Embed Size (px)
Citation preview
PEDIATRIC RHEUMATOLOGYcase presentations
• Y Uziel MD MSc
• Pediatric Rheumatology• Meir Medical Center
Case Presentation – N.R.
• 14 yr girl
• Lethargy, anorexia, weight loss,
Investigations:ESR – 52mm/hCBC 3.3/11.1/91 SMA - normal
Urine – trace protein and blood,microscopy normal
ANA 1/1280; anti Sm, dsDNA - positive C3↓- 40, C4- ↓ 5
Case Presentation – N.R.
• Diagnosis?• Further approach?• Therapy?
Case Presentation – N.R.
• 14 yr girl• Lethargy, anorexia, weight loss, • malar rash, ulcers• Investigations:
CBC 3.3/111/91 lymph 1.22 Coombs’ positiveANA 1/1280; anti Sm, dsDNA, LE prep-positiveC3 0.1, C4 0.05BUN, Cr normalU/A: protein 1.0, Hgb trace, microscopy normalRenal biopsy: diffuse proliefrative glomerular nephritis
• Rx: Prednisone 20 mg PO TID Azathioprine 100 mg PO QD
1 שאלה מספר.מופיעה תפרחת פרפר עייפות וירידה בכוח השרירי15 לנערה בת
?מהי האבחנה המשוערת
סקלרודרמה1.
זאבת אדמנתית מערכתית2.
פולימיוזיטיס3.
דרמטומיוזיטיס4.
אריתמה מולטיפורמה5.
1 שאלה מספר.מופיעה תפרחת פרפר עייפות וירידה בכוח השרירי15 לנערה בת
?מהי האבחנה המשוערת
סקלרודרמה1.
זאבת אדמנתית מערכתית2.
פולימיוזיטיס3.
דרמטומיוזיטיס4.
אריתמה מולטיפורמה5.
Systemic Lupus Erythematosus
• An episodic, multisystem disease• Widespread inflammation of blood
vessels and connective tissues• Clinical manifestations extremely
variable• A prototype of autoimmune disease in
humans
Clinical Features of SLE
• Constitutional• Cutaneous• Musculoskeletal• Vascular• Cardiovascular• Pulmonary• Gastrointestinal• Liver, spleen and nodes• Neurologic• Ocular• Renal• Hematologic
2שאלה מספר ?זאבת מה נכון לגבי ביטויים קליניים של
דפורמציות מפרקיות מתפתחות בשכיחות 1..SLEגבוהה בחולי
.SLE- ביותר ב .סובלים מנפריטיס SLEמחולי - 5% כ4.
2שאלה מספר ?זאבת מה נכון לגבי ביטויים קליניים של
דפורמציות מפרקיות מתפתחות בשכיחות 1..SLEגבוהה בחולי
.SLE- ביותר ב .סובלים מנפריטיס SLEמחולי - 5% כ4.
OUTCOME OF A NATIONAL COHORT OF
PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS
N Gorodnitski, PJ Hashkes, M Mukamel, S Padeh, R Brik,
J Barash, D Mevorach, Y Berkun, Z Tauber, J Press, L Harel, P Navon, Y Naparstek, Y Uziel,
Pediatric Rheumatology Study Group of Israel
METHODS
•Patients were identified from the Israeli national registry of children with rheumatic diseases who were diagnosed and followed between 1987-2003.
•A retrospective charts data analysis on all cases meeting the ACR diagnostic criteria of childhood onset SLE.
Web site internet access for data entry
ACR Criteria
Laboratory assessment
3שאלה מספר כל המשפטים הבאים נכונים בהקשר ל
ANTINUCLEAR ANTIBODY -ANA.:פרט ל
.1ANA חיובי בכייל נמוך ניתן למצוא באחוז גבוה באוכלוסיה.הבריאה
חיובי ANAעם הגיל עולה מספר בני האדם שלהם 2.
-חיובי ויש חשד קליני מתאים כדאי לבדוק ANA- אם ה 3.dsDNA ANTI
.4ANA חיובי מוצאים לעיתים קרובות ב- JUVENILEIDIOPATHIC ARTHRITIS בצורה
.OLIGOARTICULAR -הכמעט SLEחיובי יהיה בעתיד ANAלאדם שיש לו 5.
.בביטחון
3שאלה מספר כל המשפטים הבאים נכונים בהקשר ל
ANTINUCLEAR ANTIBODY -ANA.:פרט ל
.1ANA חיובי בכייל נמוך ניתן למצוא באחוז גבוה באוכלוסיה.הבריאה
חיובי ANAעם הגיל עולה מספר בני האדם שלהם 2.
-חיובי ויש חשד קליני מתאים כדאי לבדוק ANA- אם ה 3.dsDNA ANTI
.4ANA חיובי מוצאים לעיתים קרובות ב- JUVENILEIDIOPATHIC ARTHRITIS בצורה
.OLIGOARTICULAR -הכמעט SLEחיובי יהיה בעתיד ANAלאדם שיש לו 5.
.בביטחון
Growth parameters
Therapy
JSLE SLEDAI
RESULTS
AT DIAGNOSIS - 102 patients 81% females Mean age - 13.3 ± 2.6 years (range 6.9 - 17.7)Median age – 13.4
PRINTO - 557 patients – 39 countries
82% femalesMedian age – 12.2
At Diagnosis
Initial clinical manifestations: Hematological - 94%Malar rash - 49%Musculoskeletal (non erosive arthritis)-45%Renal involvement - 41%Oral or nasal ulcerations - 21% Serositis -16%. (pleuritis 13, pericarditis – 6)CNS - 7%
Clinical manifestations any time
At presentation % any time %
Hematological - 94% 100Malar rash - 49% 56Musculoskeletal -45% 58Renal involvement - 41% 53Oral or nasal ulcerations - 21% 26 Serositis -16%. 19CNS - 7% 8
Renal-41%
27 had biopsiesDPGN – 15MPGN - 4Mesangial – 5Focal segmental – 6Some had more than 1 biopsyNephrotic syndrome – 2
1 had renal transplant
Hematological - 94%
Anemia– 77%Leukopenia < 5000 – 53%Lymphopenia < 1500 – 47%Thrombocytopenia < 150000 - 35%
ESR – 70mm/h (PRINTO -57)Mean HgB – 10.9 g/dL (PRINTO -10.9)
Mean lymphocyte count - 1450
CNS - 7%Psychosis –3Seizures –4
Pseudotumor - 3Ataxia – cerebelitis – 3Chorea – 1TIA – 2Brain infarction - 1CT – 5 patients – 1 infarction,EEG – 1 slow activity
At Diagnosis
Mean SLEDAI -17.2 ± 9.0 (range 2 - 60). Median - 17 TREATMENT - 80 children (80%) started therapy with corticosteroids, 19 (19%) with immunosuppressive drugs.
PRINTO – Median SLEDAI - 17
Epidemiology
• Incidence 0.6/100,000 (<15 yrs)• Most common between 10 and 14 years
of age• F:M= 4.5:1• Worldwide distribution• More common in Black, Asian or
Hispanic children
Etiology and Pathoegnesis
• Unknown• Multifactorial causes in a genetically
predisposed hostEnvironmental – viruses, drugs, sun – lightGenetic, HormonalImmune – B – T cells interactionActivation of apoptosis related oncogens
Autocure-www.autocure.org curing autoimmune diseases• Autocure is an EU funded research project
within the FP6. Involved in the project are 26 different partners, of which 6 are industrial partners and 20 are from the academia, from all over Europe
STAT4 and the risk of rheumatoid arthritis and
systemic lupus erythematosus. • N Engl J Med.
Sep 2007
USA- Sweden (Genetech)
• New publication – N Engl J Med. 2008 Jan vol 358
• 2 new genetic loci for SLE• - B lymphoid tyrosine kinase BLK- C8orf13 (chr
8)• ITGAM-ITGAX (chr 16)• OR - odds ratio- 1.39
Immune Dysregulation
Ag driven T cell dependent processAnti dsDNA Ab’s, auto Ab’sLymphopenia (T cells )sIL2R ( T cell activity)B cell - polyclonal hypergammaglobulinemiaImmune complexesC’ deficiency
Case Presentation – A.P.
• 9 year old pale girl• Investigations: Hgb 5.1, platelets 78, Coombs’ positive• Rx: PO Prednisone: steroid dependent
Case Presentation – A.P. (Cont’d)
6 months later - • Referred to Lupus clinic• fevers, weight loss, joint symptoms, malar rash• Investigations: ANA 1/1280
dsDNA, anti Sm positiveDiagnosis- SLER: Prednison 50 mg PO QD Hydroxychloroquine 200 mg PO QD
Systemic LupusErythematosus - Cytopenias
• Anemia• Thrombocytopenia• Leukopenia
SLE - Leukopenia
• Occurs in 20 – 40% of patients• Lymphopenia 2° to BM suppression
splenic sequestration antigranulocyte
antibodies• INFECTION
SLE - Thrombocytopenia
• Occurs in 15 – 45% of patients• Secondary to peripheral
destruction• May present as classic ITP• Chronic ITP – THINK SLE!• Evan’s Syndrome
M.S. – 13 year old girl
Abdominal pain, vomiting, cough, hemoptysis
Lab: Hb-8.8, WBC-5.3
CXR: Pneumonia
Rx: Erythromycin and iron
M.S. (Cont’d)
FatigueCoughPallorLab: Hb-5.3, WBC-6.5, Plt- 172CXR: Pulmonary hemorrhagePFT: DLCO- 146 %
Serology
Lab: LE prep positiveANA > 1/1280Anti- dsDNA positiveAnti Sm positiveC3 0.17 (0.51-0.95)C4 0.04 (0.08-0.44)
Course and Treatment
• Rx: Blood transfusion• CS
• Recurrent bleeding [on CS]• Arthritis/Arthraglia• Treated with CS and Cyclophosphamide
Pulmonary Manifistations of Childhood Onset SLE• Sub-clinical: Abnormal PFT• Pleuritis: 50% - 70%• Isolated or recurrent pleural effusion• Acute and chronic pneumonitis• Pulmonary haemorrhage: < 5%
(10 – 20% of SLE deaths)• Shrinking lungs• Pneumothorax• Nodules• Pulmonary emboli• Pulmonary hypertension• Infection!
Cardiac Manifestation of Childhood Onset SLE
Pericarditis (25 – 30%)Rarely tamponadeMyocarditis < 10%Endocarditis: Libman-SacksCoronary arteritisPremature atherosclerosis
Renal Involvement
• Degree of proteinuria• Urine sediment-casts!
• Bx- 10 glomeruli, Interstitium
• Degree of proliferation• Degree of fibrosis (scarring)• LM-EM-IF sub-endothelial
• EM- Deposits sub-epithelial
Renal Involvement
I – NormalII – MesangialIII – Focal-segmental GNIV – Diffuse proliferative GNV - Membraneous
L.M. – 18 year old girl
Malar rash Mouth ulcers Pleuritic chest pain Headache ANA positive
Diag: SLERx: OH-CLQ, CS, optalgin
L.M. – 18 year old girl
• Further investigations?
Acute confusion-disorientationGeneralized T.C. seizure
L.M. (Cont’d)
Acute confusion-disorientationGeneralized T.C. seizureBrain CT: left temporal infarct
with a central haemorrhage lateral sinus thrombosis
Seizures, thrombocytopenia ~ 5x109/LRx: Heparin – CS – IVIGICP neurosurgery PICUPlasmapheresis – IV bolus Cyclophosphamide
L.M. (Cont’d) Discharged- complete recovery
Proteinuria 13.9 g/day TP/Alb: 41/91
Renal biopsy: membranous nephropathy Continued on CS and
Cyclophosphoamide
F/U: Renal and CNS recovery On Coumadin, Phenobarbital, CS
Cyclophosphamide
R.Y. – 15 year old girl
Change in behaviour;anxiety attacks, agitation,delusions, hallucinations
Admission-psychosistreated with Chlorpromazine, Chloral hydrate
Lab: ANA- 1/160Rheumatology consult: Is it SLE?
Is it CNS SLE?
R.Y. (Cont’d)
O/E: Bilateral anterior uveitisLab: ANA 1/160 – 1/320
LP protein 0.45 gCerebral SPECT: Mild patchy decreased
perfusion
Is it CNS SLE?
• Psychosis• Inflammatory eye disease• Slight Protein (0.45) in CSF• Mildly abnormal SPECT scan• ANA: 1/160 – 1/320
R.Y. (Cont’d)
Psychotic symptoms still present, started on CS
F/U: Gradual improvementBack to school on CS
Neuropsychiatric Lupus
Neurologic Psychiatric
Seizures
PsychosisNeuropathies
O.B.S
Neuropsychiatric Manifestations of Childhood SLE
• Organic brain syndrome• Seizures• Functional psychosis• Aseptic meningitis• Cranial nerve palsies• Peripheral neuropathy• Mononeuritis multiplex
Neuropsychiatric Manifestations of Childhood SLE (Cont’d)
Less common:• Chorea• CVA• Transverse myelitis• Cerebellar ataxia• Pseudotumor cerebri• Papilledema• Guillain-Barré-like syndrome• Anorexia nervosa
R/O: CNS InfectionHypertensive encephalopathySteroid induced psychosis
Pathogenesis
• Multifocal impairment of neurologic function at anatomically distinct sites
• Readily reversible diffuse impairment of higher cerebral function
• Immune complex-mediated vasculitis• Action of autoantibodies on cell
membrane
Disease Activity Scores
LAISLEDAISLAM
JSLE concept
DISEASE ACTIVITY: reversible manifestations resulting directly from inflammatory processes.
DISEASE DAMAGE: persistent changes in anatomy, physiology, pathology or function which result from prior active disease (causing scarring, fibrosis and atrophy), as well as from complications of therapy or other events. Changes associated with damage are often irreversible and cumulative and/or present for at least 6 months
Final JSLE Disease Activity core set
MD DA global assessment: 10 cm VASHealth Related Quality of Life: Physical well
beingParents/patients DA global assessment: 10 cm
VASKidney assessment: urine protein/24 h Global DA tool: ECLAM (or SLEDAI or SLAM)Immunological laboratory parameter: anti-DNA only descriptive→
JSLE – Improvement definition
2 of any 5 improved by at least 50%No more than 1 worse by more than 30%(proteinuria only if above 0.5 g/day)
Functional Ability (CHAQ-Childhood Health Assessment Questionnaire)multinational – all languages
• Physical – football, biking, walk 100 meters, climb one floor
• Eat, dress, wash…• Psychological – argue a lot, anger attacks,
cry, • Family activities…• Pain!!!
Therapy
• Supportive, sunscreens• NSAIDS• Hydroxychloroquine• Corticosteroids• Cyclophosphamide• Azathioprine• IVIG• Cellcept• Rituximab• Bone marrow transplant
4שאלה מספר פרט לכל הבאים הם תופעות לוואי של טיפול בקורטיקוסטרואידים :
אוסטאופורוזיס1.
4שאלה מספר פרט לכל הבאים הם תופעות לוואי של טיפול בקורטיקוסטרואידים :
אוסטאופורוזיס1.
“The arrival of a good clown exercises more beneficial influence upon the health of a townthan a twenty asses laden with drugs”
Thomas Sydenham (1624-1689)
5שאלה מספר כוללים את Hydroxychloroquine- יתרונות הטיפול ב
:פרט לכל הבאים
.SLEטיפול זה עשוי למנוע התלקחויות של 1.Steroid - מהווה טיפול לחולים עם נפריטיס כ.2
Sparing Agent..ניתן לשימוש בזמן היריון במידת הצורך3.-Anti(אגרגנטי על טסיות -בעל אפקט אנטי4.
Aggregate.(.בעל אפקט מועיל על פרופיל השומנים בדם5.
5שאלה מספר כוללים את Hydroxychloroquine- יתרונות הטיפול ב
:פרט לכל הבאים
.SLEטיפול זה עשוי למנוע התלקחויות של 1.Steroid - מהווה טיפול לחולים עם נפריטיס כ.2
Sparing Agent..ניתן לשימוש בזמן היריון במידת הצורך3.-Anti(אגרגנטי על טסיות -בעל אפקט אנטי4.
Aggregate.(.בעל אפקט מועיל על פרופיל השומנים בדם5.
Rituximab - Mabtera
• Anti CD 20• For resistant cases• As first line therapy in SLE nephritis,
other main organ involvements• 2 IV doses 2 weeks apart
AUTOLOGUS STEM CELL TRANSPLANTATION
Priming by G-CSF
Obtain stem cells from peripheral blood
CD3 depletion – CD34 positive selection
Conditioning – Cyclophosphamide, irradiation, ATG
Recovery phase (infections..)
AUTOLOGUS STEM CELL TRANSPLANTATION
Is it ethical to propose a potentially fatal treatment
for a disease that is usually non fatal,although occasionally severely disabling?
Long time results?
Re – active memory T cells?
Patient selection and time is crucial
AUTOLOGUS STEM CELL TRANSPLANTATION
• Abnormal auto reactive T cell clonesMassive immunosuppression to delete theseclones
• Bone marrow reconstruction with non auto reactive T cell precursors will hopefully produce normal T cell repertoire without memory cells
• Early observations of long term remission following BMT for malignancy or aplastic anemia
PrognosisChronic course: exacerbations and remission5 year survival rate ≈ 99%
Disease complication Therapy complicationKidney C.S. – ImmunosuppressionLungCNS… Infection
Short-term Long-termAvascular necrosis SterilityOsteopenia-fractures.. Malignancy…
OUTCOME OF A NATIONAL COHORT OF
PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS
N Gorodnitski, PJ Hashkes, M Mukamel, S Padeh, R Brik,
J Barash, D Mevorach, Y Berkun, Z Tauber, J Press, L Harel, P Navon, Y Naparstek, Y Uziel,
Pediatric Rheumatology Study Group of Israel
Damage Index
1 YEARS FOLLOW UP - 83 children
Mean SLEDAI of 8.2 ± 8.0 (range 0 - 46). TREATMENT - 55 (66%) were still on corticosteroids 27 (32%) were on immunosuppressive drugs
3 YEARS FOLLOW UP - 60 children
Mean SLEDAI of 9.5 ± 7.3 (range 0 - 36). TREATMENT - 44 (73%) were on corticosteroids 23 (38%) were on immunosuppressive drugs. Mean SLICC/ACR damage index was 0.4 ± 1.1 (0 - 7).
HSC – 1.76 (3.3 years)
5 YEAR FOLLOW UP - 44 children
Mean SLEDAI of 6.7 ± 5.2 (0 - 21). TREATMENT - 28 (64%) of them were on steroids 22 (50%) on immunosuppressive drugs. Mean SLICC/ACR damage index was 0.5 ± 1.2 (0 - 7).Death - 1 Chronic Renal Failure – 5
SUMMARY
Major organ involvement Renal -53%Serositis -19%. CNS - 8%
Malar rash, arthritis – most common signsLaboratory – hematological most common
CONCLUSIONS The 5-year outcome of our national pediatric SLE cohort was in general good, with a progressive decrease in the disease activity (SLEDAI) score.
Damage index was very low after 5 years.
It is possible that relatively early and prolonged use of immunosuppressive medications in many patients led to the good outcome.
Mean SLICC/ACR was 0.4 ± 1.1 (0 - 7). HSC – 1.76 (3.3 years)
(Cumulative disease activity over time – the single most predictor of damage.Immunosuppressive was protective - A@R 2002)
FUTURE STUDY
• Are difference in clinical manifestations related to genetic and environmental factors?
• SLERI project – DNA for genetic• Looking for risk factors for worse outcome
Neonatal Lupus Syndromes
Clinical Syn: CC Heart BlockDermatitisHepatitisThrombocytopenia (Anemia)
Maternal autoantibodies: Anti Ro/SSALa/SSB
Clinical care – Teaching- Research
Pediatric RheumatologyArt of clinical diagnosis
Thank You!
