9 treatment of paediatric rheumatic diseases
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Treatment of PaediatricRheumatic Diseases
Traudel Saurenmann, MD
University Childrens HospitalZrich, Switzerland
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Aim of treatment
1. Complete remission of disease >98% of JIA (with Biologics) 80-90% of JIA (without Biologics)
80-90% of SLE, JDM, Vasculitis
Stop the damaging process
2. Resolution of symptoms Pain
Fatigue
Limitations in daily living
Physical and psychosocial well-being
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Treatment options
Non steroidal anti-inflammatory drugs(NSAIDs)
Corticosteroids Immunosuppressive drugs
Methotrexate Azathioprine (Imurek, Imuran) Cyclophosphamide (Endoxan) (Biologics)
Other drugs Sulfasalazine Hydroxychloroquine
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Non steroidal anti-inflammatory
drugs (NSAIDs)
Interfere with prostaglandine synthesis
(Cox1 Cox2)
Pain relief Better movement, physiotherapy
Antiphlogistic and anti-inflammatory effect:
only with higher doses!!
Individual differences: if effect is insufficient
try other substance
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NSAIDNSAID -- dosingdosing
Naproxen 15-20mg/kg/d in 2x Diclofenac 2-3 mg/kg/d in 3x (Voltaren)
Ibuprofen 40- 50mg/kg/d in 3x
Indomethacin 2(-3)mg/kg/d in 3x (Indocid)
Acetylsalicylic acid (Aspirin)
50-100mg/kg/d in 4-6x : liver toxicity!!
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Corticosteroids:
local
Intra-articular steroid injections Triamcinolone hexacetonide (acetonide)
(Lederlon, Aristospan, (Kenacort))
High doses compared to adult doses
Rapid effect, median duration 4-6 months, may last>2-3 years
Local creams Lupus rash, psoriasis, circumscript morphea
No systemic side effects with local corticosteroids!!
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Corticosteroids:
systemic
High dose(life threatening or organ threatening disease)
i.v. methylprednisolone pulses (30mg/kg/day, max
1000mg/day) on 3 consecutive days (if necessary) 2mg/kg/day in 2-3 doses, max 60 (-80mg)/day, for 3-4
weeks
2mg/kg/day in 1 morning dose, for 2-3 weeks
After 6 weeks taper dose slowly to low dose
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Corticosteroids:
systemic
Low dose(for maintenance or rapid relief of symptoms)
0.2 (-0.5mg)/kg/d
1 morning dose or alternate day dosing
bridge until effect of immunosuppressive drugsets in
Vasculitis or SLE remission maintenance: tapervery slowly
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Corticosteroid side effects
Cushing syndrome Hypertension
Glucose tolerance
Adrenal insufficiency Bone metabolism
Growth
Osteoporosis
Artherosclerosis
Infections (Candida, )
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Immunosuppressive drugs:
Methotrexate
Cytotoxic in high doses (cancer therapy) Immunosuppressive in low doses
(autoimmune diseases)
Intestinal absorption very variable between
individuals
Reliable effect if given parenterally(s.c., i.m., i.v.)
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Bioavailability of MTX
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Methotrexate side effects Hematopoiesis (add folic acid)
Liver toxicity (add folic acid),
often intermittently raised liver enzymes, especially at times
of (viral) infections
If transaminases >3x upper normal value: stop MTX,
continue after normalisation
Interstitial pneumonitis: very rare toxic reaction, first
3 months of treatment
Nausea
tends to increase over time
may lead to discontinuation of treatment
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Methotrexate indications
Arthritis Uveitis
Myositis
Skin disease (Psoriasis, SLE, JDM)
Inflammatory bowel disease
Vasculitis (maintenance)
Not useful: systemic features, renal disease
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Methotrexate dosing
Once weekly !!! 15-17.5mg/m2/dose, max. 25mg
Start s.c. continue until remission, thenchange to oral
First effect after ~6 weeks!
Maximum effect after 6 months!
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Immunosuppressive drugs:
Azathioprine (Imurek)
Dose: 2-3mg/kg/d in 1 dose Start with 1mg/kg/d and increase every
2-3 weeks after blood test (rare toxic
reaction) Usually very well tolerated
Side effects: liver, lymphopenia
Long term: increased risk for lymphoma?
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Azathioprine indications
Glomerulonephritis (SLE, Vasculitis) Induction of remission if not rapidly progressive
disease
Maintenance therapy
CNS Lupus: mild disease or maintenance of remission
Other severe SLE/Vasculitis manifestations
Inflammatory bowel disease Uveitis
Does not work for: arthritis, severe CNS-disease
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Immunosuppressive drugs:
Cyclophosphamide (Endoxan)
Potent immunosuppressive and cytostatic drug
Oral or i.v. administration
Side effects dose dependent!
short term: Nausea / vomiting / hair loss / (stomatitis)
Neutropenia/ Lymphopenia: infections
Hemorrhagic cystitis long term (cummulative dose!):
Infertility
Neoplasia (bladder, leucemia, lymphoma)
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Cyclophosphamide dosing Oral: 2-3mg/ kg/ d in 1 dose
Usually very well tolerated Monitoring for Neutropenia/Lymphopenia required (dose
adjustment!)
i .v. pulses: 500-1000mg/ m2 every 3-4 w eeks Hyperdiuresis (bladder protection) 24 hours, Uromitexan
Antiemetic drugs needed
Monitoring for Neutropenia/Lymphopenia required (doseadjustment!)
Equally effective as oral treatment but only ~45% total dose forsame duration of treatment
Use for induct ion of remission (3-6 months) , thenchange to other immunosuppressive for maintenance
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Cyclophosphamide indications
Organ threatening or life threatening disease Rapidly progressive GN (diffuse proliferative GN)
CNS Lupus or CNS vasculitis
Diffuse pulmonary hemorrhage
Refractory disease
Severe refractory uveitis, arthritis, myositis
Induction therapy for bone marrow transplantation
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Sulfasalazine Anti-inflammatory and anti-infective
(intestine) component of action 50mg/kg/d in 2-3 doses, max 3g
Start with 10-20mg/d and increase
Side effects: Liver
Hematopoiesis
Abdominal pain (transient)
Agranulocytosis (toxic reaction) infrequent
Reversible Aspermia
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Sulfasalazine indications
Inflammatory bowel diseaseArthritis
Combination therapy with MTX andPlaquenil for severe arthritis
Not useful for connective tissuediseases, vasculitis, uveitis
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Hydroxychloroquine Anti-Malaria drug
Stabilizing effect on autoimmune processes
Very well tolerated
Side effect: retinopathy => ophthalmologicexamination every 6 months!
Dosing: 5-6mg/kg/d, max 400mg/d
In SLE: with Hydroxychloroquine
Less flares, smaller cummulative steroid dose
Less arteriosclerosis, better long term outcome
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Hydroxychloroquine indications
Mild arthritis Combination therapy for severe arthritis
(with MTX + Sulfasalazine)
Skin manifestations
Every patient with SLE !!!
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Other drugs
Gastro-protective drugs (ranitidine - Zantic,omeprazole - Antra)
Combination of steroids AND NSAIDs: significantly increased
risk of GI-bleeding!
Anti-hypertensive drugs (propanolol -Inderal,
nifedipine - Adalat)
ACE-inhibitors (enalapril - Reniten): anti-hypertensive,
but will also reduce proteinuria and has nephroprotective effect
Acute Rheumatic Fever: Treatment
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Acute Rheumatic Fever: Treatment
Voltaren
Haloperidol/Phenobarbitone
Prophylaxis: penicill in 2x250mg
Voltaren
2-3mg/ kg/ d
TaperNO / MI LD
CARDI TI S
MOD/ SEVERE
CARDI TI S
2 .0 mg/ kg/ d
50% Dose
TaperPrednisoneI M or PO
penicillinon
Diagnosis
CHOREA
2-3 w 2-3 w 2-3 w
Adapted from American HeartAssociation (AHA) guidelines 1995
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Acute Rheumatic Fever:
Prophylaxis Continuous sub-clinical GAS pharyngitis can trigger
recurrent ARF (recurrence risk up to 60% !) Recurrence risk particularly high in the fi rst 5 years,
in young children and in those with rheumatic heartdisease
Additional organ involvement may occur insubsequent attacks
Suggested regimes:
Penicillin V 250 mg po BID (penicillin allergy: Sulfadiazine 0.5-1.0g daily or
erythromycin 250mg BID) Benzathine Penicillin G 1.2 MU Q3-4 weekly i.m.
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Acute Rheumatic Fever:
Prophylaxis
Post ARF with persistent rheumatic heart disease (RHD):10years and at least unt il age 40 ( consider li felong)
Prophylaxis
Duration(AHA, 1995)
Post ARF without carditis;
5 years or unt il age 21 ( w hichever is longer)
Post ARF with carditis but NO residual RHD:
10 years or w ell int o adult hood (w hichever islonger)
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Treatment of JIATreatment of JIA
oligoarticularoligoarticular4 joints
polyarticularpolyarticular
>4>4jointsjoints
NSAID, physiotherapy
methotrexate
(systemic steroids)
intra-articular
steroid injection
after 1-3 months
plus intraarticular
steroid injections
Diagnosis of JIA
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Triamcinolone hexacetonide doses for intra-articular injection
patient's
weight
big joints
(hip, knee, shoulder)
medium joints
(wrist, elbow, ankle, subtalar)
small joints
(finger, toes)
< 20kg 20 mg 10 mg 5 mg20-40kg 30 mg 15 mg 5 (-10) mg
> 40 kg 40 mg 20 mg 5 (-10) mg
for triamcinolone acetonide: use double dose!!
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Refractory JIA
Biologics: TNF Blocking agents (Enbrel, Remicade, Humira)
Abatacept (Orencia): co-stimulation moderator
Combination therapy:
Methotrexate/Sulfasalazine/Hydroxychloroquine
Experimental:
Rituximab (anti CD20), Anakinra (anti Il-1)
Autologous stem cell transplantation
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JDM treatment High dose steroids 6 weeks, than taper over next 6
months Muscle weakness may worsen during first weeks
despite treatment! If dysphagia is present: start with
methylprednisolone pulses for quicker effect! Always use methotrexate!
Efficacious and safe
Reduced steroid use Same outcome with less steroids
Aggressive treatment => earlier and sustainedremission => less calcifications
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Treatment of SLE
Depends on organ manifestation!
Treat the patient, not the antibodies!
Only give as much and as aggressive medication
as needed!
Careful monitoring for new disease
manifestations (regular urinalysis, bloodpressure, system history, physical examination)
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Severe SLE or Vasculitis
High dose steroids 6 weeks, then taper to0.2mg/kg/d over next ~6 months
Slowly taper further to complete stop over next
2-3 years, use alternate day dosing if possible Combination with immunosuppressive drug
(usually azathioprine):
Better long term outcome
Longer duration of remission
Less corticosteroid use / less side effects
E l 1
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Example 1:
Pat 30kg, SLE with renal disease Treat concomittant infection!
Prednisone 40-0-20mg/d for 3 weeks Then 60-0-0mg/d for 3 weeks Then 50mg/d for 4 weeks
Then 40mg/d for 4 weeks Then 30mg/d for 4 weeks Then 20mg/d for 4 weeks Then 15mg/d for 4 weeks
Then 12.5mg/d for 4 weeks (~7months) Then 10mg/d for 3 months, then 7.5mg/d for 3 months, then
5mg/d for 3 months, Then 10mg/d every other day for 3 months,
Then 7.5mg/e.o.d. for 6 months, then 5mg/e.o.d. for 6 months,then 2.5mg/e.o.d. for 6 months, then stop (~3 years)
E l 1
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Example 1:
Pat 30kg, SLE with renal disease
Imurek:
Start with 50mg/d
Blood test (liver function, CBC) after 2-3 weeks
Increase to 75mg/d (~2mg/kg)
Next blood test after 2-3 weeks If well tolerated: increase to 100mg/d, next blood test after 2-3
weeks, then every 2-3 months
Hydroxychloroquine:
200mg/d
Other drugs according to symptoms
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SLE-treatment
Prednisone
Imurek
Hydroxychloroquine
NSAI D (as necessary)
Gastro-protective drugs, anti-hypertensive drugs, calcium substitution, as necessary
Example 2: pat 30kg
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Example 2: pat 30kg,
SLE with severe CNS-disease Start with methylprednisolone infusions 1000mg once daily for 3
days Then use the same protocol for prednisone dosing as in
example 1
Endoxan infusion 1x per month 500mg/m2, with 24h
hyperdiuresisOR
Endoxan oral 50-75mg/d (blood tests!)
After 4-6 months stop Endoxan and start Imurek same as in
Example 1 During Endoxan therapy give Bactrim prophylaxis 2x 480mg/d
on 3 days of each week (or continously). After stop of Endoxancontinue Bactrim until lymphocytes are >1000/ul
Hydroxychloroquine same as in Example 1
Treatment of
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Treatment of
severe renal or CNS disease
Prednisone
Imurek
Hydroxychloroquine
Gastro-protective drugs, anti-hypertensive drugs, calcium substitution, as necessary
Endoxan i.v. OR oral
E l 3 t 30k
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Example 3: pat 30kg,
SLE polyarthritis + hemolytic anemia
Severe hemolytic anemia (hbg80g/l):
Hydroxychloroquine 200mg/d
Prednisone 30mg/d for 3 weeks, 20mg/d for 3 weeks, 15mg/dfor 4 weeks, 12.5mg/d for 4 weeks, 10mg/d for 4 weeks,(continue same as in example 1)
If hemolytic anemia returns: increase prednisone to 3 steps
higher and add Imurek (same as example 1) If polyarthritis returns, add MTX 15mg/m2 once weekly + folic
acid 5mg once weekly
(do NOT combine Imurek and MTX, use only one or the other!)
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Treatment of mild SLE
Prednisone
Hydroxychloroquine
NSAI D
(as necessary)
Gastro-protective drugs, anti-hypertensive drugs, calcium substitution, as necessary
May need I murek or methot rexate in the later course
~1mg/kg/d
Example 4: pat 20kg
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Example 4: pat 20kg,
juvenile dermatomyositis With dysphygia: methylprednisolone infusions 600mg once daily
for 3 days in addition at start Without dysphagia: Methotrexate 15mg/m2 once weekly + folic acide 5mg Prednisone: Start with 30-0-10mg for 3 weeks, then 40mg/d for 3 weeks, then 30mg/d for 4 weeks, 25mg/d for 4 weeks, 20mg/d for 4 weeks, 15mg/d for 4 weeks, 10mg/d for 4 weeks 7.5mg/d for 4 weeks 5 mg/d for 4 weeks 2.5mg/d for 4 weeks 2.5mg e.o.d. for 4 weeks, then stop (~10 months) Continue MTX for at least 2 years
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JDM-treatment
Prednisone
NSAI D (as necessary)
Gastro-protective drugs, anti-hypertensive drugs, calcium substitution, as necessary
Methotrexates.c. oral
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Patient management Hospitalize until stable condition and all
necessary information understood
Early medication side effects: hypertension,
diabetes, constipation (steroids) Disease can worsen despite treatment! (kidney,
JDM increasing weakness)
Information about risk for infection andhygiene
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What to look for at control visits?
History:All medication taken?
Side effects? Problems with medication?
Infections in the meantime?
Disease symptoms?
Systems check (every time!)
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Systems history General: Fever, weakness, fatigue, participation in
school activities, chores at home, weight CNS: school performance, headaches, concentration,
memory,
Resp: dyspnea, chest pains, cough, nose bleeds Cardiovasc: palpitation, free walking distance,
circulation (Raynauds), ulcers (fingers, toes)
GI: ulcers, dysphagia, abdominal pains,diarrhoea/constipation
Urogenital: dysuria, nykturia, edema, menstruation
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ExaminationAlways check:
Lab: CBC, transaminases, creatinine, ESR,CRP, urine (hematuria, proteinuria,glucosuria, infection)
Blood pressure
Ulcers (mouth, nose, finger, toes)
Rash (face, vasculitic rash of palms) Signs of infection? (candida, auscultation,
abdomen palpation)
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Summary Use few drugs, but know them well!
Have a very structured approach, usethe same protocol and stick to it!
Variations only with good reasons!Always document exactly what you do
Very careful history and examinationevery time => find signs of worseningdisease or complications early!