Rheumatology 2013;52:1999–2003 doi:10.1093/rheumatology/ket256 Advance Access publication 27 July 2013

RHEUMATOLOGY

Concise report Disease activity of idiopathic juvenile arthritis continues through adolescence despite the use of biologic therapies Krista-Liisa Vidqvist1, Merja Malin2, Tuire Varjolahti-Lehtinen3 and Markku M. Korpela1 Abstract Objectives. To investigate the use of DMARDs and biologic treatments and disease activity in patients with JIA referred to the adult rheumatology clinic and to provide further information regarding the need for long-term rheumatologic care. Methods. We studied the data of 154 patients retrospectively from hospital records if they met the following criteria: diagnosis of JIA and at least one visit to the adult rheumatologic unit. Previous and current antirheumatic treatment, duration of biologic therapy and disease activity were recorded.

Conclusion. Almost one-third of adolescents and young adults with JIA who needed specialist care were on biologics. The need for treatment in many cases is long term (>5 years). Most patients (58%) still showed evidence of mild disease activity. Adolescents and young adults with JIA are a distinct patient group in adult health care and a specialized multidisciplinary approach to treatment is needed. Key words: adolescents, arthroplasty, biologic therapy, disease activity, disease-modifying antirheumatic drug, juvenile idiopathic arthritis, temporomandibular joint, uveitis.

Introduction In the past 20 years the treatment of JIA has evolved considerably, with widespread and common use of MTX and intra-articular glucocorticoid injections. Biologic therapies are being increasingly introduced in cases that prove refractory to DMARDs [1–5]. There is, however, a shortage of conclusive data about the kind of impact modern

treatment of JIA has on the long-term prognosis of the disease during transition to an adult clinic and during adulthood. Such information is vital to the planning of adult health care resources for such patients. The aim of this study was to ascertain the disease activity of JIA and the need for medication during the transition of care to an adult clinic. The necessity of further follow-up in a specialist clinic was also evaluated.

1

Patients and methods

Department of Internal Medicine, Centre for Rheumatic Diseases, Department of Pediatrics and 3Department of Rheumatology, Tampere City Hospital, Tampere, Finland. 2

Submitted 15 May 2012; revised version accepted 10 June 2013. Correspondence to: Krista-Liisa Vidqvist, Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, PO Box 2000, 33521 Tampere, Finland. E-mail: [email protected]

Study population We analysed the medical records of consecutive adolescents with JIA first seen in the adult rheumatology units of Tampere University Hospital (TUH) and Tampere City Hospital (TCH) between September 2005 and September

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CLINICAL SCIENCE

Results. At the end of patient follow-up, the median age of the eligible patients was 19 years (range 16–24 years) and the disease duration was 8 years (range 0–20 years). Twenty-nine per cent of the patients were still on biologic therapies. The total median duration of treatment with at least one biologic agent was 4.2 years, and 44% of treatment durations lasted >5 years. Some disease activity was present in the last year in 58% of patients. Activity in the temporomandibular joint was detected in 14% and uveitis in 8%. Thirteen per cent did not need further specialist care and in 14% all antirheumatic medication could be tapered off.

Krista-Liisa Vidqvist et al.

2011. The population of the Pirkanmaa Hospital District is 470 000 and, in practice, all adolescents with JIA who need adult health care services in the area are referred to these centres. The study population comprised 154 patients: 129 seen at TUH and 25 at TCH. The study was carried out in compliance with the Helsinki Declaration and approval for the study was obtained from the ethical committee of TUH.

Data collection All consecutive patients were studied retrospectively from hospital records if they met the following criteria: diagnosis of JIA and at least one visit to the adult rheumatologic care unit. We recorded sex, age at diagnosis, disease duration and JIA subtype based on the International League of Associations for Rheumatology (ILAR) classification criteria [6]. In these two adult rheumatology centres, the care of JIA patients was assigned to one rheumatologist each (K.-L.V. at TUH and T.V.-L. at TCH) and a multidisciplinary approach adopted. Biologic therapy was initiated if the treatment goal (remission or low disease activity) was not achieved with traditional DMARD combinations. Patients first seen during the 6-year period (9/2005–9/ 2011) were followed up until the end of the study. The number of inflamed joints was not only evaluated at the last visit, but also during the previous 12 months. Disease activity was assessed clinically and with US examinations. The criterion for active arthritis was a clinically swollen joint, but subclinical synovitis detected by US (synovial hypertrophy and hyperaemia as demonstrated by power Doppler activity) [7] was also considered. MRI was used if the status of the joint could not be otherwise evaluated. Previous and current DMARD and biologic therapy, duration of biologics and possible tapering of the medication were recorded. We collected details about uveitis and temporomandibular joint (TMJ) involvement and joint operations. Suspected TMJ involvement was confirmed by orthodontic examination and contrast-enhanced MRI. Finally, the need for further care in a specialist centre was assessed.

Statistical analysis The descriptive values of the variables were expressed as median and range. Unpaired comparisons were made using Pearson’s 2 and Fisher’s exact tests. Non-parametric comparisons were carried out by Mann–Whitney test.

Results Patient characteristics During follow-up, 154 adolescents with JIA (ages 16–21 years) were referred to adult rheumatologic care. The indications for the referrals were ongoing antirheumatic treatment or disease activity, or both. Sixty-six per cent of referrals belonged to the Department of Pediatric Rheumatology, TUH. During the same follow-up period,

2000

TABLE 1 Demographic characteristics of the study population Patient characteristics No. of patients Female, n (%) Age at diagnosis, median (range), years Age at end of follow-up, median (range), years Duration of disease, median (range), years Oligoarticular, n (%) Oligoarticular extended, n (%) Polyarticular, RF-negative, n (%) Polyarticular, RF-positive, n (%) PsAa, n (%) Enthesitis-related arthritis, n (%) Systemic arthritis, n (%)

154 101 11 19 8 68 14 50 6 9 5 2

(66) (1–21) (16–24) (0–20) (44) (9) (33) (4) (6) (3) (1)

26 adolescents (14%) with JIA were not transferred to specialist care from the same clinic. Their disease was in remission and they were not on antirheumatic medication. To our knowledge, none of these young adults have experienced recurrence during the follow-up (three of them had no up-to-date hospital records). Patient characteristics are shown in Table 1. Four patients were lost to follow-up during the study period; two of them had active disease according to the last available records. The median follow-up time of the adolescents in the adult clinics was 2 years (range 0–6 years).

DMARD therapy Most patients received MTX (92%), antimalarials (81%) and SSZ (55%) during paediatric or adult care. MTX was the most frequently used medication at the last visit (66%), followed by antimalarials (37%) and SSZ (21%). Half the patients had been on oral glucocorticoids, but mostly as a short-term bridge therapy during paediatric care; during the last visit, 9% were using glucocorticoids. At the end of follow-up, 84% of the patients were on DMARD therapy, with 84%, 86% and 78% in the persistent oligoarticular, oligoarticular extended and polyarticular groups, respectively.

Biologic therapy Forty-one per cent of the patients (n = 63) had been on biologic therapy at some point. In 19 of these 63 patients (30%), the therapy had been tapered off and the median biologics-free follow-up time thereafter was 1.5 years (range 0–9 years). The reasons for discontinuation of biologic therapy were remission (n = 12), low disease activity and aversion to injectable medication (n = 3), low disease activity and repeated upper respiratory tract infections (n = 2), allergic reaction (n = 1) and anorexia combined with neutropenia (n = 1). At the time of transfer to an adult clinic, 36 of 154 patients (23%) were on biologic therapy. This needed to be initiated in 18 patients (12%) during adult care and only 1 had been on biologics during the paediatric care period. In 10 of 54 patients (19%) using biologics in adult care, the treatment could be discontinued. Thus, at the last visit,

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Modern treatment and disease activity of JIA

44 of 154 (29%) patients were using biologics. The most commonly used biologics at some time were etanercept (31% of the patients), infliximab (19%) and adalimumab (18%). The median duration of biologic therapy in paediatric care was 2.9 years (range 0–9.4 years) and in adult care 1.4 years (range 0–5.1 years). The total median duration of the treatment was 4.2 years (range 0–10.4 years). Twenty-eight of 63 patients (44%) who had ever received biologic therapy had used it for >5 years. In the three largest subgroups, biologics had been used most frequently in the extended oligoarthritis group (79%), P < 0.001 compared with the persistent oligoarthritis group (24%) and P = 0.038 compared with the polyarthritis group (46%). There was also a statistically significant difference in the use of these agents as recorded during the last visit: 43% of oligoarthritis extended patients, 36% of polyarthritis patients and 16% of persistent oligoarthritis patients (P = 0.019).

Disease activity At the last visit, 60% of the JIA patients showed no signs of active joint inflammation (63% in the persistent oligoarthritis group, 43% in the oligoarthritis extended group and 60% in the polyarthritis group; P = 0.39), while the remainder had mostly one to three synovitic joints. During the last year of follow-up, 42% of the patients had no active joints (Fig. 1). Differences in disease activity during the last year were found in the three largest disease groups: no active joints were observed in 52% of persistent oligoarthritis patients, in 21% of oligoarthritis extended patients and in 34% of polyarthritis patients (P = 0.044). Recurrences after discontinuation of medication were observed in 29% of the patients (no difference between the subgroups). The median interval between discontinuation and recurrence was 1.4 years (range 0.1–7.6 years). Half the drug-free recurrences were observed during adult care.

TMJ and eye involvement Sixty-six of 154 (43%) patients had had TMJ joint inflammation at some point during treatment. Most of this

FIG. 1 Cumulative numbers of the various inflamed joints per patient during the last year of follow-up. 100 90 80 No. of patients

70

42%

60 50 40 19%

30

12%

20

8%

6%

10

3%

5%

1%

3%

1%

1%

7

9

12

15

0 0

1

2

3

4 5 6 No. of swollen joints

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involvement was detected during paediatric care (61 patients). During the last year of follow-up, 14% of patients showed activity in TMJ arthritis. Twenty-eight patients (18%) had a history of uveitis and in all except two, the involvement had begun in childhood. Thirteen (8%) had active uveitis during the last year of follow-up. Patients with active ongoing uveitis were distributed equally among the three largest subgroups. In five patients the main reason for medication was uveitis.

Reason for joint operations In total, 22 of 154 patients (14%) underwent a joint operation; in 18 (12%) during paediatric care and in 5 (3%) during adult rheumatologic care (1 patient was operated on during both paediatric and adult care). Thirty separate operations were done: 17 synovectomies, 4 epiphyseal disclosure operations of the knee joint, 4 orthodontic operations, 4 reconstructive finger or toe joint operations, and 1 hip joint prosthesis operation for a 20-year-old patient after 7 years of juvenile oligoarthritis.

Further need for care and medication At the end of the follow-up, further care was arranged by a specialist centre in 134 cases (87%). The responsibility for care was transferred to basic health care in 20 cases (13%). All antirheumatic medication was discontinued in 22 cases (14%). The median drug-free follow-up time thereafter was 10 (range 0–107) months.

Discussion In this study, most of the patients with JIA who needed medical care during late adolescence (between the ages of 16 and 22 years) and early adulthood still showed inflammatory joint activity. The results are, surprisingly, of the same magnitude as those previously published before the time of biologics (37–66%) [8–13]. Inflammation was detected mostly in a few joints. This suggests the possibility that the inflammatory load of the disease has decreased, which is also the clinical impression of the situation. In any case, comparison of results is a complex task by reason of differences in structure and study populations and variable classification and remission criteria for JIA [8–14]. In previous studies [8–13], the activity of the disease has traditionally been evaluated by clinical means. In contrast, in our clinics, US examination done by rheumatologists is part of the routine evaluation of joint disease, which probably increased the proportion of patients with active joints. Both US and MRI have proved to be more sensitive in finding inflammation in RA [15–17]. There is no doubt about their additional value in detecting synovitis in JIA. Furthermore, subclinical inflammation of the joints is common in JIA and growing evidence shows the usefulness of US in monitoring synovitis in JIA [18–20]. To our knowledge there are no up-to-date data about the use of biologic therapies for JIA adolescents after they leave paediatric care. In our study, a fourth of these adolescents were on biologics when they were first assessed

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Krista-Liisa Vidqvist et al.

by an adult rheumatologist. We feel that there is a need to initiate treatment for such patients in adult care. Although some of the biologic therapy courses might be discontinued, the use of biologics increased slightly during adolescence (from 23% to 29% of patients). The need for therapy was long term in many cases. The need for joint surgery was less than reported before the use of biologics [11, 12, 14]. The difference is probably at least partly explained by the longer disease duration in the earlier studies and also the different treatment options administered in the 1970s and 1980s. In contrast, the percentage of active uveitis and TMJ inflammation in our study was similar to that reported in earlier studies [21–24]. Close collaboration with ophthalmologists and orthodontists is as necessary in adult rheumatology clinics as it is in paediatric care. When interpreting our results, the referral-based nature of the study must be noted, which probably caused selection bias towards more serious cases. The follow-up time into adult health care was also relatively short (median 2 years). Acquiring up-to-date information from long-term follow-up studies about the influence of modern treatment strategies on the prognosis of JIA patients is challenging, as the relevant studies are inevitably less reflective of modern treatment strategies. Nonetheless, our study provides a realistic picture of the situation of JIA adolescents who are referred to adult rheumatology care. In the future, a prospective study has been planned to follow these patients with JIA into adulthood. In conclusion, JIA patients referred to adult rheumatology centres have a high disease burden and are in need of long-term specialist follow-up and medical treatment. There are several barriers to the provision of transitional care for these patients and the lack of adolescent-specific training in adult rheumatology is the most important [25]. Our findings confirm that JIA patients are a special patient group in adult health care with special needs, and a tailored multidisciplinary approach is required. Rheumatology key messages JIA patients referred to adult rheumatology centres need long-term specialist follow-up and medical treatment. . Despite the frequent use of biologics, most JIA adolescents still showed evidence of disease activity during last year of follow-up. .

Disclosure statement: M.M. has received the cost of medical congresses or education courses from Wyeth, Pfizer, Abbott and Roche. All other authors have declared no conflicts of interest.

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Acknowledgements The authors would like to thank adolescent clinic special nurse Heidi Marika Ma¨kinen for assistance in processing the patient data and biostatistician Mika Helminen for statistical advice. Funding: This work was supported by grants from Competitive Research Funding of the Pirkanmaa Hospital District (9M124).

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