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. .
1. Connecting The Connective Tissue Disorders ( Lupus, Mixed Connective Tissue Disorder) Joseph Cleaver M.D.
Director of Clinical Research
The Cooper Institute
Cooper Clinic, Dallas Texas
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%
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 %
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
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)
Complement split products (increase)
? Complement C1q (decrease)
23. Severity of Disease Number of organ involved
24. Significance of Autoantibodies in SLE
25. Prognosis Female sex
Younger age at presentation
Poor socioeconomic status
Renal disease (especially diffuse proliferative glomerulonephritis
Presence of antiphospholipid antibodies
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%)
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:
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
Duration < 1 year
Black/ African American
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
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
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.
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
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.
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What else to do want to know?
41. Case 3 CBC is normal
HOS is normal
Rheumatoid factor normal.