1. Systemic Lupus
Erythematosus SLE
and APLS

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

3. What is the most likely
diagnosis?

4. 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

5. 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

6. 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

7. Drug induced Lupus (DILE)
• Triggered by certain medications
• Resolution after DC of the drug
• Anti-Histone ab test positive
• Absence of anti-DsDNA

8. Drug-induced lupus: definite
drug associations
• Hydralazine
• Procainamide
• Minocycline
• Chlorpromazine
• Isoniazid
• Penicillamine
• Methyldopa
• Interferon-alpha

9. Drug-induced lupus: possible
drug associations
• Anticonvulsants • Diltiazen
• Quinidine • Hydrazine
• Propylthiouracil • Interferon gamma
• Sulfonamides • TNF inhibitors
• Lithium
• Beta-blockers
• Nitrofurantoin
• Sulfasalazine

10. 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

11. 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

12. 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

13. 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

14. SLE Clinical Presentation
• Most commonly affected organ
systems:
– Musculoskeletal
– Dermatological
– Renal
– Hematological
• Any organ can be affected

15. 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,PIP’s)
– Wrists

16. SLE Clinical Presentation
• Knees are less affected
• Jaccoud’s arthropathy:
– Progressive ulnar deviation
– Swan-necking deformaties
– Reversible or correctible
• Typically non erosive bony changes

17. Jaccoud’s Arthropathy

18. 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

19. Malar Rash – Butterfly Rash

20. Systemic lupus erythematosus:
bullous lesions, palate

21. 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”

22. SLE Dermatological-neck rash

23. 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

24. Discoid Lupus

25. Discoid Lupus

26. SLE Dermatological
• Subacute Cutaneous Lupus
Erythematosus (SCLE)
– Photosensitive lesions
– Nonscaring rash
– Psoriaform form
– Annular – polycyclic form
• ½ of patients with SCLE have SLE

27. SCLE- Annular rash

28. 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

29. 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

30. Renal Involvement
• Membranous nephritis (V) manifested by
Nephrotic Syndrome

31. 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

32. 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)

33. Hematological abnormalities
• Most common
• Leukopenia and Lymphopenia
• Medication induced cytopenias
– Corticosteroids associated lymphopenia
• Thrombocytopenia
– Antiphospholipid antibodies
– Immunosupressive drugs
– Heparin administration

34. Hematological abnormalities
• Hemolytic anemia
– Coombs positive
– Elevated reticulocyte count
– Decreased haptoglobin
• Anemia of chronic disease
(inflammation)
• Anemia from chronic renal disease
• Iron deficiency anemia

35. 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

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

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

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

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

40. 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

41. Malignancy risk
• Lymphoma and Solid tumors risk is
increased independent to therapy
• Patients with secondary Sjogren’s
syndrome may have special risk of non-
Hodgkin’s Lymphoma

42. 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

43. Clinical Manifestations of SLE

45. Laboratory tests/Ab testing for
SLE
• Tests for diagnosis
• Tests for prognosis
• Tests to determine appropriate
treatment (What organ involvement is
occurring?)

46. 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

47. 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

48. 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

49. Frequent ANA patterns
• Speckled
• Homogeneous / Diffuse
• Nucleolar
• Rim / Peripheral
• Centromere

51. 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

52. 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

53. 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

54. 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

55. 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

56. 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)

57. 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 Sjogren’s S.
– can increase the risk of congenital heart
block in babies whose moms are +

58. 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

59. Does she have SLE?
• + ANA
• Low WBC and plt
• + anti Sm
• Malar rash
• Photosensitivity
• Possible inflammatory arthritis
• She has at least 5 criteria

60. Laboratory tests/Ab testing for
SLE

61. 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

62. 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)

63. 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)

64. 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

65. Management - treatment
• Patient Education and prophylactic measures
to avoid flares :
• Sunscreens SPF >30 and protective clothing
– Photosensitivity, Raynaud’s Phen.
• Avoid estrogen containing oral contraceptives
– Lupus flares, hyperthrombotic states
• Avoid medications such as:
– Sulfonamides, Echinacea, and Melatonin

66. 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

67. Management – treatment
• Enforce regularly scheduled:
– Colonoscopy
– Pap smears
– Mammograms
– Increased risk of cancer

68. 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

69. 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

70. 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.

71. 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

72. 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

73. Management – treatment
• Persistent Synovitis
– Methotrexate
– Leflunomide
– Abatacet
– Rituximab

74. 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

75. 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

76. 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

77. 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

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

79. 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?

80. • 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.

81. • 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.

82. • 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

83. 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.

84. Renal Biopsy
• 24 Apr 07 - Renal biopsy from 13 months ago was consistent with lupus nephritis
Class IV (no crescents noted).
QuickTime™ and a
decompressor
are needed to see this picture.

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

86. 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

87. • 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

88. 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.

89. • 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

90. • 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.

91. • 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

92. 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

93. Dyslipidemia is a potential consequence of
proteinuria; LDL-C levels should be checked
regularly. Abnormal lipid levels deserve vigorous
treatment.
• Triglycerides 173 mg/dL
• 0 - 150
• Total Cholesterol 225 mg/dL
• 0 - 200
• LDL Cholesterol 110 mg/dL
• 62 - 130
• HDL Cholesterol 79 mg/dL
• 50 - 60

94. Renal biopsy:
Class IV lupus nephritis with a high level of activity
(crescents)
QuickTime™ and a
decompressor
are needed to see this picture.

95. • 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

96. • 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

97. • 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

98. 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.

99. • 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

100. • 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

101. • 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.

102. • Standard Dosing Ranges
• 1,000-1,500 mg of mycophenolate mofetil 500
mg oral tablet BID maximum, 2,000-3,000 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