Prognosis in children with rheumatic diseases: justification for consideration of new therapies

Series Editor: P. Woo

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

Correspondence to: 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 dissatisfaction with the effectiveness or the side-effects of current therapy, i.e. the prognosis of the disease as it is currently treated. In order to determine the appropriateness of a new therapy such as autologous bone marrow transplantation (ABMT), it is important to have an understanding of the anticipated long-term prognosis of the diseases for which it is proposed. Although ABMT is being considered for a number of rheumatic diseases of childhood, the present discussion will focus on chronic arthritis. Three aspects will be considered:

  1. What are the difficulties in evaluating the outcome of a chronic disease such as juvenile rheumatoid arthritis (JRA)?
  2. What is the outcome of the diseases as currently treated?
  3. What are the disease or demographic characteristics that predict unfavourable outcome at disease onset?

Evaluating outcome

Studies of the outcome of systemic or polyarticular arthritis are few and fraught with difficulty in interpretation because of a number of factors. The orderly evaluation of studies of outcome requires that the patients studied meet recognized diagnostic or classification criteria. The criteria of the American College of Rheumatology (ACR) [1], the European League Against Rheumatism (EULAR) [2] or the International League of Associations for Rheumatology (ILAR) [3] are acceptable for the description of chronic childhood arthritis. Unfortunately, not all studies of prognosis have faithfully adhered to accepted diagnostic and classification criteria, thereby making the interpretation of data somewhat difficult. Furthermore, rheumatic diseases may be difficult to diagnose accurately at onset, and changes in diagnosis over time must be taken into account.

All studies of the outcome of childhood arthritis describe the results of treatment instituted a decade or more earlier. It is likely that current therapy is more efficacious and, therefore, long-term studies of prognosis may have little relevance to prognosis in patients in whom optimal treatment is initiated today. The outcome of published studies is, thus, likely to be less optimistic than is actually the case at present.

What is meant by `outcome'?
A number of parameters must be considered when evaluating the outcome of childhood arthritis. Examples of such measurements include mortality, morbidity, erosions, drug toxicity, function and quality of life. Mortality is seldom an imminent issue in most patients with chronic arthritis. However, the long-term effects of childhood arthritis on lifespan are not yet known. In disorders in which mortality may increase with disease 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 estimated [4] that the lifespan is shortened by from 3 to 18 yr. This increased mortality is contributed to by complications of therapy as well as the disease itself.

Function, health status and assessment of the quality of life are somewhat overlapping aspects of outcome [5]. Estimates of functional outcome in chronic arthritis have most frequently used the Steinbrocker scale [6]. Measurement of health status in childhood arthritis most often uses the Childhood Health Assessment Questionnaire (CHAQ) [7], which is useful in children with chronic arthritis of all types, over a wide range of ages. The Juvenile Arthritis Functional Assessment Scale (JAFAS) [8] and Juvenile Arthritis Functional Assessment Report (JAFAR) [9] are somewhat more complicated and do not adequately evaluate children under the age of 8 yr. Quality of life scales [1012] are being developed, and have also been used recently in limited studies.

Current outcome of chronic childhood arthritis

Mortality
Studies of mortality in children with chronic arthritis are few. In a 1976 survey, Baum and Gutowska [13] calculated the mortality from JRA to be 4.2% in Europe and 1.1% in the USA. This discrepancy was ascribed almost totally to the much higher frequency of amyloidosis in children with systemic or severe polyarticular disease in Europe. More recent estimates have placed the mortality rate at <1% [14]. A 1991 USA–Canada survey [15] estimated mortality in JRA to be <0.29%, a figure that is very likely to reflect the current experience in Europe as well, where the frequency of amyloidosis complicating chronic arthritis has fallen dramatically and inexplicably. Data from elsewhere in the world are not available. These data show encouraging improvements in mortality rate, but De Inocencio and Lovell [16] have pointed out that these rates are still much higher than the standardized death rate of 0.08% for ages 1–24 in the USA.

As shown in Table 1Go, mortality is very clearly related to onset type. Children with systemic-onset JRA, the least common onset type, account for almost two-thirds of all deaths among children with arthritis. However, even children with polyarticular or oligoarticular JRA 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 2Go). The disease-related causes of death are primarily secondary to cardiac disease or amyloidosis, whereas infection leads the list of treatment-related causes.


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TABLE 1.  Mortality in juvenile rheumatoid arthritis
 

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TABLE 2.  Causes of death in juvenile rheumatoid arthritis
 
Disability is also clearly related to disease type. In a study published in 1977, Stillman and Barry [16] reported that 30 yr after disease onset >50% of patients with polyarticular onset JRA had very limited independence or were confined to bed or a wheelchair. Approximately 25% of those with systemic onset and 10% of those with oligoarticular onset had such a serious outcome. Furthermore, most of the patients were not in remission at the time of last follow-up. There is no doubt that this outcome has dramatically improved in the last three decades, but some children with polyarticular or systemic-onset disease still encounter significant impairment of function. In a study published in 1984 [14], 8.7% of children followed for >10 yr were in Steinbrocker functional classes III or IV; 70% of those had polyarticular disease and 30% had systemic disease.

The persistence of active arthritis is a problem in arthritis of all onset types. Even in quite recent reports [15], active arthritis 10 or more years after onset was present in from 22 to 41% of those with oligoarticular onset, 45–50% of those with polyarticular onset and 27–48% of those with systemic-onset disease. As a result, many disease-modifying anti-rheumatic drugs (DMARDs) are used. Wallace and Levinson [15] reported that almost 85% of patients with polyarticular disease received two or more DMARDs and 42% received three or more such agents. This indicates the severity and persistence of the disease, and suggests the potential of considerable drug-related toxicity.

Predictors of outcome

If the clinician could predict with accuracy that any individual patient was going to have a high probability of a bad outcome when treated conventionally, the use of advanced or experimental therapies such as ABMT could be justified early in the disease course. Based on clinical experience, most paediatric rheumatologists believe that, of all children with chronic arthritis, those with systemic arthritis who have polyarticular disease, and children with extensive symmetrical polyarthritis, especially with rheumatoid factor, are most likely to have a poor prognosis, i.e. they are most likely to have a prolonged course, least likely to go into remission, most likely to have a poor functional outcome, most likely to have complications of disease or therapy, and most likely to experience a poor quality of life. The evidence to support the clinical impression is somewhat limited, however. The results of some of the more recent studies will be summarized below.

Flato et al. [18] have described outcome 10 yr after onset of disease in a group of 54 children with JRA, 25 of whom had persistently oligoarticular disease and 28 of whom had a polyarticular disease course after oligoarticular, polyarticular or systemic onsets. The purpose of their study was to identify factors assessed on first admission, or within the first 5 yr of disease, that predicted an unfavourable outcome. Evaluation of disease outcome, as measured by the presence of remission, the presence of erosions and the score on a disability index, was studied with respect to disease onset and course. Remission, based on the ACR criteria, required fulfilment of five or more of the following criteria for at least 6 months, irrespective of drug therapy: (a) <15 min of morning stiffness; (b) no fatigue; (c) no joint pain; (d) no joint tenderness; (e) no swelling in joints or tendon sheaths; (d) erythrocyte sedimentation rate (ESR) <20 mm in the first hour. The remission rate was not different for oligoarticular and polyarticular onset; however, remission rates were significantly higher for those with an oligoarticular course compared to those with a polyarticular course (Table 3Go). The remission rate was highest (84%) in patients with oligoarticular onset and course of disease, and lowest in those with oligoarticular onset who pursued a polyarticular course (28%), and those with systemic onset who pursued a polyarticular course (0%). The bad risk groups with respect to disease remission are, therefore, patients with oligoarticular onset and polyarticular course (extended oligoarticular group of the ILAR classification), polyarticular onset and polyarticular course and systemic onset. Remission rates did not vary with age at disease onset in girls or boys with oligo- or polyarticular onset in this study. Persistently active disease during the entire course of observation occurred in 12 patients with JRA (ACR criteria). Remission without medication for 2 yr or more was present in 27 JRA patients at follow-up.


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TABLE 3.  Onset and course of juvenile rheumatoid arthritis
 
Radiographs of affected joints at follow-up demonstrated erosions more commonly in children with arthritis of systemic onset, polyarticular onset, and oligoarticular onset with polyarticular course, than in those with persistent oligoarthritis (Table 3Go). HLA B27 or antinuclear antibody frequencies were not different between those with or without erosions. These observations indicate that disease onset may be less important than disease course with respect to rate of remission and erosive disease, and that children with oligoarticular onset pursuing a polyarticular course could be appropriate potential candidates for ABMT.

Schneider et al. [19] studied 38 consecutive patients seen between 1980 and 1987 with systemic-onset JRA in order to identify early clinical and laboratory observations that predict destructive polyarthritis in this group of patients.

Thirty-eight patients met study criteria and were examined further. All patients were seen within the first 3 months of symptoms, and were followed for at least 2 yr or until both systemic symptoms and arthritis had been inactive for 1 yr. Persistent systemic symptoms were defined as the presence of fever with or without rash, or the requirement for steroids to control fever.

Twelve patients (group 1) had severe destructive polyarthritis 2 yr after disease onset and had at least 10 clinically active joints, radiological evidence of joint space narrowing of 50% or more, and erosions in at least one joint. The remaining 26 patients (group 2) had less severe disease. Factors at onset and 3 and 6 months of disease that predicted disease severity are summarized in Table 4Go. Using multivariate analysis of clinical and laboratory characteristics after 6 months of disease, the investigators found that persistent systemic disease (fever, or the requirement for corticosteroids to control the fever) and a platelet count exceeding 600000 were strongly associated with severe disease outcome (group 1) (Table 4Go). All patients with both persistent systemic symptoms and a high platelet count at 6 months were in group 1 at follow-up. Those with resolution of systemic symptoms and a platelet count under 600000 at 6 months were in group 2 at follow-up.


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TABLE 4.  Results of multivariate analysis of predictors at 6 months of severe disease outcome in systemic-onset juvenile rheumatoid arthritis
 
Ruperto et al. [10, 11] studied early predictors of future disability, pain and well-being in 227 individuals with JRA who had been followed for a mean of 15 yr (range 5.3–36.1 yr). Factors within the first 6 months of disease that were related to later disability (measured by CHAQ) and overall well-being (derived from a visual analogue scale) included the number of joints with active arthritis, the articular severity score, the presence of symmetrical arthritis and the presence of early hand involvement. On the contrary, the presence of antinuclear antibody, a young age at disease onset and the presence of HLA C3 were predictive of a good outcome from the viewpoint of disability.

Summary

It is evident that current approaches to the treatment of childhood arthritis, although much improved in the past decade, are still insufficient to halt the destructive progress of these diseases in many children. Furthermore, the treatment itself is associated with toxicity which may be prohibitive. The need for new and innovative treatments is urgent. ABMT is one possible avenue that offers hope to children with severe unresponsive disease. It will be important to select carefully those children who are likely to benefit from such an approach. An appreciation of the prognosis and possible predictors of disease severity should aid in this task.

References

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  2.  European League against Rheumatism: EULAR Bulletin No. 4. Nomenclature and classification of arthritis in children. Basel: National Zeitung, 1977.
  3.  Petty RE, Southwood TR, Baum J et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban 1997. J Rheumatol.
  4.  Felson DT. Epidemiology of the rheumatic diseases. In: Koopman WJ, ed. Arthritis and allied conditions, 13th edn. Baltimore: Williams and Wilkens, 1996:9.
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  8.  Lovell DJ, Howe S, Shear ER, Hartner S, McGirr G, Schulte M et al. Development of a disability measurement tool for juvenile rheumatoid arthritis: The Juvenile Arthritis Functional Assessment Scale. Arthritis Rheum 1989;32:1390–5.[ISI][Medline]
  9.  Howe S, Levinson J, Shear E, Hartner S, McGirr G, Schulte M et al. Development of a disability measurement tool for juvenile rheumatoid arthritis: the Juvenile Arthritis Functional Assessment Report for Children and their Parents. Arthritis Rheum 1991;34:873–80.[ISI][Medline]
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Accepted 15 March 1999