Rheumatology 1999;38:739742

Paediatric Rheumatology Workshop/Series Editor: P. Woo

Prognosis in children with rheumatic diseases:
justication for consideration of new therapies
R. E. Petty
Division of Rheumatology, Department of Paediatrics, University of British
Columbia, Vancouver, Canada and Division of Immunology, Department of
Paediatrics, University of Utrecht, Utrecht, The Netherlands
The introduction of any new therapy is based on dissatis- All studies of the outcome of childhood arthritis
describe the results of treatment instituted a decade or faction with the eectiveness or the side-eects of current
more earlier. It is likely that current therapy is more therapy, i.e. the prognosis of the disease as it is currently
ecacious and, therefore, long-term studies of prognosis treated. In order to determine the appropriateness of a
may have little relevance to prognosis in patients in new therapy such as autologous bone marrow trans-
whom optimal treatment is initiated today. The outcome plantation (ABMT), it is important to have an under-
of published studies is, thus, likely to be less optimistic standing of the anticipated long-term prognosis of the
than is actually the case at present. diseases for which it is proposed. Although ABMT is
being considered for a number of rheumatic diseases of
What is meant by outcome?
childhood, the present discussion will focus on chronic
A number of parameters must be considered when
arthritis. Three aspects will be considered:
evaluating the outcome of childhood arthritis. Examples
1. What are the diculties in evaluating the outcome
of such measurements include mortality, morbidity,
of a chronic disease such as juvenile rheumatoid
erosions, drug toxicity, function and quality of life.
arthritis (JRA)?
Mortality is seldom an imminent issue in most patients
2. What is the outcome of the diseases as currently
with chronic arthritis. However, the long-term eects of
treated?
childhood arthritis on lifespan are not yet known. In
3. What are the disease or demographic characteristics
disorders in which mortality may increase with disease
that predict unfavourable outcome at disease onset?
duration, we are often left with incomplete data, since
long-term studies of children with rheumatic diseases
are limited. In adults with rheumatoid arthritis, it is
Evaluating outcome
estimated [4] that the lifespan is shortened by from 3 to
Studies of the outcome of systemic or polyarticular
18 yr. This increased mortality is contributed to by
arthritis are few and fraught with diculty in interpret-
complications of therapy as well as the disease itself.
ation because of a number of factors. The orderly
Function, health status and assessment of the quality of
evaluation of studies of outcome requires that the
life are somewhat overlapping aspects of outcome [5].
patients studied meet recognized diagnostic or classi-
Estimates of functional outcome in chronic arthritis
cation criteria. The criteria of the American College
have most frequently used the Steinbrocker scale [6].
of Rheumatology (ACR) [1], the European League
Measurement of health status in childhood arthritis
Against Rheumatism ( EULAR) [2] or the International
most often uses the Childhood Health Assessment
League of Associations for Rheumatology (ILAR) [3]
Questionnaire (CHAQ) [7], which is useful in children
are acceptable for the description of chronic childhood
with chronic arthritis of all types, over a wide range of
arthritis. Unfortunately, not all studies of prognosis
ages. The Juvenile Arthritis Functional Assessment Scale
have faithfully adhered to accepted diagnostic and classi-
(JAFAS) [8] and Juvenile Arthritis Functional Assessment
cation criteria, thereby making the interpretation of
Report (JAFAR) [9] are somewhat more complicated and
data somewhat dicult. Furthermore, rheumatic dis-
do not adequately evaluate children under the age of 8 yr.
eases may be dicult to diagnose accurately at onset,
Quality of life scales [1012] are being developed, and
and changes in diagnosis over time must be taken into
have also been used recently in limited studies.
account.
Current outcome of chronic childhood
arthritis
Accepted 15 March 1999.
Correspondence to: R. E. Petty, Division of Rheumatology,
Mortality
Department of Paediatrics, University of British Columbia,
Studies of mortality in children with chronic arthritis Vancouver, Canada and Division of Immunology, Department of
Paediatrics, University of Utrecht, Utrecht, The Netherlands. are few. In a 1976 survey, Baum and Gutowska [13]
1999 British Society for Rheumatology 739
R. E. Petty 740
calculated the mortality from JRA to be 4.2% in Europe outcome. Furthermore, most of the patients were not in
remission at the time of last follow-up. There is no and 1.1% in the USA. This discrepancy was ascribed
almost totally to the much higher frequency of amyl- doubt that this outcome has dramatically improved in
the last three decades, but some children with polyarticu- oidosis in children with systemic or severe polyarticular
disease in Europe. More recent estimates have placed lar or systemic-onset disease still encounter signicant
impairment of function. In a study published in 1984 the mortality rate at <1% [14]. A 1991 USACanada
survey [15] estimated mortality in JRA to be <0.29%, [14], 8.7% of children followed for >10 yr were in
Steinbrocker functional classes III or IV; 70% of those a gure that is very likely to reect the current experience
in Europe as well, where the frequency of amyloidosis had polyarticular disease and 30% had systemic disease.
The persistence of active arthritis is a problem in complicating chronic arthritis has fallen dramatically
and inexplicably. Data from elsewhere in the world are arthritis of all onset types. Even in quite recent reports
[15], active arthritis 10 or more years after onset was not available. These data show encouraging improve-
ments in mortality rate, but De Inocencio and Lovell present in from 22 to 41% of those with oligoarticular
onset, 4550% of those with polyarticular onset and [16] have pointed out that these rates are still much
higher than the standardized death rate of 0.08% for 2748% of those with systemic-onset disease. As a
result, many disease-modifying anti-rheumatic drugs ages 124 in the USA.
As shown in Table 1, mortality is very clearly related (DMARDs) are used. Wallace and Levinson [15]
reported that almost 85% of patients with polyarticular to onset type. Children with systemic-onset JRA, the
least common onset type, account for almost two-thirds disease received two or more DMARDs and 42%
received three or more such agents. This indicates the of all deaths among children with arthritis. However,
even children with polyarticular or oligoarticular JRA severity and persistence of the disease, and suggests the
potential of considerable drug-related toxicity. have an increased mortality. The causes of death are
quite evenly divided between disease-related causes and
treatment-related causes, with trauma causing death in
a few children ( Table 2). The disease-related causes of
Predictors of outcome
death are primarily secondary to cardiac disease or
If the clinician could predict with accuracy that any
amyloidosis, whereas infection leads the list of treat-
individual patient was going to have a high probability
ment-related causes.
of a bad outcome when treated conventionally, the use
Disability is also clearly related to disease type. In a
of advanced or experimental therapies such as ABMT
study published in 1977, Stillman and Barry [16]
could be justied early in the disease course. Based on
reported that 30 yr after disease onset >50% of patients
clinical experience, most paediatric rheumatologists
with polyarticular onset JRA had very limited independ-
believe that, of all children with chronic arthritis, those
ence or were conned to bed or a wheelchair.
with systemic arthritis who have polyarticular disease,
Approximately 25% of those with systemic onset and
and children with extensive symmetrical polyarthritis,
10% of those with oligoarticular onset had such a serious
especially with rheumatoid factor, are most likely to
T 1. Mortality in juvenile rheumatoid arthritis have a poor prognosis, i.e. they are most likely to have
a prolonged course, least likely to go into remission,
Onset type n %
most likely to have a poor functional outcome, most
likely to have complications of disease or therapy, and
Systemic 21 63.6
Polyarticular 6 18.2 most likely to experience a poor quality of life. The
Oligoarticular 4 12.1
evidence to support the clinical impression is somewhat
Unknown 2 6.0
limited, however. The results of some of the more recent
studies will be summarized below.
Adapted from Wallace and Levinson [ 15].
Flato et al. [18] have described outcome 10 yr after
onset of disease in a group of 54 children with JRA, 25
T 2. Causes of death in juvenile rheumatoid arthritis
of whom had persistently oligoarticular disease and
Disease related 12
28 of whom had a polyarticular disease course after
Cardiac 9
oligoarticular, polyarticular or systemic onsets. The pur-
Renal amyloid 1
pose of their study was to identify factors assessed on
Encephalitis 1
Macrophage activation syndrome 1 rst admission, or within the rst 5 yr of disease, that
Treatment related 12
predicted an unfavourable outcome. Evaluation of dis-
Infection 4
ease outcome, as measured by the presence of remission,
Surgery/anaesthesia 3
the presence of erosions and the score on a disability
Adrenal insuciency 1
index, was studied with respect to disease onset and Acute myocardial infarct (steroid) 1
Transfusion reaction 1
course. Remission, based on the ACR criteria, required
Duodenal perforation 1
fullment of ve or more of the following criteria for at
Reyes syndrome 1
least 6 months, irrespective of drug therapy: (a) <15 min
Trauma related 9
of morning stiness; (b) no fatigue; (c) no joint pain;
(d) no joint tenderness; (e) no swelling in joints or Adapted from Wallace and Levinson [ 15].
Prognosis in children with rheumatic diseases 741
tendon sheaths; (d) erythrocyte sedimentation rate Schneider et al. [19] studied 38 consecutive patients
( ESR) <20 mm in the rst hour. The remission rate seen between 1980 and 1987 with systemic-onset JRA
was not dierent for oligoarticular and polyarticular in order to identify early clinical and laboratory observa-
onset; however, remission rates were signicantly higher tions that predict destructive polyarthritis in this group
for those with an oligoarticular course compared to of patients.
those with a polyarticular course ( Table 3). The remis-
Thirty-eight patients met study criteria and were
sion rate was highest (84%) in patients with oligoarticu-
examined further. All patients were seen within the rst
lar onset and course of disease, and lowest in those with
3 months of symptoms, and were followed for at least
oligoarticular onset who pursued a polyarticular course
2 yr or until both systemic symptoms and arthritis had
(28%), and those with systemic onset who pursued a
been inactive for 1 yr. Persistent systemic symptoms
polyarticular course (0%). The bad risk groups with
were dened as the presence of fever with or without
respect to disease remission are, therefore, patients with
rash, or the requirement for steroids to control fever.
oligoarticular onset and polyarticular course (extended
Twelve patients (group 1) had severe destructive
oligoarticular group of the ILAR classication), polyar-
polyarthritis 2 yr after disease onset and had at least 10
ticular onset and polyarticular course and systemic
clinically active joints, radiological evidence of joint
onset. Remission rates did not vary with age at disease
space narrowing of 50% or more, and erosions in at
onset in girls or boys with oligo- or polyarticular onset
least one joint. The remaining 26 patients (group 2) had
in this study. Persistently active disease during the entire
less severe disease. Factors at onset and 3 and 6 months
course of observation occurred in 12 patients with JRA
of disease that predicted disease severity are summarized
(ACR criteria). Remission without medication for 2 yr
in Table 4. Using multivariate analysis of clinical and
or more was present in 27 JRA patients at follow-up.
laboratory characteristics after 6 months of disease, the
Radiographs of aected joints at follow-up demon-
investigators found that persistent systemic disease
strated erosions more commonly in children with
(fever, or the requirement for corticosteroids to control
arthritis of systemic onset, polyarticular onset, and
the fever) and a platelet count exceeding 600 000 were
oligoarticular onset with polyarticular course, than in
strongly associated with severe disease outcome (group
those with persistent oligoarthritis ( Table 3). HLA B27
1) ( Table 4). All patients with both persistent systemic
or antinuclear antibody frequencies were not dierent
symptoms and a high platelet count at 6 months were
between those with or without erosions. These observa-
in group 1 at follow-up. Those with resolution of
tions indicate that disease onset may be less important
systemic symptoms and a platelet count under 600 000
than disease course with respect to rate of remission
at 6 months were in group 2 at follow-up.
and erosive disease, and that children with oligoarticular
Ruperto et al. [10, 11] studied early predictors of
onset pursuing a polyarticular course could be appro-
future disability, pain and well-being in 227 individuals
priate potential candidates for ABMT.
with JRA who had been followed for a mean of 15 yr
(range 5.336.1 yr). Factors within the rst 6 months of
disease that were related to later disability (measured
T 3. Onset and course of juvenile rheumatoid arthritis
by CHAQ) and overall well-being (derived from a visual
Remissiona (%) Erosions (%)
analogue scale) included the number of joints with active
arthritis, the articular severity score, the presence of
Oligo onset 32
symmetrical arthritis and the presence of early hand
Oligo course 25 21 (84) 1 (4)
Poly course 7 2 (28) 3 (43) involvement. On the contrary, the presence of anti-
Poly onset 17
nuclear antibody, a young age at disease onset and the
Poly course 17 11 (65) 4 (24)
presence of HLA C3 were predictive of a good outcome
Systemic onset 4
from the viewpoint of disability.
Poly course 4 0 (0) 4 (100)
aRemission based on ACR preliminary criteria for remission in RA
irrespective of medication (see the text).
Summary Adapted from Flato et al. [ 18].
It is evident that current approaches to the treatment of
T 4. Results of multivariate analysis of predictors at 6 months of
childhood arthritis, although much improved in the past
severe disease outcome in systemic-onset juvenile rheumatoid arthritis
decade, are still insucient to halt the destructive pro-
Variable n Relative risk (95% CI ) P gress of these diseases in many children. Furthermore,
the treatment itself is associated with toxicity which may
Persistent systemic symptoms 38 84.34 (7.85, 906.3) <0.0001
be prohibitive. The need for new and innovative treat-
Platelet count >600 000 33 94.50 (7.57, 1179.5) <0.0001
ments is urgent. ABMT is one possible avenue that
WBCCa 12 000 33 12.00 (1.99, 72.36) <0.002
Polyarthritis 38 8.4 (1.79, 39.44) <0.004 oers hope to children with severe unresponsive disease.
Haemoglobin 100 33 5.95 (1.22, 28.95) 0.02
It will be important to select carefully those children
ESR increase of 1 mm/h 32 1.03 (1.00, 1.06) 0.05
who are likely to benet from such an approach. An
appreciation of the prognosis and possible predictors of
Adapted from Schneider et al. [ 19].
aWBCC=white blood cell count. disease severity should aid in this task.
R. E. Petty 742
Murray K et al. Longterm health outcomes and quality
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