Therapy of children with juvenile idiopathic arthritis. New drug therapy

1. Therapy of children with juvenile idiopathic arthritis. New drug therapy Rik Joos, M.D. Centre for Paediatric Rheumatology University hospital, Gent, Belgium

2. JIA – JCA – JRA??? What’s in a name?

3. J C A – J R A – J I ASystemic Onset • Arthritis • High spiking fever • Fugitive rash • Adenopathy • Hepatosplenomegaly • Serositis • No specific age at onset • Boys = Girls

4. J C A – J R A – J I APolyarticular Onset • Age at onset: 3-6 and 10 – 14 years • Girls > or = Boys • Symmetrical polyarthritis • Rapid ankylosis (wrists, neck, feet) • Systemic symptoms are possible

5. J C A – EOPA J R A - OLIGOJ I A – OLIGO • Age at onset 2 - 4 years • Girls >>> Boys • Arthritis of one or both knees • Chronic posterior uveitis (30 %) • ANA positive (> 80 %)

6. J C A- LOPA J A SJ I A – E R A • Age at onset: 10 - 15 years • Boys >> Girls • Asymmetrical oligoarthritis (lower limbs) • Enthesitis • Acute anterior uveitis (33 %) • Association with HLA B27 (>85 %)

7. Ultimate goal If cure is not achievable If control is not achievable In all circumstances Cure Control Comfort of the patient Maintain function What are the goals of therapy in rheumatic diseases?

8. 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

9. Medical Non medical What is the general therapeutic approach?

10. Medical treatment • general treatment • local treatment • eyes • joints

11. anti – inflammatory immunomodulatory short term/ rapid effect/ short action/ short effect after stop long term/ slower effect/ long action/ long effect after stop General medical treatment

12. Anti-inflammatory treatment non steroidal • aspirin • “classic” NSAID’s • selective cox 2 inhibitors (coxib’s) steroids

13. Aspirin • first non steroidal anti – inflammatory drug • high dose needed 50 – 100 mg/kg/day • short action 4 –6 times per day dosage • side effects! • Salicylism • Bleeding disorders • GI side effects • in low dose: anti sludge – anti thrombotic

14. “classic” NSAID’si.e. Naproxen, Ibuprofen, Diclofenac, Indomethacin, Piroxicam, ... • Indications: symptomatic treatment of • inflammation of joints • fever of systemic origin • pain treatment • way of administration • oral • Rectal • IM

15. “classic” NSAID’s • side effects • Dyspepsia • GI ulcer – bleeding • Fluid retention • Edema • Hypertension • Renal insufficiency • Allergy • Bleeding disorder • relatively cheep and widely available

16. Selective cox 2 inhibitors • mechanism of cox 2 inhibition

17. Mechanism of action of NSAIDs Membrane phospholipids Arachidonic acid COX-1 (constitutive) COX-2* (inducible) COX-2 selective inhibitor NSAIDs Gastroprotective prostaglandins Proinflammatory prostaglandins • Stomach • Intestine • Kidney • Platelet • Macrophages • Synoviocytes Pennisi E, Science 280:1191–1192, 1998 Spangler RS, Semin Arthritis Rheum26:435–446, 1996 *COX-2 constitutively present

18. Coxib • impact on side effects the same as “classic” NSAID’s except GI ulcer – bleeding Bleeding disorder • impact on effect depending on “strength” of anti-inflammatory effect

19. Coxib • indications in children the same as for “classic” NSAID’s but no proven efficacy no proven safety no approval yet • expensive and not widely available yet

20. Immunomodulatory treatmentDisease modifying antirheumatic drugs = DMARDSlow acting antirheumatic drugs = SAARD Mode of action • Aim to alter the immune reaction • By that reduce the chronic aggression towards the joint • By that preserve the joint structure and function • By that preserve the quality of life

21. DMARD What treatments? • Older treatments • Actual “ traditional” treatments • Biologicals • Experimental treatments

22. What treatments? • older treatments (not used anymore, but still exceptionally ....) • gold salts • levamisole • d-penicillamin • “traditional” DMARD’s • Methotrexate • Sulphasalazine • Hydroxychloroquine • Leflunomide

23. Methotrexate • “gold standard” • mostly indicated in polyarticular disease • low dose (5 mg/m²/week) versus medium ( 10 mg/m²/week) and high dose (20 mg/m²/week) • Oral versus IM or SC

24. Methotrexate e. side effects • Leukopenia • liver function tests • rare side effects (lung, bone,...) f. monitoring • blood sampling every two weeks, than every four weeks, than every eight weeks • no liver biopsy needed!

25. Sulphasalzine Efficacy proven – Oral – 30-50 mg/kg/day Indicated merely in oligoarticular patients and spondyloarthropathies Side 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

26. Hydroxychloroquine • More seldom use in JIA – Oral – 6mg/kg/day • Indicated in SLE and related auto-immune diseases such as Sjögren syndrome • Side effects • Blood cell count • Retinopathy d. Monitoring • Blood sampling every six weeks - two months • Eye control 2/year

27. Leflunomide • Recently developed in adults • Some sparse trials in children with good results • No approval • Only trials in polyarticular JIA

28. Approved Advanced trial development Experimental Etanercept – Enbrel Infliximab – Remicade Adalimumab – Humira CTLA4 Monoclonal antibodies Biologicals

29. Placebo (n = 26) ENBREL (n = 25) Treatment with ENBREL inpolyarticular-course JRA Part 1 Open-label Part 2 Double-blind Open-label extension Months 1–3 Months 4–7 Months 8–21 ENBREL (n = 69) ENBREL (n = 58) Responders randomized All patients Dose: ENBREL 0.4 mg/kg/dose SC 2X/week (maximum 25 mg/dose) Lovell DJ, Giannini EH, ACR, 1999

30. Patients achieving JRA definition of improvement after randomization Placebo (n = 26) ENBREL (n = 25) *P < 0.01 Lovell DJ et al, N Engl J Med 342:763–769, 2000

31. Summary With more than 1 year of continuous treatment with ENBREL 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

32. Approved Advanced trial development Experimental Etanercept – Enbrel Infliximab – Remicade Adalimumab – Humira CTLA4 Monoclonal antibodies Biologicals

33. 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????