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Systemic Lupus Erythematosus, ANA’s, etc.

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1 Systemic Lupus Erythematosus, ANA’s, etc.
Hermine Brunner, MD MSc Assistant Professor of Pediatrics Division of Rheumatology Cincinnati Children’s 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/1:10 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 4p 6p11-21 12p24 16q12 Tsao, BP, Curr Opinion Rheum, 2004; 16:

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 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

17 IMMUNOLOGIC DISORDER A) Anti-dsDNA: antibody to native DNA in abnormal titer OR 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

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 1:20 - 1:40 Screening titer Pattern 1: x titer
speckled ENA’s 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):

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 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:

25 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!!!!!!!

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

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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
Raynaud’s 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

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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

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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 Coomb’s, 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 gm/m² up to 7 pulses Cont’d on 1) cyclophosphamide, 2) azathioprine 1-3mg/kg, or 3)M ycophenolate mofetil (Cellcept, MMF) 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): , 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-α Houssian FA, J Am Soc Neprol, 2004; 15:

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

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55 Case 1: Physical Examination
T 101.8, Wt 27.1 kg (30%), Ht (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 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 ( ) 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; 184:33-39

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 >10 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 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

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 16: , 2004 Schanberg LE, Sandborg C, Current Rheum Reports 2004;6:

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, >300 mg protein, moderate blood 30.7 ALC – ESR - >140; CRP – 5.26 C3 – 153; C [Thrombotic Profile – normal] [DAT – positive] ANA – positive at 1:2560; 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:

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 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.2002;46:

72 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 ;29:

73 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

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.

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