1. Systemic Lupus Erythematosus

2. Introduction Autoimmune disease Multi system involvement Organs damage – Autoantibodies – Immune complexes

3. Epidemiology All genders, ages, and ethnic groups Women of childbearing years (90%) Female/ men: 9/1 * Iran: 9/1 Prevalence – 10 to 400 per 100,000 (United States) – 40 per 100,000 (Iran) – Highest in black women – Lowest is in white men

4. PATHOGENESIS OF SLE 1- Genetic bases 2- Environmental factors 3- Autoantibodies 4- B-cell abnormalities 5- T-cell abnormalities 6- Immunoregulation inability

5. Susceptibility Abnormal immune response Auto Abs & ICs Inflammation Damage Pathogenesis ?

6. Pathogenesis and Etiology

7. Pathogenesis Abnormal immune responses (1) Activation of innate immunity – Dendritic cells, monocyte/macrophages (2) Lowered thresholds and abnormal activation activation in adaptive immunity cells – T and B lymphocytes

8. Pathogenesis (3) Ineffective regulatory – CD4+ and CD8+ T cells (4) Reduced clearance – Immune complexes – Apoptotic cells

9. Pathogenesis Immune cell activation Proinflammatory cytokines – IFNs – Tumor necrosis factor – Interleukin (IL)-17 – B cell–maturation/survival cytokines B lymphocyte stimulator (BLyS/BAFF) – IL-10

10. Pathogenesis Immune cell activation Lupus T and natural killer (NK) cells fail to produce – IL-2 – Transforming growth factor (TGFβ)

11. Clinical Manifestations

12. Systemic (95%) – Fatigue – Malaise – Fever – Anorexia – Weight loss

13. Musculoskeletal (95%) Arthralgias/myalgias Intermittent polyarthritis – Hands, wrists, and knees Joint deformities (hands and feet) – Only 10% – Erosions on joint x-rays are rare

14. Musculoskeletal (95%) Ischemic necrosis of bone (15%) Myositis (5%) Muscle weakness – Glucocorticoid therapies (commonly) – Antimalarial therapies (rarely)

16. Cutaneous Manifestations (80%) Acute – Localized – Generalized

17. Butterfly rash (discoid type)

18. Cutaneous Manifestations (80%) Oral ulcer (40%) Erythema on soft and hard palate Buccal mucosa Without pain Malar rash (50%) Nasal ulcer lower nasal septum Bilateral Active disease

19. Cutaneous Manifestations (80%) Subacute cutaneous LE (SCLE) Annular Papulosqumous (psoriasiform)

20. Cutaneous Manifestations (80%) Chronic – DLE (20%) Localized Generalized – Lupus panniculitis (profundus) – Mucosal LE – Tumid lupus

21. Cutaneous Manifestations (80%) Vasculitis (20%) – Palpable purpura – Urticarial vasculitis – Polyarteritis nodosa–like – Livedo reticularisa

22. Renal Manifestations (50%) Nephritis – Most serious manifestation – Asymptomatic (most lupus patients) Urinalysis should be ordered in any person suspected of having SLE

23. Renal Manifestations Nephritis – Proteinuria 500 mg/24 h, cellular casts (30–50%) – Nephrotic syndrome (25%) End-stage renal disease (5–10%)

24. Nervous System Manifestations (60%) Central nervous system (CNS) Peripheral nervous system Cognitive dysfunction (most common)(50%) – Difficulties with memory and reasoning Headaches Psychosis Glucocorticoid-induced psychosis Myelopathy Infection

27. Cardiopulmonary (60%) Pleurisy, pericarditis, effusions (30–50%) Myocarditis, endocarditis (10%) Coronary artery disease (10%)

28. Cardiopulmonary (60%) Lupus pneumonitis (10%) Interstitial fibrosis (5%) Shrinking lung syndrome (<5%) Pulmonary hypertension, ARDS, hemorrhage (<5%)

29. Gastrointestinal (40%) Nonspecific (30%) – Nausea – Mild pain – Diarrhea Abnormal liver enzymes (40%) Vasculitis (5%) Thrombosis (15%)

30. Ocular (15%) Sicca syndrome (15%) Conjunctivitis, episcleritis (10%) Vasculitis (5%)

31. Clinical Manifestations Thrombosis (15%) – Venous (10%) – Arterial (%5)

32. Hematologic (85%) Anemia (chronic disease) (70%) Leukopenia (<4000/L) (65%) Lymphopenia (<1500/L) (50%) Thrombocytopenia (100,000/L) (15%) Lymphadenopathy (15%) Splenomegaly (15%) Hemolytic anemia (10%)

33. SLE in IRAN: 2280 patients (1976-2009) Musculoskeletal: 83.2% Cutaneous: 81% Renal: 65.4% Neuropsychiatric: 23.4% Pulmonary: 21.5% Cardiac: 17.2% Hematologic: 66.4% Renal involvement more than some european countries

34. Laboratory Tests Aims – Establish or rule out the diagnosis – Follow the course of disease Flare or organ damage – Identify adverse effects of therapies

35. Laboratory Tests Autoantibodies ANA (>95%) High-titer IgG antibodies to double-stranded DNA (dsDNA) Antibodies to Sm (specific) Anti phospholipid antibody Anti-Ro – Neonatal lupus – Sicca syndrome – SCLE. Declining levels of C3 or C4 complement

36. Immunofluorescent staining of ANAs 1. Homogenous (diffuse) deoxy RNA protein, histone (SLE, DIL, RA ) 2. Rim (peripheral) dsDNA, histone characteristic of SLE

37. Urine sediment Hematuria: RBC > 5 Dysmorphic (fragmented, abnormal sizes and shapes) Pyuria: WBC > 5 RBC, WBC, mixed cast NEPHRITIC Granular, fatty cast PROTEINURIC Broad, waxy cast CRF

38. WHO Classification of Nephritis Class I Normal Class II Mesangial GN Class III Focal Segmental GN Class IV Diffuse Proliferative GN Class V Diffuse Membranous GN Class VI Glomerulosclerosis

40. Class II Mesangial proliferative GN

43. Class IV Diffuse proliferative GN Normal glomerulus

45. Membranous GN

47. Laboratory Tests Skin biopsy Deposition of Ig at the dermal-epidermal junction (DEJ) – Clinically unaffected skin

48. Laboratory Tests Standard Tests for diagnosis – Auto antibodies Screening tests – Complete blood count – Platelet count – Urinalysis may detect abnormalities

49. Diagnosis Diagnosis ACR Criteria for Systemic Lupus Erythematosus 1.Malar rash 2.Discoid rash 3.Photosensitivity 4.Oral ulcers 5.Arthritis – Nonerosive arthritis of two or more peripheral joints 6.Serositis – Pleuritis or pericarditis documented by ECG or rub or evidence of effusion

50. Diagnosis Diagnosis ACR Criteria for Systemic Lupus Erythematosus (cont.) 7. Renal disorder Proteinuria > 0.5 g/d or 3+ Or cellular casts 8. Neurologic disorder – Seizures or psychosis without other causes 9. Hematologic disorder – Hemolytic anemia or leukopenia (<4000/L) or – Lymphopenia (<1500/L) or – Thrombocytopenia (<100,000/L)

51. Diagnosis Diagnosis ACR Criteria for Systemic Lupus Erythematosus (cont.) >/= 4 criteria, Specificity and sensitivity are 95% and 75%, respectively 10. Immunologic disorder – Anti-dsDNA, anti-Sm, and/or anti-phospholipid 11. Antinuclear antibodies – An abnormal titer of ANA – Absence of drugs known to induce ANAs

53. Treatment

55. Major organ involvement Nephritis Proliferative or membranous nephritis Hematologic Severe thrombocytopenia (< 20 × 103/μL) TTP–like syndrome, AA, sever hemolytic Lupus pneumonitis or alveolar hemorrhage Cardiac Myocarditis, pericarditis (impending tamponade) Abdominal vasculitis Nervous system Transverse myelitis, Cerebritis Vasculitis, neuropathy Psychosis resistance to GC

56. NSAIDs Side effects – Aseptic meningitis – Transaminitis – Decreased renal function – Vasculitis of skin – Myocardial infarction (esp cox2 I) Drugs Both GI events and symptoms Allergic Reactions Dermatitis Dizziness Acute Renal Failure Edema Hypertension

57. Drugs Topical glucocorticoids – Atrophy of skin – Contact dermatitis – Folliculitis – Hypopigmentation, infection Topical sunscreens – Contact dermatitis

58. Drugs Hydroxychloroquine 200–400 mg qd Retinal Damage Agranulocytosis Aplastic Anemia Ataxia Cardiomyopathy Dizziness Myopathy Ototoxicity Peripheral Neuropathy Pigmentation Of Skin Seizures Thrombocytopenia Quinacrine Diffuse yellow skin coloration

59. Antimalarial agents* Reduce the frequency of disease flares (nephritis) Contribute to the maintenance of remission Prolong the onset of disease Reduce the risk of complications *Nature, 2010

60. Antimalarial agents* Immunomodulatory effects – Protect against thrombotic events – Improve glucose and lipid profiles – Prevent renal damage – Reduced cardiovascular risk Increased rate of survival lower risk of major infections *Nature, 2010

61. Drugs Methotrexate Dermatitis, arthritis 10–25 mg once a week Anemia bone marrow suppression leukopenia Thrombocytopenia Hepatotoxicity Nephrotoxicity Infections Neurotoxicity Pulmonary fibrosis Pneumonitis Severe dermatitis Seizures

62. Drugs Prednisolone – 0.5–1 mg/kg per day (severe SLE) – 0.07–0.3 mg/kg per day (milder disease) Methylprednisolone sodium – 1 g IV qd x 3 days (severe disease)

63. Drugs Side effects of steroids Infection, VZV infection, hypertension Hyperglycemia, hypokalemia, acne Allergic reactions, anxiety Aseptic necrosis of bone Cushingoid changes, CHF, fragile skin, insomnia Menstrual irregularities, mood swings Osteoporosis Psychosis

64. Drugs Cyclophosphamide – 7–25 mg/kg q month x 6 Infection Bone marrow suppression Hemorrhagic cystitis (less with IV) Carcinoma of the bladder, alopecia, nausea, diarrhea, malaise Malignancy Ovarian and testicular failure

65. Drugs Mycophenolate mofetil – 2–3 g/d PO Infection leukopenia lymphoproliferative disorders Malignancy Alopecia Cough, diarrhea, fever, GI symptoms, headache Hypertension, hypercholesterolemia, hypokalemia Insomnia, peripheral edema, transaminitis, tremor Rash

66. Drugs Azathioprine – 2–3 mg/kg per day PO Infection Bone marrow suppression Pancreatitis Hepatotoxicity Malignancy Alopecia, fever, flulike illness, GI symptoms

67. Drugs Rituximab – 1 g q 2 wks x 2 Infection Infusion reactions Headache Arrythmias Allergic responses

68. Preventive Therapies Vaccinations – Influenza and pneumococcal vaccines Prevent osteoporosis Control of hypertension Prevention strategies for atherosclerosis Suppressing recurrent urinary tract infections Monitoring and treatment – Dyslipidemias – Hyperglycemia – Obesity

69. Patient Outcomes, Prognosis, and Survival Survival – 95% at 5 years – 90% at 10 years – 78% at 20 years The leading causes of death – First decade of disease Systemic disease activity Renal failure Infections – Thromboembolic events (later)

70. Patient Outcomes, Prognosis, and Survival Poor prognosis High serum creatinine levels (>1.4 mg/dL) Hypertension Nephrotic syndrome (24-h urine protein excretion >2.6 g) Anemia (hemoglobin < 12.4 g/dL) Hypoalbuminemia Hypocomplementemia Apl Male sex Ethnicity (African American, Hispanic)

71. Pregnancy and Lupus Fertility rates for men and women with SLE are probably normal Rate of fetal loss is increased – Two- to threefold High disease activity Antiphospholipid antibodies Active nephritis

72. Pregnancy and Lupus Glucocorticoids (category A) Cyclosporine, Tacrolimus, Rituximab (category C) Azathioprine, Hydroxychloroquine and Mycophenolate mofetil (category D) Methotrexate is (catrgory X)

73. Pregnancy and Lupus Adverse effects of prenatal glucocorticoid exposure (primarily betamethasone) – Low birth weight – Abnormalities in the CNS – Predilection toward adult metabolic syndrome

74. Pregnancy and Lupus Women with SLE usually tolerate pregnancy without disease flares Severe flares (small proportion) – Poor maternal outcomes – Active nephritis – Irreversible organ damage Kidneys Brain Hear t

75. Drug induced SLE A syndrome of positive ANA – Fever – Malaise – Arthritis or intense arthralgias/myalgias – Serositis – Rash

76. SLE INDUCING DRUGS Hydralazine Procainamide Isoniazid Hydantoins Chlorpromazine Statins Penicillamine Minocycline TNF-α inhibitors Interferon-α Methyldopa

77. Drug induced SLE Rare – kidneys or Brain – Association with anti-dsDNA Antibodies to histones (commonly) Resolves – Several Weeks after discontinuation drug

78. IN THE NAME OF GOD THE END