A real-life study of Juvenile Idiopathic Arthritis from two Brazilian Centers of Pediatric Rheumatology

doi:10.21203/rs.3.rs-4101906/v1

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A real-life study of Juvenile Idiopathic Arthritis from two Brazilian Centers of Pediatric Rheumatology

https://doi.org/10.21203/rs.3.rs-4101906/v1

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Background

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood, but its outcomes are still difficult to determine. We aimed to obtain outcome measurements of disease activity, functional capacity, disease damage and therapeutic response, in a one-year follow-up study on a real-life basis.

Methods

An observational study from an Inception cohort of JIA from two Brazilian Pediatric Rheumatology Centers was conducted for one year. Clinimetric validated outcome measurements were applied over four visits (baseline: Vbaseline, week 12: V12, week 26: V26 and week 52: V52). The multivariable logistic regression was performed to evaluate baseline variables associated with disease activity, minimal disease activity, disease flare, remission on medication and remission off medication at one year of follow-up.

Results

A total of 127 patients were included in the study. Eighty-three (65.4%) were females, and median time to diagnosis was 6.0 months. The most frequent JIA subtypes were persistent oligoarticular and rheumatoid factor-negative polyarticular, 30.7% each. The clinimetric measurements used to assess disease activity and functional capacity showed significant improvement over the one-year follow-up period (p < 0.001 in both cases) as well as the therapeutic response assessed by the Ped-ACR-30,50,70,90 (p < 0.05). Inactive disease was present in 33% of patients at baseline, vs 67.9% at V52. Remission on medication and off medication was present in 46% and in 11% of patients at V52, respectively. Extra-articular and articular damage were not common at baseline and did not decrease significantly during the period of the study. The presence of active joints at baseline reduced the chance of the patient achieving remission off medication at the last visit by 84% (p = 0.039). Minimal disease activity was present in 80.6% at V52.

Conclusion

This study showed progressive improvement of several clinimetric outcome measurements and therapeutic response in an inception cohort of JIA patients. The presence of active joints at baseline represented a risk of not achieving remission at last visit. Long-term prospective and multicenter studies are needed to better assess the follow up of JIA and the differences between subtypes in real life.

juvenile idiopathic arthritis

remission

inactive disease

disease activity

minimal disease activity

treatment

Juvenile idiopathic arthritis (JIA) is the most frequent autoimmune rheumatic disease in childhood and is characterized by chronic arthritis with different phenotypes ⁽¹⁾. Therapeutic advances have increased significantly and consequently the prognosis has become progressively better ⁽²⁾. In view of this, therapeutic response criteria and disease activity scores have been developed and improved over the last few decades, and also definitions of disease inactivity, disease remission, and functional limitation, in order to better define the outcomes ^(3–5).

Inactivity can be difficult to achieve in some patients, especially those with severe or long-term disease. A relatively new concept, minimal disease activity, has been used for those patients with favorable response but who have not achieved disease inactivity ⁽⁶⁾. Both articular and extra-articular damage from the disease could also be measured through clinimetric definitions ⁽⁷⁾.

International studies are scarce, in relation to epidemiological, clinical, diagnostic and follow up of patients with JIA, particularly using overall clinimetric evaluation, such as visual analogic scale (VAS), Juvenile Arthritis Disease Activity Score (JADAS)⁽⁴⁾, Childhood Health Assessment Questionnaire (CHAQ) ⁽⁸⁾, Juvenile Arthritis Damage Index (JADI)⁽⁷⁾, and JIA-American College of Rheumatology (ACR) response ⁽³⁾, in real life scenarios in Latin American centers^(9,10). However, none of them evaluated, concomitantly, several clinimetric outcome measurements, and therapeutic response, over one-year in pediatric rheumatology centers in a single Latin America country.

Therefore, the aims of this study were to obtain outcome measurements of disease activity, functional capacity, disease damage and therapeutic response in JIA patients from two Brazilian pediatric rheumatology centers, during one-year of a real-life follow-up, and to study predictors for these outcomes. Characteristics of JIA were also compared according to the different subtypes.

This was an observational study of JIA patients followed in two reference centers in pediatric rheumatology in Brazil. This study was adapted from the INCA study – Inception Cohort of JIA in Latin America. The patients were followed for a period of one-year, between March 2021 and December 2022. The inclusion criteria were: patients aged ≤ 18 years at the beginning of the study, and patients who met the International League of Associations for Rheumatology (ILAR) classification criteria for JIA ⁽¹¹⁾. Patients who did not have adequate data collection were systematically excluded.

The study was approved by the Ethics and Research Committee of these two university hospitals. Informed assent and consent were obtained from all JIA patients and their legal guardians, respectively.

The inclusion of the patients occurred at any point of the disease duration. They underwent four visits over a period of 12 months: baseline (Vbaseline), week 12 (V12), week 26 (V26) and week 52 (V52). Demographic, clinical, laboratory, and treatment data were collected. Clinimetric definitions were used to assess disease activity, therapeutic response, disease remission, recurrence, functional capacity, and joint and extra-articular disease damage at all visits.

The following clinimetric parameters were systematically used:

Disease activity according to JADAS 71 ⁽⁴⁾.

Minimal disease activity according to Magni-Manzoni⁽⁶⁾

Therapeutic response criteria according to the JIA-ACR 30/50/70/90 responses ⁽³⁾

Inactive Disease according to Wallace criteria ⁽⁵⁾

Disease flare, according to definition of disease flare by Brunner ⁽¹²⁾

Remission on medication according to Wallace criteria ⁽⁵⁾ at the V26 and V52.

Remission off medication according to Wallace criteria ⁽⁵⁾ at the V52.

Functional capacity by the Childhood Health Assessment of childhood (CHAQ) ⁽⁸⁾.

Index of joint and extra-articular damage by Juvenile Arthritis Damage Index (JADI) ⁽⁷⁾.

Global assessment of the physician and the patient/caregiver by VAS.

The following were considered extra-articular complications related to JIA:

Osteoporosis: defined by the presence of fracture with vertebral compression or 2 or more fractures of long bones up to 10 years of age or 3 or more fractures of long bones at any age up to 19 years associated with low bone mass with Z-score< -2 ⁽¹³⁾.
Growth retardation
Delay in puberty
Local lower limb growth changes.

Statistical analysis

Statistical analysis was performed with software R 4.2.0. Quantitative variables were described as means and standard deviations (SD) or medians [IQR], according to the Kolmogorov-Smirnov normality tests. Qualitative variables were described as absolute numbers (n) and frequencies (%). To compare the quantitative variables, the Student t test (comparison between 2 groups), ANOVA (comparison between more than 2 groups) or mixed model (for measurements taken more than once in the same patient) were used. When the distribution of variables did not follow the normal distribution, the Wilcoxon-Mann-Whitney test (comparison between 2 groups) or Kruskal-Wallis test (more than 2 groups compared) were used. For categorical variables, comparisons between the two groups were carried out using Fisher's exact test or Chi-square test. The multivariable logistic regression was performed with a stepwise selection, to evaluate different baseline variables as explanatory of different outcomes of interest at V52, such as: disease activity, minimal disease activity, disease flare, remission on medication and remission off medication. All statistical tests had a p-value ≤ 0.05 to be considered significant.

A total of 127 JIA patients were included, 113 (89%) completed all four visits, and 83 (65.4%) were female. 111 (87.4%) patients had been diagnosed prior to study initiation and 16 (12.6%) had JIA diagnosis at study enrollment. Ninety-five (74.8%) patients had prospective evaluation. Median age at disease onset and median elapsed time between first symptom and diagnosis were 4.1 years [2,2; 7,4] and 6.0 months [3,0; 12,0], respectively. Mean age at baseline was 11.0 years [± 4.2], and mean disease duration was 5.8 years [± 4.1]. Demographic and clinical data of the patients and the JIA subtypes are presented in Table 1.

Table 1

– Demographic and clinical data of patients with Juvenile Idiopathic Arthritis (JIA) at baseline assessment
Variables	Total (n = 127)
Female	83 (65.4)
Age at baseline assessment, years	11.0 ± 4.2
Age at disease onset, years	4.1 [2.2; 7.4]
Age at JIA diagnosis, years	6.2 ± 4.0
Duration of the disease, years	5.8 ± 4.1
Elapsed time between the first symptom and diagnosis (months)	6.0 [3.0; 12.0]
Subtypes of JIA (%)
Persistent oligoarticular	39/127 (30.7)
Extended oligoarticular	14/127 (11.0)
RF positive polyarticular	5/127 (3.9)
RF negative polyarticular	39/127 (30.7)
Systemic	16/127 (12.6)
ERA	7/127 (5.5)
Undifferentiated	7/127 (5.5)

JIA- Juvenile Idiopathic Arthritis, RF - rheumatoid factor, ERA – Enthesitis-Related Arthritis.

Results of numerical variables represented by median (IQR) or mean ± SD and n (%)

Table 2 (the end of the document text file) shows musculoskeletal involvement and laboratory data, according to the different subtypes of JIA at the baseline assessment. There was a difference in joint manifestations between the different subtypes: a greater number of patients with joint pain (p = 0.001) and a greater number of joints with pain in systemic JIA (p = 0.001). We observed a significant decrease in the number of patients with increased CRP over time, and there were differences among groups (systemic JIA vs extended oligoarticular JIA, p = 0.011); (systemic JIA vs persistent oligoarticular JIA, p = 0.003); and (systemic JIA vs RF-negative polyarticular JIA, p = 0.012).

Table 2

– Musculoskeletal involvement and laboratory data in different categories of JIA ILAR classification at the baseline
Measure	Persistent oligoarticular (n = 39)	Extended oligoarticular (n = 14)	Polyarticular RF+ (n = 5)	Polyarticular RF- (n = 39)	Systemic (n = 16)	ERA (n = 7)	Undif (n = 7)	p-value
Number of Patients: Hip	2 (5.1)	0 (0.0)	1 (20.0)	4 (10.2)	4 (25.0)	2 (28.6)	2 (28.6)	0.073
Sacroiliac	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (14.2)	0.893
Thoracic	0(0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (6.2)	0 (0.0)	0 (0.0)	0.322
Active Joints	11 (28.2)	8 (57.1)	3 (60.0)	16 (41.0)	10 (62.5)	2 (28.6)	2 (28.6)	0.182
Limited Joints	14 (35.9)	9 (64.3)	5 (100.0)	23 (59.0)	11 (68.8)	4 (57.1)	4 (57.1)	0.066
Joints with Pain	6 (15.4)	6 (42.9)	1 (20.0)	6 (15.4)	11 (68.8)	2 (28.6)	2 (28.6)	0.001
Increased ESR	8/35 (22.9)	3/12 (25.0)	1 (20.0)	5/34(14.7)	5/13 (38.5)	4 (57.1)	3 (42.9)	0.223
Increased CRP	5/33 (15.2)	1/12 (8.3)	0 (0.0)	6/31 (19.4)	8/13 (61.5)	1 (14.3)	2/6 (33.3)	0.013
Rheumatoid factor +	0 (0.0)	0 (0.0)	5 (100.0)	0 (0.0)	0 (0.0)	0 (0.0)	4/ (57.1)	< 0.001
ANA +	28 (71.8)	9 (64.3)	2 (40.0)	24 (61.5)	4 (25.0)	3 (42.9)	1 (14.3)	0.009
Presence of HLA B27	0/4 (0.0)	0/4 (0.0)	0 (0.0)	0/4 (0.0)	0/5 (0.0)	2 (28.6)	1/4 (25.0)	0.480
ESR	10.0 [5.5; 17.5] (n = 35)	10.0 [4.8; 22.5] (n = 12)	6.0 [5.0; 4.0]	9.0 [5.0; 14.2] (n = 34)	8.0 [5.0; 56.0] (n = 13)	33.0 [9.5; 38.0]	7.0 [5.5; 32.0]	0.694
Number of Joints
Active joints	0.0 [0.0; 1.0]	1.0 [0.0; 4.0]	3.0 [0.0; 5.0]	0.0 [0.0; 4.0]	1.5 [0.0; 6.2]	0.0 [0.0; 1.0]	0.0 [0,0; 0,5]	0.030
Limited joints	0.0 [0.0; 1.0]	3.0 [0.0; 3.8]	3.0 [20; 6.0]	2.0 [0.0; 6.0]	2.5 [0.0; 6.0]	1.0 [0.0; 1.5]	1.0 [0.0; 2.5]	0.001
Joint pain	0.0 [0.0; 0.0]	0.0 [0.0; 1.0]	0.0 [0.0; 0.0]	0.0 [0.0; 0.0]	2.0 [0.0; 4.5]	0.0 [0.0; 1.0]	0.0 [0.0; 0.5]	0.001
ERA: Enthesitis Related Arthritis, Undif: undifferentiated, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, ANA: antinuclear antibody, HLA B27: human leukocyte antigen B27.
Results in median (IQR) and n (%).

The baseline variables associated with disease activity, minimal disease activity, disease remission, disease flare and remission on medication at V52 were assessed (Table 3) (the end of the document text file). The following factors at baseline were associated with disease activity at V52: presence of active joints (p = 0.009), presence of limited joints (p = 0.002), number of active joints (p = 0.002), number of joints with pain (p = 0.003), and number of limited joints (p = 0.001). For each additional number of joints with pain at baseline, the chance of having high disease activity at V52 increased by 34% (OR = 1.34; CI 95% from 1.15 to 1.63, p = 0.001). The following factors at baseline were associated with minimal disease activity at V52: presence of active joints (p = 0.027), presence of limited joints (p = 0.003), number of active joints (p = 0.004), number of joints with pain (p = 0.015) and number of limited joints (p = 0.001). The presence of each additional unit in the number of joints with pain at the baseline visit decreased the chance of having minimal disease activity by 21% (OR = 0.79; CI 95% from 0.65 to 0.96, p = 0.018). No variable was associated with the presence of flare or with the remission on medication at V52. The presence of active joints at baseline was associated with a lower remission rate at V52, with an 84% reduction in the chance of the patient going into remission off medication (OR = 0.16; CI 95% from 0.03 to 0.91, p = 0.039). Disease duration was assessed but no association with the remission rate (p = 0.644) was found.

Table 3

– Clinimetric data of JIA patients during the four visits (V) of the study.
Variables		V12	V26	V52	p-value
JADAS 71, mean ± SD	7.05 ± 9.3 (n = 119)	4.24 ± 7.1 (n = 126)	3.59 ± 7.2 (n = 124)	3.52 ± 8.4 (n = 110)	< 0.001
Parents/patients’ VAS of pain, mean ± SD	1.75 ± 2.3 (n = 122)	1.25 ± 2.1 (n = 126)	1.15 ± 2.1 (n = 123)	1.0 ± 2.2 (n = 111)	< 0.001
Parents/patients’ VAS overall well-being, mean ± SD	2.49 ± 2.7 (n = 122)	1.17 ± 1.7 (n = 126)	1.10 ± 2.0 (n = 122)	0.85 ± 1.7 (n = 111)	< 0.001
Physician’s VAS, mean ± SD	2.50 ± 2.8 (n = 122)	1.72 ± 2.6 (n = 126)	1.29 ± 2.2 (n = 122)	1.06 ± 2.3 (n = 111)	< 0.001
CHAQ, mean ± SD	0 ± 0.5 (n = 114)	0.21 ± 0.4 (n = 120)	0.19 ± 0.5 (n = 112)	0.14 ± 0.4 (n = 101)	0.018
JADI-A, mean ± SD	1.15 ± 3.4 (n = 122)	0.87 ± 2.9 (n = 126)	1.08 ± 3.4 (n = 126)	1.22 ± 3.8 (n = 111)	0.407
JADI-E, mean ± SD	0.33 ± 0.7 (n = 127)	0.42 ± 1.2 (n = 127)	0.33 ± 0.7 (n = 127)	0.36 ± 0.9 (n = 113)	0.366
Number of Patients CHAQ amended > 0 n (%)	45/114 (39.5)	41/120 (34.2)	26/112 (23.2)	20/101 (19.8)	< 0.001
Inactive disease, n (%)	41/123 (33.3)	60/126 (47.6)	82/124 (66.1)	74/109 (67.9)	< 0.001
Minimal disease activity n (%)	64/109 (58.7)	80/111 (72.0)	85/108(78.7)	79/98(80.6)	0.035
Disease flare, n (%)	12/120 (10.0)	9/124 (7.3)	7/122 (5.7)	8/109 (7.3)	0.635
Remission on medication n (%)			52/127 (40.9)	52/113 (46.0)
Remission off medication n (%)				12/113 (10.6)
JIA-ACR 30, n (%)	95/119 (79.8)	105/122 (86.1)	108/119 (90.8)	95/107 (88.8)	0.027
JIA-ACR 50, n (%)	85/119 (71.4)	99/122 (81.1)	105/119 (88.2)	90/107 (84.1)	0.003
JIA-ACR 70, n (%)	71/119 (59.7)	83/122 (68.0)	91/119 (76.5)	83/107 (77.6)	0.010
JIA-ACR 90, n (%)	59/119 (49.6)	74/122 (60.7)	80/119 (67.2)	74/107 (69.2)	0.003
JADAS: Juvenile Arthritis Disease Activity Score, VAS: Visual Analogue Scale, CHAQ: Childhood Health Assessment Questionnaire, JADI-A: Juvenile Arthritis Damage Index-Joint, JADI-E: JADI-Extra-articular, JIA-ACR: Therapeutic Response Criteria of the Pediatric ACR

There was no difference in relation to disease activity in the last visit among the different subtypes of JIA.

Musculoskeletal involvement and laboratory data of the total of JIA patients during the study visits are illustrated in Table 4 (the end of the document text file). There was a significant decrease in the number of JIA patients with active, limited, and painful joints (p < 0.05). There was also a significant decrease in the number of active joints (at baseline compared to the 12-week visit, p = 0.003) and limited joints over the follow-up time (p = 0.002). Significant decrease in the number of JIA patients with increased ESR (> 20mm/1st hour) was revealed (p = 0.001), with significant reduction in ESR value at the 26-week visit compared to the 12-week visit (p = 0.006). A significant decrease in the number of patients with increased CRP over the follow-up time (p < 0.001) was found.

Table 4

– Musculoskeletal involvement and laboratory data of JIA patients during the study visits
Variables	V baseline N = 127	V12 N = 127	V26 N = 127	V52 N = 113	p-value
N° of patients
Hip involvement (%)	15 (11.8)	9 (7)	9 (7.1)	11 (9.7)	0.126
Sacroiliac involvement (%)	0 (0)	0 (0)	0 (0)	1 (0.9)	> 0.999
Thoracic involvement (%)	1 (0.8)	1 (0.8)	0 (0)	0 (0)	> 0.999
Active joints (%)	52 (40.9)	40 (31.5)	29 (22.8)	21 (18.6)	< 0.001
Limited joints (%)	70 (55.1)	67 (52.8)	57 (44.9)	49 (43.4)	< 0.001
Joints with pain (%)	34 (26.8)	28 (22.0)	20 (15.7)	16 (14.2)	0.002
ESR increase (%)	29/113 (25.7)	31/111 (27.9)	14/97 (14.4)	16/95 (16.8)	0.001
CRP increase (%)	23/106 (21.7)	17/96 (17.7)	11/94 (11.7)	11/93 (11.8)	< 0.001
Rheumatoid factor + (%)	9 (7.1)	-	-	-	-
ANA + (%)	71 (55.9)	-	-	-	-
HLA B27 + (%)	3/29 (10.3)	-	-	-	-
ESR value Number of joints	10.0 [5.0; 21.0] (n = 113)	8.0 [5.0; 24.5] (n = 111)	10.0 [5.0;16.0] (n = 97)	10.0 [5.0;17.0] (n = 95)	0.387
Active joints	2.37(± 5.2)	1.25 (± 3.4)	1.19(± 3.7)	1.35(± 4.1)	< 0.001
Limited joints	2.97 (± 5.4)	2.56 (± 5.47)	2.40 (± 5.7)	2.07 (± 5.17)	0.002
Joint pain	1.40 (± 4.2)	0.87 (± 3.4)	0.92 (± 3.7)	1.05 (± 3.8)	0.186
ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, ANA: Antinuclear Antibody, HLA B27: human leukocyte antigen B27, V: visit. Results in median (IQR) or mean ± SD and n (%)

Enthesitis was observed in 4 (3.1%) patients at baseline, with improvement during follow-up, occurring in one (0.78%) at V52. Active uveitis occurred in 17 (13.4%) patients: 10 (7.9%) at baseline, 7 (5.5%) at V12, 4 (3.1%) at V26, and 3 (2.7%) at V52 with significant improvement during follow-up (p = 0.047). The most frequent subtype of JIA in patients with uveitis was persistent oligoarticular JIA (8 [6.3%]), followed by ERA JIA (4 [3.1%]), RF-negative polyarticular JIA (3 [2.4%]), RF positive polyarticular JIA (1 [0.8%]) and undifferentiated JIA (1 [0.8%]).

Growth retardation was observed in 9 (7.1%) patients at baseline, 11 (8.7%) at V12, 6 (4.7%) at V26 and 6 (4.7%) at V52; 2/112 (1.8%) patients had delay in puberty at baseline and at all visits, and 4 (3.1%) had localized lower limb growth changes that continued over time. Osteoporosis was diagnosed in 2 (1.6%) patients without statistical difference between the evaluations.

Regarding the treatment at baseline, 12% of patients were on systemic corticosteroids, 11.9% were on non-steroidal anti-inflammatory drugs (NSAIDs), 84.9% were on synthetic disease-modifying antirheumatic drugs (sDMARDs) and 51.2% were on biological DMARDs (bDMARDs). There was a significant decrease in the use of sDMARDs between V26 and V52 (p = 0.006). The most used sDMARDs at baseline visit was methotrexate (used by 61.1% of the patients), followed by leflunomide (20.6%), cyclosporine (6.3%) and sulfasalazine (0.8%). Regarding bDMARDs, there was no difference in their use over time. Adalimumab was the most used bDMARD (used by 27.1% of the patients) at baseline visit, followed by tocilizumab (13.0%), etanercept (10.6%) and infliximab (1.6%).

This study assessed clinical, laboratory, and outcome data of patients with JIA in two Brazilian referral centers in Pediatric Rheumatology during 12 months of follow-up. Some aspects of this study, such as scarcity of JIA studies in Latin America, assessment of the applicability of JIA treatment protocols in a country with low resources, clinimetric measures over one year of follow-up in real life, and the assessment of minimal active disease, a relatively new concept in pediatric rheumatology and JIA ^(6,14), give it great relevance.

Clinimetric measures, although relevant for follow-up and monitoring of therapeutic response, have rarely been used in the pediatric literature, especially in developing countries. In our sample, we observed an improvement in disease activity status, measured by JADAS71, over 12 months of follow-up. At the final assessment, approximately half of patients were in remission on medication, about 10% in remission off medication and more than two-thirds were inactive. The literature also shows favorable outcomes in contrast to the pre-biological era. In a multicenter study from North America with 2904 patients with JIA, a high proportion of patients with inactive disease was observed after one year of follow-up, measured by the clinical JADAS10 (cJADAS10), parents and patients’ VAS and the physician’ VAS ⁽¹⁵⁾. Castillo-Vilella et al. observed that 70% of the patients in their cohort achieved clinical remission and 29% remission off medication in an observation period of 2 years in a prospective cohort, and one year in a retrospective cohort ⁽¹⁶⁾. In another study, the authors observed that 47% of patients were in remission off medication, 25% in remission on medication, 27% with active disease, and 51% were using at least one DMARD (of these, 22% were biological) after 3 years of follow-up ⁽²⁾. A recent review included JIA studies with patients that were followed for a minimum period of 2 years, and revealed that almost half of them were in disease remission in the final assessment ⁽¹⁷⁾.

Of note, the regression analysis revealed some predictors for outcomes at final assessment. The presence of active joints at baseline reduced the chance of the patient going into remission off medication, the presence of each additional unit in the number of joints with pain at the baseline, decreased the chance of having minimal disease activity, and finally the presence of active joints at baseline was associated with a lower remission off medication. Predictors of severity and remission have been studied in JIA, and some variables such as high disease activity, involvement of ankles, wrists, and hips, and delay in the beginning of treatment seemed to predict long-term disease severity ⁽¹⁸⁾.

Our study revealed a significant increase in patients with minimally active disease over the follow-up. A cross-sectional study showed minimally active disease in 44.8 to 62.4% and in 44.6 to 50.4% of two cohorts of patients with oligoarticular JIA and polyarticular JIA, respectively ⁽¹⁹⁾. In our cohort, we observed minimal disease activity in 80.6% at the final visit. To the best of our knowledge, there are no longitudinal studies in the literature regarding minimally active disease.

Although most patients were not included at the beginning of the diagnosis and treatment, follow up revealed a favorable evolution. Regarding the patients included soon after diagnosis, we observed that the clinical characteristics and the classification of subtypes did not differentiate them from the other patients (data not shown).

Confirming a favorable follow up, we observed that although about half of the patients presented joint limitations throughout the follow-up, these were restricted to a small number of joints (with a maximum mean of two joints). The functional capacity of these patients, as measured by CHAQ, also showed improvement during the follow-up.

We observed that the number of patients using sDMARDs decreased over time, especially the use of methotrexate. On the other hand, the number of patients using bDMARDs did not present significant differences over time, which is in accordance with what we use to do in our clinical practice (tapering first the sDMARDs). Therefore, a probable explanation for the reduction in the use of sDMARDs was the clinical improvement presented by the patients during the follow-up. Regarding the corticosteroid dose, we observed that few patients continued the medication, with no significant decrease in the dose over time. This was due to the presence of disease flare in some patients with the need for increase or resumption of this medication.

This study revealed a relatively short time (6 months) to JIA diagnosis, which surprised us, positively, since it shows greater awareness about the disease on the part of physicians, with consequent earlier referral to the specialist, compared to previously. A study conducted in the city of Sao Paulo in 2002 showed a mean delay to diagnosis of 1.4 years, which ranged from a few days to 10 years, and a mean of non-specialist physicians consultations before visiting the specialist, of 3.6 ⁽²⁰⁾. The good outcome of the patients in our study could be explained in part by the early treatment, and it is also demonstrated by the low frequency of comorbidities. However, the subtypes with polyarticular involvement presented more joint limitation.

This study has strengths, particularly use of concomitant validated clinimetric tools to evaluate disease activity, disease remission, functional capacity, damage, and therapeutic response. Indeed, these instruments are relevant to assess overall JIA during follow-up. However, the main limitation of our study was that most patients were included at different times of diagnosis, with only a small portion (12.6%) inserted at the time of diagnosis, which made it difficult to analyze the follow-up variables of this group.

This real-life study with JIA patients conducted over one-year of follow up revealed improvement of the disease in several parameters, measured through validated scores of disease activity, functional capacity, therapeutic response and disease damage. An association between the presence of active joints at baseline and reduced chance of achieving remission after one year was observed. However, more than half of the patients were in remission of the disease after this time. Long-term prospective and multicenter studies are needed to better assess the outcome of JIA and the differences among JIA subtypes.

ACR

American College of Rheumatology. ANA +:antinuclear antibody. bDMARDs:biological disease-modifying antirheumatic drugs. CHAQ:Childhood Health Assessment Questionnaire. CRP:C-reactive protein. ERA:Enthesitis Related Arthritis. ESR:erythrocyte sedimentation rate. HLA B27:human leukocyte antigen B27. ILAR:International League of Associations for Rheumatology (ILAR). JADAS:Juvenile Arthritis Disease Activity Score. JADI:Juvenile Arthritis Damage Index. JADI-A:Juvenile Arthritis Damage Index-Joint Damage. JADI-E:Juvenile Arthritis Damage Index-Extra-articular Damage. JIA:Juvenile idiopathic arthritis. JIA-ACR:Therapeutic Response Criteria of the Pediatric American College of Rheumatology. N°:number. NSAIDs:non-steroidal anti-inflammatory drugs. RF:rheumatoid fator. sDMARDs:synthetic disease-modifying antirheumatic drugs. Undif:undifferentiated. V:visit

Ethics approval and consent to participate:

The study protocol was approved by the Institutional Review Board of Universidade Federal de São Paulo (CAAE: 27544919.1.0000.5505) and Research Ethics Committee Children’s Institute, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo (CAAE: 27544919.1.2008.0068). All participants and their legal guardians, when appropriate, provided written informed consent. All procedures were performed in accordance with the 1964 Declaration of Helsinki and its later amendments, or comparable ethical standards.

Consent for publication:

Publication consent was acquired on the original consent form.

Competing interests:

Ana María Loroño Terrazas^, Gleice Clemente, Raúl Gutiérrez Suárez, Reinan Tavares Campos, Claudio Arnaldo Len, Nadia Emi Aikawa, Jade Dib Fernandez, Mayra Lisyer Dantas, Clóvis Artur Silva, Maria Teresa Terreri declare that they have no conflict of interest.

Authors' information (optional)

Ana María Loroño Terrazas, Pediatric Rheumatologist Sector at Escola Paulista de Medicina/ Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

Gleice Clemente, Affiliated Professor of the Department of Pediatrics and Assistant Physician of the Pediatric Rheumatology Sector at Escola Paulista de Medicina/ Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

Raúl Gutiérrez Suárez, Pediatric Rheumatologist, Shriners Hospital for Children Mexico City. México. Hospital para el Niño. IMIEM. Estado de México. México.

Reinan Tavares Campos, Pediatric Rheumatologist at the Institute for Children and Adolescents HC-FMUSP.

Claudio Arnaldo Len, Pediatrics - Pediatric Rheumatology, Associate Professor of the Department of Pediatrics - Escola Paulista de Medicina/ Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

Nadia Emi Aikawa, Attending physician of the pediatric rheumatology discipline at Child and Adolescent Institute HC-FMUSP.

Jade Dib Fernandez, Pediatric Rheumatologist Sector at Escola Paulista de Medicina/ Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

Mayra Lisyer Dantas, Pediatric rheumatology resident at Escola Paulista de Medicina/ Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

Clovis Artur Almeida da Silva, M.D., Ph.D. Full Professor of Pediatric Department, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brazil. Head of Adolescent and Pediatric Rheumatology Units, Child and Adolescent Institute HC-FMUSP.

Maria Teresa Terreri, Associate Professor, Head of the Rheumatology Sector of the Department of Pediatrics and Escola Paulista de Medicina/ Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

Footnotes

Not applicable.

Funding

Main Sponsor: Own Financing

Authors' contributions:

Conception and design: AMLT, GC, and MMT. Data colletion and processing: AMLT, GC, RTC, NEA, CAS and MMT. Statistical analysis and interpretation: AMLT, GC and MMT. Literature review: ALT and GC. Writing: AMLT, GC and MTT. Critical review: GC, RGS, RTC, CAL, NEA, JDF, MLD, CAS and MMT. All authors read and approved the final manuscript.

Acknowledgements:

Not applicable

Availability of data and materials:

All data generated during this study are available from the corresponding author on reasonable request.

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A real-life study of Juvenile Idiopathic Arthritis from two Brazilian Centers of Pediatric Rheumatology

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References

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