Abstract
Systemic lupus erythematosus (SLE), otherwise known as lupus, is an autoimmune disease caused by varying and often unknown sources. There are different types of lupus, with SLE being the most common. Other types include lupus nephritis, cutaneous lupus erythematosus, drug-induced lupus, and neonatal lupus. SLE can affect different organ systems including the skin, kidneys, liver, blood cells and brain. There is no direct known cause for this disease, but it is thought to be caused by a combination of factors such as certain medications, hormones, genetics and the environment. There are currently few treatments available for this disease and of the ones that are used, rituximab is the most common. Unfortunately, this medication comes with moderate to sometimes severe side effects. This paper looks at the signs and symptoms of SLE, it’s potential causes and current medications and treatments. It also looks into past and present research in order to look at potential biomarkers for future improved treatments.
According to the Mayo Clinic, Lupus, more formally called systemic lupus erythematosus (SLE), is a chronic inflammatory disease where the immune system attacks its own organs and tissues. It can affect the joints, skin, kidneys, blood cells, brain, heart and lungs. This particular disease is hard to diagnose because it can mimic other disorders. One major indication however, is a facial rash that tends to spread across the face in the shape of butterfly wings, although this is not the case for everyone. It is thought that some people are born with a predisposition to the disease and it can be triggered by infections, certain medications, or even sunlight. Symptoms tend to vary among people and could be sudden or slow, mild to severe and temporary or permanent. SLE usually comes in what are known as flare-ups, which can be long lasting or short-lived. Common symptoms include fatigue, fever, joint pain, stiffness of the body, swelling, skin lesions, shortness of breath, chest pain, dry eyes, headache, confusion, memory loss and fingers turning white or blue when exposed to cold. It’s more common in women than men and usually begins between the ages of 15 and 40. It is also more common in African-Americans, Hispanics and Asians. Medications used to treat SLE include nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarial drugs, corticosteroids, and immuno-suppressants.
There are different types of lupus, with SLE being the most common. When certain organs become involved it then becomes a particular type of lupus. For example, inflammation of the kidneys becomes known as lupus nephritis (Lupus Foundation of America, 2016). This can affect the body’s ability to eliminate waste from the blood. Sometimes this can result in the need for dialysis or in worse cases, a transplant. It can cause pulmonary hypertension, resulting in difficulty breathing and can lead to a heart attack in cases where it causes the hardening of the arteries (Lupus Foundation of America, 2016). A second form of lupus, known as cutaneous lupus erythematosus, is localized to the skin. This type usually results in rashes over the body, but most commonly on places where the skin has been exposed to the sun (Lupus Foundation of America, 2016). Approximately 10% of people who show symptoms of cutaneous lupus will either go on to develop systemic lupus, or already have it with the rashes being their first symptom. (Lupus Foundation of America, 2016). A third form of lupus, called drug-induced lupus, results from the use of certain medications. With this type of lupus, more men are affected than women, usually because they are the ones who are prescribed these medications. They include Hydralazine, used to treat high blood pressure, Procainamide, used for irregular heartbeat, and Isoniazid, used to treat tuberculosis (Lupus Foundation of America, 2016). Not everyone will develop drug-induced lupus, but for those that do, symptoms usually go away within six months of discontinued use of the medication(s). Finally, there is neonatal lupus. According to the Lupus Foundation of America, this is not a “true” form of lupus. It is quite rare and it affects the newborns of women who have lupus. It is caused by antibodies from the mother which can act on the fetus while in the womb. When born, the baby may have a skin rash, liver problems, or low blood cell counts, but these usually disappear within a few months, with no lasting effects.
Research has shown that SLE is caused by both hereditary and environmental factors, such as sunlight, which can lead to abnormal immune responses. UV rays in particular are considered one of the foremost environmental factors that contribute to SLE (Zhang, Xu, Tang, Liang & Liu, 2011). According to Zhang et al., (2011), UV light can create auto-antigenic apoptotic particles which can cause the up-regulation of cytokines, resulting in SLE. These particles can also cause DNA peroxidation (Zhang et al., 2011). It is because of this that there is a loss of tolerance to nuclear antigens which then results in cell destruction and tissue inflammation (Magro-Checa, Zirkzee, Huizinga & Steup-Beekman, 2016). It is believed that alterations in B cell activations are central to the disease process (Magro-Checa et al., 2016; Vadasz et al., 2012). Vadasz et al., (2012) also conducted a study in which they looked at Semaphorin 3A and neuropilin-1 because of their role in immune response. Semaphorins are a family of membrane-bound proteins located in the nervous system. Neuropilins are the ligand binding sites (Vadasz et al., 2012). They wanted to compare the effects of Semaphorin 3A on auto-reactive properties of B cells in both healthy patients and those with SLE. Using 32 serum samples from patients with SLE, they found that semaphorin 3A levels were lower in those with SLE compared to the healthy group. This suggested that when expression is lower, B cells may lose their regulatory ability and end up becoming auto-reactive (Vadasz et al., 2012). The good news is that semaphorin 3A can now be used as a marker for SLE disease activity (Vadasz et al., 2012) and B cells can be a target for new therapies (Reddy, Jayne, Close & Isenberg, 2013).
Currently, doctors use a medication called rituximab. This is a monoclonal antibody against the protein CD20, which is found on the B cell surface (Reddy et al., 2013). This drug has been shown to temporarily deplete the B cells, showing some positive results for those who don’t seem to respond to standard therapy. It was licensed for use in 1997 for low-grade lymphoma, after a study was conducted showing its efficacy (Reddy et al., 2013). It is mostly used to treat rheumatoid arthritis and can have adverse side effects, such as cardiac arrest, cytokine release syndrome and tumor lysis syndrome (Reddy et al., 2013). Thus it is not the treatment of choice for mild cases, and as of yet, there are no biomarkers that can tell the difference between protective B cells and pathogenic B cells (Reddy et al., 2013). Besides rituximab, which was only considered after its approval for lymphoma, another drug has been approved for use specifically for SLE. It is called belimumab and it is the first of its kind to be approved for this disease in more than 50 years (Ramos-Casales, Sanz, Bosch, Stone & Khamashta, 2012). This drug specifically targets B lymphocytes. In a study conducted by Wallace et al., (2009), as cited in Ramos-Casales et al., (2010), 296 patients with SLE were treated with belimumab and results showed a significant improvement in symptoms as well as a decrease in flare ups over a six-year period. Another study by Navarra et al., in 2011, as cited by Ramos-Casales et al., (2012), showed that of the 1864 patients who participated in two trials over 52 weeks, there was a clinical response in 34% of the placebo group, compared to 41% of the 1mg/1kg group and 43% of the 10mg/1kg group. The overall analysis of those results not only showed a reduction in disease activity, but it also showed prevention of the internal organs from becoming involved.
Since there are different types of lupus it is impossible to come up with one single biomarker in order to provide diagnoses. In order to get around this, researchers have come up with biomarker panels. These panels use microarrays or proteomics in order to identify certain biosignatures of SLE (Liu, Kao, Manzi & Ahearn, 2013). Developed recently is a gene expression array that consists of 30 genes that are thought to contribute to the development of SLE (Liu et al., 2013). Juang et al., (2011) as cited in Liu et al., (2013) conducted a study with healthy individuals, those with rheumatoid arthritis, and those with diagnosed SLE in order to determine if this gene expression array was effective. Results showed that the array correctly identified those with SLE versus those with the other two disorders. These results show promise as far as being able to accurately predict the onset of SLE in particular people or in development of flares in those already diagnosed.
More recently, it has been suggested that epigenetic factors also play a role in the development of SLE (Duroux-Richard et al., 2015). Current research has looked at micro(mi)RNA in particular. MiRNAs are small non-coding molecules that regulate certain processes such as cell cycle, cell differentiation and immune response (Duroux-Richard et al., 2015). Research within the last few years has looked specifically at patterns of miRNA expression in relation to SLE. All studies to date have shown abnormal levels of miRNA in those with SLE, but there has been no sign of a common signature (Duroux-Richard et al., 2015). In their most recent study, Duroux-Richard et al., (2015), recruited Latin Americans patients with severe SLE. By using microarray technology, they found a panel of eleven and six miRNAs that were abnormally expressed in comparison to their healthy controls. One of them specifically, miR-29c, was associated with lupus nephritis. This study was the first to find this particular miRNA. These results suggest that this profiling may be of use during the monitoring of the variations present after a B cell depleting therapy such as the CD-20 antibody treatment (Duroux-Richard et al., 2015). While it also suggests that these miRNA patterns could be useful for diagnosis of SLE, the researchers believe that finding B lymphocyte subset-specific miRNA profiles while the disease is progressing could actually provide more information about the pathogenesis of SLE overall.
Conclusion
Systemic lupus erythematosus is an autoimmune disease whereby the immune system begins to attack its own tissues and organs. While there is currently no cure for this disease, there are treatment options available and research has shown that there are promising prospects for future treatments as well as potential bionarkers in order to identify those who are predisposed to the disease. This could be of use in order to potentially minimize the symptoms of those who will most likely develop the disease or to begin treatment early so that it could potentially be prevented from developing altogether.
References
Duroux-Richard, I., Cuenca, J., Ponsolles, C., Badilla Pineiro, A., Gonzalez, F., Roubert, C., . . . Apparailly, F. (2015). MicroRNA profiling of B cell subsets from systemic lupus erythematosus patients reveals promising novel biomarkers. International Journal of Molecular Sciences, 16953-16965.
Liu, C.-C., Kao, A. H., Manzi, S., & Ahearn, J. M. (2013). Biomarkers in systemic lupus erythematosus: challenges and prospects for the future. Therapeutic Advances in Musculoskeletal Disease, 210-233.
Lupus. (2016, August 2). Retrieved from Mayo Clinic: http://www.mayoclinic.org/diseases-conditions/lupus/basics/definition/con-20019676
Magro-Checa, C., Zirkzee, E. J., Huizinga, T. H., & Steup-Beekman, G. M. (2016). Management of neuropsychiatric systemic lupus erythematosus: current approaches and future perspectives. Drugs, 459-483.
Ramos-Casals, M., Sanz, I., Bosch, X., Stone, J. H., & Khamashta, M. A. (2012). B-Cell-Depleting therapy in systemic lupus erythematosus. American Journal of Medicine, 327-336.
Reddy, V., Jayne, D., Close David, & Isenberg, D. (2013). B-Cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Research and Therapy, S2.
Understanding lupus. (2016, Aug 2). Retrieved from Lupus Foundation of America:
http://www.lupus.org/answers/entry/forms-of-lupus
Vadasz, Z., Haj, T., Halasz, K., Rosner, I., Slobodin, G., Attias, D., . . . Toubi, E. (2012). Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus. Arthritis Research and Therapy, R146.
Zhang, H.-L., Xu, S.-C., Tang, D.-S., Liang, D., & Liu, H.-F. (2011). Seasonal distribution of active systemic lupus erythematosus and its correlation with meterological factors. Clinics (Sao Paulo), 1009-1013.
