Systemic Lupus

Erythematosus SLE
and APLS

Case Study
22 year old college student
New onset of red cheeks, hives in the
sun, fatigue, Raynauds, weight loss,
hair loss and stiff hands in the morning
Her cousin has JRA

What is the most likely

diagnosis?

Lupus
Represent a range of disease
processes characterized by the
development of autoantibodies with
associated manifestations and organ
damage
Some forms limited to skin , or occur
after exposure to a drug

SLE
Systemic lupus erythematosus:
Prototypical form of lupus
Multiorgan autoimmune disease that often
presents insidiously with significant
heterogeneity of expression in individuals
Severity from mild to life threatening
depending on the affected organ
Medications used for treatment increase
morbidity - organ damage

Chronic Cutaneous Lupus

(CCL)
Limited to the skin
No systemic manifestations
Includes:
Discoid lupus
Subacute cutaneous lupus erythematosus
Lupus paniculitis

Only 5% of CCL develop SLE

Drug induced Lupus (DILE)

Triggered by certain medications

Resolution after DC of the drug
Anti-Histone ab test positive
Absence of anti-DsDNA

Drug-induced lupus: definite

drug associations

Hydralazine
Procainamide
Minocycline
Chlorpromazine
Isoniazid
Penicillamine
Methyldopa
Interferon-alpha

Drug-induced lupus: possible

drug associations

Anticonvulsants
Quinidine
Propylthiouracil
Sulfonamides
Lithium
Beta-blockers
Nitrofurantoin
Sulfasalazine

Diltiazen
Hydrazine
Interferon gamma
TNF inhibitors

SLE

More common in Female than male

Female : Male ratio 9:1
Incidence of SLE in US is :
Women 9.4 per 100,000
Men
1.54 per 100,000
More common in African-American and
Hispanic population

SLE
Disease onset more common in the 20s,
and 30s
May occur at any age
Symptoms/disease activity waxes and
wanes
Flares sometimes evident by clinical
symptoms, other times only by laboratory
results changes

SLE
Pathogenesis :
Exact cause is unk.
Genetic factors -10% of SLE patients
have a family member with lupus
Environmental factors - UV light (most
important)
Possible Also infections, smoking, and
toxin exposure

SLE
Autoantibodies bind to proteins and
tissues
Deposition of immune - complexes
leads to an inflammatory cascade
With activation of complement system
And production of inflammatory
cytokines

SLE Clinical Presentation

Most commonly affected organ
systems:
Musculoskeletal
Dermatological
Renal
Hematological

Any organ can be affected

SLE Clinical Presentation

Musculoskeletal lupus
Isolated arthralgias ( more often stiffness
rather than pain)
Synovitis.arthritis similar to RA
Morning stiffness
Gel phenomenon after immobility
Small joints of the hands( MTPs,PIPs)
Wrists

SLE Clinical Presentation

Knees are less affected
Jaccouds arthropathy:
Progressive ulnar deviation
Swan-necking deformaties
Reversible or correctible

Typically non erosive bony changes

Jaccouds Arthropathy

SLE Dermatological
Several skin manifestations
Malar Rash Butterfly Rash
Erythematous
Photosensitive
Flat or raised - maculopapular
On the cheeks and Bridge of the nose
Spares naso-labial folds

Malar Rash Butterfly Rash

Systemic lupus erythematosus:

bullous lesions, palate

SLE Dermatological
Maculopapular rash also common on:
V-area of the neck, and extremities
Areas associated to sun exposure

Biopsy of the skin demonstrate

immunoglobulin and complement
deposition at the dermal-epidermal
junction: lupus band sign

SLE Dermatological-neck rash

SLE Dermatological
Discoid lupus(chronic cutaneous)
Involve deeper Dermis, raised patches,
keratotic scaling, follicular plugging
May lead to permanent loss of hair follicle
Disfiguring hyper- or hypopigmented scars
may occur after resolution
Typically on face ( inside ears, above eye
brows, upper palate )
Neck, scalp and forearms

Discoid Lupus

Discoid Lupus

SLE Dermatological
Subacute Cutaneous Lupus
Erythematosus (SCLE)
Photosensitive lesions
Nonscaring rash
Psoriaform form
Annular polycyclic form

of patients with SCLE have SLE

SCLE- Annular rash

SLE Renal Involvement

Proteinuria alone
Proteinuria and Hematuria
Cellular casts in urine : RBCs
Glomerular involvement
Elevated serum creatinine level
Possible Renal Failure
May result in Nephrotic Syndrome:
Low serum albumin, and elevated cholesterol

Renal Involvement
International society of Nephrology
Classification for lupus nephritis
I minimal mesangial
II Mesangial proliferative
III focal proliferative
IV diffuse proliferative
V membranous
VI irreversible renal sclerosis
Done by Kidney Biopsy
Class IV most dangerous can rapidly progress to
Renal Failure

Renal Involvement
Membranous nephritis (V) manifested by
Nephrotic Syndrome

SLE Serositis
Pleurisy
Occurs most commonly as pleurisy:
Pain on deep inspiration
Sometimes associated with pleural effusion
Listen for inspiratory / expiratory rub
Exudative effusion if tapped

Differentiate from pulmonary emboli and

infection pleuritic chest pain

Serositis
Pericarditis:
Positional pain
Worse with recumbency
Better leaning forward

Ascites:
Possible due to serositis
r/o infarcted bowel, infection, or Budd-Chiari
syndrome (oclussion hepatic or IVC)

Hematological abnormalities
Most common
Leukopenia and Lymphopenia
Medication induced cytopenias
Corticosteroids associated lymphopenia

Thrombocytopenia
Antiphospholipid antibodies
Immunosupressive drugs
Heparin administration

Hematological abnormalities
Hemolytic anemia
Coombs positive
Elevated reticulocyte count
Decreased haptoglobin

Anemia of chronic disease

(inflammation)
Anemia from chronic renal disease
Iron deficiency anemia

Neurologic manifestations
Most likely as a result of immunecomplex
deposition in small blood vessels
Rarely attributable to vasculitis
Most common neurologic complaint in SLE:
Cognitive impairment 80%of SLE patients by 10
years after Dx.
Represents accumulated damage and not ongoing
CNS SLE
Formal cognitive function testing to establish
baseline

Neurologic manifestations
Mild to severe
Seizures: also from thrombosis,uremia,toxic
Psychosis: think about steroids psychosis
Encephalopathy
Coma

Neurologic manifestations
Meningitis
Stroke: vasculitis or APhospholipids Abs
thrombosis, HTN, atherosclerosis
Mononeuritis multiplex
Transverse myelitis
Peripheral neuropathy
Cranial neuropathy

Organ Damage
In >50% of SLE patients over time
Significant % from corticosteroids therapy
Obesity/ Diabetes
HTN/ Hyperlipedimia
Cataracs/Glaucoma
Osteoporosis/Osteonecrosis
Infections
Depression/Psychosis

Organ Damage
Accelerated Atherosclerosis the major
cause of death in SLE
Risk of MI increased 50 fold
Counsel about modifiable
cardiovascular risks

Organ Damage
Renal damage occurs in at least 25% of
patients with lupus nephritis in spite of
maximal therapy
Recommendation for renal biopsy:
In patients with 500mg/day proteinuria
Active urinary sediment
Rising serum creatinine

Malignancy risk
Lymphoma and Solid tumors risk is
increased independent to therapy
Patients with secondary Sjogrens
syndrome may have special risk of nonHodgkins Lymphoma

Diagnosis
Often difficult multiple manifestations
which evolve over time / more in the early
stage
Clinical diagnosis supported by Hx,
Physical Exam and Laboratory tests
Make take months to years for the typical
picture to unfold
ACR classification criteria for SLE is
helpful but not needed for Dx

Clinical Manifestations of SLE

Laboratory tests/Ab testing for

SLE
Tests for diagnosis
Tests for prognosis
Tests to determine appropriate
treatment (What organ involvement is
occurring?)

Laboratory tests/Ab testing for

SLE

CBC,diff, ESR, CRP

Creatinine, urinalysis
Chemistry Panel
ANA, anti DsDNA, anti-SM, anti-RNP
anti-SSA /SSB, RF, C3,C4,total
complement

Ab testing for SLE

ANA(anti-nuclear antibodies)
Positive in 95-99% of SLE
Occurs in 20% of healthy people,
elderly, with drugs, thyroid disease,
RA,SS, pulmonary fibrosis.
If positive + clinical symptoms continue
workup

What is ANA?
Antinuclear antibody is an autoantibody
against part of the cell nucleus
It is a screening test for SLE: so if
negative, it makes SLE highly unlikely

Frequent ANA patterns

Speckled
Homogeneous / Diffuse
Nucleolar
Rim / Peripheral
Centromere

Positive test
Titers: stronger positive, the dilution is
larger (higher denominator)
Ex. 1/1280 is a strong positive

Pattern can change depending on the

dilution
Ex. 1/80 speckled and homogenous and
1/640 homogenous

Is there utility in following the

titer?
No
In general repeating the test is a waste
of money
A positive test in past or at any time can
count in the diagnostic criteria for SLE

When do I order anti DNA?

It is an auto-antibody directed against
the DNA in the cells nuclei
Only order anti DNA in the presence of
a positive ANA, when you are clinically
suspecting SLE
It is very specific for SLE, but very
insensitive

What does anti DNA correlate

with?
It is highly specific for SLE
It correlates with renal SLE (but not
100%)
Thus, it can be a bad prognosticator
and it is part of the diagnostic criteria

What is an ENA
ENA is extractable nuclear antigens
The lab will do a screen to see if it is
positive or negative
If positive, more assays are done to
determine which antibody is positive

ENA examples

Anti Ro, (anti SSA)

Anti La, (anti SSB)
Anti Sm (Smith fairly sensitive for SLE)
Anti RNP (goes with MCTD and SLE)
Anti Scl 70 (Topoisomerase 1) goes with
diffuse scleroderma esp with interstitial lung
disease
Other: anti Jo1(myositis)

Anti-Ro(anti-SSA) and
La(anti-SSB)
+ Anti Ro:
is associated with cutaneous SLE features
including rash and photosensitivity
is often + in ANA negative SLE
can go with anti La in Sjogrens S.
can increase the risk of congenital heart
block in babies whose moms are +

The results of the college

student
WBC 2.8, Hbg 11.1, Plt 43
Creatinine 1.0, urine neg for protein and
blood
ANA 1/320 speckled
ENA: + for anti Smith (Sm)
antiDNA negative

Does she have SLE?

+ ANA
Low WBC and plt
+ anti Sm
Malar rash
Photosensitivity
Possible inflammatory arthritis
She has at least 5 criteria

Laboratory tests/Ab testing for

SLE

Antiphospholipid antibody
syndrome (APS)
Half are associated with SLE
Occurs in 10-20% of SLE patients
Syndrome of arterial and or venous
clotting (CVA, DVT, PE), recurrent
abortions and often livedo reticularis,
low platelets

Antiphospholipid antibody
syndrome (APS)
Positive tests may include
Lupus anticoagulant (false prolongation of PTT)
Anticardiolipin antibody (aCL) or other
antiphospholipid antibodies
False positive VDRL
Abnormal RVV time (Russel venon viper time)

APS
Treatment varies on symptoms and
signs
ASA or LMW heparin in pregnancy
Warfarin if DVT
ASA and possibly warfarin if CVA
(Cerebro-vascular-accident)

SLE Management - treatment

No cure chronic condition
TTo aimed at:
Reducing inflammation
Suppressing immune system
Closely monitoring patients to ID and to treat
disease features as early as possible
Minimize therapy adverse effects

Management - treatment
Patient Education and prophylactic measures
to avoid flares :
Sunscreens SPF >30 and protective clothing
Photosensitivity, Raynauds Phen.

Avoid estrogen containing oral contraceptives

Lupus flares, hyperthrombotic states

Avoid medications such as:

Sulfonamides, Echinacea, and Melatonin

Management treatment
Low dose ASA for patients with
+Antiphospholipid Abs
Potentially avoid thrombosis

Psychological support
Depression and anxiety

Routine immunizations
Influenza (yearly) and pneumococcus vaccine
(every 5-10 years)
- Live virus vaccines not recommended

Management treatment
Enforce regularly scheduled:
Colonoscopy
Pap smears
Mammograms
Increased risk of cancer

Management treatment
Baseline and periodic bone
densitometry
Biphosphonates not given to patients
with renal insufficiency or potential to
have pregnancies
Osteopenic patients: Biphosphonates,
CaCO3 and Vit D
Management of HTN and Lipid levels

Management treatment
Pregnancy
High risk
90 % successful
Flares can occur
High disease activity with increased
DsDNA level and decreased complement
levels
Increased pre-eclampsia, preterm births,
and fewer live births

Management treatment
Risk of Neonatal Lupus in + Ro(anti SSA) AB
Cross placenta
2-5 % risk of congenital heart block in the
baby, hemolytic anemia, and rashes
Women with medium to high titer
anticardiolipin /anti-B2 glycoprotein, hx of
pregnancy loss or severe preeclampsia
ASA and Heparin during pregnancy and 6
months after.

Management treatment
Cutaneous Lupus:
Hydroxychloroquine (Plaquenil)
200 mg PO BID
Risk for retinopathy (<1 of 5000 exposed)
Eye exam once a year

Alternate: Quinacrine 100mg PO QD

Higher ocular toxicity

If no response: Cellcept, Methotrexate,or

Imuran

Management treatment
Musculoskeletal symptoms
NSAIDS mild arthralgias
COX 2 inhibitors

Do not use for long periods of time

Proton pump inhibitors- PRN
Hydroxychloroquine 200mg PO BID
Low Dose Prednisone <7.5mg/day

Management treatment
Persistent Synovitis
Methotrexate
Leflunomide
Abatacet
Rituximab

Management treatment

Serositis
Mild serositis: may respond to NSAIDS
Moderate S: Triamcinolone 100mg IMx1
Severe : Methylprednisolone IV pulse
(1000mg over 90minutes x 3days ) followed
by oral Prednisone tapering dose
Maintenance immunosupressive regimen if
persistent / recurrent serositis

Management treatment
Lupus Nephritis
Mycophenolate Mofetil (Cellcept)
induction and maintenance therapy
Recent studies show potential
superiority of Cellcept as induction and
safety profile when compared to
Cytoxan

Neprhitis (cont)
Cyclophosphamide (Cytoxan)
induction therapy- IV pulse
Induction IV 500-750 mg/m2 body
surface, monthly, for 6 months
Maintenance IV quaterly for 2 years
Hemorrhagic Cystitis
Long term risk for Urinary Bladder
malignancy

Management treatment

CNS Lupus
IV Methylprednisolone pulse
IV monthly Cyclophosphamide
Additional antiepileptic medication in the
case of seizures/ Neuro-consult
Psychosis-antipsychotic drugs and
mood stabilizers

Management treatment
Hematological Lupus
Plt count < 30,000 bleeding may occur
Severe hemolytic anemia /
thrombocytopenia
High dose steroids, if no improvement
intravenous immunoglobulin
Rituximab

Case study
Patient Name: Melisa T.
Age: 19
Sex: Female
Description: Melisa, a young Latina student, is taking
mycophenolate mofetil (MMF) for lupus nephritis
(LN) has come in for a routine follow-up visit. How
would you monitor progress, and, based on the lab
results, are there any changes you would make to
her regimen?

 19-year-old Latina patient with systemic

lupus erythematosus (SLE) is seen today
for a routine follow-up visit. She was
referred 1 year ago with polyarthritis,
thought by her primary care provider to
be due to rheumatoid arthritis (RA). After
confirmation of SLE, she was found to
have 3+ proteinuria, 10 RBCs/HPF, and
class IV diffuse proliferative nephritis
seen on renal biopsy. Treatment with
high-dose prednisone plus
mycophenolate mofetil (MMF; first 2
g/day, then 3 g/day) stabilized her lupus
nephritis (LN): urine protein decreased to
0.3 g/day and revealed no RBCs.

 Eventually, prednisone was tapered down to

10 mg.Today she denies significant joint pain
or swelling, rashes, chest pains, skin or
mucous membrane abnormalities, or
neurological symptoms. Past history and
family history are unremarkable. She has
never been pregnant, but is determined to
have children with her fiance in the future. At
present she uses barrier methods (estimated
90% of the time). She is willing to use other
forms of contraception for a period of time,
but despite her present monogamy she
rejects use of an IUD due to prior pelvic
inflammatory disease. Review of systems is
otherwise normal. Physical exam reveals
obesity without evidence of malar or other
rash.

Current Conditions
Lupus nephritis
Obesity
Systemic lupus erythematosus

Current Medications
10 mg prednisone daily
1500 mg mycophenolate mofetil bid
600 mg-200 units calcium-vitamin D bid
Daily multivitamin

Original Lab results

Anticardiolipin antibodies: medium
positive titer
Lupus Anticoagulant: not detected
Beta2 Glycoprotein I: negative
Urine hCG Negative
Urine protein/creatinine ratio =
0.3, which correlates with 300 mg
proteinuria/day.

Renal Biopsy

24 Apr 07 - Renal biopsy from 13 months ago was consistent with lupus nephritis
Class IV (no crescents noted).

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anti-CCP
2 IU/mL
Note:
0-19 (negative)
20-39 (weak positive)
40-59 (moderate positive)
>60 (strong positive)

AB testing
Anti-Sm (Smith): Positive
ANA positive at 320 in a homogeneous
pattern
DsDNA Positive at 1:80
C3 Complement
61 mg/dL
82 - 235
C4 Complement
44 mg/dL
16 - 70

Glucose (FPG) 92 mg/dL

70 - 110
Creatinine 0.8 mg/dL
0.6 - 1.3
Albumin 3.7 g/dL
3.4 - 5.0
Bilirubin, Total
0.7 mg/dL
0.0 - 1.0
Alkaline Phosphatase 121 IU/L
50 - 136
AST (SGOT)
23 IU/L
15 - 37
ALT (SGPT)
18 IU/L
15 - 37

Current lab tests

A CBC should be ordered several
times a year in patients with SLE
(every 3 months if taking MMF) to
screen for leukopenia,
thrombocytopenia, and/or anemia.

Hb (Hemoglobin) 9.8 g/dL

9.6 - 18.0
HCT (Hematocrit) 29 %
37 - 47
Platelet Count
214 1000/mm3
50 - 350
WBC (White Blood Cell Count)
3.2
1000/mm3
4.0 - 10.8

 A chemistry panel that checks

fasting glucose, creatinine, lipids,
and hepatic enzymes should be
ordered several times a year
(every 3 months if taking MMF) in
patients with SLE.

Glucose (FPG) 82 mg/dL

70 - 110
Creatinine 1.2 mg/dL
0.6 - 1.3
Albumin 3.6 g/dL
3.4 - 5.0
Bilirubin, Total
0.6 mg/dL
0.0 - 1.0
Alkaline Phosphatase 113 IU/L
50 - 136
AST (SGOT)
28 IU/L
15 - 37
ALT (SGPT)
18 IU/L
15 - 37

In anticipation of obtaining a renal

biopsy, coagulation studies are
indicated.
Prothrombin Time
12 seconds
11 - 15
Partial Thromboplastin Time
29
seconds
25 - 40
International Normalized Ratio 1.0
0.8 - 1.2

Dyslipidemia is a potential consequence of

proteinuria; LDL-C levels should be checked
regularly. Abnormal lipid levels deserve vigorous
treatment.

Triglycerides 173
0 - 150
Total Cholesterol
0 - 200
LDL Cholesterol
62 - 130
HDL Cholesterol
50 - 60

mg/dL
225 mg/dL
110 mg/dL
79

mg/dL

Renal biopsy:
Class IV lupus nephritis with a high level of activity
(crescents)

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Color
yellow
Turbidity cloudy
Specific Gravity 1.013 1.006 - 1.030
Urine Glucose negative
Ketones negative
Blood
negative
Protein
2+
Bilirubin negative
Urobilinogen
negative
Nitrites
negative
Leukocyte Esterase
negative
Casts
negative
RBCs
negative
Crystals negative
WBCs
negative

 A urine protein/creatinine ratio is an efficient

and reasonably accurate method to quantitate
proteinuria. Values > 0.5 (correlating to > 0.5
g (500 mg)/24 h) suggest the need for a renal
biopsy to stage possible lupus nephritis
(3659).

Urine protein/creatinine ratio = 2.0

 Antiphospholipid Antibodies: With her

repeatedly positive anticardiolipin
.
antibody determinations and intrinsic
high risk for thrombotic complications,
continued monitoring is prudent.
Anticardiolipin antibodies: 80 GPL U/mL
(high positive)
Lupus anticoagulant: not present
Beta2 Glycoprotein I: negative

Possible options
Due to the failure of MMF for decreasing
proteinuria to below 500-1,000 mg/day in this
patient, discontinuation of its use and
substitution of rituximab, or the combination
of cyclophosphamide with leuprolide
premedication, or perhaps azathioprine is a
reasonable next step.

 Patients with lupus nephritis and this degree

of ongoing pathologic activity require use of
an immunosuppressive agent, such as
cyclophosphamide lyophilized, azathioprine,
tacrolimus, or an experimental therapy such
as rituximab
Although cyclophosphamide remains the
standard for use in rapidly-progressive
crescentic lupus nephritis, its use is highly
associated with infertility noted in about 50%
of patients using this drug. The incidence of
infertility can be decreased to approximately
15%, however, with leuprolide injections 2
weeks prior to the monthly cyclophosphamide

 Some success has been reported in

open-label series using rituximab ,which
peripherally depletes B-lymphocytes
and is approved for use in rheumatoid
arthritis.
While not FDA-approved for use in
lupus nephritis, the anti-rejection agent
tacrolimus has been associated with
some degree of success in a small
number of patients

 Azathioprine has been shown to have

equivalent efficacy to MMF in
maintenance trials, but patients are
unlikely to have a better response to
azathioprine than they had to MMF.

 Standard Dosing Ranges

1,000-1,500 mg of mycophenolate mofetil
500 mg oral tablet BID maximum, 2,0003,000 mg daily maximum
1-80 mg of predniSONE 10 mg oral tablet
QID maximum, 1-80 mg daily maximum
1-4 ea of calcium-vitamin D 600 mg-200 units
oral tablet QID maximum, 1-4 ea daily
maximum
1 ea of Multiple Vitamins oral capsule once a
day maximum