Systemic Lupus Erythematosus, ANAs, etc'

1
Systemic Lupus Erythematosus, ANAs, etc.

• Hermine Brunner, MD MSc
• Assistant Professor of Pediatrics
• Division of Rheumatology
• Cincinnati Childrens Hospital Medical Center

2
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

3
SLE - EPIDEMIOLOGY

• 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/110 ratio

4
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

5
Genetics in SLE

• Eight of the best supported SLE susceptibility
  loci are the following
• 1q23
• 1q25-31
• 1q41-42
• 2q35-37
• 4p16-15.2
• 6p11-21
• 12p24
• 16q12

Tsao, BP, Curr Opinion Rheum, 2004 16 513-521
6
THE 1982 REVISED CRITERIA FOR CLASSIFICATION OF
SLE

• Malar rash Serositis
• Discoid rash Renal disorder
• Photosensitivity Neurologic disorder
• Oral ulcers Hematologic disorder
• Arthritis Immunologic disorder
• Antinuclear antibody

Revised 1997
7
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.

8
MALAR RASH

• Fixed erythema, flat or raised, over the malar
  eminences
• tending to spare the nasolabial folds

9
DISCOID RASH

• Erythematous raised patches with adherent
  keratotic scaling and follicular plugging
• Atrophic scarring may occur in older lesions

10
PHOTOSENSITIVITY

• Skin rash as a result of unusual reaction to
  sunlight
• by patient history or physician observation

11
ORAL ULCERS

• Oral or nasopharyngeal ulceration
• Usually painless, observed by a physician

12
ARTHRITIS

• Nonerosive arthritis involving 2 or more
  peripheral joints
• Characterized by tenderness, swelling, or joint
  effusion.

13
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

14
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

15
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

16
HEMATOLOGIC DISORDER

• A) Hemolytic anemia - with reticulocytosis
• OR
• B) Leukopenia - less than 4,000/mm3 total on 2
  or more occasions
• OR
• C) Lymphopenia - less than 1,500/mm3 on 2 or
  more occasions
• OR
• D) Thrombocytopenia - less than 100,000/mm3 in
  the absence of offending drugs

17
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

18
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

19
Drug-Induced Lupus

• Minocycline (Minocin)
• Phenytoin (Dilantin)
• Carbamazepine (Tegretol)
• Ethosuximide (Zarontin)

20
ANTINUCLEAR ANTIBODY

• 120 - 140 Screening titer
• 1 x titer
• Pattern
• speckled - ENAs
• rim - ds DNA
• homogeneous - DNA (LE prep)
• nucleolar - Scl - 70

21
SLE

• Tissue Specific Nuclear
• Antibodies Antibodies
• ATA Ro/SSA
• Anti ASMA La/SSB
• Anti-MITO RNP
• Anti-LKM Sm
• Anti-PC ds DNA
• Hep-2 ss DNA

22
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

23
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
24
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 1160, 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, 95892-895
25
Clinical Utility of Antinuclear ANA Tests in
ChildrenMcGhee JL et al, BMC Pediatrics 2004, 4
13

• 110 pts referred to Rheum for ANA
• 80 children with musculoskeletal problems
  syndromes
• 10 pts subsequently dxd SLE, 1 MCTD, 1 Prim
  Raynauds, 18 with JIA
• Nonurticarial rash more common in SLE, p0.007
• Children with SLE were older 14.2 vs 11 yrs,
  p0.001
• ANA gt 1640 was predictor for SLE while titers
  of lt1360 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!!!!!!!

26
SLE - CLINICAL MANIFESTATIONS

• Most common signs/symptoms
• Unexplained fever, any pattern
• Malaise
• Weight Loss
• Arthralgia

27
SLE - MUCOCUTANEOUS INVOLVEMENT

• Butterfly Rash - 1/3 at onset
• Angiitic papules
• Periungual erythema
• Urticaria / angioedema
• Palatal ulcer / aphthous ulcer
• Alopecia

28
(No Transcript)
29
(No Transcript)
30
SLE - MUCOCUTANEOUS INVOLVEMENT

• Discoid lupus
• Subacute cutaneous lupus
• Livedo reticularis
• Nailfold capillary changes
• Vasculitic ulceration
• Panniculitis
• Nasal septal perforation

31

• Ulcerated
• leukocytoclastic
• vasculitis in SLE

32
SLE - MUSCULOSKELETAL DISEASE

• Arthralgia / Arthritis
• Myalgia / Myositis
• Ischemic necrosis of bone - AVN

33
SLE - VASCULOPATHY

• Small vessel vasculitis
• Palpable purpura
• Raynauds phenomenon
• Antiphospholipid antibody syndrome

34
SLE - CARDIAC INVOLVEMENT

• Pericarditis
• Myocarditis
• Endocarditis, Libman-Sacks
• Accelerated atherosclerosis

35
SLE - PLEUROPULMONARY DISEASE

• Pleuritis/Pleural effusion
• Infiltrates/Atelectasis
• Acute lupus pneumonitis
• Pulmonary hemorrhage
• Shrinking lung - diaphragm dysfunction
• Subclinical restrictive disease

36
(No Transcript)
37
SLE - GASTROINTESTINAL MANIFESTATIONS

• Anorexia, weight loss, nonspecific abdominal pain
• Pancreatitis
• Mesenteric arteritis
• Esophageal dysmotility

38
SLE LIVER , SPLEEN LYMPH NODE

• Generalized lymphadenopathy
• Lupoid hepatitis vs SLE hepatic involvement
• Functional asplenia

39
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

40
(No Transcript)
41
SLE - NEUROPSYCHIATRIC INVOLVEMENT

• Behavior/Personality changes, depression
• Cognitive dysfunction
• Psychosis
• Seizures
• Stroke
• Chorea
• Pseudotumor cerebri
• Transverse myelitis
• Peripheral neuropathy
• Total of 19 manifestations described

42
SLE - RENAL INVOLVEMENT

• Usually asymptomatic
• Gross hematuria
• Nephrotic syndrome
• Acute renal failure
• Hypertension
• End stage renal failure

43
SLE - NEPHRITIS

• Nephritis remains the most frequent cause of
  disease-related death.

44
WORLD HEALTH ORGANIZATION CLASSIFICATION OF LUPUS
NEPHRITIS

• Class I Normal
• Class II Mesangial
• IIA Minimal alteration
• IIB Mesangial glomerulitis
• Class III Focal and segmental proliferative
  glomerulonephritis
• Class IV Diffuse proliferative
  glomerulonephritis
• Class V Membranous glomerulonephritis
• Class VI Glomerular sclerosis

45
SLE - LABORATORY EVALUATION

• Antinuclear antibody profile
• Anti dsDNA abs, Sm abs
• C3, C4, IgA, IgG, IgM
• Direct Coombs, DAT
• Antiphospholipid antibodies
• ACLA - Anticardiolipin antibodies
• LAC - Lupus anticoagulant
• CBC with Diff, U/A, CMP, TSH, ESR

46
Comprehensive Evaluation of a Child with SLE

• 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)

47
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

48
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

49
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

50
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
• Contd on 1) cyclophosphamide, 2) azathioprine
  1-3mg/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 (P0.05 and P0.009,
  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
51
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-a

Houssian FA, J Am Soc Neprol, 2004 15 2694-2704
52
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

53
Case 1 9 yo AAF with SLE

• 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

54
(No Transcript)
55
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

56
Case 1 Laboratory Investigation

• Hgb 9.5 gm, WBC 4.05, 55 PMN
• platelets 257,000
• U/A essentially negative
• RF negative
• ANA 15120, diffuse, membranous
• Ro (SSA) ?, La (SSB) ?, RNP ?, Sm ?,
• ds DNA 15120, APA negative
• ?C3-55 (83-177),?C4-4 (21-75),?IgG 3260
  (608-1572)
• DAT ?

57
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

58
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 18433-39
59
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 gt10 years

60
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 EDs she was
  dxd with MI unable to stent 2º distal disease
• Now cardiac invalid, continues to smoke tobacco
  and has active SLE
• Multiple cholesterol lowering agents, Plaquenil

61
Risk Factors of Premature CVD in cSLE

• 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 16577-587,
2004
Schanberg LE, Sandborg C, Current Rheum Reports
20046425-433
62
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.

63
Ultrasound Results
IVC
Clot
64
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.

65
Laboratory Evaluation

• 9.3 U/A 1.015, pH 6.0,
• 9.7 137 gt300 mg protein,
• moderate blood
• 30.7
• ALC 1360
• ESR - gt140 CRP 5.26
• C3 153 C4 - 21.2
• Thrombotic Profile normal
• DAT positive
• ANA positive at 12560 other autoantibodies
  all negative
• APA Profile positive

66
Pathology Findings Class V
Light Microscopy with Silver Stain showing
epimembranous deposits.
Electron Microscopy showing epimembranous
deposits.
Light Microscopy showing increased mesangial
cells.
67
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
68
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

69
Combined Oral Contraceptives Are Not Associated
with an Increased Rate of Flare in SLE Patients
in SELENA

• SELENA- Safety of Estrogen in Lupus
  Erythematosus-National 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
70
Adjunct Therapy for SLE

• 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.

71
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.200246436-44.

72
Long-term Followup ofSLE Nephritis Toronto

• 67 pt, MF 13.8, 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. 2002292635-42.
73
Long-Term Outcomes of Childhood-Onset SLE

• 77 pts (prev 9.6/100,000 FM 101), 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 SDIgt0, 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
74
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.

75
(No Transcript)