Transcript Slide 1

Aysin Bakkaloglu, M.D.
Hacettepe University Faculty of Medicine
Pediatric Nephrology and Rheumatology
Ankara, TURKIYE
TREATING DIFFICULT PATIENTS
OF RENAL VASCULITIS
ESPN 2008 Lyon, FRANCE
Plan of the talk
Treatment of difficult patients of renal
vasculitis
– ANCA associated vasculitis
- Wegener granulamatosis
- Microscopic polyangiitis
– Classic polyarteritis nodosa
– Takayasu arteritis
ANCA ASSOCIATED VASCULITIS
Wegener’s granulomatosis
Histologic similarities
Microscopic polyangiitis
Potential contribution of
ANCA to their
pathogenesis
Renal limited vasculitis
Churg-Strauss syndrome
Similar responses to
immunosuppressive therapy
Nat Clin Rheumatol 2006; 2: 661-670
GOALS of TREATMENT
in ANCA ASSOCIATED VASCULITIS
Patient survival
Induce remission of active state
Reduce disease relapse
Minimize therapeutic toxicity
– Least toxic and most effective therapy
– Prevent and monitor toxicity
CHALLENGES in TREATING ANCA
ASSOCIATED VASCULITIS
Rarety of ANCA associated vasculitis in
children
High morbidity and mortality
Definitions of
– disease stages
– activity stages
– outcome measures
Duration of treatment
CASE 1
12 year old girl
Weakness, periumblical abdominal pain
Loss of appetite
Nausea, vomiting
Pallor
Decreased urine output with hematuria
Besbas N et al. Pediatr Nephrol 2003;18: 696-699
Laboratory Tests
Hb
: 7.8 g/dl
WBC
: 7300 /mm3
Platelet : 240 x103 /mm3
CRP
Urinary pH
: 6.5
density : 1020
protein : 4 +
7-8 RBC / hpf
: 10.2 mg/dl
: 120 mm/hr
Urinary protein : 87.5 mg/m2/hr
BUN
: 51 mg/dl
GFR
: 18 ml/min/ 1.73 m2
Cre
: 5.84 mg/dl
ANA
: Negative
T. prot : 7.3 g/dl
Anti ds-DNA
: Negative
Alb
ANCA:
ESR
: 3.2 g/dl
– p-ANCA: strong positive (IFA)
– MPO-ANCA: 250 EU/ml (ELISA)
Anti-GBM: positive
Besbas N et al. Pediatr Nephrol 2003;18: 696-699
Renal Biopsy
Besbas N et al. Pediatr Nephrol 2003;18: 696-699
Serum creatinine (mg/dl)
MPZ
Plasma exchange
0.5 mg/kg/d prednisone
1 mo
2 mo
3 mo
4 mo
5 mo
6 mo
9 mo
12 mo
15 mo
2 mg/kg/d
cyclophosphamide
2 mg/kg/d azathiopurine
Etanercept
Rituximab
MMF
18 mo
21 mo
24 mo
Nine years after successful
renal transplantation
– Cre: 0.98 mg/dl
– GFR: 112 ml/min/1.73 m2
CASE 2
10 year old, girl
URTI
Hoarseness,
swollen
edematous
tongue, speech
abnormality,
Glossitis,
iv penicilin
Fever
Subcutaneous nodules
(fingertips, nose)
Generalized
maculopapular rash
Necrotic lesions
(right foot sole)
Generalized edema
wt loss
days
4
0
2
Fatigue, worsening
of the symptoms and
myalgia
Ceftriaxone and
clindamicin iv
6
Necrotic tissue (soft
palate, digits and uvula)
Arthritis
Myalgia
Limitation of motion
Iloprost, Pentoxiphyllin
Amlodipine, Captopril
Piperacillin-Tazobactam, Vancomycin,
Rifampicin, Fluconazole
Physical Examination
BP: 130/60 mmHg
Pulse: 92 /min
BW: 40 kg (75p)
Height: 146 cm (50-75p)
Maculopapular rash
Edema (pretibial and
dorsum of hand)
Tongue atrophy and
tissue loss
Necrotic lesions
Laboratory Tests
Hb
: 7.4 g/dl
IgA
: 158 mg/dl (68-378)
WBC : 20100 /mm3
IgM
: 144 mg/dl (50-250)
Platelet: 550x103 /mm3
IgG
: 2050 mg/dl
(650-1600)
CRP
: 14.9 mg/dl
ESR
: 90 mm/hr
ANA : Negative
BUN
: 8 mg/dl
Anti-DNA : Negative
T. prot : 6.17 g/dl
Alb
: 2.39 g/dl
Urinary ph: 6.5
density:1020
protein: - , 1-2 RBC
c-ANCA : Mild staining at IIF
Negative for MPO, PR3
Thrombotic panel including
ACLs all (-)
MEFV : V726A/-
Paranasal CT
Necrotizing Vasculitis
Hematuria,
proteinuria, dyspnea
Pulse steroid
Plasma exchange
Plasma exchange
Plasma exchange
Plasma exchange
Plasma exchange
Plasma exchange
Oral cyclophosphamide (2 mg/kg/day)
Oral prednisone (2 mg/kg/day)
14
15
17
19
21
23
25
32 60
days
Classification of a child as WG:
3 of the following six should
be present:
1. Abnormal urinalysis*
2. Granulomatous
inflammation on biopsy*
3. Nasal-sinus inflammation*
4. Subglottic, tracheal or
endobronchial stenosis
5. Abnormal chest x-ray or CT*
6. PR3 ANCA or C-ANCA
staining
Classification of a child as C-PAN:
Biopsy showing small and/or mid-size
artery necrotizing vasculitis and/or
angiographic abnormalities
+2 out of the following 7 criteria
1. Skin involvement*
2. Myalgia or muscle tenderness*
3. Systemic hypertension
4. Mononeuropathy or polyneuropathy
5. Abnormal urinalysis and/or impaired
renal function*
6. Testicular pain or tenderness
7. Signs or symptoms suggesting
vasculitis of any other major organ
system (gastrointestinal, cardiac,
pulmonary, or CNS)*
EULAR/PRES Criteria. Ann Rheum Dis; 2006
Prednisolone
– oral 2 mg/kg
– IV 15 mg/kg/dose
CYC
– Oral 2 mg/kg
– 500 mg/m2
Cre (> 500 mmol/l )
Vital organ involvement
plasma
exchange
3-6 months
• AZA: 1-2 mg/kg/d
• CS: 0.25 mg/kg/alternate day
12 months or longer
Bakkaloglu A et al. Arch Dis Clin 2001; 85: 427-430.
Besbas N et al. Pediatr Nephrol 2000; 14: 325-327.
Risk factors for ERSD and relapse:
•
Upper or lower respiratory
tract disease
•
Proteinase-3 ANCA
seropositivity
•
Severe kidney disease
•
Female sex
INDUCTION THERAPY
Prednisone ( 1-2 mg/kg/day) ± MP ( 3 pulses)
Cyclophosphamide ( 2 mg/kg/day) or iv pulses
3 - 6 mo.
Maintenance therapy
NORAM: MTX vs CYC
MEPEX: PE vs MP
CYCLOPS: CYC iv vs oral
WEGET: Etanercept vs placebo
SOLUTION: ATG
NORAM: MTX vs CYC
CYCAZAREM: AZA vs CYC
IMPROVE: AZA vs MMF
REMAIN: AZA, 24 mo vs 48 mo
Recent Alternative Therapies
Rituximab (RITUXVAS):
– Several, uncontrolled studies (refractory)
Many reports observed disease remissions in relapsing
and refractory patients with ANCA associated or other
vasculitides
Leflunomide
Deoxypergualin
Anti CD52:
– Predominantly leads to T-lymphocyte depletion
– Its use has been complicated by a high frequency of
infection
Anti-thymocyte globulin (ATG):
– Should be reserved for severe refractory WG
CASE 3
3 year old girl
Poor appetite, fatigue, weight loss for one month
Over the past five days
– Severe and frequent vomiting
– Subsequently developed drowsiness and unconsciousness
– High blood pressure
– Subarachnoid hemorrhage
Topaloglu R et al. Pediatr Nephrol 2005 Jul; 20 (7): 1011-5.
Physical examination
Body temperature: 36.6 C
Pulse rate: 104 /min
Respiratory rate: 20 /min
Blood pressure:
– 180/110 mm Hg (left arm)
– 175/105 mm Hg (right arm)
She was unconscious
Mydriasis
Diminished light
reaction in the right eye
Right third nerve and
left six nerve palsies
Left hemiparesis
Deep tendon reflexes
were all diminished
Topaloglu R et al. Pediatr Nephrol 2005 Jul; 20 (7): 1011-5.
Laboratory Tests
Hb
: 9.9 g/dl
IgA
: 168 mg/dl (68-378)
WBC
: 22100 /mm3
IgM
: 1220 mg/dl (50-250)
IgG
: 1450 mg/dl
(650-1600)
Platelet: 675x103 /mm3
CRP
: 10.2 mg/dl
ESR
: 60 mm/hr
BUN
: 8 mg/dl
Cre
: 0.5 mg/dl
Urinary pH: 6.5
density: 1011
protein: protein- , 1-2 WBC /hpf
ANA : Negative
Anti-DNA : Negative
ANCA : Negative
HBsAg : Negative
Anti-HCV: Negative
CT/MRI
Topaloglu R et al. Pediatr Nephrol 2005; 20: 1011-1015.
Angiography
Topaloglu R et al. Pediatr Nephrol 2005; 20: 1011-1015.
CLASSIC POLYARTERITIS NODOSA
Hypertensive emergency
Subarachnoidal hemorrhage
Angiography: Diffuse aneurysmal changes
Steroid intravenous, followed by p.o. route
Cyclophosphamide 2 mg/kg, p.o., 6 mo.
Azathiopurine (12 mo.)
MMF (12 mo.)
Low dose steroid (alternate day continuing)
CASE 4
12 year old girl
Abdominal pain, myalgia
Nausea
Fever
Rash on extremities
Recurrent abdominal pain and fever- FMF?
Blood pressure: 150/90 mmHg
Laboratory Tests
Hb
: 11.7 g/dl
IgA
: 184 mg/dl (68-378)
WBC
: 12400 /mm3
IgM
: 770 mg/dl (50-250)
Platelet: 558 x103 /mm3
IgG
: 1850 mg/dl (650-1600)
CRP
: 18 mg/dl
ANA : Negative
ESR
: 55 mm/hr
Anti-DNA : Negative
BUN
: 12 mg/dl
ANCA :
Cre
: 0.6 mg/dl
Urinary pH: 6.5
density: 1018
protein: +++
10-15 RBC/hpf
– c-ANCA: positive (IFA)
PR-3 ANCA : positive (ELISA)
HBsAg : Positive
HBV DNA: 330 pg/ml (0-5)
MEFV: M694 V/-
Renal Angiography
Liver biopsy-Chronic hepatit B infection grade 1
– Lamuvidine therapy (1 year)
Polyarteritis nodosa
– 1 mg/kg/day oral prednisone
– 4 months later steroids tapered and stopped
FMF
– More inflammation, more vasculitis among FMF patients
– Increased MEFV mutations among vasculitis patients
– 0.03 mg/kg colchicum dispert
8 years follow up, BP (normal), renal function test
(normal)
Medicine (Baltimore). 2005; 84: 1-11.
CASE 5
9 month old girl
Fever and irritability
Mother-carrier for HBs Ag
Blood pressure: 180/100 mmHg
ESH: 70 mm/hr
Urinalysis: protein +++
Angiogram: Renal and mesenteric
microaneurysms
HBs Ag (+)
HBe Ag (+)
HBV DNA > 2000 pg/ml
Duzova A et al. Eur J Pediatr 2001; 160: 519-520
>2000
HBV DNA pg/ml
HBs Ag
HBe Ag
>2000
>2000
>2000
714
+ + + + + + + + + + + + + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + + + + + + +
Antihypertensive drugs
*: anaemia and
leukocytopenia
Prednisolone
(2 mg/kg)
Cyclophosphamide
*
(2 mg/kg)
Interferon
5x106 U/m2
10x106 U/m2
200
Blood pressure (mmHg)
180
160
140
120
100
80
60
Diastolic BP
40
Systolic BP
0
2
4
6
8
16
18
Months
Figure 1: Time course of blood pressure,
treatment and virological parameters
20
22
30
Duzova A et al. Eur J Pediatr 2001; 160: 519-520
CASE 6 & 7
Patient 6
Age at diagnosis: 12 y
Angiography
Headache
RRA: Normal
BP: 150/100 mm Hg
LRA: Stenosis
ESR: 44 mm/hr
Entire thoracic and
abdominal artery
involvement, presence of
aneurysms
ppd: positive
Urinalysis: Proteinuria
TREATMENT
Medical treatment
Anti-tbc treatment
– Prednisolone
(bolus, po)
Surgical treatment
– CYC (po)
– MTX (po/sc)
Duration of follow up:
10 years
– Anti-hypertensive
Low dose steroid
• CCB
• Alpha-blocker
• Beta-blocker
– Left nephrectomy
Patient 7
Age at diagnosis: 16 y
Angiography
Arthralgia
RRA:
stenosis at the origin
MEFV : E148Q/FMF? 4 years
Headache
BP: 180/100 mm Hg
ESR: 16 mm/hr
LRA:
stenosis at the origin
Involvement of SMA and
suprarenal abdominal aorta
TREATMENT
Medical treatment
– Prednisone (po)
– MTX (po)
– Anti-hypertensive
• CCB
• Beta blocker
Surgical treatment
• Thoraco-abdominal by pass, left aorta renal
by pass
• Right aorta renal by pass
Duration of follow up: 1 year
Low dose steroid and MTX
Takayasu Arteritis
Mainstay of the treatment is to attenuate
inflammatory process and control HTN
Corticosteroids: Therapy is continued until
patients achieve remission
Cyclophosphamide (1-2 mg/kg/d)
Azathioprine (1-2 mg/kg)
Methotrexate (0.3 mg/kg/wk)
Anti-TNF
Ozen S et al. J Pediatr 2007; 150: 72-76
Hoffman et al. Arthritis Rheum 2004; 50: 2296-2304
Summary
Vasculitis should be excluded in any patient with renal or
extrarenal symptoms and:
– Elevated acute phase reactants
– Constitutional symptoms
– Organ involvement
Diagnosis is typically delayed 3 mo.; and the absence of
extra-renal disease is associated with a longer delay.
Longterm outcomes are closely related to the severity of
organ dysfunction at diagnosis
ANCA testing enables earlier identification.
In last 3 decades: MP+CYC therapy enables 75-90%
remission at 6 mo.
A variety of treatment options now available for AAV.
Balance should be made between disease suppression and
treatment toxicity.