Gender Disparities in Systemic Lupus Erythematosus and the Impact on Diagnostic and Treatment Outcomes

Gender Disparities in Systemic Lupus Erythematosus and the Impact on Diagnostic and Treatment Outcomes Nora Wuest NSG 502: Advanced Nursing Research Wilkes University, Passan School of Nursing Dr. Marcia Derby-Davis March 8, 2025 Gender Disparities in Systemic Lupus Erythematosus and the Impact on Diagnostic and Treatment Outcomes Introduction Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterized by inflammation and damage to various body parts, such as the skin, joints, kidneys, and the cardiovascular system (Fanouriakis et al., 2021). It is a chronic disease that has no cure and needs to be controlled for the rest of the patient's life to avoid significant consequences such as organ failure and early death. SLE has a high predilection for women, with 90% of the patients being female, which gives a female-to-male ratio of 9:1 (Fairweather et al., 2024). This gender difference is attributed to hormonal, genetic, and environmental factors, and it is accepted that estrogen is pivotal in immune system regulation (Mansur & Kep, 2024). SLE mainly affects females in their childbearing age; SLE research mainly focuses on female patients, which has a limited understanding of male patients with SLE in terms of disease presentation, prognosis, and response to therapeutics (Zen et al., 2023). Nonetheless, clinical practice guidelines and treatment algorithms are remarkably similar for men and women, not taking into account sex differences in symptom manifestation and therapy response. This study seeks to explore the effects of gender differences in SLE diagnosis and the treatment measures adopted by doctors to address the condition, arguing for the necessity of considerate gender-specific care plans. Background SLE has been described as a specific disease since the 13th century, and the name was derived from the Latin word lupus, which referred to skin lesions resembling bites from a wolf (Winstead, 2024). Nonetheless, it was only in the 19th century that physicians began to identify lupus as a disease involving internal organs. SLE was often confused with tuberculosis or severe skin disease in the early twentieth century because the symptoms, such as fever, weight loss, and joint pain, are similar to those of other chronic diseases (Mansur & Kep, 2024). The discovery of SLE as an autoimmune system disease dates back to the 1940s when it was established that autoantibodies and immune dysfunctions cause the disease (Fanouriakis et al., 2021). A cross-sectional study was conducted in the 1950s that pointed out that more women than men were affected by SLE, making female patients the focus of most studies. This gender bias in medical research meant that even diagnostic criteria, treatment plans, and clinical trials were developed with female patients in mind, omitting or marginalizing males (Fairweather et al., 2024). Consequently, male SLE patients were excluded as candidates for treatment, which contributed to delayed diagnosis and treatment plans. This historical bias is still reflected in the current times. Moreover, men with SLE have worse prognoses, more severe disease manifestations, higher rates of organ dysfunction, and higher mortality than female SLE patients; however, diagnostic criteria and management protocols for SLE have not been modified to reflect these gender differences (Winstead, 2024). To address these inequalities regarding SLE, strategies must be put in place that will lead to equal treatment of male and female patients with SLE. Significance Men are diagnosed with SLE later than women by 2-3 years, which results in higher disease severity, organ involvement, and more deaths (Zen et al., 2023). However, diagnostic criteria and treatment plans remain standardized and are still insensitive to hormonal or genetic factors affecting the course of the disease (Fairweather et al., 2024). Consequently, this research is important because applying gender-specific approaches to the early detection and treatment of diseases could enhance the chances of positive outcomes and decrease mortality among these patients while also improving the overall quality of life of every patient. In nursing practice, knowledge of the differences in SLE by sex is crucial in evaluating the disease, patient counseling, and care management. If this issue persists, male patients are going to get diagnosed and treated poorly, and this will only worsen healthcare inequalities (Winstead, 2024). Thus, formulating gender-sensitive and fair clinical practice guidelines will facilitate fair and effective care provision for all patients with SLE by nursing and other healthcare practitioners. Problem Statement The knowledge gap that has been highlighted in this proposal is that the existing diagnostic criteria and management of SLE do not take into consideration gender differences, which results in delayed diagnosis, more organ damage, and high mortality among male patients. All these disparities should be addressed to ensure that patients are treated fairly and receive the best services they deserve. Purpose Statement This study aims to determine the effects of gender-related factors on SLE diagnosis and management. In this respect, it will help establish gender-specific, evidence-based approaches to monitoring and managing symptoms, disease progression, and treatment outcomes that ensure early diagnosis and optimal therapeutic outcomes. PICOT Question The PICOT question is: In patients with Systemic Lupus Erythematosus (P), how does diagnosis and treatment incorporating gender-related variables (I) compared to usual diagnosis and treatment without gender-specific considerations (C) influence treatment outcomes and the success of individualized care plans (O) within one year (T)? Literature Review Search Strategies PubMed, CINAHL, and Google Scholar were searched to select only the most relevant and recent articles, emphasizing articles published between 2018 and 2024. The keywords used included Systemic Lupus Erythematosus (SLE), gender disparities in SLE, SLE diagnosis, SLE treatment outcomes, hormonal influence on SLE, and sex-based autoimmunity. Inclusion criteria ü Peer-reviewed journal articles. ü The literature review focused on research on Gender differences in SLE. ü Cross-sectional studies and meta-analyses that address diagnostic delay and/or therapeutic efficiency by gender. Exclusion criteria * Non-English articles. * Studies that did not make distinctions based on gender. * Studies that were conducted using samples that were restricted to children or elderly persons with no gender disaggregation Review Article 1: Mechanisms Underlying Sex Differences in Autoimmunity (Fairweather et al., 2024) This paper aimed to evaluate the hormonal and genetic factors that may influence the differences in autoimmune diseases such as SLE between males and females. Autoimmune diseases are estimated to occur in 3-10% of the global population; they rank third among diseases in developed countries in terms of prevalence after cardiovascular diseases and malignant tumors (Fairweather et al., 2024). In contrast, testosterone seems to have more beneficial roles; it decreases inflammation and slows the disease process in men. Safety concerns are also mentioned in the context of genetics; the presence of two X chromosomes in females makes them more likely to have autoimmune reactions. Most autoimmune diseases are acquired during adulthood, and the most common ones affect females compared to males. Several decades of evidence from animal models and human studies support the notion that estrogen enhances autoreactive T and B cells, autoantibodies, and clinical disease (Fairweather et al., 2024). However, the outcomes of research on the involvement of sex hormones and estrogen, particularly in innate immune cells, have been highly inconclusive. Sex chromosome genes are also involved in autoimmune diseases, but the main factors are the environment and epigenetics. Emerging and expanding fields of investigation involve hormone-dependent miRs and EVs in autoimmune disorders (Fairweather et al., 2024). Article 2: Management of Systemic Lupus Erythematosus: An Update (Fanouriakis et al., 2021) This article aimed to give the readers a general perspective on the problems associated with SLE diagnosis and treatment, especially in the male population. According to this article, it is noted that SLE affects men, where organ damage increases by an average period of 2.5 years before diagnosis. SLE has a clear female preponderance, which is manifested in the fact that nine out of ten patients affected by the disease are women (Fanouriakis et al., 2021). It affects between 0.3 to 31.5 patients per 100,000 people per annum and has risen in the last 40 years, most likely because more subtle cases have been diagnosed. The overall adjusted prevalence rates are almost 50-100 per 100,000 adults 5, and most of the patients in community-based Caucasian registries are middle-aged women, and about 50% of them have milder disease at disease presentation. The study claims that these delays could be due to the low index of suspicion of SLE in male patients, as physicians associate autoimmune diseases with the female gender. Furthermore, it identifies treatment differences since men are likely to be immunosuppressive therapy since they are more likely to be diagnosed at a later stage, putting them at increased risk of complications. Article 3: Systemic Lupus Erythematosus: A Comprehensive Guide (Mansur & Kep, 2024) Lupus erythematosus systemic (SLE) can, therefore, be described as a multisystemic chronic syndrome for which the clinical presentation varies from minor skin lesions to significant organ dysfunction. Regarding the primary systems involved in death, the Asian population had a higher rate of renal involvement. Specifically, most studies in this field have been conducted to examine female patients of SLE, and hence, there is a lack of or skewed approach to diagnosing and treating male patients. Mansur Kep (2024) went further to point out that, for the most part, clinical trials conducted between 1950 and 1980 involved only women, and no information was available on how male patients’ diseases progressed, how they presented, or how they responded to treatments. Therefore, it is necessary to include the diagnosis of male patients with SLE to enhance scientific research and improve the diagnosis of SLE for both male and female patients. Article 4: Mortality and Causes of Death in SLE Over the Last Decade (Zen et al., 2023) This study, conducted on many SLE patients, explored SLE's mortality rate. The mortality rate of male patients is 30% higher than that of female patients within five years of diagnosis (Zen et al., 2023). There was a trend towards higher mortality of SLE patients as compared to the general population. Interestingly, it was higher in patients that were below the age of 44, and these patients had a significantly 5.59 times increased risk of death than their counterparts in the group. This means that lupus mortality is still higher than in the general population, and the disparity is worse among young individuals. The study attributes this increased risk to: * Higher rates of cardiovascular and renal complications in men. * The severity of the disease prognosis is also affected by more advanced syllabi insofar as the diagnosis is concerned. * Lack of compensation for male patients due to most clinical research with female patients in mind. According to Zen et al.’s (2023) findings, there was a 2.6 times higher death rate among patients with SLE when compared with the general population; men and women, particularly young ones, with SLE had an extraordinarily 5.5 deaths per 100 patients each year. Cardiovascular diseases and cancer were the leading causes of death in this group, while the cause of death resulting from infectious diseases was found to be less than has been described. Article 5: A Person Like Me: SLE, Gender, and Racial Immunity (Winstead, 2024) Analyzing the gender and race in SLE disparities, Winstead (2024) has found that the worst situation is observed in black and Hispanic male patients, who experience the most significant difficulties in early diagnosis and treatment. During the 1970s and 1980s, an advocacy structure emerged through women's memoirs of SLE, focusing on the narratives of white, non-disabled, and economically privileged women simultaneously as discussions of SLE in Black feminisms and SLE narratives by Black authors became more complex. As cited by Winstead (2024), in the twentieth century, SLE was described as a gendered, racialized, and culturally inflected process of immunity. The cure for SLE was a triumph of postwar American medicine and a God-sent affirmation of order. The first recorded case of using ACTH and cortisone, drugs that copied or boosted the effect of adrenal corticosteroid hormones, to treat rheumatoid arthritis was in 1949 by Philip Hench, a rheumatologist at the Mayo Clinic. According to Winstead (2024), the study will further argue that two approaches are necessary to overcome these disparities: gender-sensitive and race-sensitive healthcare models. Article 6: Female-Bias in Systemic Lupus Erythematosus: How Much is the X Chromosome to Blame? (Vieira et al., 2024) This study by Vieira et al. (2024) explores the role of the X chromosome in causing the gender differences in SLE. The scholars note that there is a striking female bias in SLE manifesting through higher susceptibility of women compared to men, with some ethnicities recording up to 14 times the incidence of SLE in women than in men. The premise of the study is that the supernumerary X chromosome syndromes, for example, Tripple X (XXX) and Klinefelter (XXY), are associated with higher SLE prevalence, suggesting a possible link between the likelihood of acquiring SLE and the number of X chromosomes. Vieira et al. (2024) also examined how the X chromosomes work to increase the risk of SLE. According to the researchers, the majority of X chromosome genes can be permanently silenced by X-chromosome inactivation (XCI) via the X-inactive-specific transcript (XIST) pathway. The article's primary purpose was to research this relationship, focusing on what has been established in past studies. As a review, the article focuses primarily on past empirical studies on various interrelated aspects of the research subject. The first aspect comprises an examination of the female bias, where the scholars establish SLE as an exemption from the norm because women are generally less affected by infectious diseases. In this regard, all evidence examined points to a female bias attributed to the X chromosomes. The second aspect explores the XCI to offer further information regarding the mechanisms by which the X chromosomes increase the SLE risk. In this regard, the researchers reach an agreement based on empirical data that X chromosomes, with the exception of one, undergo transcriptional silencing irrespective of sex in order to avoid the negative consequences of gene overload of many active X chromosomes. During this process, few X-linked genes escape and are responsible for the sex- or individual-specific disparities in disease susceptibility. Another vital aspect of this paper is examining the relationship between XCI and SLE. For this part, Vieira et al. (2024) present ample evidence suggesting that it is not the XCI that causes SLE. Rather, it is the presence of factors that regulate XCI that trigger SLE. Additionally, a higher level of escape from the Xi in women with SLE triggers SLE onset and/or progression. Therefore, this article offers a comprehensive view of the research topic by providing ample empirical evidence to support its premise. Article 7: Sex Differences in Systemic Lupus Erythematosus: Epidemiology, Clinical Considerations, and Disease Pathogenesis (Nusbaum et al., 2020) The article by Nusbaum et al. (2020) is a thematic review of the sex differences in SLE, focusing on epidemiology and pathogenesis. Regarding the research design, thematic analyses are qualitative studies that involve identifying themes and patterns within data to comprehend meaning and context. This study focuses on secondary data from past studies, meaning the design can also be considered a systematic literature review. The analysis results are organized into core sections, including the epidemiology, clinical considerations, fertility issues, and sex differences in pathogenesis. The article discloses through epidemiological research that SLE’s prevalence in women conceals how it manifests quickly among the few male patients. Nusbaum et al. (2020) demonstrate that SLE affects men through a rapid and progressively damaging clinical course that leads to worse outcomes than observed in female SLE patients. Current studies indicate that male SLE patients experience serositis, cytopenias and cardiovascular disease, nephritis and seizures, and hemolytic anemia and thrombotic events. Nusbaum et al. (2020) discovered alcohol consumption, smoking, kidney complications, and lupus anticoagulants substantially influence SLE development. Based on the high female SLE incidences, Nusbaum et al. (2020) examine the clinical care needs of the patients. The safety and effectiveness of human papillomavirus (HPV) stands out during this assessment since women with HPV face more significant risks of developing cancerous and precancerous cervical lesions. The success rates, the dangers associated with SLE, and pregnancy complications depend heavily on when a woman becomes pregnant. Similarly, SLE poses serious risks to both the fetus and mother throughout the pregnancy. Another vital component of the thematic analysis involves fertility issues in men and women. In this regard, the study establishes a possible relationship between SLE and infertility in women and testis damage in men. Regarding sex differences, the study finds that sex chromosomes, specifically the X chromosomes, significantly raise the risk for SLE. For example, males with SLE are approximately 14 times more likely to have Klinefelter syndrome (47, XXY) than men without SLE. Similarly, women with 47, XXX (karyotype) face about 25 times the risk of SLE. Unlike most studies, Nusbaum et al. (2020) go beyond the genetic component of gender differences and include other aspects, such as sex hormones and receptors. For example, the onset of SLE is higher at the stage of life when estrogen is at its peak. Article 8: Sex Differences in Systemic Lupus Erythematosus (SLE): An Inception Cohort of the Chinese SLE Treatment and Research Group (CSTAR) Registry XVII (Gui et al., 2022) A cross-sectional study by Gui et al. (2022) explores the gender differences in SLE, focusing on clinical characteristics and treatment preferences. Cross-sectional study designs entail collecting data from a population or a representative sample at a single point in time, thus giving a snapshot of the research phenomenon within the target population. Following these requirements of a cross-sectional design, Gui et al. (2022) collected data from the Chinese SLE Treatment and Research Group between 2009 and 2021. The sample size was 8713 patients, and the ratio was 795 men to 7918 women. Additionally, the sample population comprises 2900 patients with lupus nephritis at a ratio of 347 men to 2553 women. A cross-sectional analysis considered the baseline demographic features, laboratory parameters, clinical manifestations, renal pathology, initial treatment regimes, and organ damage. All these issues were analyzed according to sex. As opposed to many past studies, the main premise of this research is that few studies focus on SLE in men despite the effects or clinical manifestations being more severe in men. Their premise is presumably based on the fact that SLE is mostly associated with the female gender, as proven by prevalence statistics. In this case...