Best Practice & Research in Clinical Rheumatology最新文献

The young age of onset and chronic/relapsing nature of systemic lupus erythematosus (SLE) make SLE patients prone to develop and accrue organ damage as a result of long-standing disease activity and side effects of treatment. There is a growing interest in objectifying damage and identifying its risk factors. Still, the lack of therapeutic alternatives has led to difficulties in avoiding immunosuppressives particularly corticosteroids, which have been implicated in a large spectrum of organ damage in SLE patients. Moreover, it continues to be very challenging to determine what actually causes damage in different organ-systems. Cardiovascular disease continues to be one of the leading types of damage in patients with SLE, reported as early as 1976. Since then, many researchers have focused on identifying SLE or treatment-related and traditional risk factors. The same considerations are valid for other conditions, such as the occurrence of metabolic syndrome, osteoporosis, avascular necrosis, susceptibility to infections, etc. On the other hand, diverse risk factors contribute to the development of chronic kidney disease (CKD) in SLE. Most evidence suggests that high initial levels of serum creatinine, hypocomplementemia, nephrotic range proteinuria, concomitant uncontrolled hypertension, Black and Hispanic ancestry, non-adherence to treatment, and biopsy findings such as diffuse proliferative lupus nephritis (LN), a high chronicity index, tubular atrophy, and tubulointerstitial inflammation are risk factors for progression to end stage renal disease (ESRD) in LN. While cardiovascular disease, CKD and infections are leading causes of mortality in patients with SLE, hospitalizations are caused mostly by SLE disease flares and infections. Cognitive impairment and mood disorders are common in SLE but continue to impose a challenge on how to measure, manage and decipher the underlying pathogenesis. Nevertheless, they have a great impact on SLE patients' health-related quality of life (HRQoL) and social functioning. Also, skin manifestations, such as alopecia and scaring, cataracts, and sicca symptoms result in a significant decrease in HRQoL. In light of recent developments in SLE treatment, we can expect to enter a period of new-age targeted therapies that will enable us to reduce disease activity and glucocorticoid usage further and positively alter the trajectory of damage development and accrual in SLE.

Systemic Lupus Erythematosus is a systemic autoimmune disease characterized by a great heterogenicity in course and clinical manifestations. Although prognosis improved in the last decades of the 20th century, mortality remains higher than in the general population and uncontrolled disease activity and therapy-related adverse effects have been identified as major contributors to damage accrual and poor outcomes. Assessment of disease activity and damage in SLE represents a great challenge even to the expert rheumatologist. Global disease activity indices are tools developed to assess activity across multiple organ systems. Several disease activity indices have been developed over the years, each with its own strengths and weaknesses, and knowing them is essential for understanding research studies, such as clinical trials, in which they are used. Organ-specific activity indices have been developed concurrently to represent organ involvement such as glomerulonephritis, cutaneous and musculoskeletal lupus manifestations. Regarding damage, the SLICC/ACR damage index has proven to be an effective tool for damage accrual assessment, yet not devoid of drawbacks. This review provides an overview of the most frequently utilized indices developed for the assessment of activity and damage in SLE highlighting their pros and cons when applied to the research and clinical setting.

MSK is the most common and impactful symptom of lupus at a population level. It has a variety of different presentations, but joint swelling is often not present despite imaging-proven synovitis. Imaging with US and MRI has been shown to improve detection of inflammation and identify treatment-responsive patients. In contrast, the SLEDAI shows poor sensitivity, specificity, and responsiveness. While BILAG and SLE-DAS are superior, they are still less accurate than imaging. These issues may explain why the evidence for conventional and biologic therapies for MSK lupus is complex. In clinical practice, physicians must take care not to underestimate MSK inflammation and consider using imaging. Future research should investigate new therapeutic targets specifically for synovitis and more sensitive outcome measures and trials to evaluate them.

Systemic lupus erythematosus (SLE) is a complex disease with an insidious clinical presentation. In up to half of the cases, SLE onset is characterized by clinical and serological manifestations that, although specific, are insufficient to fulfill the classification criteria. This condition, called incomplete SLE, could be as challenging as the definite and classifiable SLE and requires to be treated according to the severity of clinical manifestations. In addition, an early SLE diagnosis and therapeutic intervention can positively influence the disease outcome, including remission rate and damage accrual. After diagnosis, the disease course is relapsing-remitting for most patients. Time in remission and cumulative glucocorticoid exposure are the most important factors for prognosis. Therefore, timely identification of SLE clinical patterns may help tailor the therapeutic intervention to the disease course. Late-onset SLE is rare but more often associated with delayed diagnosis and a higher incidence of comorbidities, including Sjogren's syndrome. This review focuses on the SLE disease course, providing actionable strategies for early diagnosis, an overview of the possible clinical patterns of SLE, and the clinical variation associated with the different age-at-onset SLE groups.

The introduction of targeted biological agents in systemic lupus erythematosus (SLE) has created a momentum for improving overall disease management and patients' prognosis. To achieve this, a comprehensive strategy is required spanning the entire patient journey from diagnosis to prevention and management of late complications and comorbidities. In this review, we focus on four aspects that are closely linked to SLE prognosis, namely early disease recognition and treatment initiation, reduction of the cumulative glucocorticoid exposure, attainment of well-defined targets of remission and low disease activity, prevention of flares and, kidney-protective strategies with non-immune-directed agents. We review the recent literature related to these topics in conjunction with the existing treatment recommendations, highlighting areas of uncertainty and providing guidance towards facilitating the care of SLE patients.

Following better understanding of molecular pathways involved in the pathogenesis of Systemic lupus erythematosus (SLE), pharmaceutical companies have been investigating new targeted drugs for SLE. The purpose of this scoping review is to provide an updated view of the most promising targeted therapies currently in clinical development or recently approved for SLE treatment as well as of the most promising potential future therapeutic strategies in SLE. In the past several years, two new drugs have been developed for lupus treatment along with an extended indication for belimumab. Anifrolumab, the anti-interferon medication, to treat non-renal lupus; voclosporin, a calcineurin inhibitor, for the treatment of lupus nephritis; and belimumab for lupus nephritis. More than 90 investigational drugs are currently in clinical development for SLE treatment, with various targets including inflammatory cytokines and their receptors, intracellular signaling, B cells or plasma cells, co-stimulation molecules, complement fractions, T cells, plasmacytoid dendritic cells as well as various other immunological targets of interest. Researchers are also actively engaged in the development of new therapeutic strategies, including the use of monoclonal antibodies in combination with bispecific monoclonal antibodies, nanobodies and nanoparticles, therapeutic vaccines, utilizing siRNA interference techniques, autologous hematopoietic stem-cell transplantation and Chimeric Antigens Receptor (CAR)-T cells. The therapeutic management and prognosis of SLE have profoundly evolved with changes in the therapeutic armamentarium. With the broad pipeline of targeted treatments in clinical development and new treatment strategies in the future, current challenges are transitioning from the availability of new drugs to the selection of the most appropriate strategy at the patient level.

In the last few years, several studies have provided new evidence for the diagnosis, management, and follow-up of patients with lupus nephritis. Evidence showing dissociation between clinical and histological findings has prompted reevaluation of the role of the kidney biopsy as a tool for diagnosis and follow-up. In therapeutics, four immunosuppressive schemes now have supporting evidence for use as initial therapy. Current challenges include individualized selection of the best immunosuppressive regimen, an unmet need for non-invasive biomarkers of disease activity to inform treatment responses and guide subsequent therapy, holistic patient management in this complex, multisystem disease, and ultimately the development of more targeted therapies directed at specific effector pathways driving glomerular inflammation and damage in order to improve treatment response. In this communication, we review the diagnostic and therapeutic approach to lupus nephritis, as well as evaluation of response to therapy and disease control.

SLE is a highly variable systemic autoimmune disease. Its immunopathological effector phase is partly understood. However, the background of its variability is not. SLE classification criteria have been relying on the clinical manifestations and standard autoimmune serology. This still holds true for the 2019 EULAR/ACR classification criteria. On one hand, this has led to significant precision in defining patients with SLE. On the other hand, the information in the criteria neither helps understanding the individual patient's pathophysiology, nor does it predict the efficacy of the available immunomodulatory therapies. Chances of further improvement of clinical criteria are most likely limited. This is where new multi-omic approaches have started to make an impact. While not yet able to differentiate diseases with the same precision as the classification criteria, the results of these studies go far beyond the scope of the criteria with regard to immune dysregulation. Looking at both sides in detail, we here try to synthesize the available data, aiming at a better understanding of SLE and its immune pathophysiology.

Improved characterization of relevant pathogenic pathways in systemic lupus erythematosus (SLE) has been further delineated over the last decades. This led to the development of targeted treatments including belimumab and anifrolumab, which recently became available in clinics. Therapeutic targets in SLE encompass interferon (IFN) signaling, B-T costimulation including immune checkpoints, and increasing modalities of B lineage targeting, such as chimeric antigen receptor (CAR) T cells directed against CD19 or sequential anti-B cell targeting. Patient profiling based on characterization of underlying molecular abnormalities, often performed through comprehensive omics analyses, has recently been shown to better predict patients' treatment responses and also holds promise to unravel key molecular mechanisms driving SLE. SLE carries two key signatures, namely the IFN and B lineage/plasma cell signatures. Recent advances in SLE treatments clearly indicate that targeting innate and adaptive immunity is successful in such a complex autoimmune disease. Although those signatures may interact at the molecular level and provide the basis for the first selective treatments in SLE, it remains to be clarified whether these distinct treatments show different treatment responses among certain patient subsets. In fact, notwithstanding the remarkable amount of novel clues for innovative SLE treatment, harmonization of big data within tailored treatment strategies will be instrumental to better understand and treat this challenging autoimmune disorder. This review will provide an overview of recent improvements in SLE pathogenesis, related insights by analyses of big data and machine learning as well as technical improvements in conducting clinical trials with the ultimate goal that translational research results in improved patient outcomes.