Systemic lupus erythematosus ana s etc
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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

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Systemic lupus erythematosus ana s etc

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


  • 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

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

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

The 1982 revised criteria for classification of sle


Malar rashSerositis

Discoid rashRenal disorder

PhotosensitivityNeurologic disorder

Oral ulcersHematologic disorder

ArthritisImmunologic disorder

Antinuclear antibody

Revised 1997

The 1982 revised criteria for classification of sle1


  • 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



  • 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



  • Nonerosive arthritis involving 2 or more peripheral joints

  • Characterized by tenderness, swelling, or joint effusion.



A)Pleuritis - convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion


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


B)Cellular casts - may be red cell,hemoglobin, granular, tubular, or mixed

Neurologic disorder


A)Seizures - in the absence of offending drugs or known metabolicderangements, e.g., uremia,ketoacidosis, or electrolyte imbalance


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)Lymphopenia - less than 1,500/mm3 on 2 or more occasions


D)Thrombocytopenia - less than 100,000/mm3 in the absence of offending drugs

Immunologic disorder


A)Anti-dsDNA: antibody to native DNA in abnormal titer


B)Anti-Sm: presence of antibody to Sm nuclear antigen


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

Drug-Induced Lupus

  • Minocycline (Minocin)

  • Phenytoin (Dilantin)

  • Carbamazepine (Tegretol)

  • Ethosuximide (Zarontin)

Antinuclear antibody1


  • 1:20 - 1:40 Screening titer

    • 1: x titer

  • Pattern

    • speckled - + ENA’s

    • rim- ds DNA

    • homogeneous- DNA (LE prep)

    • nucleolar- Scl - 70

Systemic lupus erythematosus ana s etc


Tissue Specific Nuclear

Antibodies Antibodies




Anti-LKM Sm

Anti-PCds DNA

Hep-2ss DNA

Arthralgia and positive ana or rf

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

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

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

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 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


  • “Butterfly Rash” - 1/3 at onset

  • Angiitic papules

  • Periungual erythema

  • Urticaria / angioedema

  • Palatal ulcer / aphthous ulcer

  • Alopecia

Sle mucocutaneous involvement1


  • Discoid lupus

  • Subacute cutaneous lupus

  • Livedo reticularis

  • Nailfold capillary changes

  • Vasculitic ulceration

  • Panniculitis

  • Nasal septal perforation

Systemic lupus erythematosus ana s etc



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


  • 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





Pseudotumor cerebri

Transverse myelitis

Peripheral neuropathy

Total of 19 manifestations described

Sle renal involvement


  • 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 INormal

Class IIMesangial

IIAMinimal alteration

IIBMesangial glomerulitis

Class IIIFocal and segmental proliferative glomerulonephritis

Class IVDiffuse proliferative glomerulonephritis

Class VMembranous glomerulonephritis

Class VIGlomerular sclerosis

Sle laboratory evaluation


  • 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

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)

Long term management issues

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

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

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

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 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 (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

Targeted Immune Intervention

  • Directed against B Cells: Rituximab, anti-CD20 B cell depleting monoclonal antibody

  • LJP 394, anti-dsDNA-producing B cells

  • Co-stimulatory signalsCD40-CD40L (CD154) blockadeCTLA41g, abatacept: binding to CD80 and CD86 prevents engagement to CD28 to T cells thereby prevents co-stimulation

  • Cytokine blockadeIL10, INF-α

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

Major clinical syndromes in sle requiring vigilance

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

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

Case 1 physical examination

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

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 (608-1572)

  • DAT 

Case 1 course

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

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

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

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

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 16:577-587, 2004

Schanberg LE, Sandborg C, Current Rheum Reports 2004;6:425-433

Case 3 clinical presentation

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

Ultrasound Results



Clinical presentation

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

Laboratory Evaluation

9.3U/A: 1.015, pH 6.0,

9.7 137>300 mg protein,

moderate blood


ALC – 1360

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

Pathology Findings : Class V

Light Microscopy with Silver Stain showing epimembranous deposits.

Electron Microscopy showing epimembranous deposits.

Light Microscopy showing increased mesangial cells.

Antiphospholipid antibodies in csle

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

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

Systemic lupus erythematosus ana s etc

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

Adjunct therapy for sle

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.

Risk factors for damage in childhood onset sle

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

Long-term Followup ofSLE 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 childhood onset sle

Long-Term Outcomes of Childhood-Onset 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.

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