Title: Connecting The Connective Tissue Disorders Lupus, Mixed Connective Tissue Disorder
1Connecting 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
2Autoimmmune or Connective Tissue Disorders
- An illness that occurs when the body is attacked
by its own immune system. - The bodys 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.
3Autoantibodies
- Autoantibody-mediated inflammation and cell
damage and destruction can affect blood cells,
skin, joints, kidneys, lungs, nervous system, and
other organs of the body.
4Development of Autoimmunity
5ANA 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.
6ANA patterns
homogeneous
peripheral
speckled
nucleolar
7ANA 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, Raynauds Syndrome
8ANA Low titer? High titer?
- Low - lt 180 - no signs or symptoms good
prognosis - High titer gt1640 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 1160 in a pt. with joint swelling,
butterfly rash, fatigue, and a low white count is
significant!
9ANA Diagnostic Significance
- SLE 95
- Scleroderma 85
- MCTD 93
- Poly/Dermatomyositis- 61
- Rheumatoid arthritis 33
- Sjogrens 48
- Drug induced lupus 100
- Discoid lupus 15
- Pauciarticular Juvenile Chronic arthritis 71
- Hashimotos thyroiditis 46
- Graves Disease 50
- Autoimmune hepatitis 63
- PBC 10
- Autoimmune cholangitis 100
- PAH 40
- Infections, hepatitis, TB, HIV, some cancers
- False positives 140 up to 32 of pop.
10Systemic Lupus Erythematosus
11Systemic 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.
12Diagnosis of SLE
- Malar rash
- Discoid rash
- Photosensitivity
- Oral ulcers
- Arthritis-nonerosive 2 or more joints-inflammatory
- Serositis
- Renal disorder-proteinuria gt0.5gm/dl or casts
- Neurologic-seizures, psychosis
- Hematologic-leukopenia, lymphopenia, low
platelets - Immunologic anti-ds DNA, anti-Sm,
antiphospolipid ab - ANA
- 1997 Criteria - 4 of 11 TO DIAGNOSE SLE
13Organ 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
Cardiac, CNS, Renal involvement have worst
prognosis
14Pathogenesis of SLE
15The Phases of SLE
Genetic Predisposition Gender Environmental
stimuli start Immune Responses Autoantibodies
Appear Regulation of the Autoantibodies Fails
Clinical disease Chronic inflammation
and progressive damage
16Autoantibodies Precede Disease By Years
Some AutoAbBefore Dx 88
ANA 3 yrs Anti-Ro/La
Anti-DNA 2 yrs
ANTI-Sm anti-RNP
Arbuckle et al NEJM 2003
17Autoantibodies
18Concordance For SLE In Twins
MONOZYGOTIC 24-69 DIZYGOTIC
2-9 Risk for Sibling of SLE 10-20
19Evidence that SLE is Influenced by Sex Hormones
- 91 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.
20Systemic Lupus Erythematosus
- Disease activity refers to degree of inflammation
- Severity refers to impairment of organ function.
(Brain, kidney, lung, heart, blood, joints)
21Disease Activity
- Disease activity is determined using a
combination of clinical history, physical exam,
specific functional tests , and serological
studies.
22Disease 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)
23Severity of Disease
- Number of organ involved
- Kidney
- Brain
- Myocarditis
- Inflammatory arthritis
- Hemolytic anemia
- Pneumonitis
24Significance of Autoantibodies in SLE
25Prognosis
- 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
26Mortality in SLE
27Mortality- 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.
Cervera, R Medicine, 2003
28Renal Involvement Increases Mortality
Cervera R, Medicine, 2003
29Lupus Nephritis
- LN is thus divided into 6 classes according to
severity of the lesions observed16 - 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.
30Mortality in SLE
- 9547 patients, 23 centers
- Overall SMR 2.4
- Highest SMR
- Duration lt 1 year
- Female sex
- Black/ African American
- Younger age
Bernatsky Arthritis Rheum 2006, Aug54 (8) 2550-7
31Mortality in SLE
32Case 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), Raynauds phenomenon, and
ANA 180 speckled. - r/o CTD SLE vs MCTD
- Treating MD - Very possible she has CTD
- Prednisone 40 mg daily
- Referred to Rheumatology
33Case 1
- 10.11.02 headache, urticaria
- ANA 1160 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.
34Case 1
- 1903 - Dx of depression treated with
psychotherapy with good response. - 1904 Fatigue, exhausted, depression treated
with Zoloft.
35Diagnosis of SLE
- Malar rash
- Discoid rash
- Photosensitivity
- Oral ulcers
- Arthritis-nonerosive 2 or more joints-inflammatory
- Serositis
- Renal disorder-proteinuria gt0.5gm/dl or casts
- Neurologic-seizures, psychosis
- Hematologic-leukopenia, lymphopenia, low
platelets - Immunologic anti-ds DNA, anti-Sm,
antiphospolipid ab - ANA
- 1997 Criteria - 4 of 11 TO DIAGNOSE SLE
36Case 1
- ANA. 1160 speckled
- Rash
- Raynauds
- Fatigue
- Depression (CNS)
37Case 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 11280 homogeneous pattern
38Case 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.
39Case 2
- Risk assessment
- ANA
- Butterfly rash
- photosensitivity
- Renal failure
- Serositis
- Hematologic anemia, leukopenia
40Case 3
- 27 year old female develops persistent
polyarthralgias since 2004. Otherwise normal
exam and no constitutional symptoms treated with
NSAIDS. - ANA 180 homogeneous pattern.
- Rheumatoid factor is negative.
- August 2008 applies for life insurance.
- What else to do want to know?
41Case 3
- CBC is normal
- HOS is normal
- LFTs normal
- Rheumatoid factor normal.