The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

[CHANGING CONCEPTS IN THE CLINICAL APPROACH FOR EPILEPSY SURGERY].

INTRODUCTION: Epilepsy is a common disease state, occurring in approximately 1% of the population worldwide, including both pediatric and adult populations. It is characterized by recurrent episodes of unpredictable pathologic cortical brain activity. One-third of patients develop drug intractability and experience recurrent seizures, despite optimal treatment. These result in cognitive decline, behavioral changes, decreased quality of life, and increased risk for trauma and death (SUDEP- sudden unprovoked death from epilepsy). Therefore, the international league against epilepsy (ILAE) recommends referral of intractable patients to highly specialized epilepsy centers, for further evaluation for epilepsy surgery.

Deep, spontaneous intracerebral hemorrhages: Clinical differences and risk factors associated with anterior versus posterior circulation.

BACKGROUND: spontaneous intracerebral hemorrhages (ICH) in different anatomical locations are considered different clinical entities, associated with different vascular etiologies. However, such a distinction between deep ICH in the posterior vs. the anterior circulation is not well documented. OBJECTIVE: to look for different demographic, clinical, laboratory and radiological variables in order to clarify any distinction between deep ICH of the posterior versus the anterior circulations. MATERIAL AND METHODS: Retrospective study on patients diagnosed with deep, spontaneous ICH at a single tertiary center. Patients were divided into two groups: posterior circulation (group 1) and anterior circulation (group 2). Computerized medical records were extracted for multiple variables. RESULTS: A total of 142 patients with deep ICH were included in the study; 54.9 % (n = 78) with posterior (group 1) and 45.1 % (n = 64) with anterior circulation hemorrhages (group 2). In group 1, 67.9 % (n = 53) of hemorrhages were in the cerebellum and 28.2 % (n = 22) in the thalamus. Patients in group 1 were older at time of hemorrhage (68.69 ± 11.66 vs. 64.95 ± 13.34, p = 0.073) and had nearly threefold increased rate of BMI≥ 35 (22.0 % vs. 8.6 %, p = 0.071). In multivariate analysis, use of anti-aggregates (OR=2.391; 95 % CI 1.082-5.285, p = 0.031) and past medical history of HTN (OR=2.904; 95 % CI 1.102-7.654, p = 0.031) were significantly associated with ICH of the posterior circulation. When excluding patients with thalamic hemorrhages, BMI ≥ 35 was also associated with significant risk of having a deep hemorrhage in the posterior circulation vs. the anterior circulation (OR=3.420; 95 % CI 1.011-11.574, p = 0.048). No significant differences were found between the two groups in terms of functional and survival outcomes. CONCLUSION: HTN, use of anti-aggregates and morbid obesity are associated with deep ICHs of the posterior circulation and should be considered significant risk factors for this major clinical event. The growing data on pathophysiology of distinct subgroups of ICH will provide useful tools that will aid in preventing and treating these neurological emergencies. Future epidemiological and clinical studies should use the distinction between ICH subgroups based on their anatomical location and vascular territories as accurately as possible in order to reach solid conclusions.

Postoperative hydrocephalus management may cause delays in adjuvant treatment following paediatric posterior fossa tumour resection: a multicentre retrospective observational study.

INTRODUCTION: Hydrocephalus persists in 10-40% of children with posterior fossa tumours (PFT). A delay in commencement of adjuvant therapy (AT) can negatively influence survival. The objective of this study was to determine whether postoperative cerebrospinal fluid (CSF) diversion procedures caused potentially preventable delays in AT. METHODS: A retrospective study of children diagnosed with PFT requiring AT from 2004 to 2018 from two large centres was conducted. Data on histology, timing of ventriculo-peritoneal shunt (VPS) insertion, and AT was collected. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) score was calculated. The primary outcome was delay in AT beyond 40 days post-resection. Progression-free and overall survival were assessed. RESULTS: Out of 196 primary PFT resections, 144 fitted the inclusion criteria. Mean age was 6.57 ± 4.62. Histology was medulloblastoma (104), ependymoma (27), and others (13). Forty patients had a VPS inserted; 17 of these experienced a delay in AT. A total of 104 patients were not shunted; 15 of these had delayed AT (p = 0.0007). Patients who had a VPS insertion had longer intervals from surgery to commencement of AT (34.5 vs 30.8, p = 0.05). There was no significant difference in mCPPRH score between those who had a VPS (4.03) and those who did not (3.61; p = 0.252). Multivariable linear regression modelling did not show a significant effect of VPS or mCPPRH on progression-free survival or OS. CONCLUSION: CSF diversion procedures may cause a preventable delay in the initiation of adjuvant therapy. Early post-operative VP shunt insertion, rather than a 'wait and see policy' should be considered in order to reduce this delay.

Quick cell-free DNA testing for the prediction of postconcussion syndrome: a single-center prospective pilot trial.

OBJECTIVE: Mild traumatic brain injury (mTBI) is a major cause of emergency room (ER) admission. Thirty percent of mTBI patients have postconcussion syndrome (PCS), and 15% have symptoms for over a year. This population is underdiagnosed and does not receive appropriate care. The authors proposed a fast and inexpensive fluorometric measurement of circulating cell-free DNA (cfDNA) as a biomarker for PCS. cfDNA is a proven, useful marker of a variety of acute pathological conditions such as trauma and acute illness. METHODS: Thirty mTBI patients were recruited for this prospective single-center trial. At admission, patients completed questionnaires and blood was drawn to obtain cfDNA. At 3-4 months after injury, 18 patients returned for cognitive assessments with questionnaires and the Color Trails Test (CTT). The fast SYBR Gold assay was used to measure cfDNA. RESULTS: Seventeen men and 13 women participated in this trial. The mean ± SD age was 50.9 ± 13.9 years. Of the 18 patients who returned for cognitive assessment, one-third reported working fewer hours, 4 (22.2%) changed their driving patterns, and 5 (27.7%) reduced or stopped performing physical activity. The median cfDNA level of the mTBI group was greater than that of the matched healthy control group (730.5 vs 521.5 ng/ml, p = 0.0395). Admission cfDNA concentration was negatively correlated with performance on the CTT1 and CTT2 standardized tests (r = -0.559 and -0.599), meaning that greater cfDNA level was correlated with decreased cognitive performance status. The performance of the patients with normal cfDNA level included in the mTBI group was similar to that of the healthy participants. In contrast, the increased cfDNA group (> 800 ng/ml) had lower scores on the CTT tests than the normal cfDNA group (p < 0.001). Furthermore, patients with moderate/severe cognitive impairment according to CTT1 results had a greater median cfDNA level than the patients with scores indicating mild impairment or normal function (1186 vs 473.5 ng/ml, p = 0.0441, area under the receiver operating characteristic curve = 0.8393). CONCLUSIONS: The data from this pilot study show the potential to use cfDNA, as measured with a fast test, as a biomarker to screen for PCS in the ER. A large-scale study is required to establish the value of cfDNA as an early predictor of PCS.

Lymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function.

Exogenous administration of lymphangiogenic growth factors is widely used to study changes in lymphatic function in pathophysiology. However, this approach can result in off-target effects, thereby generating conflicting data. To circumvent this issue, we modulated intracellular VEGF-C signaling by conditionally knocking out the lipid phosphatase PTEN using the Vegfr3 promoter to drive the expression of Cre-lox in lymphatic endothelial cells (LECs). PTEN is an intracellular brake that inhibits the downstream effects of the activation of VEGFR3 by VEGF-C. Activation of Cre-lox recombination in adult mice resulted in an expanded functional lymphatic network due to LEC proliferation that was independent of lymphangiogenic growth factor production. Furthermore, compared with lymphangiogenesis induced by VEGF-C injection, LECPTEN animals had mature, nonleaky lymphatics with intact cell-cell junctions and reduced local tissue inflammation. Last, compared with wild-type or VEGF-C-injected mice, LECPTEN animals had an improved capacity to resolve inflammatory responses. Our findings indicate that intracellular modulation of lymphangiogenesis is effective in inducing functional lymphatic networks and has no off-target inflammatory effects.

TWEAKing the Hippocampus: The Effects of TWEAK on the Genomic Fabric of the Hippocampus in a Neuropsychiatric Lupus Mouse Model.

Neuropsychiatric manifestations of systemic lupus erythematosus (SLE), specifically cognitive dysfunction and mood disorders, are widely prevalent in SLE patients, and yet poorly understood. TNF-like weak inducer of apoptosis (TWEAK) has previously been implicated in the pathogenesis of neuropsychiatric lupus (NPSLE), and we have recently shown its effects on the transcriptome of the cortex of the lupus-prone mice model MRL/lpr. As the hippocampus is thought to be an important focus of NPSLE processes, we explored the TWEAK-induced transcriptional changes that occur in the hippocampus, and isolated several genes (Dnajc28, Syne2, transthyretin) and pathways (PI3K-AKT, as well as chemokine-signaling and neurotransmission pathways) that are most differentially affected by TWEAK activation. While the functional roles of these genes and pathways within NPSLE need to be further investigated, an interesting link between neuroinflammation and neurodegeneration appears to emerge, which may prove to be a promising novel direction in NPSLE research.

Deep versus Superficial Spontaneous Cerebellar Hemorrhages: Separated Vascular Etiologies with Different Clinical Consequences.

BACKGROUND: Spontaneous cerebellar hemorrhage (CH) is a critical neurosurgical event. It is usually categorized as a homogenous group under the general term of deep/nonlobar intracerebral hemorrhage. However, increasing evidence suggests it is composed of 2 subgroups, separated from each other by their anatomic location (deep vs. superficial), as well as by their vascular etiology (small vessel disease vs. cerebral amyloid angiopathy). OBJECTIVE: To identify any clinically significant differences between anatomically separated subgroups of CHs: deep versus superficial. METHODS: This is a retrospective study on patients who were diagnosed with spontaneous CHs at a single tertiary center. On the basis of the radiologic location of the hematoma, patients were divided into 2 groups: deep (group 1) and superficial (group 2). Computerized medical records were extracted for multiple variables. RESULTS: A total of 69 patients fulfilled the inclusion criteria. Fifty-three (77%) were in group 1, and 16 (23%) were in group 2. Having any vascular risk factor was associated with the highest odds ratio for having a deep CH. Morbid obesity (body mass index ≥30) and the use of antiplatelets were also associated with increased odds ratios. Group 1 is also associated with high prevalence of intraventricular hemorrhage, acute hydrocephalus, and less favorable outcome. CONCLUSIONS: This study supports the notion that CH is most likely a heterogenous condition, composed of 2 subgroups, separated from each other in terms of anatomic location, vascular etiologies, and clinical consequences. Further studies on large cohort of patients are needed in order to accurately define the subgroups of this life-threatening event.

Remodeling of Neurotransmission, Chemokine, and PI3K-AKT Signaling Genomic Fabrics in Neuropsychiatric Systemic Lupus Erythematosus.

Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/lpr (that manifest lupus-like phenotype) and MRL/lpr-Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on cortical gene expression in lupus. We found that the TWEAK/Fn14 pathway strongly affects the expression level, variability and coordination of the genomic fabrics responsible for neurotransmission and chemokine signaling. Dysregulation of the Phosphoinositide 3-kinase (PI3K)-AKT pathway in the MRL/lpr lupus strain compared with the MRL/+ control and Fn14ko mice was particularly prominent and, therefore, promising as a potential therapeutic target, although the complexity of the transcriptomic fabric highlights important considerations in in vivo experimental models.

Cognitive dysfunction in autoimmune rheumatic diseases.

For people with chronic autoimmune rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis (SSc), normal cognitive functions are essential for performing daily activities. These diseases may be associated with cognitive dysfunction (CD). In RA, CD has been associated with age, lower education and disease duration and activity. Great advances have been achieved in neuropsychiatric SLE in the identification of pathogenic pathways, assessment and possible treatment strategies. SSc rarely exerts direct effects on the brain and cognitive function. However, the psychological burden that includes depression, anxiety and social impact may be high. AIRD patients with sustained disease activity, organ damage or lower education should be evaluated for CD. The control of systemic inflammation together with tailored behavioural cognitive therapies may benefit these patients.

The Utility of Early Postoperative Neuroimaging in Elective/Semielective Craniotomy Patients: A Single-Arm Prospective Trial.

BACKGROUND: The necessity and timing of early postoperative imaging (POI) are debated in many studies. Despite the consensus that early POI does not change patient management, these examinations are routinely performed. This is the first prospective study related to POI. Our aims were to assess the necessity of early POI in asymptomatic patients and to verify accuracy of the presented algorithm. METHODS: This was an algorithm-based prospective single-center study. The algorithm addressed preoperative, perioperative, and postoperative considerations, including estimated pathology type, device placement, and postoperative neurologic change. Early computed tomography scans were obtained in all patients, but if postoperative algorithm indications did not recommend a scan, the treating team was blinded to them, and patient management was conducted based on clinical examinations alone. A neuroradiologist and study-independent neurosurgeon reviewed all the scans. RESULTS: Of 103 enrolled patients, 88 remained asymptomatic, and 15 experienced symptoms postoperatively. Pathology was present on POI in 1% of the asymptomatic patients and 53% of the symptomatic patients (P < 0.001). In the asymptomatic group, no treatment modifications were made postoperatively. Blinding of the surgical team was not removed, and 20% of the symptomatic patients returned to the operating room because of imaging and neurologic findings. The goal of <5% algorithm failure was reached with statistical significance. CONCLUSIONS: In asymptomatic postoperative patients in whom early imaging is not performed for oncologic indications, device placement verification, or similar reasons, POI is unnecessary and does not change the management of these patients.

Pregnancy outcome after multifetal pregnancy reduction of triplets to twins versus reduction to singletons.

RESEARCH QUESTION: Does fetal reduction of triplet pregnancies to singleton result in superior obstetric and neonatal outcomes compared with triplets reduced to twins? DESIGN: A historical cohort study including 285 trichorionic and dichorionic triplet pregnancies that underwent abdominal fetal reduction at 11-14 weeks in a single tertiary referral centre. The study population comprised two groups: reduction to twins (n = 223) and singletons (n = 62). Main outcome measures were rates of pregnancy complications, preterm delivery and neonatal outcomes. Non-parametric statistical methods were employed. RESULTS: Triplet pregnancies reduced to twins delivered earlier (36 versus 39 weeks, P < 0.001) with higher prevalence of Caesarean section (71.1% versus 32.2%, P < 0.001) compared with triplets reduced to singletons. Preterm delivery rates were significantly higher in twins compared with singletons prior to 37 weeks (56.9% versus 13.6%, P < 0.001), 34 weeks (20.2% versus 3.4%, P = 0.002) and 32 weeks (9.6% versus 0%, P = 0.01). No significant difference was found in the rate of pregnancy loss before 24 weeks (1.3% in twins versus 4.8% in singletons, P = 0.12) or in the rate of intrauterine fetal death after 24 weeks (0.4% versus 0%, P = 1.0). Both groups had comparable obstetrical complications and neonatal outcomes, except for higher rates of neonatal intensive care unit admission in twins (31.9% versus 6.8%, P < 0.001). CONCLUSIONS: Reduction of triplets to singletons rather than twins resulted in superior obstetric outcomes without increasing the procedure-related complications. However, because the rate of extreme prematurity in pregnancies reduced to twins was low, the overall outcome of those pregnancies was favourable. Therefore, the option of reduction to singletons should be considered in cases where the risk of prematurity seems exceptionally high.

Lymphatic Function in Autoimmune Diseases.

Lymphatic vessels are critical for clearing fluid and inflammatory cells from inflamed tissues and also have roles in immune tolerance. Given the functional association of the lymphatics with the immune system, lymphatic dysfunction may contribute to the pathophysiology of rheumatic autoimmune diseases. Here we review the current understanding of the role of lymphatics in the autoimmune diseases rheumatoid arthritis, scleroderma, lupus, and dermatomyositis and consider the possibility that manual therapies such as massage and acupuncture may be useful in improving lymphatic function in autoimmune diseases.

Neuropsychiatric lupus: new mechanistic insights and future treatment directions.

Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system (CNS) involvement, termed neuropsychiatric SLE (NPSLE). The CNS manifestations of SLE are diverse and have a broad spectrum of severity and prognostic implications. Patients with NPSLE typically present with nonspecific symptoms, such as headache and cognitive impairment, but might also experience devastating features, such as memory loss, seizures and stroke. Some features of NPSLE, in particular those related to coagulopathy, have been characterized and an evidence-based treatment algorithm is available. The cognitive and affective manifestations of NPSLE, however, remain poorly understood. Various immune effectors have been evaluated as contributors to its pathogenesis, including brain-reactive autoantibodies, cytokines and cell-mediated inflammation. Additional brain-intrinsic elements (such as resident microglia, the blood-brain barrier and other neurovascular interfaces) are important facilitators of NPSLE. As yet, however, no unifying model has been found to underlie the pathogenesis of NPSLE, suggesting that this disease has multiple contributors and perhaps several distinct aetiologies. This heterogeneity presents a challenge for clinicians who have traditionally relied on empirical judgement in choosing treatment modalities for patients with NPSLE. Improved understanding of this manifestation of SLE might yield further options for managing this disease.

The pathogenesis, diagnosis and treatment of lupus nephritis.

PURPOSE OF REVIEW: Renal involvement is a major cause of morbidity and mortality in systemic lupus erythematosus. In this review, we provide an update on recent discoveries in the pathogenesis, diagnosis, and treatment of lupus nephritis. RECENT FINDINGS: Localized long-lived plasma cells have been identified as playing an important role in lupus nephritis. In addition, the roles of aberrant expression of microRNAs and proinflammatory cytokines have been explored. Early diagnosis is important for effective treatment and multiple biomarkers have been identified; however, none has been yet validated for clinical use. Biomarker panels may turn out to be more accurate than each individual component. Biologic agents for the treatment of lupus nephritis are being studied, including belimumab which was recently approved for nonrenal systemic lupus erythematosus. Rituximab has not proven itself in large, placebo-controlled trials, although it is still being used in refractory cases of lupus nephritis. SUMMARY: Lupus nephritis is a potentially devastating complication of systemic lupus erythematosus. Immune cells, cytokines, and epigenetic factors have all been recently implicated in lupus nephritis pathogenesis. These recent discoveries may enable a paradigm shift in the treatment of this complex disease, allowing the tailoring of treatment to target specific pathogenic mediators at specific points in time in the progression of disease.

Headaches related to rheumatologic disease.

Headaches are a common, but under-recognized and understudied symptom in the context of the rheumatic diseases. They can result from intracranial pathology, such as parenchymal and meningeal inflammation, thrombosis, space-occupying lesions, and more. Inflammation, irritation, or degeneration of anatomically related structures such as the eyes, neck, and sinuses can equally cause headaches. In addition, patients with rheumatologic disorders have the same tendencies as the general population to develop primary headaches. While the latter are benign in nature, and generally require only symptomatic relief, the former type of headaches may signal disease manifestation, progression, or complication. Thus, familiarity with common and uncommon headache syndromes related to rheumatologic disorders as well as with their possible underlying disease processes and mechanisms is important. This will help to successfully develop an effective approach toward the evaluation of patients presenting with headaches in a rheumatologic context, and, ultimately, diagnose and treat potentially severe underlying disease.

Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis.

OBJECTIVES: Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis. METHODS: Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit's uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort. RESULTS: uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort. CONCLUSIONS: uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.

Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study.

INTRODUCTION: TNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF-kappaB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity. METHODS: Multicenter cohorts of systemic lupus erythematosus (SLE) patients and controls were recruited for cross-sectional and longitudinal analysis of urinary TWEAK (uTWEAK) and/or serum TWEAK (sTWEAK) levels as potential biomarkers of LN. The performance of TWEAK as a biomarker for nephritis was compared with routinely used laboratory tests in lupus patients, including anti-double stranded DNA antibodies and levels of C3 and C4. RESULTS: uTWEAK levels were significantly higher in LN patients than in non-LN SLE patients and other disease control groups (P = 0.039). Furthermore, uTWEAK was better at distinguishing between LN and non-LN SLE patients than anti-DNA antibodies and complement levels, while high uTWEAK levels predicted LN in SLE patients with an odds ratio of 7.36 (95% confidence interval = 2.25 to 24.07; P = 0.001). uTWEAK levels peaked during LN flares, and were significantly higher during the flare than at 4 and 6 months prior to or following the flare event. A linear mixed-effects model showed a significant association between uTWEAK levels in SLE patients and their disease activity over time (P = 0.008). sTWEAK levels, however, were not found to correlate with the presence of LN or the degree of nephritis activity. CONCLUSIONS: High uTWEAK levels are indicative of LN, as opposed to non-LN SLE and other healthy and disease control populations, and reflect renal disease activity in longitudinal follow-up. Thus, our study further supports a role for TWEAK in the pathogenesis of LN, and provides strong evidence for uTWEAK as a candidate clinical biomarker for LN.

TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus.

TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.