Therapy of children with juvenile idiopathic arthritis. New drug therapy

Rik Joos, M.D.Centre for Paediatric RheumatologyUniversity hospital, Gent, Belgium

JIA – JCA – JRA???

What’s in a name?

J C A – J R A – J I ASystemic Onset

ArthritisHigh spiking feverFugitive rash AdenopathyHepatosplenomegalySerositisNo specific age at onsetBoys = Girls

J C A – J R A – J I APolyarticular Onset

Age at onset: 3-6 and 10 – 14 yearsGirls > or = BoysSymmetrical polyarthritisRapid ankylosis (wrists, neck, feet)Systemic symptoms are possible

J C A – EOPA J R A - OLIGO

J I A – OLIGO

Age at onset 2 - 4 years Girls >>> BoysArthritis of one or both kneesChronic posterior uveitis (30 %)ANA positive (> 80 %)

J C A- LOPA J A S

J I A – E R A

Age at onset: 10 - 15 yearsBoys >> GirlsAsymmetrical oligoarthritis (lower limbs)EnthesitisAcute anterior uveitis (33 %)Association with HLA B27 (>85 %)

What are the goals of therapy in rheumatic diseases?

Ultimate goal

If cure is not achievable

If control is not achievable

In all circumstances

Cure

Control

Comfort of the patient

Maintain function

Does the therapy depend on the type of rheumatism?? And by consequence is it important to put a thorough diagnosis?No, to a certain point Yes, beyond that point

What is the general therapeutic approach?

Medical Non medical

Medical treatment

1. general treatment2. local treatment

a. eyesb. joints

 

General medical treatment

1. anti – inflammatory

2. immunomodulatory

short term/ rapid effect/ short action/ short effect after stop

long term/ slower effect/ long action/ long effect after stop

Anti-inflammatory treatment

non steroidalaspirin“classic” NSAID’sselective cox 2 inhibitors (coxib’s)

steroids

Aspirin

first non steroidal anti – inflammatory drughigh dose needed 50 – 100 mg/kg/day short action 4 –6 times per day dosageside effects!

• Salicylism• Bleeding disorders• GI side effects

in low dose: anti sludge – anti thrombotic 

“classic” NSAID’si.e. Naproxen, Ibuprofen, Diclofenac,

Indomethacin, Piroxicam, ... 1. Indications: symptomatic

treatment of • inflammation of joints• fever of systemic origin• pain treatment

2. way of administration• oral• Rectal• IM

“classic” NSAID’s

1. side effectsa. Dyspepsiab. GI ulcer – bleedingc. Fluid retention

a. Edemab. Hypertensionc. Renal insufficiency

d. Allergye. Bleeding disorder

2. relatively cheep and widely available

Selective cox 2 inhibitors                    

mechanism of cox 2 inhibition

Mechanism of action of NSAIDs

Membrane phospholipids

Arachidonic acid

NSAIDs

Gastroprotectiveprostaglandins

Proinflammatoryprostaglandins

COX-1(constitutive)

Pennisi E, Science 280:1191–1192, 1998Spangler RS, Semin Arthritis Rheum 26:435– 446, 1996

COX-2*(inducible)

COX-2 selective inhibitor

Stomach Intestine Kidney Platelet

Macrophages Synoviocytes

*COX-2 constitutively present

Coxib

1. impact on side effectsthe same as “classic” NSAID’s except

GI ulcer – bleedingBleeding disorder

2. impact on effectdepending on “strength” of anti-inflammatory effect

Coxib

1. indications in childrenthe same as for “classic” NSAID’s but

no proven efficacy no proven safetyno approval yet

2. expensive and not widely available yet

Immunomodulatory treatment Disease modifying antirheumatic drugs = DMARDSlow acting antirheumatic drugs = SAARD

Mode of action

a. Aim to alter the immune reactionb. By that reduce the chronic aggression towards

the joint c. By that preserve the joint structure and functiond. By that preserve the quality of life

DMARD

What treatments?

a. Older treatmentsb. Actual “ traditional” treatmentsc. Biologicalsd. Experimental treatments

What treatments?

1. older treatments (not used anymore, but still exceptionally ....)

a. gold saltsb. levamisolec. d-penicillamin

2. “traditional” DMARD’sa. Methotrexateb. Sulphasalazinec. Hydroxychloroquined. Leflunomide

Methotrexate

a. “gold standard”b. mostly indicated in polyarticular diseasec. low dose (5 mg/m²/week) versus medium

( 10 mg/m²/week) and high dose (20 mg/m²/week)

d. Oral versus IM or SC

Methotrexate

e. side effectsa. Leukopeniab. liver function testsc. rare side effects (lung, bone,...)

f. monitoring

a. blood sampling every two weeks, than every four weeks, than every eight weeks

b. no liver biopsy needed!

SulphasalzineEfficacy proven – Oral – 30-50 mg/kg/dayIndicated merely in oligoarticular patients and

spondyloarthropathiesSide effects

Blood cell count Liver function tests Allergy Rare side effects (hair loss, reduced male

fertility, ...)

Monitoring Blood sampling every month forst three months,

later every three months

Hydroxychloroquine

a. More seldom use in JIA – Oral – 6mg/kg/dayb. Indicated in SLE and related auto-immune

diseases such as Sjögren syndromec. Side effects

a. Blood cell countb. Retinopathy

d. Monitoringa. Blood sampling every six weeks - two monthsb. Eye control 2/year

Leflunomide

a. Recently developed in adultsb. Some sparse trials in children

with good resultsc. No approvald. Only trials in polyarticular JIA

Biologicals

Approved

Advanced trial development

Experimental

Etanercept – Enbrel

Infliximab – RemicadeAdalimumab – Humira

CTLA4Monoclonal antibodies

Treatment with ENBREL inpolyarticular-course JRA

Dose: ENBREL 0.4 mg/kg/dose SC 2X/week (maximum 25 mg/dose)

Part 1 Open-label

Months 1–3

Respondersrandomized

ENBREL (n = 69)

Placebo (n = 26)

ENBREL (n = 25)

Part 2 Double-blind

Months 4–7

All patients

ENBREL (n = 58)

Open-labelextension

Months 8–21

Lovell DJ, Giannini EH, ACR, 1999

19%23%

35%44%

72%80%*

0

20

40

60

80

100

JRA 30% JRA 50% JRA 70%

Response level

Pat

ient

s (%

)

Patients achieving JRA definition of improvement after randomization

*P < 0.01

ENBREL (n = 25)Placebo (n = 26)

Lovell DJ et al, N Engl J Med 342:763–769, 2000

Summary

With more than 1 year of continuous treatment withENBREL in patients with JRA

Benefits of ENBREL continue to be maintained 50/58 (86%) remain on treatment

70% demonstrate a 50% improvement in JRA Core Set Criteria

Generally well tolerated with prolonged use

No significant increase in adverse events over time

Lovell DJ, Giannini EH, ACR, 1999

Biologicals

Approved

Advanced trial development

Experimental

Etanercept – Enbrel

Infliximab – RemicadeAdalimumab – Humira

CTLA4Monoclonal antibodies

Biologicals - monitoring

Prevention: Screening for tuberculosis Prevent contact with (some) virusses Use more often antibiotics

Side effects? Possible allergy Possible (pseudo) asthmatic reaction

(remicade) More infectious episodes

Long term side effects???? Tumor????