Epidemiology and Etiology

Epidemiology

• Prevalence in the United States:
  • Overall: 20–150 per 100,000
  • Women: 100–400 per 100,000
  • Pediatric systemic lupus erythematosus (SLE): approximately 2.5 per 100,000
• More prevalent in people of African American or Asian descent
• More common in urban areas
• 10 times more common in women than men (no gender preference in drug-induced lupus)
• Peak age at onset: 
  • Adults: 18–55 years
  • Children: 9–15 years

Etiology

• The exact etiology is unknown.
• Predisposing factors:
  • Genetic:
    • HLA-DR2
    • HLA-DR3
    • Congenital deficiencies of complement factors C1q, C2, and C4
  • Hormonal:
    • Increased estrogen (e.g., oral contraceptives, hormonal replacement)
    • Decreased testosterone
    • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia
    • Thyroid abnormalities
  • Environmental:
    • Cigarette smoking
    • EBV exposure
    • Ultraviolet (UV) light exposure
    • Silica exposure
  • Drug induced

Pathophysiology

The exact mechanism is unknown. Patients likely have a genetic predisposition to autoreactive immune cells (B and T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells).

• Cell damage due to an environmental trigger → defective apoptosis and clearance of cellular debris → ↑ exposure to nuclear antigens ( DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure from damaged cells)
• Autoreactive T and B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells are activated → production of autoantibodies:
  • ANA
  • Anti-double-stranded DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure (anti-dsDNA) antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • Anti-Smith (anti-Sm) antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • Anti-histone antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • Anti-Ro and anti-La antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • Anti-ribonucleoprotein antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • Antiphospholipid antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
• Antibody-antigen immune complexes form → endocytosis by B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and dendritic cells 
  • B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells: activation of Toll-like receptors in endosomes → immune complexes are broken down by proteases → resulting peptides presented to T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells → T cell activation → further B cell activation
  • Dendritic cells: release of interferon → further B cell activation
• Perpetual T and B cell activation results in persistent ↑ in antibody levels
• Antibodies cause organ damage through: 
  • Immune (antigen-antibody)-complex deposition in microvasculature → excessive complement activation → inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Immune-complex deposition in the basement membrane of organs (e.g., skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys)
  • Direct interaction with nuclear antigens on cell surfaces → complement activation → cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death and apoptosis

Management

As there is no definitive treatment available, management is aimed at controlling acute flares, suppressing symptoms, and preventing organ damage.

General

• Educate the patient about the disease.
• Smoking cessation
• UV protection:
  • Sunscreen
  • Avoid medications that cause photosensitivity.
  • Avoid tanning.
• Isometric exercise
• Relaxation techniques to curb stress
• Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen and NSAIDs to manage pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Cutaneous treatment

• Topical corticosteroids
• Topical calcineurin inhibitors
• Hydroxychloroquine

Systemic management

• All patients must be on hydroxychloroquine.
• Mild-to-moderate symptoms:
  • Low dose of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids 
  • Steroid-sparing immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants may be added:
    • Methotrexate
    • Azathioprine
• Severe symptoms with organ damage:
  • High dose of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
  • Immunosuppressive or biological agents:
    • Cyclophosphamide
    • Mycophenolate
    • Rituximab
    • Belimumab (used if disease is resistant to the above therapies)

Prevention of complications

• Prophylaxis for osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
• Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, human papillomavirus Human papillomavirus Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV, and pneumococcal vaccines
• Suppression of recurrent urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections
• Blood pressure should be managed to prevent renal damage.

Complications and Prognosis

Lupus nephritis

• Seen in 30% of patients with SLE
• Due to subendothelial deposition of immune complexes
• Patients usually present with nephritic or nephrotic syndromes.
• Management depends on the severity of the disease and may include:
  • Antihypertensive/antiproteinuric therapy:
    • ACE inhibitors
    • Angiotensin II receptor blockers (ARBs)
  • High dose of corticosteroids
  • Immunosuppressants:
    • Azathioprine
    • Mycophenolate
    • Tacrolimus
    • Cyclophosphamide
  • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis

Antiphospholipid syndrome Antiphospholipid syndrome Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome (APS)

• 40% of patients with SLE are positive for APS antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins.
• Only 20% of patients exhibit symptoms (thrombosis).
• Management: 
  • Anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants
  • Hydroxychloroquine

Libman-Sacks endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis

• One of the most common cardiac presentations of SLE
• Non-bacterial endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis:
  • Deposition of sterile platelet thrombi on heart valves
  • Commonly affects mitral-aortic valves
• Patients usually present with:
  • Valvular insufficiency
  • Heart failure
  • Embolism
  • Secondary infective endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis
• Management:
  • SLE management
  • Systemic anticoagulants
  • Surgery in severe disease

Prognosis

• Rate of survival is very good with optimal therapy.
• 5-year survival: > 90%
• Most common causes of death: 
  • Cardiovascular disease
  • Infections
  • End-stage renal disease
• Poor prognosis has been associated with:
  • ↑ Serum creatinine levels and nephrotic syndrome 
  • Hypertension
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, hypoalbuminemia, or hypocomplementemia 
  • Antiphospholipid antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • Male gender
  • African American ethnicity 
  • Low socioeconomic status

Mnemonic

To recall the 3 most common causes of death in SLE, remember: “Lupus patients die with Redness In their Cheeks.”

• Renal disease
• Infections
• Cardiovascular disease

Differential Diagnosis

• Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis: an autoimmune disease resulting in joint inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and destruction. Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis is typically symmetric with tenderness and swelling of the joints of the hands and feet. Systemic manifestations may include Sjögren’s syndrome, interstitial lung disease, pleural effusion, pericarditis, vasculitis, and anemia. Positive rheumatoid factor and anti-cyclic citrullinated peptide antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins may be seen. Treatment is with NSAIDs, disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs (DMARDs), steroids, and immunosuppressive medications.
• Adult Still’s disease: a rare, systemic inflammatory disease characterized by daily fevers, arthritis, and an evanescent, salmon-colored rash on the trunk and extremities. Laboratory evaluation will show leukocytosis, transaminitis, negative ANA, and elevated inflammatory markers. Overall, the diagnosis of adult-onset Still’s disease is based on exclusion. Management depends on the severity of the condition. Treatment is with NSAIDs, glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, DMARDs, and biological agents.
• Behcet’s disease: inflammatory vasculitis of small and large vessels. Symptoms can include arthritis and painful oral and genital ulcers. Ocular, neurologic, GI, and vascular manifestations are also seen. The diagnosis is based on clinical criteria, and the characteristic SLE antibody test will be negative. Management depends on clinical manifestations. Treatment is with corticosteroids, DMARDs, and TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) inhibitors.
• Fibromyalgia Fibromyalgia Fibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia: a nonarticular disorder of unknown etiology that causes generalized pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in the muscles, points of tendon insertion, and soft tissues. Associated symptoms include fatigue, muscle stiffness, cognitive disturbances, depression, and anxiety. Diagnosis is based on clinical criteria. Imaging and laboratory testing will be unremarkable. Management includes exercise and non- opioid analgesics Opioid analgesics Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, and is aimed at improving sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep and reducing stress.
• Sjogren’s syndrome: an autoimmune, inflammatory condition of the glandular tissues, resulting in decreased tear and saliva production. Symptoms include dry eyes and mouth. Systemic manifestations include Raynaud’s phenomenon, neuropathy, and cutaneous vasculitis. Diagnosis is based on symptoms, clinical findings, determination of anti-Ro and anti-La antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, and salivary-gland biopsy. Management is targeted at achieving symptomatic relief and immunosuppressive therapy is reserved for severe symptoms.
• Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis: an inflammatory disorder causing non-caseating granulomas in organs and tissues. The etiology is unclear, and symptoms can vary widely. Patients may develop cough, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, fatigue, fever, arthritis, erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum, uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea, heart block, and neuropsychiatric manifestations. Diagnosis is based on biopsy findings, as the antibody test tends to be negative. Management is with corticosteroids.
• Non-Hodgkin’s lymphoma: a diverse group of malignancies of B cell, T cell, and NK cell origin. Most cases involve the lymph nodes. Non-Hodgkin’s lymphoma often presents with fatigue, fevers, night sweats, weight loss, anemia, and lymphadenopathy. Other symptoms can occur in patients with extranodal involvement (e.g., GI, CNS). Lymph node or bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy is helpful in diagnosis. Management is primarily with chemotherapy, immunotherapy, and targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted Therapy and Other Nontraditional Antineoplastic Agents.