1. Musculoskeletal Health in Europe Juvenile Idiopathic Arthritis

2. Juvenile idiopathic arthritis (JIA) Definition: Juvenile idiopathic arthritis = arthritis of unknown etiology that begins before the 16th birthday and persists for at least 6 weeks. Other known conditions are excluded.

3. Practitioner- or register-based study Incidence per 100,000 Savolainen, Finland, 200323 Pruunsild, Estonia, 200722 Berntson, Norway, Finland, Sweden, Denmark, Iceland, 2003 15 Riise, Norway, 200814 Hanova, Czech Republic, 200613 Modesto, Spain, 20107 Danner, France, 20063 JIA - Incidence

4. JIA – Age at Disease Onset 0-1 2-3 4-5 6-7 8-910-1112-1314-15 0% 5% 10% 15% 20% 25% 30% 35% Systemic arthritis Psoriatic arthritis Enthesitis-related arthritis Rheumatoid factor negative polyarthritis Age at onset in years Oligoarthritis Rheumatoid factor positive polyarthritis

5. Practitioner- or register-based study Prevalence per 100,000 Pruunsild, Estonia, 200784 Hanova, Czech Republic, 2006140 Modesto, Spain, 201040 Danner, France, 200620 Solau-Gervais, France, 201016 JIA - Prevalence

6. JIA - Categories Oligoarthritis Rheumatoid factor negative polyarthritis Enthesitis-related arthritis Psoriatic arthritis Systemic arthritis (Still´s disease) Rheumatoid factor positive polyarthritis 52% 16% 15% 5% 4% Patients with recent onset JIA

7. JIA-categoryHLA-alleles conferring susceptibility Protective alleles Systemic arthritisDRB1*04, DRB1*11, DQA1*05- Oligoarthritis A2, DRB1*01, DRB1*08, DRB1*11, DRB1*13, DPB1*02, DQA1*04, DQB1*04 DRB1*04, DRB1*07, DQA1*03 Seronegative PolyarthritisA2, DRB1*08, DQA1*04, DPB1*03- Seropositive PolyarthritisDRB1*04, DQA1*03, DQB1*03DQA1*02 Psoriatic arthritisDRB1*01, DQA1*0101 DRB1*04, DQA1*03 Enthesitis-related arthritisB27, DRB1*01, DQA1*0101, DQB1*05- JIA - HLA associations

8. Definition: Arthritis affecting one to 4 joints during the first 6 months of disease. Two subcategories are recognized: 1. Persistent oligoarthritis: affecting not more than 4 joints throughout the disease course 2. Extended oligoarthritis: affecting a total of more than 4 joints after the first 6 months of disease JIA - Oligoarthritis

9.  Joints:1 joint with arthritis 1 joint with limited range of motion  Function:CHAQ-score 0.63 (median)  Eyes:4% uveitis  Lab:ESR 17 mm/h, CrP 7 mg/l (mean) 60-70% ANA, 0% RF Phenotype at onset: JIA - Oligoarthritis

10. Course and outcome: After 5 yearsPersistent OAExtended OA Percentage of patients2/31/3 (up to 50%) After 15 years Patients in remission, %43-8412-50 Functional limitations (HAQ>0), % 2247 Frequency of erosions, % 533

11. JIA - Rheumatoid factor negative polyarthritis Definition: Polyarthritis (Rheumatoid Factor [RF] Negative) Arthritis affecting 5 or more joints during the first 6 months of disease A test for RF is negative ICD10-Code: M08.3

12. JIA - RF negative polyarthritis Phenotype at onset:  Joints:9 active joints and 6 with LOM  Function:CHAQ 1.25 (median)  Eyes:3% uveitis  Lab:ESR 22 mm/h, CrP 14 mg/l (median) 40-70% ANA, 0% RF

13. JIA - RF negative polyarthritis

14. Course and outcome: Follow-up > 10 years Patients in remission, %15-30 Patients with functional limitations (HAQ>0), % 47 Prevalence of erosions, % 40-75

15. JIA - Enthesitis related arthritis Definition: Arthritis and enthesitis, or arthritis or enthesitis with at least 2 of the following: 1. The presence of or a history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain 2. The presence of HLA-B27 antigen 3. Onset of arthritis in a male over 6 years of age 4. Acute (symptomatic) anterior uveitis 5. History of ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis in a first- degree relative

16. JIA - Enthesitis related arthritis Phenotype at onset:  Joints:2 active joints and 2 with LOM  Function:CHAQ 0.56 (median)  Eyes:9% uveitis  Lab:ESR 10 mm/h, CrP 3 mg/l (median) 20% ANA, 0% RF

17. JIA - Enthesitis related arthritis Course and outcome: Follow-up > 10 years Patients in remission, %17-44 Patients with functional limitations (HAQ>0), % 47 Prevalence of sacroiliits, % 35

18. JIA - Psoriatic arthritis Definition: Arthritis and psoriasis, or arthritis and at least 2 of the following: 1. Dactylitis 2. Nail pitting or onycholysis 3. Psoriasis in a first-degree relative ICD10-Code: M09.0*, L40.5 †

19. JIA - Psoriatic arthritis Phenotype at onset:  Joints:3 active joints and 2 with LOM  Function:CHAQ 0.56 (median)  Eyes:3% uveitis  Lab:ESR 26 mm/h, CrP 7 mg/l 45% ANA, 0% RF

20. JIA - Psoriatic arthritis Course and outcome: 68% oligoarticular onset  65% polyarticular course Outcome after > 15 years Patients in remission off medication (> 1 year), %55 Patients with functional limitations (HAQ>0), % 45 Prevalence of erosions, % 23

21. JIA - Systemic arthritis Definition: Arthritis in one or more joints with or preceded by fever of at least 2 weeks’ duration that is documented to be daily (“quotidian”) for at least 3 days, and accompanied by one or more of the following: 1. Evanescent (non-fixed) erythematosus rash 2. Generalized lymph node enlargement 3. Hepatomegaly and/or splenomegaly 4. Serositis

22. JIA - Systemic arthritis Phenotype at onset:  Joints:2 active joints and 0 with LOM  Function:CHAQ 1.0 (median)  Eyes:0% uveitis  Lab:ESR 93 mm/h, CrP 98 mg/l (median) 15% ANA, 0% RF

23. JIA - Systemic arthritis Complications: Macrophage activation syndrome 1.5-6.8% Growth failure20-41% Osteopenia/osteoporosis 0-7.5% Amyloidosis 1.4-9%

24. JIA - Systemic arthritis Course: 42% monocyclic  remission within 2-4 years 7% relapsing  flares of systemic features and mild arthritis 51% persistent  chronic progressive polyarthritis

25. JIA - Systemic arthritis Follow-up > 10 years Patients in remission, %20-76 Patients with functional limitations (HAQ>0), % 47 Prevalence of erosions, % 40-75 Course and outcome:

26. JIA - Rheumatoid factor (RF) positive polyarthritis Definition: Polyarthritis (RF positive) Arthritis affecting 5 or more joints during the first 6 months of disease 2 or more tests for RF at least 3 months apart during the first 6 months of disease are positive ICD10-Code: M08.0

27. JIA - RF positive polyarthritis Phenotype at onset:  Joints:9 active joints and 7 with LOM  Function:CHAQ 1.0 (median)  Eyes:0% uveitis  Lab:ESR 15 mm/h, CrP 12 mg/l (median) 55% ANA, 100% RF

28. JIA - RF positive polyarthritis Course and outcome: Follow-up > 10 years Patients in remission, %0-46 Patients with functional limitations (HAQ>0), % 46 Prevalence of erosions, % 39-77

29. JIA - Estimated annual health care cost per patient (in Euro) Study Patients (n) Biologic drugs Health care cost (in €)Cost components Minden et al. Germany, 1999 JIA (215) 0%1,800 (mean) Medication: 15% Inpatient care: 55% Haapasaari et al. Finland, 2000 JIA (31) 100% 27,700 (median) converted from 2000 US$ Medication: 56% Inpatient care: n.r. Minden et al, Germany, 2003 JIA (369) 6%4,200 (mean) Medication: 47% Inpatient care: 39% Thornton et al. U.K., 2005 JIA (297) n.r.2,400 (mean) Medication: 11% Inpatient care: 0%

30. JIA - Estimated annual total cost per patient (in Euro) 02,0004,0006,0008,000 cost (€) Functional limitation (CHAQ) Disease activity (NRS) Pain intensity (NRS) moderate/severe mild none 4-10 1-3 0 p = 0.012 p < 0.001 p = 0.020

31. JIA - mortality in children 1950-1980entire JIA group (90/2,076) 4% systemic JIA (84/611) 14% 1990 entire JIA group (33/11,287) 0.29% systemic JIA 3% 2010entire JIA group (19/9,604) 0.2%

32. JIA - mortality SMR 5.1 women (95% CI 3.2-7.8) 3.4 men (95% CI 2.0-5.5)  4-fold increase in mortality in JIA compared to the general population in adults

33. JIA - malignancy Malignancy n Standardized rate (per 100,000 p-ys) SIR (95% CI) Simard et al., 2010, Sweden JIA: 13 cases/5,296 Controls: 30/26,480n.r.* 2.3 (1.2-4.4) Beukelman et al. 2010, U.S. JIA: < 11 cases/7,321592-3 ADHS: 63/308,45423 Asthma: 183/23,66327 Bernatsky et al., 2011, Canada JIA: 1 case/1,843 General population 40.12 (0-0.7)

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