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Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus
Abstract
To examine the relationship between changes in anti-double-stranded DNA (anti-dsDNA) antibody levels and the risk of renal flare in patients with systemic lupus erythematosus (SLE), using data from 2 randomized, controlled trials.
Analyses were based on 487 patients with SLE and a history of lupus nephritis who had an anti-dsDNA antibody titer >/=15 IU/ml at baseline, as measured by Farr assay. Results are presented for the combined population of patients, the placebo arms, and the drug treatment arms in which a dsDNA-based bioconjugate (abetimus sodium; LJP 394) was used.
Changes in anti-dsDNA antibody levels were inversely correlated with changes in the C3 level (P < 0.0001 in both trials). Cox proportional hazards regression models showed that changes in anti-dsDNA antibody levels correlated with the risk of renal flare. The models predicted that a point estimate of a 50% reduction in anti-dsDNA antibody levels is associated with a 52% reduction (95% confidence interval [95% CI] 26-68%, nominal P = 0.0007) and a 53% reduction (95% CI 33-69%, nominal P < 0.0001) in the risk of renal flare in the 2 trials, respectively. In the 2 trials, the incidence of renal flare was lower in patients with sustained reductions in anti-dsDNA antibodies (3.0% and 4.1%, respectively) than in patients with stable or increasing antibody levels (21.3% and 20.3%, respectively).
Changes in anti-dsDNA antibody levels were directly correlated with the risk of renal flare and inversely correlated with changes in the C3 level. Reducing anti-dsDNA antibody levels may represent a therapeutic objective in SLE patients with lupus nephritis, because it is associated with a reduced risk of renal flare.
... A reduction in autoantibodies, or even reversal to negativity, upon immunosuppressive treatment has been found to be associated with a beneficial clinical outcome in SLE [10][11][12][13][14]. These autoantibodies can be secreted by two distinct antibody-secreting cell (ASC) populations: short-lived proliferating plasma blasts (PBs) and non-dividing long-lived plasma cells (PCs) [15][16][17]. ...
... The characteristics of SLE patients (n ¼ 42) who were treated with RTX [22] (n ¼ 16), a combination of RTXþBLM [9] (n ¼ 15) or BTZ [28,29] (n ¼ 11) are summarized in Table 1. Briefly, most patients were females (86%), with a median age of $35 (IQR: 30-41) years and a median disease duration of $9 [6][7][8][9][10][11][12][13][14][15][16] years. SLE organ involvement included renal (69%), cardiorespiratory (64%) or neurologic (31%) disease. ...
... SLE organ involvement included renal (69%), cardiorespiratory (64%) or neurologic (31%) disease. All SLE patients had comparable high DASs at baseline of $14 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), which decreased significantly for all approaches (Table 1, Supplementary Fig. S2A, available at Rheumatology online). The refractory nature of the SLE was illustrated by previously used immunosuppressants (Supplementary Table S1, available at Rheumatology online). ...
Objectives:
SLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell-targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation.
Methods:
Autoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation.
Results:
Reductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ.
Conclusion:
This study demonstrated the impact of different B cell-targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.
... Several studies have sought to determine whether biomarkers can predict flare in SLE [9][10][11][12][13], including titres of autoantibodies to double stranded DNA (anti-dsDNA) [12,14]. However, studies of flare prediction lack standardized methodology, and analyses of cross-sectional data have limited ability to guide strategies in the clinic [15]. ...
... Hazard ratio b (95% CI) P-value Hazard ratio b (95% CI) P-value many centres, anti-dsDNA antibodies are measured repeatedly during SLE management, based on studies suggesting they can correlate with or predict disease flare [9][10][11]14]. For example, Ho et al. described an increase in dsDNA prior to a flare with a subsequent decrease at the time of flare [33]. Gladman et al. described a subset of SLE patients who have persistent serological activity but remain clinically quiescent [17], and we and others have shown that such patients are at higher risk of flare than serologically negative patients [34], but whether absolute levels or fluctuations in anti-dsDNA predict disease flare in patients who are persistently positive is poorly understood. ...
Objective
Disease activity monitoring in systemic lupus erythematosus (SLE) includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive.
Methods
Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorised based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare.
Results
Data from 37,582 visits of 3,484 patients were analysed. 1,029 (29.5%) of patients had persistently positive anti-dsDNA and 1,195 (34%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio (95% confidence interval) 1.56 (1.30, 1.87) (p < 0.001) and fluctuating cohort (adjusted HR (95%CI) 1.46 (1.28, 1.66)), both for a ratio >3. Both increases and decreases in anti-dsDNA more than two-fold compared to the previous visit were associated with increased risk of flare in the the fluctuating cohort (adjusted HR(95%CI) 1.33(1.08, 1.65) p = 0.008) and the persistently positive cohort (adjusted HR (95%CI) 1.36 (1.08, 1.71) p = 0.009).
Conclusion
Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.
... The patients with the two autoantibodies; anti-C1q and anti-dsDNA antibodies simultaneously positive presented with the most severe renal histopathological disease activity, such as end capillary hyper cellularity, karyorrhexis/fibrinoid necrosis, sub endothelial hyaline deposits, leukocyte infiltration 15 . High level of anti-dsDNA antibody often precedes an exacerbation by weeks 13 . the ELISA exhibits a sensitivity and specificity of 56-67% and 91-96%, respectively where as in Farr radioimmunoassay the sensitivity 42-85% and specificity of 95-99% 16 . ...
... In this study no significant association between serum ANA, anti-dsDNA, and immune deposits in kidney tissue. It has been proven in different studies that lupus flares often preceded by increase in serum anti-dsDNA antibodies moreover using prophylactic treatment of patients After rises in anti-dsDNA antibodies levels lead to reduction in incidence of consequent flares of disease [12][13][14][15] . Furthermore, serum levels may be a weak reflection of changes at tissue levels and this was mentioned in a study done by Nossent JC 42 . ...
... Many studies proved that Anti-dsDNA antibodies are considered as'serological markers' for SLE and associated with LN activity and prognosis [22,23] . Linnik et al., in a multicenter study of 487 lupus nephritis cases found that changes in the titer of anti-dsDNA measured by a Farr assay correlated with a risk of renal flares and was inversely correlated with serum C3 levels [24] . Narayanan et al., found that the anti-dsDNA levels were elevated in all patients with predominant renal flare. ...
... However, in a prospective study of 53 SLE patients, Ho et al., reported that at the time of lupus flares including renal flares, the serum titer of anti-dsDNA often decreased after a previous rise. As per the authors, the decrease may represent deposition of immune complexes during the disease flare [24] . In Fu et al., review provides evidence that anti-dsDNA antibodies have a limited value in the diagnosis of SLE. ...
... Moreover, monitoring those antibodies in patients is also important, as changes in α-dsDNA antibodies correlate with the risk of renal flares in SLE [4]. Thus, analytical methods for the detection and quantitation of anti-DNA, and specifically, α-dsDNA antibodies in serum can be important for both clinical and biotechnological applications. ...
... with HRP-conjugated α-human IgG antibodies (purple, with HRP represented with a blue star). The mixture is added to the surface of the working electrode an incubated for 30 minutes (4). After the incubation period, the electrode is washed to remove unbound reactants and a mixture containing TMB and hydrogen peroxide is added (5). ...
Electrochemical biosensors have shown great promise as useful point-of-care tests since they operate on electronic circuits which can be miniaturized and whose readout process can be easily automated. Here, we describe a method for the electrochemical sensing of antibodies directed against double-stranded DNA (α-dsDNA), which are often present at higher-than-normal levels in the sera of autoimmune disease patients. The method can be easily implemented in any lab and requires little investment in equipment, namely a potentiostat. An artificial reference serum sample containing known amounts of spiked-in α-dsDNA antibodies enables reporting results in absolute scale rather than titer. Once electrodes are modified with DNA and the calibration curves are made (i.e., after the biosensor construction phase), individual measurements in test samples can be obtained in as low as 35 min.
... Several autoantibodies, especially those against double-stranded DNA (anti-dsDNA), are believed to play a major role in the induction of glomerular inflammation [30][31][32][33]. Antibodies to dsDNA are specific to SLE and are detected in 70-80% of LN patients [34,35], while in the remaining LN cases, levels are undetectable (5-30%) [36]. Serum anti-dsDNA titres correlate with disease activity, can precede renal manifestations, and their immune complexes have been detected in the glomerulus [37]. ...
Despite conventional therapy, lupus nephritis (LN) remains a significant contributor to short- and long-term morbidity and mortality. B cell abnormalities and the production of autoantibodies against nuclear complexes like anti-dsDNA are recognised as key players in the pathogenesis of LN. To address the challenges of chronic immunosuppression associated with current therapies, we have engineered T cells to express chimeric autoantibody receptors (DNA-CAART) for the precise targeting of B cells expressing anti-dsDNA autoantibodies. T cells from LN patients were transduced using six different CAAR vectors based on their antigen specificity, including alpha-actinin, histone-1, heparan sulphate, or C1q. The cytotoxicity, cytokine production, and cell–cell contact of DNA-CAART were thoroughly investigated in co-culture experiments with B cells isolated from patients, both with and without anti-dsDNA positivity. The therapeutic effects were further evaluated using an in vitro immune kidney LN organoid. Among the six proposed DNA-CAART, DNA4 and DNA6 demonstrated superior selectively cytotoxic activity against anti-dsDNA+ B cells. Notably, DNA4-CAART exhibited improvements in organoid morphology, apoptosis, and the inflammatory process in the presence of IFNα-stimulated anti-dsDNA+ B cells. Based on these findings, DNA4-CAART emerge as promising candidates for modulating autoimmunity and represent a novel approach for the treatment of LN.
... Lupus nephritis was found in 31.4% of our patients, which is lower than the previous studies in Saudi Arabia and Arab countries. Positive anti-dsDNA antibodies are well known to be strongly associated with lupus nephritis [22], which could explain the lower prevalence of anti-dsDNA antibodies in our patients. ...
Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystemic involvement. The clinical presentation and immunological findings of SLE patients from different regions in Saudi Arabia have been studied. There have been no studies on the clinical manifestations of SLE in patients in Saudi Arabia's southern region. This article aims to explore the clinical manifestations of SLE in a tertiary center in the southern region of Saudi Arabia. Methods A retrospective study was carried out on 108 SLE patients who were seen in the rheumatology clinic at Aseer Central Hospital over six months from January 2022 to June 2022. Patients' demographics, clinical and serological characteristics, and therapeutic data were reviewed. Results The male-to-female ratio was 1:12.5, with a mean age at presentation of 28.6 ± 10 years. The mean disease duration was 9.06 ± 5.96 years. Mucocutaneous and musculoskeletal manifestations were the most common, accounting for 76% and 57% of all cases, respectively. Neuropsychiatric involvement and lupus nephritis were present in 29% and 31% of patients, respectively. The hematological abnormalities that were present included anemia (60%), leukopenia (37%), and thrombocytopenia (15%). Antinuclear antibody (ANA) was detected in 100%, anti-double-stranded DNA (anti-dsDNA) antibody in 55%, anti-Smith antibody in 13%, and hypocomplementemia in 52% of patients. Hydroxychloroquine was received by 98% and oral steroids by 41% of the patients. Other drugs include azathioprine (23%), mycophenolate mofetil (15%), methotrexate (23%), belimumab (9%), cyclophosphamide (10%), and rituximab (6%). Conclusion The main clinical features of our patients were in parallel with previous studies in Saudi Arabia as well as in Arab countries. We found a lower prevalence of lupus nephritis, serositis, and anti-dsDNA antibody. Further multicenter studies are required to investigate the long-term outcome and survival of SLE patients.
... LN is the one of the principal causes of morbidity and mortality among various major organ manifestations of lupus (1). The development of glomerulonephritis in SLE was associated with the presence of some specific nephritogenic autoantibodies, such as anti-doublestranded DNA (anti-dsDNA) antibodies (2)(3)(4), anti-Sm antibodies, anti-C1q antibodies (5)(6)(7)(8), and anti-C-reactive protein (CRP) antibodies (9, 10), whereas more than 150 autoantibodies were reported in SLE. It is still controversial that which autoantibodies are associated with renal clinical and pathological activity and the renal outcome. ...
Objective:
The aim of this study is to explore the prevalence and clinicopathological associations between anti-C1qA08 antibodies and anti-monomeric CRP (mCRP) a.a.35-47 antibodies and to explore the interaction between C1q and mCRP.
Methods:
Ninety patients with biopsy-proven lupus nephritis were included from a Chinese cohort. Plasma samples collected on the day of renal biopsy were tested for anti-C1qA08 antibodies and anti-mCRP a.a.35-47 antibodies. The associations between these two autoantibodies and clinicopathologic features and long-term prognosis were analyzed. The interaction between C1q and mCRP was further investigated by ELISA, and the key linear epitopes of the combination of cholesterol binding sequence (CBS; a.a.35-47) and C1qA08 were tested by competitive inhibition assays. The surface plasmon resonance (SPR) was used to further verify the results.
Results:
The prevalence of anti-C1qA08 antibodies and anti-mCRP a.a.35-47 antibodies were 50/90 (61.1%) and 45/90 (50.0%), respectively. Levels of anti-C1qA08 antibodies and anti-mCRP a.a.35-47 antibodies were negatively correlated with serum C3 concentrations ((0.5(0.22-1.19) g/L vs. 0.39(0.15-1.38) g/L, P=0.002) and (0.48(0.44-0.88) g/L vs. 0.41(0.15-1.38) g/L, P=0.028), respectively. Levels of anti-C1qA08 antibodies were correlated with the score of fibrous crescents and tubular atrophy (r=-0.256, P=0.014 and r=-0.25, P=0.016, respectively). The patients with double positive antibodies showed worse renal prognosis than that of the double negative group (HR 0.899 (95% CI: 0.739-1.059), P=0.0336). The binding of mCRP to C1q was confirmed by ELISA. The key linear epitopes of the combination were a.a.35-47 and C1qA08, which were confirmed by competitive inhibition experiments and SPR.
Conclusion:
The combination of anti-C1qA08 and anti-mCRP a.a.35-47 autoantibodies could predict a poor renal outcome. The key linear epitopes of the combination of C1q and mCRP were C1qA08 and a.a.35-47. A08 was an important epitope for the classical pathway complement activation and a.a.35-47 could inhibit this process.
... Pathological analyses of renal tissues have identified autoantibodies targeted against antigens such as DNA, histone and nucleosome [5,6]. The existence of anti-dsDNA, anti-nucleosome and/or anti-histone antibodies is associated with proliferative glomerulonephritis and LN activity [7][8][9]. An association of the presence of a single autoantibody type with the development of LN has been demonstrated in LN patients, and the presence of multiple autoantibodies has been suggested in the development and progression of LN. ...
Objective
The aim of this study was to define the clinical, histopathologic, and prognostic features associated with simultaneous positivity for anti-dsDNA, -nucleosome, and -histone antibodies (3-pos) in Korean patients with biopsy-proven lupus nephritis (LN).
Methods
The 102 patients included in the study had undergone kidney biopsy prior to the start of induction treatment, were treated with immunosuppressives, and followed-up for >12 months.
Results
In total, 44 (43.1%) of the 102 LN patients were 3-pos. Patients with 3-pos had a higher SLEDAI-2K score (p = .002), lower lymphocyte count (p = .004), and higher rates of proteinuria > 3.5 g/24 h (p = .039) and positivity for urinary sediments (p = .005) at the time of renal biopsy than non-3-pos patients. 3-pos patients had a more proliferative form of LN (p = .045) in the renal histopathologic findings, and as co-positivity gradually increased from 0 to 3, the total activity score in the renal biopsy findings increased significantly (p = .033). In addition, 3-pos patients had a more rapid eGFR decline than non-3-pos patients after a follow-up of 83.2 months (p = .016).
Conclusions
Our findings suggest that 3-pos is related to severe LN and that 3-pos patients are more likely to experience a rapid decline of renal function than non-3-pos patients.
•
KEY MESSAGE
• Patients with co-positivity for anti-dsDNA, -nucleosome, and -histone antibodies (3-pos) had higher disease activity and a worse renal histopathology than those without co-positivity.
• 3-pos patients had a more rapid decline of renal function than non-3-pos patients.
... Accordingly, they are part of all relevant recent sets of SLE classification criteria, from the ACR 1982 criteria and their 1997 revision, via the SLICC to the new European League Against Rheumatism / American College of Rheumatology (EULAR/ACR) [2]. Moreover, several studies assessed their potential in predicting the disease [3], in evaluating disease activity and tissue/organ damage, especially nephritis [4], and in monitoring treatment efficacy [5][6][7][8][9]. However, anti-dsDNA antibodies are heterogeneous due to the diversity and polyclonality of the autoimmune response to native DNA in individual patients [10][11][12] which may affect the performance of the assay used for their detection. ...
Anti‐double stranded DNA antibodies (anti‐dsDNA) are considered a specific marker for systemic lupus erythematosus (SLE). Though the Farr technique was once the reference method for their detection, it has been almost entirely replaced by more recently developed assays. However, there is still no solid evidence of the commutability of these methods in terms of diagnostic accuracy and their correlation with the Crithidia luciliae immunofluorescence test (CLIFT). Anti‐dsDNA antibody levels were measured in 80 subjects: 24 patients with SLE, 36 disease controls drawn from different autoimmune rheumatic diseases (14 systemic sclerosis, 10 Sjögren’s syndrome, nine autoimmune myositis, three mixed connective tissue disease), 10 inflammatory arthritis and 10 apparently healthy blood donors by eight different methods: fluorescence enzyme immunoassay, microdot array, chemiluminescent immunoassay (two assays), multiplex flow immunoassay, particle multi‐analyte technology immunoassay and two CLIFT. At the recommended manufacturer cutoff, the sensitivity varied from 67% to 92%, while the specificity ranged from 84% to 98%. Positive agreement among CLIFT and the other assays was higher than negative agreement. Mean agreement among methods assessed by the Cohen’s kappa was 0.715, ranging from moderate (0.588) to almost perfect (0.888). Evaluation of the concordance among quantitative values by regression analysis showed a poor correlation index (mean r2, 0.66). The present study shows that current technologies for anti‐dsDNA antibody detection are not fully comparable. In particular, their different correlation with CLIFT influences their positioning in the diagnostic algorithm for SLE (either in association or sequentially). Considering the high inter‐method variability, harmonization and commutability of anti‐dsDNA antibody testing remains an unachieved goal.
... Além de obter um histórico clínico detalhado e realizar um exame físico minucioso, podem ser utilizados exames laboratoriais para ajudar a avaliar a atividade da doença do LES e monitorar as possíveis complicações específicas como o acometimento neurológico (Mosca et al., 2009). Os testes laboratoriais mais úteis para prever uma instauração do LES são o aumento do título de soro de anticorpos anti-dsDNA e uma queda nos níveis de complemento, especialmente C3, C4 e CH50 (Linnik et al., 2005). No entanto nem todos os pacientes com esses marcadores sorológicos têm doença ativa e tampouco esses marcadores necessariamente preveem exacerbação da doença (Esdaile et al., 1996). ...
Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune que é conhecido por estar associado a manifestações neuropsiquiátricas com uma prevalência de 17 a 75% nos portadores da doença. A catatonia tem sido descrita no espectro clínico das manifestações neuropsiquiátricas (MNP) do LES. O objetivo desse estudo foi caracterizar, por meio de uma revisão sistemática, as manifestações clínicas e a terapêutica da catatonia induzida por Lúpus Eritematoso Sistêmico (LES). Foi realizado uma revisão sistemática de relato e série de casos utilizando os descritores “Systemic Lupus Erythematosus” e “Catatonia”, no período de 1977 a 2021, nas bases de dados Medline©, PubMed©, Lilacs©, Scielo© e EMBASE© publicados em Espanhol, Francês, Inglês e Português. De um total de 50 pacientes analisados nos estudos selecionados, cerca de 54% tinham idade entre 18 e 35 anos, com prevalência total no sexo feminino, 90%. Evidenciou-se que o quadro clínico é bem variado com predominância de mutismo (75%), imobilidade/estupor (55%), rigidez (40%) e flexibilidade cérea (40%). 46% dos pacientes apresentaram alterações do sistema nervoso central detectado através da ressonância magnética de cérebro, tomografia computadorizada de crânio, eletroencefalograma ou punção lombar. Em relação ao tratamento proposto a cada paciente, com descrição de melhora, tem-se o uso de benzodiazepínicos, eletroconvulsoterapia, glicocorticoides e imunossupressores como responsáveis por quase todas as respostas de resolutividade. Conclui-se que os transtornos psiquiátricos não são bem descritos no LES. Este estudo evidencia a importância do diagnóstico e tratamento de transtornos psiquiátricos, especialmente a síndrome catatônica. LES deve, portanto, ser incluído no diagnóstico diferencial de pacientes apresentando a síndrome catatônica.
... Attaining ANA negativity showed statistical significance in the high dose group, attaining anti-dsDNA negativity that showed statistical significance in the low-dose group. With treatment of LN, autoantibodies may disappear in varying percentages [13,14]. Early changes in autoantibodies with treatment may not distinguish responders from nonresponders [12]. ...
... These scoring systems have been used in clinical trials or research and are recommended to identify the degree of severity among different subsets of patients with SLE in clinical practice. Anti-double-stranded DNA (ds-DNA) antibody and complement levels are used as disease activity biomarkers, with high anti-dsDNA antibody titers or low complement levels indicating high disease activity [15]. In addition, the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index could predict organ damage and mortality as a tool for evaluating the long-term outcomes of SLE [16]. ...
Systemic lupus erythematosus (SLE) is a heterogeneous disorder with diverse clinical manifestations. This study classified patients by combining laboratory values at SLE diagnosis via hierarchical cluster analysis. Linear discriminant analysis was performed to construct a model for predicting clusters. Cluster analysis using data from 389 patients with SLE yielded three clusters with different laboratory characteristics. Cluster 1 had the youngest age at diagnosis and showed significantly lower lymphocyte and platelet counts and hemoglobin and complement levels and the highest erythrocyte sedimentation rate (ESR) and anti-double-stranded DNA (dsDNA) antibody level. Cluster 2 showed higher white blood cell (WBC), lymphocyte, and platelet counts and lower ESR and anti-dsDNA antibody level. Cluster 3 showed the highest anti-nuclear antibody titer and lower WBC and lymphocyte counts. Within approximately 171 months, Cluster 1 showed higher SLE Disease Activity Index scores and number of cumulative manifestations, including malar rash, alopecia, arthritis, and renal disease, than did Clusters 2 and 3. However, the damage index and mortality rate did not differ significantly between them. In conclusion, the cluster analysis using the initial laboratory findings of the patients with SLE identified three clusters. While disease activities, organ involvements, and management patterns differed between the clusters, damages and mortalities did not.
... Both dsDNA and BAFF are markers of SLE disease activity. 19,20 To determine whether the SNS was impaired in MRL/lpr mice, we measured the expression of tyrosine hydroxylase (TH) and GFAP, an astrocyte marker, in the locus ceruleus, the major source of noradrenaline. 21 Expression of TH was significantly lower in MRL/lpr mice than in MRL/MPJ mice, whereas expression of GFAP was significantly higher (Fig. 1A). ...
Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonomic nerves and Schwann cells occurred in the bone marrow and central nervous system of SLE model mice. A neurotoxic drug increased mortality and induced severe neuropathy and multiple organ damage, while a neuroprotective drug prevented multiple organ damage. The administration of bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on a 3-dimensional fiber scaffold improved bone marrow neuropathy, skin lesions, kidney function, and mortality. Our results reveal that bone marrow neuropathy influence multiple organ damage associated with SLE, and improvement of bone marrow neuropathy by intrathecal injection of BMSC may be a target for SLE multiple-organ damage.
... 19,20 DsDNA and anti-C1q antibody titers correlate with LN flares and fall following cessation of disease activity. 21,22 However, absence of these antibodies does not rule out active LN and many SLE patients with high anti-dsDNA never develop LN. 19,20 In some patients, anti-dsDNA levels were lower in active nephritis, suggesting sequestration in immune complexes within the kidney. 23,24 Anti-Smith, antiribonucleoprotein, anti-nucleosome, anti-Sjogren-syndrome-related antigen A, 20,25,26 anti RNA polymerase I, and anti-Sjogren-syndrome-related antigen B 25,27,28 are also increased in LN and may correlate with disease activity, 7,26 but have low sensitivity and are seen in other autoimmune diseases. ...
Pro-inflammatory immune system development, metabolomic defects, and deregulation of autophagy play interconnected roles in driving the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis (LN) is a leading cause of morbidity and mortality in SLE. While the causes of SLE have not been clearly delineated, skewing of T and B cell differentiation, activation of antigen-presenting cells, production of antinuclear autoantibodies and pro-inflammatory cytokines are known to contribute to disease development. Underlying this process are defects in autophagy and mitophagy that cause the accumulation of oxidative stress-generating mitochondria which promote necrotic cell death. Autophagy is generally inhibited by the activation of the mammalian target of rapamycin (mTOR), a large protein kinase that underlies abnormal immune cell lineage specification in SLE. Importantly, several autophagy-regulating genes, including ATG5 and ATG7, as well as mitophagy-regulating HRES-1/Rab4A have been linked to lupus susceptibility and molecular pathogenesis. Moreover, genetically-driven mTOR activation has been associated with fulminant lupus nephritis. mTOR activation and diminished autophagy promote the expansion of pro-inflammatory Th17, Tfh and CD3⁺CD4⁻CD8⁻ double-negative (DN) T cells at the expense of CD8⁺ effector memory T (EMT) cells and CD4⁺ regulatory T cells (Tregs). mTOR activation and aberrant autophagy also involve renal podocytes, mesangial cells, endothelial cells, and tubular epithelial cells that may compromise end-organ resistance in LN. Activation of mTOR complexes 1 (mTORC1) and 2 (mTORC2) has been identified as biomarkers of disease activation and predictors of disease flares and prognosis in SLE patients with and without LN. This review highlights recent advances in molecular pathogenesis of LN with a focus on immuno-metabolic checkpoints of autophagy and their roles in pathogenesis, prognosis and selection of targets for treatment in SLE.
... 55 We also identified studies that evaluate the prognostic effect of serological activity not at a predetermined timepoint but during the disease course after controlling for confounding factors such as clinical activity or background treatment (Supplementary Table S7). 24,28,29,34,[60][61][62][63][64][65][66][67][68][69] In a study involving 2228 SLE patients followed for a median period of 8.9 years, prolonged LLDAS state (≥50% of observation time) was negatively predicted by history of hypocomplementemia (OR 0.60; 95% CI 0.47-0.75) and high anti-dsDNA (OR 0.74; 95% CI 0.59-0.93) in a multivariable analysis including several clinical and treatment parameters. ...
Introduction
Serological markers such as anti-double stranded (ds)DNA antibodies and complement fractions C3/C4, are integral components of disease activity assessment in patients with systemic lupus erythematosus (SLE). However, it remains uncertain whether treatment should aim at restoration of serological abnormalities.
Objectives
To analyze and critically appraise the literature on the prognostic impact of active lupus serology despite clinical disease quiescence.
Methods
A systematic literature review was performed in PubMed and EMBASE using the PICOT(S) (population, index, comparator, outcome(s), timing, setting) system to identify studies evaluating the association of serum anti-dsDNA, C3 and C4 levels assessed at the time of clinical remission or during the disease course, against the risk for impending flares and organ damage. Risk of bias was determined by the Quality in Prognosis Studies and ROB2 tools for observational and randomized controlled studies, respectively.
Results
Fifty-three studies were eligible, the majority having moderate (70.6%) or high (11.8%) risk of bias and not adequately controlling for possible confounders. C3 hypocomplementemia during stable/inactive disease was associated with increased risk (2.0 to 3.8-fold) for subsequent flare in three out of seven relevant studies. Three out of four studies reported a significant effect of C4 hypocomplementemia on flare risk, including one study in lupus nephritis (likelihood ratio-positive 12.0). An increased incidence of flares (2.0 to 2.8-fold) was reported in 11 out of 16 studies assessing the prognostic effect of high anti-dsDNA, and similarly, the majority of studies yielded significant relationships with renal flares. Six studies examined the effect of combined (rather than individual) serological activity, confirming the increased risk (2.0 to 2.7-fold) for relapses. No consistent association was found with organ damage.
Conclusion
Notwithstanding the heterogeneity and risk of bias, existing evidence indicates a modest association between abnormal serology and risk for flare in patients with stable/inactive SLE. These findings provide limited support for inclusion of serology in the treat-to-target approach but rationalize to further investigate their prognostic implications especially in lupus nephritis.
... 10 Rise of levels may also lead to relapse of kidney disease. 11,12 Surprisingly, 2-30% of SLE patients have negative result for anti-dsDNA. 7 Patients negative for anti-dsDNA have higher chance of polyserositis. ...
Systemic lupus erythematosus (SLE) presents with diverse clinical features causing diagnostic challenges. Apart from the clinical features, autoantibodies are important for diagnosis along with certain laboratory parameters. Diagnosis is made with the European League against Rheumatism/American College of Rheumatology 2019 Criteria. The case series presented here signifies the correlation between anti ds DNA positivity and its association with poor prognosis and renal disease, whereas antidouble stranded DNA (anti-dsDNA) negativity may lead to lack of renal involvement and may be associated with polyserositis. The importance lies in the fact that these patients with anti-dsDNA negativity should be followed up for assessing conversion to positivity of anti-dsDNA, thus altering the prognosis and leading to renal involvement. Moreover, anti-SSA positive SLE patients must be followed up for possible development of sicca symptoms.
... The deposition of immune complexes and the subsequent complement activation are considered major mechanisms by which tissue injury occurs in LN [15][16][17]. Many studies have reported the pathogenic role of IgG type autoantibodies, such as anti-dsDNA antibodies, anti-C1q antibodies, anti-mCRP antibodies, in complement activation and renal injuries in LN [18][19][20][21]. Natural IgM antibody is generally regarded as an activator of complement classical pathway. ...
Background
The aim of the study was to investigate the clinical relevance of IgM deposition in patients with lupus nephritis (LN) in a large cohort.
Results
217 patients with renal biopsy-proven active LN were enrolled. The associations between glomerular IgM deposition and clinicopathological parameters were further analyzed. IgM deposition was positively correlated with glomerular C1q and C3 deposition moderately (r = 0.436, P < 0.001; r = 0.408, P < 0.001, respectively), and inversely correlated with plasma levels of C3 and CFH mildly (r = − 0.138, P = 0.043; r = − 0.147, P = 0.037, respectively). By multivariate analysis, we found that glomerular IgM deposition independently contributed to glomerular C3 deposition in patients with LN (OR = 2.002, 95% CI 1.295–3.094, P = 0.002). In addition, we also found that patients with IgM 0–2+ had similar plasma CFH levels, but in patients with IgM3+–4+, plasma CFH levels were significantly lower (300.4 ± 155.8 μg/mL vs. 429.9 ± 187.5 μg/mL, P < 0.001). Furthermore, patients with high density of glomerular IgM and low levels of CFH had heavier proteinuria, higher serum creatinine and lower plasma C3 levels (5.7 ± 3.1 g/d vs. 4.7 ± 3.5 g/d, P = 0.037; 150.1 ± 121.0 μmol/L vs. 105.6 ± 97.1 μmol/L, P = 0.005; 0.3 ± 0.2 μg/L vs. 0.4 ± 0.2 μg/L, P = 0.04, respectively), comparing with those with low density of glomerular IgM and low levels of CFH.
Conclusions
Our results suggested the involvement of glomerular deposited IgM in complement activation and renal injury in LN.
... При этом участие анти-дсДНК антител [141] и особенно анти-C1q антител [142,143], активирующих систему комплемента по классическому и лектиновому пути, в образовании «патогенных» ИК, является строго доказанным. Снижение уровня аутоантител ассоциируется с клинической эффективностью терапии СКВ, том числе РТМ [144][145][146][147]. Эти антитела синтезируются 2 субпопуляциями клеток: короткоживущими пролиферирующими плазмабластами (ПБ) и длительно живущими ПК [148]. ...
Currently, strong evidence has been obtained for the fundamental role of pathological activation of B cells in the pathogenesis of immunoinflammatory (autoimmune) rheumatic diseases (IMRD), and drugs that specifically modulate the function or cause depletion of various subpopulations of B cells and plasma cells are considered a promising direction. pharmacotherapy of these diseases. of particular interest is belimumab (BLM), a human monoclonal antibody (mAb) (IgG1λ) to BAFF (B cell-activating factor belonging to the TNF family), which is the first “targeted” biological drug specially developed for the treatment of systemic lupus erythematosus (SLE). The efficacy and safety of BLM in SLE in adults and children, including lupus nephritis, in combination therapy with rituximab, steroid-sparing effect, the ability to prevent irreversible damage to internal organs dictate the need for its wider application in clinical practice.
... 7,8 Anti-dsDNA antibody titer has been reported to be consistently associated with the development of lupus nephritis and disease flare in patients with SLE. 9,10 However, the clinical significance of anti-ENA antibodies remains unclear, but it may predict the involvement of different organs as well as the severity of the disease, helping in making an early diagnosis and in the specification of involved organs as well as initiation the appropriate treatment as early as possible. 11 In this study, we aimed to estimate the frequency of ANA, anti-dsDNA, and anti-ENA antibodies among patients with JSLE and their association with the different clinical manifestations and the activity of the disease. ...
Objective:
This study was conducted to estimate the frequency of anti-nuclear antibodies (ANAs), anti-dsDNA, and anti-extractable nuclear antigen (ENA) antibodies in juvenile systemic lupus erythematosus (JSLE) patients and their association with different clinical manifestations and disease activity.
Patients and methods:
A cross-sectional study that includes 100 JSLE patients from Ain Shams University Hospital was conducted. All subjects underwent history taking, clinical examination, assessment of disease activity based on the SLE disease activity index (SLEDAI), laboratory investigations, and tests for autoantibodies, namely ANA, anti-dsDNA, and anti-ENA antibodies, including anti-Ro (SSA), anti-La (SSB), anti-Smith (Sm), and anti-U1-ribonucleoprotein (U1-RNP).
Results:
The most common clinical features were polyarthralgia (71%), haematological manifestations (65%), malar rash (54%), and nephritis (51%), respectively. All patients had positive ANA (100%), while anti-dsDNA frequency was 83%. The most common anti-ENA antibodies were anti-RNP (41%), anti-Sm (31%), anti-SSA (27%), and anti-SSB (20%), respectively. Anti-RNP had a clinical association with oral ulcer, Raynaud' phenomena, haematological, neuropsychiatric and thromboembolic manifestations. Meanwhile, anti-Sm had a significant association with serositis, mucocutaneous, constitutional, and neuropsychiatric manifestations. Anti-SSA was associated with mucocutaneous, musculoskeletal, Raynaud' phenomena, renal, haematological and cardiac manifestations, while anti-SSB was significantly associated with malar rash, serositis, thromboembolic, musculoskeletal, and neuropsychiatric manifestations. Concerning SLEADI score, anti-dsDNA antibody was significantly associated with moderate disease activity score (p=0.032) while anti-SSA significantly associated with high disease activity (p=0.045). Both anti-SSB and anti-Sm were significantly associated with both moderate and high disease activities, meanwhile anti-U1-RNP was associated with moderate disease activity (p=0.014).
Conclusion:
Anti-dsDNA and anti-ENAs antibodies were frequently found in JSLE patients (83%, 63%), respectively. They were significantly associated with variable clinical manifestations and could be used as predictors for assessment of disease activity.
... First, early detection of LN flare through the detection of early renal rearrangements could be investigated using urinary peptidomics. Some immunological parameters are associated with the risk of LN in SLE [58][59][60] but remain poorly predictive of flares [61,62]. Moreover, some patients show active renal lesions while no proteinuria, hematuria or pyuria is detected [63,64]. ...
Background: Lupus nephritis (LN) is a severe manifestation of Systemic Lupus Erythematosus (SLE). The therapeutic strategy relies on kidney biopsy (KB) results. We tested whether urinary peptidome analysis could non-invasively differentiate active from non-active LN. Design: Urinary samples were collected from 93 patients (55 with active LN and 38 with non-active LN), forming a discovery (n = 42) and an independent validation (n = 51) cohort. Clinical characteristics were collected at inclusion and prospectively for 24 months. The urinary peptidome was analyzed by capillary-electrophoresis coupled to mass-spectrometry, comparing active LN to non-active LN, and assessing chronic lesions and response to therapy. The value of previously validated prognostic (CKD273) and differential diagnostic (LN172) signatures was evaluated. Results: Urinary peptides could not discriminate between active and non-active LN or predict early response to therapy. Tubulo-interstitial fibrosis was correlated to the CKD273. The LN172 score identified 92.5% of samples as LN. Few patients developed new-onset CKD. Conclusions: We validated the CKD273 and LN172 classifiers but did not identify a robust signature that could predict active LN and replace KB. The value of urinary peptidome to predict long-term CKD, or renal flares in SLE, remains to be evaluated.
... The SLE (À) population had lower prevalence of renal disease, which appeared to be influenced by anti-dsDNA status [20]. Vascular and haematological disease manifestations were also less prevalent in the SLE (À) population, and this suggests that these manifestations may be less prevalent in patients that lack serological indicators of disease. ...
Objectives
Heterogeneity of systemic lupus erythematosus (SLE) patients in clinical trials remains a challenge for developing new therapies. This study used a combinatorial analysis of four molecular biomarkers to define key sources of heterogeneity.
Methods
Combinations of IFN(high/low), anti-dsDNA(+/-), C3 and C4(low/normal) were used to subset n = 1747 patients from two randomized phase 3 trials. A dichotomous classification scheme defined SLE(+) as: IFNhigh, anti-dsDNA(+), C3(low) and/or C4(low). SLE(-) required all of the following: IFNlow, anti-dsDNA(-), C3(normal) and C4(normal). Additional analyses subset the data further by IFN, anti-dsDNA and complement.
Results
The trials enrolled n = 2262 patients of which n = 1747 patients had data for IFN, anti-dsDNA, C3 and C4 at baseline. There were n = 247 patients in the SLE(-) population and n = 1500 patients in the SLE(+) population. The SLE(-) population had more mucocutaneous and musculoskeletal disease at baseline, while SLE(+) had more hematologic, renal and vascular involvement. There was lower concomitant medication use in the SLE(-) population for corticosteroids and immunosuppressants, except for methotrexate. Time to severe flare was significantly longer in SLE(-) vs SLE(+) (p < 0.0001) and SRI-4 response rate was significantly lower in SLE(-) vs SLE(+) (p = 0.00016). The United States had more SLE(-) patients (22%) than Mexico/Central America/South America (10%), Europe (7%) and the rest of the world (5%).
Conclusion
Combinatorial analysis of 4 molecular biomarkers revealed subsets of SLE patients that discriminated by disease manifestations, concomitant medication use, geography, time to severe flare and SRI-4 response. These data may be useful for designing clinical trials and identifying subsets of patients for analysis.
... These observations suggest that germinal centers and T/B cell aggregates select for cells that locally secrete pathogenic antibodies in the tubulointerstitium. Besides, tubulointerstitial inflammation severity does not correlate with titers of anti-dsDNA antibodies [8], whereas an increase in serum anti-dsDNA antibodies suggests an increased risk for glomerulonephritis [9]. In our case, level of antibodies to dsDNA was not significant even when the patient's renal function started to decline. ...
Predominant tubulointerstitial nephritis with negligible glomerular lesions is a rare form of lupus nephritis. Although tubulointerstitial changes occur in two-thirds of patients with lupus nephritis, these lesions were mostly accompanied by glomerulonephritis. Predominant tubulointerstitial lupus nephritis has been reported to be only 13 cases in the literature as far as we surveyed. Here, we present a case of a 72-year-old male who had pancytopenia associated with pernicious anemia and later developed a mild proteinuria and renal insufficiency. Although urinary tubulointerstitial markers increased, serological screening tests for tubulointerstitial nephritis were all negative. Three months later, the patient was diagnosed as systemic lupus erythematosus, based on polyarthritis, positive antinuclear antibody, immunological disorder and hematological disorder. Renal biopsy revealed severe infiltration of mononuclear cells in the interstitium with minimal abnormalities in glomeruli. Positive IgG and C1q staining with immunofluorescence antibody method in the tubular basement membrane and dense deposits in the same region with electron microscopy confirmed a diagnosis of predominant tubulointerstitial lupus nephritis. Since the patient's renal function declined rapidly, treatment with intravenous 500 mg methyl prednisolone followed by 40 mg/day of oral prednisolone was initiated. The patient's renal function improved and became stable even after tapering of prednisolone. Although lupus nephritis is generally accompanied by multiple symptoms such as fever, malaise, arthralgia, rashes, this case showed only pernicious anemia and tubulointerstitial nephritis initially.
... Initial trials revealed a reduction in renal flares in patients having high affinity antibodies to the DNA epitope expressed on abetimus. Unfortunately, subsequent trials failed to meet their primary endpoints though abetimus treatment decreased the titers of anti-dsDNA antibody [214,215]. ...
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with high heterogeneity but the common characterization of numerous autoantibodies and systemic inflammation which lead to the damage of multiple organs. Aberrance of B cells plays a pivotal role in the immunopathogenesis of SLE via both antibody-dependent and antibody-independent manners. Escape of autoreactive B cells from the central and peripheral tolerance checkpoints, over-activation of B cells and their excessive cytokines release which drive T cells and dendritic cells stimulation, and dysregulated surface molecules, as well as intracellular signal pathways involved in B cell biology, are all contributing to B cell aberrance and participating in the pathogenesis of SLE. Based on that rationale, targeting aberrance of B cells and relevant molecules and pathways is expected to be a promising strategy for lupus control. Multiple approaches targeting B cells through different mechanisms have been attempted, including B-cell depletion via monoclonal antibodies against B-cell-specific molecules, blockade of B-cell survival and activation factors, suppressing T-B crosstalk by interrupting costimulatory molecules and inhibiting intracellular activation signaling cascade by targeting pathway molecules in B cells. Though most attempts ended in failure, the efficacy of B-cell targeting has been encouraged by the FDA approval of belimumab that blocks B cell-activating factor (BAFF) and the recommended use of anti-CD20 as a remedial therapy in refractory lupus. Still, quantities of clinical trials targeting B cells or relevant molecules are ongoing and some of them have displayed promising preliminary results. Additionally, advances in multi-omics studies help deepen our understandings of B cell biology in lupus and may promote the discovery of novel potential therapeutic targets. The combination of real-world data with basic research achievements may pave the road to conquering lupus.
... However, there is a lack of indicators to represent changes in the SLE disease status. Currently, anti-double-stranded DNA (dsDNA) antibody and complement protein levels are used as the markers for diagnosis or monitoring of SLE [2,3]. The anti-dsDNA antibodies target the intracellular DNA and induce apoptosis. ...
We aimed to characterize the salivary protein components and identify biomarkers in patients with systemic lupus erythematosus (SLE). A proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry was performed to determine the alterations of salivary proteins between patients with SLE and healthy controls, and the concentrations of the candidate proteins were measured through Western blot analysis and the enzyme-linked immunosorbent assay. The 10 differentially expressed protein spots were immunoglobulin gamma-3 chain C region (IGHG3), immunoglobulin alpha-1 chain C region, protein S100A8, lactoferrin, leukemia-associated protein 7, and 8-oxoguanine DNA glycosylase. The patients with SLE exhibited enhanced salivary IGHG3 (3.9 ± 2.15 pg/mL) and lactoferrin (4.7 ± 1.8 pg/mL) levels compared to patients with rheumatoid arthritis (1.8 ± 1.01 pg/mL and 3.2 ± 1.6 pg/mL, respectively; p < 0.001 for both) or healthy controls (2.2 ± 1.64 pg/mL and 2.2 ± 1.7 pg/mL, respectively; p < 0.001 for both). The salivary IGHG3 levels correlated with the erythrocyte sedimentation rate (r = 0.26, p = 0.01), anti-double-stranded DNA (dsDNA) antibody levels (r = 0.25, p = 0.01), and nephritis (r = 0.28, p = 0.01). The proteomic analysis revealed that the salivary IGHG3 levels were associated with SLE and lupus disease activity, suggesting that salivary IGHG3 may be a promising noninvasive biomarker for SLE.
... Also, Farid et al. (2013) found that anti-ds-DNA was higher in the LN group compared with the non-LN group, showing that patients with active LN often have raised levels of anti-ds DNA antibodies. In addition their titers correlate well with clinical activity as was studied by Linnik et al. (2005). The mean value of C3 was statistically significant lower in group I than that of group II and group III with no statistical significant difference between group II and group III. ...
Lupus nephritis (LN) affects up to 60% of patients with systemic lupus erythematosus (SLE), either as the initial manifestation or during the disease course. Moreover, LN has a negative impact on survival of SLE patients. Accordingly, it is mandatory to identify specific and feasible markers able to guide clinicians towards the adequate therapeutic option in LN patients. The aim of this work was to evaluate the predictive value of renal resistance index (RRI), measured by Doppler Sonography in comparison with disease activity score, serologic and biopsy parameters in patients with LN. This study was carried out on forty three SLE patients, they were categorized into two groups: Group I included thirty three patients with LN and Group II included ten patients without LN and Group III included ten healthy subjects of matched age and sex as control group. All were subjected to history taking, clinical examination, assessment of disease activity by SLEDAI, laboratory investigations including FBG, blood urea, serum creatinine, serum albumin, CBC, ESR, CRP, complete urine analysis, 24 hour urine protein, eGFR, serum ANA, anti ds-DNA titre, C3, C4 and renal Doppler with measurement of RRI. Renal biopsy was done for those with LN. The mean value of RRI was statistically significantly higher in group I than that of group II and group III. Out of 33 cases of LN cases, 6 patients had RRI of 0.7 and above giving a percentage of 18.18%. LN patients with RRI higher than 0.7 had statistically significant higher age, mean serum creatinine and blood urea levels and a lower eGFR, higher chronicity index of renal biopsy. RRI is of clinical significance in predicting the chronicity index of renal biopsy which is a major determinant of renal outcome so it is useful as non invasive technique to evaluate chronicity in patients with LN, therefore justifying aggressive immune suppression but further follow-up studies are needed to evaluate its role in predicting response to treatment.
... According to several studies, anti-dsDNA strongly correlates with the presence and clinical activity of LN [10,11]. The increase in anti-dsDNA levels precedes exacerbations of the disease [12,13]. In contrast, some other studies report that not all patients with anti-dsDNA develop LN [14] or that anti-dsDNA does not correlate with LN or its flares [15]. ...
Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). LN often leads to kidney failure, affecting the quality of a patient's life. There are several classical biomarkers that assist nephrologists' daily practice. For more than 50 years, anti-double stranded DNA antibodies and complement components C3 and C4 have been used for LN disease activity evaluation. The major obstacle in the usage of conventional biomarkers is that none of them have both high specificity and high sensitivity. Moreover, an invasive kidney biopsy is still the gold standard for renal involvement detection in SLE patients. Therefore, new non-invasive biomarkers are needed for the early and accurate establishment of LN. Among the promising candidates are long non-coding RNAs (lncRNAs). Their dysregulation appears to have predictive and diagnostic potential. Furthermore, these biomarkers like other conventional biomarkers give insight into the pathogenesis of LN. This review aims to summarize the available information on lncRNAs in SLE patients and to present their future opportunities to add to the conventional biomarkers in the diagnosis and monitoring of LN.
... Because we demonstrated an expansion in the autoantibody response in TM mice relative to their DM controls, the development of nephritis in these strains could be attributed to the quality or quantity of these autoantibodies. The higher titers of autoantibodies, particularly anti-DNA, in the two TM strains may well contribute to the disease, as these autoantibodies are known to associate with renal disease exacerbations in human SLE and to possibly cross-react with other renal targets (83)(84)(85). The quality of the IgG Abs was also different, particularly in C1q 2/2 TM mice [a greater deposition of IgG2c, the IgG subtype with potent effector functions for both complement fixation and engagement of the FcgR on myeloid cells (86,87)]. ...
Lupus nephritis (LN) is a major contributor to morbidity and mortality in lupus patients, but the mechanisms of kidney damage remain unclear. In this study, we introduce, to our knowledge, novel models of LN designed to resemble the polygenic nature of human lupus by embodying three key genetic alterations: the Sle1 interval leading to anti-chromatin autoantibodies; Mfge8−/−, leading to defective clearance of apoptotic cells; and either C1q−/− or C3−/−, leading to low complement levels. We report that proliferative glomerulonephritis arose only in the presence of all three abnormalities (i.e., in Sle1.Mfge8−/−C1q−/− and Sle1.Mfge8−/−C3−/− triple-mutant [TM] strains [C1q−/−TM and C3−/−TM, respectively]), with structural kidney changes resembling those in LN patients. Unexpectedly, both TM strains had significant increases in autoantibody titers, Ag spread, and IgG deposition in the kidneys. Despite the early complement component deficiencies, we observed assembly of the pathogenic terminal complement membrane attack complex in both TM strains. In C1q−/−TM mice, colocalization of MASP-2 and C3 in both the glomeruli and tubules indicated that the lectin pathway likely contributed to complement activation and tissue injury in this strain. Interestingly, enhanced thrombin activation in C3−/−TM mice and reduction of kidney injury following attenuation of thrombin generation by argatroban in a serum-transfer nephrotoxic model identified thrombin as a surrogate pathway for complement activation in C3-deficient mice. These novel mouse models of human lupus inform the requirements for nephritis and provide targets for intervention.
... SLE is a prototypic systemic autoimmune disease, characterized by a relapsing-remitting course. A patient with SLE has around a 20-30% chance of developing a flare, defined as an increase in disease activity, per year of follow-up [1]. Although several flares are mild, recurrent SLE flares may result in irreversible organ damage and increased healthcare costs [2]. ...
Objective:
Recent evidence suggests that some urinary biomarkers, namely Vascular Cell Adhesion Molecule-1 (VCAM-1), Intercellular Adhesion Molecule-1 (ICAM-1), Monocyte Chemoattractant Protein 1 (MCP-1), Neutrophil Gelatinase Associated Lipocalcin and Lipocalin-type Prostaglandin D-Synthetase (L-PGDS), might discriminate SLE patients with ongoing renal activity from those with stable disease. The objective of this study was to assess the role of these markers in predicting renal flares in comparison with conventional biomarkers and to derive a biomarker panel which may improve diagnostic accuracy.
Methods:
Eligible participants were SLE patients prospectively followed at our clinic. Urinary biomarker levels were measured in urinary sample by ELISA assay and were compared by the unpaired Student's t test or the Mann-Whitney U test as appropriate. Receiver operating characteristic analysis was used to calculate the area under the curve. Cox regression was used to identify independent factors associated with disease flares.
Results:
Urine was collected from 61 patients. During 8 months' follow-up, eight patients experienced a renal flare. Urinary L-PGDS, ICAM-1 and VCAM-1 levels were significantly increased in the patients who subsequently experienced a renal flare with respect to the remaining 53. At Cox regression analysis, L-PGDS, ICAM-1, VCAM-1, hypocomplementemia and anti-dsDNA antibodies were factors associated with renal flares. Based on receiver operating characteristic analysis, a combination of novel and conventional biomarkers demonstrated an excellent ability for accurately identifying a flare.
Conclusion:
This study might suggest the usefulness of a novel biomarker panel in predicting a renal flare in SLE.
... The rising ESR, low complement levels, and high titres of ds DNA were suggestive of ongoing active phase of the disease [8,9]. Typically during the neurologic episodes, the ESR and plasma viscosity are elevated while C-reactive protein levels tend to be normal. ...
Introduction:
Systemic lupus erythematosus is a connective tissue disorder, which causes complex multi organ involvement. Neurological and cardiac manifestations have been well noted but complications such as status epilepticus and acute myocarditis with heart failure at presentation remains uncommon.
Case description:
A 15-year-old, previously healthy, South Asian, Sri Lankan female presented with status epilepticus and the seizures only responded to intravenous midazolam and thiopentone sodium. On the fourth day, she developed tachycardia and shortness of breath and was found to have cardiomyopathy with heart failure with an ejection fraction 40%. Along with a positive urinary sediment, a positive ANA with a very high level of ds-DNA and low C3 and C4 levels confirmed our suspicion of systemic lupus erythematosus.
Discussion and evaluation:
Systemic lupus erythematosus presents in a variety of clinical presentations and the spectrum may range from unique to ubiquitous. Clinicians should have a high index of suspicion specially when encountering atypical presentations with multi-organ involvement, especially when patients tend to be young females. Status epilepticus and myocarditis are uncommon manifestations of systemic lupus erythematosus, and should be appreciated early, as if inappropriately managed would have a deleterious impact on mortality and morbidity.
... Quite a number of therapies may induce a reduction of anti-dsDNA levels and prospective studies usually utilize this parameter as a secondary or surrogate outcome [74][75][76][77]. The same has been reported for renal flares [78]. Here the debate is about the frequency of tests since monthly sampling seems critical for an accurate determination of the association with disease activity [48,79]. ...
Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical expression. It is a potentially devastating condition affecting mostly women and leading to clinically unpredictable outcomes. Remission and flares may, in fact, alternate over time and a mild involvement limited to few articular sites may be followed by severe and widespread organ damage. SLE is the prototype of any autoimmune condition and has, for this reason, attracted the interest of basic immunologists. Therapies have evolved over time and clinical prognosis has, in parallel, been improved. What clinicians still lack is the possibility to use biomarkers of the disease as predictors of outcome and, in this area, several studies are trying to find solutions. Circulating autoantibodies are clearly a milestone of clinical research and the concrete possibility is to integrate, in the future, classical markers of activation (like C3) with target organ autoantibodies. Anti-dsDNA antibodies represent a basic point in any predictive attempt in SLE and should be considered the benchmark for any innovative proposal in the wide field of target organ pathologies related to SLE. DNA is part of the nucleosome that is the basic unit of chromatin. It consists of DNA wrapped around a histone octamer made of 2 copies each of Histone 2A, 2B, 3, and 4. The nucleosome has a plastic organization that varies over time and has the potential to stimulate the formation of antibodies directed to the whole structure (anti-nucleosome) or its parts (anti-dsDNA and anti-Histones). Here, we present an updated review of the literature on antibodies directed to the nucleosome and the nucleosome constituents, i.e., DNA and Histones. Wetriedto merge the data first published more than twenty years ago with more recent results to create a balanced bridge between old dogma and more recent research that could serve as a stimulus to reconsider mechanisms for SLE. The formation of large networks would provide the chance of studying large cohorts of patients and confirm what already presented in small sample size during the last years.
... To further elucidate the predictive value of thrombomodulin in pSLE renal involvement, we used the ROC curve to analysis our biomarkers as well as anti-dsDNA, an autoantibody with great correlation with the presence of lupus nephritis [20,21]. We discovered that thrombomodulin at a level higher than 3333.6 pg/ml, out-performed all biomarkers including anti-dsDNA in predicting renal involvement. ...
Background/purpose:
Endothelium is a key element in the regulation of vascular homeostasis and its alteration can lead to the development of vascular diseases. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with potential extensive vascular lesions, involving skin vessels, renal glomeruli, cardiovascular system, brain, lung alveoli, gastrointestinal tract vessels and more. We aimed to assess endothelial dysregulation related biomarkers in pediatric-onset SLE (pSLE) patient serum and elucidate its correlation with their clinical features, laboratory parameters, and the overall disease activity.
Methods:
Disease activities were evaluated by SLE disease activity index (SLEDAI). Patient characteristics were obtained by retrospective chart review. Six biomarkers associated with endothelial dysregulation, including Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie2, Vascular endothelial growth factor (VEGF), thrombomodulin, and a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS13) were tested through enzyme-linked immunosorbent assay (ELISA) measurement.
Results:
This study comprised 118 pSLE patients. Data from 40 age-matched healthy controls were also obtained. The mean diagnostic age was 13 ± 4.12 years-old and 90.7% are females. Serum levels of VEGF, Tie2, thrombomodulin were significantly higher while serum ADAMTS13 was lower in active pSLE patients when compared to those with inactive diseases (all p < 0.05). In organ specific association, serum thrombomodulin level was higher in pSLE patient with renal involvement, and serum ADAMTS13 levels was negatively associated with neurological involvement (p < 0.05). A cutoff of thrombomodulin at 3333.6 pg/ml best correlated renal involvement. (AUC = 0.752, p < 0.01).
Conclusion:
Endothelial dysregulation associating proteins seems to be potent biomarkers for pSLE activity as well as organ involvement in pSLE patients. These biomarkers may be beneficial in understanding of the vascular pathogenesis and disease monitoring.
SLE (Systemic Lupus Erythematosus) is, a heterogeneous disease, with ,diverse clinical manifestation disorder characterized by hyperactivity of B and T cell, creation of auto, antibodies, and, deposition, of antibody- containing immune complexes in blood vessels, during body. This study aims to investigation some immunological markers related to patients with SLE. It includes the study of the level, of Interleukin, (IL.17), antinuclear antibody (ANA), anti dsDNA, antiphospholipid and, complement, C3, C4, In addition to study the complete blood picture including hemoglobin, red blood cell monocytes, white blood cells, platelets and lymphocytes, they belong to factors that may interfere with the disease. Current study included 110 patients with SLE, and 106 (96.36%) were female and 4 (3.64%) were male. Patients with an average age of 31.61 ± 8.60 years. This work also includes 70 blood specimens as control group. Our study illustrated that most infections were on Village 71.82 % compared with the City 28.18 , and patients without history disease 57.27 % while patients with history disease42.73%. The results also showed that the concentration of IL.17 was significantly higher than p ≤ 0.05 in serum patients with lupus erythematosus (469 ± 2.25 g / ml) comparison with healthy individuals (107.39 ± 0.41 pg / ml). ELISA was used to measure some types of autoantibodies, and showed an increase in ANA and dsDNA Ab levels in SLE patients compared with healthy individuals. The results also prone that the antiphospholipid is significantly increase (P ≤ 0.05) in patients with SLE compared to controls.Evaluating serum complement level C3, C4 in the total study, our results observed significant decrease (p ≤ 0.05) in serum of patients with SLE (0.62 ± 0.01,0.13 ± 0.01g/l) respectively, compared with controls ,(1.74 ± 0.01,0.28 ± 0.01g/l) respectively.The results of the study also showed a significant decrease in hemoglobin, red blood cell monocytes, white blood cells, platelets and the number of lymphocytes for SLE patients compared with healthy individuals.The relationship between antibodies to ANA and IL-17, antibodies to dsDNA and C3, C4 and lymphocytes was identified, as well as the relationship between APA, C3 and C4 antibodies. Inconclusion ,peoples with SLE have a positive ANA, High concentration of, ds DNA Ab and anti-phospholipid which plays an important role in pathogenesis and complement C3 and C4 in patients with SLE is decreased. An increased inflammatory concentration of interleukin (IL.17) can play a critical role in the pathogenesis of SLE which leads to disease progression.
Introduction
Immunoglobulin A (IgA) is the main antibody isotype in body fluids such as tears, intestinal mucous, colostrum, and saliva. There are two subtypes of IgA in humans: IgA1, mainly present in blood and mucosal sites, and IgA2, preferentially expressed in mucosal sites like the colon. In clinical practice, immunoglobulins are typically measured in venous or capillary blood; however, alternative samples, including saliva, are now being considered, given their non-invasive and easy collection nature. Several autoimmune diseases have been related to diverse abnormalities in oral mucosal immunity, such as rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus (SLE).
Methods
We decided to evaluate the levels of both IgA subtypes in the saliva of SLE patients. A light chain capture-based ELISA measured specific IgA1 and IgA2 levels in a cohort of SLE patients compared with age and gender-matched healthy volunteers.
Results
Surprisingly, our results indicated that in the saliva of SLE patients, total IgA and IgA1 subtype were significantly elevated; we also found that salivary IgA levels, particularly IgA2, positively correlate with anti-dsDNA IgG antibody titers. Strikingly, we also detected the presence of salivary anti-nucleosome IgA antibodies in SLE patients, a feature not previously reported elsewhere.
Conclusions
According to our results and upon necessary validation, IgA characterization in saliva could represent a potentially helpful tool in the clinical care of SLE patients with the advantage of being a more straightforward, faster, and safer method than manipulating blood samples.
To estimate the risk of systemic lupus erythematosus (SLE) flares based on the autoantibody positivity at the time of SLE diagnosis. This retrospective cohort study included 228 patients with newly diagnosed SLE. Clinical characteristics including autoantibody positivity at the time of diagnosis of SLE were reviewed. Flares were defined as a new British Isles Lupus Assessment Group (BILAG) A score or BILAG B score for at least one organ system. Multivariable Cox regression analyses were performed to estimate the risk of flares according to autoantibody positivity. Anti-dsDNA, anti-Sm, anti-U1RNP, anti-Ro, and anti-La antibodies (Abs) were positive in 50.0%, 30.7%, 42.5%, 54.8%, and 22.4% of the patients, respectively. The incidence rate of flares was 28.2/100 person-years. Multivariable Cox regression analysis, adjusted for potential confounders, revealed that anti-dsDNA Ab positivity (adjusted hazard ratio [HR]: 1.46, p = 0.037) and anti-Sm Ab positivity (adjusted HR: 1.81, p = 0.004) at the time of diagnosis of SLE were associated with higher risk of flares. To better delineate the flare risk, patients were categorized as double-negative, single-positive, double-positive for anti-dsDNA and anti-Sm Abs. Compared with double-negativity, double-positivity (adjusted HR: 3.34, p < 0.001) was associated with higher risk of flares, while anti-dsDNA Ab single-positivity (adjusted HR: 1.11, p = 0.620) or anti-Sm Ab single-positivity (adjusted HR: 1.32, p = 0.270) was not associated with higher risk of flares. Patients who are double-positive for anti-dsDNA and anti-Sm Abs at the time of the diagnosis of SLE are at higher risk of flares and may benefit from stringent monitoring and early preventive treatment.
Background:
SLE is a common connective tissue disease in Indians (mostly women) which is frequently underdiagnosed due to limited awareness and knowledge regarding the disease.
Methods:
This is a retrospective observational study conducted in a tertiary care hospital in Western India among patients of SLE attending outpatient Rheumatology Clinic and inpatient admissions of Topiwala Medical College and BYL Nair Charitable Hospital, Mumbai. Sixty patients were recruited based on inclusion and exclusion criteria.
Results:
In clinical profile, arthralgia was the most common manifestation seen in 53 patients (88.3%) followed by alopecia in 46 patients (76.7%). In systemic involvement, CNS lupus was the most common manifestation seen in 27 patients (45%) followed by renal involvement in 13 cases (21%). Pulmonary hypertension (PH) was another noticeable finding seen in 24 cases (40%) of which 18 (75%) had mild PH, 6 (25%) patients had severe PH. The mean SLEDAI score was 11.85 at baseline which reduced to 2.65 at 6 months and remained 3.65 at the end of 3 years of the study. In immunological profile, ANA was positive in all patients. Speckled pattern of ANA was the most common pattern seen in 34 patients (56.7%). A titre of above 1:100 was noted in 53 patients (88.3%). ds DNA was positive in 26 patients (43.3%). Anti Ro/La was positive in 3 patients (5%) and U1RNP in 2 patients (3.3%). Autoimmune hemolytic anemia (AIHA) was the most common autoimmune association seen in 25 patients (41.7%), antiphospholipid antibody(APLA) was seen in 15 patients (25%), 7 patients (11.6%) were anti TPO antibody positive, 3 patients (5%) were Ro/La positive while only 2 patients(3.3%) were U1RNP positive.
Conclusion:
Clinical profile and immunological patterns of SLE are diverse. A systematic work up is needed to identify the multisystem involvement and asking for specific antibody tests to identify common autoimmune associations is recommended.
Introduction:
The level of expression of the immunoregulatory human leukocyte antigen-G (HLA-G) has been suggested to play a role in the immunopathogenesis of systemic lupus erythematosus (SLE). A 14 bp insertion/deletion (ins/del) polymorphism in the 3'untranslated region of HLA-G gene may influence the level of expression. The role of Toll-like receptor 9 (TLR9) in the pathogenesis of SLE has been highlighted. Data among Egyptian patients are quite limited.
Purpose:
To detect the association of HLA-G 14 bp ins/del gene polymorphism with the susceptibility to SLE and to correlate TLR9 serum level with disease activity among Egyptian patients.
Patients and methods:
A case-control study that included 102 SLE female patients and 102 healthy matched volunteers as controls was carried out. Disease activity in patients was determined using the modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). HLA-G 14 bp ins/del genotype was detected by polymerase chain reaction (PCR). TLR9 serum level was estimated using enzyme-linked immunosorbent assay (ELISA) technique.
Results:
The ins/ins genotype was significantly increased among SLE patients compared to healthy subjects (58.8% vs 9.8%; odds ratio [OR] = 11.79, P < 0.001). The 14 bp ins allele was significantly more frequent in SLE patients than in healthy subjects (65.7% vs 27.9%, respectively) and significantly associated with an increased risk of SLE (OR 4.94, P < 0.001). The mean TLR9 serum level showed a significant increase in SLE patients compared to healthy subjects (397.04±137.86 vs 195.22±45.14 ng/L, p < 0.001) and was significantly associated with disease activity as well as to patients' HLA-G genotypes (p < 0.001).
Conclusion:
Among Egyptian population, HLA-G 14 bp ins/ins homozygous genotype and ins allele may constitute a potential risk for SLE susceptibility, while TLR9 serum level is significantly associated with disease activity.
Anti-double-stranded DNA (anti-dsDNA) autoantibodies are archetypal biomarkers found in systemic lupus erythematosus (SLE). Although they can exist in any isotype, very little is understood about the IgA isotype for which most of our knowledge is derived from observational studies. This review article summarises our knowledge of this autoantibody isotype to date. Attention will be spent on clinical associations as well as its potential links with lupus nephritis for which there is still some controversy. Further understanding of this serological parameter may facilitate diagnosis, prognosis and treatments of systemic lupus erythematosus patients.
Objectives
Systemic Lupus Erythematosus (SLE) is a serious autoimmune disease often resulting in major end-organ damage and increased mortality. Currently, no data exists focussing on the presentation, long-term management and progression of SLE in the Australian paediatric population. We conducted the first Australian longitudinal review of childhood SLE, focussing on response to treatment and outcomes.
Methods
Detailed clinical and laboratory data of 42 children diagnosed with SLE before 16 years from 1998 to 2018 resident in Western Australia was collected. Data was collected at diagnosis and key clinical review time points and compared using the Systemic Lupus Collaborating Clinics (SLICC) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) criteria. End organ damage was assessed against Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Incidence rates of disease complications and end organ damage were determined.
Results
Of the 42 children, 88% were female with average age at diagnosis of 12.5 years. Indigenous Australians were over represented with an incidence rate 18-fold higher than non-Indigenous, although most children were Caucasian, reflecting the demographics of the Australian population. Median duration of follow-up was 4.25 years. On final review, 28.6% had developed cumulative organ damage as described by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (incidence rate: 0.08/PY (95% CI 0.04–0.14)), and one child died. Twenty-nine children had renal involvement (incidence rate: 0.38/PY (95% CI 0.26–0.56)). Of the 27 patients with biopsy proven lupus nephritis, 70% had Class III or IV disease. Average length of prednisolone use from diagnosis was 32.5 months. Hydroxychloroquine ( n = 36) and mycophenolate mofetil ( n =21) were the most widely used steroid sparing agents. 61.9% received rituximab and/or cyclophosphamide.
Conclusion
This is the first longitudinal retrospective review of Australian children with SLE, with a markedly higher incidence in Indigenous children. Although improving, rates of end organ complications remain high, similar to international cohort outcomes. Longitudinal multi-centre research is crucial to elucidate risk factors for poor outcomes, and identifying those warranting early more aggressive therapy.
Background
We compared serum levels of S100A12, a proinflammatory protein predominantly secreted by neutrophils, in children with newly diagnosed childhood-onset systemic lupus erythematosus (cSLE), systemic juvenile arthritis (sJIA), and systemic undefined recurrent fevers (SURFS) to examine its role as a diagnostic and discriminative marker of inflammation and to indirectly point out the importance of neutrophils and innate immunity in the pathogenesis of these diseases.Materials and methodsIn a cross-sectional study, the serum levels of S100A12 protein of 68 children (19 with cSLE, 18 with sJIA, 7 with SURFS, and 24 controls) were determined by enzyme-linked immunosorbent assay and compared between groups and with clinical and laboratory findings.ResultsThe median serum S100A12 levels were 469 ng/mL in the cSLE group, 6103 ng/mL in the sJIA group, 480 ng/mL in the SURFS group, and 44 ng/mL in the control group. Children with cSLE, sJIA, and SURFS had significantly higher serum S100A12 levels compared to the control group (p < 0.0001). sJIA patients had the highest levels of S100A12 in comparison to other patients (p < 0.0001), while there was no significant difference between children with cSLE and SURFS.Conclusion
Elevated serum SA100A12 levels in children with cSLE, sJIA, and SURFS may indicate intense neutrophil activation, which may play an important role in innate immunity in chronic inflammation in these diseases. Serum S100A12 levels could be used as a diagnostic marker of inflammation and be suitable for distinguishing sJIA and other disorders.
Objective
Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk.
Approach and Results
Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms.
Conclusions
Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the formation of antigen–antibody complexes which trigger an immune response. We investigate certain autoantibodies including nucleosome, double-stranded DNA (dsDNA), Smith, ribonucleoprotein, and Sjögren’s syndrome-related antigens, and examine their associations with disease activity, damage accrual, and SLE-related clinical and serological manifestations in patients with SLE. We conducted a cross-sectional study with a total 293 patients (90.4% female, mean age 46.87±12.94 years) and used the Systemic Lupus Erythematosus Disease Activity Index 2000 and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) to evaluate disease activity and disease-related damage, respectively. Systemic Lupus Erythematosus Disease Activity Index scores were significantly higher in anti-nucleosome-positive (3.87±2.72 vs 2.52±2.76, p=0.004) and anti-dsDNA-positive (3.08±2.91 vs 2.04±2.48, p=0.010) patients compared with patients without these antibodies. SDI scores were also significantly higher in anti-nucleosome-positive patients (1.61±1.99 vs 0.89±1.06, p=0.004). The presence of antinucleosome (p=0.019) and anti-dsDNA antibodies (p=0.001) both correlated significantly with the incidence of nephritis; anti-La antibodies were associated with arthritis (p=0.022), and we also observed a relationship between the presence of antinucleosome antibodies and leukopenia (p=0.011). Patients with antinucleosome or anti-dsDNA antibodies had a higher disease activity and were likely to have nephritis. Antinucleosome was also associated with more damage accrual. A greater understanding of these autoantibodies could lead to the development of new approaches to more accurate assessments of SLE.
Despite the expansion of available in-vitro laboratory tests at a rate far exceeding that of dermatological pharmaceuticals, the existing literature is dominated by discussion of the latter. With the advent of numerous new tests, it can be difficult for practicing dermatologists to stay up to date on the available options, methodologies, and recommendations for when to order one test over another. Understanding inherent strengths and weaknesses of these options is necessary to inform appropriate ordering and proper interpretation of results. The first article in this continuing medical education series summarizes information on methodology, test characteristics, and limitations of several in-vitro laboratory tests used for the workup of undifferentiated patients suspected of having dermatologic autoimmune diseases and provides a general guide to ordering these tests.
Objectives
To evaluate a potential role of albumin-to-globulin ratio (AGR) in the development of lupus nephritis (LN) and determine the potential to use AGR as a marker for future LN in systemic lupus erythematosus (SLE) patients.
Methods
194 newly diagnosed SLE patients without renal impairment were followed. The clinical data were collected and analyzed at the time of initial diagnosis of SLE and the end of follow-up. We compared baseline characteristics between those who did or did not develop LN on follow-up. Univariate and multivariate Cox hazard analysis were used to identify predictors of lupus nephritis.
Results
Among the 194 newly diagnosed SLE patients without renal impairment, 26 (13.40%) patients were diagnosed with LN during a median follow-up of 53.87 months. On univariate Cox analysis, patients with the history of alopecia, higher SBP, lower AGR, lower CRP, lower C3, lower C4, higher anti-dsDNA Ab, presence of ANA homogeneous patterns or higher SLEDAI had an increased probability of developing LN. In a multivariate model, the history of alopecia (adjust hazard ratio, aHR = 3.614, 95%CI 1.365-9.571 P = 0.010), lower AGR (aHR = 6.968, 95%CI 1.873-25.919, P = 0.004), lower CRP (aHR = 4.230, 95%CI 1.591-11.247, P = 0.004) and higher level of anti-dsDNA (aHR = 2.675, 95%CI 1.008-7.093, P = 0.048) were independently associated with an increased risk of developing LN after adjusting for covariates.
Conclusion
Our findings indicated that SLE patients with low AGR, low CRP, high anti-dsDNA and the history of alopecia were more likely to develop LN in the course of SLE. AGR shown the greatest hazard for developing LN among them, it may be a strong predictor.
Background/objectives:
Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis (LN). The purpose of this study was to assess the effect of mycophenolate mofetil (MMF) on the timing of urine protein-to-creatinine ratio reaching 200 mg or less after starting MMF as initial therapy for class III, IV, or V in immunosuppressant-naive patients with LN.
Methods:
Patients who had a diagnosis of biopsy-proven LN were included in this cohort study. The initial dose of MMF was 1000 mg twice daily. If no improvement, it was increased to 1500 mg twice daily after 1 month. For statistical analysis, exact binomial distribution 95% confidence intervals were calculated.
Results:
Nine patients were identified. There were 3 patients with class III, 3 with class IV, 1 with class III to V, 1 with class II to V, and 1 with class V lupus nephritis. The majority were African Americans (70%). At baseline, proteinuria ranged between 0.41 and 4 g, and 88% had normal estimated glomerular filtration rate. Forty-four percent of patients reached 0.28 g of proteinuria within 8 weeks of starting MMF (95% confidence interval, 14%-79%), all of which maintained the same level of response and normal estimated glomerular filtration rate at 12 months. Thirty-three percent of patients achieved the American College of Rheumatology complete response at 8 weeks.
Conclusions:
This study demonstrates that only a minority of immunosuppressant-naive LN patients achieved the American College of Rheumatology complete response at 8 weeks after initiation of MMF. A rapid decline in the proteinuria to 0.28 g within the first 8 weeks of the treatment correlated strongly with achieving the same level of response at 12 months.
Background
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies and systemic inflammatory response. We aimed to characterize the salivary protein components and find biomarkers in patients with SLE.
Methods
The pooled salivary proteins of patients with SLE and healthy controls were subjected to 2-dimensional gel electrophoresis. The spots exhibiting > 2-fold intensity change between SLE and healthy controls were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis.
Results
The proteomic analysis using 2-dimensional gel electrophoresis and mass spectrometry revealed 10 differentially expressed protein spots, which included immunoglobulin gamma-3 chain C region (IGHG3), immunoglobulin alpha-1 chain C region (IGHA1), protein S100, lactoferrin, leukemia-associated protein 7, and 8-oxoguanine deoxyribonucleic acid glycosylase. The patients with SLE exhibited enhanced salivary IGHG3 (3.9 ± 2.15 pg/mL) and lactoferrin (4.7 ± 1.8 pg/mL) levels than patients with rheumatoid arthritis (1.8 ± 1.01 pg/mL and 3.2 ± 1.6 pg/mL, respectively, p < 0.001 for both) or healthy controls (2.2 ± 1.64 pg/mL and 2.2 ± 1.7 pg/mL, respectively, p < 0.001 for both). The salivary IGHG3 levels correlated with erythrocyte sedimentation rate (r = 0.26, p = 0.01), anti-double-strand deoxyribonucleic acid antibody levels (r = 0.25, p = 0.01), and nephritis (r = 0.28, p = 0.01).
Conclusions
Patients with SLE exhibited elevated salivary IGHG3 and lactoferrin levels, and the salivary IGHG3 levels correlated with disease activity markers of SLE. Salivary IGHG3 may be a promising non-invasive biomarker in SLE.
Background
Wire-loop lesion (WL) is one of the active lesions of lupus nephritis (LN). However, few reports have focused on the clinicopathological relationships of WL to serological immune abnormality and renal prognosis.
Methods
We enrolled 126 Japanese LN patients subjected to renal biopsy in 11 hospitals from 2000 to 2018. In patients with class III or IV of the International Society of Nephrology/Renal Pathology Society classification, we retrospectively compared clinicopathological findings between those with WL (WL+ group) and without WL (WL– group) to detect factors associated with WL. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate of <60 mL/min/1.73m ² for more than three months. We also compared these findings between those with CKD (CKD+ group) and without CKD (CKD– group) at the last visit to investigate factors associated with renal prognosis.
Results
Of 126 patients, 100 (79.4%) were classified as class III or IV. WL was found in 36 (36.0%) of them. Although the renal function did not differ, the WL+ group had a higher titre of serum anti-dsDNA antibodies and lower serum complement 3 levels than the WL– group. Linear regression analysis revealed a significant association only between anti-dsDNA antibodies and WL (β = 0.27, 95% confidence interval (CI) 0.001–0.100, p = 0.01). Of these patients, 69 were tracked for 59.6 ± 55.1 months. Kaplan–Meier analysis showed no difference in renal prognosis between these groups. Next, the CKD+ group included 15 (22.1%) patients. They were older and had higher frequencies of hypertension and hyperuricaemia, serum creatinine (Cr) level, glomerulosclerosis, interstitial inflammation, interstitial fibrosis and tubular atrophy than the CKD– group at the time of renal biopsy. The frequency of WL was not significantly different. Cox regression analysis revealed significant associations of CKD with hypertension, hyperuricaemia, serum Cr level at the time of renal biopsy clinically and with tubular atrophy histologically.
Conclusions
WL was associated with serum anti-dsDNA antibodies but not with renal prognosis, suggesting that WL reflects immune abnormality but is not an independent factor predictive of renal prognosis in LN.
Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide.Background Long-term intravenous cyclophosphamide (IVC) in combination with corticosteroids is standard therapy for proliferative lupus nephritis, but it has limitations. There are few data on long-term remission rates, predictors of relapse, and the ability to achieve a second remission with currently recommended IVC regimens.
Significant differences in both specificity and avidity of anti-DNA antibodies were observed in the sera of groups of patients with active systemic lupus erythematosus glomerulonephritis, active systemic lupus erythematosus without nephritis, and in IgG eluates obtained by DNAase digestion of isolated glomeruli from glomerulonephritic kidneys. With methylated albumin-kieselguhr fractionated 3H-HeLa DNA as a source of native or single-strand DNA antigen in a modified Farr assay, an increased level of antibody to native DNA was associated with active systemic lupus erythematosus, particularly active nephritis. The avidity of antinative DNA estimated from plots of the reciprocals of bound and free antigen according to the Sips distribution formula was significanly lower in active glomerulonephritis sera than in sera from patients with active systemic lupus erythematosus without nephritis. However, antinative DNA of uniformly high avidity was found in the glomerular eluates. Avidity of single-strand DNA antibodies did not differ in the various patient groups. The data stronly supprot a major role for high avidity antinative-DNA in DNA/antiDNA immune complex-induced glomerular injury in systemic lupus erythematosus.
Antibodies to DNA are quite specific for systemic lupus erythematosus (SLE) and occur in the majority of SLE patients. Therefore, their detection is an important diagnostic aid to the clinician. Detection of anti-dsDNA may precede the diagnosis of SLE by more than a year. Fluctuations in the level of anti-dsDNA in an individual patient may give important information on the clinical status of the patient. Four of the most important methods developed for the measurement of anti-dsDNA antibodies will be discussed in this paper: the Farr assay, the PEG assay, the indirect immunofluorescence test on Crithidia luciliae and the ELISA. They will also be compared with one commercially available (Farr) assay, the Amersham anti-dsDNA kit. Each method, detects a part of the spectrum of anti-dsDNA antibodies produced by a patient. The Farr assay is the most specific for SLE; however, milder forms of the disease in which patients have only low avidity anti-dsDNA may easily be missed by this technique. Clinically, high avidity anti-dsDNA is related more frequently to the occurrence of nephritis, whereas low avidity anti-dsDNA antibodies are found more often in patients with central nervous system involvement. Traditionally, SLE is considered an immune-complex disease, in which inflammatory processes are initiated by local deposition of DNA/anti-dsDNA complexes. More recently, a major role was thought to be played by crossreactions of anti-dsDNA with tissue constituents. Our current view, however, is that such a crossreactivity plays only a minor role; we postulate that binding to glomerular constituents is caused by anti-dsDNA antibodies complexed with DNA and histones.
The course of systemic lupus erythematosus (SLE) is characterized by exacerbations (or flares) and remissions of disease activity. As part of an ongoing prospective cohort study, 3 disease activity indices, the physician's global assessment, the Lupus Activity Index, and the University of Toronto SLE Disease Activity Index, have been recorded, at least quarterly since 1987, on 185 SLE patients. We developed a definition of SLE flare and a description of its clinical epidemiology. Disease flare was defined as a change of greater than or equal to 1.0 in the physician's global assessment of disease activity (measured on a 0-3 scale) from the previous visit or from a visit within the last 93 days. Of the 185 patients, 98 (53%) had greater than or equal to 1 flare; the total number of flares was 146. The incidence of flare was 0.65 per patient-year of followup. The median time from the first study visit to a flare was 12 months. Flares were frequently characterized by constitutional symptoms, musculoskeletal involvement, cutaneous involvement, and decreasing levels of C3 and C4. At the time of flare, the mean University of Toronto SLE Disease Activity Index score increased by 3.0 and the mean Lupus Activity Index score (modified to omit the physician's global assessment) increased by 0.26. Overall, 44.8% of the flares prompted a change in treatment. Patients who experienced flares fulfilled more of the SLE criteria at entry and had been followed up for a longer duration after entry into the study, compared with those who did not have flares.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies were eluted from the isolated glomeruli prepared from the kidneys of 10 patients with the nephritis of systemic lupus erythematosus. Antibodies reacting primarily with buffer extracts of nuclei were eluted by acid treatment, and antibodies reacting mainly with DNA and nucleoprotein were eluted with deoxyribonuclease. Quantitative immunochemical studies revealed a high concentration of antinuclear antibody per milligram of γ-globulin in glomerular eluates compared with that in the corresponding serums. The γ-globulin of two eluates was found to consist predominantly of antinucleoprotein antibody. The selective elution of antinuclear antibodies was also indicated by the absence of other serum antibodies in the eluates.
DNA antigen was demonstrated in the glomeruli of two kidneys with nephritis by means of isolated anti-DNA antibody labeled with fluorescein. In one of these cases, anti-DNA antibodies were also found concentrated in the glomeruli and, in the second, circulating anti-DNA antibodies were demonstrated in the patient's serum.
The immunochemical evidence for the high specific activity of antinuclear antibodies and the association of DNA antigen with DNA antibody in glomeruli add further support for the antigen-antibody complex hypothesis for renal injury in systemic lupus erythematosus.
We used an ELISA employing extracts of human glomerular basement membrane (GBM) to detect, characterize, and evaluate the clinical significance of glomerular-binding IgG in patients with SLE nephritis. Most patients with SLE nephritis exhibited GBM-binding IgG, although many patients with active nonrenal SLE or symptomatic, drug-induced lupus had similar reactivity, albeit at lower levels. IgG binding to GBM in SLE nephritis patients was decreased by DNase pretreatment of GBM, restored after DNase with nuclear antigens (most notably with nucleosomes), inhibited by exogenous nuclear antigens (particularly nucleosomes), but unaffected by exposure of serum to DNase/high ionic strength. The characteristics of IgG binding to GBM largely paralleled the patients' underlying autoimmune response, which was dominated either by antibodies to DNA/nucleosomes or to nucleosomes alone. Binding of lupus sera to nonrenal extracellular matrix (even with nucleosomes) was not equivalent to GBM. Collagenase pretreatment of GBM variably decreased IgG binding, depending on the level and type of binding. SLE nephritis patients with high levels of GBM-binding IgG exhibited more severe disease clinically, but the same renal histopathology, as patients with lower levels. The level of GBM-binding IgG at presentation did not predict the therapeutic response, but decreased in responders to therapy. In sum, glomerular-binding IgG in lupus nephritis binds to epitopes on chromatin, which adheres to GBM in part via collagen. These autoantibodies appear necessary, but not sufficient, for the development of nephritis, and correlate with clinical rather than histopathologic parameters of disease activity.
This chapter focuses on the clinical application of selected serologic abnormalities in establishing the diagnosis, in assessing disease activity, and predicting specific organ system involvement and overall prognosis. Serum immunoglobulins and other serum protein changes are reviewed. Serologic and other important laboratory tests that are available in most clinical laboratories as well as promising tests are discussed.
Objective
To determine the degree to which changes in anti–double‐stranded DNA (anti‐dsDNA), as determined by Crithidia and enzyme‐linked immunosorbent assays (ELISAs), precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 clinical indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M‐SLEDAI), modified Lupus Activity Index (M‐LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M‐BILAG).
Methods
Disease activity and anti‐dsDNA were measured monthly in 53 SLE patients who were followed up for 1 year. Lupus flare was defined as an increase in PGA of ≥1.0, M‐SLEDAI ≥3, M‐LAI ≥0.1, SLAM ≥3, and M‐BILAG ≥4 within a 1‐month period. Flare rates were calculated for groups, which were defined by “previous” (1 month prior to the flare) or “concurrent” (at the time of the flare) changes in anti‐dsDNA. Logistic regression models were used to determine the significance of the association between recent changes in anti‐dsDNA and flare, controlling for the prednisone dosage.
Results
Flares occurred at 12% of visits, based on the PGA measure of disease activity. Using the other indices, flare rates were 19% (M‐SLEDAI), 25% (M‐LAI), 13% (SLAM), and 12% (M‐BILAG). A concurrent decrease in anti‐dsDNA (ELISA) was associated with significantly higher flare rates based on PGA (18 of 84, 21%; P = 0.0014), M‐SLEDAI (27 of 89, 30%; P = 0.0019), M‐LAI (37 of 89, 42%; P = 0.0001), and M‐BILAG (19 of 89, 21%; P = 0.0264) scores. Flare rates were also significantly higher after a previous increase in anti‐dsDNA (ELISA) based on M‐SLEDAI (26 of 93, 30%; P = 0.0022) and M‐LAI (34 of 93, 37%; P = 0.0117) scores. Flare rates tended to be lowest when there was a concurrent increase in anti‐dsDNA (ELISA). Analysis of specific organ systems showed that a concurrent decrease in anti‐dsDNA (ELISA) was significantly associated with increases in renal disease activity. Similar results were obtained using the Crithidia assay.
Conclusion
A previous increase in anti‐dsDNA levels occurred before SLE flares, as measured by the M‐SLEDAI and M‐LAI only. However, during lupus flares, including the subset of renal flares, anti‐dsDNA levels frequently decreased. We hypothesize that this decrease in anti‐dsDNA represents deposition in tissue at the time of flare.
This monograph contains many ideas on the analysis of survival data to present a comprehensive account of the field. The value of survival analysis is not confined to medical statistics, where the benefit of the analysis of data on such factors as life expectancy and duration of periods of freedom from symptoms of a disease as related to a treatment applied individual histories and so on, is obvious. The techniques also find important applications in industrial life testing and a range of subjects from physics to econometrics. In the eleven chapters of the book the methods and applications of are discussed and illustrated by examples.
Background: Systemic lupus erythematosus (SLE) is characterised by the presence of antibodies to double stranded DNA (dsDNA), which are involved in the pathogenesis of SLE. Previous studies showed that at least two thirds of patients develop a clinical relapse within six months after a significant rise in the anti-dsDNA level, and most relapses were prevented by the administration of corticosteroids at the time of the rise. Objective: To determine whether mofetil mycophenolate (MMF) can prevent a clinical relapse without the side effects associated with corticosteroids. Methods: 36 patients with SLE were examined monthly to determine whether a rise in anti-dsDNA level had occurred. A rise was defined as an increase of 25% of the level of the previous sample of at least 15 IU/ml within a four month period. After a rise patients were treated with MMF 2000 mg daily for six months. Patients were monitored monthly for the occurrence of a clinical relapse and to assess the serological activity and state of activation of CD4+, CD8+, and CD19+ lymphocyte subsets. Results: Anti-dsDNA rose in 10 patients. Treatment with MMF was started in all these patients, and after six months no clinical relapse had occurred. Side effects were minimal. Antibodies to dsDNA decreased during the treatment (p<0.001), associated with a decrease in the state of activation of CD19+ lymphocytes. No changes were found in the state of activation of CD4+ or CD8+ lymphocyte subsets. Conclusion: Administration of MMF after a rise in antibodies to dsDNA is well tolerated, decreases anti-dsDNA and B cell activation, and seems to prevent the occurrence of a clinical relapse in patients with SLE.
Objective. To establish the correlation between lupus nephritis-associated autoantibody levels and the presence activity of lupus nephritis and global disease activity using cross-sectional data in patients with systemic lupus erythematosus (SLE). Methods. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index. Antibody levels against single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), histones, nucleosomes and heparan sulphate (HS) were analysed by ELISA in SLE patients with (n = 11) and without (n = 22) nephritis and in normal controls (n = 21). Antibody subclasses were also analysed. Results. Higher levels of anti-dsDNA and anti-HS antibodies were found in patients with lupus nephritis, the level of anti-HS antibodies correlating with the BILAG renal score. Predominant subclasses were IgGI and IgG3 for dsDNA antibodies, IgG2 for anti-nucleosome antibodies, and IgG2 and IgG3 for anti-HS antibodies. Conclusion. Correlation was demonstrated between antibodies to dsDNA, ssDNA, histones, nucleosomes and HS. There is a strong correlation between the level of anti-HS antibodies and disease activity in patients with lupus nephritis as measured by BILAG.
Introduction. Survival distributions. Single sample nonparametric methods. Dependence on explanatory variables. Model formulation. The multiplicative log-linear hazards model. Partial likelihood. Several types of failure. Further problems. Exercises. Bibliography. Index.
To evaluate the predictive power of changes in levels of antibodies to double-stranded DNA (anti-dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6–35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti-dsDNA antibody (by the Crithidia luciliae assay, an enzymelinked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty-seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti-dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty-four of these exacerbations were preceded by a significant increase in anti-dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti-dsDNA antibody levels preceded the exacerbation by 8–10 weeks. Significant increases in anti-dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti-dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P < 0.03). Serial assessment of anti-dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.
In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine ≤1.4 mg/dL [≤123 μmol/L] and proteinuria ≤330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0.0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.
We retrospectively analyzed the courses of 70 patients with lupus nephritis followed for 5 to 30 years (median 127 months). Patients survival was 100% at 10 years and 86% at 20 years. The probability of not reaching the end point (persistent doubling of plasma creatinine) was 85% at 10 years and 72% at 20 years. A multivariate analysis of variables at presentation showed that male sex (P = 0.005) and hematocrit lower than 36% (P = 0.01) were associated with the end point (relative risk 7.5 and 14). We then analyzed for the role of renal flare-ups, defined either as a rapid increase in plasma creatinine or by an increase in proteinuria. Patients with renal flares of any type had more probabilities of reaching the end point than patients who never had flares (P = 0.03; relative risk 6.8). The hazard of the end point was 27 times higher in patients with flares along with rapid increased in plasma creatinine than in patients without flares or with flares with proteinuria alone (P < 0.00001). This hazard was higher when plasma creatinine did not return to the basal levels within two months after treatment (P < 0.00001).
Antibodies to dsDNA, tested with circular DNA in the Farr assay, are specific for systemic lupus erythematosus. A longitudinal study showed a clear relation between the clinical state, the anti-dsDNA titer (expressed in units), and the C1q and C3 levels: when anti-dsDNA levels remained high, no exacerbations were observed. A sharp drop in anti-dsDNA, usually preceded by a rise, was related to a serious exacerbation. Only during the exacerbation when both C1q and C3 were very low was renal involvement seen.
Eighteen patients with systemic lupus erythematosus (SLE) and proliferative glomerulonephritis, underwent serial serum determinations of C3, C4, and native DNA binding capacity, as well as repeat renal biopsy 7 to 48 months (median 25 months) following initial biopsy. Highly significant correlations were found between serum C3 levels and renal histologic changes (P less than 0.0001), and between serum C3 levels and DNA binding capacity (P less than 0.03). Histologic deterioration correlated with depressed C3 levels, while improvement was associated with normalization of C3 levels. No correlation between renal histologic changes and either serum C4 levels or DNA binding capacity was found. The data suggest that the serum level of C3 is the best index of activity of lupus nephritis.
It has been suggested that crossreactivity of anti-DNA antibodies plays a central role in the development of lupus nephritis. Experiments with monoclonal anti-DNA antibodies initially seemed to sustain this intriguing hypothesis but such studies may easily lead to incorrect conclusions. In this short article, Kees Brinkman and colleagues discuss the validity of these studies and challenge the role of crossreactivity in the pathogenesis of lupus nephritis.
To distinguish the properties of anti-DNA antibodies in patients with lupus from those in normal individuals, we compared the ligand binding, idiotypic and charge properties of serum anti-DNA antibodies derived from: patients with active lupus; normal individuals; and among Ig eluted from the kidneys of two patients with active lupus nephritis (one with mesangial proliferation and the other with membranous nephropathy). The kidney eluate anti-DNA antibodies were the most cross-reactive; they cross-reacted with ssDNA, poly(GdC), poly(dT), poly(dG), poly(dC), ZDNA, SmRNP and the phospholipids cardiolipin and phosphatidyl serine. Lupus serum anti-DNA antibody cross-reacted with polynucleotides but not with phospholipids, whereas anti-DNA antibodies derived from normal serum reacted only with poly(dT). An anti-idiotype (anti-IdD; produced against serum anti-DNA antibodies from one patient) reacted with: anti-DNA antibodies in 8/9 lupus sera; antibodies in both kidney eluates; and anti-DNA antibodies from 5/7 normal sera. Anti-IdD did not react with Ig that did not bind to DNA. Isoelectric focusing of Ig showed that the charge of anti-DNA antibodies from lupus serum and normal serum were similar and unrestricted (pI 5.4-9.0); Ig in kidney eluates varied: membranous lupus pI 4.5-8.6; mesangial lupus pI 8.1-9.1. We conclude that idiotypically related anti-DNA antibodies in tissue lesions, lupus serum and normal serum from different individuals can be distinguished on the basis of their cross-reactive antigen-binding properties. Furthermore the cross-reactive properties of lupus auto-antibodies may influence their capacity to form glomerular immune deposits.
To evaluate the predictive power of changes in levels of antibodies to double-stranded DNA (anti-dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6-35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti-dsDNA antibody (by the Crithidia luciliae assay, an enzyme-linked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty-seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti-dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty-four of these exacerbations were preceded by a significant increase in anti-dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti-dsDNA antibody levels preceded the exacerbation by 8-10 weeks. Significant increases in anti-dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti-dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P less than 0.03). Serial assessment of anti-dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.
In a prospective study of 143 patients with systemic lupus erythematosus (SLE) the relation between clinical exacerbations, anti-dsDNA levels, and serum levels of complement components, C1q, C4, C3, C5, and C9 was investigated. In 33 out of these 143 patients a major clinical exacerbation of the disease developed. Evaluation of anti-dsDNA levels in relation to disease activity confirmed our earlier finding that anti-dsDNA levels rose before a major exacerbation and decreased after it. In the remaining 110 SLE patients a nearly constant anti-dsDNA level was seen, but none of these patients experienced a major exacerbation. In the 21 SLE patients who developed deterioration in renal function a decrease of C4 followed by decreases of C1q and C3 levels was seen first, starting about 25 to 20 weeks before the first signs of renal involvement. In the 12 SLE patients who developed an exacerbation without renal involvement an inconsistent profile of the complement components C4, C1q, and C3 was observed. C5 levels were hardly affected at all, while C9 levels were in general higher than normal during the exacerbation, irrespective of the type of exacerbation. These results show that, by following the complement and anti-dsDNA profiles, not only can exacerbations be predicted but also a pointer can be obtained about the pattern of disease well before the first clinical signs of an exacerbation appear.
Relative complement-fixing activity of antibodies to nuclear antigens, including DNA, were determined in serums of 15 patients
with, and 65 patients without, active lupus nephritis, by comparing titers obtained in two methods. High complement-fixing
activity of antibody was found in the nephritis group and low activity in the others. Results with immunoglobulin G fractions
were similar.
To clarify the association between certain immunologic factors and clinical activity in patients with systemic lupus erythematosus, 96 patients were studied. Those with antibodies to deoxyribonucleic acid (DNA) or heat-denatured DNA, or with serum complement levels of less than 50 C′H50 units per ml, were more likely to have renal involvement. Very low complement levels and high titers of complement-fixing antibodies to DNA were always associated with active disease, especially active renal disease, whereas the absence of these abnormalities usually indicated inactive renal disease. A 50 per cent fall in serum complement levels in 22 patients was accompanied by, or preceded the onset of, active nephritis in 19 patients. These serologic factors may thus reflect the in vivo formation of immune complexes that cause nephritis. Serial immunochemical observations may be useful in the management of patients with systemic lupus erythematosus.
The sensitivity and specificity of the presence of antibodies to native DNA and low serum C3 levels were investigated in a prospective study in 98 patients with systemic lupus erythematosus who were followed for a mean of 38.4 months. Hospitalized patients, patients with other connective tissue diseases, and subjects without any disease served as the control group. Seventy-two percent of the patients with systemic lupus erythematosus had a high DNA-binding value (more than 33 percent) initially, and an additional 20 percent had a high DNA-binding value later in the course of the illness. Similarly, C3 levels were low (less than 81 mg/100 ml) in 38 percent of the patients with systemic lupus erythematosus initially and in 66 percent of the patients at any time during the study. High DNA-binding and low C3 levels each showed extremely high predictive value (94 percent) for the diagnosis of systemic lupus erythematosus when applied in a patient population in which that diagnosis was considered. The presence of both abnormalities was 100 percent correct in predicting the diagnosis os systemic lupus erythematosus. Both tests should be included in future criteria for the diagnosis and classification of systemic lupus erythematosus.
The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification. The 1982 revised criteria include fluorescence antinuclear antibody and antibody to native DNA and Sm antigen. Some criteria involving the same organ systems were aggregated into single criteria. Raynaud's phenomenon and alopecia were not included in the 1982 revised criteria because of low sensitivity and specificity. The new criteria were 96% sensitive and 96% specific when tested with SLE and control patient data gathered from 18 participating clinics. When compared with the 1971 criteria, the 1982 revised criteria showed gains in sensitivity and specificity.
Many relapses of systemic lupus erythematosus (SLE) are preceded by a rise in antibodies against double-stranded DNA (anti-dsDNA). We investigated whether these relapses can be prevented by giving prednisone when a rise in anti-dsDNA occurs. 156 patients with SLE were studied. Anti-dsDNA was measured by Farr assay monthly. When a rise in anti-dsDNA was found, patients were randomly assigned either conventional treatment or 30 mg prednisone added to the current daily dose and tapering off to baseline over 18 weeks. A rise in anti-dsDNA was detected in 46 patients (24 assigned conventional treatment and 22 prednisolone). The relapse rate was higher in the conventional group than in the prednisolone group (20 vs 2, p < 0.001). Although rises in anti-dsDNA in the prednisone group were treated with additional prednisone, the cumulative oral doses of prednisone in the two groups did not differ significantly (p = 0.025). 7 major relapses requiring additional cytotoxic immunosuppressive treatment occurred in the conventional group versus 2 in the prednisone group. Treatment with prednisone as soon as a significant rise in anti-dsDNA occurs prevents relapse in most cases, without increasing the cumulative dose of prednisdone given.
Two types of oligonucleotides were synthesized with linker groups attached at the 5'-end. Both were repeating dimers of deoxyribocytidine and deoxyriboadenosine. A 20-mer was prepared with a thiol-containing linker, masked as a disulfide, and a 50-mer was prepared with a vicinal diol-containing linker. A tetraiodoacetylated poly(ethylene glycol) (PEG) derivative was synthesized and reacted with the thiol-containing 20-mer to provide an oligonucleotide PEG conjugate of precisely four oligonucleotides on each PEG carrier. The vicinal diol on the 50-mer was oxidized to an aldehyde and conjugated to keyhole limpet hemocyanin (KLH) to provide an oligonucleotide-KLH conjugate by reductive alkylation. The conjugates were annealed with complementary (TG)n strands. While the double-stranded oligonucleotide-KLH conjugate is an immunogen, eliciting the synthesis of antibodies against oligonucleotides, the PEG conjugate has the biological property of specifically suppressing (tolerizing) B cells which make antibodies against the immunizing oligonucleotide.
To evaluate whether changes in laboratory test values are either simultaneous with or precede disease exacerbations in patients with systemic lupus erythematosus (SLE).
At 9, 6, and 3 months preceding a flare in disease activity (defined as a rise of > or = 6 points in the modified SLE Disease Activity Index), laboratory tests were performed to measure patients' hematocrit levels, white blood cell, lymphocyte, and platelet counts, erythrocyte sedimentation rate, C1q binding, DNA binding, and levels of C3 and C4. Flares were classified as either present or absent, and were divided into renal, vasculitic, central nervous system, skin, serosal, and musculoskeletal subgroups. The predictive patterns were 1) the simultaneous change in the test value from the mean of 9, 6, and 3 months preceding a flare to the time of the flare; 2) the gradual change, following a linear time trend, in test results for the same time points; and 3) the change from the mean of 9 and 6 months to 3 months preceding a flare, as a measure of predictive ability. These analyses used repeated-measures analysis of variance models. Multiple linear regression was used to study the cross-sectional association of average-over-time differences in test results with patients' flare subgroup.
Among 202 patients with SLE (median followup 86.5 months), 83 flares occurred in 53 patients. Of 189 statistical contrasts performed, only 14 were significant (versus 10 expected), and the differences were of minor importance. Nonetheless, evaluation of all test results over each patient's observed disease course revealed significant differences between selected test values in association with specific types of flare.
Fluctuations in laboratory test values are poor predictors of disease exacerbations in SLE. Cross-sectional evaluation of some test results revealed differences at the time of flare for those patients who were destined to have different types of flares, because these values differed over the entire study period. This pattern explains the frequent cross-sectional association of disease activity with laboratory test results, and the inconsistent association of flares with recent changes in test values.
To examine the safety and immunological effects, in patients with systemic lupus erythematosus (SLE), of LJP 394, a novel B cell toleragen designed to lower dsDNA antibodies.
Four women with stable SLE were given a 100 mg infusion of LJP 394 and were followed for 4 weeks. Routine safety variables were measured, as well as anti-dsDNA, circulating immune complexes, complement, and complement split products.
Anti-dsDNA titers were promptly lowered. At 4 weeks postinfusion, 2 patients' titers remained below baseline and 2 returned to pretreatment levels. Transient increases in some complement split products were noted; however, no adverse clinical events occurred during or immediately after infusion.
LJP 394 successfully and safely lowered anti-dsDNA in 4 patients with SLE. Immune complex formation and rapid elimination is the most likely explanation for the observed findings.
Antibodies to DNA are of interest to a broad spectrum of physicians and other scientists. The presence of large amounts of serum antibodies to double-stranded DNA is specific for systemic lupus erythematosus, and some subgroups of these antibodies are pathogenic. It is likely that people are predisposed to have systemic lupus erythematosus if they can make pathogenic subgroups of antibodies to DNA and if they cannot down-regulate them appropriately. Studies of patients with systemic lupus erythematosus and of murine models of the disease have provided information regarding the different types of antibodies to DNA, their role in pathogenesis, and new . . .
The relationship between chemical properties of anti-DNA antibodies (Abs) and lupus nephritis was investigated. The anti-DNA Abs in sera from systemic lupus erythematosus (SLE) patients were separated by two-dimensional electrophoresis (2-DE) and immunoblotting with goat anti-human IgG Abs. Highly cationic anti-DNA Abs were detected in deoxyribonuclease I (DNase I)-treated sera from patients with lupus nephritis (in 8 of 9 cases) but not in the sera from SLE patients without nephritis (in 0 of 9 cases), normal subjects, or patients with other renal diseases (in 0 of 7 cases). The mean titers of anti-dsDNA Abs in patients with lupus nephritis were not significantly different from those in SLE patients without nephritis. The highly cationic anti-DNA Abs in the sera disappeared after incubation with heparin-Sepharose. These results suggest that highly cationic anti-DNA Abs are specific for lupus nephritis and may be involved in development of lupus nephritis via the binding to glycosaminoglycans on the endothelial cell surface.
In the present study we assessed the frequency and characteristics of the main causes of morbidity and mortality in SLE during a 5-year period and analyzed the prognostic significance for morbidity and mortality of the main immunologic parameters used in clinical practice. We started in 1990 a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 5 years (1990-1995). Four hundred thirteen patients (41.3%) presented 1 or more episodes of arthritis, 264 (26.4%) had malar rash, 222 (22.2%) active nephropathy, 139 (13.9%) fever, 136 (13.6%) neurologic involvement, 132 (13.2%) Raynaud phenomenon, 129 (12.9%) serositis (pleuritis and/or pericarditis), 95 (9.5%) thrombocytopenia, and 72 (7.2%) thrombosis. Two hundred seventy patients (27%) presented infections, 113 (11.3%) hypertension, 75 (7.5%) osteoporosis, and 59 (5.9%) cytopenia due to immunosuppressive agents. Sixteen patients (1.6%) developed malignancies, with the most frequent primary localizations the uterus and the breast. Several immunologic parameters (anti-dsDNA or antiphospholipid antibodies) were found to have a predictive value for the development of SLE manifestations during the period of the study. Forty-five patients (4.5%) died; the most frequent causes of death were divided similarly among active SLE (28.9%), infections (28.9%), and thromboses (26.7%). A survival probability of 95% at 5 years was found. A lower survival probability (92%) was detected in those patients who presented at the beginning of the study with nephropathy.
Charts of 180 patients (147 women, 33 men) with systemic lupus erythematosus (SLE) complicated by renal involvement were retrospectively analyzed from a series of 436 patients. Mean age at renal disease onset was 27 years. Thirty-six percent of the patients had renal involvement after diagnosis of lupus, for 30.7% of that group it was more than 5 years later. Renal involvement occurred more frequently in young male patients of non-French non-white origin. Patients with renal involvement suffered more commonly from malar rash, psychosis, myocarditis, pericarditis, lymphadenopathy, and hypertension. Anemia, low serum complement, and raised anti-dsDNA antibodies were more frequent. According to the 1982 World Health Organization classification, histologic examination of initial renal biopsy specimen in 158 patients showed normal kidney in 1.5% of cases, mesangial in 22%, focal proliferative in 22%, diffuse proliferative in 27%, membranous in 20%, chronic sclerosing glomerulonephritis in 1%, and other forms of nephritis in 6.5%. Distribution of initial glomerulonephritis patterns was similar whether renal involvement occurred before or after the diagnosis of lupus. Transformation from 1 histologic pattern to another was observed in more than half of the analyzable patients (those who underwent at least 2 renal biopsies). Nephritis evolved toward end-stage renal disease in 14 patients despite the combined use of steroids and cyclophosphamide in 12. Initial elevated serum creatinine levels, initial hypertension, non-French non-white origin, and proliferative lesions on the initial renal biopsy were indicators of poor renal outcome. Twenty-four patients died after a mean follow-up of 109 months from SLE diagnosis. Among our 436 patients, the 10-year survival rate was not significantly affected by the presence or absence of renal involvement at diagnosis (89% and 92%, respectively).
This paper presents the equations and methodology for the measurement and interpretation of apparent dissociation constants for polyclonal populations of antibodies, where antigen is kept trace relative to antibody concentration. Surface plasmon resonance is used to determine K(d)s for the binding of anti-DNA antibodies to trace amounts of DNA antigen on a chip. Since the approach taken relies on equilibrium measurements, kinetic mass transport artifacts are avoided. The apparent K(d) is a weighted average of all the K(d)s for the clonally related subpopulations within the polyclonal pool, where each weighting factor is the relative titer (fractional presence) of the subpopulation. Titration curves appear as if there is one monoclonal population with that titer-weighted-average K(d). Implications of changes in the antibody affinity distribution within the population are discussed. The equations described herein provide a better physical understanding of the apparent K(d) that is obtained when a heterogeneous population of receptors is titrated against a trace ligand.
Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide.
Long-term intravenous cyclophosphamide (IVC) in combination with corticosteroids is standard therapy for proliferative lupus nephritis, but it has limitations. There are few data on long-term remission rates, predictors of relapse, and the ability to achieve a second remission with currently recommended IVC regimens.
A cohort of 85 patients with proliferative lupus glomerulonephritis (focal N = 33, diffuse N = 52) treated with IVC was assembled in three institutions. Timing and predictors of remission, relapse, and re-remission were evaluated with Kaplan-Meier analyses and Cox models.
The median time to remission was 10 months, whereas an estimated 22% of patients had not remitted after 2 years. The median time to relapse among 63 patients who had achieved remission was 79 months. In multivariate models, adverse predictors of remission were a delay in the initiation of therapy from the time nephritis was clinically diagnosed [hazard ratio (HR) 0.58, P = 0. 063] and a higher amount of proteinuria (HR 0.86 per 1 g/24 hours, P = 0.014). Predictors of earlier relapse for patients entering remission included a longer time to remission (HR 1.029 per month, P = 0.025), a history of central nervous system involvement (HR 8.41, P = 0.002), and World Health Organization histology (P = 0.01). Among the 23 patients who relapsed during follow-up, the median time to re-remission was 32 months, and with three exceptions, all patients took substantially longer time to remit the second time compared with their first remission (P = 0.01). The time to re-remission was longer in patients who had taken longer to remit the first time (HR 0.979 per month, P = 0.16), in patients who had relapsed earlier after the first remission (HR 1.071 per month, P = 0.002), and in those with evidence of chronicity in the original kidney biopsy (P = 0.015).
Prolonged courses with a cumulative risk of toxicity are needed to achieve remission in many first-treated patients and in most patients treated for a second time. The optimal management of patients with identified adverse predictors of response needs further study.
In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine < or =1.4 mg/dL [< or =123 micromol/L] and proteinuria < or =330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0. 0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.
The availability of more effective treatments for severe lupus nephritis may have influenced the rate at which end-stage renal disease (ESRD) develops in these patients.
To examine changes in the incidence of ESRD due to lupus nephritis from 1982 to 1995.
All patients with incident ESRD included in the US Renal Data System from 1982 to 1995 were studied. The US Renal Data System includes information on all patients who receive Medicare-reimbursed renal replacement therapy, who constitute approximately 94% of all patients with ESRD in the United States. The incidence of ESRD due to lupus nephritis in each year, standardized to the age-sex-ethnicity composition of the US general population in 1990, was computed in this serial cross-sectional study.
The standardized incidence rate of ESRD due to lupus nephritis increased steadily from 1.16 cases per million person-years in 1982 to 3.08 cases per million person-years in 1995. The rate of increase was comparable to that of ESRD due to all other primary renal diseases.
The incidence of ESRD due to lupus nephritis increased steadily over the 14-year study period, despite the introduction of efficacious new treatment regimens for lupus nephritis during this time.
LJP 394 is a novel therapy under development for the treatment of systemic lupus erythematosus (SLE). We investigated the optimal LJP 394 dosing regimen required to maximally reduce serum dsDNA antibodies. We also evaluated the safety and tolerability of repeated doses of LJP 394 as well as the effects of therapy on SLE related disease activity and health related quality of life.
This was a multicenter, partially randomized, placebo controlled, double blind, dose-ranging trial. Study drug or placebo was administered at weekly, biweekly, or monthly intervals for a total of 17, 9, or 5 doses, respectively. Fifty-eight patients were randomly assigned to receive 1, 10, or 50 mg LJP 394 or placebo. After a 2 month pretreatment period, dosing visits continued for 16 weeks, after which there was a 2 month posttreatment period.
The greatest reductions in mean dsDNA antibody titers were observed in the group of patients who received 50 mg LJP 394 weekly (38.1% and 37.1 % at Weeks 16 and 24, respectively). A reduction (29.3%) in dsDNA antibody titers was also observed at Week 24 in the group of patients who received 10 mg LJP 394 weekly. The frequencies of adverse events were comparable in the placebo and active treatment groups.
This clinical trial, in which a large number of patients with SLE were treated with LJP 394, expanded the safety profile of LJP 394 and demonstrated its capacity to reduce dsDNA antibodies.
Five prospective clinical studies in lupus patients have shown that LJP 394 can reduce circulating anti-dsDNA antibody levels without causing generalized immunosuppression. The compound is currently being evaluated in a phase III clinical trial for the prevention of renal flares in patients with high-affinity antibodies to LJP 394 and a history of lupus nephritis. The current study analyzed the affinity of patient IgG for LJP 394 prior to and following 4 months of treatment with LJP 394 to determine if pretreatment affinity influenced pharmacodynamic response. Patient serum samples from a multicenter, double-blind, placebo-controlled trial were evaluated prior to and following 4 months of weekly, biweekly or monthly treatment with placebo (n = 9) or weekly treatment with 10 mg LJP 394 (n = 6) or 50 mg LJP 394 (n = 4). After treatment there was a dose-dependent reduction in affinity in the 10 mg/week and 50 mg/week groups (P < 0.05 and P < 0.01, respectively), whereas the placebo group was unchanged. This study demonstrates that weekly treatment with LJP 394 produces a dose-dependent reduction in titer-weighted average affinity. These results suggest it may be possible to use an affinity assay to define prospectively patients that are most likely to exhibit the desired pharmacodynamic response to LJP 394.
Objective:
To determine the degree to which changes in C3 and C4 precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 global activity indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M-SLEDAI), modified Lupus Activity Index (M-LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M-BILAG), and to evaluate the association between changes in C3 and C4 levels and SLE activity in individual organ systems.
Methods:
Fifty-three lupus patients were observed monthly for 1 year in a longitudinal study. Lupus disease activity and complement levels were measured at each visit. Lupus flare was defined as a 1.0 (or greater) increase in the PGA, a 3-point increase in the M-SLEDAI, a 0.1 increase in the M-LAI, a 3-point increase in the SLAM, or a 4-point increase in the M-BILAG within a 1-month period. Flare rates were calculated for subgroups defined by previous (1 month before) or concurrent changes in complement levels. Logistic regression models were used to determine the significance of the association between recent changes in complement levels and flare, controlling for prednisone dosage. Similar models were used to assess the association between changes in C3 or C4 levels and increased SLE activity in specific organ systems.
Results:
Lupus flares occurred at 12% of visits based on the PGA, 19% based on the M-SLEDAI, 25% based on the M-LAI, 13% based on the SLAM, and 12% based on the M-BILAG. Recent changes in C3 and C4 levels were not associated with flares based on 3 of the 5 activity indices. Flares defined by the M-LAI were more frequent when there was a concurrent decrease in C3 (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.1-3.1) or C4 (OR 2.1, 95% CI 1.3-3.6). Higher flare rates, as defined by the SLAM, were associated with previous increases in C3 (OR 1.6, 95% CI 1.0-2.6) and C4 (OR 2.2, 95% CI 1.2-3.9). When individual organ systems were analyzed, decreases in C3 and C4 were associated with a concurrent increase in renal disease activity (OR 2.2, 95% CI 1.4-3.5 and OR 1.9, 95% CI 1.1-3.4, respectively). Decreases in C3 were also associated with concurrent decreases in the hematocrit (OR 4.6, 95% CI 1.7-12.3), platelet (OR 2.5, 95% CI 1.5-4.1), and white blood cell (OR 2.2, 95% CI 1.3-3.6) counts. Previous increases in C3 levels were associated with a decrease in platelets (OR 1.7, 95% CI 1.1-2.7). A decrease in C4 was associated with a concurrent decrease in the hematocrit level (OR 3.2, 95% CI 1.3-7.5) and platelet count (OR 1.6, 95% CI 1.0-2.5).
Conclusion:
Decreases in complement levels were not consistently associated with SLE flares, as defined by global measures of disease activity. However, decreasing complement was associated with a concurrent increase in renal and hematologic SLE activity.
Objective:
To determine the degree to which changes in anti-double-stranded DNA (anti-dsDNA), as determined by Crithidia and enzyme-linked immunosorbent assays (ELISAs), precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 clinical indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M-SLEDAI), modified Lupus Activity Index (M-LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M-BILAG).
Methods:
Disease activity and anti-dsDNA were measured monthly in 53 SLE patients who were followed up for 1 year. Lupus flare was defined as an increase in PGA of > or = 1.0, M-SLEDAI > or = 3, M-LAI > or = 0.1, SLAM > or = 3, and M-BILAG > or = 4 within a 1-month period. Flare rates were calculated for groups, which were defined by "previous" (1 month prior to the flare) or "concurrent" (at the time of the flare) changes in anti-dsDNA. Logistic regression models were used to determine the significance of the association between recent changes in anti-dsDNA and flare, controlling for the prednisone dosage.
Results:
Flares occurred at 12% of visits, based on the PGA measure of disease activity. Using the other indices, flare rates were 19% (M-SLEDAI), 25% (M-LAI), 13% (SLAM), and 12% (M-BILAG). A concurrent decrease in anti-dsDNA (ELISA) was associated with significantly higher flare rates based on PGA (18 of 84, 21%; P = 0.0014), M-SLEDAI (27 of 89, 30%; P = 0.0019), M-LAI (37 of 89, 42%; P = 0.0001), and M-BILAG (19 of 89, 21%; P = 0.0264) scores. Flare rates were also significantly higher after a previous increase in anti-dsDNA (ELISA) based on M-SLEDAI (26 of 93, 30%; P = 0.0022) and M-LAI (34 of 93, 37%; P = 0.0117) scores. Flare rates tended to be lowest when there was a concurrent increase in anti-dsDNA (ELISA). Analysis of specific organ systems showed that a concurrent decrease in anti-dsDNA (ELISA) was significantly associated with increases in renal disease activity. Similar results were obtained using the Crithidia assay.
Conclusion:
A previous increase in anti-dsDNA levels occurred before SLE flares, as measured by the M-SLEDAI and M-LAI only. However, during lupus flares, including the subset of renal flares, anti-dsDNA levels frequently decreased. We hypothesize that this decrease in anti-dsDNA represents deposition in tissue at the time of flare.
To establish the correlation between lupus nephritis-associated autoantibody levels and the presence/activity of lupus nephritis and global disease activity using cross-sectional data in patients with systemic lupus erythematosus (SLE).
Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index. Antibody levels against single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), histones, nucleosomes and heparan sulphate (HS) were analysed by ELISA in SLE patients with (n=11) and without (n=22) nephritis and in normal controls (n=21). Antibody subclasses were also analysed.
Higher levels of anti-dsDNA and anti-HS antibodies were found in patients with lupus nephritis, the level of anti-HS antibodies correlating with the BILAG renal score. Predominant subclasses were IgG1 and IgG3 for dsDNA antibodies, IgG2 for anti-nucleosome antibodies, and IgG2 and IgG3 for anti-HS antibodies.
Correlation was demonstrated between antibodies to dsDNA, ssDNA, histones, nucleosomes and HS. There is a strong correlation between the level of anti-HS antibodies and disease activity in patients with lupus nephritis as measured by BILAG.
IgG subclasses of autoantibodies differ in their potential to induce an inflammatory response as they interact differentially with complement and Fcgamma receptors.
The IgG subclass distribution of anti-nucleohistone and anti-dsDNA antibodies was analysed longitudinally in patients with systemic lupus erythematosus before and at the moment of an extra-renal (n=23) or a renal relapse (n=l7). Kidney biopsy specimens of patients with a renal relapse were analysed for IgG subclass deposition.
IgG1 anti-nucleohistone and IgG1 anti-dsDNA antibodies were present in plasma of 39 out of 40 patients. At the moment of a relapse, IgG2 and IgG3 anti-nucleohistone and IgG2 anti-dsDNA antibodies were more frequently present in patients with renal disease compared with those with extra-renal disease. Increases in levels of IgG1 anti-dsDNA were observed in 10 out of 11 patients prior to a renal relapse but only 10 out of 22 patients with an extra-renal relapse (91 vs 45%, P=0.02). Rises in IgG2 anti-dsDNA occurred at an equally low rate prior to both renal and extra-renal relapses. A rise in IgG2 anti-nucleohistone antibodies preceded a renal relapse in eight of 11 patients and an extra-renal relapse in only four out of 22 patients (73 vs 18%, P=0.006). In kidney biopsies all IgG subclasses could be detected. IgG1 and IgG2 subclass antibodies to nucleohistone and to dsDNA are the predominant subclasses found in plasma of lupus patients with renal disease.
The frequent occurrence of a rise in IgG2 anti-nucleohistone and IgG1 anti-dsDNA in patients prior to a renal relapse suggests that, besides IgG1 subclass autoantibodies, IgG2 subclass antibodies to nucleohistone have a particular pathophysiological role in lupus nephritis.
Anti-DNA Abs commonly found in patients with systemic lupus erythematosus are thought to play an important pathogenic role in lupus nephritis. Anti-DNA Abs may contribute to renal disease by cross-reactivity with renal Ags, the identity of which remain elusive. To identify a target Ag for pathogenic anti-DNA Abs, we performed Western blotting and immunoprecipitations of mesangial cell lysates from the lupus-prone MRL-lpr/lpr mouse and a nonautoimmune BALB/c mouse with the pathogenic anti-DNA Ab R4A. We found that R4A (but not a nonpathogenic Ab mutant of R4A) binds to and immunoprecipitates a 100-kDa protein expressed on the cell surface and in lysates of MRL-lpr/lpr mesangial cells. DNase treatment of the lysate and of the R4A Ab did not effect binding, indicating that the binding of R4A to the 100-kDa protein was direct and not mediated by an antigenic bridge containing DNA. Binding was greatly diminished in BALB/c lysates, suggesting that Ag expression or availability at the level of the target organ may be a factor in determining susceptibility to lupus nephritis. Following identification of this 100-kDa protein as nonmuscle alpha-actinin, binding of R4A to alpha-actinin was confirmed by Western blot, ELISA, inhibition studies, and immunofluorescence. High titers of anti-alpha-actinin Abs were present in sera and kidney eluates of lupus mice with active nephritis. These results indicate that the nephritogenicity of some anti-DNA Abs may be mediated via cross-reactivity with alpha-actinin. Furthermore, variations in target Ag display between individuals may underlie differential susceptibility to anti-DNA Ab-induced renal disease.