CHAPTER ONE INTRODUCTION
Background of the study
Systemic lupus erythematosus (SLE or lupus) is an autoimmune condition of poorly understood pathogenesis which is known to affect women six times more frequently than men and commonly affects women of African descent (Rees et al., 2016). The disease has been reported to be the second most prevalent autoimmune condition which mostly affect women in their reproductive year (Bongu et al., 2002). However, the causes and the medical course of the condition is unclear. A recent international study by the Lupus Foundation of America showed a low global understanding of the disease (Lupus Foundation of America, 2018). In the United States, specifically in North America, the prevalence of SLE is estimated to be between 20 and 150 cases per 100,000 individuals a year (Rees et al., 2016). Africa also recorded 0.3 cases per 100,000 person-years from 1946 to 2016 which according to Rees, et al. (2016) is the lowest incidence. SLE is a disorder in which a person’s immune system attacks the tissues and organs of the body, causing inflammation, damage and dysfunction (Shiel, 2018).
The incidence of SLE has increased over the years, primarily due to improvement in the diagnosis of the condition. The predicted occurrence rates varies yearly in the western world between two to eight cases per 100 000 people; Further, disease onset has been estimated to be between the ages of 16 and 55 years among sixty-five per cent of SLE patients (Bertsias et al., 2012).
The epidemiology of SLE in Africa is still unclear (Tiffin et al., 2014), however, some studies have reported SLE cases in South Africa (Tikly et al., 1996; Faller et al., 2005). Furthermore, Molokhia et al. (2001) reported a high occurrence of SLE in immigrants from West Africa.
Abdou et al., (2003) reported on lupus nephritis from all regions of Senegal. Adelowo and Oguntona (2009) reported SLE cases where they defined sequences of the disease diagnosed at a rheumatology clinic in Lagos, Nigeria. It is therefore clear that SLE cases are not uncommon in Africa (Tiffin et al., 2014).
SLE affects any structure of the body (Avina-Zubieta, 2007). The presentation and medical course of the disease are highly variable with some individuals experiencing minimal symptoms such as malar rash and inflammation of the joints and skin, whereas others present with life-threatening involvement of major organs (Bartels, 2017). Further, SLE manifests in different ways and can imitate other conditions making diagnosis difficult (Mayo clinic, 2017). The initial symptoms include fatigue, sun sensitivity and arthralgia, which are ever-present and often short-lived, are frequently ignored or unrecognized, making diagnosis difficult. No two cases of SLE are precisely the same as the appearances of the disease varies from individual to individual and often progresses over time (Mayo clinic, 2017). Symptoms differ from person to person depending on the organs affected and they include excessive tiredness, inflammations and joint pains, headaches, a rash on the cheeks or nose, alopecia, anaemia, blood clotting problems, and discolouration of fingers (Herndon, 2016).
The exact cause of SLE is not known however, several factors including genetics, some environmental factors like excessive exposure to sunlight, infrared lights, certain medications, viruses, physical or emotional stress, and trauma have been associated with the disease (Herndon, 2016). According to Bertsias et al., (2012), ‘‘epigenetic effects such as DNA methylation and post-translational modifications of histones, which can be either inherited or modified by environmental factors may influence the risk for SLE. Further, they postulated that DNA methylation, which plays a role in a range of human processes, such as X chromosome
inactivation is the most well understood type of epigenetic and has also been implicated in SLE’’.
Possible environmental triggers of SLE include excessive exposure to sunlight, infectious viruses like Epstein– Barr virus (EBV), ultraviolet rays, and stress (Herndon, 2016). Demethylating drugs such as procainamide and hydralazine have also been reported to cause drug induced SLE but a genetic predisposition may play a role (Bertstias et al., 2012). These preparations may hinder DNA methylation and prompt over-representation of LFA-1 antigens, there by altering gene expression in CD4+ T cells, promoting auto-reactivity. The response of the immune system against internal nuclear antigens has further been identified as features of SLE (Bertstias et al., 2012). Apoptotic cells release auto-antigens which are delivered by dendritic cells to T cells causing them to be activated; these activated T cells support B cells to generate antibodies to these self-components by releasing cytokines like IL23 and interleukin 10 (IL10) and also by secreting CTLA-4 and CD40L (Bertsias et al., 2012). Current data further supports the self-directing action of T and B cells stimulation; thus numerous cells and molecules are involved in the inherent, adaptive immune reactions and apoptosis that leads to the onset of SLE (Bertsias et al., 2012).
There are a number of treatment options depending on the organs affected. These treatments mostly focus on silencing the immune system to reduce distress with the condition. Hence individuals are able to live a manageable life (Herndon, 2016). Treatment usually involves a combination of antimalarial drugs (Wallace, 2002a) and non-steroidal anti-inflammatory medications (Yousefi & Weisman, 2002). Cytokine drugs (McCune & Riskalla, 2002) and steroids (Kirou & Boumpas, 2002) are also prescribed depending on the organs affected and the severity of symptoms. SLE patients are instructed to try and minimise their stress levels,
avoid very high radiations, get enough rest, and build a good support structure to assist during times of disease activity (Kuper & Failla, 2000; Wallace, 2002).
SLE and Cognitive functions
The impact of central nervous system problems are varied in SLE, and of particular concern is the cognitive decline (Butt et al., 2017).
Neuropsychiatric conditions in SLE include psychotic episodes to mood changes, cognitive problems, headaches, seizures, and stroke (West, 2013). Cognitive dysfunction which is defined as a notable deficit in any of the various cognitive domains including memory, attention, executive function, visual-spatial processing, psychomotor speed and verbal fluency has been highlighted as a key neuropsychiatric complaint in SLE (Huerta et al., 2015). Some studies have also reported central nervous system (CNS) involvement in SLE, these include structural changes to the amygdala and hippocampus (Jung et al., 2010).
Other studies have suggested autoantibody activity and cerebral ischemia as the likely mechanisms responsible for cognitive deficits in SLE (Hanly, 2013). Health characteristics such as disease mechanism and duration, usage of some medications, pro-inflammatory cytokines and behavioural elements have further been suggested (Prabu et al., 2010). Another possible mechanism of cognitive impairment in SLE could be attributed to the function of a subset of anti-DNA antibodies that inter-reacts with particular sequences available on NR2 receptors (Conti et al., 2012). Glutamate binds to these NR2 receptors and causes an activation effect; these NR2 receptors have been identified to be highly present in the hippocampus, which then has a negative impact on memory and learning (El-Shafey, 2012).
SLE patients often experience complications with such intellectual functions such as attention to details, memory, expressing their thoughts, decision making, or calculation (Lupus
International, 2011). These deficiencies may range from slight thought instabilities to more serious states of confusion and they can be quite worrying to the patient experiencing them and also for their caregivers since these problems are difficult to identify objectively (Lupus International, 2011).
Earlier neuroimaging studies have shown cognitive deficits in SLE sufferers and proposed that it may be linked to disturbed or injured brain white matter (WM) connectivity (Zhao et al., 2018; Lee et al., 2014). Further, the occurrence and degree of cognitive deficit is also uncertain, where more permanent brain injury has been linked to neural damage that might be as a result of diseases of the cerebrovascular system (Benedict et al., 2008). It has been predicted that roughly thirty three percent of SLE patients who have never exhibited signs of neuropsychiatric SLE will have noticeable cognitive deficits and about eighty eight percent of SLE patients who have had a prior neuropsychiatric episode displayed some level of cognitive challenges, probably due to some outstanding damage to the nervous system (Lupus International, 2011). The neuropsychological deficits associated with SLE include memory, visuo-spatial and visuo- constructional abilities, executive function (eg. planning, initiation and self-monitoring), visuo- motor coordination and speed. (Federman et al., 1998). In addition, neuropsychiatric symptoms include severe confusional state, headaches, depression and anxiety (Bhatt et al., 2007).
