Connecting The Connective Tissue Disorders Lupus, Mixed Connective Tissue Disorder

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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

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Autoimmmune 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.
  

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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.

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Development of Autoimmunity
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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.

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ANA patterns
homogeneous
peripheral
speckled
nucleolar
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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, Raynauds Syndrome

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ANA 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!

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ANA 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.

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Systemic Lupus Erythematosus
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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.

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Diagnosis 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

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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

Cardiac, CNS, Renal involvement have worst
prognosis
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Pathogenesis of SLE
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The 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
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Autoantibodies 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
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Autoantibodies
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Concordance For SLE In Twins
MONOZYGOTIC 24-69 DIZYGOTIC
2-9 Risk for Sibling of SLE 10-20
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Evidence 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.

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Systemic Lupus Erythematosus

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

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Disease Activity

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

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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)

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Severity of Disease

• Number of organ involved
• Kidney
• Brain
• Myocarditis
• Inflammatory arthritis
• Hemolytic anemia
• Pneumonitis

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Significance of Autoantibodies in SLE
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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

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Mortality in SLE
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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.

Cervera, R Medicine, 2003
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Renal Involvement Increases Mortality
Cervera R, Medicine, 2003
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Lupus 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.

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Mortality 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
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Mortality in SLE
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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), 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

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Case 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.

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Case 1

• 1903 - Dx of depression treated with
  psychotherapy with good response.
• 1904 Fatigue, exhausted, depression treated
  with Zoloft.

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Diagnosis 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

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Case 1

• ANA. 1160 speckled
• Rash
• Raynauds
• Fatigue
• Depression (CNS)

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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 11280 homogeneous pattern

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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.

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Case 2

• Risk assessment
• ANA
• Butterfly rash
• photosensitivity
• Renal failure
• Serositis
• Hematologic anemia, leukopenia

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Case 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?

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Case 3

• CBC is normal
• HOS is normal
• LFTs normal
• Rheumatoid factor normal.