SLE & Azathioprine Medical Training PDF

SLE & Azathioprine medical training Ahmed Elrashedy MSL Immunology care line - Egypt cluster 1 1 Corporate Slides / EVA Pharma...

SLE & Azathioprine medical training Ahmed Elrashedy MSL Immunology care line - Egypt cluster 1 1 Corporate Slides / EVA Pharma 2 Introduction Introduction September 24 2 Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 3 Introduction Lupus is a Latin for wolf and erythro is a Greek for red (Red wolf). Defenition of SLE : Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by antibodies to nuclear and cytoplasmic antigens, multisystem inflammation, protean clinical manifestations, and a relapsing and remitting course. More than 90% of cases of SLE occur in women, frequently starting at childbearing age. September 24 3 ---. “Systemic Lupus Erythematosus (SLE): Practice Essentials, Pathophysiology, Etiology.” Company Confidential Medscape.com, © 2021 2 Feb. 2019, emedicine.medscape.com/article/332244-overview. Eli EVA and Company Corporate Slides / EVA Pharma 4 Introduction o SLE is a chronic inflammatory disease that can affect almost any organ system, although it mainly involves the Skin, joints, kidneys, blood cells, and nervous system. o Its presentation and course are highly variable, ranging from indolent to fulminant. September 24 4 ---. “Systemic Lupus Erythematosus (SLE): Practice Essentials, Pathophysiology, Etiology.” Company Confidential Medscape.com, © 2021 2 Feb. 2019, emedicine.medscape.com/article/332244-overview. Eli EVA and Company Corporate Slides / EVA Pharma 5 childhood-onset SLE o The following clinical manifestations are more commonly found than in adults: Malar rash Ulcers/mucocutaneous involvement Kidney involvement, proteinuria, urinary cellular casts Seizures Thrombocytopenia Hemolytic anemia Fever Lymphadenopathy. September 24 5 ---. “Systemic Lupus Erythematosus (SLE): Practice Essentials, Pathophysiology, Etiology.” Company Confidential Medscape.com, © 2021 2 Feb. 2019, emedicine.medscape.com/article/332244-overview. Eli EVA and Company Corporate Slides / EVA Pharma 6 childhood-onset SLE September 24 “NAA Associated Systemic Lupus Erythematosus (SLE) - Creative Biolabs.” CompanyWww.creative-Biolabs.com, www.creative-biolabs.com/natural-autoantibody/systemic-lupus-erythematosus.htm. Confidential © 2021 Eli EVA and Company  Epidemiology Company Confidential / EVA Pharma 7 Corporate Slides / EVA Pharma 8 Epidemiology o The complexity of the clinical manifestations and challenges brought by diagnosis make SLE epidemiological studies difficult to conduct. Incidence of systemic lupus erythematosus for overall population by country. Tian, Jingru, et al. “Global Epidemiology of Systemic Lupus Erythematosus: A Comprehensive Systematic Analysis and Modelling Study. September 24 8 ” Annals of the Rheumatic Diseases, vol. 82, no. 3, 14 Oct. 2022, ard.bmj.com/content/early/2022/10/13/ard-2022-223035, https://doi.org/10.1136/ard-2022-223035. Company Confidential © 2021 Eli EVA and Company  Corporate Slides / EVA Pharma 9 Epidemiology o For the overall population, the global SLE incidence and newly diagnosed population were estimated to be 5.14 (1.4 to 15.13) per 100000 person-years and 0.40 million annually, respectively. The incidence of SLE in the general population varied from Asia Europe 1.18 (0.16 to 3.68) per 100000 person-years 13.74 (3.2 to 31.82) per 100000 person-years September 24 9 : Tian J, Zhang D, Yao X, et al. Ann Rheum Dis 2023;82:351–356 Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 10 The incidence of SLE differed greatly by country. 81.84 PER 100000 PERSON - YEARS 12.13 10.37 8.57 0.57 POLAND USA BARBADOS CHAINA KAZAKHSTAN September 24 10 : Tian J, Zhang D, Yao X, et al. Ann Rheum Dis 2023;82:351–356 Company Confidential © 2021 Eli EVA and Company  Corporate Slides / EVA Pharma 11 The incidence of SLE differed greatly by country. o Women were more likely to have SLE than men. o The global SLE incidence and newly diagnosed population in women were estimated to be 8.82 (2.4 to 25.99) per 100 000 person-years and 0.34 million annually, respectively. September 24 11 : Tian J, Zhang D, Yao X, et al. Ann Rheum Dis 2023;82:351–356 Company Confidential © 2021 Eli EVA and Company  Corporate Slides / EVA Pharma 12 The incidence of SLE differed greatly by Age. o In addition to regional differences, age could also show variation. o Based on our estimate, the SLE incidence in adults was approximately 1.42-fold higher than that in the total population. September 24 12 : Tian J, Zhang D, Yao X, et al. Ann Rheum Dis 2023;82:351–356 Company Confidential © 2021 Eli EVA and Company  Corporate Slides / EVA Pharma 13 Newly diagnosed patients annualy o Approximately 0.68 million adult women worldwide were newly diagnosed with SLE annually. o Approximately 0.06 million adult men worldwide were newly diagnosed annually. September 24 13 : Tian J, Zhang D, Yao X, et al. Ann Rheum Dis 2023;82:351–356 Company Confidential © 2021 Eli EVA and Company  Disease burden Company Confidential / EVA Pharma 14 Corporate Slides / EVA Pharma 15 Impact of SLE on health-related quality of life Nearly everyone with SLE experiences fatigue, which can be so incapacitating that participation in social gatherings and daily activities may be impossible. It may have an impact on every facet of a patient’s quality of life and have an impact on their physical and mental health. In a European survey, 85.3% of patients pinpointed fatigue as their most incapacitating symptom5. Refai, Rania H., et al. “A Case–Control Study on Health-Related Quality of Life of Systemic Lupus Erythematosus Patients. September 24 15 ” Scientific Reports, vol. 14, no. 1, 4 Mar. 2024, p. 5234, www.nature.com/articles/s41598-024-55833-9, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.1038/s41598-024-55833-9. Accessed 14 Mar. 2024. Corporate Slides / EVA Pharma 16 Aspects of life that are impacted by health, such as functional, social, or emotional HRQoL status, are referred to as health-related quality of life Severity , Chronic nature of the disease and the incidence of organ damage had a substantial impact on the HRQoL The quality of life in patients with SLE is SLE patients reported low HRQoL comparable with the quality of life in other and high medical costs that chronic diseases: rheumatoid arthritis, correlate with disease activity Sjögren’s syndrome or acquired immune deficiency syndrome (AIDS) Refai, Rania H., et al. “A Case–Control Study on Health-Related Quality of Life of Systemic Lupus Erythematosus Patients. September 24 16 ” Scientific Reports, vol. 14, no. 1, 4 Mar. 2024, p. 5234, www.nature.com/articles/s41598-024-55833-9, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.1038/s41598-024-55833-9. Accessed 14 Mar. 2024. Corporate Slides / EVA Pharma 17 The impact of systemic lupus erythematosus on the quality of life Olesińska, Marzena, and Agata Saletra. “Quality of Life in Systemic Lupus Erythematosus and Its Measurement. September 24 17 ” Reumatologia/Rheumatology, vol. 56, no. 1, 2018, pp. 45–54, www.ncbi.nlm.nih.gov/pmc/articles/PMC5911658/, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.5114/reum.2018.74750. Corporate Slides / EVA Pharma 18 The impact of systemic lupus erythematosus on the quality of life Patients are worried about the recurrence of pain, intensification of weakness, and fatigue. They fear the disease progression and even death Patients often obtain older data on the disease, in which the prognosis is very serious and the risk of mortality is high. Although even patient with great acceptance of disease have tough moments. Patients often react with angry and exasperation to situation, which in normal life would not cause such feelings Olesińska, Marzena, and Agata Saletra. “Quality of Life in Systemic Lupus Erythematosus and Its Measurement. September 24 18 ” Reumatologia/Rheumatology, vol. 56, no. 1, 2018, pp. 45–54, www.ncbi.nlm.nih.gov/pmc/articles/PMC5911658/, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.5114/reum.2018.74750.  Corporate Slides / EVA Pharma 19 Body image & Emotional disorders In systemic lupus erythematosus, the skin is frequently affected. Classic erythema on the face, discoid rash, lesions with tendency to scarring, skin atrophy and loss of hair are often unsightly and lower the self-esteem of a patient. More than 2/3 of patients with SLE suffer from emotional disorders. The disease triggers the feeling of helplessness and exhaustion by everyday struggle that the patient cannot win. These symptoms cause people with SLE often feel embarrassed by their appearance. Feeling sad, depression, fear, anxiety, They also fear weight gain due to the use of guilt, anger, wrath GC Olesińska, Marzena, and Agata Saletra. “Quality of Life in Systemic Lupus Erythematosus and Its Measurement. September 24 19 ” Reumatologia/Rheumatology, vol. 56, no. 1, 2018, pp. 45–54, www.ncbi.nlm.nih.gov/pmc/articles/PMC5911658/, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.5114/reum.2018.74750. Corporate Slides / EVA Pharma 20 Burden of the disease 95% of patients with 90% of patients The patients give up exercises SLE report sleep disorders suffer from joint pan due to depression Result from the symptoms of Pain significantly influences Low level of physical activity basic disease: pain, stress, everyday functioning of in patients with SLE influences depression and side effects of patients, limits their abilities the development of medications to discharge professional cardiovascular disease, duties as well as household osteoporosis, obesity, fatigue responsibilities and sleep disorders. Olesińska, Marzena, and Agata Saletra. “Quality of Life in Systemic Lupus Erythematosus and Its Measurement. September 24 20 ” Reumatologia/Rheumatology, vol. 56, no. 1, 2018, pp. 45–54, www.ncbi.nlm.nih.gov/pmc/articles/PMC5911658/, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.5114/reum.2018.74750. Corporate Slides / EVA Pharma 21 Burden of the disease after 5 years of the disease 15–40% The disease has a negative impact Sexual dysfunctions are result of both, of patients lose their jobs also on family and social life. physical and psychological problems. High disease activity, The patients do not fulfill their Many symptoms of lupus that accompanying fatigue and pain household and family have negative impact on sexual prevent the patients from responsibilities due to constant activity can be observed. continuing work. fatigue and bad mood. Joint pain is one of them. patients are also concerned about the Patients point as the most problematic: costs of illness: medical costs and moving heavy objects, doing laundry, additional healthcare insurance costs shopping and taking care after children Olesińska, Marzena, and Agata Saletra. “Quality of Life in Systemic Lupus Erythematosus and Its Measurement. September 24 ” Reumatologia/Rheumatology, vol. 56, no. 1, 2018, pp. 45–54, www.ncbi.nlm.nih.gov/pmc/articles/PMC5911658/, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.5114/reum.2018.74750. Corporate Slides / EVA Pharma 22 Burden of the disease Patients with SLE fear that their The implementation of treatment Increased mortality occurs more children might suffer from the often evokes mixed feelings. often in patients with SLE disease as well. Mainly due to cardiovascular On the one hand the patients Pregnancy complications are optimistic that the diseases. Hyperlipidemia and and anomalies in the fetus symptoms of the disease will be hypertension are independent occur more often in the controlled and its activity factors of the increased risk of course of SLE than in the reduced, on the other hand they cardiovascular events. general population. fear side effects of the therapy. Olesińska, Marzena, and Agata Saletra. “Quality of Life in Systemic Lupus Erythematosus and Its Measurement. September 24 22 ” Reumatologia/Rheumatology, vol. 56, no. 1, 2018, pp. 45–54, www.ncbi.nlm.nih.gov/pmc/articles/PMC5911658/, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.5114/reum.2018.74750.  Pathophysiology Company Confidential / EVA Pharma 23  Corporate Slides / EVA Pharma 24 The systemic nature of SLE The systemic nature of SLE reflects the The diversity of clinical manifestations and the multiple widely distributed alterations in immune molecular pathways implicated in patients diagnosed with system activity that result in autoimmunity SLE have raised the possibility that lupus represents many targeting nucleic acids and their associated diseases rather than variable presentations of one disease. proteins, as well as tissue-damaging inflammation. There is a rationale for viewing lupus as a disorder attributable to immune system mediators that represent common denominators across most patients, specifically type I interferon (IFN-I) and characteristic autoantibodies. Crow, Mary K. “Pathogenesis of Systemic Lupus Erythematosus: Risks, Mechanisms and Therapeutic Targets. September 24 ” Annals of the Rheumatic Diseases, vol. 82, no. 8, 15 Feb. Company 2023,Confidential © 2021 Eli EVA p. ard-2022-223741, and Company https://doi.org/10.1136/ard-2022-223741. Corporate Slides / EVA Pharma 25 Broad view of the pathogenesis of SLE Crow, Mary K. “Pathogenesis of Systemic Lupus Erythematosus: Risks, Mechanisms and Therapeutic Targets. September 24 ” Annals of the Rheumatic Diseases, vol. 82, no. 8, 15 Feb. Company 2023,Confidential © 2021 Eli EVA p. ard-2022-223741, and Company https://doi.org/10.1136/ard-2022-223741. Corporate Slides / EVA Pharma 26 Pathophysiology The pathogenesis of SLE is complex The understanding of SLE pathogenesis is constantly evolving. A break in the tolerance in genetically susceptible individuals on exposure to environmental factors leads to the activation of autoimmunity. Cell damage caused by infectious and other environmental factors exposes the immune system to self-antigens leading to activation of T and B cells, which become self-sustained by a chronic self-aimed immune response. Cytokine release, complement activation, and autoantibody production lead to organ damage. Crow, Mary K. “Pathogenesis of Systemic Lupus Erythematosus: Risks, Mechanisms and Therapeutic Targets. September 24 ” Annals of the Rheumatic Diseases, vol. 82, no. 8, 15 Feb. Company 2023,Confidential © 2021 Eli EVA p. ard-2022-223741, and Company https://doi.org/10.1136/ard-2022-223741. Corporate Slides / EVA Pharma 27 The complex interactions between the various susceptible factors implicated in lupus etiology. Implications of genetics known to directly regulate the disease manifestations or indirectly through epigenetic modifications induced by environmental factors. These indirect modifications can also regulate the immunobiology and mitochondrial health which combines to affect immunometabolism, an An important aspect in lupus pathology. Akhil, Akhil, et al. “Systemic Lupus Erythematosus: Latest Insight into Etiopathogenesis. September 24 ” Rheumatology International, vol. 43, no. 8, 1 Aug. 2023, pp. 1381–1393, Company pubmed.ncbi.nlm.nih.gov/37226016/, Confidential © 2021 Eli EVA and Company https://doi.org/10.1007/s00296-023-05346-x. Corporate Slides / EVA Pharma 28 SLE immunobiology The pathophysiology of SLE is complex involving the interplay between factors and cells of innate/adaptive immunity in the microenvironment and triggers an immune response. A very important innate trigger is neutrophil, which is deregulated in SLE due to high reactive oxygen species (ROS) levels and get triggered by enhanced IL-18 receptors Neutrophil extracellular traps (NETs) are enhanced and are known to be associated with enhanced IgG2 production from B cells in lupus Akhil, Akhil, et al. “Systemic Lupus Erythematosus: Latest Insight into Etiopathogenesis. September 24 ” Rheumatology International, vol. 43, no. 8, 1 Aug. 2023, pp. 1381–1393, Company pubmed.ncbi.nlm.nih.gov/37226016/, Confidential © 2021 Eli EVA and Company https://doi.org/10.1007/s00296-023-05346-x. Corporate Slides / EVA Pharma 29 SLE immunobiology The pathophysiology of SLE is complex involving the interplay between factors and cells of innate/adaptive immunity in the microenvironment and triggers an immune response. Neutrophil degranulation is known to increase the secretion of pro-inflammatory cytokines (IFN-ϒ) that can fan the flames of lupus etiology Innate immune receptors such as the Toll-like receptors (TLRs) have the unique capacity to recognize pathogen-associated molecular patterns (PAMPs) while inducing immune system activation by linking the innate and adaptive immunity responses. Akhil, Akhil, et al. “Systemic Lupus Erythematosus: Latest Insight into Etiopathogenesis. September 24 ” Rheumatology International, vol. 43, no. 8, 1 Aug. 2023, pp. 1381–1393, Company pubmed.ncbi.nlm.nih.gov/37226016/, Confidential © 2021 Eli EVA and Company https://doi.org/10.1007/s00296-023-05346-x. Corporate Slides / EVA Pharma 30 SLE immunobiology The pathophysiology of SLE is complex involving the interplay between factors and cells of innate/adaptive immunity in the microenvironment and triggers an immune response. TLRs 7 and 9 have been strongly implicated in SLE pathogenesis since they mediate IFNα production by plasmacytoid dendritic cells (pDCs) upon their activation by circulating immune complexes containing self nucleic acid components. TLR-7 can regulate the extra-follicular B cells response in the germinal center which may enhance autoantibody generation, While TLR-9 can limit the TLR-7 stimulatory activity, demonstrating its protective function in lupus etiology. Akhil, Akhil, et al. “Systemic Lupus Erythematosus: Latest Insight into Etiopathogenesis. September 24 ” Rheumatology International, vol. 43, no. 8, 1 Aug. 2023, pp. 1381–1393, Company pubmed.ncbi.nlm.nih.gov/37226016/, Confidential © 2021 Eli EVA and Company https://doi.org/10.1007/s00296-023-05346-x. Corporate Slides / EVA Pharma 31 Dendritic cells The dendritic cells play an important role in linking the innate and adaptive immune systems and serve as both a “break” and “engine” for lupus pathology It has been shown that monocytes from healthy individuals may be differentiated into myeloid dendritic cells (mDCs) in the presence of serum from a lupus patient. These mDCs can also have the ability to phagocytize nuclear material and present antigens to naive CD4+ T cells, which can later activate the cytotoxic activity of CD8+ T cells and thus support the proliferation and differentiation of B cells. September 24 Sim TM et al (2022) Type I interferons in systemic lupus erythematosus: a journey Company Confidential from © 2021 Eli bench toCompany EVA and bedside. Int J Mol Sci 23(5):2505 Corporate Slides / EVA Pharma 32 Autoreactive IgE The binding of IgE to pDCs also enhances the follicular T cell expansion and reduces the Treg population, which increased the inflammatory condition in lupus patients IFN-α can also activate the IL-1 receptor-associated kinase that further induces apoptosis in Treg cells from SLE patients September 24 Charrier M et al (2021) The role of dendritic cells in systemic lupus erythematosus. Systemic Lupus Erythematosus. Company Confidential © 2021 Eli EVA and Company Elsevier, Amsterdam, pp 143–150 Corporate Slides / EVA Pharma 33 T-regs The binding of IgE to pDCs also enhances the follicular T cell expansion and reduces the Treg population, which increased the inflammatory condition in lupus patients IFN-α can also activate the IL-1 receptor-associated kinase that further induces apoptosis in Treg cells from SLE patients Tregs have potent anti-inflammatory activity, therefore their apoptosis will further enhance the immune response in lupus patients. September 24 Scherlinger M et al (2021) Selectins impair regulatory T cellCompany functionConfidential and contribute to Eli © 2021 systemic EVA andlupus erythematosus pathogenesis. Sci Transl Med 13(600):eabi4994 Company Corporate Slides / EVA Pharma 34 Over-activation of T cells has led to its exhaustion, which can be further correlated with tolerance mechanisms such as prolonged remission in lupus patients. The type-I interferon has been demonstrated to affect the metabolic fitness of CD8+ T cells, which may increase their death and lupus severity IL-17 can further expand the proliferation of Th17 and autoreactive T and B cells which can worsen the lupus symptoms. September 24 Buang N et al (2021) Type I interferons affect the metabolic Company fitness ofConfidential CD8+ T cells from © 2021 Eli patients with systemic lupus erythematosus. Nat Commun 12(1):1–15 EVA and Company  Corporate Slides / EVA Pharma 35 CD4+ T cells autoreactive T cells such as nuclear antigen-specific CD4+ T cells are elevated in lupus patients and were further correlated with kidney manifestations such as lupus nephritis. CD4+ follicular T cells were also found to be associated with B cell maturation and generation of autoantibodies in lupus patients The failure of an immune regulatory system such as Treg cells, and the over-activation of plasma cells are well-known mechanisms in lupus etiology. September 24 Abdirama D et al (2021) Nuclear antigen–reactive CD4+ T cells expand inCompany active systemic lupus Confidential erythematosus, © 2021 produce effector cytokines, and invade the kidneys. Kidney Int 99(1):238–246 Eli EVA and Company  Corporate Slides / EVA Pharma 36 Cytokine network in SLE Cytokines have an important role in the immunobiology of lupus which connects the innate and adaptive immune systems in many ways. The increase in various pro-inflammatory cytokines such as CXCL10, IL-6, IL-2, and interferon-ϒ production in SLE patients results in reinforcement of Th1 differentiation and naïve T cell proliferation leading to IgG production from B cells. Exacerbated production of CXCL10, IL-6, IL-2, and interferon-ϒ was associated with a memory-like phenotype in CD4+ polarized B cells toward pro-inflammatory B cells in SLE patients The complex immunobiology of lupus includes the over immune response triggers due to the overactive immune cells towards self-antigens. Various factors including the pro-inflammatory cytokines, chemokines, apoptosis, overactivated APCs. Failure of phagocytotic activity have been well-defined to be involved in lupus etiology. September 24 Simon Q et al (2019) A pathogenic cytokine network is associated with pro-inflammatory Company Confidential B and © 2021 Eli EVA cells in systemic lupus erythematosus patients. SSRN J Company Corporate Slides / EVA Pharma 37 Genetic factors Current evidence in the genetic susceptibility of lupus shows that genes can also potentially regulates the dysregulated immunological mechanisms associated with disease manifestation that will be further modified through various epigenetic phenomena. Therefore, the genetic analysis may lead to the identification of novel susceptible targets which are associated with the complex network of lupus and will be further targeted with potent therapeutics. Akhil, Akhil, et al. “Systemic Lupus Erythematosus: Latest Insight into Etiopathogenesis. September 24 37 ” Rheumatology International, Company Confidential © no. vol. 43, 20218,Eli1 EVA Aug.and Company 2023, pp. 1381–1393, pubmed.ncbi.nlm.nih.gov/37226016/, https://doi.org/10.1007/s00 Corporate Slides / EVA Pharma 38 Different arms involved in SLE September 24 38 Company Confidential © 2021 Eli EVA and Company  Clinical picture Company Confidential / EVA Pharma 39 Corporate Slides / EVA Pharma 40 Clinical picture of SLE SLE is a multisystem disease with several phenotypes. Clinical features may vary from o A very mild disease with only mucocutaneous involvement to o Severe life-threatening disease with multiorgan involvement. All organ systems can be involved in SLE. Several studies have indicated the development of serological abnormalities several years before the onset of clinical lupus. his is termed pre-clinical lupus, where a patient may have serological abnormalities consistent with SLE and may have some clinical features but still does not meet the criteria for SLE. September 24 40 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” CompanyPubMed, StatPearls Confidential © 2021 Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 41 Constitutional Symptoms Constitutional symptoms are seen in more than 90% of patients with SLE and are often the initial presenting feature. Fatigue, malaise, fever, anorexia, and weight loss are common. While more than 40% of patients with SLE may have lupus flare as a cause of fever, infections must always be ruled out first, Further, SLE is an infrequent cause of fever of unknown origin. Kanderi T, Kim J, Chan Gomez J, Joseph M, Bhandari B. Warm Autoimmune Hemolytic Anemia as the Initial Presentation of SystemicSeptember 24 Lupus Erythematosus 41 (SLE): A Case Report. Am J Case Rep. 2021 Dec 12;22:e932965. Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 42 Mucocutaneous Manifestations More than 80% of patients with SLE suffer from mucocutaneous involvement, one of the most well- known and identified clinical features. SLE skin lesions may be lupus-specific, while several nonspecific lesions are also seen. Lupus-specific lesions include: Acute cutaneous lupus Subacute cutaneous lupus Chronic cutaneous lupus erythematosus (ACLE) erythematosus (SCLE) erythematosus (CCLE) includes localized, malar, and includes annular and includes classic discoid lupus generalized, papulosquamous erythematosus (DLE) hypertrophic/verrucous, lupus panniculitis/profundus, lupus tumidus, chilblains lupus, mucosal discoid lupus, and lichenoid discoid lupus. September 24 42 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” CompanyPubMed, StatPearls Confidential © 2021 Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 43 Acute cutaneous lupus erythematosus (ACLE) may be localized or generalized. The hallmark ACLE lesion is the malar rash or the butterfly rash. An erythematous raised pruritic rash involving the cheeks and nasal bridge. The rash may be macular or papular and spares the nasolabial folds (photoprotected). It usually has an acute onset but may last several weeks and cause induration and scaling. The malar rash may also fluctuate with lupus disease activity. ACLE lesions usually heal without scarring. Other rashes in this location that must be differentiated from ACLE malar rash include rosacea, erysipelas, seborrheic dermatitis, and perioral dermatitis. September 24 43 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” CompanyPubMed, StatPearls Confidential © 2021 Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 44 Subacute cutaneous lupus erythematosus (SCLE) SCLE rash is seen in patients with a positive Anti-Ro (SSA) antibody in up to 90% of the cases. Photosensitive, widespread, nonscarring, nonindurated rash. SCLE may be either papulosquamous resembling psoriasis or an annular/polycystic lesion with central clearing and peripheral scaling. SCLE can also be caused by some drugs such as hydrochlorothiazide. It has also been reported in patients with Sjogren syndrome and rheumatoid arthritis. September 24 44 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” CompanyPubMed, StatPearls Confidential © 2021 Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company  Corporate Slides / EVA Pharma 45 Discoid lupus erythematosus (DLE) is the most common form of chronic cutaneous lupus erythematosus (CCLE). The lesions are disk-shaped erythematous papules or plaques with adherent scaling and central clearing. DLE heals with scarring and can be associated with permanent alopecia when present on the scalp. Mucosal DLE lesions can be seen in the oral cavity, and these tend to be painful erythematous round lesions with white radiating hyperkeratotic striae. September 24 45 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” PubMed, Company StatPearls Publishing, Confidential 2023, © 2021 Eli www.ncbi.nlm.nih.gov/books/NBK535405/. EVA and Company  Corporate Slides / EVA Pharma 46 Ulcers with SLE Oral and nasal ulcers are common in SLE, and acutely, often are painless. They may present as gradual onset erythema,erosions, or ulcers involving any part of the oral cavity. The most common locations are the hard palate, and the buccal mucosa September 24 46 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” PubMed, Company StatPearls Publishing, Confidential 2023, © 2021 Eli www.ncbi.nlm.nih.gov/books/NBK535405/. EVA and Company  Corporate Slides / EVA Pharma 47 Photosensitivity & Alopecia Photosensitivity is present in SLE in more than 90% of cases. It is characterized by abnormal skin reaction on exposure to ultraviolet A/B and visible light A reaction that may last weeks to months. These patients also experience worsening of their systemic symptoms on sun exposure. Alopecia in SLE may be due to DLE (scarring), or the brittle, easily breaking lupus hair (non-scarring) in the temporal/parietal area. September 24 47 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” PubMed, Company StatPearls Publishing, Confidential 2023, © 2021 Eliwww.ncbi.nlm.nih.gov/books/NBK535405/. EVA and Company  Corporate Slides / EVA Pharma 48 Skin manifestations Several other skin manifestations are seen in SLE that are not specific. o These include o Cutaneous vasculitis (leukocytoclastic or urticarial), vasculopathy (livedo reticularis, superficial thrombophlebitis, Raynaud's phenomenon, erythromelalgia, periungual telangiectasia), sclerodactyly, rheumatoid nodules, calcinosis cutis, bullous lesions, urticaria, erythema multiforme, acanthosis nigricans, lichen planus, and leg ulcers. September Emorinken A, Dic-Ijiewere MO, Erameh CO, Ugheoke AJ, Agbadaola OR, Agbebaku FO. Clinical and laboratory profile of systemic lupus erythematosus 24a rural tertiary48 patients at centre in South-S Company Confidential © 2021 Eli EVA and Company Nigeria: experience from a new rheumatology clinic. Reumatologia. 2021;59(6):402-410.  Corporate Slides / EVA Pharma 49 Musculoskeletal Manifestations Approximately 80 to 90% of patients with SLE suffer from musculoskeletal involvement at some point during their disease course and may range from mild arthralgias to deforming arthritis. Lupus arthritis is typically a non-erosive, symmetrical inflammatory polyarthritis affecting predominantly the small joints of the hands, knees, and wrists, although any joint can be involved. Jaccoud arthropathy results from the joint capsule and ligament laxity, leading to non-erosive deformities of the hands, including ulnar deviation and subluxation of the metacarpophalangeal joints that may mimic rheumatoid arthritis. Usually, these deformities are reducible, although rarely, they may become fixed. September 24 49 Justiz Vaillant, Angel A., et al. “Systemic Lupus Erythematosus.” PubMed, Company Confidential StatPearls © 2021 Publishing, Eli www.ncbi.nlm.nih.gov/books/NBK535405/. 2023, EVA and Company Corporate Slides / EVA Pharma 50 Other comorbidities Patients with SLE are at high Rheumatoid nodules risk for the development of have been reported in fibromyalgia, with incidences patients with SLE. as high as 20% reported Mukkera S, Mannem M, Chamarti K, Pillarisetty L, Vulasala SS, Alahari L, Ammu A, Mukkera A, Vadlapatla RK. September 24 50 Company Systemic Lupus Erythematosus-Associated Serositis Managed With Confidential Intravenous © 2021 Eli EVA Belimumab: and Company A Case Report. Cureus. 2022 Feb;14(2):e22639. Corporate Slides / EVA Pharma 51 Hematologic and reticuloendothelial manifestations: Anemia is present in more than 50 % of patients with SLE and most commonly is anemia of chronic disease. Other causes of anemia in SLE may include o Iron deficiency anemia, coomb's positive autoimmune hemolytic anemia, red blood cell aplasia, and microangiopathic hemolytic anemia, which may be associated with antiphospholipid antibody syndrome. Leukopenia secondary to neutropenia or lymphopenia is also very frequent and severe. Thrombocytopenia can be mild or severe and may be associated with antiphospholipid antibody syndrome and autoantibodies against platelets, glycoprotein IIb/IIIa, or thrombopoietin receptor. Pancytopenia is not infrequent and may occasionally be associated with myelofibrosis. Soft non-tender lymphadenopathy is common in SLE, although rare cases of histiocytic necrotizing lymphadenitis have been reported (Kikuchi-Fujimoto disease). Splenomegaly is common in SLE, while splenic atrophy and asplenism have been reported. September 24 51 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK535405/. Company Confidential © 2021 Eli EVA and Company  Corporate Slides / EVA Pharma 52 Neuropsychiatric Manifestations Both central (CNS) and peripheral (PNS) nervous systems may be involved in SLE in addition to several psychiatric manifestations. Although the diagnosis can be difficult. The most common CNS manifestation is intractable headaches, reported in more than 50% of cases. Focal or generalized seizures may be seen, and are associated with disease activity, o Psychiatric manifestations are difficult to diagnose and manage and may range from depression and anxiety to frank psychosis. September 24 52 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls CompanyPublishing, Confidential 2023, © 2021www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company  Corporate Slides / EVA Pharma 53 Renal Manifestations Lupus nephritis is a well-known and common complication of SLE. The involvement may range from mild sub nephrotic proteinuria to diffuse progressive glomerulonephritis → leading to chronic kidney damage. Lupus nephritis usually occurs early in the course of SLE. New-onset hypertension, hematuria, proteinuria, lower extremity edema, and elevation in creatinine shall raise suspicion for lupus nephritis. A biopsy is crucial in staging lupus nephritis and ruling out other causes. There are six classes of lupus nephritis Lupus nephritis can involve the glomeruli, interstitium, tubules, and vessels with immune complex deposition in all four compartments. September 24 53 Ruacho G, Lira-Junior R, Gunnarsson I, Svenungsson E, Boström EA. Inflammatory markers in saliva and urine reflect disease activity in patients with Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 54 Stages of Lupus Nephritis World Health Organization classification criteria for lupus nephritis describes six classes of lupus nephritis, all with distinct pathological features and significant differences in clinical outcomes. This has led to a different treatment approach for each class and knowing the class of lupus nephritis before initiating treatment is vital. September 24 54 Ruacho G, Lira-Junior R, Gunnarsson I, Svenungsson E, Boström EA. Inflammatory markers in saliva and urine reflect disease activity in patients with Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 55 Histopathological classification of Lupus Nephritis The biopsy findings dictate the treatment of lupus nephritis. The prognosis varies for each class, with an excellent prognosis for classes I and II and poor outcomes with classes III and IV. Class V usually carries a favorable prognosis except for complications of nephritis syndrome such as thromboembolism which are common in this class. September 24 55 Pinheiro, Sergio Veloso Brant, et al. “Pediatric Lupus Nephritis.” Brazilian CompanyJournal of Nephrology, Confidential vol.and © 2021 Eli EVA 41,Company no. 2, June 2019, pp. 252–265, https://doi.org/10.1590/2175-8239-jbn-2018-0097. Corporate Slides / EVA Pharma 56 Pulmonary Manifestations Pleuritis is the most common pulmonary manifestation and may not always be associated with pleural effusion. Other pulmonary manifestations include exudative pleural effusions, acute lupus pneumonitis with bilateral pulmonary infiltrates, an interstitial lung disease which may be nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP), diffuse alveolar hemorrhage associated with capillaritis, pulmonary arterial hypertension, pulmonary embolism (with or without antiphospholipid antibody syndrome) and shrinking lung syndrome. September 24 56 ---. “Systemic Lupus Erythematosus.” PubMed, Company StatPearls Publishing, Confidential 2023, © 2021 Eliwww.ncbi.nlm.nih.gov/books/NBK535405/. EVA and Company Corporate Slides / EVA Pharma 57 Cardiovascular Manifestations SLE may involve any layer of the heart, including the pericardium, myocardium, endocardium, and even the coronary arteries. Pericarditis associated with exudative pericardial effusions is the most common cardiac manifestation. patients with SLE are especially at high risk for coronary artery disease, either due to coronary vasculitis or more frequently due to generalized atherosclerosis. September Tayem MG, Shahin L, Shook J, Kesselman MM. A Review of Cardiac Manifestations in Patients With Systemic Lupus Erythematosus and Antiphospholipid 24 Syndrome 57 With Focus on Endocarditis. Cureus. 2022 Jan;14(1):e21698. Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 58 Gastrointestinal Manifestations Any part of the gastrointestinal tract may be involved in SLE. o These manifestations include Esophageal dysmotility (especially the upper one-third of the esophagus), mesenteric vasculitis, lupus enteritis, peritonitis and ascites, protein-losing enteropathy, pancreatitis, and lupoid hepatitis. Further, patients with SLE and antiphospholipid antibody syndrome can develop Budd-Chiari syndrome, mesenteric vessel thrombosis, and hepatic veno-occlusive disease. September 24 58 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls CompanyPublishing, Confidential 2023, © 2021www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 59 Pregnancy Complications SLE patients with positive antiphospholipid antibodies are at a HIGH RISK of spontaneous abortions and fetal loss, pre- eclampsia, and maternal thrombosis. Anti-Ro (SSA) and Anti-La (SSB) antibodies can cross the placenta leading to fetal heart block and neonatal lupus presenting with a photosensitive rash, cytopenias, and transaminitis. September 24 59 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls CompanyPublishing, Confidential 2023, © 2021www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 60 Pregnancy Complications The risk is 2% with the first pregnancy but increases to 20% if there is a history of neonatal lupus in a past pregnancy. SLE usually flares in pregnancy, especially if the disease was uncontrolled in the six months preceding pregnancy. September 24 60 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls CompanyPublishing, Confidential 2023, © 2021www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 61 Pregnancy Complications Lupus nephritis can be challenging to differentiate from pre-eclampsia Although several clinical and laboratory features (low complements, positive Anti-Ds- DNA antibody, normal serum uric acid level, and active urinary sediment) may help. Patients with more severe SLE manifestations such as pulmonary hypertension, severe cardiovascular disease, or cerebrovascular accident are especially at a very high risk of mortality during pregnancy. September 24 61 Cavalli S, Lonati PA, Gerosa M, Caporali R, Cimaz R, Chighizola CB. Beyond Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome: Company The Relevance of Complement From Pathogenesis to Pregnancy Confidential Outcome © Systemic in Other 2021 Eli EVA and Company Rheumatologic Diseases. Front Pharmacol. 2022;13:841785. Corporate Slides / EVA Pharma 62 Other Manifestations Eye involvement Eye involvement is common, and keratoconjunctivitis sicca is frequently seen in SLE in the presence or absence Ear involvement of secondary Sjogren syndrome. Ear involvement may lead to Patients with SLE are also more sudden sensorineural hearing loss susceptible to drug-induced ocular damage, including steroid-induced glaucoma or cataract and hydroxychloroquine induced maculopathy. September 24 62 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls CompanyPublishing, Confidential 2023, © 2021www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 63 Differential Diagnosis SLE is a systemic disease with multiorgan involvement, and several other diseases can mimic SLE. Other Autoimmune Diseases Rheumatoid Arthritis Drug-induced lupus Can present with several extra-articular May be difficult to differentiate from SLE, manifestations in addition to the classic especially due to a significant overlap in the polyarticular inflammatory arthritis and may be clinical and serological features. difficult to differentiate from SLE. Positive ANA, Anti-Ro, and Anti-La can also be seen in Drug-induced lupus is characterized by the RA, resolution of symptoms after drug withdrawal SLE can be associated with a positive rheumatoid and lack of more severe manifestations, factor, but the Anti-CCP is negative in SLE September 24 63 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls CompanyPublishing, Confidential 2023, © 2021www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Corporate Slides / EVA Pharma 64 Differential Diagnosis SLE is a systemic disease with multiorgan involvement, and several other diseases can mimic SLE. Other Autoimmune Diseases Adult-onset Still disease Behcet disease Characterized by arthralgia, fever, Presents with aphthous ulcers, uveitis, and lymphadenopathy, and splenomegaly but no malar arthralgia but lacks the other systemic and rash or other organ manifestations and lacks the serological features of SLE. SLE-specific autoantibodies. September 24 64 ---. “Systemic Lupus Erythematosus.” PubMed, StatPearls CompanyPublishing, Confidential 2023, © 2021www.ncbi.nlm.nih.gov/books/NBK535405/. Eli EVA and Company Assessment and diagnosis 65 Corporate Slides / EVA Pharma 66 SLE Classification Criteria over the years Huang, Xin, et al. “A Contemporary Update on the Diagnosis of Systemic Lupus Erythematosus. September 24 66 ” Clinical Reviews in Allergy & Immunology, vol. 63, no. 3, 22 Jan. 2022, Company pp. 311–329, Confidential https://doi.org/10.1007/s12016-021-08917-7. © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 67 EULAR/ACR Clinical & Immunologic Domains and Criteria for SLE. In September 2019, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) published new criteria for the classification of SLE , The EULAR/ACR criteria have a specificity of 93.4% and sensitivity of 96.1%. Huang, Xin, et al. “A Contemporary Update on the Diagnosis of Systemic Lupus Erythematosus. September 24 67 ” Clinical Reviews in Allergy & Immunology, vol. 63, no. 3, 22 Jan. 2022, Company pp. 311–329, Confidential https://doi.org/10.1007/s12016-021-08917-7. © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 68 EULAR/ACR Clinical Domains and Criteria for SLE The EULAR/ACR classification requires an antinuclear antibody (ANA) titer of at least 1:80 on HEp-2 cells or an equivalent positive test at least once; otherwise, the patient is considered not to have SLE. Comprising seven clinical domains and three immunologic domains. Each criterion is assigned points, ranging from 2 to 10. Patients with at least one clinical criterion and 10 or more points are classified as having SLE. September 24 68 Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 69 Definitions of SLE classification criteria September 24 Aringer, Martin, et al. “2019 European League against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. 69 ” Arthritis & Rheumatology, vol. 71, no. 9, 6 Aug. 2019, pp. 1400–1412, www.rheumatology.org/Portals/0/Files/Classification-Criteria-Systemic-Lupus-Erythematosus.pdf, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.1002/art.40930. Corporate Slides / EVA Pharma 70 Definitions of SLE classification criteria September 24 Aringer, Martin, et al. “2019 European League against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. 70 ” Arthritis & Rheumatology, vol. 71, no. 9, 6 Aug. 2019, pp. 1400–1412, www.rheumatology.org/Portals/0/Files/Classification-Criteria-Systemic-Lupus-Erythematosus.pdf, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.1002/art.40930. Corporate Slides / EVA Pharma 71 Definitions of SLE classification criteria September 24 Aringer, Martin, et al. “2019 European League against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. 71 ” Arthritis & Rheumatology, vol. 71, no. 9, 6 Aug. 2019, pp. 1400–1412, www.rheumatology.org/Portals/0/Files/Classification-Criteria-Systemic-Lupus-Erythematosus.pdf, Company Confidential © 2021 Eli EVA and Company https://doi.org/10.1002/art.40930.  Corporate Slides / EVA Pharma 72 Histopathology Tissue pathology in SLE can demonstrate a variety of aberrant immunologic mechanisms, including immune complex formation, autoantibody formation, and immunologically mediated tissue injury. LE body or hematoxylin body is a hallmark of SLE pathology. It is a homogeneous globular mass of nuclear material that stains bluish-purple with hematoxylin. It can be observed in the lungs, kidneys, spleen, heart, lymph nodes, and serous and synovial membranes. They contain immunoglobulins and DNA, and ph