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.

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.

The Dose-Response Association between Nitrogen Dioxide Exposure and Serum Interleukin-6 Concentrations.

Systemic inflammation is an integral part of chronic obstructive pulmonary disease (COPD), and air pollution is associated with cardiorespiratory mortality, yet the interrelationships are not fully defined. We examined associations between nitrogen dioxide (NO2) exposure (as a marker of traffic-related air pollution) and pro-inflammatory cytokines, and investigated effect modification and mediation by post-bronchodilator airflow obstruction (post-BD-AO) and cardiovascular risk. Data from middle-aged participants in the Tasmanian Longitudinal Health Study (TAHS, n = 1389) were analyzed by multivariable logistic regression, using serum interleukin (IL)-6, IL-8 and tumor necrosis factor-α (TNF-α) as the outcome. Mean annual NO2 exposure was estimated at residential addresses using a validated satellite-based land-use regression model. Post-BD-AO was defined by post-BD forced expiratory ratio (FEV1/FVC) < lower limit of normal, and cardiovascular risk by a history of either cerebrovascular or ischaemic heart disease. We found a positive association with increasing serum IL-6 concentration (geometric mean 1.20 (95% CI: 1.1 to 1.3, p = 0.001) per quartile increase in NO2). This was predominantly a direct relationship, with little evidence for either effect modification or mediation via post-BD-AO, or for the small subgroup who reported cardiovascular events. However, there was some evidence consistent with serum IL-6 being on the causal pathway between NO2 and cardiovascular risk. These findings raise the possibility that the interplay between air pollution and systemic inflammation may differ between post-BD airflow obstruction and cardiovascular diseases.

The Australian and New Zealand Haemostasis Registry: ten years of data on off-licence use of recombinant activated factor VII.

BACKGROUND: Recombinant activated factor VII (rFVIIa) has been widely used as an off-licence pan-haemostatic agent in patients with critical bleeding. However, outside the trauma setting, there is relatively little high quality evidence on the risks and benefits of this agent. The Haemostasis Registry was established to investigate the extent of use, dosing, safety and outcomes of patients after off-licence rFVIIa treatment of critical bleeding. MATERIALS AND METHODS: The Registry recruited non-haemophiliac patients treated with rFVIIa from 2000-2009 (inclusive) in Australia and New Zealand. Detailed information was gathered on patients' demographics, context of bleeding, rFVIIa administration, laboratory results, blood component and other therapies, and outcomes. Outcome measures included subjectively assessed effect of rFVIIa on bleeding (response), adverse events (thromboembolic and other) and 28-day mortality. RESULTS: The registry included 3,446 cases in 3,322 patients (median [IQR] age 56 [33-70] years, 65% (n=2,147) male). Clinical indications included cardiac surgery (45%), other surgery (18%), trauma (13%), medical bleeding (6%), liver disease (6%), and obstetric haemorrhage (5%). The median [IQR] dose was 91 [72-103] µg/kg and 77% received a single dose. Reduction or cessation of bleeding was reported in 74% and 28-day survival was 71% but outcomes varied depending on clinical context. pH strongly correlated with outcome measures; 81% of patients with pH <7.1 died. Approximately 11% of patients had thromboembolic adverse events. In multivariate analysis, pH prior to administration and bleeding context were independently associated with reported response to rFVIIa and 28-day mortality. DISCUSSION: The Haemostasis Registry is the largest dataset of its kind and provides observational data on the off-licence use of rFVIIa over a 10-year period. It has been an invaluable resource for rigorously tracking adverse events and helping to inform clinical practice.

Use of recombinant activated factor VII in Jehovah's Witness patients with critical bleeding.

INTRODUCTION: The Australian and New Zealand Haemostasis Registry (ANZHR) included patients who received off-licence recombinant activated factor VII (rFVIIa) for critical bleeding from 2000 to 2009. Approximately 1.3% of the ANZHR patients were Jehovah's Witnesses (JWs). We compared them with the non-JW patients in the registry. METHODS: Patient characteristics (e.g. gender, context of bleeding), factors influencing rFVIIa use (e.g. body temperature and pH) and outcomes (e.g. bleeding response (stopped/attenuated or unchanged) to rFVIIa, mortality) were compared between JW and non-JW patients using Fisher's exact chi-square tests and Kruskal-Wallis tests. RESULTS: A total of 42 JW and 3134 non-JW patients were included in the analysis. Approximately 99% (n = 3098) of non-JWs received blood products compared with only 30% (n = 13) of JWs (P < 0.01). The distribution of gender and contexts of critical bleeding in the two groups was significantly different. Approximately 17% of the non-JW patients were hypothermic (T < 35°C) and about 19% were acidotic (pH < 7.2) at the time of initial rFVIIa administration. Conversely, none of the JWs were hypothermic and only one was acidotic. The proportion of positive responders to rFVIIa (stopped/attenuated bleeding following rFVIIa use) was similar in both groups (75% non-JWs, 74% JWs; P = 1.0). Approximately 28% of non-JW and 17% of JW patients were deceased by day 28 following rFVIIa use (P = 0.16). DISCUSSION: Several factors were observed to be significantly different between JW and non-JW patients, yet the proportions of responders to rFVIIa were similar in both groups. The actual factors influencing response to rFVIIa are yet to be determined.