SYSTEMIC LUPUS ERYTHEMATOSUS

1. SYSTEMIC LUPUS ERYTHEMATOSUS Pardis Nematollahi MD,ACP June,2014

2. SYSTEMIC LUPUS ERYTHEMATOSUS • Autoimmune multisystem disease characterized by widespread microvascular inflammation and production of autoantibodies • This means wide spectrum of presentation • Chronic with relapsing and remitting course • Ranging from indolent to fulminant

3. The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLE

4. Etiology • Etiology is unknown Most probable causes • Genetic influence • At least 35 genes are known to increase the risk of SLE. • A genetic predisposition is supported by 40% concordance in monozygotic twins; if a mother has SLE, her daughter's risk of developing the disease has been estimated to be 1:40, and her son's risk, 1:250. • Immunological factors Many immune disturbances, both innate and acquired, occur in SLE • Studies of human leukocyte antigens (HLAs) reveal that HLA-A1, HLA-B8, and HLA-DR3 are more common in persons with SLE than in the general population. The presence of the null complement alleles and congenital deficiencies of complement (especially C4, C2, and other early components) are also associated with an increased risk of SLE

5. Etiology • Environmental and exposure-related causes of SLE are • Silica dust and cigarette smoking • Administration of estrogen to postmenopausal women • Photosensitivity is clearly a precipitant of skin disease Ultraviolet light stimulates keratinocytes, which leads not only to overexpression of nuclear ribonucleoproteins • Vitamin D deficiency • Drugs • Numerous studies have investigated the role of infectious etiologies that may also perpetuate autoimmunity. Patients with SLE have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral loads, and make antibodies to retroviruses

6. Pathophysiology • Systemic lupus erythematosus (SLE) is characterized by a global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury. • Autoimmune reactions directed against constituents of cell nucleus, DNA

7. Y Y Y AUTOREACTIVITY Y Y Y APOPTOSIS Protease (caspase) cascade Death signal Receptor ligation ex: TNF, Fas DNA fragmentation Chromatin condensation Cytoplasmic blebbing Clearance by phagocytes Apoptotic bodies

8. Immune complex formation Y C’ Y Y RBC Y Y Y Y Endo BM Intima Complement fixation Release of inflammatory, vasoactive and chemotactic mediators RBC C’ Y Disruption of endothelium Y Y Y Y C’ Y C’ Thickening of BM Y Y Y Y Y Y Infiltration of inflammatory cells Tissue damage

9. EPIDEMIOLOGY • Age : peak 20s and 30s but any age can be affected before 8 yrs unusual • Sex :more women affected ,10:1 during childbearing age • Prevalence:1/2500 • 1 in 700 among women of childbearing age . By comparison, the female-to-male ratio is only 2 : 1 for disease developing during childhood or after the age of 65

10. Clinical Features of SLE • Constitutional symptoms • Musculoskeletal disease • Mucocutaneous involvement • Renal Disease • Central nervous system disease • Cardiopulmonary disease • Hematologic abnormalities • Gastrointestinal involvement

11. Clinical Manifestations • Ranges from a relatively mild disorder to rapidly progressing, affecting many body systems • Most commonly affects the skin/muscles, lining of lungs, heart, nervous tissue, and kidneys

12. General clinical manifestation • Severe fatigue • Fever • Weight loss • Anorexia • Lymphadenopathy

13. Mucocutaneous manifestation • Frequency: 76% • Malar rash • Discoid lupus • Vasculitis (purpura, petechiae) • Raynaud’s phenomenon • Nail involvement • Alopecia • Photosensitivity • Oral/ nasal ulcers

14. MALAR RASH • Fixed erythema, flat or raised, over the malar eminences • Tending to spare the nasolabial folds • 30-60 %

15. Dermatologic Manifestations Fig 65-10

16. MALAR RASH

17. Photosensitivity Rash over the sun exposed areas.Face,neck and V shaped area of chest.See rash varies in severity depending on exposure.Less under the orbit protected areas.

18. DISCOID RASH • Erythematous raised patches with adherent keratotic scaling and follicular plugging • Atrophic scarring may occur in older lesions

19. Oral lesions of SLE • Erythema of hard and soft palate, papules ,vesicles and petechiae • Erythematous rash of the tongue.

21. Oral Ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician

22. Joint • arthralgia, arthropathy, myalgia, frank arthritis, avascular necrosis • Joint involvement is typically a nonerosive synovitis with little deformity, which contrasts with rheumatoid arthritis

23. Serositis • Pleuritis : convincing history of pleuritic pain ,pleural rub heard by a physician or evidence of pleural effusion or • Pericarditis: documented by ECG ,pericardial rub or evidence of pericardial effusion

24. Pulmonary Findings In SLE • Incidence: 5-67% • May be subclinical (abnormal PFTs) • Pleuritis • Pleural effusion • Pneumonitis • Pulmonary hemorrhage • Pulmonary hypertension • Restrictive pulmonary disease & diffusion defects most commonly observed abnormalities on PFTs

25. Cardiovascular Findings In SLE • Pericarditis • Myocarditis • Sterile valvular vegetations (rarely clinically significant except for risk of bacterial endocarditis) • Arrhythmias • Cor pulmonale • Vasculitis (small vessels) • Atherosclerosis/ Coronary Heart disease • Dyslipoproteinemias

26. Renal Findings In SLE Most common cause of morbidity & mortality • Lupus nephritis affects up to 50% of SLE patients. The principal mechanism of injury is immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or larger blood vessels • A variety of clinical findings may point toward renal involvement, including hematuria, red cell casts, proteinuria, and in some cases the classic nephrotic syndrome

27. Neuropsychiatric Manifestations Of SLE • Frequency: 20-40% • Difficult to diagnose and treat • Second to nephritis as most common cause of morbidity & mortality • Can occur at any time; even at presentation

28. Pathophysiology of CNS involvement • The pathologic basis of central nervous system symptoms is not entirely clear, but antibodies against a synaptic membrane protein have been implicated. Neuropsychiatric symptoms of SLE have often been ascribed to acute vasculitis, but in histologic studies of the nervous system in such patients significant vasculitis is rarely present. Instead, noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted, which may be due to endothelial damage by antiphospholipid antibodies

29. Neuropsychiatric Manifestations Of SLE • COMMON: Depression, organic brain syndrome, functional psychosis, headaches, seizures, cognitive impairment, dementia, coma • OCCASIONAL:Cerebral vascular accidents (thrombosis or vasculitis), aseptic meningitis, peripheral neuropathy, cranial nerve palsies • RARE:Paralysis, transverse myelopathy, chorea

30. Leukopenia, especially lymphopenia Anemia mild to moderate, common, due to chronic disease and mild hemolysis severe, uncommon (5%), due to immune mediated hemolysis (Coombs +) Thrombocytopenia mild 100-150/micoL, common due to immune mediated damage severe <20/microL, uncommon (5-10%), immune mediated damage Bone marrow suppression/arrest--very rare, due to antibodies against precursors Hematologic Findings In SLE

31. Coagulopathy In SLE • Hypocoagulable states: • Anti-platelet antibodies--decreased numbers of platelets or decreased function (increased bleeding time) • Other platelet dysfunction and thrombocytopenia • Anti-clotting factor antibodies • Hypercoagulable states: • Antiphospholipid Antibody Syndrome (APS): more later • Protein C and S deficiencies • Thrombotic thrombocytopenic purpura

32. Infection • because of their underlying immune dysfunction and treatment with immunosuppressive drugs • Fever should be considered serious

33. Ocular • Conjunctivitis • Photophobia • Monocular blindness transient or permanent • Blurred vision • Cotton-Wool spots on retina due to occlusion retinal blood vessels

34. GI INVOLVEMENT IN SLE • Uncommon SLE manifestations • Mild LFT elevation--not significant clinically--BUT NEED TO EXCLUDE AUTOIMMUNE HEPATITIS • Colitis • Mesenteric vasculitis • Protein-losing enteropathy • Pancreatitis • Exudative ascites

35. 1997 ACR CRITERIA FOR THE CLASSIFICATION OF SLE • Malar (butterfly) rash: • Fixed erythema, flat or raised, sparing the nasolabial folds • Discoid lupus rash: • Raised patches, adherent keratotic scaling, follicular plugging; may cause scarring • Photosensitivity: • Rash as a result of unusual reaction to sunlight, by patient history or physician observation • Oral or nasal mucocutaneous ulcerations: • Usually painless

36. 1997 ACR CRITERIA FOR THE CLASSIFICATION OF SLE (cont) • Inflammatory arthritis: • Nonerosive, in two or more peripheral joints • Pleuritis or pericarditis • Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion, or • Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion • Cytopenias: • Hemolytic anemia with reticulosis or • leukopenia (<4,000/mm3) or • lymphopenia (<1,500/mm3) or • thrombocytopenia (<100,000/mm3) • Nephritis: • Proteinuria >0.5 gm/dL or >3+ or • Cellular casts

37. 1997 CRITERIA FOR THE CLASSIFICATION OF SLE (cont) • Encephalopathy: • Seizures • Psychosis • Positive ANA • Positive immunoserology: Anti-DNA antibody to native DNA in abnormal titer, or Anti-Sm, or Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test for lupus anticoagulant using a standard test, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by negative Treponema pallidum immobilization or fluorescent treponemal antibody absorption test

38. 1. Serositis 2. Oral Ulcers 3. Arthritis 4. Photosensitivity 5. Blood disorders: -Hemolytic anemia -Leukopenia (Lymphopenia) -Thrombocytopenia 6. Renal disorders 7. ANA positive 8. Immunologic abnormalities: -Anti-ds- DNA -Anti- Sm -Antiphospholipid -False +ve VDRL 9. Neurologic abnormalities 10. Malar rash 11. Discoid rash – rimmed with scaling, follicular plugging The revised criteria for the classification of systemic lupus erythematosus

39. CLASSIFICATION CRITERIA • Must have 4 of 11 for Classification • Sensitivity 96% • Specificity 96%(In children 100%) • Not all “Lupus” is SLE • Chronic discoid Lupus erythematosus • Drug induced lupus • Subacute Cutaneous Lupus erythematosus

40. Chronic Discoid Lupus Erythematosus • Chronic discoid lupus erythematosus is a disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare. • It is characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border. • The face and scalp are usually affected, but widely disseminated lesions occasionally occur

41. Chronic Discoid Lupus Erythematosus • The disease is usually confined to the skin, but 5% to 10% of patients with discoid lupus erythematosus develop multisystem manifestations after many years. • Approximately 35% of patients show a positive ANA test, but antibodies to double-stranded DNA are rarely present. • Immunofluorescence studies of skin biopsy specimens show deposition of immunoglobulin and C3 at the dermoepidermal junction similar to that in SLE.

42. Subacute Cutaneous Lupus Erythematosus. • This condition also presents with predominant skin involvement and can be distinguished from chronic discoid lupus erythematosus by several criteria. • The skin rash in this disease tends to be widespread, superficial, and nonscarring, although scarring lesions may occur in some patients. • Most patients have mild systemic symptoms consistent with SLE. Furthermore, there is a strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype. • Thus, the term subacute cutaneous lupus erythematosus seems to define a group intermediate between SLE and lupus erythematosus localized only to skin.

43. Drug-Induced Lupus Erythematosus • A lupus erythematosus–like syndrome may develop in patients receiving a variety of drugs, including hydralazine, procainamide, isoniazid, and d-penicillamine, Many of these drugs are associated with the development of ANAs, but most patients do not have symptoms of lupus erythematosus. • For example, 80% of patients receiving procainamide test positive for ANAs, but only one third of these manifest clinical symptoms, such as arthralgias, fever, and serositis.

44. Drug-Induced Lupus Erythematosus,cont. • Although multiple organs are affected, renal and central nervous system involvement is distinctly uncommon. • There are serologic and genetic differences from classical SLE, as well. Antibodies specific for double-stranded DNA are rare, but there is an extremely high frequency of antibodies specific for histone • Persons with the HLA-DR4 allele are at a greater risk of developing lupus erythematosus after administration of hydralazine. • The disease remits after withdrawal of the offending drug.

45. DIFFERENTIAL DIAGNOSIS • Rheumatic: RA, Sjogren’s syndrome, systemic sclerosis, dermatomyositis • Nonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritis

46. Testing • The following are useful standard laboratory studies when SLE is suspected: • CBC with differential • Serum creatinine • Urinalysis with microscopy

47. Other laboratory tests that may be used in the diagnosis of SLE are as follows • ESR or CRP results • Complement levels • Liver function tests • Spot protein/spot creatinine ratio • Autoantibody tests

48. PROGNOSIS • Unpredictable course • The outcome has improved significantly, and an approximately 90% 5-year and 80% 10-year survival can be expected • Most SLE patients die from renal failure and infection, probably related to therapy which suppresses immune system • Recommend smoking cessation, yearly flu shots, pneumovax q5years

49. Refrences • Robbins and Cotran,Pathologic basis of disease,8th edition,2010 • http://emedicine.medscape.com/article Updated: Feb 19, 2014 • Livingston B, Bonner A, Pope J. Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis. Lupus. Nov 2011;20(13):1345-55. [Medline] • American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Available at http://tinyurl.com/1997SLEcriteria. Accessed March 15, 2012

50. Thank You