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SYSTEMIC LUPUS ERYTHEMATOSUS

By targeting specific immunologic responses, administration of these biologic agents may avoid nonspecific immunosuppression lupus, lupis, systemic lupus erythematosus. More aggressive treatments under investigation include gene therapy and stem cell transplantation lupus, lupis, systemic lupus erythematosus.

Pharmaceutic treatments used for many years include hydroxycholoroquine and corticosteroids, including methylprednisolone, cyclophosphamide, and azathioprine, all of which have been demonstrated to be effective in one or more controlled trials. Weekly methotrexate and cyclosporine therapy has offered benefit in SLE; controlled trials to demonstrate their efficacy are currently underway. Promising pharmaceutic treatments include several immunomodulators and agents designed to 

BIOLOGIC AGENTS

T-Cell Activation and T-cell-B-Cell Collaboration

Several agents currently under investigation have been designed to inhibit the coactivation steps necessary for T-cell interaction and 

 
Anti-CD40 ligand (CD40L) monoclonal antibodies (mAbs)
 
CTLA-4Ig
 
Anti-B7-1 and B7-1 mAbs
 
Anti-CD40L mAbs

 

CTLA-4Ig

Another coactivation step that regulates T-cell-B-cell interactions includes CTLA-4/B7. Although low in number, CTLA-4 is expressed on the surface of T-cells after activation and has a high affinity for the B7 antigen present on B cells and antigen-presenting cells. A soluble receptor, CTLA-4Ig is a fusion protein derived from the extracellular domain of CTLA-4 and the Fc portion of IgG1, which serves as a soluble receptor, thereby preventing CTLA-4/B7 interactions. Studies have

Anti-B7 Monoclonal Antibodies

Apparently, inhibition of both B7-1 and B7-2 antigens simultaneously is required to downmodulate T-cell-B-cell collaboration. When NZB/W mice are treated with mAbs to both B7-1 and B7-2, anti-DNA antibody production is decreased, with

Inhibition of Production of Anti-dsDNA Antibodies

Murine models of SLE have shown that development of glomerulonephritis is the result of an underlying process of deposition of cationic DNA-anti-DNA immune complexes in the negatively charged glomerular basement membrane. Complement activation and neutrophil chemotaxis follow immune complex deposition. It seems that the anti-DNA antibodies cross-react with 

A therapy used for many years in the treatment of SLE, intravenous immunoglobulin (IVIg), may partially reverse severe organ system manifestations by decreasing anti-DNA Ab levels.  It is useful in treating thrombocytopenia associated with SLE and during pregnancy in the presence of antiphospholipid antibodies, although controlled clinical trials are lacking.  Its use remains controversial, however, in the treatment of SLE nephritis. A recent study in patients with SLE class III or IV glomerulonephritis

3E10: Murine Monoclonal Antibody Idiotypic Vaccine

One therapy currently in development, referred to as 3E10, is a murine IgG2a mAb prepared using isolated anti-dsDNA antibodies from MRL/lpr mice. When 3E10 mAb was used to immunize MRL/1 mice, survival increased compared with that of

The 3E10 therapy has been tested in a phase 1-2 placebo-controlled study. Twelve patients with stable SLE and a previous history of nephritis were enrolled, and all had been taking less than 20 mg of prednisone daily without immunosuppressive agents for at least 3 months. The 12 patients were evenly assigned to one of four groups: 50, 100, or 200 mug/mL of 3E10 or placebo.

LJP 394: B-Cell Toleragen

LJP 394 is a B-cell toleragen and consists of a trietheleneglycol backbone with four attached oligonucleotides. Its administration cross-links anti-dsDNA on the B-cell surface, resulting in downregulation of anti-dsDNA Ab production. This treatment has

Inhibition of Anti-dsDNA Antibody Deposition

Recombinant Human DNAase

Daily treatment with 5 mg of recombinant murine DNAse for 3 weeks reduced the number of splenic B cells secreting anti-DNA Abs and the amount of IgG anti-DNA Abs in experiments with NZB/W mice with active nephritis. The researchers suggested

Inhibition of Complement Activation and Deposition

Active SLE is associated with complement activation with decreased levels of C3, C4, and CH50. Complement activation can be predictive of long-term outcome and serves as a measure to assess treatment efficacy in some patients. Both classic and

Anti-Complement 5 Monoclonal Antibody

In NZB/W mice that developed dsDNA Abs at approximately 4 months, treatment with a mAb to murine C5 delayed proteinuria, improved renal histology, and prolonged survival when these mice were compared with control animals. Proteinuria was also significantly reduced in SCID mice implanted with PBMCs from patients with SLE producing anti-dsDNA mAbs.

Cytokine Activation and Modulation

Another characteristic of active SLE disease includes increases in serum IL-10 levels and spontaneous and stimulated PBMC production of IL-10. Increased levels of IL-10 are evident in first-degree relatives and spouses in multicase SLE families, which

Anti-Interleukin-10 Monoclonal Antibody

Research in preautoimmune NZB/W mice has demonstrated that although continuous administration of IL-10 accelerated disease onset, treatment with anti-IL-10 mAbs retarded the onset of disease. Similarly, anti-dsDNA antibody production in SCID mice

Gene Therapy

Currently, clinical trials are being conducted in RA patients undergoing metacarpal joint replacements using ex vivo gene transfer with a retroviral vector to encode human IL-1 receptor antagonist production. Theoretically, similar interventions could be

Stem Cell Transplantation

Following a precedent set from the treatment of a variety of autoimmune diseases in which bone marrow aplasia or malignant lymphoproliferative disorders have been induced by drug therapies, bone marrow transplantation has been proposed for the

PHARMACEUTIC INTERVENTIONS

Promising pharmaceutic interventions for the treatment of SLE include a variety of immunomodulators and therapies designed to alter sex hormone levels or function.

Immunomodulators

Thalidomide

Despite its controversial history, thalidomide has recently been approved in the United States for the treatment of erythema nodosum leprosum. Other indications under study include graft versus host disease. The most common adverse event associated with thalidomide is peripheral neuropathy, which occurs in 20% to 50% of patients treated. Symmetric painful paresthesias of 

AS101

Primarily studied as a cancer therapy, AS101 has been shown to decrease the spontaneous production of IL-10 when added to peripheral blood adherent cell cultures from patients with SLE. This response was confirmed in SCID mice reconstituted with

2-Cholordeoxyadenosine (Cladaribine)

By depleting resting and proliferating T and B lymphocytes while sparing neutrophils, monocytes, red blood cells, and platelets, 2-cholordeoxyadenosine (2CdA) has proved to be effective in the treatment of hairy cell leukemia and

Mycophenolate Mofetil

Approved for treatment of renal allograft rejection, mycophenolate mofetil has been used in patients with SLE following renal transplantation. Its immunomodulatory properties may be directly applied to the treatment of SLE. It reversibly inhibits inosine 

Bindarit

In models of acute and chronic inflammation, including murine nephritis, bindarit appears to regulate cytokine and chemokine production and thus inhibits the acute phase response. This agent has increased the length of survival in NZB/W mice without 

Methimazole

Methimazole has been shown to be effective in the treatment of Grave's disease, in which it has been demonstrated to inhibit class I major histocompatibility complex expression in thymocytes. A slow-release formulation of methimazole was given to BALB/c mice immunized with the 16/6 idiotype mAb, resulting in significant reductions in dsDNA and other autoantibodies 

Sex Hormones

Based on the observation that female NZB/W mice develop nephritis earlier and with more severity than male mice, researchers have suggested that treatment with male hormones or estrogen antagonists may delay the onset of disease or reduce its severity. An early attempt used 19-nortestosterone, a synthetic androgen. Although four women showed subjective improvement, three

Dehydroepiandrosterone

Levels of dehydroepiandrosterone (DHEA), a naturally occurring mild androgen, peak at puberty and decline thereafter. Low endogenous levels of DHEA and other androgens are typical for patients with autoimmune diseases such as SLE and RA; augmentation of androgen levels has been suggested for their treatment. Benefits from DHEA treatment may be derived from changes in endogenous adrenal sex hormone levels or stimulation of hypothalmic or adrenal production of mineralocorticoid or

Selective Estrogen Receptor Modulators

The use of oral contraceptives in the treatment of SLE has long been controversial. Recent studies, however, suggest that their use may be safe. Treatment with a selective estrogen receptor modulator for 7 months in female MRL/1 mice normalized thymic lymphocyte phenotype, decreased renal disease, and increased length of survival. These data suggest a potential role for

Bromocriptine

Elevated levels of prolactin produced by the anterior pituitary gland have been linked to the severity of SLE, possibly through mediating the immunostimulatory effects of estrogen. The recent publication of data on 35 patients with active SLE suggests

    Agent Target
Anti-CD40L (gp 39) mAbs T-cell activation/T-cell-B-cell collaboration
CTLA-4Ig
3E10 mAb vaccine Inhibition of Ab production
LJP 394: B-cell toleragen Inhibition of Ab production
rHuDNAse Inhibition of Ab production
Anti-C5 mAb Complement activation/immune complex deposition
Anti-IL-10 mAbs Cytokine activation/modulation
AS101 (anti-IL-10) Cytokine activation/modulation
Gene therapy Cytokine activation/modulation
Thalidomide (anti-tumor necrosis factor-alpha) Cytokine activation/modulation
IVIg Immunomodulation
Bindarit Immunomodulation
Plasmapheresis Immunomodulation
Mycophenolate mofetil Immunomodulation
Immunoadsorption Immunomodulation
2CdA Immunomodulation
Fludaribine Immunomodulation
Methimazole Immunomodulation
Stem cell transplantation Stem cells
Immunoablative treatment
DHEA Sex hormones
Selective estrogen receptor modulators Sex hormones