This document provides an overview of systemic lupus erythematosus (SLE), an autoimmune disorder characterized by inflammation of multiple organ systems. It discusses the epidemiology, etiology, clinical manifestations, diagnostic criteria, treatment approaches, and new developments for SLE. Key points include that SLE affects multiple organ systems, is associated with various autoantibodies, and treatment involves managing symptoms, preventing flares and organ damage through immunosuppression and addressing traditional cardiovascular risk factors.

1. SYSTEMIC LUPUS ERYTHEMATOSIS GEETA KATWA M.D., FACP. Clinical Associate Professor Division of Rheumatology Dept. of Internal Medicine Brody School of Medicine – ECU March 2010

2. Systemic Lupus Erythematosus SLE is an chronic autoimmune disorder characterized by inflammation of many organ systems HALLMARK- Diversity Mild, severe to life threatening Severe morbidity and mortality Unifying laboratory abnormality-ANA Ginzler EM, Rheum Dis Clin North Am 1988;14: 67-78. Boumpas DR. Ann Int Med 1995;123:42-53

3. 13 th century- Rogerices- Lupus “wolf” 1846- “C lassical” period- Ferdinand von Hebra- malar rash 1872- “Neoclassical”period – Moriz Kaposi- Lupus a systemic disease 1903- Osler & Jadassohn- firmly established systemic form 1909- Reinhart & Hauck- false +ve test for Syphilis 1923- Libman-Sacks Endocarditis in SLE 1935- Bachs- typical glomurular changes

4. Mordern Era 1948- Hargraves- LE cell 1950- Friou (USA) & Holbora (UK) ANA 1950-1960’s- Dr Hughes- Sticky blood

5. Demographics Incidence: 7/100,000/yr Peak incidence: 15 & 40 yrs of age Prevalence: 1 in 2000 Adult female:male - 6 to 10:1 Children & older pts female: male – 3:1 Race: African Americans female : 1/250 Influence of heredity : Monozygotic concordance>>dizygotic

6. Etiology & Pathogenesis Unknown Sex steroids Monozygotic twins-concordance-30%, dizygotic twins & siblings-5% Environmental risk factors HAL-B8, DR2, DR3 Complement deficiency

7. SLE: PREDISPOSING FACTORS 10% have affected first- or second-degree relatives Sibs 2%, Dizygotic twins 3%, Monozygotic twins 34% HLA-DR2, HLA-DR3, XX Deficiencies in early complement components: C1q, C1r-C1s, C2, C4 C4a null alleles-deficiency high risk for SLE, Deficient C3b/C4b receptors Candidate genes-Classical complement, Fc gamma R, C-reactive protein,MHC, gene influencing the program cell death

8. Pathology Inflammation, vasculopathy, vasculitis, & immune-complex deposition Pathogenic autoantibodies Self antigens implicate immune cell dysfunction- B-cell hyperactivity Genetic susceptibility - polygenic Triggering events for SLE initiation & flares

10. ACR Criteria for Classification of SLE

11. PITFALLS IN DIAGNOSING SLE 25 yo woman, pain all over, fatigue. Tender points over tendon insertions. FANA +. 35 yo woman, Raynaud’s phenomenon. Small ulcer tip of R 5 th finger. FANA +. 50 yo man, no signs/sx of SLE. Cr 3. Renal biopsy proliferative glomerulonephritis. 60 yo woman, erythema upper chest and back with red, scaly rash over extensor surfaces of MCP, PIP, and DIP joints. 30 pound weight loss. FANA +. 69 yo woman, joint pain. Thin scalp hair, erythema and prominent small vessels over nose and cheeks. FANA +.

12. Manifestations of SLE USUAL Fever Joint & muscle pain Skin Cognitive impairment Positive FANA High anti-DNA Low serum complement LESS USUAL Pleurisy Lymphadenopathy Pleural/pericardial effusion Anemia, Leukopenia Anti-phospholipid Ab High immunoglobulin Proteinuria

13. Organ systems involved More common Mucocutaneous Musculoskeletal Renal Nervous system Cardiovascular Pleura and Lungs Less common Gastrointestinal tract Liver Ocular System

14. Autoantibodies in SLE FANA ANTI-DS DNA ANTI-Sm SPECIFIC + ++++ ++++ COMMON ++++ +++ +

15. Conditions associated with ANA Other rheumatic diseases-RA, Sjogren’s syndrome, Scleroderma, Myositis Drug induced Hepatic-chronic hepatitis, Primary biliary cirrhosis Infections Malignancy Neurologic- multiple sclerosis Hematologic-Immune thrombocytopenic purpura, hemolytic anemia Endocrine- Thyroid disease, DM Pulmonary- pulmonary fibrosis, IDL

16. Malar Rash Butterfly rash Involves cheeks and nose Patient also has rash on chin and some telangiectasia Systemic lupus erythematosus

17. Interarticular dermatitis Also has periungual erythema This rash is distinct from that seen in dermatomyositis that occurs over the joints Systemic lupus erythematosus

18. Annular Subtype

19. Annular Subtype

20. Papulosquamous Subtype

23. Discoid lupus

26. Musculoskeletal Manifestations Arthralgias/arthritis Jaccoud’s arthropathy Myalgias Inflammatory myositis Osteonecrosis Fibromyalgia

28. Renal- You are the EXPERT Urinary neutrophil gelatinase- associated lipocalin (uNGAL) as a novel biomarker for disease activity in lupus nephritis ( Rheumatology: February 9, 2010)

30. CNS MANIFESTATIONS OF SLE Headache Aseptic meningitis/ encephalitis Psychosis and severe depression Generalized seizures Organic brain syndrome Focal disease- stroke syndromes, movement disorders & transverse myelitis Antibodies associated with CNS-SLE: antiphospholipid, antineuronal & ant-P antibodies

31. HEART AND SLE Pericarditis Myocarditis Valvular disease ( Libman-Sacks atypical verrucous endocarditis ) Vasculitis Accelerated atherosclerosis Hypertension & hypercholesterolemia

32. SLE & Atherosclerosis Atherosclerosis occurred prematurely in pt with SLE & independent of traditional risk factors for SLE Plaque was independently associated with age, long disease duration & less frequent with use of cytoxan and HOCl. (Roman MJ, N engl J Med 2003;349:2399-2406) SLE pt had higher coronary Ca scores independent of other risk factors Coronary artery calcification at younger ages than controls (Asanuma Y, J Rheumatol 2006;33:539-545)

33. Atherosclerosis in SLE Prompt and aggressive Rx Risk factor management Address traditional CV risk factor Elevated homocysteine-Rx with folic acid Hydroxchloroquine ASA

34. Acute presentation A 25 yr hispanic female presents dizziness, fatigue, myalgias and SOB. PE: pale, lethargic, mildly dyspnic, and bilateral crackles Labs: Hb- 6.0 mg/dL, UA- normal, ANA-1:1280, positive anti ds-DNA, CT Chest and bronchoscopy done

35. Diagnosis? CT chest showed bilateral alveolar infiltrates Bronchoscopy – pulmonary hemorrhage with few inflammtory cells. Treatment – high doses of steroids initially followed by Cytoxin.

36. PULMONARY MANIFESTATIONS IN SLE Pleuritis & pleural effusion Pneumonitis Pulmonary hemorrhage Pulmonary embolism Pulmonary HTN Shrinking lung syndrome Chronic interstitial lung disease/fibrosis Secondary infections

37. ALVEOLITIS

38. PULMONARY FIBROSIS

39. SHRINKING LUNG SYNDROME Also called “Vanishing Lung Syndrome” Suspect this dx in individuals presenting dyspnea, persistent episodes of pleuritic chest pain, a progressive decrease in lung volume, with no evidence of interstitial fibrosis or pleural disease on Chest CT, but elevated diaphragms Pathogenesis: Uncertain

40. Hematologic Abnormalities Anemia Leukopenia ( lymphopenia) Thrombocytopenia Severe thrombocytopenia (5%) Thrombocytopenia associated with APS Elevated ESR and C-reactive protein

41. Antibodies associated with SLE Anti-dsDNA (50-70%) Anti-Sm Ab (30-40%) Anti-RoSSA (20-60%) Anti-LaSSB (15-40%) Antiphospholipid (50%) Anti-RNP (30-40%) Antiribosmal P protein Anti-Histone Ab – epitope of glutamate/N-methyl-D-aspartic acid receptors Glomerulonephritis IDL, GN, CNS disease SCLE, SS, Neonatal lupus SCLE, SS, neonatal lupus Arterial & venous thrombosis, fetal loss SLE & MCTD Psychosis, depression SLE & Drug induced SLE Neuropsychiatric

42. Autoantibodies Diffuse: DNA - low titer = non-specific Histones – Drug-induced lupus Peripheral: ds-DNA -50% of SLE specific Speckled: Sm -30% 0f SLE specific Ro (SSA) – SLE, Sjogren’s 60%, Neonatal La (SSB) - SLE 15%, Sjogren’s 50% Cytoplasmic: Ro, ribosomal P - SLE psychosis Cardiolipin – Thrombosis, abortion, thrombocytopenia

44. Drug induced SLE Procainamide Hydralzine Quinidine Sulfasalazine Minocycline Isoniazid Chlorpromazine TNF inhibitors

45. TREATMENT Patient education Identify & treat conditions that contribute to fatigue Adequate rest & energy conservation Avoid sunlight, routine use of sunscreen & protective clothing Immunizations Minimize the risk factors for premature CAD Effective birth control.

46. TREATMENT (cont.) NSAID’s Corticosteroids Antimalarials Thalidomide Azathioprine Cyclophosphamide Methotrexate Cyclosporine Mycophenylate Mofetil

47. “ Ideal” immunomodulatory Rx HOCl-rebirth (pleiotrophic effects) Prevents severe flares Reduces the risk of nephritis Organ damage Cardiovascular risk factors-lipid profile Thrombosis Survival

48. When should immunosuppressive Rx be added to minimize prednisone use ? ( J. Rheumatol.2009;36:560-4 ) Hopkins Lupus Cohort (525 pt’s) Cumulitive dose of prednisone(0-180mg/mth)- hazard ratio, 1.16 Dose of180-360 mg/mth- hazard ratio,1.50 Dose of 360-540 mg/mth- harzard ratio, 1.64 Dose of >540 mg/mth- harzard ratio, 2.51 (risk of organ damage)

49. INDICATIONS FOR HIGH DOSE STEROIDS Severe lupus nephritis CNS lupus with severe manifestation Autoimmune thrombocytopenia(<30,000) Autoimmune hemolytic anemia Acute pneumonitis Severe vasculitis with visceral organ involvement

50. Mycophenolate Motefil Trial Schanz S, et al. Successful treatment of subacute cutaneous lupus erythematosus with mycophenolate mofetil. Br J Dermatol. 2002 Jul;147(1):174-8.

51. Mycophenolate Motefil Trial Schanz S, et al. Successful treatment of subacute cutaneous lupus erythematosus with mycophenolate mofetil. Br J Dermatol. 2002 Jul;147(1):174-8.

52. New Developments in SLE Landscape B-cell depletion - Rituximab, Epratuzumab (J. Rheumatol 2008 May; 35(5):826 ) Inhibition of B-cell survival – Belimumab (LymphoStat-B) B-cell-specific Toleragen: Abestimus Na (LJP 394) decreases ds-DNA Inhibition of Costimulatory Interaction- Abatacept & RG2077 Cytokine blockade- anti TNF alpha, Ab against IL-10, IL-6, IFN-alpha modulation

53. Conclusions SLE is a compositeof clinically unrelated manifestations, acummulates overtime associated with autoantibodies Greater awareness to both physician & pt Physicians maintain high vigilance Accurate prediction of flares & premptive treatment Search for biomarkers & biologic offers promise