9 Treatment of Paediatric Rheumatic Diseases

7/31/2019 9 Treatment of Paediatric Rheumatic Diseases

1/48

Treatment of PaediatricRheumatic Diseases

Traudel Saurenmann, MD

University Childrens HospitalZrich, Switzerland


2/48

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


3/48

Treatment options

Non steroidal anti-inflammatory drugs(NSAIDs)

Corticosteroids Immunosuppressive drugs

Methotrexate Azathioprine (Imurek, Imuran) Cyclophosphamide (Endoxan) (Biologics)

Other drugs Sulfasalazine Hydroxychloroquine


4/48

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


5/48


6/48

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!!


7/48

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!!


8/48

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


9/48

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


10/48

Corticosteroid side effects

Cushing syndrome Hypertension

Glucose tolerance

Adrenal insufficiency Bone metabolism

Growth

Osteoporosis

Artherosclerosis

Infections (Candida, )


11/48

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.)


12/48

Bioavailability of MTX


13/48

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


14/48

Methotrexate indications

Arthritis Uveitis

Myositis

Skin disease (Psoriasis, SLE, JDM)

Inflammatory bowel disease

Vasculitis (maintenance)

Not useful: systemic features, renal disease


15/48

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!


16/48


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?


17/48

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


18/48


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)


19/48

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


20/48

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


21/48

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


22/48

Sulfasalazine indications

Inflammatory bowel diseaseArthritis

Combination therapy with MTX andPlaquenil for severe arthritis

Not useful for connective tissuediseases, vasculitis, uveitis


23/48

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


24/48

Hydroxychloroquine indications

Mild arthritis Combination therapy for severe arthritis

(with MTX + Sulfasalazine)

Skin manifestations

Every patient with SLE !!!


25/48

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


26/48

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


27/48

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.


28/48

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)


29/48

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


30/48

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!!


31/48

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


32/48

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


33/48

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)


34/48

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


35/48

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


36/48

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


37/48

SLE-treatment

Prednisone

Imurek

Hydroxychloroquine

NSAI D (as necessary)

Gastro-protective drugs, anti-hypertensive drugs, calcium substitution, as necessary

Example 2: pat 30kg


38/48

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


39/48

Treatment of

severe renal or CNS disease

Prednisone

Imurek

Hydroxychloroquine


Endoxan i.v. OR oral

E l 3 t 30k


40/48


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!)


41/48

Treatment of mild SLE

Prednisone

Hydroxychloroquine

NSAI D

(as necessary)


May need I murek or methot rexate in the later course

~1mg/kg/d

Example 4: pat 20kg


42/48


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


43/48

JDM-treatment

Prednisone

NSAI D (as necessary)


Methotrexates.c. oral


44/48

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


45/48

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!)


46/48

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


47/48

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)


48/48

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!

9 Treatment of Paediatric Rheumatic Diseases

Documents