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Systemic lupus erythematosus (SLE)

Chronic, life threatening process that affects women of childbearing age.

A chronic, multifaceted inflammatory disease that can affect every organ system of the body.

Its pathogenesis includes tissue inflammation caused by immunologic aberrations that affect both the innate and adaptive aspects of the human immune system.

Characterized by unpredictable flares, irreversible organ damage, adverse impact on quality of life, and increased mortality.

Characterized by auto antibody production and immune complex mediated tissue damage.

Multiple innate and adaptive immune pathways are disturbed in SLE.

Associated with acute recurrent inflammatory flares upon a back drop of chronic progressive injury in diverse organs and tissues.

Protean manifestations and follows a relapsing and remitting course.

Rare process, with an incidence of 2.2-5.6 cases per hundred thousand person-years and a prevalence of 24-207 cases per 100,000 persons-years.

Currently there are approximately 200,000 patients in the US with the criteria for lupus, but up to 500,000 have features that fall on a spectrum that overlaps with that of lupus, such as undifferentiated and mixed connective tissue disease and antiphospholipid syndrome.

It affects approximately 3.4 million people worldwide, and of these individuals, an estimated 3 million are female.

Poland, the US, Barbados, and China have the highest incidence of SLE.

The estimated incidence of SLE in the US is approximately 5 to 12 per hundred thousand person-years.

Newly diagnosed in approximately 400,000 people each year worldwide.

The incidence among females compared with males is 8.7 versus 1.2 per hundred thousand person-years.

The annual incidence of SLE in the US is higher in black females compared with white females by 3 to 1.

SLE is one of the leading causes of death in young women.

Among women between the ages of 15 and 24, it is the 10th most common cause among women of all races and 5th in black or Hispanic women.

Half of the women who have organ threatening SLE die within 20 years after illness, and most have had a poor quality of life.

Specific cause is unknown.

Nearly 100% of patients with SLE are ANA positively

Multiple factors are associated with the development of the disease, including genetic, racial, hormonal, and environmental factors.

Autoantibody-mediated organ damage occurs and antiphospholipid antibody mediated hypercoagulability may be present.

The zinc finger transcription factors Ikaros and Aiolos affect immune cell development and homeostasis in or implicated in genetic predisposition to SLE.

Ikaros induces development of B cells and plasmacytoid dendritic cells, which are the major producers of type 1 interferon.

Blood dendritic cell antigen 2 (BDCA 2) is a receptor that exclusively expressed on plasmacytoid dendritic cells  and are implicated in the pathogenesis of lupus erythematosus.

Aiolos supports B cell differentiation.

Messenger RNA is for genes  en coding Ikaros and Aiolos are expressed in patients with SLE.

Autoantibodies appear a few years before the first symptoms.

Autoimmune disease almost always accompanied by autoantibodies.

Auto antibody secreting plasma cells are increasingly recognized as essential drivers of chronic inflammation in lupus.

Antibodies against double stranded DNA, single stranded DNA, DNA protein complexes, RNA protein complexes are found to 95-99% of patients.

A proposed mechanism for the development of autoantibodies involves a defect in apoptosis that causes increased cell death and a disturbance in immune tolerance by redistribution of cellular antigens leading to a cell-surface display of plasma and nuclear antigens in the form of nucleosomes.

Chronic activation of plasmacytoid dentritic cells by circulating immune complexes triggers autoimmunity in patients with SLE.

Immune complexes cause plasmacytoid dendritic cells to secrete type I interferons.

In SLE the number of circulating plasmacytoid dendritic cells is significantly reduced compared to normal individuals as these cells migrate to the tissues and remain there: Nevertheless, plasmacytoid cells produce interferon-alpha normally in large amounts with systemic effects.

Type 1 interferons play an important role in the pathogenesis of SLE as indicated by elevated interferon alpha levels, the expression of interferon response genes, and the efficacy of an antibody drug against type 1  interferon receptors (Anifrolumab).

Plasmacytoid dendritic cells, the produces of type 1 interferons, other cytokines and chemokines constitute a small proportion of peripheral blood leukocytes, but they accumulate in skin lesions and organs of patients with SLE.

The surface receptor blood dendritic cell antigen 2 (BDCA 2), a negative regulator of type 1 interferon production is unique to plasmacytoid dendritic cells.

Immune complexes bind to tissues, fix complement, activate inflammatory responses, and cause tissue damage.

Monocytes, macrophages, plasmacytoma dendritic cells, natural killer cells, neutrophils, and neutrophils extracellular traps all promote T cell activation and release pro-1inflammatory cytokines and type 1 interferon in SLE.

Presence earlier, and in the more severe form in African-Americans, Hispanics, Native Americans, and Asians.

95% of children and 70% of adults with SLE have a type I interferon signature, with interferon-alpha as the hallmark.

Neutrophil specific genes is the second most prevalent peripheral blood mononuclear cell transcriptional signature in children with SLE (Villanueva E et al).

Neutrophil specific genes correlates with disease activity.

Neutrophil specific proteins in urine is a surrogate marker of disease activity in lupus.

With autoantibody formation immune complexes form in the microvasculature, leading to complement activation and inflammation.

Autoimmune disease characterized by loss of tolerance to nuclear antigens, deposition of immune complexes into tissues and multiorgan involvement.

Antibody-antigen complexes deposit on the basement membranes of skin and kidneys.

Vascular involvement may be manifested as inflammation of blood vessels that lead to vasculitis, thromboembolism may be fostered by coexisting antophosholipid syndrome, reactive vasospasm leading to Raynaud’s phenomenon, and systemic hypertension with pulmonary arterial hypertension.

Associated with a high risk of arteriosclerotic vascular disease.

With active disease complexes of nuclear antigens such as DNA, immunoglobulins, and complement proteins are present at basement membranes of involved organs.

Serum antinuclear antibodies (ANAs) are found in virtually all patients with active disease.

Antibodies to native double-stranded DNA (dsDNA) are relatively specific for the diagnosis.

Activation of type I interferon has been shown to be central pathological mediator of SLE on the basis of MicroArray analysis of gene expression of peripheral blood cells, which show overexpression of hundreds of gene transcripts induced by type I interferon, collectively known as the type I interferon gene signature.

Mini genetic risk factors for SLER in the pathway of type I interferon.

Most commonly occurs in women of childbearing age.

No evidence suggests the SLE reduces fertility, but subfertility can occur as a result of active disease, immunosuppressive drugs, and age related declines in fertility related to delays in childbearing.

The female-to-male ratio is estimated to be 9 to 1.3.

Approximately 1.5 million Americans and 5 million people worldwide have systemic lupus.

Associated with risk in pregnancy that contribute to poor maternal and fetal outcomes.

Higher rates reported among black and Hispanics.

Prevalence of SLE is approximately 40 per 100,000 whites in Rochester, Minnesota, and 100 per 100,000 Hispanic persons Arizona.

Disease is rarely reported among blacks who live in Africa.

Incidence about 7.3 per 100, 000.

Prevalence in adult population about 124 cases per 100, 000.

Prevalence in the USA 0.24% in people age 17 or older.

Prevalence is 20-70 cases per hundred thousand women and varies with race and ethnic background.

The highest prevalence rates are among Latinos, blacks, and Afro-Caribbeans.

The lowest prevalence rates are among whites and Asians.

Most common in women and African Americans.

Estimated 70-90% of affected persons are women.

Onset is typically in the childbearing years.

20% of patients with lupus have a parent or sibling who already has or may develop the disease.

Annual costs $13-20,000 per individual.

Prevalence 2-3 times more common among African-Americans, Hispanics, Asians and native Americans compared to white individuals.

Occurs ten times more frequently among females.

Use of exogenous hormones has been associated with lupus onset and flares, suggesting a role for hormonal factors in the pathogenesis of the disease.

The risk in men is similar to that in prepubertal or postmenopausal women.

More common in men with Klinefelter disease than in men without the disease.

Prevalence is highest among women aged 14-64 years, but does not have an age predilection in males.

Usually develops between ages 15-44.

Most patients present with nonspecific symptoms to include fatigue, fever, arthralgia, and weight changes.

Approximately 80% of patients have persistently active disease or frequent flare-ups.

Fatigue is the the most common constitutional symptom associated with SLE.

Joint pain is one of the most common initial clinical presentation.

Arthralgia, myalgia, and arthritis may involve the small joints of the hands, wrists, and knees.

One third of patients with musculoskeletal manifestations cannot work.

In contrast to rheumatoid arthritis, arthritis or arthralgias may be asymmetrical.

Malar rash, which is characterized by an erythematous rash over the cheeks and nasal bridge lasting from days to weeks may occur.

Photosensitivity is common.

Discoid lesions often also develop in sun-exposed areas.

Alopecia often affects the temporal regions or creates a patchlike pattern of hair loss.

Other cutaneous manifestations include Raynaud phenomenon, livedo reticularis, panniculitis, bullous lesions, vasculitic purpura, telangiectasias, and urticaria.

The kidney is the most commonly involved visceral organ.

Approximately 50% of patients develop clinical renal disease.

Patients who have systemic lupus erythematosus (SLE) possess Foxp3 mutations that affect the thymopoiesis process, preventing the proper development of Treg cells within the thymus.

Biopsy studies demonstrate some degree of glomerular involvement in almost all patients.

Glomerular disease usually develops within the first few years and is usually asymptomatic.

Among patients with proliferative forms of glomerulonephritis 10-30% develop ESRD.

Renal involvement is the strongest predictor of morbidity and mortality.

The incidence of end-stage renall disease has not declined, despite improvement in management.

Widespread variations in neuropsychiatric symtoms can occur.

Cognitive disorders may be preseny in patients with SLE.

Pulmonary manifestations of SLE may manifest acutely or indolently, with pleuritic chest pain with or without pleural effusions being the most common feature of acute pulmonary.

Gastrointestinal symptoms are common among persons with SLE.

Abdominal pain may be related to active lupus, including peritonitis, pancreatitis, mesenteric vasculitis, and bowel infarction.

Nausea and dyspepsia are common symptoms.

Chest pain is the most common cardiac manifestation of SLE.

Libman-Sacks endocarditis is noninfectious but may manifest as symptoms similar to those of infectious endocarditis.

The classic malar rash, also known as a butterfly rash, characteristically spares the nasolabial folds.

Photosensitive rash is often macular or diffusely erythematous in sun-exposed areas of the face, arms, or hands, as in the image below.

Oral ulcers may be seen, with palatal ulcers being most specific.

Raynaud phenomenon may be observed at the distal digital tips.

Pain out of proportion to synovitis or swelling.

Jaccoud arthropathy, the nonerosive hand deformities due to chronic arthritis and tendonitis develops in 10% of patients with SLE.

Myositis that may manifest as weakness.

Fibromyalgia is common in SLE.

Renal findings of edema of periorbital or peripheral regions and anasarca are common physical findings with nephrotic syndrome or volume overload.

Altered mental status, seizures, psychosis, or organic brain syndrome may be manifest, as may focal neurological deficits, stroke, TIA, or mononeuritis.

Majority of patients will develop irreversible organ damage over a period of six years or more, often from the disease itself and/or treatments, particularly glucocorticoids.

More than 10 gene loci are known to increase the risk of SLE.

25% concordance among monozygotic twins versus 2% in dizygotic twins.

HLA-A1, B8, and DR3 are more common in persons with SLE than in the general population.

Approximately 4000 white males, 41,000 white females, 31,0000 black males and 163,0000 black females have the disease in the U.S.

Mean age at diagnosis 30-39 years.

Autoantibodies are usually present many years before the diagnosis is made.

Auto antibodies like ANA, anti-Ro, anti-La, anti-double-stranded DNA, and antiphosholipis antibodies may be present years prior to the onset of SLE

10- year survival 75-85% with more than a 90% 5-year survival.

Overall survival rates may vary with race and ethnic background, with the five-year survival rate of 95% among whites, 90% among blacks, and 87% among Hispanics.

The lowest survival rates with the SLE are in men, the poor, and patients with nephritis.

Varies from relatively benign disease to rapidly progressive and fatal process.

SLE often waxes and wanes in affected individuals throughout life, and features of the disease vary greatly between individuals.

The disease course is milder and survival rate higher among persons with skin and musculoskeletal involvement than in those with renal and CNS disease.

Decreasing mortality rates associated with earlier diagnosis, improvement in treatments, and advances in general medical care.

One third of SLE-related deaths occur in patients younger than 45 years.

Leading causes of death are active disease particularly with nephritis, infections, and accelerated cardiovascular disease.

The leading cause of death in SLE  is infection.

 

Active disease is associated with younger age at death. 

 

Median age at death was 58.5 years, with median duration of disease of 14.5 years. 

 

Constitutional and mucocutaneous features were the most common items scoring on disease activity, seen in 68.2% and 45.45%, respectively. 

Bimodal mortality in early versus late SLE, noting that SLE-related deaths usually occur within the first 5-10 years of symptom onset.

Infectious complications related to active SLE and immunosuppressive treatment are now the most common cause of death in early active SLE.

The Framingham Offspring Study demonstrated that women aged 35-44 years with SLE were 50 times more likely to develop myocardial ischemia than healthy women.

Causes of accelerated coronary artery disease include endothelial dysfunction, inflammatory mediators, corticosteroid-induced atherogenesis, and dyslipidemia associated with renal disease.

Early deaths due to active disease while late deaths due to atherosclerosis.

Myocardial infarction rate 52 fold higher in women compared to control group.

Association of atherosclerosis suggests that chronic inflammation is atherogenic.

Infection is the major cause of mortality in all stages of SLE.

Coronary artery disease is a leading cause of death in patients with long-standing SLE.

Virtually all anatomic areas of the heart may be involved with SLE including, the pericardium, myocardium, endocardium, coronary arteries and valves.

Myocarditis identified in about 9% of patients with SLE.

Autopsy studies from the 1950’s-1960’s on patients with SLE revealed an average prevalence of myocarditis of 57% suggesting subclinical myocardial disease common in patients who die of SLE.

Primary nonischemic myocardial manifestations include myocarditis, cardiomyopathy, and heart failure.

Cardiac disease affects patients with SLE and pericarditis is the most common cardiac manifestation with a preference rate of 60%.

Cardiac manifestations occur usually at the time of the diagnosis of SLE, or within six months.

Features associated with mortality include renal damage, thrombocytopenia, and lung involvement.

Tends to flare during pregnancy and are associated with increased prematurity and actives.

Association with antiphospholipid syndrome is a strong predictor for thrombosis.

Renal disease seen in almost all patients o’n histopathological examination, even if no clinical disease is present.

Renal disease is usually an immune complex mediated glomerulonephritis process.

B cells are responsible for the production of autoantibodies.

Diffuse proliferative glomerulonephritis has a 5-year cumulative probability of 11-48% for end stage renal disease.

Arthritis and arthralgias are often the initial clinical manifestations and commonly involve the small joints of the hands and wrists.

Skin lesions are raised, reddened plaques with scale and commonly appear o’n the face scalp and neck.

SLE is associated with characteristic skin exanthems, including: acute, subacute, and chronic cutaneous lupus exanthems.

Acute cutaneous SLE  is defined as a maculopapular rash in a generalized or malar distribution.

Up to 50% of patients with SLE will have acute cutaneous lupus erythematosus sometimes during their disease course.

Subcutaneous lupus is a photosensitive annular or papulosquamous  rash that affects 10 to 15% of patients with SLW.

Chronic cutaneous lupus, discoid lupus, is defined by well demarcated scaly  erythematous  papules that evolve into circular plaques, often affecting the head and neck.

Oral ulcers occur in 40% of patients.60% of patients have neuropsychiatric symptoms including impaired memory, headaches, seizures, mood disorders, cerebrovascular accidents, transverse myelitis, sensory and autonomic neuropathy.

Joint involvement usually does not lead to joint erosions or destruction.

2-12% of patients present with lymphadenopathy at diagnosis.

Affects mucocutaneous system in 80-90% of patients.

Butterfly facial rash occurs in about 30% of patients.

Neutropenia occurs in about 50% of patients.

Associated neutropenia important factor in predisposing patients to bacterial infections.

Approximately two thirds of patients have antibodies to neutrophils.

Frequently associated with anemia, hemolysis, leukopenia, and thrombocytopenia.

Vascular and inflammatory changes in the CNS occurs in up to 90% of children ad adolescent patients with SLE.

Cardiac manifestations affect many patients, and pericarditis is the most common cardiac complication with a prevalence rate of 60 percent.

Other cardiac / respiratory problems associated with SLE include pericardial effusion,pleurisy, and myocarditis.

Cardiac manifestations in SLE usually occur at the time of diagnosis or within 6 months.

Common clinical manifestations of pericardial effusion in SLE are Raynauds phenomenon, arthralgias, and lupus nephritis.

Cardiomyopathy in SLE may lead to severe cardiac dysfunction despite corticosteroid therapy but is responsive cytotoxic therapy.

Neuropsychiatric problems associated with SLE include cerebrovascular disease, impaired cognition, seizures, and confusional states.

Seizures may be present in approximately 50% of pediatric patients with SLE.

The American College of Rheumatology (ACR) criteria necessary to diagnose SLE :

The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE.

Serositis – Pleurisy, pericarditis

Oral ulcers – Oral or nasopharyngeal

Arthritis

Photosensitivity

Blood disorders:Leukopenia, Lymphopenia, Thrombocytopenia, hemolytic anemia

Renal involvement – Proteinuria or cellular casts

ANAs

Immunologic phenomena – dsDNA; anti-Smith (Sm) antibodies; antiphospholipid antibodies, biologic false-positive serologic test results for syphilis

Neurologic disorder – Seizures or psychosis

Malar rash

Discoid rash

ANA as a screening test has a sensitivity of 95% but is not diagnostic without accompanying clinical features.

Anti-dsDNA has a high specificity but a sensitivity of only 70%.

Anti-Sm is the most specific antibody for SLE but only 30-40% sensitivity.

Anti-SSA (Ro) or Anti-SSB (La) antibodies present in 15% of patients with SLE.

Anti-ribosomal P antibodies may correlate with lupus cerebritis.

Levels of inflammatory markers, including the erythrocyte sedimentation rate or C-reactive protein (CRP), may be elevated,

Patients with biopsy proven lupus ephritis with either positive anti-nuclear or anti-double-stranded DNA antibodies can also be classified as having lupus nephritis, which is not possible with the above ACR criteria.

Complement levels C3 and C4 levels are often depressed in patients with active disease because of consumption by immune complex�induced inflammation.

Creatinine kinase levels may be elevated in myositis.

The most common radiographic changes include periarticular osteopenia and soft-tissue swelling.

With CNS disease nonspecific elevations in cell count and protein level and decrease in glucose level may be found in the cerebrospinal fluid.

Renal biopsy is used to identify the specific type of glomerulonephritis.

Skin biopsy can help to diagnose SLE.

Management:

Lupus has been divided into organ threatening or non-organ threatening manifestations, with the former managed with non-steroidal anti-inflammatory drugs, hydroxychloroquine or low dose glucocorticoids, or both, methotrexate, or aazothioprine.

When viscera are involved management includes higher doses of glucocorticoids and immune suppressed of therapies such as mycophenolate or cyclophosphamide.

No current known cure.

Goals of treatment include achieving remission will low disease activity, preventing flares, minimizing the use of corticosteroids, not treating patients who are seologically active but clinically quiescent and addressing factors affecting health related quality of life such as depression and pain

Early recognition of lupus nephritis and maintaining immunosuppressive therapy for at least three years is recommended.

Hydroxychloroquine treatment is recommended for all patients with lupus because of substantial benefits it manifests.

Treatment with hydroxychloryquine is associated with increase survival, reduced disease activity, prevention of organ damage, and prevention of thrombosis.

Treatment is often based on the type and severity of organ involvement.

Management of comorbidities and attention to bone health, increased cardiovascular risk, and immunization status are part of medical care.

Cyclophoshamide mainstay of treatment for flares.

Biologic agents that inhibit the B lymphocytes activating factor such as belimumab has diminished the sequelae of lupus and reduced the long-term use of glucocorticoids, as has  the use of rituximab.

Belimumab (Benlysta) a fully human immunoglobulin G1 monoclonal antibody approved for use in systemic lupus erythematous.

Belimumab (Benlysta) benefits modest and confined to musculoskeletal and mucocutaneous systems, as the testing of the drug excluded patients with active kidney or CNS disease.

Belimumab (Benlysta) not proven to be beneficial in blacks, as they made up too small of the study population.

Belimumab (Benlysta) administered by intravenous infusion, and inhibits biological actvity of soluble human B lymphocyte stimulator, associated with SLE.

Belimumab (Benlysta) utilized with standard therapy including corticosteroids, antimalarials, immunosuppressive agents and NSAIDs.

Anifrolumab, acfully human IgG 1 onoclonal antibody to type I interferon receptor subunit 1 that inhibits signaling by all type 1 interferons.

Monthly administration of anifrolumab resulted in the higher percentage of patients with a response at 52 weeks than did placebo (TULIP-2 trial).

 

 

Affects women more frequently men 9:1.

 

 

SLE is one of the most sex differentiated autoimmune diseases.

 

 

The disease in black women is approximately 2-4 times more prevalent than in white women.

 

 

Hispanic women and Asian women experience SLE at higher rates than white women.

 

 

Black, Hispanic, and Asian women experience increased lupus severity compared to white women.

 

 

SLE may have a more rapid and severe course in the group of men it affects.

 

 

Men with SLE are reported to have more frequent serositis, cardiovascular disease, pancytopenia, hemolytic anemia, nephritis, anti-phospholipid antibodies, thrombotic events, and seizures.

 

 

Males with SLE frequently smoke, use alcohol, have renal involvement, and have lupus anticoagulants.

 

 

Men with SLE experience a higher rate of nephritis.

 

 

Musculoskeletal involvement is less common in men than women.

 

 

The presence of lupus anticoagulant is more frequently in men, but other auto antibodies occur at the same rate as women.

 

 

No significant evidence exists suggest that SLE reduces fertility, but subfertility maker due to the presence of active disease, the use of immunosuppressive drugs, and age related declines in fertility related to delays in child bearing.

 

 

SLE has risks to mother and baby throughout pregnancy including a disease flare, preeclampsia, spontaneous abortion, intrauterine growth restriction, and preterm birth.

 

 

There are poorer maternal and fetal outcomes in women with SLE compared with the women in the general population.

 

 

African-American and Hispanic women experience a two fold greater incidence of adverse outcomes during pregnancy than white women.

 

 

Cyclophosphamide may impair fertility.

 

 

Maternal and fetal outcomes for women with SLE have improved significantly in recent decades: up to 81% of pregnancies are uncomplicated with stable with my leg active disease at the time of conception.

 

 

The use of cyclophosphamide in the treatment of severe lupus reduces mortality to 10%.

 

 

Cyclophosphamide may cause temporary amenorrhea, infertility, and premature ovarian failure through the depletion of ovarian follicles.

 

 

Currently lower doses of cyclophosphamide are used, and most women who complete treatment or able to have spontaneous conception and good pregnancy outcomes.

 

 

SLE is associated with increased prevalence of testicle damage in men.

 

 

Men with SLE have decreased testis volume on ultrasound and decrease levels inhibin is produced in the testicles.

 

 

Males with SLE have a lower mean sperm  volume and percentage of normally formed sperm.

 

 

Despite the above, men with SLE have normal fertility levels.

 

 

To preserve female fertility ovarian tissue cryo-conservation is considered.

 

 

Sperm cryopreservation is the mainstay of male  fertility preservation and should be offered to male patients before initiating treatments.

 

In adults with active lupis nephritis, more patients who received belimumab  plus standard therapy had a primary efficacy renal response and those who receive standing therapy alone (Furie R).

 

Daratumumab A human monoclonal antibody that targets CD 38, depletes  plasma cells and in SLE is utilized against long-lived plasma cells.

Iberdomide promotes ubiquitination of Ikaros and Aiolos and its use results in a higher percentage of patients with clinical response in SLE than placebo.

Iberdomide Is an oral medication of the immuno modulator imide drug.

Litigilimab, a humanized monoclonal antibody that binds to blood dendritic cell antigen 2 (BDCA2),which is expressed exclusively on plasmacytoid dendritic cells which produce type one interferon and when inhibited resulted in a reduction in the number of swollen and tender joints then placebo over a period of 24 weeks (Furie RA).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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