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Novel Pathogenic Pathways and Therapeutic Implications in Lupus Nephritis: The Emerging Role of PTX3-Related Immunity
Full text linkBackground. Abnormalities affecting regulatory molecules and pentraxin (PTX) 3 have been suggested to contribute to development of lupus glomerulonephritis (LN). Characterization of novel pathogenic pathways could pave the way to targeted therapeutic approaches.
Aims. To investigate the role and relevance of PTX3/anti-PTX3 related immunity in systemic lupus erythematosus (SLE) patients and in lupus murine models and to explore the in vivo effects of restoration of SERPINB3 levels.
Methods. The overall project comprised four experimental phases. Three out of four experiments were carried out on murine models of SLE, either New Zealand Black/White (NZB/W F1) or Mrl/lpr mice, while one experiment was conducted in humans.
In the first experiment, intraperitoneal administration of recombinant SERPINB3 (7.5 μg/0.1mL or 15 μg/0.1mL) or placebo (PBS 0.1 ml) was carried out in 40 NZB/W F1 mice divided into four groups of 10 mice each. Group 1 and 2 were treated before (preventive approach and group 3 and 4 after (therapeutic approach) development of proteinuria ≥100mg/dl. Two additional groups included 20 MRL/lpr mice which were prophylactically injected with SERPINB3 (10 mice, group 5) or PBS (10 mice, group 6).
The second experiment involved 30 NZB/W F1 mice which underwent subcutaneous immunization with PTX3+alum (n=10), PBS+alum (n=10) or PBS alone (n=10) three times three weeks apart, starting before development of proteinuria. For both experiments, time of occurrence and levels of anti-dsDNA and anti-C1q antibodies, proteinuria and serum creatinine, overall- and proteinuria-free survival were assessed in mice followed up to natural death. Subanalysis regarding anti-PTX3 antibody levels and function were performed in the second experiment.
The last experiment on mice involved 22 NZB/W F1 female littermates divided into two groups of 10 mice each and treated with the same approach described in the second experiment. Ten mice (5 from each group) were sacrificed at week 22 and the other 10 at 29 weeks. Histological and ultrastructural lesions were compared using optical microscopy, immunoelectron microscopy (IEM), immunofluorescence (IF) and confocal microscopy.
Data on humans were retrieved enrolling 38 SLE patients (12 with biopsy-proven LN and 26 without LN) and 22 matched healthy donors (HD). Characterization and comparison of circulating levels of PTX3 specific (PTX3+) B cells between patients and controls was performed by flow-cytometry.
The differences between groups for nonparametric continuous variables were analyzed using Mann-Whitney U test or Kruskal-Wallis’s ANOVA test when appropriate; proteinuria-free survival rate (proteinuria <300 mg/dl) and survival rates were evaluated by Kaplan-Meyer method using Mantel-Cox test for comparison. Chi-squared test was used for histological comparison. A p value<0.05 was considered statistically significant.
Results. Experiments on mice showed positive results in terms of clinical effects deriving from restoration of SERPINB3 levels or immunization with PTX3. SERPINB3-administered mice displayed a milder LN, with lower and delayed occurrence of nephritogenic antibodies and milder proteinuria at several timepoints, as well as a prolonged survival versus PBS groups. Immunization with PTX3 evoked a vaccine-like response with occurrence of anti-PTX3 antibodies only in immunized mice and delayed and decreased levels of nephritogenic antibodies and proteinuria, resulting in a significantly longer disease-free and overall survival.
Among mice sacrificed at given timepoints, notable differences were observed at IEM, IIF and confocal microscopy. PTX3-immunized mice displayed less or no electron-dense deposits (EDD) along the glomerular basement membrane and the mesangium, and remarkably decreased glomerular deposition of IgG, C1q and PTX3 compared to PBS-treated mice. Moreover, PTX3 was found inside the EDD at IEM and was shown to co-localized with nuclear material.
LN patients displayed significantly lower levels of circulating PTX3+ B cells in comparison to SLE and HD, showing a persistent decrease among naïve and memory PTX3+ specific subsets.
Conclusions. Clinical improvement of a lupus-like disease following restoration of SERPINB3 levels and immunization with PTX3 in lupus murine models suggests that very early abnormalities affecting molecules involved in tissue homeostasis, apoptosis and removal of apoptotic debris may induce further development of SLE and SLE-specific manifestations within an unpredictable lag time. PTX3 more strikingly emerged as a novel antigen in LN progression and PTX3/anti-PTX3 immunity appear to function as an early level of regulation which may fail in patients developing LN. Consistently, acquisition of a targeted anti-PTX3 immunity could hinder the progression from the preclinical to the clinical stages of disease. Altogether, these findings may add a piece of knowledge on the mechanisms supporting LN development and progression, and suggest that a targeted modulation of the native immunity could improve renal manifestations in selected patients. In the short term, dosage of serum anti-PTX3 antibodies may become a handful tool to help in stratifying lupus patients according to the risk of developing LN.
A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab--comments on article by Fredericks et al.
No full textPhysician’s global assessment is often useful in SLE, but not always: the case of clinical remission
Full text linkLupus nephritis: clinical presentations and outcomes in the 21st century
No full textLupus nephritis (LN) is a frequent and severe manifestation of SLE. Along the decades, the epidemiology of LN and its clinical presentation have been changing. However, even though retrospective cohort studies report a decreased mortality rate and an improvement in the disease prognosis, the percentage of patients progressing into end stage renal disease (ESRD) keeps steady despite the improvements in therapeutic strategies. Current in-use medications have been available for decades now, yet over the years, regimens for optimizing their efficacy and minimizing toxicity have been developed. Therapeutic research is now moving towards the direction of precision medicine and several new drugs, targeting selectively different pathogenetic pathways, are currently under evaluation with promising results. In this review, we address the main changes and persistent unmet needs in LN management throughout the past decades, with a focus on prognosis and upcoming treatments
Advances in the Diagnosis and Classification of Systemic Lupus Erythematosus
No full textINTRODUCTION:
Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune diseases. Patients with SLE display a wide spectrum of clinical and serological findings that can mislead and delay the diagnosis. Diagnostic criteria have not been developed yet, whereas several sets of classification criteria are available; however, none of them has 100% sensitivity and 100% specificity, i.e. the hallmark of diagnostic criteria. Nevertheless, classification criteria are often misused as diagnostic criteria, which may affect earliness of diagnosis and lead to more misdiagnosed cases.
AREAS COVERED:
In this review, we compare old and new classification criteria, discussing their application and pinpointing their limitations in the management of patients. Moreover, we will focus on current and novel biomarkers for SLE diagnosis, highlighting their predictive value and applicability in clinical practice. Expert Commentary: SLE diagnosis still represents a challenge, remaining largely based on a clinical judgment. Besides SLE diagnosis, even its classification is still challenging to date. Indeed, although classification of SLE seems to be achieved more frequently with the 2012 SLICC criteria than with the previous 1997 ACR criteria, this last-updated 2012 set might be improved. Notably, diagnostic and classification criteria should be applied to any subject in the world, and consequently they should include immunological variables validated in different populations, which is still an unmet need
Assessment of disease activity and damage in SLE: Are we there yet?
No full text: 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
Current clinical and therapeutic approach to tumour-like mass lesions in granulomatosis with polyangiitis
No full text: Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disorder classified among the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and characterized by a triad of upper and lower respiratory tract disease, systemic vasculitis involving small-to-medium vessels and renal manifestations. Mass lesions, also described as inflammatory lesions, pseudotumor or tumour-like masses, are uncommon manifestations of GPA and are often called granuloma since histology examination shows granulomatous inflammation and rarely vasculitis. Masses could represent a localized manifestation of GPA or develop as part of a systemic disease. Unusual clinical presentation together with nonspecific radiological and histological features may delay the correct diagnosis leading to disease progression and organ damage. Diagnosis of GPA in such cases may be challenging and malignancy or infections must be considered as alternative diagnostic options. Here we reviewed all the different sites where mass lesions were reported in GPA, focusing on atypical localization, and summarized current therapeutic options and their different outcomes. We retrieved and discussed the cases reported since 2010, bearing in mind the advances in the therapeutic management of AAV patients in the last decade, namely biological therapy such as rituximab. Despite treatment regimens with glucocorticoids and immunosuppressive agents, mass lesions have a refractory course in a high proportion of patients. Invasive surgical procedures may be considered only when drug therapy fails
New therapeutic strategies in systemic lupus erythematosus management
No full textThe current treatment approach for systemic lupus erythematosus (SLE), as outlined in the recommendations by international medical associations including EULAR and the ACR, is mostly eminence-based rather than evidence-based. However, knowledge on SLE is growing quickly, and such new advances need to be translated into clinical practice. Questions remain regarding the choice and timing of drug administration and tapering until withdrawal, which both can affect the balance between the control of disease activity and damage to organs triggered by long-standing and/or disproportionate immunosuppression. Currently, the treating physicians of patients with SLE are required to weigh the present with the future situation of their patients in an optimized balance between therapeutic harm and benefit. In this Review, the available therapeutic strategies and main challenges in the approach to SLE treatment are discussed. Remission and low disease activity are desirable therapeutic goals. Although the drug armamentarium for SLE has not expanded much in the past few decades, there are nonetheless opportunities to make better choices and explore combination therapies; such opportunities offer the potential of a personalized medicine strategy
Value and goals of treat-to-target in systemic lupus erythematosus: knowledge and foresight.
No full textTreat-to-target is a therapeutic strategy aimed at improving disease outcome through the achievement of shared treatment goals, which has dramatically ameliorated the prognosis of widespread disorders, such as hypertension or diabetes. Conversely, efforts to delineate treat-to-target in systemic lupus erythematosus (SLE) have failed in pinpointing common goals and treatment strategies, probably because of disease heterogeneity and lack of measurable biomarkers predicting disease course and ensuring a safe treatment tapering during quiescence. Given the detrimental effects of persistent disease activity and protracted corticosteroid therapy on patients' outcome in lupus, disease remission should be pursued whenever possible. Fortunately, clinical remission is currently realistic for a greater number of patients than it was in the past, yet tight monitoring is required in order for patients to benefit from disease- and corticosteroid-free intervals, while minimizing the risk of disease flares. In everyday practice, patients should be brought to the lowest level of disease activity ensuring a significant benefit over a persistently active disease, being either clinical remission or low disease activity
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