LUPUS NEPHRITIS Jomanah A. Hmood

THERAPEUTIC GOALS IN LUPUS NEPHRITIS: WHY THE NEED FOR NEWER PROTOCOLS AND DRUGS?

Therapeutic goals are (1) to achieve renal remission;

(2) to avoid renal flares; (3) to avoid chronic renal impairment; and (4) to achieve these objectives with

minimal toxicity.

THERAPEUTIC GOALS IN LUPUS NEPHRITIS: WHY THE NEED FOR NEWER PROTOCOLS AND DRUGS? Although patient and renal survival rates have

improved over the past decade, the current immunosuppressive regimens still achieve suboptimal results :

First, the rate of renal remission after a first-line therapy is at best 81%.

Second, renal relapses occur in one third of LN patients ,

Third, between 5-20% of LN patients experience ESRD 5 to 10 years after the disease onset.

Finally, treatment-related toxicity remains a major concern.

1. B-CELL DEPLETION THERAPIES:B lymphocytes play an integral role in this

process, they are the precursors of plasma cells that produce these pathogenic autoantibodies

RITUXIMAB

Rituximab is the antibody directed against CD20, expressed on almost all β cells. Therefore, through the elimination of β cells,

rituximab may prevent the generation and expansion of antibody secreting autoreactive cells ,

Most patients demonstrated complete β cell depletion within 1 to 3 months of treatment.

2. TARGETING B-CELL SURVIVAL FACTORS

BELIMUMAB Belimumab is a fully humanized

monoclonal antibody against BLyS, which can cause depletion of circulating B cells.

BLyS (B lymphocyte stimulator) plays an essential role in B-cell survival and development.

BELIMUMAB (BENLYSTA®):

 approval by the FDA in March of 2011.

Belimumab is given by monthly infusion after initial loading (one intravenous dose every two weeks for the first six weeks, then one infusion every four weeks).

3.BLOCKADE OF T-CELL CO-STIMULATION

Abatacept by blockade of co-stimulatory

interactions between T and B lymphocytes.

Abatacept is containing CTLA-4(cytotoxic T-lymphocyte antigen) ,

CTLA-4 activation resulting in a negative feedback mechanism that inhibits T cell activation.

4.CYTOKINE THERAPIES A.ANTI-INTERLEUKIN-6

Tocilizumab is a fully humanized monoclonal antibody against the α-chain of the IL-6 receptor, (interleukin-6) , which has a role in the pathogenesis of lupus nephritis.

B. ANTI-TNF-Α THERAPIESINFLIXIMAB However the role of anti-TNF blocking

agents in the treatment of SLE remains controversial.

TNF is overexpressed in the serum, kidneys and skin of SLE patients and high serum levels of TNF correlate with lupus disease activity.

5.COMPLEMENT THERAPIES Activation of terminal complement is

associated with exacerbations of disease, particularly in lupus nephritis.

Eculizumab a monoclonal antibody directed against the complement protein C5,

AUTOLOGOUS HEMATOPOIETICSTEM CELL TRANSPLANT The process of autologous Hematopoietic

Stem Cell Transplantation (HSCT) involves removing patients hematopoietic stem cells before giving an aplasia inducing dose of cyclophosphamide;

this is followed by giving the patient an autologous HSCT. The potential of autologous HSCT as a treatment to induce lasting remission has not yet been borne out,

however its use may lie in its ability to revert the progression of severe disease towards a more benign course that could be more amenable to conventional immunotherapy