Transcript SLE jacobi july2009

Case Report
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A 44-year-old African-American woman presented with
complaints of worsening dyspnea and chest discomfort
for several months
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Review of systems revealed long-standing dyspnea on
exertion, orthopnea, and paroxysmal nocturnal
dyspnea.
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Physical exam was significant for JVD, decreased
breath sounds in the lung bases, tachycardia, and lower
extremity edema to the knees. Notably, the exam was
lacking rales and an S3 gallop.
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Differential Diagnosis?
Chest radiograph revealed an enlarged cardiac sillouette and bilateral
pleural effusions (Figure 1).
Bedside echocardiography revealed a pericardial effusion
(Figure 2).
Data
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Laboratory findings included a macrocytic anemia
(MCV 114.6 fL, HCT 22.2%) with a high corrected
reticulocyte count (14.5) and normal B12 and folate
levels.
Auto-immune hemolytic anemia was confirmed by a
decreased haptoglobin (<14 mg/dL), an elevated LDH
(1411 U/L), and the detection of a warm IgG autoantibody.
ANA testing revealed a 160 titer and an anti-DNA DS
level of 101 IU. Right heart catheterization revealed
tamponade physiology.
Discussion
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This case represents a rare presentation in a patient with SLE.
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The patient's symptoms were secondary to both tamponade and hemolytic
anemia, perhaps two of the most morbid of the diagnostic criteria.
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The eventual diagnosis may have been delayed were it not for careful
attention to the physical exam and prompt diagnostic testing to validate
those findings.
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Standard treatment for congestive heart failure based solely on reported
symptoms would have greatly increased her morbidity, and could have
been fatal.
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This case emphasizes the importance that our history AND physical
examinations guide our diagnostic and therapeutic measures.
Systemic Lupus
Erythematosus
July 13, 2009
Julie Schwartzman, MD
Associate Program Director, Rheumatology
Director of Arthritis and Lupus Clinics
SLE: Subsets
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Discoid LE
Drug Induced SLE
Neonatal SLE
Antiphospholipid Syndrome
SLE
Benign, incomplete
 Subacute cutaneous, ANA negative, Ro + lupus
 DNA positive, complement fixing,
hypocomplementic
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Drug Induced SLE
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Hydralazine
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Procainamide
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Minocycline (ANCA+)
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Chlorpromazine
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Isoniazid
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Penicillamine
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Methyldopa
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Interferon-alpha
SLE: Demographics
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Affects .5 million (.2%) vs 1.5 million (.6%) of US
population (epidemiologic vs LFA random digit dialing
telephone survey)
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Female:Male ratio of 10:1
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Closer to 2:1 during childhood and after menopause, suggesting
hormonal influence
Disease in males is often more severe
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70% of SLE: females between ages 15-45
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African American to Caucasian ratio 3:1
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Highest prevalence in Afro-Caribbean females 1:250
Demographics
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Genetic factors HLA-A1, B8, Dr3 - C4A null genes - Fc
receptor polymorphisms -gene linked to chromosome 1
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Environmental factors - Concordance for monozygotic twins
is 30% (70% of genetically identical twins will not share the
disease)
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Child of SLE mother risk of SLE 1:15 (7%)
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ANA positive in 5-20% of population. 10 times more likely
to have false positive ANA than disease
Null alleles that cause a deficiency of one of the
early complement components — C1q, C2, or C4
— are a strong risk factor for lupus.
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Family studies have identified genes that are more
likely to occur in patients with lupus than in their
healthy relatives.
Many of these genes encode components
of the immune system.
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SLE: ETIOLOGY
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AUTOANTIBODY PRODUCTION
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GENERATION OF CIRCULATING
IMMUNE COMPLEXES
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EPISODIC COMPLEMENT
ACTIVATION
SLE: Pathobiology
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Autoantibodies (AIHA, AITP, Anti-neuronal antibody,
APS)
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Immune complex disease (microangiitis and vasculitis)
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Neutrophil and endothelial cell adhesive interaction with
leukoaggregation
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Thrombophilia: Antibody mediated thrombosis in
secondary APLS with micro and macrovascular noninflammatory occlusion
SEROLOGY
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ANA (Titer and pattern: diffuse, speckled, rim,
nucleolar, centromere)
double stranded-DNA- highly specific, correlates with disease
activity
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Sm- highly specific for SLE, no correlation with disease activity
RNP- also seen in MTCD/UCTD
Ro (SS-A)/La (SS-B)- neonatal lupus, SS, subacute cutaneous
lupus, photosensitivity (Ro)
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C3
C4
POSITIVE ANA
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SLE
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Non SLE CTD (RA, SS, PSS, CREST, DM/PM)
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DRUG-INDUCED
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NORMALS (FALSE POSTIVE)
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LYMPHOPROLIFERATIVE DISORDER
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CHRONIC INFECTION (HIV, Leprosy)
1982 ACR Classification Criteria
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Malar rash
Discoid rash
Photosensitivity
Oral ulcers
Arthritis
Serositis
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Renal disorder
Neurologic disorder
Hematologic disorder
Immunologic disorder
Anti-nuclear antibody
Require four simultaneously or serially
Mucocutaneous Manifestations
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* Malar rash
* Discoid rash
* Photosensitivity
*Oral ulcers
Vasculitis
Periungual erythema
Alopecia
(*classification criteria)
“Butterfly” or Malar Rash
1. Malar rash: Fixed erythema, flat or
raised, over the malar eminences, tending to
spare the nasolabial folds
Discoid Rash
2. Discoid rash:
Erythematous
raised patches with
adherent keratotic
scaling and
follicular plugging;
atrophic scarring
may occur in older
lesions
IgG Deposition at Dermo-epidermal Junction in Discoid Lupus
Photosensitivity
“allergic to the sun”
3. Photosensitivity: Skin rash as a result of
unusual reaction to sunlight, by patient history or
physician observation
Oral Ulcers
4. Oral ulcers: Oral or
nasopharyngeal ulceration, usually
painless
Subacute Cutaneous Lupus Erythematosus
Left, Papulosquamous lesions are characterized by erythematous scaling papules and plaques that
resemble psoriasis. The distribution in light-exposed areas suggests photosensitivity.
Right, The annular polycyclic lesions have an erythematous, slightly scaling border with central
clearing.
Cutaneous Vasculitis with Infarcts
Alopecia
Arthritis
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5. Arthritis: Non-erosive arthritis involving 2 or more
peripheral joints, characterized by tenderness, swelling, or
effusion
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80%
Single or multiple joints
Reducible deformities
Pain may be out of proportion with appearance
Jaccoud’s arthritis
Serositis
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6. Serositis
a) Pleuritis--convincing history of pleuritic pain or rubbing heard by a
physician or evidence of pleural effusion
 OR
b) Pericarditis--documented by ECG or rub or evidence of pericardial
effusion
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Peritonitis - diffuse abdominal pain, nausea and
vomiting, ascites is rare
Lupus Serositis
Pleuritis
Chest X-ray
Peritonitis
Abdominal X-ray
Pericarditis
Chest X-ray
Renal
7. Renal disorder
a) Persistent proteinuria greater than 0.5 grams per day
OR
b) Cellular casts--may be red cell, hemoglobin, granular,
tubular, or mixed
Lupus Nephritis
(WHO Classification)
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I Normal glomeruli
a) Nil by all techniques
b) Normal by light but deposits on EM or IF
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II Mesangial nephritis
III Focal glomerulonephritis
IV Diffuse proliferative glomerulonephritis
V Membranous nephritis
VI Membranoproliferative glomerulonephritis
VII Advanced sclerosing glomerulonephritis
Lupus Nephritis (light microscopy)
Mesangial nephritis
Diffuse proliferative glomerulonephritis
Focal glomerulonephritis
Membranous glomerulonephritis
Lupus Nephritis (immunofluorescent staining)
Staining with anti-Ig FITC
Lupus Nephritis (Electron Microscopy)
A – subepithelial deposits
B – intramembranous deposits
C – basement membrane
D – epithelial foot processes
Neurologic disorder
8. Neurologic disorder
a) Seizures--in the absence of offending drugs or known metabolic
derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance
OR
b) Psychosis--in the absence of offending drugs or known metabolic
derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance
Neuropsychiatric Lupus
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Seizures
Psychosis
Headache
Coma
Dementia
Aseptic meningitis
Chorea
Ataxia
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Depression
Cranial neuropathy
Peripheral neuropathy
Mononeuritis multiplex
Stroke syndrome
Transverse myelitis
SLE Brain
gross specimen
photomicrograph
fibrin thrombus
leukoaggregation
Left, Gross specimen reveals multiple cerebral infarctions.
Right, Photomicrograph demonstrates occlusion of small vessels by both leukoaggregation
(A) and a fibrin thrombus (B) as the causes of the infarctions. Vasculitis was not found
Hematologic Manifestations
9. Hematologic disorder
a) Hemolytic anemia--with reticulocytosis
OR
b) Leukopenia--less than 4,000/mm on 2 or more occasions OR
c) Lymphopenia--less than 1,500/mm on 2 or more occasions OR
d) Thrombocytopenia--less than 100,000/mm in the absence of offending drugs
10. Immunologic disorder
a) Anti-DNA OR
b) Anti-Sm OR
c) Positive finding of antiphospholipid antibodies
11. ANA: in the absence of drugs known to be associated with "drug-induced
lupus" syndrome
Classification Criteria
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4/11 criteria >90% sensitivity and specificity
Criteria designed for classification, especially for
entrance into laboratory studies and clinical trials
but not for diagnosis
For mild and early disease may not be as
sensitive
Examples: patient with malar rash and +ANA
patient with GN, +ANA and elevated dsDNA Abs
Mortality
90% survive 5 years, 80% 10 years
 Worse if renal disease
 AA more aggressive and treatment resistant
disease
 Bimodal distribution of etiology
Early: disease activity and infection
Late: disease activity, ESRD,
arteriosclerotic and thromboembolic
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CAD in SLE
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Risk is 10-times increased in SLE patients, 50-times increased in SLE
pts 35-44 yrs old
Factors contributing to increase:
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Steroid therapy
Hyperlipidemia
HTN
Smoking
Coagulation abnormalities
Homocystinemia
Obesity
Vasculopathy from Immune Injury>>increased circulating endothelial cells
activation
*All modifiable risk factors are important targets of intervention
by both PMD and Rheum MD
APLS
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The anti-phospholipid Ab syndrome (APS) is vascular
thrombosis and/or pregnancy morbidity developing in
persistently anti-phospholipid antibody (aPL)-positive
individuals.
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The most commonly used aPL tests are the lupus
anticoagulant test, the anti-cardiolipin antibody ELISA,
and/or the anti- b2-glycoprotein I ELISA.
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APS is present if more than 1 clinical and 1 lab criteria met
ANTIPHOSPHOLIPID SYNDROME
Sapporo Criteria, Sydney revision
Miyakis, J Thromb Haemost. 2006 4:295-306
Clinical
• Thrombosis: one or more confirmed episodes:
venous, arterial or small vessel (exclude other
causes, male 55+ female 65+)
• Confirmed by imaging or Doppler or histopathology
and without evidence of inflammation in vessel wall
on histopathologic confirmation
ANTIPHOSPHOLIPID SYNDROME
Sapporo Criteria, Sydney revision
Miyakis, J Thromb Haemost. 2006 4:295-306
Clinical
• Pregnancy:
– one or more unexplained deaths >10 wk
– one or more pre-eclampsia/placental
insufficiency < 34 wk
– 3 or more unexplained consecutive
spontaneous abortions <10 wk
– exclude other causes
ANTIPHOSPHOLIPID SYNDROME
Sapporo Criteria, Sydney revision
Miyakis, J Thromb Haemost. 2006 4:295-306
Laboratory
• Medium/high IgG or IgM aCL, b2GP1
dependent on 2+ occasions 12 wk apart
• LAC 2+ occasions 12 wk apart
–prolonged PL-dependent screening test
–failure to correct with mixing
–shortening with excess PL
–exclusion of other coagulopathies
ANTIPHOSPHOLIPID SYNDROME
Sapporo Criteria, Sydney revision
Miyakis, J Thromb Haemost. 2006 4:295-306
aPL-associated findings (individual
diagnosis)
• cardiac valve disease
• livedo reticularis
• thrombocytopenia
• nephropathy
Current Recommendations
Vascular
Thrombosis prevention
{Asymptomatic aPL +
No treatment}
Venous thrombosis
Warfarin INR 2.0-3.0
Arterial thrombosis
Warfarin INR 3.0
Recurrent thrombosis
Warfarin INR 3.0-4.0+ASA
CAPS
Anticoagulation +
corticosteroid + IVIG or
plasmapheresis
Erkan, Lockshin, Rheum Dis Clin North Am 2006;32:129-48
Lim, Crowther, Eikelboom, JAMA 2006;295:1050-1057
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
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PREGNANCY
 ASA 81 mg, Prednisone 20-40 mg, sc Heparin, sc
LMWH (IVIG)
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CAPS (Catastrophic APS)
 Heparin, steroids, pheresis, IVIG, cytoxan
SLE: CLINICAL FEATURES
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CONSTITUTIONAL
CUTANEOUS
JOINTS
SEROSAL
CYTOPENIAS
RENAL
NEUROLOGIC
ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
TREATMENT
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Sunscreen
Topical Steroids
NSAIDs
Antimalarials
STEROIDS
CYTOTOXICS
Calcium, Vitamin D, Folate supplementation
INFLUENZA VACCINE (annual)
PNEUMOCCOCAL VACCINE (decade)
Treatment
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Avoid possible disease triggers: sulfa Rx, sun, high
estrogen
Prevent atherosclerosis
Prevent OP
Prevent clots in patients with APL Ab (not already on
AC): ASA, avoid unnecessary surgeries and vascular
catheterizations, avoid exogenous estrogen
Treat infections promptly
Treat fatigue: r/o hypothyroidism, metabolic
disturbances, myopathy, anemia, depression
Use of Steroid Therapy
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ACUTE LUPUS CRISIS
ACTIVE NEPHRITIS
ACUTE ACTIVE CNS
ACUTE CYTOPENIAS (AIHA,AITP)
REFRACTORY SEROSITIS
VASCULITIS
SEVERE CONSTITUTIONAL (fever, fatigue,
wgt loss, synovitis, anemia)
CYTOTOXIC THERAPY
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Azathioprine (Imuran): purine inhibitor, cytotoxic, decreases cell proliferation <
USES: nephritis, cytopenia>
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Methotrexate: inhib DHFR and DNA synthesis suppressing lymphocyte
proliferation, also down regulates inflammatory pathways by increasing extracellular
Adenosine (potent neut inhibitor) <USES: articular>
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Leflunomide (Arava): inhibits pyrimidine synthesis
 Steroid sparing (constitutional, serositis, immune cytopenias)
 Articular
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Mycophenolate mofetil (cellcept): inhibits lymphocyte production and
migration, <USES: Nephritis>
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Cyclophosphamide (cytoxan): alkylates DNA
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USES: Nephritis, CNS, immune cytopenias, vasculitis
CONSTITUTIONAL
SYMPTOMS
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Reassurance
Rest/exercise
NSAID
Antimalarials
Steroids (e.g. Prednisone < 0.25 mg/kg/day)
TCA/SSRI/Behavioral or cognitive therapy
Referral to Lupus Foundation, Support Groups
CUTANEOUS
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Sun avoidance/sunblock
Steroids (topical and intralesional)
Hydroxychloroquine (plaquenil)
Chloroquine (aralen)
Quinacrine (atabrine)
Dapsone
Retinoids (isotretinoin)
Clofazamine
Azathioprine
ARTICULAR
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NSAID
Antimalarials (HCQ, CQ)
Methotrexate
Azathioprine
Leflunomide
Steroids (e.g. Prednisone < .25 mg/kg/day)
HEMATOLOGIC (AIHA/AITP)
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Steroids (e.g. Prednisone 1 mg/kg/day;
Decadron 40 mg day x 4 days)
Danazol
Dapsone
Vincristine
Cyclophosphamide
Intravenous immunoglobulin (IVIG)
Pheresis
Rituximab
Splenectomy
CSF (Epogen, Neupogen)
SEROSITIS
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NSAID (e.g. Indomethacin)
Antimalarials (HCQ, CQ)
Steroids (e.g. Prednisone < .5 mg/kg/day)
Aspiration
VASCULITIS
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Steroids (e.g. Prednisone 1 mg/kg/day)
Cyclophosphamide
Plasmapherisis (especially TTP/HA)
Intravenous immunoglobulin (IVIG)
Nephritis
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Goals:
To induce remission with a stringent
immunosuppressive tx combining moderate to HD
GC and a cytotoxic drug, given for short period of
time (3-12 mo, induction phase)
 To achieve a response and
 To maintain this response in the long term by
prescribing a safer immunosuppressive Rx for a
longer period (5-10yrs, maintenance phase)
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Definition of Response, Nephritis
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Fair clinical response: 50% reduction of
proteinuria and stabilization of renal function
VS:
Complete remission – absence of proteinuria
and completely nl UA
Only 5-20% SLE pts experience complete
remission in 6mo
Current Management of Lupus
Glomerulonephritis
Steroids oral daily or QOD
Prednisone
Pulse solumedrol
Pulse cytoxan
Cyclophosphamide
Azathioprine
Cyclosporine
Methotrexate
Plasmapheresis  synchronized
Intravenous gammaglobulin
Mycophenolate mofetil
2 chlorodeoxyadenosine
Fludarabine
Recombinant human DNAse
ACE inhibitors/ARB
Low protein diet
Combination
pulse solumedrol
plus cytoxan
MMF
Sequential:pulse
cytoxan to
MMF or imuran
NERVOUS SYSTEM
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Steroids (e.g. Prednisone 1 mg/kg/day)
Cyclophosphamide
IVIG
Psychotropics (e.g. Haloperidol)
TCA/SSRI
NOVEL THERAPY
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Immunoablative chemotherapy with or without
autologous stem cell transplant
B-cell toleragen (Single signal anergy)
B cell depletion (Rituximab/antiCD20,
Epratizumab/antiCD22)
Complement inhibitors (anti-C5, C5aRecptor
antagonists, soluble CR1)
Adhesion molecule inhibitors (anti-ICAM 1
antiCD11b/CD18)
Co-stimulatory pathway inhibitors (CTLA-4Ig
inhibitor of B7(CD80,86)-CD28, anti-CD40ligand)
PITFALLS
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ANA positive Fibromyalgia
Steroids for musculoskeletal symptoms
Excessive duration of steroids
Inadequate monitoring of disease activity
Poor compliance
Diagnostic or therapeutic delays: renal biopsy,
initiation of cytotoxic therapy
Role of the Primary Care Physician
Assessments to Order
Initial: CBC, SMA-20, ANA,
dsDNA, C3/C4, ESR, CRP, UA,
Rheumatoid Factor, Vit D 25OH
If possible overlap or other:
centromere, Scl-70, CPK,
aldolase
If Signficant Arthritis: XRAYS
If prior diagnosis of SLE,
patient seeking continuation
of care: Subserologies: Ro, La,
Sm, RNP, LAC, Cardiolipin Ab
Reasons for Referral to Rheumatology
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To confirm a diagnosis
To assess disease activity and severity
To provide general disease management
To manage uncontrolled disease
To manage organ involvement or lifethreatening disease
To manage/prevent treatment toxicities
Other circumstances: APLS, pregnancy, surgery
Follow Up Visits
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Frequency depends on activity, severity, and
extent of SLE, response to treatment, type of
treatment, need for toxicity monitoring
At routine visits, CBC, SMA, UA should be
checked, even in patients with previously normal
values
Patients with known renal disease should also
have either 24 hour urine or spot
protein/creatinine checked every 6-8 weeks
Follow Up
Active disease can be diagnosed by
Assessment of clinical features such as rash, arthritis,
serositis, etc
 Laboratory features: dsDNA Ab, complement levels,
CBC
 Imaging: CXR, ECHO, etc
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Severe or Life Threatening Complications
Monitoring for Specific Medications
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Patients on chronic steroid therapy must also be
on Calcium/Vitamin D
Anticipate the need for possible bisphosphonate
therapy, check DEXA
Role of the Primary Care Physician
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Patients may have more frequent access to their
primary care physician as compared to Rheum
or Renal Services
Understand the importance of disease severity:
lupus and it’s treatments are highly toxic and
clinical status can decline rapidly
Do not hesitate to call the Rheumatology
Consult Service when initiating work-up or to
discuss continued care
Case Report
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19 yo HF no PMH p/w 3 weeks of intermittent
fevers (Tmax 103.4), weakness, retrosternal
discomfort, proximal muscle weakness.
Denies weight loss, chills, HA, CP, SOB,
GI/GU sx.
DDX?
Case Presentation
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Initial PE: HR 92, RR 22, O2 sat 99% on RA
Positives: trace alopecia, UE/LE 2/5
Initial labs: pancytopenia, SMA-10 WNL,
AST/ALT 560/340, bilis nl, alb 2.3, UA: 3+prot
and blood, EKG tachy, CXR NL
CPK: 3750, LDH 1221, ECHO: small effusion
Case Report
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Subsequent Data: ANA 1:1280, +dsDNA,
C3 28, C4 6 +Sm/RNP
Patient with clinical picture and lab data
consistent with acute presentation of SLE, with
acute cytopenia, myositis, serositis, and nephritis