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 References of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. I. Outcome 1. Brewer EJ, Bass J, Baum J et al. Current proposed revision status. J Rheumatol 1997;24:94551. of JRA criteria. Arthritis Rheum 1997;20(suppl.):1959. 11. Ruperto N, Ravelli A, Levinson JE, Shear ES, Murray K, 2. European League against Rheumatism: EULAR Bulletin Tague BL et al. Longterm health outcomes and quality of No. 4. Nomenclature and classication of arthritis in life in American and Italian inception cohorts of patients children. Basel: National Zeitung, 1977. with juvenile rheumatoid arthritis. II. Early predictors of 3. Petty RE, Southwood TR, Baum J et al. Revision of the outcome. 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