Transcript Slide 1

Systemic Lupus
Erythematosus,
ANA’s, etc.
Hermine Brunner, MD MSc
Assistant Professor of Pediatrics
Division of Rheumatology
Cincinnati Children’s Hospital Medical
Center
SYSTEMIC LUPUS ERYTHEMATOSUS
(SLE)- DEFINITION/DIAGNOSIS
• Prototype of auto-immune, multi-system
disease
• Onset maybe acute, episodic, or insidious
• “Anything” can happen to “any organ
system”
• Antinuclear antibodies are almost always
present
• Serositis & Immune complexes
SLE - EPIDEMIOLOGY
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20% of all SLE is pediatric age group
Incidence 0.6/100,000
Prevalence 5-10/100,000
Overall 5-10,000 children in U.S.A.
Approximately 5% of new diagnoses in
Pediatric Rheumatology clinics
• SLE : JRA/1:10 ratio
Pediatric SLE versus Adult Onset SLE
• More severe symptoms at onset
• More aggressive clinical course than adults
• Increased need for corticosteroid; 77% vs 16%
• Children tend to die during acute SLE phase
Adults tend to die secondary to complications
• African American and Hispanic children have a
higher incidence of disease
• African American patients have
– higher prevalence and severity of renal
– higher prevalence neuropsychiatric SLE
– higher titers of anti-DNA and anti-SSA antibodies in
association with cardiac disease
Genetics in SLE
• Eight of the best supported SLE susceptibility loci
are the following
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1q23
1q25-31
1q41-42
2q35-37
4p16-15.2
6p11-21
12p24
16q12
Tsao, BP, Curr Opinion Rheum, 2004; 16: 513-521
THE 1982 REVISED CRITERIA FOR
CLASSIFICATION OF SLE
Malar rash
Discoid rash
Photosensitivity
Oral ulcers
Arthritis
Revised 1997
Serositis
Renal disorder
Neurologic disorder
Hematologic disorder
Immunologic disorder
Antinuclear antibody
THE 1982 REVISED CRITERIA FOR
CLASSIFICATION OF SLE
• For the purpose of identifying patients
in clinical studies, a person shall be
said to have SLE if any 4 or more of the
11 criteria are present, serially or
simultaneously, during any interval of
observation.
– Sensitivity 96%
– Specificity 96% in adults
– Similar percentages in pediatric group.
MALAR RASH
• Fixed erythema,
flat or raised, over
the malar
eminences
• tending to spare
the nasolabial folds
DISCOID RASH
• Erythematous
raised patches with
adherent keratotic
scaling and
follicular plugging;
• Atrophic scarring
may occur in older
lesions
PHOTOSENSITIVITY
• Skin rash as a
result of unusual
reaction to sunlight
• by patient history
or physician
observation
ORAL ULCERS
• Oral or
nasopharyngeal
ulceration
• Usually painless,
observed by a
physician
ARTHRITIS
• Nonerosive arthritis involving 2
or more peripheral joints
• Characterized by tenderness,
swelling, or joint effusion.
SEROSITIS
A) Pleuritis - convincing history of
pleuritic pain or rub heard by a
physician or evidence of pleural
effusion
OR
B) Pericarditis - documented by ECG
or rub or evidence of
pericardial effusion
RENAL DISORDER
A)
Persistent proteinuria greater
than 0.5 grams per day or
greater than 3+ if quantitation
not performed
OR
B)
Cellular casts - may be red
cell,hemoglobin, granular,
tubular, or mixed
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
HEMATOLOGIC DISORDER
A)
Hemolytic anemia - with reticulocytosis
B)
Leukopenia - less than 4,000/mm3 total on
2 or more occasions
C)
D)
OR
OR
Lymphopenia - less than 1,500/mm3 on 2
or more occasions
OR
Thrombocytopenia - less than
100,000/mm3 in the absence of offending
drugs
IMMUNOLOGIC DISORDER
A) Anti-dsDNA: antibody to native DNA in
abnormal titer
OR
B) Anti-Sm: presence of antibody to Sm
nuclear antigen
OR
C) Antiphospholipid antibodies by positive
IgG or IgM anticardiolipin antibodies
or positive test for lupus anticoagulant
ANTINUCLEAR ANTIBODY
• An abnormal titer of antinuclear
antibody by immunofluorescence or
an equivalent assay
– at any point in time
– and in the absence of drugs known to
be associated with
• “drug-induced lupus” syndrome
Drug-Induced Lupus
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Minocycline (Minocin)
Phenytoin (Dilantin)
Carbamazepine (Tegretol)
Ethosuximide (Zarontin)
ANTINUCLEAR ANTIBODY
• 1:20 - 1:40 Screening titer
– 1: x titer
• Pattern
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speckled
rim
homogeneous
nucleolar
+ ENA’s
- ds DNA
- DNA (LE prep)
- Scl - 70
SLE
Tissue Specific
Antibodies
ATA
Anti ASMA
Anti-MITO
Anti-LKM
Anti-PC
Hep-2
Nuclear
Antibodies
Ro/SSA
La/SSB
RNP
Sm
ds DNA
ss DNA
Arthralgia and Positive ANA or RF
• Remember that objective signs of joint
inflammation substantiate diagnosis of
arthritis
• Comprehensive review of systems may
uncover clues
• Perform a critical, complete physical
examination
• Serial re-evaluations may be necessary
• Most children do not progress to a C.T.D.
• Positive serologies may be seen in:
– Normal children - approximately 3-12%
– Response to infection
Persistent ANA
• 24/108 children with musculoskeletal problems had
positive ANA
• 21/24 had persistent ANA, mean duration 38 mo
• No patient developed an overt autoimmune or
inflammatory disease, mean F/U 61 mo (13-138)
• Conclusion: a child with positive ANA and
musculoskeletal problems , but with no evidence at
presentation of AID or inflammatory disease is at low
risk of developing such a disease.
Cabral, DA, et al Pediatrics 1992, 89(3):441-444
Outcome of Children referred to
Pediatric Rheumatology Clinic with a
positive ANA but without AID
• 500 new patients reviewed, 113 had positive ANA
• 72 (64%) had an autoimmune disease AID,
10 (9%) were lost to F/U, 31 (27%) had no AID,
• Mean ANA titer 1:160, varied pattern
• Mean clinical F/U 37 mos
• 25 (81%) cleared their symptoms, 5 (16%) had
improvement, 1 developed autoimmune hepatitis
• Prognosis with +ANA is excellent in absence of AID
at presentation
Deane, PMG, et al, Pediatrics 1995, 95:892-895
Clinical Utility of Antinuclear ANA Tests
in Children
McGhee JL et al, BMC Pediatrics 2004, 4: 13
• 110 pts referred to Rheum for +ANA
– 80 children with musculoskeletal problems syndromes
• 10 pts subsequently dx’d SLE, 1 MCTD, 1 Prim
Raynaud’s, 18 with JIA
– Nonurticarial rash more common in SLE, p=0.007
– Children with SLE were older 14.2 vs 11 yrs, p=0.001
– ANA > 1:640 was +predictor for SLE while titers of <1:360
were negative predictors
• Conclusion:
– Age and ANA titer assist in Dx SLE, no diagnostic value in Dx
JRA
– Remember the AID have objective evidence of disease!!!!!!!
SLE - CLINICAL MANIFESTATIONS
Most common signs/symptoms
• Unexplained fever, any pattern
• Malaise
• Weight Loss
• Arthralgia
SLE - MUCOCUTANEOUS
INVOLVEMENT
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“Butterfly Rash” - 1/3 at onset
Angiitic papules
Periungual erythema
Urticaria / angioedema
Palatal ulcer / aphthous ulcer
Alopecia
SLE - MUCOCUTANEOUS
INVOLVEMENT
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Discoid lupus
Subacute cutaneous lupus
Livedo reticularis
Nailfold capillary changes
Vasculitic ulceration
Panniculitis
Nasal septal perforation
• Ulcerated
leukocytoclastic
vasculitis in SLE
SLE - MUSCULOSKELETAL DISEASE
• Arthralgia / Arthritis
• Myalgia / Myositis
• Ischemic necrosis of bone - AVN
SLE - VASCULOPATHY
• Small vessel
vasculitis
• Palpable purpura
• Raynaud’s
phenomenon
• Antiphospholipid
antibody syndrome
SLE - CARDIAC INVOLVEMENT
• Pericarditis
• Myocarditis
• Endocarditis, Libman-Sacks
• Accelerated atherosclerosis
SLE - PLEUROPULMONARY DISEASE
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Pleuritis/Pleural effusion
Infiltrates/Atelectasis
Acute lupus pneumonitis
Pulmonary hemorrhage
“Shrinking lung” - diaphragm
dysfunction
• Subclinical restrictive disease
SLE - GASTROINTESTINAL
MANIFESTATIONS
• Anorexia, weight loss, nonspecific
abdominal pain
• Pancreatitis
• Mesenteric arteritis
• Esophageal dysmotility
SLE – LIVER , SPLEEN & LYMPH NODE
• Generalized lymphadenopathy
• “Lupoid hepatitis” vs SLE hepatic
involvement
• Functional asplenia
SLE - NEUROPSYCHIATRIC
MANIFESTATIONS
• Must be differentiated from infection
or hypertensive or metabolic
complications
• Any level of the CNS/PNS can be
affected
• Thorough evaluation necessary - CSF,
EEG, CT, MRI, EMG / NCV, NP testing
SLE - NEUROPSYCHIATRIC
INVOLVEMENT
Behavior/Personality changes, depression
Cognitive dysfunction
Psychosis
Seizures
Stroke
Chorea
Pseudotumor cerebri
Transverse myelitis
Peripheral neuropathy
Total of 19 manifestations described
SLE - RENAL INVOLVEMENT
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Usually asymptomatic
Gross hematuria
Nephrotic syndrome
Acute renal failure
Hypertension
End stage renal failure
SLE - NEPHRITIS
Nephritis remains the
most frequent cause of
disease-related death.
WORLD HEALTH ORGANIZATION
CLASSIFICATION OF LUPUS NEPHRITIS
Class I
Class II
IIA
IIB
Class III
Class IV
Class V
Class VI
Normal
Mesangial
Minimal alteration
Mesangial glomerulitis
Focal and segmental proliferative
glomerulonephritis
Diffuse proliferative
glomerulonephritis
Membranous glomerulonephritis
Glomerular sclerosis
SLE - LABORATORY EVALUATION
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Antinuclear antibody profile
Anti dsDNA abs, Sm abs
C3, C4, IgA, IgG, IgM
Direct Coomb’s, DAT
Antiphospholipid antibodies
ACLA - Anticardiolipin antibodies
LAC - Lupus anticoagulant
• CBC with Diff, U/A, CMP, TSH, ESR
Comprehensive Evaluation
of a Child with SLE
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Cumulative medication burden
Serial DEXA while on corticosteroids
Lipid panels
Repeat APA profile, ? Frequency
HRQL and damage indices, SLEDAI, SDI
Neuropsychiatric testing ?
ECHO
Complement factor deficiency (C1q)
Long-term Management Issues
• Long term morbidity of corticosteroids:
short stature, cataracts, osteoporosis
• How to manage ongoing active disease after
multiple medications during childhood
• Long term morbidity of immunosuppressive
agents
– Non-sustained durable disease: ? remission
– Cumulative risk re: malignancy and
premature ovarian failure
Therapeutic Goals in SLE:
Still Unmet Expectations
• Rate of renal remission after first line therapy still
81% at best
• Renal relapse in 1/3 pts mostly still
immunosuppressed
• 5- 20% experience ESRD 5-10 yrs after disease
onset
• Treatment related toxicity remains a concern;
osteoporosis, premature ovarian failure, severe
infections, etc.
• Prognostic factors have been identified but are
difficult to modify in order to improve outcomes
Treatment Regimens for LN
• Glucocorticoids plus cyclophosphamideinduction
& maintenance for 3 years
– NIH protocol
• Glucocorticoids plus low dose cyclophosphamide
with maintenance with MMF or AZA
• Immunoablative doses of cyclophosphamide
• Autologous stem cell transplantation
• Plasmapharesis is not recommended
•Reviewed: Houssian FA, J Am Soc Nephrol 2004; 15: 2694
Sequential Therapies for WHO III- V
• 60 adult SLE pts randomized 3 groups
– 12 Class III, 46 Class IV and 1 Class Vb
• All received initial therapy with Cyclophosphamide
0.5-1.0 gm/m² up to 7 pulses
– Cont’d on 1) cyclophosphamide, 2) azathioprine 13mg/kg, or 3)M ycophenolate mofetil (Cellcept, MMF)
0.5-3.0 gm/d for 1-3 years
• 5 pts died- 4CYC, 1 MMF; 5 CRF- 3 CYC,1 AZA, 1 MMF
• 72 month event free survival rate higher in MMF and
AZA than in CYC (P=0.05 and P=0.009, respectively)
• Incidence of hosp, amenorrhea, infections, nausea
and vomiting lower in the MMF and AZA groups than
in the CYC group
Contreras, G et al: NEJM 350(10): 971-980, 2004
Targeted Immune Intervention
• Directed against B Cells: Rituximab, anti-CD20 B
cell depleting monoclonal antibody
• LJP 394, anti-dsDNA-producing B cells
• Co-stimulatory signals
CD40-CD40L (CD154) blockade
CTLA41g, abatacept: binding to CD80 and
CD86 prevents engagement to CD28 to T
cells thereby prevents co-stimulation
• Cytokine blockade
IL10, INF-α
Houssian FA, J Am Soc Neprol, 2004; 15: 2694-2704
Major Clinical Syndromes in
SLE Requiring Vigilance
• Antiphospholipid Antibody Syndrome with
thrombosis
• Premature atherosclerosis and marked risk
of myocardial infarction
• Neurocognitive dysfunction with
deterioration of mental capacity
• Iatrogenic syndromes of osteoporosis and
premature ovarian failure 2° therapy
Case 1: 9 yo AAF with SLE
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Fever T 101-102, 3-4 x/week
Weight loss
Swollen fingers
Facial, malar, and eyelid rash
Weakness
Gradual decline in school performance
Family history positive for “arthritis” in
mother & maternal aunt
Case 1: Physical Examination
• T 101.8, Wt 27.1 kg (30%), Ht 130.6
(40%)
• BP 90/50
• Scleral/conjunctival injection
• Nasal and oral ulcerations
• Patchy parietal alopecia
• Shoddy lymphadenopathy
• Symmetric PIP swelling
• Depressed affect
Case 1: Laboratory Investigation
• Hgb 9.5 gm%, WBC 4.05, 55% PMN
platelets 257,000
• U/A “essentially negative”
• RF negative
• ANA 1:5120, diffuse, membranous
Ro (SSA) , La (SSB) , RNP , Sm ,
ds DNA 1:5120, APA negative
• ↓C3-55 (83-177),↓C4-4 (21-75),↑IgG 3260 (6081572)
• DAT 
Case 1: Course
• Within 6 months:
– pleural effusion, pulmonary infiltrates (prednisone)
– Episodic photosensitive cutaneous flares (Plaquenil)
– Digital angiitis
• DPGN (WHO IV)  progressive renal involvement
 HBP (cyclophosphamide, prednisone)
• School failure, psychosocial disruption
• Marked non-adherence to medication regimen
• ESRD, TTP, cerebritis, hemodialysis, depression
• Shunt infections, on/off transplantation registry
Cognitive Dysfunction in SLE
• Variable between pts with overt NPSLE and
nSLE
• 52-80% NPSLE vs 27-40% nSLE
• Verbal and non-verbal long-term memory,
and visuospatial memory in both groups;
and visuoconstructional abilities in NPSLE
• Coexistent depression amplifies the deficits
• Maybe present without overt active SLE sxs
Monastero R, et al, J of the Neurological Sci 2001; 184:33-39
Case 2: Learn from old experience
• 17 yo WF initially evaluated for rheumatoid
arthritis with polyarthritis and +ANA
• History of photosensitive rash and
subsequent development of pericarditis led
to dx of SLE
• Renal biopsy done: WHO class II
• Off/on low C3 and C4 and elevated dsDNA
abs
• Notable elevated cholesterol, LDL and
triglycerides PLUS tobacco smoking for >10
years
Case 2: continued
• Had a full term normal pregnancy with healthy
infant; followed by a Bacteroides sepsis 5 days
postpartum
• Approximately 1 year later developed chest pain
• Several ED visits later at adult ED’s she was dx’d
with MI; unable to stent 2º distal disease
• Now cardiac invalid, continues to smoke tobacco
and has active SLE
• Multiple cholesterol lowering agents, Plaquenil
Risk Factors of Premature CVD in cSLE
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Elevated levels of homocysteine
Metabolic syndrome with hyperinsulinemia
Hypertension
Nephrotic range proteinuria
Dyslipoproteinemia/hyperlipidemia
Arterial vasculitis
Antiphospholipid antibodies
Increased oxidative state, anti-Ox-LDL IgG ab
Steroid induced obesity and hyperlipidemia, etc.
Sustained SLE disease activity, ↑ SDI
Stichweh, D , Curr Opin Rheumatol 16:577-587, 2004
Schanberg LE, Sandborg C, Current Rheum Reports 2004;6:425-433
Case 3: Clinical Presentation
• Patient is a 10 yo WF who was admitted to
inpatient psychiatric team for treatment of
PTSD/depression
• Due to worsening abdominal pain, decreased
oral intake, and peripheral edema she was
evaluated by abd U/S which showed clot in IVC
as well as edematous/ enlarged kidneys.
• Further evaluation by CT scan of her
abdomen/thorax showed the clot went from her
right atrium to her infrarenal IVC; there was
extension of clot into renal veins bilaterally.
Ultrasound Results
IVC
Clot
Clinical Presentation
• Anticoagulation with heparin.
• Laboratory evaluation to help determine the
etiology of her clot was undertaken.
Rheumatology service consulted.
• HPI: abd pain since beginning of June; no
fevers, skin rashes, mucosal changes, joint
pain/swelling.
• PMH: no h/o thrombotic events; depression,
PTSD thought to be secondary to alleged
abuse and diagnosed during this admission.
• Family Hx: Maternal grandmother diagnosed
with lupus at 23 years of age.
Laboratory Evaluation
9.3
9.7
30.7
ALC – 1360
137
U/A: 1.015, pH 6.0,
>300 mg protein,
moderate blood
ESR - >140; CRP – 5.26
C3 – 153; C4 - 21.2
[Thrombotic Profile – normal]
[DAT – positive]
ANA – positive at 1:2560; other autoantibodies all negative
[APA Profile – positive]
Pathology Findings : Class V
Light Microscopy
showing increased
mesangial cells.
Light Microscopy
with Silver Stain
showing
epimembranous
deposits.
Electron Microscopy
showing
epimembranous
deposits.
Antiphospholipid Antibodies in cSLE
• Associated with venous and arterial thrombosis,
thrombocytopenia, neurologic disorders and fetal
loss
– Found in 65% of children with SLE
• +LAC, ACLA and false positive VDRL
• Prolonged partial thromboplastin time
• All are associated with thrombosis; esp LAC and
ACLA
• Anticoagulation required if a patient has a
thrombotic event
• Aspirin in everybody else
Seaman DE, et al, Pediatrics. 1995; 96: 1040-5
Management Goals for cSLE
• Counseling, education
• Recommend adequate rest and activity
• Decrease inflammation; prevent end-organ injury
failure
• Preserve renal function; provide HBP Rx; prevent flare
• Provide photo protection
• Maintain up-to-date immunizations
• Management of infection
• Minimize osteoporosis
• Identify patients at risk of thrombo-occlusive events
• Evaluate and treat ASHD risk; dyslipoproteinemia, etc.
• Family planning/contraceptive issues
Combined Oral Contraceptives Are Not
Associated with an Increased Rate of
Flare in SLE Patients in SELENA
• SELENA- Safety of Estrogen in Lupus ErythematosusNational Assessment
• 183 premenapausal pts, mean age 30 y
• Inactive 76%, stable/active 24%
• Randomized, double blind OC vs placebo for 12 28-day
OC cycles
• Primary end point, severe flare, rare; 7/91 (7.7%) OC
vs 7/92 (7.6%) placebo
• Mild/moderate flares 1.41 vs 1.40 flares/person-year
(OC vs P) RR= 1.01, P= 0.96
• 3 or more mild/moderate flares 15% vs 16%
• OC does not increase rate of severe or mild/moderate
flare in SLE
Petri,M, Arthritis Rheum 2004, 50(9): S239, abstract 523
Adjunct Therapy for SLE
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Antimalarials; hydroxychloroquine
Nonsteroidal anti-inflammatory drugs
ASA
Folic Acid
ACE Inhibitors
Glucocorticoids; variable dose ranges
Immunosuppressives non CYC, azathioprine,
mycophenalate mofetil MMF, cyclosporin,
methotrexate
• Herpes Zoster prophylaxis
• Vaccinations
• Organ specific medications; e.g. anti-HTN,
osteoporosis, infection, etc.
Risk Factors for Damage in
Childhood-Onset SLE
• Disease activity and damage in 66 pts
• SLICC/ACR Damage Index 1.76 (mean FU
3.3 y)
• Cumulative disease activity single best
predictor of damage (R2 = 0.30)
• Corticosteroid treatment, APA, acute
thrombocytopenia
• Immunosuppressive agents protective
Brunner, HI, et al. Arthritis and Rheumat.2002;46:436-44.
Long-term Followup of
SLE Nephritis: Toronto*
• 67 pt, M:F 1:3.8, FU mean 11 y
• 15 Class II, 8 Class III, 32 Class IV, 11
Class V
• 4/67 died, 6/67 ESRD, 94% survival rate
• Non-Caucasian pts may be at increased
risk for renal failure
• Azathioprine most commonly employed
immunosuppressive agent
Hagelberg, S. J Rheumatol. 2002;29:2635-42.
Long-Term Outcomes of ChildhoodOnset SLE
• 77 pts (prev 9.6/100,000; F:M 10:1), 39 interviewed
• Mean age at dx 14.6 yrs, 57% Cauc, 40% AA and 3%
Asian
• 8 pts died (86.9% survival) mean F/U 7.6 yrs
• Mean SLEDAI score 6.2 (range: 0-26),
• 42% SDI>0, mean 1.4 (0-10)
– NPL, renal, ocular, and MS accounted for 79% of damage
• AA had higher SLEDAI and SDI scores
• cSLE pts develop 2 times damage of adults and continue
to have active disease
• CYC used in 39%,
– higher rate of ovarian damage (36%); dose related
• HRQL compared to healthy controls much lower mental
and physical component
Brunner et al, Lupus 2006, in press
Conclusion(s)
• SLE in children has the same clinical
expression as in adults but a more
aggressive disease course.
• Numerous potential complications loom
behind the scenes and must be anticipated
and monitored.
• Better understanding of the pathogenesis
will enable better targeted and safer
therapy.
• Multiple trials are ongoing at CCHMC to
investigate better health outcomes for cSLE.