Review: Targeted Therapies in Systemic Lupus Erythematosus

New research shows even more potential for targeted therapies in systemic lupus erythematosus (SLE), a disease that is often characterized as a combination several systemic autoimmune diseases.

Although great strides have been made in SLE research - as demonstrated by reduced mortality and morbidity rates - systemic lupus erythematosus remains a life-threatening condition for some patients and, costs associated with treating SLE continue to be substantial. The etiology of lupus remains elusive, however, current thought points to an imbalance between cell death and the clearance of apoptotic cells, write researches in the November issue of Nature Reviews Rheumatology.

To date, conventional therapy for systemic lupus erythematosus primarily consists of immunosuppression, but new advances in research are opening avenues for targeted therapies.

“Many of the advances made over the past decade are driving interest in developing targeted therapeutics and in repurposing drugs. Cytokines, tolerance pathways, local tissue mediators, and epigenetic mechanisms show promise as novel targets in SLE,” wrote researchers who were led by George C. Tsokos of Beth Israel Deaconess Medical Center in Boston.

In this article, we summarize the review which focuses on environmental and genetic factors that contribute to the risk of developing SLE.

Environmental Risk Factors

Twin studies reveal differences in systemic lupus disease activity in identical siblings suggesting that environmental factors must contribute to the disease process. Because of the disproportionate number of women affected by lupus, hormonal factors such as estrogen and prolactin are thought to augment the immune responses via multiple mechanisms. Further, ultraviolet light is known to stimulate cell death such that exposure to sunlight may increase the rate of apoptosis enough to overload the clearance mechanisms leading to nucleic exposure and an auto immune response.

Data exists suggesting an important role for microorganisms in both triggering systemic lupus erythematosus and protecting against it. This process involves antigen presentation to T cells implicating chronic microbial DNA translocation in the pathogenesis of SLE.

The authors point out that a microbiome exists in the human body comprised of many different organisms and that it is highly unlikely that any one organism would be causative in systemic lupus erythematosus. Instead, combinations of microorganisms may predispose lupus while others are protective. In any case, altering the microbiome in mouse models has been promising.

“While some SLE patients present with relatively mild symptoms, others can develop life-threatening symptoms. Today, the mortality rate for SLE -10 percent in 10 years - is significantly lower than the 1960s when 50 percent of patients died within three years, write the authors of a review published in the November issue of Nature Reviews Rheumatology.”

Genetic Predisposition and Gene Expression

Looking at twin studies again it is clear that SLE is heritable and linked to alleles in the major histocompatibility complex (MHC) strongly implicating T cells in the disease process. In addition to the major histocompatibility complex, over 40 DNA loci are implicated in lupus with each alone contributing <2% to the relative risk of developing systemic lupus erythematosus.

Genome wide association studies (GWAS) point to three pathways to development of systemic lupus erythematosus:

• T cell or B cell lymphocyte signaling.
• Interferon signaling pathways related to nucleic acid sensing or production.
• Clearance of immune complexes.

Epigenetic Mechanisms in Systemic Lupus Erythematosus

Epigenetics describes durable changes in gene expression without changes in gene sequencing. Methylation of DNA is an example of an epigenetic phenomenon and it is know that hypo-methylation and drugs that block methylation can induce lupus or lupus like syndromes. Additionally it is know that histone regulation is an important epigenetic factor in patients with lupus. These “genome-wide” approaches may become strong tools in the search for new therapies.

MicroRNA regulation in Systemic Lupus Erythematosus

MicroRNA regulate the removal of messenger RNA. An absence of these microRNA has been found in the kidney tissue and blood samples of patients with lupus. MicroRNA derived drugs have been produced and this may lead to new therapies for systemic lupus erythematosus in the future.

Differences in Gene Expression

Wide differences exist between the genome and its expression. Other disciplines have utilized expression patterns to risk stratify patients and such a methodology could be used to profile lupus patients.

Apoptosis and Nucleic Acid Sensors

As mentioned previously accumulation of dead cell debris accentuates autoimmune exposure and is at least influenced by infection, ultraviolet light and cytokine levels. An imbalance between mechanisms to clear these products of apoptosis and higher degrees of cell death are central to this concept. Genetic loss of protective mechanisms likely also leads to development of systemic lupus erythematosus.

The Role of the Toll-Like Receptors

Toll-like receptors are crucial to intracellular trafficking. These receptors have been strongly implicated in the development of inflammation, interferon production and loss of tolerance. The most current thought is that, in systemic lupus erythematosus, toll like receptors drive an interferon response.

Cytosolic Nucleic Acid Sensors

Sensors in the cell recognize infections and initiate defenses through the interferon pathway however; they can also be triggered by nucleic acids released from dying cells and produce inflammation as a result. These sensors or inflammasomes respond to DNA by unknown mechanisms but appear to have a role in the etiology of systemic lupus erythematosus. Again, over stimulation of interferon mediated inflammation is a key feature.

Soluble Mediators

Cytokines are soluble mediators implicated in organ damage and loss of tolerance in systemic lupus erythematosus. A wide array of cytokines contribute to the autoantibody response and inflammation and include interferon, interleukins and tumor necrosis factor (TNF) as key players. To spite the obvious and sweeping role of interferon in lupus, interferon inhibitors have not emerged as effective treatments. Small improvements have been see in lupus patients receiving anti-B cell activating factor, the first drug to gain approval for the treatment of systemic lupus erythematosus in 50 years.

Major Cell Types in Systemic Lupus Erythematosus:

Dendritic Cells

These cells present antigen and through their dysfunction may lead to a loss of tolerance in T-cells and B-cells. Interferon secreted by certain dendritic cells promotes the formation of immune complexes and is critical for the development of nephritis in mice with lupus.

Myeloid Cells

Neutrophils are widely implicated in susceptibility to infection in those with systemic lupus erythematosus possibly through reductions in reactive oxygen species leading to organ damage. Lack of adequate reactive oxygen species may also hinder clearance of apoptotic byproducts. Monocytes and neutrophils roles in intracellular extrusion and direct infiltration and organ damage in the case of monocytes drive the secondary manifestations and systemic pathogenesis of lupus.

T Cells

At the core of systemic lupus erythematosus is the concept of loss of T-cell tolerance. Whether by aberrant receptor signaling, failed thymic clearance of auto-reactive T-cells, reductions in interlukin-2 or the presence of double negative T-cells, the typical check the T-cells place on auto-reactive B cells is lost. Treatment with low dose interleukin 2 therapy has been tried with uncertain clinical implications.

B Cells and Autoantibody Production

The loss of tolerance described earlier results from activation of B cells. Toll like receptors can accelerate B cell maturation skipping traditional tolerance checkpoints in their lifecycle. Autoantibodies produced by B cells are a nearly universal feature of systemic lupus erythematosus. Immune complexes formed by autoantibodies along with complement activation cause end organ damage in lupus. Drugs reducing Immunoglobulin E may have a role in treating systemic lupus erythematosus.

Organ-Specific Disease Features

Local tissue effects are responsible for kidney, skin, and central nervous system involvement and are independent to the loss of T cell tolerance.

Nephritis

Lupus nephritis is associated with high morbidity and mortality. Kidney damage is caused by deposition of immune complexes and cellular proliferation. HER2 expression is common in lupus nephritis and may lead to treatments similar to those in existence for HER2 positive breast cancer.

Skin

The skin may be the only organ involved in some cases of systemic lupus erythematosus. Ultraviolet light is a precipitating factor by damaging cells and promoting immune complex deposition. Specific autoantibodies differentiate between organs affected.

Central Nervous System

Failure of the blood-brain barrier caused by complement activation allows immunologic substrates access to typically protected central neurologic tissues. In a mouse model complement receptor antagonists reduced inflammation and improved neuronal survival. Autoantibodies that promote neuronal death appear to be the cause of neuropsychiatric symptoms in lupus.

Conclusions

• The mainstays of treatment for systemic lupus erythematosus remains immunosuppression.
• Targeting pathogenesis shows promise and may be a better way to target therapies for specific heterogeneous lupus patient populations.
• Drugs used for other disorders that target know pathways in systemic lupus erythematosus could be repurposed to treat it.
• Targeting tolerance pathways, local tissue mediators and epigenetic mechanisms could lead to new therapeutic modalities.

References:

George C. Tsokos, Mindy S. Lo, Patricia Costa Reis and Kathleen E. Sullivan. "New insights into the immunopathogenesis of systemic lupus erythematosus," Nature Reviews Rheumatology. Published online Nov. 22, 2016. DOI: 10.1038/nrrheum.2016.186