LN-ESRD patients, with studies confirming its survival benefits, primarily due to reduced deaths from cardiovascular disease and infection.
Single-cell RNA sequencing has provided insights into the immune cell landscape in LN kidneys, identifying 21 immune cell clusters, including B cells, T cells, natural killer cells, myeloid cells, and epithelial cells. Gene expression profiles of immune cells in urine correlated highly with those in kidney biopsies, suggesting the potential for urine tests to replace invasive kidney biopsies in the future.
Neuropsychiatric SLE (NP-SLE)
Neuropsychiatric SLE (NP-SLE) encompasses a broad spectrum of neurologic and psychiatric manifestations, ranging from subtle cognitive dysfunction to acute confusion states, psychosis, and stroke. A comprehensive review summarized the frequencies of 19 neuropsychiatric manifestations in SLE, with 12 relating to the central nervous system (CNS) and seven to the peripheral nervous system (PNS). Autoantibodies, such as anti-myelin oligodendrocyte glycoprotein, anti-phospholipid, anti-ribosomal P, and anti-aquaporin 4 antibodies, are promising biomarkers for NP-SLE diagnosis. However, no gold standard for NP-SLE diagnosis has been established, highlighting the need for further research.
Musculoskeletal Involvement
Inflammatory musculoskeletal symptoms are common in SLE, varying from inflammatory arthralgia to frank synovitis and Jaccoud arthropathy. Ultrasound has become increasingly valuable in detecting musculoskeletal abnormalities and assessing disease activity. A large observational study found that ultrasound detected inflammation in 27% of SLE patients with arthralgia but no clinical arthritis. Ultrasound-only inflammation was associated with worse clinical symptoms and serology, suggesting that traditional clinical outcome measures may underestimate treatment efficacy.
Other Manifestations
Hematological and cardiovascular systems are commonly involved in SLE. A meta-analysis revealed that SLE patients with positive anti-phospholipid antibodies had a higher risk of thrombocytopenia. SLE is also associated with a higher prevalence of atherosclerotic cardiovascular disease compared to non-SLE individuals. Pulmonary arterial hypertension (PAH) is a devastating complication of SLE, identified as the third leading cause of mortality in SLE patients. A nationwide cohort study found that 2.13% of SLE patients developed PAH, mostly within the first five years after SLE onset, with overall 1-, 3-, and 5-year survival rates of 87.7%, 76.8%, and 70.1%, respectively.
New Understanding of Disease Prognosis
Despite significant improvements in survival rates, SLE remains a life-threatening condition. A long-term follow-up cohort study found that SLE patients were three times more likely to die from any cause compared to non-SLE individuals. The standardized mortality ratio (SMR) was particularly higher in patients younger than 40 years, highlighting the need for increased attention in this sub-population. Racial disparities in SLE mortality were also evident, with black SLE patients experiencing significantly higher cumulative mortality compared to Caucasian patients.
Comorbidities at SLE diagnosis accounted for 27.6% of the apparent difference in mortality between SLE patients and matched controls, emphasizing the importance of thorough comorbidity screening in SLE management.
Therapeutic Advances in SLE
Belimumab and Beyond
Belimumab, the first biological drug approved for SLE, has demonstrated long-term efficacy and safety. A 13-year follow-up study confirmed that belimumab plus standard therapy was well-tolerated, with no new safety concerns. Propensity score-matched comparative analysis showed that belimumab-treated patients experienced significantly less progression of organ damage compared to those receiving standard therapy.
Targeting the IFN and JAK Pathways
Activation of the type I IFN pathway is a central mediator of SLE pathogenesis. Anifrolumab, a human monoclonal antibody to the type I IFN receptor subunit 1, showed significantly higher response rates compared to placebo in a phase III trial. IFN-α-kinoid (IFN-K), a vaccine composed of inactivated recombinant human IFN-α2b, significantly reduced the IFN gene signature in a phase IIb trial, although it failed to achieve the primary endpoint.
Janus kinase (JAK) inhibitors, such as baricitinib and tofacitinib, have shown promise in treating SLE. Baricitinib, a selective JAK1/JAK2 inhibitor, improved the signs and symptoms of active SLE in a phase II trial. Tofacitinib, a JAK1/JAK3 inhibitor, rapidly alleviated arthritis and improved skin rash in SLE patients, with some achieving clinical remission.
Targeting B Cells
Autoreactive B cells are key effector cells in SLE pathogenesis. Atacicept, a dual inhibitor of BAFF and APRIL, showed significant improvement in SLE sub-populations with high disease activity. Telitacicept, a novel dual APRIL/BAFF inhibitor, demonstrated significantly higher SRI-4 response rates compared to placebo in a phase II/III trial. Anti-CD20 antibodies, such as ocrelizumab, obinutuzumab, and ofatumumab, are under investigation for their efficacy in SLE.
Other Promising Therapies
Low-dose interleukin-2 (IL-2) treatment has shown efficacy in regulating CD4+ T cell subsets in SLE. A randomized, double-blind, placebo-controlled trial confirmed that low-dose IL-2 resulted in higher SRI-4 response rates with no additional adverse events. Omalizumab, a monoclonal antibody against IgE, improved disease activity in SLE patients with good tolerance. Traditional Chinese medicine, such as artemisinin, has also shown potential in treating mild/moderate SLE.
Conclusion
The year 2019 witnessed significant advancements in the understanding and management of SLE. Updated classification criteria and management recommendations have provided clearer guidelines for clinicians. Novel insights into SLE pathogenesis have paved the way for the development of targeted therapies. Advances in clinical manifestations and disease prognosis have highlighted the importance of early detection and comprehensive management. The approval of belimumab and the exploration of new therapeutic agents offer hope for improved outcomes in SLE patients. As research continues to unravel the complexities of SLE, the future holds promise for more effective and personalized treatments.
doi.org/10.1097/CM9.0000000000000983
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