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Systemic Lupus Erythematosus (SLE)

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Epidemiology, Etiology, Pathophysiology, Clinical Representation, Diagnostic Tests, and Management of SLE

  • SLE
  • autoimmune disease
  • inflammation
  • diagnostic tests
  • disease management

By Dr. Ayesha Fatima

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  1. Slide 1. SYSTEMIC LUPUS ERYTHROMATOUS By DR. AYESHA FATIMA Assistant Professor Dept. Of Pharmacy Practice
  2. Slide 2. Systemic lupus erythematosus (SLE) is an autoimmune disease associated with autoantibody production. SLE is a multisystem disease. The term “lupus” (Latin for wolf) was first used in the 13th century to describe erosive lesions that looked like skin that had been gnawed by a wolf. EPIDEMIOLOGY 1. SLE occur most frequently in women of reproductive age (15–50 years old) 2. Rates are nine times higher in women than in men. 3. It is affected by ethnicity, which includes genetic, geographic, 4. cultural, social, and other aspects within a group. 5. Rates are higher in non - whites than in the white population. 6. It is most common in those of African origin.
  3. Slide 3. ETIOLOGY The exact etiology for SLE is unknown but many factors have been identified that appear to play a role in the disease . Predisposing factors 1. Genetic influences : a. First-degree relatives of patients with SLE are 20 times more likely to develop the disease than those in a general population. b. The genetic predisposition to SLE is a result of the interplay of a combination of genes. c. The major histocompatibility complex (MHC) class II alleles HLA-DR2 and HLA-DR3 are known to be linked to SLE. 2. Epigenetic regulation of gene expression : a. Gene expression is regulated by deoxyribonucleic acid (DNA) methylation and histone modifications. b. These epigenetic changes can cause alterations that may influence SLE. c. Hydralazine and procainamide, two drugs that may induce lupus, inhibit DNA methylation.
  4. Slide 4. 3. Environmental factors : A. Cigarette smoke is phototoxic and associated with cutaneous lupus. B. Ultraviolet light can cause keratinocytes in the skin to release nuclear material that can further stimulate the immune system and autoantibody production by B cells. C. Viruses Epstein–Barr virus. D. Other include : infections, medications (eg, vaccines and biologics) psychological stress, silica dust, hydralazines, petroleum, solvents (eg, nail polish remover and metal cleaners), dyes, and pesticides. 4. Hormones , and 5. Abnormalities in immune cells and cytokines
  5. Slide 5. PATHOPHYSIOLOGY • Interaction between susceptibility genes and environmental factors results in abnormal immune responses by formation of various autoantibodies. • Some of the important antinuclear antibodies (ANAs) or antinuclear factors (ANFs) against different nuclear antigens are as under: I. Antinuclear antibodies (ANA) These are the antibodies against common nuclear antigen that includes DNA as well as RNA. These are demonstrable in about 98% cases and are used as screening test. II. Antibodies to double-stranded (anti-dsDNA) This is the most specific for SLE, is present in 70% cases. III. Anti-Smith antibodies (anti-Sm) These anti bodies appear against Smith antigen which is part of ribonucleoproteins. It is also specific for SLE but is seen in about 25% cases.
  6. Slide 6. iv) Other non-specific antibodies Besides above, there are several other antibody tests which lack specifi city for SLE. These are as follows: A. Anti-ribonucleoproteins ( anti-RNP ) seen in 40% cases of SLE but seen more often in Sjögren’s syndrome. B. Anti-histone antibody , which is antibody against histone associated with DNA in chromatin, is seen particularly in cases of drug-induced lupus than in SLE. C. Antiphospholipid antibodies (APLA) or lupus anticoagulant are tests for thrombotic complications in cases of SLE. D. Anti-ribosomal P antibody is antibody against protein in ribosomes and is seen in CNS lupus.
  7. Slide 7. The source of these autoantibodies as well as hyper gammaglobulinaemia seen in SLE is the polyclonal activation of B cells brought about by following immunologic derangements: i) an inherited defect in B cells; ii) stimulation of B cells by micro-organisms; iii) T helper cell hyperactivity; and iv) T suppressor cell defect. Two types of immunologic tissue injury can occur in SLE: 1. Type II hypersensitivity is characterised by formation of autoantibodies against blood cells (red blood cells, platelets, leucocytes) and results in haematologic derangement in SLE. 2. Type III hypersensitivity is characterised by antigenanti body complex (commonly DNA-anti-DNA anti body; sometimes Ig-anti-Ig antibody complex) which is deposited at sites such as renal glomeruli, walls of small blood vessels etc.
  8. Slide 8. • Pathogenesis is related in large part to production of increased quantities and immunogenic forms of nucleic acids and other self- antigens, which drive autoimmune- inducing activation of innate immunity, autoantibodies, and T cells. • Interactions between genes, environment, and epigenetic changes drive increased autophagy, Ag presentation, neutrophil NETosis, autoantibody formation with increased plasma cells, and production of pathogenic effector T cells in Th1, Th17, and Tfh subsets, with ineffective regulatory networks.
  9. Slide 9. • The exact mechanism of autoantibody tissue destruction is unclear. • Immune complexes form when autoantibodies bind to nuclear material and deposit in tissues. • They activate the complement cascade, leading to an influx of inflammatory cells and tissue injury. • Autoantibodies might also directly react with proteins in tissues. • There are increased T helper cells type 2 and 17 and diminished number and function of T regulatory (Treg) cells. • Cytokines, such TNF-α, interferon-gamma, and interleukin-10, produced by activated T cells can stimulate B cells. • Cytokines play multiple roles in SLE and contribute to inflammation and tissue damage. • Interleukin-10 stimulates B cell proliferation and autoantibody production in renal cells and may affect skin and joint symptoms. • Increased T cell production of interleukin-17 correlates with disease activity and may contribute to kidney and other tissue damage.
  10. Slide 12. CLINICAL PRESENTATION Symptoms 1. Fatigue, 2. Depression, 3. Anxiety, 4. Photosensitivity, 5. Joint pain, 6. Headache, 7. Weight Loss, 8. Nausea/abdominal pain Signs 1. Rash, Butterfly rash 2. Alopecia, 3. Fever, 4. Oral and nasal ulcers, 5. Arthritis, 6. Renal dysfunction, 7. Seizure, psychosis, 8. Pleuritis, pleural effusion, 9. Cardiovascular disease - pericarditis/ myocarditis, heart murmur, hypertension, 10. Anemia, leukopenia, thrombocytopenia, 11. Lymphadenopathy, 12. Raynaud’s phenomenon, 13. Vasculitis
  11. Slide 14. Diagnostic Tests 1. Serology: autoantibodies, antiphospholipid antibodies, complement; 2. Inflammatory markers: C- reactive protein, ESR; 3. Blood chemistries; CBP; urinalysis; lumbar puncture; 4. Renal biopsy
  12. Slide 15. SLE flare : A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. Cutaneous lupus erythematosus – Affecting skin Three main types of cutaneous lupus erythematosus have been observed. 1. Acute cutaneous lupus erythematosus is seen in patients with SLE a. Characterized by a photosensitive malar rash over the cheeks and nose with sparing of the nasolabial folds. b. The arms and trunk may be involved. c. The manifestations usually wax and wane without scarring.
  13. Slide 16. 2. Severe SLE is less common with the other forms of cutaneous lupus. 3. Subacute cutaneous lupus erythematosus is highly photosensitive A. Manifested by annular or papulosquamous lesions that usually heal without scarring. B. It can be accompanied by musculoskeletal complaints and patients have anti-rossa autoantibodies. C. Subtypes of chronic cutaneous lupus erythematosus - common is discoid lupus. 1. Chronic discoid lupus A. Confined to the head and neck B. Chronic discoid lupus is associated with a lower incidence of arthritis, end-stage renal disease, and immunologic markers such as ana, anti-dsdna, and antiphospholipid antibodies. C. It is more common in smokers and african americans. D. It may be associated with scarring, scarring alopecia, malar rash, photosensitivity, oral ulcers, leukopenia, vasculitis, and chronic seizures.
  14. Slide 17. Lupus nephritis Affecting kidneys Neuropsychiatric lupus 1. About 50% of neuropsychiatric events appear within the first 2 years after the diagnosis of SLE. 2. Mild nonspecific neuropsychiatric findings such as headache, mood disorders, and mild cognitive dysfunction are common in SLE. 3. Findings more indicative of neuropsychiatric lupus include cerebrovascular disease (ischemic stroke and/or transient ischemic attack), anxiety, and seizures ; severe cognitive dysfunction, acute confusional state, peripheral neuropathy, and psychosis; and chorea, movement disorders, cranial nerve neuropathies, and aseptic meningitis abnormalities. 4. The diagnostic depending on the clinical presentation and preliminary findings - a thorough history and physical, lumbar puncture with cerebrospinal fluid analysis, EEG, serology, CBP, blood chemistries, neuropsychological assessment of cognitive function, nerve conduction studies, and MRI.
  15. Slide 18. Cardiovascular lupus 1. Cardiovascular disease is a leading cause of death in patients with SLE. 2. Cardiac manifestations of SLE, such as pericarditis and myocarditis, patients with SLE are also at increased risk for accelerated atherosclerosis. 3. This is probably related to the chronic inflammation associated with the disease and adverse effects of the drugs (eg, high-dose corticosteroids) used to treat it. 4. Antiphospholipid antibodies and type I interferons may play a role in the pathogenesis. 5. Drugs such as hydroxychloroquine and mycophenolate mofetil may have a cardioprotective effect.
  16. Slide 19. MANAGEMENT OF SLE Treatment of SLE is determined by the • Patient’s symptoms, • Organ involvement, • Comorbidities, and • Other patient-specific factors. Goals of therapy 1. To prevent disease flares and involvement of other organs, 2. Decrease disease activity and prevent damage, maintain remission, reduce use of corticosteroids, 3. Improve quality of life, while minimizing adverse effects and costs.
  17. Slide 20. General Approach • Patients with SLE should be counseled lifestyle modifications such as protection from the sun, smoking cessation, exercise, and weight control. • Immunization status should be assessed in consideration with immunosuppressive drugs. • The effects of disease activity and treatment on pregnancy outcomes should be discussed. • Mild symptoms can be managed with NSAIDs. • Corticosteroids are used in low doses indefinitely as maintenance therapy. • If the above therapy is ineffective or major organs are involved, immunosuppressive drugs are added.
  18. Slide 21. Nonpharmacologic Therapy 1. Provide social and Psychological Support 2. Aerobic cardiovascular exercise may help decrease patients’ risk for cardiovascular events and osteoporosis and may also improve fatigue and sleep disturbances, which are frequently experienced in SLE. 3. Photosensitivity is common in SLE, patients should wear protective clothing and hats and use sunscreens to protect themselves from the sun. 4. They should avoid tanning salons. 5. Patients with SLE should use sunscreens with high SPF values and apply them every 2 hours while in the sun. 6. Patients should be counseled to stop smoking. Smoking cessation is important, not only because it decreases cardiovascular risk, but because smoking can exacerbate SLE and diminish the effectiveness of antimalarials. Smokers also have a higher incidence of active rashes with skin damage and scarring.
  19. Slide 22. Pharmacologic Therapy • Treatment is determined by the manifestation of SLE in individual patients. • It consists of a combination of immunosuppression and symptomatic and supportive therapies. • The only drugs approved by the FDA for treatment of SLE are aspirin, prednisone, hydroxychloroquine, and belimumab. • The use of other drugs for SLE, even those considered “standard of care,” is considered to be “off-label” use. Drugs used in SLE 1. Glucocorticoids – Prednisolone, Methylprednisolone 1. NSAIDS 2. Antimalarials - Hydroxychloroquine 3. Biologics - Belimumab 4. Immunosuppressants – Cyclophosphamide, Mycophenolate mofetil, Azathioprine, Methotrexate 5. Tacrolimus 6. Leflunomide 7. IV IG
  20. Slide 24. General approach to the management of SLE.
  21. Slide 25. Management of different manifestations of SLE
  22. Slide 26. Management of different manifestations of SLE
  23. Slide 27. SLE Drugs indication and doses
  24. Slide 28. SLE Drugs Adverse Effects with monitoring parameters
  25. Slide 29. Nonsteroidal Anti-inflammatory Drugs Mechanism of Action • Inhibit cyclooxygenase (COX) enzymes (COX-1 & COX-2), reducing prostaglandin synthesis. • Decrease inflammation, pain, and fever by blocking prostaglandin-mediated pathways. • COX-1 inhibition: Leads to gastric protection loss, platelet inhibition, and renal side effects. • COX-2 inhibition: Reduces inflammation with fewer gastrointestinal effects but increases cardiovascular risks. Indications • Used as first line treatment for arthritis, Musculoskeletal complaints, fever and serositis Adverse effects • GI Bleeding, Hepatic toxicity, renal toxicity, HTN, CV Events, Aseptic meningitis
  26. Slide 30. Corticosteroids MOA Binds to glucocorticoid receptors → modifies gene transcription → suppresses inflammation. Reduces capillary permeability and polymorphonuclear neutrophil activity. Inhibits T-cell proliferation, induces apoptosis, and impairs lymphocyte function. Decreases antibody production by B-cells (delayed effect). Stabilizes lysosomal membranes, preventing further tissue damage. Drug and doses • Prednisone (oral) – Standard corticosteroid for SLE treatment. • Methylprednisolone (IV) – Used for pulse therapy in severe cases. • Prednisolone and methylprednisolone – Initial 0.1 to 1.5 mg/kg/day , Maintenance <10mg/day • Hydrocortisone (topical) – For mild cutaneous manifestations. • Dexamethasone (IV/oral) – Alternative for CNS lupus. • Used to control flares and maintain low disease activity. • Doses should be targeted to lowest effective dose for most forms of SLE. • High doses are associated with infections, myopathy, psychological disturbances, osteonecrosis and stroke. Adverse effects Osteoporosis, Cataract, Glaucoma, DM, HTN, Dyslipidemia, Thinning of skin, Weight increases, Skin atrophy
  27. Slide 31. Antimalarials • The antimalarials chloroquine and hydroxychloroquine have long been used in treatment of SLE. • Hydroxychloroquine is thought to have fewer adverse reactions and is the preferred drug. MOA • Hydroxychloroquine has anti-inflammatory, immunomodulatory, and antithrombotic effects. • It reduces concentrations of inflammatory cytokines such as interleukins 1, 2, 6, 17, and 22, interferon alpha and gamma, and TNF-α. • It alters antigen presentation and T-cell proliferative responses. • It decreases activation of receptor which are involved in antiphospholipid syndrome. • It reduces RBC Sludging, blood viscosity and platelet aggregation. • It delays UV light absorption and may decrease the no. of skin antigen presenting cells.
  28. Slide 32. • Hydroxychloroquine is used for skin and joint manifestations of SLE. • It can prevent lupus flares and improve long-term survival. • It has a beneficial effect on lipids and fasting blood glucose, decreases the risk of thrombosis in patients with antiphospholipid antibodies, and decreases infections. • It can allow corticosteroid doses to be decreased. • Patients receiving hydroxychloroquine often have disease flares when the drug is discontinued. • Adverse effects with hydroxychloroquine are usually mild. • Most common are GI and skin reactions and they usually improve with dose reduction. • The main concern is retinal toxicity, but the incidence is low and may be less than that seen with chloroquine. DOSE- Hydroxychloroquine – 200 – 400 mg OD
  29. Slide 33. Immunosuppressive drugs 1. Cyclophosphamide • It is used to treat SLE such as Lupus nephritis, CNS Lupus, Lung disease and Severe systemic vasculitis • It is an alkylating agent that causes cross-linkage of DNA leading to cell death. • It also reduces B cell and Ig G production and adhesion molecule and cytokines. • ADR – Myelosuppression, opportunistic infection, hemorrhagic cystitis, bladder malignancy, infertility • Dose – In above mention table slide no 26
  30. Slide 34. 2. Methotrexate • It is an inhibitor of folic acid reductase which needed for DNA synthesis and cell growth. • It is indicated for arthritis, skin disease and steroid sparing drug • It is dosed once weekly in management of SLE • ADR – Hepatitis, Hematologic, Pulmonary toxicity, Stomatitis • Dose – In above mention table slide no 26 3. Azathioprine • It is a purine analogue, inhibits DNA synthesis and prevents immune cell proliferation. • It is used as an alternative to MMF, and less effective than cyclophosphamide • It is indicated for SLE related arthritis, serositis, mucocutaneous manifestations, hematologic • ADR- Myelosuppression, Hepatotoxicity • Dose – In above mention table slide no 26
  31. Slide 35. 4. Mycophenolate Mofetil (MMF) • It is hydrolyzed to mycophenolic acid which reversible inhibits the enzyme inosine 5 monophosphate dehydrogenase, important for de novo synthesis of purine inhibits proliferation and differentiation of lymphocytes. • The drug also have immunomodulating effects such as 1. Induction of activated T cell apoptosis 2. Inhibition of adhesion molecule expression 3. Antiproliferative effect on fibroblast, dendritic cell and vascular SMC • It is indicated in Cutaneous lupus, Arthritis, Hematologic manifestations. • ADR – Nausea , vomiting, diarrhea, Red cell Aplasia. • Contraindicated in Pregnancy.
  32. Slide 36. Biologic Agents • Autoantibody formation is an important feature of SLE, B Cell make logical target for SLE Therapy • B-lymphocyte stimulator (BLyS) is a cytokine that is important for B cell survival, maturation, and differentiation. 1. Belimumab • It is a fully human IgG1-λ monoclonal antibody that binds to soluble B Lymphocytes Stimulator (BLyS), which prevents BLyS from binding to receptors on B cells and promotes apoptosis of B lymphocytes. • Belimumab is FDA-approved for treatment of autoantibody positive active SLE in addition to standard therapy. • It is the first drug approved by the FDA in over 50 years for management of SLE. • No Live vaccination should be given 30 days before and after the therapy. • Premedication with acetaminophen, Diphenhydramine should be administered • Contraindicated with other biologics and Cyclophosphamide • ADR – Infusion reaction, Hypersensitivity rex, Nausea, diarrhea, depression, fever, bronchitis, Insomnia, migraine.

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