Connecting The Connective Tissue Disorders Lupus, Mixed Connective Tissue Disorder

1. Connecting The Connective Tissue Disorders ( Lupus, Mixed Connective Tissue Disorder) Joseph Cleaver M.D. Director of Clinical Research The Cooper Institute Staff Physician Cooper Clinic, Dallas Texas Medical Director Optimum Re Insurance

2. Autoimmmune or Connective Tissue Disorders An illness that occurs when the body is attacked by its own immune system. The body’s immune system malfunctions and produces large amounts of harmful substances called autoantibodies. Autoantibodies, unlike normal antibodies that target foreign invaders such as viruses and bacteria, attack the bodies own tissue and cells.

3. Autoantibodies Autoantibody-mediated inflammation and cell damage and destruction can affect blood cells, skin, joints, kidneys, lungs, nervous system, and other organs of the body.

4. Development of Autoimmunity

5. ANA Blood Test The ANA (antinuclear antibodies test) is commonly used as a screening test in patients suspected of having an autoimmune or connective tissue disorder. The ANA is directed against components of the cell nucleus. ANAs are characteristic of SLE and are found in more than 95% of LUPUS patients.

6. ANA patterns

7. ANA Patterns Homogeneous – SLE, rheumatoid arthritis, normal subjects (low titer) Peripheral – SLE – highly specific Speckled – SLE, Sjogrens, Scleroderma, other autoimmune disorders, normal subjects (low titer) Nucleolar – Scleroderma, Raynaud’s Syndrome

8. ANA – Low titer? High titer? Low - < 1:80 - no signs or symptoms – good prognosis High titer >1:640 – no signs or symptoms risk for underlying autoimmune disease increased With significant clinical evidence of autoimmune disease, the ANA becomes a supporting criteria for the diagnosis at any titer. So, an ANA 1:160 in a pt. with joint swelling, butterfly rash, fatigue, and a low white count is significant!

9. ANA Diagnostic Significance SLE – 95% Scleroderma – 85% MCTD – 93% Poly/Dermatomyositis- 61% Rheumatoid arthritis – 33% Sjogren’s – 48% Drug induced lupus – 100% Discoid lupus – 15% Pauciarticular Juvenile Chronic arthritis – 71% Hashimoto’s thyroiditis – 46% Graves Disease – 50% Autoimmune hepatitis – 63 % PBC 10% Autoimmune cholangitis – 100% PAH – 40% Infections, hepatitis, TB, HIV, some cancers False positives – 1:40 up to 32% of pop.

10. Systemic Lupus Erythematosus

11. Systemic Lupus Erythematosis SLE is a prototypic autoimmune disease. Production of antibodies to the components of the cell nucleus It is chronic It is a multisystem disorder. Young women ages 15 to 40. Prognosis depends upon disease activity and the severity and type of organ involvement.

12. Diagnosis of SLE

13. Organ Involvement Skin – malar rash, discoid rash Arthritis - non-erosive arthritis Hematologic – hemolytic anemia, thrombocytopenia, leukopenia. Cardiac - myocarditis CNS - seizures, psychosis, cerebritis, stroke. Renal - proteinuria, glomerulonephritis

14. Pathogenesis of SLE

15. The Phases of SLE

16. Autoantibodies Precede Disease By Years

17. Autoantibodies

18. Concordance For SLE In Twins

19. Evidence that SLE is Influenced by Sex Hormones 9:1 female: male ratio in child-bearing years Nurses’ Health Study showed increased RR for SLE in women on HRT or OC. Treating women with SLE with HRT increases flares (OCP do not) Metabolism of E and A may be altered in women and men with SLE. Elevated levels of prolactin in some. Some mouse models influenced by E/A.

20. Systemic Lupus Erythematosus Disease activity refers to degree of inflammation Severity refers to impairment of organ function. (Brain, kidney, lung, heart, blood, joints)

21. Disease Activity Disease activity is determined using a combination of clinical history, physical exam, specific functional tests , and serological studies.

22. Disease Activity-Serological Studies Anti-double-stranded DNA titers (increases) Complement levels (CH50, C3, C4), (decrease) ESR (increase) CRP (increase) Complement split products (increase) ? Complement C1q (decrease)

23. Severity of Disease Number of organ involved Kidney Brain Myocarditis Inflammatory arthritis Hemolytic anemia Pneumonitis

24. Significance of Autoantibodies in SLE

25. Prognosis Female sex Younger age at presentation Poor socioeconomic status African American Hypertension Renal disease (especially diffuse proliferative glomerulonephritis Presence of antiphospholipid antibodies Antiphospholipid syndrome High overall disease activity

26. Mortality in SLE

27. Mortality- 1,000 patients -10 years Most disease activity in first five years. Deaths were divided between: Active SLE (26.5%) Thrombosis, stroke (26.5%) Infections (25%) Renal involvement 88% survival vs 94% survival at 10 years. Conclusion: most inflammatory manifestations less common after first five years.

28. Renal Involvement Increases Mortality

29. Lupus Nephritis LN is thus divided into 6 classes according to severity of the lesions observed[16]: Class I, minimal mesangial LN; Class II, mesangial proliferative LN; Class III, focal LN; Class IV, diffuse segmental LN; Class V, membranous LN; and Class VI, advanced sclerosing LN.

30. Mortality in SLE 9547 patients, 23 centers Overall SMR = 2.4 Highest SMR Duration < 1 year Female sex Black/ African American Younger age

31. Mortality in SLE

32. Case 1 Female, age 32 Moved to Dallas with her son after divorce 03.01.02 Hx of Fatigue and fibromyalgia 09.12.02 –headache, fatigue, ch. Pain, with malar rash (sun exposure), Raynaud’s phenomenon, and ANA 1:80 speckled. r/o CTD SLE vs MCTD Treating MD - “Very possible she has CTD” Prednisone 40 mg daily Referred to Rheumatology

33. Case 1 10.11.02 – headache, urticaria ANA 1:160 Speckled Double stranded negative RNP and SM negative Complements normal CBC with diff. –normal HOS – normal ESR - 20 “I would like to leave lupus a DX of last resort, even with a + ANA”. “It may be this is Lupus, but I want to r/o everything else first. “Leave her on Prednisone for now”.

34. Case 1 1903 - Dx of depression treated with psychotherapy with good response. 1904 – Fatigue, exhausted, depression treated with Zoloft.

35. Diagnosis of SLE

36. Case 1 + ANA. 1:160 speckled Rash Raynauds Fatigue Depression (CNS)

37. Case 2 18 year old male develops spiking fevers, chest pain, and butterfly rash while on spring break in Daytona Beach Fl. On exam, he has swelling of his feet. Laboratory results WBC = 3.1, H/H = 9/29. Creatinine = 3.4 HOS – numerous RBC casts, protein 3+ ANA 1:1280 homogeneous pattern

38. Case 2 Treated with Cytoxan and Prednisone pulse. Pt. renal function returns with normal in 4 weeks, creatinine clearance and normal BUN/CR, and HOS. Renal disease in remission for 4 years. APS – occasional visits to PCP for arthritic pain and rash treated with NSAIDS.

39. Case 2 Risk assessment +ANA Butterfly rash photosensitivity Renal failure Serositis Hematologic – anemia, leukopenia

40. Case 3 27 year old female develops persistent polyarthralgias since 2004. Otherwise normal exam and no constitutional symptoms treated with NSAIDS. ANA = 1:80 homogeneous pattern. Rheumatoid factor is negative. August 2008 applies for life insurance. What else to do want to know?

41. Case 3 CBC is normal HOS is normal LFTs normal Rheumatoid factor normal.