Fibromyalgia, mood disorders, cognitive test results, cognitive symptoms and quality of life in systemic lupus erythematosus.

OBJECTIVES: Cognitive dysfunction, and comorbidities such as mood disorder and fibromyalgia, are common in SLE. This study aims to explore the associations between fibromyalgia, mood disorders, cognitive symptoms and cognitive dysfunction in SLE patients, and their impact on quality of life. METHODS: We tested cognition in SLE patients and healthy controls, and evaluated cognitive symptoms, mood disorder, fibromyalgia, fatigue and quality of life using patient-reported outcome measures. We examined associations of these comorbidities with both patient-reported cognitive symptoms and cognitive test performance. RESULTS: High fibromyalgia symptom score and history of depression or anxiety were associated with cognitive dysfunction. There were no significant associations between current depression, anxiety symptoms or fatigue score and objective cognitive dysfunction. In contrast, mood disorder symptoms, history of mood disorder, fibromyalgia symptoms and fatigue all had significant associations with patient-reported cognitive symptoms. There were no significant associations between patient-reported cognitive symptoms and objective cognitive dysfunction. Objective cognitive dysfunction, patient-reported cognitive symptoms, history of mood disorder and fibromyalgia symptoms all had significant associations with poorer quality of life; fibromyalgia had the biggest impact. CONCLUSIONS: Cognitive symptoms are common in SLE, but there were no associations between cognitive symptoms and objective cognitive dysfunction. Depression, anxiety and fibromyalgia were more consistently associated with patient-reported cognitive symptoms than with objective cognitive dysfunction. These factors all have a significant impact on quality of life. Understanding the discrepancy between patient-reported cognitive symptoms and cognitive test performance is essential to advance care in this area of unmet need.

Evaluation of the Montreal Cognitive Assessment as a screening tool for cognitive dysfunction in SLE.

OBJECTIVES: Cognitive dysfunction in SLE is common and associated with significant morbidity but is currently underdetected. Early detection requires the use of screening tests, as formal diagnostic cognitive testing is time-consuming. This study aims to evaluate the Montreal Cognitive Assessment (MoCA) as a screening tool for cognitive dysfunction in SLE. METHODS: Patients with SLE (n=95) and demographically matched healthy control participants (n=48) underwent cognitive testing using the 1-hour neuropsychiatric test battery recommended by the American College of Rheumatology for use in SLE and the MoCA. We used regression analyses to determine associations between MoCA and cognitive test scores. We assessed several MoCA cut-offs for predicting cognitive impairment in terms of sensitivity, specificity, positive predictive value and negative predictive value. Receiver operating curve analyses were used to determine the diagnostic accuracy of the MoCA cut-off thresholds. RESULTS: We found a significant correlation between MoCA score and 9 of the 10 cognitive endpoints studied (all p<0.001). Receiver operating curve analysis suggested that a MoCA cut-off of <27 had highest diagnostic accuracy across the cognitive impairment definitions (area under the curve 0.76-0.78). Using a screening cut-off of <28, the MoCA had sensitivity of 83%-94% and specificity of 46%-59%, depending on the impairment definition used. CONCLUSIONS: The MoCA correlates strongly with cognitive test results in SLE and has sufficient sensitivity for use as a screening tool with a cut-off of <28 as the optimal threshold. This tool can be incorporated into clinical practice for screening for cognitive dysfunction in SLE.

Granulocyte colony-stimulating factor is not pathogenic in lupus nephritis.

Systemic lupus erythematosus (lupus) is an autoimmune disease characterized by autoantibodies that form immune complexes with self-antigens, which deposit in various tissues, leading to inflammation and disease. The etiology of disease is complex and still not completely elucidated. Dysregulated inflammation is an important disease feature, and the mainstay of lupus treatment still utilizes nonspecific anti-inflammatory drugs. Granulocyte colony-stimulating factor (G-CSF) is a growth, survival, and activation factor for neutrophils and a mobilizer of hematopoietic stem cells, both of which underlie inflammatory responses in lupus. To determine whether G-CSF has a causal role in lupus, we genetically deleted G-CSF from Lyn-deficient mice, an experimental model of lupus nephritis. Lyn-/- G-CSF-/- mice displayed many of the inflammatory features of Lyn-deficient mice; however, they had reduced bone marrow and tissue neutrophils, consistent with G-CSF's role in neutrophil development. Unexpectedly, in comparison to aged Lyn-deficient mice, matched Lyn-/- G-CSF-/- mice maintained neutrophil hyperactivation and exhibited exacerbated numbers of effector memory T cells, augmented autoantibody titers, and worsened lupus nephritis. In humans, serum G-CSF levels were not elevated in patients with lupus or with active renal disease. Thus, these studies suggest that G-CSF is not pathogenic in lupus, and therefore G-CSF blockade is an unsuitable therapeutic avenue.

Associations of serum soluble Fas and Fas ligand (FasL) with outcomes in systemic lupus erythematosus.

OBJECTIVE: Fas/Fas ligand (FasL) and B cell-activating factor (BAFF) signalling have pivotal roles in SLE pathogenesis. We investigated the clinical associations of serum concentrations of soluble Fas (sFas) and soluble FasL (sFasL) in SLE and their relationship with BAFF. METHODS: Serum sFas and sFasL were quantified by multiplex assay, and BAFF by ELISA, in 118 patients with SLE and 17 healthy controls (HC). SLE disease activity and organ damage were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics Damage Index. RESULTS: sFas, sFasL and BAFF were detectable in all samples. Serum sFas and sFasL were significantly higher in SLE compared with HC. In univariable regression analyses, patients with active renal disease and those with flare had significantly higher levels of sFas compared with those without. High serum BAFF in patients with SLE was associated with increased sFas but not sFasL. The association between sFas and renal disease remained significant after adjusting for BAFF, but the association with flare attenuated. High sFas levels were associated with increased time-adjusted mean SLEDAI-2K, even after adjusting for BAFF, and with higher odds of flare over time. In contrast, high sFasL was associated with reduced organ damage over time. Serum sFasL/sFas ratio was negatively associated with active overall disease, flare and organ damage. CONCLUSIONS: Serum sFas is associated with active renal SLE, and active disease and flare over time, while sFasL/sFas ratio is negatively associated with disease activity and organ damage accrual. Treatments correcting abnormal levels of sFas/FasL may be worthy of evaluation in SLE.

Analysis of serum B cell-activating factor from the tumor necrosis factor family (BAFF) and its soluble receptors in systemic lupus erythematosus.

OBJECTIVES: To determine the presence and clinical associations of the soluble receptors of B cell-activating factor from the tumor necrosis factor family (BAFF) in serum of patients with systemic lupus erythematosus (SLE). METHODS: Serum BAFF and soluble BAFF receptor (sBAFF-R) were quantified using ELISA, and soluble B cell maturation antigen (sBCMA) and transmembrane activator and cyclophilin ligand interactor (sTACI) by Luminex, in 87 SLE patients and 17 healthy controls (HC). Disease activity and organ damage were assessed using SLE Disease Activity Index 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC) SLE Damage Index (SDI), respectively. RESULTS: BAFF and all receptors were detectable in all serum samples. Serum sBCMA and sTACI, but not sBAFF-R, were significantly higher in SLE than in HC. Serum BAFF was also increased in SLE, but this association was attenuated after adjusting for age and ethnicity. Increased serum BAFF was associated with flare and organ damage. Increased serum sBCMA was associated with the presence of anti-dsDNA, but not with overall or organ-specific disease activity, flare or organ damage. Neither sTACI nor sBAFF-R was associated with any SLE clinical parameters in multivariable analysis. While serum BAFF correlated negatively with sBAFF-R in HC, no statistically significant correlations were observed between BAFF and its receptors in SLE patients. CONCLUSION: Serum BAFF was associated with flare and organ damage independent of the presence of its soluble receptors. While sBCMA was associated with anti-dsDNA positivity, other soluble BAFF receptors were not associated with SLE clinical indicators.

Analysis of urinary macrophage migration inhibitory factor in systemic lupus erythematosus.

OBJECTIVE: To characterise the clinical relevance of urinary macrophage migration inhibitory factor (uMIF) concentrations in patients with systemic lupus erythematosus (SLE). METHODS: MIF, adjusted for urine creatinine, was quantified by ELISA in urine samples from 64 prospectively recruited patients with SLE. Serum MIF and urinary monocyte chemoattractant protein 1 (uMCP-1) were quantified by ELISA in a subset of patients (n = 39). Disease activity was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K) score. RESULTS: uMIF was detectable in all patients with SLE. uMIF was positively correlated with overall SLEDAI-2K, was significantly higher in patients with SLE with high disease activity (SLEDAI-2K≥10) compared with those with inactive disease (SLEDAI-2K<4), and this association remained significant after adjusting for ethnicity, flare and use of immunosuppressants. uMIF was also significantly higher in SLE patients with flare of disease, although not confirmed in multivariable analysis. No significant differences in uMIF levels were observed according to the presence of renal disease activity, as assessed by renal SLEDAI-2K or biopsy-confirmed lupus nephritis. In contrast, uMCP-1 was significantly higher in SLE patients with active renal disease. uMIF expression was not associated with irreversible organ damage accrual or glucocorticoid use. CONCLUSIONS: These data suggest uMIF as a potential overall but not renal-specific SLE biomarker, whereas uMCP-1 is a renal-specific SLE biomarker.

Brief Report: Interleukin-38 Exerts Antiinflammatory Functions and Is Associated With Disease Activity in Systemic Lupus Erythematosus.

OBJECTIVE: Knowledge of interleukin-38 (IL-38), formerly IL-1 family member 10, is sparse, but Il1f10 polymorphisms are associated with inflammatory diseases, and recombinant IL-38 inhibits inflammatory responses similar to those reported in the context of systemic lupus erythematosus (SLE). We undertook this study to explore the function of endogenous IL-38 in human peripheral blood mononuclear cells (PBMCs) as well as its abundance in serum in a well-characterized cohort of SLE patients. METHODS: Serum IL-38 and IL-10 levels were quantified by enzyme-linked immunosorbent assay in 142 SLE patients at ≤3 consecutive visits and in 28 healthy volunteers. To assess IL-38 function, we silenced IL-38 in PBMCs from healthy donors using IL-38 small interfering RNA (siRNA). RESULTS: IL-38 (63-5,928 pg/ml) was detectable in 16% of 372 serum samples. IL-38 abundance was significantly higher in samples from SLE patients than in samples from healthy controls (P = 0.004) and 11-fold higher in patients with active disease (SLE Disease Activity Index 2000 [SLEDAI-2K] score of ≥4) than in those with inactive disease (SLEDAI-2K score of <4) (P = 0.044). Importantly, IL-38 detection was associated with increased risk of renal lupus (relative risk [RR] 1.6, P = 0.027) and central nervous system lupus (RR 2.3, P = 0.034), and detectable baseline IL-38 entailed a 1.6-fold increased risk of subsequently meeting criteria for persistently active disease (P = 0.0097). Longitudinal time-adjusted mean IL-38 concentration was also 6-fold higher in patients with persistently active disease than in those without (P = 0.023). Remarkably, PBMCs treated with IL-38 siRNA produced up to 28-fold more of the proinflammatory mediators IL-6, CCL2, and APRIL than did control siRNA-transfected cells upon stimulation with Toll-like receptor agonists. Similarly, in SLE patients, the antiinflammatory cytokine IL-10 was 5-fold more abundant when IL-38 was detectable. CONCLUSION: This is the first study of the function of endogenous IL-38, and the data suggest that IL-38 may be protective in SLE. A strong association between IL-38 and SLE severity suggests that IL-38 expression is driven by processes linked to SLE pathogenesis. Exploitation of the regulatory effects of IL-38 may represent a promising therapeutic strategy in SLE.

Clinical associations of serum interleukin-17 in systemic lupus erythematosus.

INTRODUCTION: Serum interleukin (IL)-17 concentrations have been reported to be increased in systemic lupus erythematosus (SLE), but associations with clinical characteristics are not well understood. We characterized clinical associations of serum IL-17 in SLE. METHODS: We quantified IL-17 in serum samples from 98 SLE patients studied cross-sectionally, and in 246 samples from 75 of these patients followed longitudinally over two years. Disease activity was recorded using the SLE Disease Activity Index (SLEDAI)-2k. Serum IL-6, migration inhibitory factor (MIF), and B cell activating factor of the tumour necrosis factor family (BAFF) were also measured in these samples. RESULTS: Serum IL-17 levels were significantly higher in SLE patients compared to healthy donors (P <0.0001). No correlation was observed between serum IL-17 and SLEDAI-2k, at baseline or during longitudinal follow-up. However, we observed that SLEDAI-2k was positively correlated with IL-17/IL-6 ratio. Serum IL-17 was significantly increased in SLE patients with central nervous system (CNS) disease (P = 0.0298). A strong correlation was observed between serum IL-17 and IL-6 (r = 0.62, P <0.0001), and this relationship was observed regardless of disease activity and persisted when integrating cytokine levels over the period observed (r = 0.66, P <0.0001). A strong correlation of serum IL-17 was also observed with serum BAFF (r = 0.64, P <0.0001), and MIF (r = 0.36, P = 0.0016). CONCLUSIONS: Serum IL-17 concentration correlates poorly with SLE disease activity but is significantly elevated in patients with CNS disease. IL-17/IL-6 ratio may be more useful than IL-17 or IL-6 alone to characterize Th17-driven disease, such as SLE. The association of other cytokines with serum IL-17 suggests that IL-17 may drive activation of diverse immune pathways in SLE.

Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment, glomerulonephritis, and lethality in MRL/lpr mice.

Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disease of unknown etiology. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is operative in innate and adaptive immunity and important in immune-mediated diseases such as rheumatoid arthritis and atherosclerosis. The functional relevance of MIF in systemic autoimmune diseases such as SLE is unknown. Using the lupus-prone MRL/lpr mice, we aim to examine the expression and function of MIF in this murine model of systemic autoimmune disease. These experiments revealed that renal MIF expression was significantly higher in MRL/lpr mice compared with nondiseased control mice (MRL/MpJ), and MIF was also markedly up-regulated in skin lesions of MRL/lpr mice. To examine the effect of MIF on development of systemic autoimmune disease, we generated MRL/lpr mice with a targeted disruption of the MIF gene (MIF(-/-)MRL/lpr), and compared their disease manifestations to MIF(+/+)MRL/lpr littermates. MIF(-/-)MRL/lpr mice exhibited significantly prolonged survival, and reduced renal and skin manifestations of SLE. These effects occurred in the absence of major changes in T and B cell markers or alterations in autoantibody production. In contrast, renal macrophage recruitment and glomerular injury were significantly reduced in MIF(-/-)MRL/lpr mice, and this was associated with reduction in the monocyte chemokine MCP-1. Taken together, these data suggest MIF as a critical effector of organ injury in SLE.