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.

Hermine Brunner, MD MSc

Assistant Professor of Pediatrics

Division of Rheumatology

Cincinnati Children’s Hospital Medical Center


  • 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


  • 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

    • 1q23

    • 1q25-31

    • 1q41-42

    • 2q35-37

    • 4p16-15.2

    • 6p11-21

    • 12p24

    • 16q12

Tsao, BP, Curr Opinion Rheum, 2004; 16: 513-521


Malar rashSerositis

Discoid rashRenal disorder

PhotosensitivityNeurologic disorder

Oral ulcersHematologic disorder

ArthritisImmunologic disorder

Antinuclear antibody

Revised 1997


  • 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.


  • Fixed erythema, flat or raised, over the malar eminences

  • tending to spare the nasolabial folds


  • 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 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


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


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


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


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


  • 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

  • Minocycline (Minocin)

  • Phenytoin (Dilantin)

  • Carbamazepine (Tegretol)

  • Ethosuximide (Zarontin)


  • 1:20 - 1:40 Screening titer

    • 1: x titer

  • Pattern

    • speckled - + ENA’s

    • rim- ds DNA

    • homogeneous- DNA (LE prep)

    • nucleolar- Scl - 70


Tissue Specific Nuclear

Antibodies Antibodies




Anti-LKM Sm

Anti-PCds DNA

Hep-2ss 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 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!!!!!!!


Most common signs/symptoms

  • Unexplained fever, any pattern

  • Malaise

  • Weight Loss

  • Arthralgia


  • “Butterfly Rash” - 1/3 at onset

  • Angiitic papules

  • Periungual erythema

  • Urticaria / angioedema

  • Palatal ulcer / aphthous ulcer

  • Alopecia


  • Discoid lupus

  • Subacute cutaneous lupus

  • Livedo reticularis

  • Nailfold capillary changes

  • Vasculitic ulceration

  • Panniculitis

  • Nasal septal perforation



vasculitis in SLE


  • Arthralgia / Arthritis

  • Myalgia / Myositis

  • Ischemic necrosis of bone - AVN


  • Small vessel vasculitis

  • Palpable purpura

  • Raynaud’s phenomenon

  • Antiphospholipid antibody syndrome


  • Pericarditis

  • Myocarditis

  • Endocarditis, Libman-Sacks

  • Accelerated atherosclerosis


  • Pleuritis/Pleural effusion

  • Infiltrates/Atelectasis

  • Acute lupus pneumonitis

  • Pulmonary hemorrhage

  • “Shrinking lung” - diaphragm dysfunction

  • Subclinical restrictive disease


  • Anorexia, weight loss, nonspecific abdominal pain

  • Pancreatitis

  • Mesenteric arteritis

  • Esophageal dysmotility


  • Generalized lymphadenopathy

  • “Lupoid hepatitis” vs SLE hepatic involvement

  • Functional asplenia


  • 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


Behavior/Personality changes, depression

Cognitive dysfunction





Pseudotumor cerebri

Transverse myelitis

Peripheral neuropathy

Total of 19 manifestations described


  • Usually asymptomatic

  • Gross hematuria

  • Nephrotic syndrome

  • Acute renal failure

  • Hypertension

  • End stage renal failure


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


Class INormal

Class IIMesangial

IIAMinimal alteration

IIBMesangial glomerulitis

Class IIIFocal and segmental proliferative glomerulonephritis

Class IVDiffuse proliferative glomerulonephritis

Class VMembranous glomerulonephritis

Class VIGlomerular sclerosis


  • 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

  • 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 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

  • 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

  • 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

  • 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 (608-1572)

  • 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

  • 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



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

9.3U/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

Light Microscopy with Silver Stain showing epimembranous deposits.

Electron Microscopy showing epimembranous deposits.

Light Microscopy showing increased mesangial cells.

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 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

  • 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 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

  • 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


  • 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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