Echocardiography in Mitral Valve Disease

Or in the practice which treats business organizations as political structures? new marketing approach for products common to both, expanded dramatically. .. The use of sensitivity training with its attachment to “openness” and “leveling” in.

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A comparison of these studies revealed that whereas DHEA supplementation improved quality of life and glucocorticoid requirements, the impact on disease activity was inconsistent [ 20 ].

Systemic Lupus Erythematosus (SLE) - signs and symptoms, pathophysiology, investigations, treatment

A double-blind placebo-controlled clinical trial recently reported encouraging results in SLE women treated with an estrogen-selective receptor downregulator named fulvestrant faslodex, developed by AstraZeneca Pharmaceuticals, London, UK; Table 1 and Additional File 1. In patients who received mg fulvestrant intramuscularly for 12 months, the SLEDAI score improved significantly and conventional medications could be reduced [ 21 ].

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An increased frequency of hyperprolactinemia is observed in patients with SLE, and elevated prolactin levels have been correlated with clinical disease [ 22 ]. Prolactin administration has been demonstrated to accelerate disease progression in murine models of lupus reviewed in [ 23 ]. Taken together, these data showed that downregulation of the prolactin production may represent an interesting way to treat SLE.

As prolactin secretion is inhibited by dopamine released from the hypothalamus, the efficacy of bromocriptine Table 1 and Additional File 1 , which is a dopamine agonist, was evaluated in lupus. In an open-label trial including seven SLE patients, it was shown that bromocriptine 3. A double-blind, placebo-controlled study of low-dose bromocriptine therapy 2. A pilot clinical trial was recently conducted to explore the potential role of oral bromocriptine during pregnancy [ 26 ].

Results showed that bromocriptine may play a role in protecting pregnant lupus patients from maternal and fetal complications. During the past decade, a number of investigators have thus explored targeted strategies involving autoantigens in order to subvert or block key steps of the disease. Promising data have been raised in murine models of lupus, and a few therapeutic trials are currently in progress.

Two peptides and one peptide construct have reached advanced clinical trials in lupus patients. The efficacy of the first peptide, hCDR1 edratide, TV , although extremely promising in lupus mice, was found to be safe and well tolerated but did not meet its primary endpoint in a randomized, double-blind, placebo-controlled phase II clinical trial conducted by Teva Petach Tikva, Israel in SLE patients who received the peptide weekly by a subcutaneous route PRELUDE trial. The results of a second candidate, abetimus sodium LJP, riquent — evaluated in a randomized, placebo-controlled, multicenter phase III trial — have been recently published [ 27 ] Table 1 and Additional File 1.

Abetimus is a synthetic water-soluble molecule consisting of four double-stranded oligodeoxyribonucleotides each attached to a nonimmunogenic triethylene glycol backbone, a proprietary carrier platform [ 28 ]. Although multiple positive trends in renal endpoints were observed in the abetimus treatment group [ 27 ], it has been recently decided to halt further clinical trials of this drug in lupus.

Assessment measures in systemic lupus erythematosus

A third peptide-based strategy involving an autoantigen segment, peptide P IPP, lupuzor , holds promise Table 1 and Additional File 1. P peptide is currently being evaluated in a phase IIb, double-blind, placebo-controlled, dose-ranging study in Europe and Latin America to confirm the beneficial effects observed in the phase IIa trial.

Beside agents that are presently evaluated in clinical trials in patients with lupus, there are also a number of experimental compounds used with success in murine studies that deserve particular attention. They are described below because hopefully some of them represent interesting candidates for future clinical trials. The spleen tyrosine kinase-specific inhibitor R converted from the prodrug R developed by Rigel Pharmaceuticals Inc. Interestingly, signaling in lupus T cells is not effected by ZAP but replaced by spleen tyrosine kinase, leading to an increased calcium response upon T-cell receptor stimulation [ 33 ].

Although no clinical data from SLE lupus are yet available, results from a recent phase II clinical trial including patients with rheumatoid arthritis are encouraging [ 34 ].

Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects

The use of small molecules inhibiting intracellular mitogen-activated protein kinase and phosphoinoside 3-kinase enzymes that generate phosphatidylinositol diphosphate and triphosphate after receptor stimulation signaling pathways has also been envisaged. Promising molecules targeting the phosphoinoside 3-kinase pathway that have entered clinical trials for cancer therapy, inflammation and coronary heart disease are described in a recent review [ 38 ]. Molecules able to interfere with cell cycle should also be considered as potential candidates in the development of new lupus therapies.

Cell cycle progression is controlled by the activation of a heterodimer, formed by cyclins regulatory subunits associated with cyclin-dependent kinases catalytic subunits; Figure 1. When administered in the early stages of the disease, seliciclib was shown to delay the development of proteinuria, to reduce the production of anti-dsDNA Abs, and to prolong survival. Other agents for which efficacy has been already established in murine models of lupus may offer interesting therapeutic avenues in the future.

The ubiquitin—proteasome pathway is involved in intracellular protein turnover and its function is crucial to cellular homeostasis. These results led investigators to evaluate the efficacy of bortezomib for the depletion of plasma cells in lupus. Histone acetylation is an important regulator of gene expression, and therefore interfering with histone deacetylation could represent an interesting strategy to modulate altered gene expression in lupus. Histone deacetylase inhibitors have been used to reduce the disease in murine models of lupus.

These experimental data suggest that histone deacetylase inhibitors might have therapeutic interest to treat SLE. In lupus, the loss of self-tolerance leads to the persistence and activation of autoreactive B cells and T cells with the consecutive abnormal secretion of cytokines and production of autoAbs. The formation of immune complexes and the activation of the complement pathway also play a major role in disease pathogenicity.

These soluble proteins are thus interesting target candidates for the development of novel lupus therapies. The activation of the complement pathway in lupus amplifies both immune and inflammatory responses and is involved in the renal pathology. This therapeutic agent, named CR2-Crry, corresponds to a fusion protein that links the C3-binding region of complement receptor 2 CR2 to the complement receptor 1-related protein y Crry.

Crry is similar to human complement receptor 1 and inhibits C3 convertases of all pathways. Importantly, and contrary to observations with Crry-Ig, CR2-Crry did not increase the levels of circulating immune complexes, offering another advantage to its development for controlling the human disease. Several cytokines have been identified as major targets in lupus, leading to the development of numerous mAbs, some of them currently used in therapy or under clinical evaluation.

Another approach was recently developed, based on active immunotherapy, which consists of inducing Abs able to neutralize the interaction of the self-cytokine to its receptor.

Systemic Lupus Erythematosus Clinical Trials

Moreover, immunized transgenic mice were protected from spontaneous arthritis [ 47 ]. As cytokine network dysregulation is highly complex in lupus, further investigations are needed to evaluate whether this strategy may be advantageous in SLE in the future. FTY fingolimod , a high-affinity agonist of sphingosinephosphate type 1 receptor that induces the internalization of the receptor, thus depriving cells from normal binding of soluble sphingosinephosphate type 1, is effective in several murine models of lupus.

FTY acts primarily by sequestering lymphocytes within peripheral lymphoid organs, rendering them incapable of migrating to the sites of inflammation. Results are not yet available for patients with SLE. As described above, peptides encompassing autoantigen sequences represent interesting tools to specifically target autoreactive cells. Beside the peptides currently evaluated for their efficacy in lupus, other peptides hold promise as they gave interesting results in murine models of lupus.


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As mentioned above, however, this peptide did not give expected results when evaluated in lupus patients. Recent publications describing the successful use of new therapeutic agents in murine models support their further evaluation as therapies for SLE.

Introduction

Statins are also considered with great interest since it was demonstrated that these cholesterol-lowering drugs have immunomodulatory properties. The current literature search shows a number of promising molecules that are impressively efficient in murine models of lupus. Clearly, however, very few of these molecules reach the standard required for evaluating them in clinical trials involving patients with SLE their solubility and bioavailability, in certain cases, can represent an important limitation.

Moreover, because SLE is a syndrome with multiple manifestations, both clinical and biological, management and endpoint determinations of clinical trials for SLE are complex. In particular, a central question concerns the validity of biomarkers and surrogate markers and activity indices, which are pertinent for evaluating the performance of lupus trials [ 63 , 64 ]. Important progress has been made recently with the publication of guidelines aimed at facilitating and better controlling clinical trials for SLE [ 65 ].

Managing patients with SLE is challenging and new treatments are eagerly awaited. Establishing a valuable and solid data monitoring of patients is as crucial as designing and developing safe and efficient therapeutic molecules or biologicals. Future Rheumatol. Nat Immunol. Arthritis Rheum. Immunopathological analyses.

Clin Exp Immunol. Ann Rheum Dis. Arch Dermatol Res. Tzellos TG, Kouvelas D: Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation. Eur J Clin Pharmacol. Nat Med. Wallace DJ: Celecoxib for lupus. J Leuk Biol. J Rheumatol. Scand J Immunol.

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