Cytokine profiling in active and quiescent SLE reveals distinct patient subpopulations.

BACKGROUND: Patients with SLE display marked clinical and immunlogical heterogeneity. The purpose of the study was to investigate patterns of serum cytokines in patients with active and stable systemic lupus erythematosus (SLE) and to determine how they relate to clinical phenotype. METHODS: Serum levels of 10 cytokines were measured retrospectively in a cohort of patients with SLE and in healthy controls using a high-sensitivity multiplex bead array. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG-2004) indices. Logistic regression models were used to determine the association between cytokine levels and active SLE. Principal component analysis (PCA) and cluster analysis was then used to identify subgroups of patients on the basis of cytokine levels. RESULTS: Serum chemokine (C-X-C motif) ligand 10 (CXCL10) and CXCL13 were significantly higher in patients with SLE compared to healthy controls. Two cytokines (pentraxin-related protein (PTX3) and CXCL10) were significantly higher in patients with active disease after adjustment for potential confounding factors. Measurement of four cytokines (CXCL10, IL-10, IL-21 and PTX3) significantly improved the performance of a model to identify patients with clinically active disease. Cluster analysis revealed that the patients formed 3 distinct groups, characterised by higher levels of interferon alpha (IFNα) and B lymphocyte stimulator (BLyS) (group 1), increased CXCL10 and CXCL13 (group 2) or low levels of cytokines (group 3). Group 2 had significantly lower serum complement and higher anti-double-stranded DNA antibodies and increased prevalence of inflammatory arthritis. CONCLUSIONS: Multiplex analysis has identified a serum cytokine signature for active SLE. Within the SLE population distinct cytokine subgroups were identified, with differing clinical and immunological phenotypes that appeared stable over time. Assessment of cytokine profiles may reveal unique insights into disease heterogeneity.

Tracking of Inhaled Near-Infrared Fluorescent Nanoparticles in Lungs of SKH-1 Mice with Allergic Airway Inflammation.

Molecular imaging of inflammatory lung diseases, such as asthma, has been limited to date. The recruitment of innate immune cells to the airways is central to the inflammation process. This study exploits these cells for imaging purposes within the lung, using inhaled polystyrene nanoparticles loaded with the near-infrared fluorescence dye Itrybe (Itrybe-NPs). By means of in vivo and ex vivo fluorescence reflectance imaging of an ovalbumin-based allergic airway inflammation (AAI) model in hairless SKH-1 mice, we show that subsequent to intranasal application of Itrybe-NPs, AAI lungs display fluorescence intensities significantly higher than those in lungs of control mice for at least 24 h. Ex vivo immunofluorescence analysis of lung tissue demonstrates the uptake of Itrybe-NPs predominantly by CD68(+)CD11c(+)ECF-L(+)MHCII(low) cells, identifying them as alveolar M2 macrophages in the peribronchial and alveolar areas. The in vivo results were validated by confocal microscopy, overlapping tile analysis, and flow cytometry, showing an amount of Itrybe-NP-containing macrophages in lungs of AAI mice significantly larger than that in controls. A small percentage of NP-containing cells were identified as dendritic cells. Flow cytometry of tracheobronchial lymph nodes showed that Itrybe-NPs were negligible in lung draining lymph nodes 24 h after inhalation. This imaging approach may advance preclinical monitoring of AAI in vivo over time and aid the investigation of the role that macrophages play during lung inflammation. Furthermore, it allows for tracking of inhaled nanoparticles and can hence be utilized for studies of the fate of potential new nanotherapeutics.

Efficacy and safety of ciclesonide in patients with severe asthma: a 12-week, double-blind, randomized, parallel-group study with long-term (1-year) follow-up.

OBJECTIVE: To investigate the efficacy and safety of ciclesonide in patients with severe asthma over a 1-year period. RESEARCH DESIGN AND METHODS: Patients aged 18 - 75 years with persistent asthma were enrolled in a 12-week, double-blind, randomized study and treated with ciclesonide 320 or 640 µg twice daily (b.i.d.) with the option of continuing in a 40-week extension phase (EP). MAIN OUTCOMES MEASURES: Change in morning peak expiratory flow (PEF) from baseline to 12 weeks and safety over 1 year. RESULTS: 365 patients were randomized and 275 continued into the EP. During 12 weeks' treatment, morning peak expiratory flow significantly increased by 16 l/min (p < 0.001) and 14 l/min (p = 0.001) in the 320 and 640 µg b.i.d. groups, respectively. Both doses significantly reduced total asthma symptom scores by 0.29 (p < 0.0001). In both groups, the incidence of adverse effects (AEs) was low and mean cortisol levels in serum and urine were not suppressed during the EP. CONCLUSIONS: Ciclesonide 320 µg b.i.d. sustained lung function and asthma symptoms in patients with severe asthma over 12 weeks' treatment, and maintained lung function during a 40-week EP; ciclesonide 640 µg b.i.d. did not provide additional benefits. Long-term use of ciclesonide was not associated with increased local AEs or negative effects on cortisol levels.

5-lipoxygenase inhibitors for the treatment of COPD.

The potential for leukotrienes as mediators to target in the development of novel therapies for diseases such as COPD is underscored by their inflammatory behavior and the capacity of leukotriene receptor antagonists and synthesis inhibitors to reduce inflammatory responses when administered in vivo. Airway neutrophilia in COPD patients is believed to be a contributing source of inflammation and is associated with airway remodeling. The presence of neutrophils is mediated in part by leukotriene B(4) (LTB(4)), and the capacity for LTB(4) alone to replicate many aspects of neutrophilic inflammation has provided the focus of drug development toward its specific antagonism. More recently, the potential involvement of the monocyte-macrophage lineage in the etiology of COPD has received growing attention as a target for leukotriene inhibition. The future avenues for exploration of leukotriene inhibition could have been expanded by the realization that 5-lipoxygenase activity is primarily located at the nuclear membrane and the existence of differing cell surface and nuclear receptors to LTB(4). The success of compounds under development in this and other anti-inflammatory classes, however, depends as much on the evolution of clinical studies designed to test the "proof of concept" in efficacy through the examination of surrogate markers or physiologic readouts of changes in lung function.