How to mechanistically explain the CONDOR study data.

Results of the CONDOR study suggest that in osteoarthritis and rheumatoid arthritis patients at elevated risk of gastrointestinal (GI) events, treatment with celecoxib, a cyclooxygenase (COX)-2 selective non-steroidal anti-inflammatory drug (NSAID), demonstrated significantly lower toxicity in the upper and lower (GI) tract when compared to the non-selective NSAID diclofenac plus a proton-pump-inhibitor (PPI), omeprazole. According to current knowledge, traditional NSAIDs (tNSAIDs) as non-selective COX-inhibitors exert their damaging effects on the upper GI tract, largely by reduction of the COX-1 related synthesis of gastro-protective prostaglandins. Thus, the question arises, how NSAIDs do exert their damaging effects especially in the lower GI tract and how to explain the reduced risk of a COX-2 selective inhibitor, celecoxib. Here we hypothesize, that the toxicity of celecoxib on enteral mucosa cells is lower than observed with other NSAIDs, and can be explained COX-independently by typical physicochemical properties of the NSAID substances (e.g., acidic, lipophilic, amphiphilic, surfactant properties). As a consequence these features account for differences in (1) uncoupling effects on mitochondria, (2) effects on cell membrane integrity, and/or (3) formation of "toxic micelles" with bile salts. The evidence for these differences is mainly based on experimental findings. However, several phenomena show differences in extent (e.g., uncoupling effects). The reduced toxicity appears to be rather a substance-specific characteristic. This is an unconditional reason to carry on investigating these phenomena in experimental and large-scale clinical trials.

Prednisone chronotherapy.

Glucocorticoids (GCs) are widely used in clinical medicine because of their anti-inflammatory and immunosuppressive effects. However, these agents have a considerable potential for adverse effects, especially if used in high doses. The currently most advanced approach to improve the risk-benefit ratio of GCs is low-dose prednisone chronotherapy with modified release (MR) prednisone timing drug release to chronobiological rhythms. In RA, the circadian rhythms of pain, stiffness and functional disability show maximum symptoms in the early morning hours, which is preceded by elevated levels of pro-inflammatory cytokines, in particular interleukin 6. It was hypothesised that preventing the nocturnal rise of pro-inflammatory cytokines by GC therapy is more effective than treating established symptoms in the morning. As waking in the night for tablet intake is impracticable, modified release (MR) prednisone was developed, which releases prednisone approximately four hours after ingestion (i.e. at approximately 2 am if taken at 10 pm bedtime). Data from two large-scale trials in rheumatoid arthritis (RA) (CAPRA-1 and 2) document that MR prednisone has greater efficacy for long-term, low-dose glucocorticoid treatment in patients with RA, with a significant reduction in morning joint stiffness, in addition to all known therapeutic effects with conventional prednisone and a similar safety profile without additional suppression of hypothalamic-pituitary-adrenal (HPA) axis. For patients with RA on low to medium doses of prednisone, especially those who continue to experience a long duration of morning stiffness, MR prednisone appears a valuable additional treatment option.

Pharmacodynamics of glucocorticoids.

Exogenous glucocorticoids (GCs) are used as anti-inflammatory and immunosuppressive drugs in the treatment of a wide range of rheumatic and other inflammatory diseases. GCs exert their immunosuppressive, anti-inflammatory and anti-allergic effects on primary and secondary immune cells, tissues and organs via different mechanisms of action in a dose-dependent manner. However, their pleiotropic effects also lead to numerous adverse effects such as unwanted metabolic effects and osteoporosis. The mechanisms of action include the classical genomic mechanism resulting from activation of the cytosolic glucocorticoid receptor (cGCR), non-specific, non-genomic effects caused by interactions with cellular membranes, secondary non-genomic effects initiated by the cGCR and specific interactions with a membrane-bound glucocorticoid receptor (mGCR). Optimised glucocorticoids, such as selective glucocorticoid receptor agonists, are being developed to minimise the adverse effects many patients experience, especially if GCs are given at higher dosages over longer periods of time. Immunostimulatory effects of low concentrations of endogenous glucocorticoids and the influence of pre-receptor metabolism appear of interest for further investigation. The most important approach to optimise the risk-benefit ratio of GCs is to understand in more detail how the molecular mechanisms of genomic and non-genomic GC actions - and their dose-dependency - mediate the clinically wanted benefits but also the known adverse effects.

Methotrexate treatment in large vessel vasculitis and polymyalgia rheumatica.

In large vessel vasculitis, including giant cell arteritis and Takayasu arteritis, as well as in polymyalgia rheumatica, glucocorticoid therapy is the treatment of choice. However, there are two situations/questions for additional immunosuppressive therapies in these diseases: (i) therapy resistance to glucocorticoid mono-therapy; (ii) situations which call for sparing of glucocorticoids such as in complications of glucocorticoid therapy. This review summarises the current scientific debate on the effects of methotrexate in these diseases. Methotrexate at 10-15 mg/week appears to have a modest and delayed effect in GCA and PMR in reducing relapse rate and lowering the cumulative dose of glucocorticoid therapy. However, superiority of combination therapy in reducing the incidence of glucocorticoid-related complications has not been shown yet. The effects of higher doses and long-time effects as well as the efficacy in patients with glucocorticoid-resistance and complications are unclear. Methotrexate may thus be considered as adjunctive therapy to glucocorticoid therapy in glucocorticoid-resistance or complications. Further attempts should be made for a better identification of patients with glucocorticoid-refractory courses and a more precise formulation of guidelines on indication, optimal dosing and duration.

Effects of hypoxia and/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4+ T lymphocytes.

Oxidative phosphorylation and/or glycolysis provide energy, mainly in the form of ATP, which ensures proper functioning of immune cells such as CD4(+) T lymphocytes. However, the main substrates, namely oxygen and glucose, are known to remain for a relatively short time in the inflamed tissue and in other clinical situations where immune cells need to function properly. Therefore, we examined the effect of hypoxia and/or lack of glucose on cellular energy metabolism and on cytokine secretion in stimulated human CD4(+) T lymphocytes. Human CD4(+) T cells were MACS-isolated using peripheral blood obtained from healthy donors. Stimulated cells were incubated in medium with or without glucose for 6h in a sealed chamber which led to cumulative hypoxia. During this incubation period, (i) oxygen saturation was measured continuously using a Clark-type electrode, and (ii) samples were taken at different time points in order to quantify for each the viability of cells, intracellular reactive oxygen species (iROS), ATP levels, glycolytic enzyme activity, mRNA expression of hexokinase-1 and superoxide dismutase-1, and concentrations of several different cytokines. Stimulated CD4(+) T cells which were incubated under normoxic conditions served as controls. Under hypoxic conditions, lack of glucose exerted a biphasic effect on cellular oxygen consumption: initially higher but later lower respiration rates were measured when compared to conditions where glucose was available. Lack of glucose strongly increased the number of dead cells and the formation of iROS under normoxia but not under hypoxia. Under both normoxic and hypoxic conditions, intracellular ATP levels remained almost unchanged during the incubation period if glucose was present, but decreased significantly in the absence of glucose, despite the enhanced glycolytic enzyme activity. Measurements of stimulated cytokine production demonstrated (i) that cumulative hypoxia stimulates especially the secretion of IL-1beta, IL-10 and IL-8, and (ii) that lack of glucose results in lower cytokine concentrations. We demonstrate that CD4(+) T cells are highly adaptive in bioenergetic terms which ensure their proper function under extreme conditions of glucose and/or oxygen availability as found under physiological and pathophysiological conditions. Hypoxia seems to facilitate inflammatory reactions and angiogenesis.

Analyses of similarities and differences in glucocorticoid therapy between rheumatoid arthritis and ankylosing spondylitis - a systematic comparison.

Glucocorticoids (GCs) have powerful and potent anti-inflammatory and immunomodulatory effects and are widely established in regard to the treatment of rheumatism and other diseases. In rheumatoid arthritis (RA), GCs are used systemically at several different dosages and/or local (intraarticular) therapy. They have been shown to exert strong short-term anti-inflammatory effects but also long-term positive effects on radiographic progression of the disease. In comparison, patients with ankylosing spondylitis (AS) are considered to be less responsive to GC therapy than patients with RA, although controlled studies on the effects of low-dose GCs in AS are lacking. In AS, GCs are mainly used for local therapy and occasionally for systemic pulse therapy only. The underlying mechanisms for these differences are unclear. GCs act on primary and secondary immune cells via different mechanisms of action: cytosolic GC receptor (cGCR)-mediated genomic and non-genomic effects, membrane-bound GC receptor (mGCR)-mediated non-genomic effects and - as achieved at very high concentrations - non-specific non-genomic effects. The phenomenon of GC resistance is also known in RA. Several different mechanisms may mediate this phenomenon; among them are alterations in number, binding affinity or phosphorylation status of the GCR, polymorphic changes and/or over-expression of chaperones/ co-chaperones, increased expression of inflammatory transcription factors, the multidrug resistance pump, over-expression of the GCR beta isoform, alteration in the expression of mGCR and imbalance of 11beta-hydroxysteroid dehydrogenase type 1 & 2 activity. Translation of insights on GC action and resistance obtained in RA to AS may contribute to a better understanding of the pathophysiology of both diseases.

Membrane glucocorticoid receptors are down regulated by glucocorticoids in patients with systemic lupus erythematosus and use a caveolin-1-independent expression pathway.

BACKGROUND: Membrane-bound glucocorticoid receptors (mGCR) are up regulated on monocytes after in vitro stimulation and in patients with rheumatoid arthritis. Caveolin-1 is critical for the transport of plasma membrane oestrogen receptors to the cell surface. OBJECTIVES: To investigate the expression of mGCR in patients with systemic lupus erythematosus (SLE)-a disease with different aetiopathogenesis and treatment regimens-and to examine whether caveolin-1 is critical for the transport of mGCR to the cell surface. METHODS: Frequencies of mGCR+ peripheral blood mononuclear cells were measured using high-sensitivity immunofluorescent staining and tested for correlation with SLE disease activity and glucocorticoid treatment. Semiquantitative polymerase chain reaction, immunofluorescence, recombinant expression and confocal laser-scanning microscopy were used to search for an association of mGCR with caveolin-1. RESULTS: The frequencies of mGCR+ monocytes (CD14+) were considerably higher in patients with SLE (n = 33) than in healthy controls (n = 58), whereas B cells (CD19+) were not different in this regard. T cells (CD3+) were always mGCR-. The frequency of mGCR+ monocytes in patients with SLE did not correlate with disease activity, but did inversely correlate with glucocorticoid dosages; this inverse correlation was confirmed by corresponding in vitro experiments with stimulated monocytes. The induced up regulation of mGCR was not accompanied by an up regulation of caveolin-1, and mGCR are not colocalised with caveolin-1 in plasma membrane caveolae. CONCLUSION: mGCR are (a) up regulated in patients with SLE and by inflammatory stimuli and (b) down regulated by glucocorticoids, suggesting a negative feedback loop to control glucocorticoid action. Drugs binding selectively to mGCR may in future prove to be of therapeutic value.