A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity.

BACKGROUND: A urine 'biomarker panel' comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an 'excellent' level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally. METHODS: The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score). RESULTS: The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition. CONCLUSIONS: Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.

Anti-IFNAR treatment does not reverse neuropsychiatric disease in MRL/lpr lupus mice.

OBJECTIVE: Many systemic lupus erythematosus patients display a type I interferon (IFN) signature, and IFNα levels positively correlate with disease severity. Previous studies blocking the type I IFN pathway systemically in lupus models showed some beneficial effects. However, its effects on neuropsychiatric manifestations have yet to be carefully assessed, even though IFNα has been associated with induction of depression. Our aim was to investigate whether disrupting the type I IFN pathway would attenuate the development of murine neuropsychiatric lupus. METHODS: Female MRL/lpr mice were administered an antitype I IFN receptor (IFNAR) antibody or a control antibody intraperitoneally three times weekly for 12 weeks starting at age 4-5 weeks. Behavior was assessed during and at the end of the treatment schedule. RESULTS: No significant differences were seen between the anti-IFNAR- and control-treated mice when assessing for depression-like behavior or cognitive dysfunction, although anti-IFNAR antibody-treated mice displayed significant decreases in levels of IFN-stimulated genes. Anti-IFNAR treatment also did not significantly improve brain histology, cellular infiltration, or blood-brain barrier integrity. CONCLUSIONS: Surprisingly, our results showed no improvement in neuropsychiatric disease and suggest that the role of IFNAR signaling in the pathogenesis of neuropsychiatric lupus continues to need to be carefully assessed.

The blood-brain barrier, TWEAK, and neuropsychiatric involvement in human systemic lupus erythematosus and primary Sjögren's syndrome.

OBJECTIVE: A prevailing hypothesis for neuropsychiatric involvement in systemic lupus erythematosus (SLE) and primary Sjögren's syndrome is that brain reactive autoantibodies enter the brain through a disrupted blood-brain barrier. Our aim was to investigate whether TNF-like weak inducer of apoptosis (TWEAK) plays a role in cerebral involvement in human SLE and primary Sjögren's syndrome, and whether an impaired blood-brain barrier is a prerequisite for neuropsychiatric manifestations. METHODS: TWEAK was measured in the cerebrospinal fluid and serum and compared with markers of blood-brain barrier permeability (Q-albumin and MRI contrast-enhanced lesions) and S100B, an astrocyte activation marker in 50 SLE and 52 primary Sjögren's syndrome patients. Furthermore, we estimated the general intrathecal B-cell activation (IgG index), measured anti-NR2 antibodies in cerebrospinal fluid, and explored whether these variables were associated with neuropsychiatric manifestations. RESULTS: No associations were found between TWEAK in the cerebrospinal fluid or serum and neuropsychiatric manifestations in SLE nor in primary Sjögren's syndrome patients. Furthermore, no associations were found between neuropsychiatric manifestations and indicators of blood-brain barrier integrity or astroglial activity. Anti-NR2 antibodies were associated with impaired visuospatial processing (odds ratio 4.9, P = 0.03) and motor functioning (odds ratio 6.0, P = 0.006). CONCLUSION: No clinical neuropsychiatric manifestations could be attributed to impaired integrity of the blood-brain barrier, or to TWEAK levels in cerebrospinal fluid or serum in either patient group. The TWEAK concentration was considerably higher in the cerebrospinal fluid than in blood, which indicates intrathecal production. We hypothesize that increased TWEAK and S100B result from immunological stress caused by brain-reactive antibodies produced by brain residing immune cells.

A peptide mimic blocks the cross-reaction of anti-DNA antibodies with glomerular antigens.

Anti-DNA antibodies play a pivotal role in the pathogenesis of lupus nephritis by cross-reacting with renal antigens. Previously, we demonstrated that the binding affinity of anti-DNA antibodies to self-antigens is isotype-dependent. Furthermore, significant variability in renal pathogenicity was seen among a panel of anti-DNA isotypes [derived from a single murine immunoglobulin (Ig)G3 monoclonal antibody, PL9-11] that share identical variable regions. In this study, we sought to select peptide mimics that effectively inhibit the binding of all murine and human anti-DNA IgG isotypes to glomerular antigens. The PL9-11 panel of IgG anti-DNA antibodies (IgG1, IgG2a, IgG2b and IgG3) was used for screening a 12-mer phage display library. Binding affinity was determined by surface plasmon resonance. Enzyme-linked immunosorbent assay (ELISA), flow cytometry and glomerular binding assays were used for the assessment of peptide inhibition of antibody binding to nuclear and kidney antigens. We identified a 12 amino acid peptide (ALWPPNLHAWVP, or 'ALW') which binds to all PL9-11 IgG isotypes. Preincubation with the ALW peptide reduced the binding of the PL9-11 anti-DNA antibodies to DNA, laminin, mesangial cells and isolated glomeruli significantly. Furthermore, we confirmed the specificity of the amino acid sequence in the binding of ALW to anti-DNA antibodies by alanine scanning. Finally, ALW inhibited the binding of murine and human lupus sera to dsDNA and glomeruli significantly. In conclusion, by inhibiting the binding of polyclonal anti-DNA antibodies to autoantigens in vivo, the ALW peptide (or its derivatives) may potentially be a useful approach to block anti-DNA antibody binding to renal tissue.

Urinary high-mobility group box-1 associates specifically with lupus nephritis class V.

INTRODUCTION: High-mobility group box 1 protein (HMGB-1) has been implicated in the pathogenesis of lupus nephritis (LN). There is increased HMGB-1 expression in the kidneys and increased levels are observed in serum and urine of patients with LN. This study was performed to determine whether the increased urinary HMGB-1 was specific for active lupus or secondary to renal damage. METHODS: Urine from 61 lupus patients (32 had active LN and 29 had systemic lupus erythematosus (SLE) with no evidence of LN) and 14 control proteinuric patients (all with hypertension and eight also with diabetes) were included in this study. HMGB-1 was detected by Western blot. Urine protein was normalized to urine creatinine to account for volume of the specimen. RESULTS: Median normalized urine HMGB-1 levels were significantly elevated in LN patients compared to lupus patients without kidney disease (53.81 vs 9.46, p < 0.001). A difference in median levels was seen between LN classes, with a significant difference between proliferative and membranous disease (33.4 vs 138.8, p = 0.003). Urine protein to urine creatinine ratio (P/C) correlated with urinary HMGB-1 (r = 0.52, p < 0.001), but across the classes this was true only for membranous disease (r = 0.71, p = 0.022, proliferative, p = 0.63; mixed, p = 0.34). CONCLUSIONS: HMGB-1 is elevated in the urine of patients with active LN. Levels are associated with LN class, and higher levels of urinary HMGB-1 are seen in patients with class V when compared to both proliferative and mixed classes. Therefore, urinary HMGB-1 may be suggestive of membranous LN and warrants further evaluation in a large lupus cohort.

B7x/B7-H4 modulates the adaptive immune response and ameliorates renal injury in antibody-mediated nephritis.

Kidney disease is one of the leading causes of death in patients with lupus and other autoimmune diseases affecting the kidney, and is associated with deposition of antibodies as well as infiltration of T lymphocytes and macrophages, which are responsible for initiation and/or exacerbation of inflammation and tissue injury. Current treatment options have relatively limited efficacy; therefore, novel targets need to be explored. The co-inhibitory molecule, B7x, a new member of the B7 family expressed predominantly by non-lymphoid tissues, has been shown to inhibit the proliferation, activation and functional responses of CD4 and CD8 T cells. In this study, we found that B7x was expressed by intrinsic renal cells, and was up-regulated upon stimulation with inflammatory triggers. After passive administration of antibodies against glomerular antigens, B7x(-/-) mice developed severe renal injury accompanied by a robust adaptive immune response and kidney up-regulation of inflammatory mediators, as well as local infiltration of T cells and macrophages. Furthermore, macrophages in the spleen of B7x(-/-) mice were polarized to an inflammatory phenotype. Finally, treatment with B7x-immunoglobulin (Ig) in this nephritis model decreased kidney damage and reduced local inflammation. We propose that B7x can modulate kidney damage in autoimmune diseases including lupus nephritis and anti-glomerular basement membrane disease. Thus, B7x mimetics may be a novel therapeutic option for treatment of immune-mediated kidney disease.

Immunization with a peptide surrogate for double-stranded DNA (dsDNA) induces autoantibody production and renal immunoglobulin deposition.

Anti-double-stranded DNA (dsDNA) antibodies are the serologic abnormality characteristically associated with systemic lupus erythematosus (SLE) and may play an important role in disease pathogenesis. Although the anti-dsDNA antibodies present in SLE are indicative of an antigen-driven response, the antigen has not been conclusively identified. By screening a phage peptide display library, we demonstrated previously that the decapeptide DWEYSVWLSN is specifically bound by the pathogenic murine IgG2b anti-dsDNA antibody R4A. To investigate the possibility that a protein antigen might trigger lupus-like autoimmunity, we immunized BALB/c mice with DWEYSVWLSN in adjuvant. Mice developed significant titers of IgG anti-dsDNA antibodies 2-3 wk after the initial immunization. Immunized mice also developed antibodies against some other lupus autoantigens, and immunoglobulin deposition was present in renal glomeruli at 49 d. Although an immune response to peptide and dsDNA was evident in BALB/c mice, there was little response in other inbred strains. This study demonstrates that lupus-like anti-dsDNA reactivity can be generated in nonautoimmune mice by immunization with a peptide antigen. Peptide-induced autoimmunity may prove useful in understanding the spreading of antigenic specificities targeted in SLE. However, most importantly, the demonstration that a peptide antigen can initiate a SLE-like immune response opens a new chapter on the potential antigenic stimuli that might trigger SLE.

Identification of new SLE-associated genes with a two-step Bayesian study design.

In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

Treatment of lupus nephritis: facing the era of immunotherapy.

Lupus nephritis (LN) is a major cause of morbidity and mortality, affecting over half of SLE patients. The traditional treatment protocol with cyclophosphamide and corticosteroids dramatically improved patient and renal survival, but conferred a heavy burden of side effects. In addition, not all patients respond to first-line immunosuppression; 35% suffer at least one episode of renal relapse and 5-20% develop end-stage renal disease. Over the last decade, the increasing understanding of the complex pathogenesis underlying lupus nephritis and accelerating advances in molecular and cellular immunology have paved the way for development of immunomodulatory therapies for LN. In contrast to the global immunosuppressive effects of conventional treatment, these biologic agents target specific pathways that contribute to the inflammatory response, aiming to reduce tissue damage while preserving immunocompetence. The goal of this review is to highlight some of the more promising novel immunomodulators, including Abetimus sodium, Rituximab, Epratuzumab, Abatacept, Belimumab, Tocilizumab and Infliximab, and discuss how these agents affect central pathways in the pathogenesis of disease.

The double edged sword of the immune response: mutational analysis of a murine anti-pneumococcal, anti-DNA antibody.

Anti-double-stranded (ds) DNA antibodies are not only an important diagnostic marker for SLE, but also play an important role in tissue injury. Microbial antigen may be a stimulus for the production of these antibodies. We isolated 99D.7E, an IgG2b monoclonal antibody from a nonautoimmune BALB/c mouse that is cross-reactive with both dsDNA and phosphorylcholine, the dominant hapten on the pneumococcal cell wall. While partially protective against a bacterial challenge, 99D.7E is also pathogenic to the kidney. To identify those molecular motifs that confer on anti-PC antibodies the potential for autoreactivity, we created a panel of 99D.7E mutants with single amino acid substitutions in the heavy chain, and examined the changes in antigen binding and renal deposition. Our results support the hypothesis that charge and affinity for dsDNA are not adequate predictors of the pathogenicity of anti-DNA antibodies. Differential renal damage from anti-dsDNA antibodies may be due to differences in fine specificity, rather than differential affinity for dsDNA. Importantly, high affinity IgG antibodies cross-reactive with bacterial and self antigen exist and can display pathogenic potential, suggesting that defects in peripheral regulation of B cells, activated by foreign antigen but cross-reactive with self antigen, might lead to autoimmune disorders.

Reactive arthritis associated with Clostridium difficile pseudomembranous colitis.

Reactive arthritis is associated with several gastrointestinal pathogens, particularly Shigella, Salmonella, Campylobacter, and Yersinia. Another, less well recognized bowel infection leading to reactive arthritis is pseudomembranous colitis, caused by Clostridium difficile. An illustrative case is presented, and the clinical features and characteristics of all reported patients with this association are reviewed. The pathogenesis of the reactive arthritis seems to be related to an immunological response in joints and other tissues against bacterial antigens, which gain access to the systemic circulation through increased intestinal permeability. Therapy with nonspecific antiinflammatory drugs, anticlostridial agents, or a combination of the above is effective. Despite the possibility of persistent articular involvement after gastrointestinal symptoms have subsided, the long-term prognosis seems to be excellent.

Colchicine intoxication: clinical pharmacology, risk factors, features, and management.

The use of colchicine for acute gouty arthritis dates to ancient times. In recent years, colchicine also has been used successfully for various other rheumatic and nonrheumatic conditions. Colchicine is a safe drug when used according to established therapeutic guidelines. However, toxicity can be considerable if ingested intentionally or if the recommended doses are exceeded. Colchicine intoxication is characterized by multi-organ involvement and by the poor prognosis associated with administration of large amounts of the drug. Therapy is basically supportive and symptomatic because of the rapid distribution and binding of colchicine to the affected tissues. Use of anticolchicine antibodies is a novel approach that has shown promise in experimental models. Important research questions pertain to the effect of liver and kidney disease on colchicine metabolism, use of colchicine levels in the diagnosis of intoxication and for prognostication, and application of immunotoxicotherapy for colchicine poisoning in humans.

Idiopathic capillary leak syndrome complicated by massive rhabdomyolysis.

Idiopathic systemic capillary leak syndrome (Clarkson's disease) is characterized by recurring attacks of increased capillary permeability, resulting in severe hypovolemic shock due to plasma extravasation. Additional laboratory features include association with a monoclonal gammopathy, extreme hemoconcentration, and hypoalbuminemia. Rare manifestations of this syndrome are renal damage and rhabdomyolysis due to increased compartment pressure and ischemic myonecrosis. We present the findings in two patients with capillary leak syndrome complicated by severe rhabdomyolysis, in one case leading to acute renal failure. We review therapeutic aspects of this rare syndrome and emphasize the importance of early diagnosis and of prompt and aggressive fluid replacement.

Problems and conflicts in peer review.

The process of refereeing of scientific papers is essential in the course of their evaluation and selection for publication in a journal. Scientists who voluntarily and selflessly serve as referees may encounter situations which put them in conflict of interest. This review considers and analyses such conflicts.

Late cardiovascular and pulmonary complications of therapy in Hodgkin's disease: report of three unusual cases, with a review of relevant literature.

With the advent of modern therapeutic approaches, even patients with advanced Hodgkin's disease have high cure rates today. Therefore, more attention is gradually being focused upon the late complications of chemotherapy and irradiation, appearing long after the patient is in remission and thought to be cured. In this report, we review the incidence and presentation of some of the cardiovascular and pulmonary complications which may appear later in the course of the disease. Cardiovascular mishaps reviewed include pericardial manifestations, conduction abnormalities, cardiomyopathy, and premature coronary artery disease. Pulmonary complications discussed are lung fibrosis, spontaneous pneumothorax, pulmonary veno-occlusive disease, and hyperlucent lung. Three instructive cases from our recent experience, are also presented. One fatal case was due to cardiac failure because of radiation-induced pericarditis and coronary artery disease. Another patient with an almost fatal complication required lung transplantation because of severe bilateral radiation fibrosis of the lung and pulmonary veno-occlusive disease. The third instance was also life-threatening in nature, with radiation-induced arterial changes in the major arteries of the chest and neck, resulting in recurrent cerebral and ophthalmic thromboembolic disease. It is suggested that potentially severe cardiopulmonary complications be considered during the planning of the initial and subsequent management of patients with Hodgkin's disease, particularly in an era employing autologous and allogeneic bone marrow transplantation as part of therapy in some cases.

Right ventricular outflow tract obstruction due to extrinsic compression by non-Hodgkin's lymphoma: importance of echocardiographic diagnosis and follow up.

Acquired right ventricular outflow tract obstruction due to extrinsic compression of the pulmonary artery is a rare manifestation of non-Hodgkin's lymphoma (NHL). We report a case of a 17 year old boy who was referred for evaluation of a large anterior mediastinal mass, causing dyspnea and cough and resulting in a harsh systolic murmur. Echocardiography demonstrated compression of the pulmonary artery by the mass, with a severe pressure gradient. Biopsy revealed intermediate grade, diffuse large cell NHL. Systemic chemotherapy rapidly led to a significant decrease in the size of the mass, and virtual disappearance of the pressure gradient. In this report, the use of echocardiography for diagnosis and follow up of extracardiac tumors is reviewed. It is suggested that this technique may also be useful for the routine staging of mediastinal lymphomas because of the potential consequences of clinically undetectable hemodynamic compromise.

Adult respiratory distress syndrome: current concepts.

Adult Respiratory Distress Syndrome (ARDS) is a common diagnosis in today's intensive care units, representing a final common pathway of lung response to a variety of disease states. Mortality rates remain excessively high, despite comprehensive monitoring and intensive treatment. The incidence, etiology, clinical features, pathology and pathophysiology of ARDS are reviewed, with special emphasis on current research regarding potentially injurious mediators and possible etiopathogenetic mechanisms. Current therapy is summarized, and new therapeutic modalities are assessed. It is hoped that increased knowledge and awareness of the various aspects of ARDS will lead to further understanding and better clinical results in patients with this syndrome.

Central venous catheter related sepsis: a clinical review.

Central venous catheterization is one of the most common invasive vascular procedures performed in hospitals today. Though catheter related sepsis occurs only in a small percentage of catheterized patients, this complication has a tremendous impact due to the ubiquitous use of central venous catheters and consequent morbidity and even mortality. Recent studies have considerably advanced our knowledge regarding the pathogenesis, diagnosis, and prevention of catheter sepsis. In this paper, current concepts regarding catheter-related sepsis are reviewed, regarding the incidence, pathophysiology, diagnosis, prevention, and therapy of this complication. Particular emphasis is placed upon recent research and clinical advances in this field, which have clarified important question and suggested promising approaches to the prevention and treatment of catheter bacteremia. The excessive morbidity and mortality due to catheter-related sepsis can be markedly decreased, by attention to simple infection control methods, and by future implementation of new experimental techniques.

Early use of naloxone in shock--a clinical trial.

Naloxone hydrochloride (N) 0.4-1.2 mg i.v. was administered during 10 episodes of shock (8 septic and 2 cardiogenic) in 9 adult patients. Shock was defined as systolic blood pressure (SBP) less than or equal to 90 mmHg and urine output less than 0.5 ml/h and signs and symptoms of hypoperfusion lasting for greater than or equal to 30 min, despite fluid loading to a CVP 5 cmH2O above baseline. N was given as early as 30 min after onset of shock and resulted in an increase of SBP from a mean of 75 +/- 10 to a mean of 130 +/- 25 mmHg maximum (P less than 0.01). Within 10-60 min urine output increased from 16 +/- 12 to 122 +/- 56 ml/h, heart rate, CVP and arterial blood gas tensions remained unchanged. No side effects were observed. Naloxone, even in small doses, may improve hemodynamic parameters in human shock, provided it is administered very early.

Koch's postulates and autoimmunity: an opposing viewpoint.

Autoimmunity is characterized as a state of abnormal specific humoral and cell-mediated responses against constituents of body tissues. One time-honored approach to explaining the pathogenesis of autoimmunity has been application of the Koch's postulates, on loan from the field of microbiology suggesting that autoantibodies and/or autoreactive T cells are the presumed "pathogens" of autoimmunity, and that passive transfer of these autoimmune factors to susceptible animals will result in the induction of the autoimmune disease. We suggest that autoimmunity is not in many cases due to the presence of factors leading to the autoimmune response in those susceptible. Instead, it is the lack of a factor which leads to the development of autoimmunity, a factor (cytokine, protein, gene, etc.) which is present in the healthy individual and normally protects in from disordered immune regulation. We propose to direct more research into therapeutic modulation of autoimmunity by administration of putative "protective factors", rather than by attempts to depress or remove autoreactive cells and antibodies from the autoimmune.