Juvenile chronic arthritis into adulthood: a long-term follow-up study

M. Zak1 and F. K. Pedersen

University Clinic of Paediatrics II, Rigshospitalet, Copenhagen, Denmark

Abstract

Objective. To evaluate a group of 65 adults with a history of or persistent juvenile chronic arthritis (JCA), on average, 26.4 yr after disease onset.

Methods. Disease status at the time of the study included an evaluation of disease-related parameters assessed by the patient and the investigator.

Results.Active disease was present in 37% of the study participants, of which 80% had either extended pauciarticular or polyarticular JCA. Eleven per cent of the study subjects were in Steinbrocker functional classes III and IV and 22% had undergone JCA-related major surgery. The pain visual analogue scale, health assessment questionnaire, erythrocyte sedimentation rate and C-reactive protein (CRP) were significantly increased in those participants who had active JCA at the time of the study. Disease duration proved to be the parameter most strongly associated with an unfavourable disease outcome.

Conclusions. Although the study group was biased towards the more severe cases, the data suggest that the long-term functional outcome in JCA is, in more than one-third, associated with active disease persisting into adulthood, increasing residua and the need for surgery.

KEY WORDS: Juvenile chronic arthritis, Juvenile rheumatoid arthritis, Follow-up studies

The evaluation of chronic disease on a long-term follow-up basis is a central issue. Follow-up studies serve as important tools for the evaluation of the disease process per se and comprise an important quality control tool. Furthermore, they provide information which enables the recognition of treatment and disease-associated problems.

In juvenile chronic arthritis (JCA) more than 20 follow-up studies have been conducted over the past five decades [123]. Although the early studies may be difficult to compare with the more recent ones, due to a lack of uniform classification, disease activity and disease outcome measures, it is our impression that the prognosis for children with JCA/juvenile rheumatoid arthritis (JRA) has improved during the 20th century. This tendency is consistent with the development of new and possibly better treatment regimens and probably also to a certain extent due to an improved general health status in the population. Only a few studies have followed JCA patients into adulthood.

The objective of the current study was to evaluate a group of 65 adults with JCA, on average 26.4 yr after disease onset, to describe the course of the disease, disease outcome and identify disease-related parameters associated with a poor disease outcome.

Materials and methods

The study group
In 1979–1980 Pedersen et al. performed a referral-based 10-yr follow-up study including 93 patients with JCA [16]. All study participants were admitted to the Hornbaek Hospital of Physical Medicine during the period 1965–1977 and selected according to the EULAR criteria for JCA. Based on a relatively recent assessment of the incidence of JCA in Denmark [24], Pedersen et al.'s study group represented approximately 15% of the Danish JCA population at the time. The JCA subtypes at disease onset in the 10-yr follow-up study were as follows: 67% of the participants had pauciarticular, 27% had polyarticular and 6% had systemic JCA. The male:female ratio was 1:3.

Participants for the current study were recruited from the group previously investigated by Pedersen et al. Sixty-five Caucasians, 52 females and 13 males, with an average (S.D.) age of 32.2 (5.7) yr and a history of JCA participated. The characteristics of the study group are outlined in Table 1Go. The characteristics of those patients who participated in the 10-yr follow-up, but not in the current study, were very similar to those of the current study participants. From the original study group, two had died, one from AIDS and one from septicaemia, four wished to participate but were unable to for various reasons. The rest of the 28 non-participants had either left Denmark or did not wish to participate (tired of the ‘system’, did not like doctors and hated hospitals). One patient was excluded due to Turner's syndrome. Data from the 10-yr follow-up study in 1979–1980 were used as baseline data in the current study. The same investigator evaluated all study participants during the period 1996–1997 at the Paediatric Clinic of the Copenhagen University Hospital (Rigshospitalet, Denmark). The local ethics committee approved the study and all participants gave their informed consent.


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TABLE 1. Disease characteristics of the JCA study group

 

Disease assessment, outcome measures and laboratory evaluation
Disease status at the time of the study included an evaluation of disease-related parameters assessed by the patient and the investigator. The patient part included a self-reported health assessment questionnaire (HAQ) [25] translated into Danish by one of the investigators and two visual analogue scales (VAS), one for pain and one for general coping in life with the disease. Based on disease history, joint examination and erythrocyte sedimentation rate (ESR) (Westergren method, normal values <15 mm/h for females and <20 mm/h for males), the investigator assessed disease activity using the below outlined criteria for remission. Remission was considered when there were no symptoms or objective signs of active JCA in the presence of normal ESR for more than two consecutive years without any anti-rheumatic treatment. Joint symptoms due to JCA sequelae were not considered as evidence of ongoing arthritis. Besides persistent disease activity, the HAQ, Steinbrocker functional class [26] and history of JCA-associated surgery were used as disease outcome parameters. A HAQ score >0, Steinbrocker functional classes II–IV and history of JCA-related major surgery were regarded as disease sequelae. In addition, VAS for the physician's overall evaluation of disease activity at the time of the study, based on history and examination, was used. Disease duration, meaning years of active disease, was reconstructed from hospital records and interviews with the patients. Plasma levels of C-reactive protein (CRP), levels of antinuclear antibodies (ANA) and IgM rheumatoid factor (RF) were measured in all study participants.

Treatment
The anti-rheumatic drug treatments in the study group were primarily acetylsalicylic acid, gold salts, hydroxychloroquine and systemic and intra-articular steroids. Other disease-modifying anti-rheumatic drugs (DMARDs) included penicillamine and only in a few cases methotrexate and sulphasalazine were used. Thirteen patients had received systemic steroid treatment >1 yr and 15 patients <1 yr. Non-steroidal anti-inflammatory drugs (NSAIDs) were used in the majority of patients. Physiotherapy and occupational therapy were given in all cases. However, the paradigm of physiotherapy at the time was passive and active joint maintenance therapy, with as little as possible weight-bearing activity. In other words, the children, while hospitalized, had to put up with a wide range of restrictions and limited physical activity, and a majority of them had to spend most of the day in bed or in a wheelchair. In some cases treatment with plaster casts and night splints was used.

Statistics
Normality was assessed by the Kolmogorov–Smirnov test [27]. A comparison of subgroup means was performed either using the t-test or the non-parametric Mann–Whitney rank sum test in case of non-normality. The chi-square test or Fisher's exact test assessed differences in non-paired independent variables. The McNemar test was used to calculate differences in pairs of categorical variables. Correlations between disease outcome parameters and disease-associated parameters were calculated using the non-parametric Spearman test [28]. Those of the disease-related parameters most highly correlated to the disease outcome parameters were used for logistic regression models, the aim of which was to identify predictors of ‘poor’ disease outcome. The disease outcome parameters utilized for the logistic regression models were dichotomized HAQ and Steinbrocker functional class at the time of the study and presence/absence of JCA-related major surgical procedures. The category variable 0 represented the HAQ score = 0 and 1 represented the HAQ score >0. Steinbrocker functional class I, was coded as 0, while classes II, III and IV were coded as 1. Absence of JCA-related major surgical procedures was coded 0, while presence was coded 1. The level of significance was 5%. The statistical calculations were performed on the ‘SPSS’ statistics software, version 8.0.

Results

Course of the disease
The mean age (S.D.) at disease onset was 5.7 yr (4.1) and the mean disease duration 12.4 yr (9.5). The disease subtype distribution at disease onset was as follows: pauciarticular 43 (66.2%), polyarticular 17 (26.1%) and systemic five (7.7%). Twenty-two (33.8%) of the pauciarticular onset group developed extended pauciarticular JCA. One patient had juvenile spondylarthropathy based on the clinical manifestations (was also HLA-B27 positive) and one had juvenile psoriatic arthropathy. At the time of the current study 41 (63.1%) patients were in remission. Thirteen patients had experienced long-lasting remission followed by active JCA, of whom nine had extended pauciarticular or polyarticular JCA. Remission was most common in the pauciarticular group, where only four (6.2%) patients had active disease at the time of the study. Persistent disease was mostly seen among those patients who had either extended pauciarticular or polyarticular JCA (see Tables 2Go and 3Go). The patient fraction currently in remission did not differ significantly from the 10-yr follow-up study. For extended pauciarticular and polyarticular JCA, active disease was present in 11 and eight cases, respectively, which are the same as reported in the 10-yr follow-up. Plasma levels of CRP and ESR were on average only slightly elevated, suggesting a relatively low level of inflammation in the study group as a whole. Disease characteristics are displayed in Tables 1 and 2. In univariate analysis, active disease at the time of the study was associated with increased HAQ score (P < 0.001), increased pain VAS (P < 0.001) and decreased ability to cope in life with arthritis (P < 0.001). VAS for overall disease activity assessment by the physician was increased in the group with active disease (P < 0.001) as was the mean plasma level of CRP. Not surprisingly, those patients who had active disease at the time of the study had experienced significantly longer disease duration (P < 0.001) (see Table 1). Thirty patients (46.1%) experienced no pain at the time of the study, of which four had active disease. Univariate analysis showed that long disease duration, non-pauciarticular JCA and history of systemic steroid treatment were parameters significantly associated with increased HAQ (see Tables 4Go and 5Go). ANA positivity was present in 30 of the 65 study participants. Of the pauciarticular group that did not go on to the extended form, 15 (71%) were ANA positive. IgM RF was elevated in 10 participants, of whom seven had active disease at the time of the study.


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TABLE 2. Retrospective and current disease characteristics of the JCA study group

 

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TABLE 3. Disease activity at the time of the 26-yr follow-up study according to JCA subtype at disease onset

 

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TABLE 4. Categorical distributions of dichotomized disease outcome parameters in subgroups according to JCA subtype and history of systemic steroid treatment

 

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TABLE 5. Age at disease onset and disease duration in subgroups of JCA patients

 

JCA-related surgery
JCA-related major surgical interventions included: prosthetic hip replacements, femoral head resection, prosthetic knee replacement, leg extension, cervical spine fusion, mandibular correction, arthrodesis of the radiocarpal joint, arthrodesis of the first metacarpophalangeal joint and arthrodesis of the foot joint. At the time of the 10-yr follow-up study in 1979–1980, three patients (4.6%) had undergone one or more major surgical procedures associated with JCA. In between the two follow-up studies, an additional 11 patients (17%) had experienced major surgery. This increase was found to be statistically significant (P < 0.001). Except for one participant with pauciarticular JCA, the participants who had undergone JCA-related major surgery had extended pauciarticular, polyarticular or systemic JCA. The presence of major surgical interventions was associated with a history of systemic steroid treatment and long disease duration (see Tables 4 and 5).

Functional class
The Steinbrocker functional class distribution in the study group worsened during the period between the two follow-up studies (see Fig. 1Go). At the time of the 1979–1980 study, the Steinbrocker functional class distribution was I/II/III/IV 56/4/3/2. A significant shift from functional class I to functional class II (P = 0.002) had taken place during the period between the two follow-up studies. Of the 56 (86%) patients in functional class I in 1979–1980, 10 had shifted to functional class II and two to functional class III. Two patients had shifted from functional class III to class IV. Those patients who were in functional classes II–IV at the time of the current study had experienced a mean disease duration of 8.3 yr, unlike those in functional class I who had a mean disease duration of 8.3 yr (P < 0.001). A statistically significant correlation was found between disease duration and Steinbrocker functional class (r = 0.68, P < 0.001).



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FIG. 1. Steinbrocker functional class distribution of 65 patients with JCA at the time of 10-yr and 26-yr follow-ups. Values are the numbers of patients.

 

Logistic regression
Logistic regression analysis was performed to assess the impact of disease-associated parameters on the disease outcome variables. The disease outcome parameters used in the logistic regression models were dichotomized HAQ (0 or >0), dichotomized Steinbrocker functional class in 1996–1997 (class I or II–IV) and presence or absence of JCA-related major surgery. Table 6Go shows the disease-associated parameters that were most strongly correlated to the outcome parameters and thus selected and used as predictors in the logistic regression models. The SPSS ‘enter’ and ‘backward stepwise’ options for logistic regression analysis were used for each of the outcome parameters. The logistic regression models had an ability to explain between 50 and 85% of the variation in the outcome parameters. In five of the six models, disease duration was the statistically most significant predictor of the outcome. In addition, disease subtype other than pauciarticular and history of systemic steroid proved to be significant predictors of increased HAQ and JCA-related surgery, respectively.


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TABLE 6. Correlations between disease outcome parameters and retrospective disease-related parameters in JCA

 

Discussion

Most follow-up studies of JCA/JRA are referral based, which implicates interpretation problems due to selection bias. The patients included will most likely represent those most in need of hospital care and, therefore, the most severe cases and those living closest to the referral centres. Those in whom the disease has not yet been identified will for obvious reasons not be included. It is therefore reasonable to assume that a significant fraction of patients with pauciarticular JCA will never receive a correct diagnosis and/or get to meet a paediatric rheumatologist. In some societies, socio-economic variables may be decisive for whether the children are referred. The above arguments support the statement that population-based studies yield higher disease prevalence rates and include larger fractions of mild cases when compared with referral-based studies. What in addition complicates the picture is the fact that JCA most likely embraces a heterogeneous group of diseases where each subtype represents a clinically and prognostically different entity.

In order to assess whether the current study group resembled a true population sample, we compared the demographic and disease characteristics with previously published data from Scandinavia. The study by Andersson and Fasth [22, 23] from southwest Sweden was an obvious choice for two reasons. First, the region is very close to Denmark and its population very much like the Danish. Second, the study was based on a representative population sample. In the current study group there were more patients with extended pauciarticular and polyarticular JCA, a smaller fraction of males, and a slightly earlier age at disease onset (5.7 vs 7 yr). We had to conclude that the demographic and disease subtype characteristics in the current study group were different from those of the Swedish study and that our study group had most likely undergone selection bias. The objective of the current investigation was, however, not to undertake epidemiological research, but rather to describe functional outcome and residua in a series of 65 JCA patients 26 yr after disease onset.

In a majority of previous follow-up studies, the follow-up time has ranged between 5 and 15 yr, and only in three studies has exceeded 15 yr for all participants [3, 19, 20]. In two of the later studies, researchers demonstrated that the fraction of patients with active disease was about 30–50% and that the fraction of patients with disabling residua increased with the follow-up time. Laaksonen [3] reported 40% with active disease and 48% in Steinbrocker functional classes III and IV at the time of a 16-yr follow-up. Levinson and Wallace [20] reported 45% with persistent disease activity and 17% in functional classes III and IV at the time of a 15–20-yr follow-up. In a study of 43 polyarticular JCA patients with a mean disease duration of 19.7 yr, David et al. [21] found active disease in 48% and severe disability in 13% of the participants. In contrast, Calabro et al. [10] reported a more encouraging outcome in a 25–37-yr (mean 25) follow-up published in 1989, where 9% of the participants had persistent disease activity and 15% were in functional classes III and IV.

Except for death, which occurred in two patients (one with systemic JCA, who died aged 23 yr of sepsis and one with polyarticular onset JCA who died of AIDS), disease activity persisting into adulthood is perhaps one of the most important outcome parameters in JCA. We found that 37% of our series had active JCA at the time of the 26-yr follow-up, a fraction that had remained unaltered since the 10-yr follow-up study. A vast majority of these participants had either extended pauciarticular or polyarticular disease. This fraction was similar to the 40–45% with active disease found by Laaksonen and Levinson and Wallace [3, 20]. Our observation suggests that approximately 10 yr after disease onset a balance is reached, where the fraction of patients with persistent disease remains at a more or less constant level. This statement is consistent with the 30–50% having active disease at approximately 10-yr follow-up in the studies by Laaksonen, Hanson et al., Rennebohm and Corell, and Ansell [3, 9, 14, 17]. Perhaps, the 80% paradigm should be changed into a 60% paradigm.

In the current study, evidence for increasing disability and residua with increasing follow-up time was supported by two findings. First, an increasing need for JCA-related major surgery, and second, a significant shift of patients from Steinbrocker functional class I to II. In addition, the disease duration was the strongest predictor of an unfavourable disease outcome. Patients with polyarticular affection, history of systemic steroid treatment and long disease duration had experienced major discomfort. Persistent erosive JCA and/or increasing secondary degenerative changes may have precipitated surgical interventions performed in order to maintain acceptable pain levels and functional status. Pain was a problem in half the participants. At the time of the study, half the participants reported pain (pain VAS > 0). Participants who were in pain were those who had active JCA, but also a smaller group in remission. This finding implicates that remission does not automatically mean the end of joint-related complaints. The presence of secondary JCA-related degenerative changes is a plausible explanation for this finding. As for the pain VAS, the HAQ score was significantly increased in those patients who had active disease, but again, a fraction of those patients in remission had problems with basic everyday routines, suggesting that JCA sequelae play an important role in the lives of these individuals.

The logistic regression analysis demonstrated that disease outcome is highly dependable on the presence of various disease severity-defying variables, especially disease duration, but also polyarticular affection and systemic steroid treatment. The same variables proved to be important predictors for all three (HAQ, functional class and JCA-related major surgery) disease outcome measures used in logistic regression models.

In the current long-term follow-up study 37% of the participants had active JCA 26 yr after disease onset. We demonstrated that extended pauciarticular and polyarticular subtype was often associated with disease persisting into adulthood and that the degree of functional residua—portrayed by a negative shift in functional class and the need for surgical intervention—increased with time. Considering the questionable evidence for the efficacy of the treatment received by the current study group, in many respects these patients may represent a natural course of the disease. Modern anti-rheumatic treatment regimens may well improve the prognosis for JCA. However, we cannot substantiate clear evidence for that statement prior to new long-term follow-up studies evaluating children who at this moment receive what is considered state of the art JCA treatment. In many respects the observations made in the current study confirm previous findings in long-term follow-up of JCA.

Acknowledgments

This study was made possible by financial support from The Danish Rheumatism Association and The Danish Hospital Foundation for Medical Research, Region of Copenhagen, The Faroe Islands and Greenland.

Notes

1 Correspondence to: M. Zak, University Clinic of Paediatrics II, Department 4064, Rigshospitalet, Blegdamsvej 9, DK-2100 Ø, Copenhagen, Denmark. Back

References

  1. Edström G. Rheumatoid arthritis and Still's disease in children. A survey of 161 cases. Arthritis Rheum 1958;1:497–504.[ISI]
  2. Ansell BM, Baywaters EGL. Prognosis in Still's disease. Bull Rheum Dis 1959;9:189–92.[Medline]
  3. Laaksonen AL. A prognostic study of juvenile rheumatoid arthritis. Acta Paediatr Scand 1966;166(Suppl.):1–103.
  4. Jeremy R, Schaller J, Arkless R, Wedgwood RJ, Healey LA. Juvenile rheumatoid arthritis persisting into adulthood. Am J Med 1968;45:419–34.[ISI][Medline]
  5. Schaller J, Wedgwood RJ. Juvenile rheumatoid arthritis: a review. Pediatrics 1972;50:940–53.[Abstract]
  6. Goel KM, Shanks RA. Follow-up study of 100 cases of juvenile rheumatoid arthritis. Ann Rheum Dis 1974;33:25–31.[ISI][Medline]
  7. Ansell BM, Wood PHN. Prognosis in juvenile chronic polyarthritis. Clin Rheum Dis 1976;2:397–412.
  8. Hill RH, Herstein A, Walters K. Juvenile rheumatoid arthritis: follow-up into adulthood—medical, sexual and social status. Can Med Assoc J 1976;114:790–6.[Abstract]
  9. Hanson V, Kornreich H, Bernstein B, King KK, Singsen B. Prognosis of juvenile rheumatoid arthritis. Arthritis Rheum 1977;20(Suppl.):279–84.[Medline]
  10. Calabro JJ, Burnstein SL, Staley HL, Marchesano JM. Prognosis in juvenile rheumatoid arthritis: a fifteen-year followup of 100 patients. Arthritis Rheum 1977; 20(Suppl.):285.
  11. Stoeber E. Prognosis in juvenile chronic arthritis: follow-up of 433 chronic rheumatic children. Eur J Pediatr 1981;135:225–8.[ISI][Medline]
  12. Dequeker J, Mardjuadi A. Prognostic factors in juvenile chronic arthritis. J Rheumatol 1982;9:909–15.[ISI][Medline]
  13. Svantesson H, Akesson A, Eberhardt K, Elborgh R. Prognosis in juvenile rheumatoid arthritis with systemic onset. A follow-up study. Scand J Rheum 1983;12:139–44.[ISI][Medline]
  14. Rennebohm R, Corell JK. Comprehensive management of juvenile rheumatoid arthritis. Nurs Clin North Am 1984;19:17–32.
  15. Michels H, Häfner R, Morhart R, Schuchmann L, Truckenbrodt H. Five year follow-up of a prospective cohort of juvenile chronic arthritis with recent onset. Clin Rheumatol 1987;6(Suppl. 2):87–92.[Medline]
  16. Pedersen FKP, Heilmann C, Friis J, Jørgensen B, Thomsen K. Juvenile rheumatoid arthritis. Ugeskr Laeger 1987;149:2843–5.
  17. Ansell BM. Juvenile chronic arthritis. Scand J Rheum 1987;66(Suppl.):47–50.
  18. Cassidy JT, Levinson JE, Brewer JE. The development of classification criteria for children with juvenile rheumatoid arthritis. Bull Rheum Dis 1989;38:1–7.[ISI][Medline]
  19. Calabro JJ, Marchesano JM, Parrino GR. Juvenile rheumatoid arthritis: long-term management and prognosis. J Musculo Med 1989;6:17–32.
  20. Levinson JE, Wallace CA. Dismantling the pyramid. J Rheumatol 1992;19(Suppl. 33):6–10.[ISI]
  21. David J, Cooper C, Hickey L et al. The functional and psychological outcomes of juvenile chronic arthritis in young adulthood. Br J Rheumatol 1994;33:876–81.[ISI][Medline]
  22. Andersson BG, Fasth A. The natural history of juvenile chronic arthritis: a population based cohort study I: onset and disease process. J Rheumatol 1995;22:295–307.[ISI][Medline]
  23. Andersson BG, Fasth A. The natural history of juvenile chronic arthritis: a population based cohort study II: outcome. J Rheumatol 1995;22:308–19.[ISI][Medline]
  24. Østergaard PA, Lillquist K, Rosthøj S, Urfe P. Occurrence and types of juvenile rheumatoid arthritis in the County of Jutland 1970–1977 and 1978–1986. Ugeskr Laeger 1988;150:342–6.[Medline]
  25. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patients’ outcome in arthritis. Arthritis Rheum 1980;23:137–45.[ISI][Medline]
  26. Steinbrocker O, Traeger CH, Battman RG. Therapeutic criteria in rheumatoid arthritis. J Am Med Assoc 1949;140:659–62.[ISI]
  27. Gibbons JD. Nonparametric methods for quantitative analysis. New York: Holt, Rinehart and Winston, 1976.
  28. Altman DG. Practical statistics for medical research. London: Chapman & Hall, 1991.
Submitted 10 June 1999; revised version accepted 8 September 1999.