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Outcomes of paediatric rheumatic disease 

Outcomes of paediatric rheumatic disease
Chapter:
Outcomes of paediatric rheumatic disease
Author(s):

Kirsten Minden

DOI:
10.1093/med/9780199642489.003.0035_update_003

Update:

Description of therapeutic response measures modified to include the disease activity score for patients with juvenile spondyloarthritis and the core set criteria for JDM, defined by the International Myositis Assessment and Clinical Studies Group.

Data on mortality in PRD modified to include recently published studies.

Tables 35.1, 35.3 and 35.4 on core sets of disease activity measures, outcome studies and study summary on organ damage in PRD modified to include current outcome data.

Description of uveitis outcome and cardiovascular disease risk modified to include recently published data.

Description of societal consequences, including cost, modified to consider current literature.

Updated on 24 May 2018. The previous version of this content can be found here.
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date: 18 August 2018

Introduction

Paediatric rheumatic diseases (PRD) influence all aspects of a child’s and their family’s life, and may have multidimensional consequences. This chapter describes the instruments that have been developed to assess these consequences and the outcomes that have been reported for patients with PRD, with an emphasis on measures and outcomes in juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE), and juvenile dermatomyositis (JDM).

Outcome measures

A methodology and standardization is required for measuring and valuing the range of health states associated with PRD.

Therapeutic response measures

A variety of instruments are available for measuring disease activity in JIA, JSLE, and JDM. However, due to the high variability in the clinical presentation and outcome of PRD, no single measure can reliably capture disease activity in all patients. To achieve a standardized approach, core sets of variables (Table 35.1) and several composite indices, which usually integrate the core outcome variables, have been established.1

Table 35.1 Core sets of disease activity measures for juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE), and juvenile dermatomyositis (JDM)

JIA

JSLE

JDM

PRINTO

IMACS

Generic domains

Global assessment by physician

1) Physician global assessment of disease activity (VAS, NRS)

1) Physician global assessment of disease activity (VAS, NRS)

1) Physician global assessment (VAS, NRS)

1) Physician global assessment (VAS, NRS)

Global assessment by parents/patients

2) Patient/parent global assessment of overall well-being (VAS, NRS)

2) Patient/parent global assessment of overall well-being (VAS, NRS)

2) Patient/parent global assessment of overall well-being (VAS, NRS)

2) Patient/parent global assessment of overall well-being (VAS, NRS)

Disability or health-related quality of life

3) Functional ability (e.g. CHAQ)

3) Health-related quality of life (e.g. CHQ-Physical summary score)

  • 3) Functional ability (e.g. CHAQ)

  • 4) Health-related quality of life (e.g. CHQ-Physical summary score)

  • 3) Functional ability (CHAQ)

Disease-specific domains

Disease-specific measures

4) Active joint count

3) Functional ability (CMAS)

5) Restricted joint count

5) Muscle strength (MMT, CMAS)

4) Muscle strength (MMT)

Global disease activity tool

4) Global disease activity tool (e.g. ECLAM, SLEDAI, BILAG, SLAM)

6) Global disease activity tool (DAS, MDAAT, CAT)

5) Extramuscular disease (Extramuscular portion of the MDAAT)

Laboratory measures

6) Acute-phase reactant (ESR or CRP)

5) Renal involvement (urine protein: creatinine ratio, 24-hour proteinuria)

Muscle enzymes (CK, LDH, ALT, AST, aldolase)

6) Muscle enzymes (at least two of CK, LDH, ALT, AST, aldolase)

Additional

Spiking fever (to be used for systemic JIA)

ALT—alanine aminotransferase; AST—aspartate aminotransferase; BILAG—British Isles Lupus Assessment Group; CAT–Cutaneous Assessment Tool; CHAQ—Childhood Health Assessment Questionnaire; CHQ—child health questionnaire; CK—creatine kinase; CMAS—childhood myositis assessment scale; CRP—C-reactive protein; DAS—disease activity score; ECLAM—European consensus lupus activity measurement; ESR—erythrocyte sedimentation ratio; IMACS – International Myositis Assessment and Clinical Studies Group; LDH—lactate dehydrogenase; MDAAT—myositis disease activity assessment tool; MMT—manual muscle testing; NRS—numeric rating scale; PRINTO – Paediatric Rheumatology International Trials Organization; SLAM—systemic lupus activity measure; SLEDAI—SLE disease activity index; VAS—visual analogue scale.

Response criteria, primarily created for use in therapeutic trials, enable determination of whether individual patients demonstrate clinically important improvement or worsening in the overall level of potentially modifiable inflammatory disease at a defined point in time.1 In JIA the definition of improvement is equivalent to the so-called American College of Rheumatology (ACR) paediatric 30 response (Box 35.1). Given the increasing demand of higher response levels, ACR paediatric 50, 70, 90, and 100 levels of response were defined. The ACR paediatric response criteria do not make it possible to quantify the absolute level of disease activity. For this, a composite disease activity score for non-systemic JIA, the Juvenile Arthritis Disease Activity Score (JADAS) is available, which is based on four of the core set criteria (see ‘Composite disease activity scores for juvenile idiopathic arthritis’ in Chapter 36). Three versions have been developed, employing different joint counts (10-, 27-, 71-joint count). In addition, a simplified three-variable version is also available that does not include the acute-phase reactant (clinical JADAS = cJADAS). Each sum score denotes the current disease activity status, cut-off values for defining particular disease states have been proposed (Box 35.2).2 The JADAS cutoff values may not be extrapolated to the JIA category enthesitis-related arthritis (ERA) and psoriatic arthritis. For patients with juvenile spondyloarthritis (ERA or specific cases with psoriatic arthritis), the Juvenile Spondyloarthritis Disease Activity Index (JSpADA) is suitable for use.3.

Internationally acceptable criteria for disease flares have also been developed (Box 35.1), which have served as efficacy measures in randomized withdrawal trials. In addition, criteria for clinically inactive disease in select categories of JIA, in JSLE, and JDM are available, including a number of variables beyond the core set. (Box 35.2).4,5,6

There are other parameters that have yet to be incorporated into standard outcome assessment, but allow for a more sensitive assessment of disease activity, such as biomarkers (e.g. serum cytokine profiles, S100 proteins) or new imaging modalities (e.g. ultrasound coupled with power Doppler (USPW), MRI).7

Definition of worsening/flare in

JIA (a number of definition have been developed, the most commonly employed is given)

  • Worsening in any 3 of the 6 core set variables by ≥ 30% without concomitant improvement of more than one of the remaining core set variables by more than 30%.

Contingencies

If either the active joint count or limited joint count are included, there must be at least a

2 joint increase

If either the physician or parent global scales are included, there must be at least a 2 cm

worsening (on a 0-10cm scale)

For systemic-onset JIA: fever spikes >38_C for at least 2 of the preceding 7 days not due to infection

JSLE

  • based on SLEDAI: 0.5 x changes of SLEDAI + 0.45 × changes of protein:creatinine ratio + 0.5 × changes of physician global assessment of disease activity + 0.02 × changes of ESR ≥ 1.04.

  • based on BILAG: 0.4 x changes of BILAG + 0.65 × changes of protein:creatinine ratio + 0.5 × changes of physician global assessment of disease activity + 0.02 × changes of ESR ≥ 1.15.

Inactive disease, minimal disease activity, child and parent acceptable symptom state, and high disease activity in JIA based on the four- and three-variable JADAS.2, 8

Disease state

All JIA

Oligoarthritis

Polyarthritis

JADAS

JADAS

cJADAS

JADAS

cJADAS

Inactive disease

≤1

≤1

≤1

≤1

≤1

Parent acceptable symptom state

≤4.7

≤3.2b/3.5a,c

≤5.2b/5.4a,c

Child acceptable symptom state

≤4

≤3

≤4.3b/4.5

Low disease activity

≤2.7b

>1≤2

>1≤1.5

>1≤3.8

>1≤2.5

Moderate disease activity

>2≤4.2

>1.51≤4

>2.5≤8.5

High disease activity

>6b

>4.2

>4

>8.5b/10.5a,c

>8.5

a value for JADAS-10;

b value for JADAS-27;

c value for JADAS-71

JSLE5

Inactive disease = no signs of JSLE activity on physical examination, except for ≤2 mild or non-limiting of the following symptoms: fatigue, arthralgia, myalgia, headaches, and the following laboratory abnormalities: ANA positivity, any damage-related laboratory abnormalities, abnormally low levels of complement C4 if presumed to be due to null allele, abnormal, but stable levels of aPL ≤2 × ULN, ESR ≤2 × ULN.

Clinical remission on medication for JSLE: the criteria for inactive disease must be met for a minimum of 6 continuous months while the patient is on medication.

Clinical remission off medication: the criteria for inactive disease must be met for a minimum of 12 continuous months while off all medication prescribed for JSLE except for medication to treat damage.

ANA, antinuclear antibodies, aPL, antiphospholipid antibodies, ULN, upper limit of normal range, ESR, erythrocyte sedimentation rate.

JDM6

Clinically inactive disease = at least three of four of the following criteria must be met: creatine kinase ≤150 u/l, CMAS ≥48, MMT ≥78 and physician’s global assessment of disease activity ≤0.2.

CMAS, Childhood Myositis Assessment Scale, MMT, manual muscle testing,

Disease status measures

Physician-reported outcomes

Traditional disease status measures comprise clinically measurable signs or symptoms of the disease assessed by the physician, such as current disease activity and organ system damage. Standardized definitions of disease activity states (e.g. inactive disease, clinical remission, and minimal disease activity state) have been developed for JIA, JSLE, and JDM (Box 35.2).4,5,6

Validated, standardized, clinical measures aimed at assessing damage or permanent alterations in joint structures or extra-articular organ/systems as a result of disease or its treatment are available for JIA, JSLE, and JDM.9,10,10,11 These instruments differ somewhat from damage instruments applied in adult-onset diseases, because they also consider the potential reversibility of some damage items in children and include assessment of growth retardation and pubertal delay.

In JIA, imaging has been of particular importance to assess structural joint damage. The reference standard method for assessing growth abnormalities and joint damage, including bone erosions, joint space narrowing, joint subluxation, malalignment, and ankylosis, is plane radiography. Several radiographic scoring systems have been developed that allow for a standardized quantification of radiographic joint changes (e.g. Poznanski score, Dijkstra composite score, adapted Sharp/van der Heijde score, Childhood Arthritis Radiographic Score of the Hip). The newer imaging methods, MRI and USPD, for which corresponding scoring systems have been developed, are even more sensitive for joint damage assessment.7

Patient-reported outcomes

The patients’ perspective on outcome is equally important as the physician-based outcomes. This includes the direct effect of illness with subjectively perceived signs and symptoms: pain, fatigue, adverse effects from therapy, and disability. Given the current inability to prevent or cure rheumatic diseases, the primary aim of care is to ensure the best possible lifelong functioning and quality of life. This necessitates formal methods for measuring patient’s experience of disease. An accepted means of describing the health and functioning of an individual is the WHO International Classification of Functioning, Disability and Health (ICF). According to the ICF, ‘functioning’ comprises all different aspects of the way in which a specific health condition affects life and thus includes body functions and structures, activities, and participation related to environmental and personal factors.12

Instruments developed to measure patients’ functioning and health are summarized in Table 35.2. Of the function-oriented health status measures, the Childhood Health Assessment Questionnaire (CHAQ) in childhood or the Health Assessment Questionnaire (HAQ) in adulthood are the most widely used, mainly because of their ease of use and their validation in long-term outcome studies. Health-related quality of life (HRQoL) can be measured by different approaches. So-called generic measures allow for the valuation and comparisons of HRQoL of healthy people versus that of patients with different diagnoses. Conversely, disease-specific measures value the health of patients with a specific disease and are therefore thought to better capture changes in the degree of health.

Table 35.2 Patient-reported outcomes in juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE), and juvenile dermatomyositis (JDM)

JIA

JSLE

JDM

Function-oriented health status measures

  • Childhood Health Assessment Questionnaire (CHAQ) in childhood or Health Assessment Questionnaire (HAQ) in adulthood

  • Juvenile Arthritis Functionality Scale (JAFS)

  • Juvenile Arthritis Functional Assessment Report (JAFAR)

  • Juvenile Arthritis Self-Report Index (JASI)

  • Childhood Arthritis Impact Measurement Scales (CHAIMS)

Health-related quality of life

  • Child Health Questionnaire (CHQ) in childhood or Medical Outcomes Short-Form 36 (SF-36) in adulthood

  • Pediatrics Quality of Life Inventory (PedsQL) Generic Core Module

  • PedsQL Rheumatology Module

  • Quality of My Life Questionnaire (QoMLQ)

  • Paediatric Rheumatology Quality of Life Scale (PRQL)

Juvenile Arthritis Quality of Life Questionnaire (JAQQ) Childhood Arthritis Health Profile (CAHP)

Simple Measure of the Impact of Lupus Erythematosus in Youngsters (SMILEY)

Overall well-being

Visual analogue scale (VAS) / numerical rating scale (NRS)

Pain

VAS/NRS

Fatigue

PedsQL Multidimensional Fatigue Scale

Composite scores

  • Juvenile Arthritis Multidimensional Assessment Report (JAMAR)

  • Juvenile Arthritis Parent Assessment Index (JAPAI),

  • Juvenile Arthritis Child Assessment Index (JACAI)

Health outcomes

Given the substantial improvement in outcomes for patients with PRD over the past several decades, there has been a shift from measuring short-term mortality and morbidity to examining long-term outcomes and preventing the adult consequences of childhood-onset disease. However, many of the long-term outcome studies published have inconsistent case definitions. Studies often include patients from tertiary referral clinics, meaning they may reflect only those who have a disease severe enough to come to and remain at special healthcare facilities. Studies also vary substantially in the applied outcome indices and measures (e.g. disease activity and damage tools), in years of follow-up, and in whether they are prospective or retrospective. These factors help to explain both the variability and the limitations associated with outcome studies which are presented in the following. Yet, further variability is likely to be seen in future estimates associated with variations in availability and uptake of new treatments.

Physical consequences of juvenile rheumatic diseases for the individual

Mortality

Juvenile-onset inflammatory rheumatic diseases are associated with increased mortality rates compared with the general population. However, mortality rates have considerably decreased over the past decades. Mortality rates among children with chronic arthritis were 4–7% in the 1970s, which represented a 10-fold increase over the general population. In 2010, Hashkes reported a global mortality rate of 0.2 for children with JIA,

which did not differ significantly from the mortality rate of the general population.13 Patients with systemic-onset JIA have a higher overall mortality rate than those with non-systemic JIA (3.9/1000 person-years vs. 0.6/1000 person-years).14

JIA patients are still at increased risk of mortality in their young adult years. Two population-based studies demonstrated that adult patients with childhood-onset arthritis have a roughly fourfold higher overall mortality than the general population. Elaine Thomas and colleagues estimated standardized mortality ratios (SMR) of 5 for women and 3 for men with childhood-onset arthritis, twice as high as those calculated for men and women with rheumatoid arthritis.15

Children with systemic connective tissue diseases, such as JSLE and JDM, and primary vasculitis—except for Kawasaki’s disease and IgA vasculitis (Henoch–Schönlein purpura)—still have a significantly higher mortality risk than the general population. Patients with primary vasculitis carry the highest risk, with a mortality rate of 1.9% and a SMR of 4.71 according to the study by Hashkes.13 Patients with JSLE follow, with a rate of 1.2% and a SMR of 3.06. As in JIA, a higher mortality rate of 6.5–9% is observed later in the course of jSLE, with young adults having a greatly increased SMR of 14–20 in comparison to the background population. Moreover, patients with childhood-onset SLE are at higher risk of mortality than those with adult-onset disease.16,17,18 Data from the largest-ever direct comparison of JSLE with adult-onset SLE have shown a 6fold higher SMR in JSLE (18.3 versus 3.1).19 Of course, the lifespan of JSLE patients has improved dramatically.19. While global survival at 5 and 10 years follow-up was 59–93% and 28–85% for the patients studied in the 1980s and 1990s, respectively, these values reached 95–100% at 5 years and 90% at 10 years follow-up in the studies published in the 2000s.16, 18, 20, 21 A marked improvement in prognosis was also demonstrated for patients with JDM, for whom mortality rates of almost 40% were reported in the presteroid era as compared to 0.8%–3.1% in the year 2010.13, 22, 23

Knowledge about specific causes of death in the various PRD is very limited. In the 1970s, the major causes of death in patients with childhood-onset chronic arthritis were renal failure (in one-half of the cases due to amyloidosis) and infections. Amyloidosis accounted for more than 40% of all causes of death, but is no longer a relevant cause of death in these patients. Systemic-onset JIA still accounts for two-thirds of the mortality seen in JIA, with macrophage activation syndrome (MAS) and infection being the leading causes for mortality.14 Approximately 10% of patients with systemic-onset JIA are diagnosed with MAS which has a mortality of 6–11%.24, 25 With regard to the risk of cancer occurrence, preliminary data point to a two to fourfold increased risk of malignancies (particularly of the lymphoproliferative type) in patients with JIA and JSLE versus the general population, which in JIA cannot be explained by the introduction of biological therapies.26,27,28 The relevance of this for early mortality seems insignificant. To what extent cardiovascular diseases, infections, or even hematopoietic malignancies attribute to the increase in SMR in JIA in adulthood is unidentified.

Causes of death among JSLE patients include neuropsychiatric SLE, renal involvement, and infection.29, 30 In adulthood, infection followed by cardiovascular disease is the leading cause of mortality in these patients.16, 17, 21, 31 By early adulthood, JSLE patients have a 100-fold to 300-fold increased risk of death from cardiovascular disease as compared with age-matched controls. Death in JDM most often results from respiratory failure or interstitial lung disease, myocarditis, or from gastrointestinal ulceration with intestinal perforation and bleeding. Early illness features, such as dysphagia, Raynaud’s phenomenon, interstitial disease, and antisynthetase autoantibodies are risk factors for mortality.23 Information about causes of death in adult JDM is missing.

Disease activity

Persisting disease activity is a significant consequence of disease for patients because it is closely linked to important symptoms such as pain, fatigue, and functional limitations. Outcome studies published since the year 2000 show that rheumatic diseases beginning in childhood frequently continue into adulthood (Table 35.3).

Table 35.3 Outcome studies of juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE), and juvenile dermatomyositis (JDM) which comprised at least 20 patients with a specific disease, had a follow-up of at least 10 years, published since the year 2000

Study (year, country)

Number of patients assessed

Median or mean disease duration (years)

Patients (in %) with

Active disease

Functional limitations (Steinbrocker Class > I or HAQ > 0)

Erosive joint changes

JIA—systemic onset

Lomater et al. (2000, Italy)32

80

11

43

57

n.g.

Minden et al.* (2002, Germany)33

30

17

46

45

n.g.

Packham et al. (2002, UK)34

52

29

n.g.

63a

75b

Lurati et al. (2009, Italy)35

98

10c

66

n.g.

n.g.

Oliveira Ramos et al. (2016, Portugal)36

32

23c

63

n.g.

n.g.

JIA—Oligoarthritis

Minden et al.* (2002, Germany)33

85

17

41

28

n.g.

Arkela-Kautiainen et al.* (2005, Finland)37

78

16c

58

n.g.

n.g.

Lurati et al. (2009, Italy)35

468

10c

61

n.g.

n.g.

Flato et al.* (2009, Norway)38

137

15

30

30

13

Selvaag et al.* (2016, Norway)39

42

30c

30

n.g.

n.g.

Oliveira Ramos et al. (2016, Portugal)36

105

23c

70

n.g.

n.g.

JIA—RF-negative polyarthritis

Foster et al. (2003, UK)40

20

21c

65

n.g.d

n.g.

Minden et al.* (2002, Germany)33

27

16

59

52

n.g.

Packham et al. (2002, UK)34

41

30

n.g.

50a

56b

Lurati et al. (2009, Italy)35

94

10c

78

n.g.

n.g.

Oliveira Ramos et al. (2016, Portugal)36

58

23c

67

n.g.

n.g.

JIA—RF-positive polyarthritis

Packham et al. (2002, UK)34

41

29

n.g.

53a

60b

Lurati et al. (2009, Italy)35

26

10c

100

n.g.

n.g.

Oliveira Ramos et al. (2016, Portugal)36

50

23c

72

n.g.

n.g.

JIA—enthesitis-related arthritis

Minden et al.* (2002, Germany)33

33

15

79

45

39e

Packham et al. (2002, U.K.)34

32

27

n.g.

16a

34b

Flato et al.* (2006, Norway)41

55

15

56

51

35e/26f

Oliveira Ramos et al. (2016, Portugal)36

46

23c

61

n.g.

n.g.

JIA—psoriatic arthritis

Flato et al.* (2009, Norway)38

31

15

35

45

23

JSLE

Active disease

Functional limitations (HAQ > 0)

Irreversible renal damage

Candell Chalom et al. (2004, USA)42

29

13

52g

n.g.

46

Hersh et al. (2009, USA)43

90

17

68h

n.g.

31i

Al Hamzi et al. (2014, Saudi Arabia)44

48

15

50

n.g.

n.g.

JDM

Active disease

Functional limitations (HAQ > 0)

Muscle damage

Sanner et al.* (2009, Norway)45

59

17

51

40

65

Mathiesen et al.* (2012, Denmark)46

53

14

15

30

*More or less population-based study with a follow-up of incident cases; DAS—disease activity score; HAQ—Health Assessment Questionnaire; n.g.—not given.

a HAQ > 1.5;

b patients with joints replaced;

c disease duration of the whole JIA group;

d mean HAQ = 1.36;

e radiographic sacroiliitis;

f peripheral joint erosions;

g SLEDAI score > 4;

h receiving prednisone therapy;

i dialysis or renal transplant.

In JIA most remissions occur in the first 5 years after disease onset. After more than 10 years of disease duration 40–60% of the patients still have an active arthritis.32, 33, 35, 37,38,39,41 The probability of remission varies significantly with disease-onset type, being best for oligoarticular JIA, at approximately 50%, and worst for polyarticular JIA, in which it approaches 15%. The probability of remission decreases progressively after 10 years. If remission does not occur within 10 years of disease onset, it is unlikely to occur at all. Remission rates seem to change little beyond 10 years of follow-up, as shown by similar rates after 15 and 30 years of follow-up in a long-term outcome study from Norway.39

Similar results have been reported in JSLE, with over one-half of patients having active disease after a mean follow-up period of 13 years,42 and over two-thirds of patients receiving oral corticosteroids at a mean follow-up of 16.5 years.43 The median time to remission in JDM was estimated to be 4.7 years. In other words, one-half of patients with JDM will have achieved remission 4.5 years after diagnosis.47 A similar percentage was found in studies with a follow-up of 8 and 17 years.22,48

Organ system damage

Cumulative disease activity over time has been shown to be a highly significant predictor of disease damage in children with inflammatory rheumatic diseases. More than five years after disease onset, damage has occurred in approximately one-quarter of patients with JIA and in more than one-half of those with JSLE and JDM. Tables 35.4–35.6 summarize those studies on damage in JIA, JSLE, and JDM, which used standardized damage instruments. In JIA, articular damage is the most important component of global damage. Ocular damage, growth failure, and muscle atrophy are the most frequent extra-articular damage components in JIA.49 Among adult patients with JIA registered on the Rheumatic Diseases Portuguese Register, those with RF-positive polyarthritis, sJIA, and RF-negative polyarthritis had more articular damage (mean JADI-A scores of 18.3, 13.0 and 9.6, respectively) than patients with other JIA categories after more than 20 years of disease duration. Extraarticular damage was highest in patients with RF-negative polyarthritis, followed by patients with sJIA.36

Table 35.4 Summary of studies on cumulative organ damage assessed by JADI in juvenile idiopathic arthritis after at least 5 years of disease

Solari et al. (2008, Italy)49

Russo et al. (2008, Argentina)50

Sarma et al. (2008, India)80

Sarma et al. (2008, India)81

Susic et al. (2011, Serbia)82

Nordal et al.* (2011, Scandinavia)83

Singh et al. (2012 India)84

Patients (n)

310

43 (sJIA)

89

49 (ERA)

87

440

101 (ERA)

Median disease duration, years

6.7

6

5

6

5.2

8.2

6

Patients in % with DI ≥1

43

23

Articular damage

34.2

38

60.7

34.7

41.4

13.2

46.5

Extra-articular

26.1

19

39.3

10.2

39.1

11.9

34.7

Ocular

7.1

2

n.r.

0

8

n.r.

3

Muscular atrophy

6.8

8

3.3

6.1

1.1

n.r.

15.8

Osteoporosis

1.3

n.r.

2.2

n.r.

1.1

n.r.

2

Avascular necrosis

0.3

8

1.1

n.r.

6.9

n.r.

n.r.

Scoliosis

6.8

4

5.6

n.r.

4.6

n.r.

11.9

Leg-length discrepancy

7.7

6

3.3

n.r.

6.9

n.r.

5.9

Striae rubrae

1.3

2

1.1

n.r.

6.9

n.r.

n.r.

Subcutaneous atrophy

3.5

n.r.

2.2

n.r.

8

n.r.

n.r.

Growth failure

6.1

13

39.3

8.2

8

n.r.

10.9

Pubertal delay

1.6

2

20.2

4.1

8

n.r.

1

Diabetes

0

n.r.

n.r.

n.r.

2.3

n.r.

n.r.

Secondary amyloidosis

0

n.r.

1.1

2.0

1.1

n.r.

1

*Inception-cohort study; JADI—Juvenile Arthritis Damage Index; ERA—enthesitis-related arthritis; sJIA—systemic-onset JIA; n.r.-not reported.

Renal, neuropsychiatric, musculoskeletal, and ocular systems are the most commonly damaged organ systems in JSLE. In JDM, the skin leads the list of the most frequently affected organs, followed by the muscular, skeletal, endocrine and pulmonary systems.

Articular damage

In JIA, articular damage is most common in hip, wrist, and temporomandibular joints.50 Ten years after disease onset, at least one in four JIA patients has developed radiographic joint changes with erosions, joint space narrowing, or even destruction (Figure 35.1). Depending on the patient collective studied, between 2% and 50% of the 20–35 year old JIA patients have already been supplied with endoprostheses.33, 34, 40 Patients with systemic-onset show the highest frequency of joint replacements, and the hip is the most frequently replaced joint. As a result of change in treatment strategies—i.e. the early use of intra-articular steroids and immunomodulatory drugs, such as methotrexate and biological agents—joint damage is decreasing.51 In JSLE and JDM articular damage is rarely seen; however, joint contractures are seen in about 20% of JDM patients.

Fig. 35.1 An 18-year-old girl with extended oligoarthritis and pronounced destructive changes in the right hip (MRI, coronary T1-weighted SE).

Fig. 35.1
An 18-year-old girl with extended oligoarthritis and pronounced destructive changes in the right hip (MRI, coronary T1-weighted SE).

Extra-articular damage

Linear growth failure occurs in about 10% of children with PRD, with a decreasing trend over the past decades. Total body inflammation and corticosteroid therapy are strongly implicated as causes of growth failure. In view of the whole JIA group, growth failure is therefore more likely to develop in patients with systemic and polyarticular JIA. Simon and colleagues.52 found a mean final height standard deviation score of –2.0 in 24 patients with systemic JIA, with 41% of subjects’ height more than 2 SD below the mean. The prevalence of short stature (final height below the 3rd percentile) in 65 adult JIA patients was reported to be nearly 11% in a long-term follow-up study from Denmark, with all of the severely growth-retarded patients having polyarticular JIA.53

Local growth disturbances

In JIA local growth disturbances mainly occur at sites of inflammation and can take the form of overgrowth or undergrowth (Figure 35.2). There is a tendency to accelerated maturation of epiphyses, leading for example to increased leg length, or overcrowding and fusion of the joint in wrists and ankles. Limb length discrepancies and micrognathia (Figure 35.3) are the most frequently observed local growth disturbances in up to one-quarter of adult patients.33, 34

Fig. 35.2 Shortening of the left third toe in a child with polyarticular JIA.

Fig. 35.2
Shortening of the left third toe in a child with polyarticular JIA.

Fig. 35.3 Girl with rheumatoid-factor-negative polyarthritis since early childhood and micrognathia due to temporomandibular joint arthritis.

Fig. 35.3
Girl with rheumatoid-factor-negative polyarthritis since early childhood and micrognathia due to temporomandibular joint arthritis.

Abnormal body composition

Abnormalities in body composition, i.e. a decreased lean body mass, an increased fat mass, and a reduced bone mineral density have been documented in patients with PRD. Up to 50% of adolescents and young adults with JIA, JSLE, and JDM experience decreased bone mass at lumbar spine or femoral neck, and up to 10% osteoporosis. The abnormalities in the amount and the geometric distribution of bone mass are of concern as both determine bone strength and the fracture threshold and put the patients at increased risk of osteoporosis and fractures later in life.

Muscle loss

Muscle loss, which is critically responsible for the bone loss, occurs in all forms of PRD. Muscle mass and force are reduced in JIA patients; about 10% demonstrate persistent muscle atrophy on clinical examination. In patients with longstanding JDM muscle weakness has been found in 23–47% of patients in two series after more than 10 years of follow-up,45, 46 whereas MRI-detected muscular damage was found in one-half of the patients.54

Ocular sequelae

Apart from musculoskeletal system damage, ocular sequelae are of major concern in JIA. They develop as consequences of uveitis in at least one-fifth of affected patients within the first 7 years of disease,55, 56 and most frequently consist of band keratopathy (in 42% of eyes), cataract (25%), posterior synechiae (22%), maculopathy (22%) and ocular hypertension (13%) in adult patients.57 The ocular complications result in a permanent, significant visual loss (<0.5) in 10–30% of patients. Blindness (20/200 or worse) due to uveitis in at least one eye still occurs in 5–15% of uveitis patients.57,58,59 Most complications and reduction of visual acuity occur within the first 7 years of disease, but their prevalence increases with longer follow-up. More than 15 years after disease onset, uveitis is still active in almost one-half of the patients.57, 59

Atherosclerosis and cardiovascular disease

Patients with chronic inflammatory rheumatic diseases are at increased risk of premature atherosclerosis and early-onset cardiovascular disease.60, 61 The aetiology may be multifactorial, attributable to manifestations of the disease itself (such as chronic inflammation, chronic hypertension, renal disease, or abnormal lipid profiles), adverse effects of medication (such as steroids and non-steroidal anti-inflammatory drugs) and lifestyle issues (such as decreased physical activity due to disease-related disability).62, 63 Impaired vascular function and/or higher prevalences of dyslipidaemia and arterial hypertension compared with the general population have been shown in JIA (in particular in systemic-onset JIA), in JSLE and JDM, representing measures or risk factors of atherosclerosis. A first longitudinal study did not find an increase in cardiovascular events in patients with JIA 29 years following disease onset when compared to the general population.64 For adult patients with JSLE, however, a similar incidence of myocardial infarction as in subjects with adult-onset disease was shown, with the first infarct occurring even at a much earlier mean age. There has been also evidence of an increased prevalence of traditional cardiovascular risk factors (e.g. hypertension, dyslipidaemia) and a high prevalence of subclinical cardiac involvement in JDM. Moreover, impaired autonomic control with reduced heart rate variability, a known risk factor for cardiac morbidity and mortality, has been shown in long-standing JDM. However, data on the relationship between JDM and coronary artery disease have not been available.65

The exact extent of the increased cardiovascular risk in the various PRD is still unknown; however, it is assumed that cardiovascular disease emerges as leading cause of morbidity and mortality in this population in adulthood. A low threshold for cardiac workup in adult patients with PRD is therefore recommended.

Fertility problems

Fertility disorder is of particular concern to patients. In females with JSLE and JDM menarche is delayed by approximately one year and active disease is associated with amenorrhoea or oligomenorrhoea.66

Fertility is not impaired in females with JIA, but fecundity was found to be reduced.67 Also, pregnancy outcome was less successful in these women, with a significantly increased rate of miscarriage. Women with JIA have higher rates of instrumental delivery as well as of pre-eclampsia, postpartum haemorrhage and severe maternal morbidity than other women.68 Women with a history of JIA may also be at increased risk for adverse neonatal outcomes, notably prematurity, small for gestational age, and major congenital malformation.69

Patients with systemic connective tissue disorders or vasculitides may even be at higher risk for decreased reproductive fitness than JIA patients as a consequence of their chronic inflammatory condition or the medications used to treat it (e.g. alkylating agents such as cyclophosphamide). Their true risk of infertility or low follicular/ovarian reserve is not known, however.

Consequences of juvenile rheumatic diseases

Functional consequences

Treatment for PRD has improved dramatically, accompanied by a steady and significant reduction in disability rates. In the 1970s the frequency of patients in Steinbrocker functional class I (i.e. no functional limitation) ranged from 25% to 40% and that of patients with serious functional disability (corresponding to Steinbrocker functional classes III and IV) from 17% to 22%, but higher frequencies of patients with no functional limitation (60%) and lower frequencies of patients in Steinbrocker classes III and IV (10%) were recorded in the 1990s. Most recent outcome studies used a more sensitive functional measure, the HAQ, for the assessment of the patients’ physical disability.51, 70 According to the HAQ, approximately 40% of patients with PRD are somehow limited in their functional capacity in their young adult years (see Table 35.3). Approximately 10% of them are in need of assistance and/or aids in order to manage their activities of daily living, which corresponds well with the percentage of patients being in Steinbrocker functional class III or IV. Severe disability is most frequently seen in patients with rheumatoid factor positive polyarthritis and systemic onset of JIA, followed by patients with rheumatoid factor-negative polyarthritis and extended oligoarthritis. In contrast, patients with persistent oligoarthritis hardly ever report functional disability in early adulthood.

Societal consequences

Symptoms associated with PRD, such as fatigue, pain, stiffness, and physical disability, may lead to reduced participation in daily school and social activities. However, children and adolescents with PRD more frequently cut back on participation in social activities rather than school activities. Patients with PRD miss on average 1–2 days of school per month due to their illness. Nevertheless, their academic achievement is comparable to that of the general population, or even better.33, 34, 37, 40, 70,71,72 However, entering the labour force is difficult for young people with PRD. JIA patients have lower employment rates compared with age-matched local controls.33, 34, 40, 71 The lower employment rates result from significantly higher rates of unemployment in JIA patients in comparison with controls, extended training periods, or early retirement.36 As compared to JIA patients, young adults with JSLE have an even lower employment rate. At a mean age of 24 years, only 40% worked full time.73 In addition, many employed young adults with PRD experience challenges at work and report work absenteeism (e.g. missed workdays attributed to health), job disruptions (e.g. arriving late to work, leaving early, missing meetings, being unable to work to the schedule/shift desired), or perceived productivity loss.74 PRD have consequences not only for the individual, but also for their friends and family and for the whole of society. Parents having a child with PRD report significant work time loss compared with parents with no children having PRD75 and experience financial burdens. Klein-Gitelman and colleagues reported that one in five guardians of children with JIA, JSLE, and JDM reported having taken time off work, and 3% had stopped work in order to care for problems related to their child’s rheumatic disease. Of families queried, 24% reported having lost income, with 14% having lost over $500 within the survey period of 3 or 6 months.76 The economic burden of PRD is difficult to measure. The total costs of illness (both medical and societal costs) depend on the patient collective studied and the medical care delivery system. A cross-sectional study of JIA patients from Germany, Italy, Spain, France, the United Kingdom, and Sweden estimated annual health care costs, ranging from € 18,913 to € 36,396 (reference year: 2012). This suggests the considerable economic impact of JIA. Direct healthcare costs ranged from € 11,068 to € 22,138; direct non-healthcare costs ranged from € 7,837 to € 14,155, and labor productivity losses ranged from € 0 to € 8,715.77 The main cost driver in JIA is medication, in particular biological agents. However, costs incurred in childhood have to be seen in view of lifetime pain, disability, and patient impairment. In adulthood, indirect costs due to work disability and sick leave account for most of the total cost in the active JIA population. Those costs incurred in adulthood might decline in the future as a result of new treatment strategies which have improved the prognosis of PRD. Long-term cost-effectiveness studies are needed to prove this.

77

Quality of life

The impact of disease and its treatment on bodily, functional, and social level is reflected in impairments of patient’s health status or perceived quality of life. How adolescents and young adults with PRD value their health has been repeatedly analysed using quality of life measures, such as the SF-36. Controlled outcome studies showed that patients with PRD judge their quality of life lower than age- and sex-matched controls.22, 40, 42 They feel particularly impaired in their physical health (e.g. physical functioning, vitality, and bodily pain). Worse HRQoL is related to greater pain, fatigue, disease activity, damage, and functional disability. The effect size of JIA on HRQoL seems to be similar to that of JSLE and JDM. In general, a very high percentage of patients with PRD classify themselves as having a high quality of life in adulthood. In addition, overall HRQoL in young adults with PRD seems to have improved since 2000 as a result of the changes in the medical management.40, 51

Outcome prediction

A variety of studies have investigated factors that will predict the course of PRD, to guide a risk-adapted and cost-effective treatment. Some indicators of poor health were identified, e.g. for JIA female gender, polyarticular and symmetrical joint involvement, elevated inflammatory markers, and rheumatoid factor positivity.78, 79 Today, however, it cannot be predicted at disease onset which children will go on to have an unremitting disease and experience poor outcome or quality of life. Most interesting so far has been the prediction of prognosis based upon early treatment response, with outcomes at 3–12 months predicting response at later points in time.

Conclusion

The recent outcome studies are a testament that rheumatic diseases beginning in childhood are not benign. After 5–10 years of disease duration, approximately one-half of patients will have active disease or still require treatment. A quarter to half of the young people will have developed damage due to the disease itself or to the adverse effects of treatment. Patients face a considerable morbidity in adulthood and lower life expectancy compared to their peers. Control of disease activity is important in order to decrease the damage. Owing to improved management, including early recognition and more-sophisticated treatment options, the outlook for children with juvenile rheumatic diseases has dramatically improved. In particular, functional outcomes have improved tremendously, with most patients exhibiting no or mild disability and able to lead a normal life.

Recently established large inception-cohort studies, with follow-up into adulthood, are expected to better characterize the multidimensional outcomes of patients with PRD. The data from these studies will lead to a better understanding of the disease prognosis, and could potentially form the basis of tailor-made treatment strategies for these illnesses presenting during childhood.

Table 35.5 Selected studies on cumulative organ damage assessed by SDI in juvenile systemic lupus erythematosus (JSLE) after more than 5 years of disease

Ravelli et al. (2003, Italy)85

Miettunen et al., (2004, Canada)20

Lilleby et al. (2005, Norway)86

Lee et al. (2007, China)87

Descloux et al. (2008, France)88

Tucker et al. (2008, U.S.)89

Salah et al. (2011, Egypt)90

Al Hamzi et al. (2014, Saudi Arabia)44

Fonseca et al. (2016 Portugal)91

Lopes et al. (2017, Brazil)30

Artim-Esen et al. (2017, Turkey)21

Patients (n)

387

51

71

47

56

31

148

48

38

39 (age at diagnosis < 6 ys)

395 (age at diagnosis ≥6 < 12 ys)

216

Median/mean* disease duration, years

5.7*

7.2

9.8/10.8*

6.8*

5.9/7.1*

6.8*

6.6*

15*

17.1*

8.3

6.2

6.58*

Patients in % with DI ≥1

50.5

58.8

60.6

44.7

54.5

64.5

43.9

81

20

39

36

45

Patients with damage by organ/system in %

Ocular

10.9

11.8

4.2

12.8

10.7

9.7

6.1

n.r.

0

10

13

11.6

Neuropsychiatric

15.8

13.7

28.2

19.1

14.3

29

21

18.8

7.9

21

10

23.2

Renal

21.8

9.8

12.7

4.3

19.6

45.2

16.9

25

5.3

8

7

43.7

Pulmonary

2.3

3.9

4.2

8.5

0

3.2

6.1

n.r.

2.6

n.r.

n.r.

14.3

Cardiovascular

3.1

11.8

5.6

0

3.6

6.5

11.5

12.5

10.5

5

2

12.5

Peripheral vascular

6.2

11.8

8.5

2.1

0

0

4.8

n.r.

2.6

5

3

4.5

Gastrointestinal

3.9

3.9

4.2

0

7.1

3.2

0.7

n.r.

0

n.r.

n.r.

0.9

Musculoskeletal

11.7

27.5

12.7

14.9

12.5

19.4

3.4

18.8

10.5

10

10

16

Skin

9.6

11.8

2.8

0

12.5

9.7

9.5

4.2

2.6

10

1

13.3

Premature gonadal failure

3.9

2

4.2

6.4

1.8

12.9

0

n.r.

2.6

n.r.

n.r.

8.9

Diabetes

0.5

0

1.4

0

1.8

3.2

1.4

n.r.

2.6

n.r.

n.r.

0.9

Malignancy

0

0

1.4

0

0

3.2

0

n.r.

0

n.r.

n.r.

1.8

Growth failure

n.r.

n.r.

10

n.r.

n.r.

n.r.

28.3

50

n.r.

n.r.

n.r.

n.r.

Pubertal delay

n.r.

n.r.

n.r.

n.r.

n.r.

n.r.

15.1

27.1

n.r.

n.r.

n.r.

n.r.

Death

n.r.

0 at 5 ys; 14.3 at 10 ys

5.6

n.r.

10.7

19.4

n.r.

6.25

2.6

15

10

3.7

SDI—Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index, n.r. – not reported

Table 35.6 Summary of studies on cumulative organ damage assessed by MDI in juvenile dermatomyositis after more than 5 years of disease

Rider et al.* (2009, USA)11

Sanner et al.* (2009, Norway)45

Ravelli et al.a (2010, multicentre)22

Mathiesen et al.* (2012, Denmark)46

Patients (n)

143

60

462

53

Median/mean* disease duration, years

6.8

16.8

7.7*

13.9*

Patients in % with DI ≥1

79.1

90

69

60

Patients with damage by organ/system in %

Cutaneous

49

75

53.0

43.4

Muscle

37.8

63

34.3

30.2

Skeletal

33.6

48

27.7

26.4

Endocrine

27.3

23

18.4

17

Gastrointestinal

16.8

3

8.5

5.7

Pulmonary

15.4

17

5.9

7.5

Infection

6.3

8

6

0

Ocular

7.0

0

2.4

0

Cardiovascular

4.2

7

2.9

0

Peripheral vascular

2.8

8

1.6

0

Malignancy

0

2

0

0

*Inception-cohort study; MDI—Myositis Damage Index.

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