Clinical Remission in Patients with Systemic Juvenile

Idiopathic Arthritis Treated with Anti-Tumor Necrosis

Factor Agents
RICARDO A.G. RUSSO and MARÍA M. KATSICAS

ABSTRACT. Objective. To assess the frequency of clinical remission in a cohort of patients with systemic juve-
nile idiopathic arthritis (JIA) who received continuous anti-tumor necrosis factor (TNF) therapy; and
to identify potential predictors of remission.
Methods. Patients with systemic JIA who were treated with anti-TNF agents for > 6 months were
studied. Demographic and nosologic variables recorded at the start of anti-TNF therapy were ana-
lyzed. Association between early variables and occurrence of remission was evaluated through Cox
proportional hazard regression analysis.
Results. Forty-five patients were included (30 girls), median age 9 years (range 2–17 yrs), age at dis-
ease onset 5 years (range 0.5–15), disease duration 3 years (range 0.5–13). Twenty-one (47%) chil-
dren showed systemic symptoms at the start of anti-TNF therapy. Patients received therapy for 24
months (range 6–88): 45 (100%) were given etanercept, 17 (38%) infliximab, and 5 (11%) adali-
mumab, in combination with methotrexate. Anti-TNF switching was performed in 22 (49%) chil-
dren. Eleven (24%) met definition criteria for remission while taking etanercept (n = 8), infliximab
(2), or adalimumab (1). Remission occurred following 26 (range 9–65) months of therapy. Flares
occurred in 5 (45%) patients 2 to 14 months after remission was first recorded. Absence of systemic
symptoms at the start of therapy and fulfilment of improvement criteria at Month 3 were associated
with remission in univariate analysis; no variable showed any association in multivariate analysis.
Conclusion. Twenty-four percent of patients with systemic JIA experienced remission with
anti-TNF therapy, but only 13% experienced sustained benefit. (First Release April 1 2009;
J Rheumatol 2009;36:1078–82; doi:10.3899/jrheum.080952)

Key Indexing Terms:

JUVENILE SYSTEMIC ARTHRITIS REMISSION
ANTI-TUMOR NECROSIS FACTOR AGENTS ETANERCEPT

Systemic juvenile idiopathic arthritis (JIA) is one of the of biologic agents in JIA, remission — a more robust indi-
most severe forms of JIA, frequently leading to severe dis- cator of efficacy — has seldom been reported.
ability and significant mortality1. Additionally, according to Definitions for inactive disease and remission in JIA
different investigators, patients with systemic JIA frequent- (based on clinical criteria) have recently been elaborated.
ly show a mediocre response to therapy with methotrexate According to these definitions, remission is the presence of
(MTX) and anti-tumor necrosis factor (TNF) agents2-5. inactive disease for at least 6 consecutive months7. Although
However, some patients with systemic JIA have been remission is the ultimate goal of treatment in JIA, the per-
observed to respond to TNF inhibitors as satisfactorily as centage of children with systemic JIA who meet remission
patients with other forms of JIA, at least in controlled trials, criteria on therapy with biologic agents has not been tested
and they may even achieve remission on this therapy6. in recent controlled trials. However, rates of remission with
While the American College of Rheumatology Pediatric TNF inhibitors have been reported in some observational,
30%, 50%, 70%, and 90% improvement criteria (ACR Pedi registry-based studies in adults with rheumatoid arthritis and
30, 50, 70, and 90) have been the most widely reported out- children with JIA8-11. A recent report from a Dutch registry
comes in clinical trials and observational studies on efficacy on etanercept in JIA showed that children with systemic JIA
may reach remission rates that are similar to those achieved
From the Servicio de Inmunología y Reumatología, Hospital de Pediatría by patients with other forms of JIA11. To date, no study has
“Prof. Dr. Juan P. Garrahan,” Buenos Aires, Argentina. focused on inactive disease and remission rates achieved by
R.A.G. Russo, MD; M.M. Katsicas, MD. patients with systemic JIA treated with anti-TNF agents.
Address reprint requests to Dr. R.A.G. Russo, Servicio de Inmunología y We reviewed our experience to assess the frequency of
Reumatología, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan,”
Pichincha 1880, 1245 Buenos Aires, Argentina.
inactive disease and remission observed in a cohort of
E-mail: rrusso@garrahan.gov.ar patients with systemic JIA who have received TNF anta-
Accepted for publication December 23, 2008. gonists, and to identify potential predictors of remission.

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MATERIALS AND METHODS count, presence of systemic symptoms, WBC count, platelet count, hemo-
Patients. All patients diagnosed with systemic JIA using the criteria of the globin levels, ESR, and achievement of improvement criteria at 3 and 6
International League of Associations for Rheumatology (ILAR)12, and who months after start of anti-TNF therapy. Kaplan-Meier survival curves were
were treated with anti-TNF agents for at least 6 months between December utilized to calculate the probability of remission over time after the onset of
1999 and August 2008 at the Hospital de Pediatría Prof. Dr. Juan P. anti-TNF therapy and the probability of relapse-free intervals after remis-
Garrahan, were eligible for study. Patients were followed periodically and sion. A p level < 0.05 was considered significant. Analysis was performed
data were collected prospectively at every clinic or hospital visit, and using Statistix 7 (Analytical Software).
recorded in the database of the Service of Immunology/Rheumatology.
Intervals between visits varied between 1 and 2 months while patients were RESULTS
taking anti-TNF therapy. Clinical and biochemical assessments were per-
Demographic and baseline data. Fifty patients (34 female,
formed at baseline (time of the start of anti-TNF therapy) and at each visit.
Variables recorded were sex, age at disease onset, disease duration, active 16 male) with median age at diagnosis of 5 years [interquar-
joint count (i.e., numbers of swollen/tender joints, or joints having at least tile range (IQR) 1.5 to 8 yrs] and disease duration of 3 years
2 of the following features: heat, limited range of movement, and tender- (IQR 1.5 to 4) were studied. Five patients were excluded
ness/pain on movement), number of joints with limited range of motion, because they had poor compliance or were lost to followup.
presence of systemic symptoms (fever, rash, lymphadenopathy,
Thus, data on 45 patients were analyzed in this study.
hepatomegaly, splenomegaly, or serositis), functional ability [measured by
Childhood Health Assessment Questionnaire (CHAQ), Argentine-Spanish
Demographic and clinical data at start of anti-TNF therapy
validation13], disease activity according to the physician measured on a are presented in Table 1. Twenty-one (47%) patients showed
visual analog scale (VAS; score range 0–10), patient well-being according systemic symptoms at entry. At treatment baseline, the
to the parents (VAS; range 0–10), and laboratory results [levels of hemo- median number of active joints was 8 in patients who
globin, white blood cell (WBC) count, platelet count, and erythrocyte sed- showed systemic symptoms and 16 in patients who did not
imentation rate (ESR)].
(p = 0.02). All patients had shown an unremitting disease
Treatment. Indication for the use of anti-TNF agents was lack of or loss of
course before receiving anti-TNF treatment. Median dura-
efficacy of MTX therapy (persistent active polyarthritis despite use of high-
er-dose MTX (≥ 20 mg/m2/week) for at least 3 months] in all cases. All tion of anti-TNF therapy was 24 months (IQR 12 to 42 mo).
patients received etanercept as the initial therapy, at 0.4 mg per kilogram of Total followup time was 1454 patient-months (median 24
body weight, subcutaneously twice weekly, concomitantly with MTX 5–20 mo per patient, IQR 12 to 48 mo) and all but 5 patients were
mg/m2 weekly. Etanercept dosing was modified (increased up to 1 followed for more than 1 year. Patients were treated with
mg/kg/dose, or 25 mg/dose) if improvement was not achieved. In patients
etanercept for 18 (range 6–82) months. Etanercept dosage
who exhibited lack of or loss of efficacy after 6 months of therapy (failure
to achieve or maintain improvement, respectively), etanercept was was increased up to 0.8 to 1 mg/kg (or 25 mg) in 40 (89%)
switched to an anti-TNF-α monoclonal antibody, infliximab (5 to 10 children. It was switched to infliximab (17 patients) or adal-
mg/kg/dose, at Weeks 0, 2, and every 4 weeks thereafter) or adalimumab imumab (5 patients) in 22 (49%) patients: 9 had failed to
(20 mg in patients weighing < 30 kg, or 40 mg in patients weighing > 30 respond upon initial administration of etanercept, and 13 ini-
kg) every other week. There was no specific washout period before the tially responded but efficacy subsequently diminished and
introduction of the second anti-TNF agent (it varied between 1 and 3
weeks). Anti-TNF therapy was discontinued in patients who exhibited
they underwent flares. Infliximab was discontinued due to
moderate or severe toxicity. lack of efficacy (4 children) or toxicity (periinfusional
Outcome measures. “Improvement” was defined according to the criteria wheezing, eyelid edema, and/or urticarial rash in 6 patients).
developed by Giannini, et al14. This definition states that there should be at Forty-one patients were receiving corticosteroids (methyl-
least 30% improvement from baseline in 3 of any 6 variables in the JIA core prednisone 2–20 mg/day) at the onset of anti-TNF therapy.
set, with no more than one of the remaining variables worsening by > 30%. Corticosteroids were tapered or discontinued in 26 (63%)
The ACR Pedi American 30, 50, 70, and 90 criteria were used to assess
children while undergoing anti-TNF therapy.
effectiveness.
We used the criteria for inactive disease and remission of Wallace, et Improvement, inactive disease, and remission. ACR Pedi
al7. “Inactive disease” was defined as follows: no joints with active arthri- 30, 50, 70, and 90 were recorded in 35 (78%), 28 (62%), 21
tis; no fever, rash, serositis, splenomegaly, or generalized lymphadenopa- (47%), and 14 (31%) patients, respectively. Fourteen (31%)
thy attributable to JIA; no active uveitis; normal ESR; and physician’s over-
all assessment of disease activity that indicated no disease activity (i.e., best
and 11 (24%) children met criteria for inactive disease and
score attainable on the scale used). “Clinical remission on medication” was clinical remission on medication, respectively (Table 2).
defined as criteria for inactive disease achieved for at least 6 continuous Fifty percent of 22 inactive disease episodes were followed
months; while “clinical remission off medication” required fulfilment of by remission. Remission occurred under etanercept (8
criteria for inactive disease for at least 12 continuous months while taking
patients), infliximab (2 patients), or adalimumab (1 patient)
no medications. “Time to remission” was defined as the interval from onset
of therapy to the date remission was first recorded. “Disease relapse” was therapy. Nine patients were receiving MTX, while none was
defined as a recurrence of active arthritis or systemic signs/symptoms on corticosteroid therapy at the time of remission.
attributable to JIA following a remission period as defined above. Remission occurred following 26 (9–65) continuous months
Analysis. Comparison between groups was performed by chi-square and of therapy. It was achieved in 2 (4%) patients at 1 year, in 4
Mann-Whitney tests. Potential predictors of remission were evaluated by (9%) children at 2 years, and in 9 (20%) patients at 3 years
univariate analysis and by proportional hazards model (Cox regression)
of anti-TNF therapy. Five patients in whom therapy was
using 95% confidence intervals for hazard ratios. The following variables
were included in the analysis: age at disease onset, age at start of anti-TNF stopped after remission was achieved met the definition of
therapy, disease duration, duration of anti-TNF therapy, baseline joint remission off medications. Flares occurred in 5 (45%)

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Table 1. Clinical and laboratory features at the beginning of anti-TNF therapy. Values represent number of patients (%), or medians* (interquartile range).

Feature Total, n = 45 Patients Achieved Remission, Patients Did Not Achieve Remission, p
n = 11 n = 34

Age, yrs* 9 (5–13) 9 (6–12) 9.2 (5–14) NS

Age at disease onset, yrs* 5 (1.5–8) 6 (3–9) 4.3 (1.5–9) NS
Sex female 30 (67) 6 (55) 24 (71) NS
No. of active joints* 11 (6–28) 14 (9–28) 10.5 (5.5–28) NS
No. of joints with limited motion* 10 (5–19) 13 (7–19) 9 (5–20) NS
Systemic symptoms 21 (47) 2 (18) 19 (56) 0.03
Physician VAS (0–10)* 3.73 (1.7–4.4) 3.73 (3.0–4.06) 3.03 (1.7–4.86) NS
Parent VAS (0–10)* 4.0 (0.93–6.13) 2.96 (1.93–5.23) 4.28 (0.63–6.4) NS
CHAQ < 0.5 15 (33) 6 (54) 9 (26) NS
White blood cell count (× 109/l)* 10.8 (8.4–15.7) 10.3 (7.9–17.0) 10.8 (8.8–16.2) NS
Hemoglobin, g/dl* 11.0 (9.6–11.8) 10.9 (10.2–12.0) 11.0 (9.6–11.9) NS
Platelet count (× 109/l)* 417 (291–565) 419 (352–609) 431 (273–556) NS
ESR, mm/h 47 (21–68) 45 (36–69) 47 (22–83) NS

Physician VAS: disease activity according to physician on a visual analog scale. Parent VAS: patient well-being according to the parent, visual analog scale.
CHAQ: Childhood Health Assessment Questionnaire; ESR: erythrocyte sedimentation rate; NS: nonsignificant.

Table 2. Clinical outcomes during and after anti-TNF therapy. Values represent number of patients (%), or medians* (interquartile range).

Outcome Total, Patients Achieved Remission, Patients Did Not Achieve Remission, p
n = 45 n = 11 n = 34

Improvement 3 months after 29 (64) 10 (91) 19 (56) 0.03

onset of therapy
Improvement 6 months after 33 (73) 10 (91) 23 (68) NS
onset of therapy
Drug toxicity 13 (29) 3 (27) 10 (29) NS
Duration of anti-TNF therapy, mo* 24 (12–42) 42 (30–57) 18 (11–32) NS
Discontinuation due to toxicity 7 (16) 0 (0) 7 (21) NS
Discontinuation due to inefficacy 24 (53) 3 (27) 21 (62) NS
CHAQ < 0.5 in last visit 31 (69) 11 (100) 19 (56) 0.005

TNF: tumor necrosis factor; CHAQ: Childhood Health Assessment Questionnaire; NS: nonsignificant.

patients 2 to 14 months after remission was first recorded; disease onset or ILAR category15. However, their efficacy in
one of them was taking no medications. Indeed, 21 patients children with systemic JIA has been largely discredited by
of this cohort are still under anti-TNF therapy (4 in remis- numerous publications showing a lower response rate in
sion) and 1 patient is in remission off medications. Median such patients2-5. Moreover, since evidence of the efficacy of
duration of followup was 41 months in patients who interleukin 1-inhibiting therapies in children with systemic
achieved clinical remission on medication and 18 months in JIA became available16,17, the role of TNF blockers as the
patients who did not reach remission (p = 0.001). first therapeutic option for patients with refractory systemic
Predictive factors for remission. No demographic or base- JIA has been debatable. Our results show that continuous,
line disease variable was predictive of remission in the longterm treatment with anti-TNF agents may induce remis-
multivariate analysis. However, absence of systemic symp- sion in a small but significant proportion of patients with sys-
toms at the start of anti-TNF therapy and achievement of temic JIA. Remission was more frequent in patients who did
improvement criteria at 3 months were associated with not show systemic symptoms at the start of anti-TNF therapy
remission in univariate analysis (p = 0.03). Probability of and in those who improved after 3 months of therapy.
continuing in remission was 76% (95% CI 48–92) at 6 Comparisons with other studies are difficult due to het-
months, and 54% (95% CI 30–77) at 1 year after onset of erogeneity in the criteria for assessment of remission (con-
remission (Figure 1). sensus on preliminary criteria for remission in selected
categories of JIA was reached only recently7), patient selec-
DISCUSSION tion, and disease classification in published clinical trials or
Anti-TNF agents have become standard therapy for JIA that “real life” observational studies on the use of anti-TNF
does not respond adequately to MTX, regardless of type of agents. Our study is probably the first based on a large

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1080 The Journal of Rheumatology 2009; 36:5; doi:10.3899/jrheum.080952

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 Figure 1. Kaplan-Meier survival analysis of a group of 11 patients with systemic JIA who reached remission under continuous
anti-TNF therapy. Time 0 indicates onset of remission. *Number of patients still under observation excluding those who under-
went relapse.

cohort of patients with systemic JIA undergoing such remission: monocyclic, intermittent, and persistent18. Using
therapy that focused on inactive disease and remission as a different definition of remission, Lomater, et al19 found
clinical outcomes. Preliminary consensus criteria for remis- that a significant proportion of their patients, who had
sion in JIA include clinical (arthritis, systemic symptoms, received different therapeutic interventions, entered remis-
and physician’s global assessment) and laboratory features sion at some point. In our cohort, no patient had achieved
(C-reactive protein and ESR) to define clinical remission as remission before anti-TNF therapy was initiated. Although
having inactive disease for at least 6 consecutive months. As there is a possibility that remission achieved by some of our
noted by their authors, the selected duration times are arbi- patients was part of the natural history of the disease, the
trary, there are no biologic markers that can reliably identi- observational, uncontrolled design of the study did not allow
fy active disease, and no radiologic measures are included in confirmation of this hypothesis. Remission rates in the
these guidelines7. However, they are a useful clinical tool course of systemic JIA have ranged from 20% to 34% in
that may allow comparisons among studies. several studies19-23. These studies are heterogeneous mainly
In our observational study of response to anti-TNF ther- in sample size, definition of remission, and length of fol-
apies, no early features emerged as independent predictors lowup. On the other hand, remission has not been used as an
of remission. However, there was an association between outcome measure in most clinical trials that included
absence of systemic symptoms at the beginning of anti-TNF patients with systemic JIA. Additionally, patients with
therapy and subsequent achievement of remission, in spite active systemic symptoms have been included only recently
of patients with systemic symptoms at baseline having less in trials of tocilizumab24, making comparisons difficult.
active joints. A survey conducted by Kimura, et al3 found no Our study investigated remission, an outcome not report-
differences in terms of baseline systemic symptoms between ed in previous studies on the efficacy of anti-TNF agents in
patients who responded and those who were nonresponsive patients with systemic JIA. Lovell, et al6 reported the out-
to etanercept3. In addition, the majority of patients in our come of a cohort of 58 children with JIA treated with etan-
cohort who achieved remission had shown an early satisfac- ercept in a clinical trial. After 4 years of therapy, 28% of
tory response (improvement after 3 months of treatment) to patients reached a state of disease inactivity similar to the
TNF inhibitors. Thus, early improvement might be a poten- one required by the definition of remission from Wallace, et
tially useful marker of effectiveness that may aid in clinical al7 (no active joints, physician overall assessment of disease
decisions. activity that indicated no disease activity). Patients with sys-
The course of systemic JIA has been classified into 3 pat- temic JIA represented 33% of the cohort, and none had sys-
terns according to the succession of phases of activity and temic features at entry to the study. A report from a German

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Russo and Katsicas: JIA and anti-TNF therapy 1081

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registry showed that 13% of 66 patients with systemic JIA remission and sustained halting of radiographic progression with
reached remission taking etanercept10. A recent publication combination etanercept and methotrexate in patients with
rheumatoid arthritis. Arthritis Rheum 2007;56:3928-39.
based on a Dutch registry11, which included patients fol- 9. Burmester GR, Ferraccioli G, Flipo RM, et al. Clinical remission
lowed for a mean 2.5 years, documented a remission rate of and/or minimal disease activity in patients receiving adalimumab
38% in a cohort of 39 children with systemic JIA receiving treatment in a multinational, open-label, twelve-week study.
etanercept, which is higher than the rate we observed in our Arthritis Care Res 2008;59:32-41.
sample. Our patient group was a referral-based cohort with 10. Horneff G, Schmeling H, Biedermann T, et al. The German
etanercept registry for treatment of juvenile idiopathic arthritis. Ann
probably more severe disease than unselected cohorts from Rheum Dis 2004;63:1638-44.
the general population. Interestingly, 3 of our patients 11. Prince FH, Twilt M, ten Cate R, et al. Long-term follow-up on
achieved remission only after TNF inhibitors were switched effectiveness and safety of etanercept in JIA: the Dutch national
(from etanercept to an anti-TNF monoclonal antibody). register. Ann Rheum Dis 2008 Apr 15. [Epub ahead of print]
Although to date there are no controlled studies, anti-TNF 12. Petty RE, Southwood TR, Manners P, et al. International League of
Associations of Rheumatology classification of juvenile idiopathic
switching may prove useful in the treatment of systemic arthritis: second revision, Edmonton, 2001. J Rheumatol
JIA25. 2004:31:390-2.
This study should be interpreted in light of its limitations, 13. Moroldo MB, DeCunto C, Hubscher O, et al. Cross-cultural
such as assessment of patients from a single center. The adaptation and validation of an Argentine-Spanish version of the
sample size was small and therefore the statistical signifi- Stanford Childhood Health Assessment Questionnaire (CHAQ).
Arthritis Care Res 1998;11:382-90.
cance of associations may be different in larger populations. 14. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini
Moreover, since this was an uncontrolled study, changes A. Preliminary definition of improvement in juvenile arthritis.
observed in disease activity might be related to the natural Arthritis Rheum 1997;40:1202-9.
history of systemic JIA (in spite of the unremitting disease 15. Cassidy JT, Petty RE. Chronic arthritis in children. In: Cassidy JT,
course observed prior to the start of anti-TNF therapy). Petty RE, Laxer RM, Lindsley CB, editors. Textbook of pediatric
rheumatology. 5th ed. Philadelphia: Elsevier Saunders;
Finally, questions of duration of remission and radiological 2005:206-60.
progression among patients classified as in remission should 16. Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of
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Our data demonstrate that remission is attainable in about idiopathic arthritis and clinical response to IL-1 blockade. J Exp
one-quarter of patients with systemic JIA receiving Med 2005;20:1479-86.
17. Gattorno M, Piccini A, Lasiglie D, et al. The pattern of response to
anti-TNF therapy, but it was sustained in only 13% of our anti-interleukin-1 treatment distinguishes two subsets of patients
cohort. Patients who do not show fever or other systemic with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum
symptoms at the start of therapy and those who achieve cri- 2008;58:1505-15.
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benefitting from this outcome. Further studies in larger patients with juvenile idiopathic arthritis. Arthritis Rheum
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cohorts are needed to confirm these observations. 19. Lomater C, Gerloni V, Gattinara M, Mazzotti J, Cimaz R, Fantini F.
Systemic onset juvenile idiopathic arthritis: a retrospective study of
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