Enhancing the precision of clinical assessment in juvenile idiopathic arthritis through the JADAS

Abstract

The use of composite disease activity scores enables a pragmatic approach to the measurement of the level of disease activity in children with juvenile idiopathic arthritis (JIA). These tools are constructed through the combination of individual measures and provide a quantification of the absolute level of disease activity in one summary number on a continuous scale. The first composite score for JIA, named Juvenile Arthritis Disease Activity Score (JADAS), was published in 2009. It includes the following four variables: physician global assessment, parent/patient global assessment, active joints count, and an acute phase reactant. Its score is calculated as the arithmetic sum of the scores of its four items. Additional versions of the JADAS, which lack the acute phase reactant (clinical JADAS, cJADAS) or are specific to systemic JIA (systemic JADAS, sJADAS), were developed over the years. An important progress in the field has been represented by the definition of the cutoff values in the JADAS that distinguish the states of inactive disease or minimal, moderate, and high disease activity in JIA. These cutoffs may serve as therapeutic targets in the treat-to-target strategy. Recently, a JADAS version entirely composed of parent/patient-reported outcome measures has been developed and validated. This tool is well suited to implement remote patient monitoring, a form of telemedicine that may help to optimize disease control and reduce the pressure on healthcare systems. This review is aimed to describe the different versions of the JADAS and the main aspects of their developmental process.

Introduction

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease with widely variable clinical course and outcome [1]. Evaluation of disease activity is a fundamental component of the clinical assessment of children with JIA because persistently active disease plays a major role in causing joint damage and functional disability [2] or, in systemic JIA, may herald the occurrence of macrophage activation syndrome or inflammatory lung disease [3, 4]. Regular estimation of the level of disease activity over time is important to monitor the course of the disease over time and to evaluate the effectiveness of therapeutic interventions. To ensure reliable and precise documentation of the state of the inflammatory process, measurements should be performed using standardized and well validated clinical outcome measures.

The first attempt to enhance the quality of clinical assessments in JIA dates to 1982, when Ed Giannini and Earl Brewer promulgated the standard methodology for the conduction of clinical trials by the Pediatric Rheumatology Collaborative Study Group [5, 6]. However, despite this proposal and several subsequent efforts aimed to develop new instruments, pediatric rheumatologists continued to use multiple outcome measures, and the criteria employed to assess the effectiveness of antirheumatic drugs were not harmonized. This lack of standardization hindered the comparison of data across diverse patient series or therapeutic studies.

A breakthrough in the field occurred in 1997, when a “core set” of outcome measures for JIA was published [7]. The core set includes the following six variables: (1) physician global assessment of overall disease activity (PhGA); (2) parent/patient global assessment of overall wellbeing (PaGA); (3) physical functional ability; (4) count of joints with active arthritis; (5) count of joints with limited range of motion; and (6) an acute-phase reactant. This ensemble of variables was intended to be robust enough to cover all phenotypes of JIA. A definition of improvement for clinical trials (so-called American College of Rheumatology, ACR, Pediatric response criteria) was derived, which established the magnitude of change in the 6 variables that should led to classify a patient as responder or nonresponder [7].

Other important achievements in clinimetrics of JIA were represented by the establishment of definitions for the states of clinical inactive disease, clinical remission and minimal disease activity [8–10]. However, neither these criteria, which are based on multiple items, all of which should be met, nor the ACR Pediatric response criteria, which emphasize a change in disease activity, are suited to measure the patients’ actual disease activity or to compare one patient’s level of disease activity with that of another patient. Furthermore, they do not allow discernment of whether one group of patients has more active disease than another group.

These considerations prompted us to propose a new approach to the measurement of disease activity, based on composite disease activity scores [11]. These tools, which have long been used in adults with rheumatoid arthritis [12–16], are made up by pooling individual measures of disease activity into a single instrument and are aimed to quantify the absolute level of disease activity by providing one summary number on a continuous scale. Composite scores are thought to increase consistency in disease activity evaluation across physicians, to allow patients to better understand the meaning of disease activity by reading a simple score number, and to reduce the sample size requirement in therapeutic studies [16]. They can be used in the assessment of therapeutic efficacy in clinical trials and in monitoring disease activity in individual patients in standard clinical practice.

The first composite disease activity score for JIA, named Juvenile Arthritis Disease Activity Score (JADAS), was published in 2009 [11]. Over the years, additional versions of the tools have been developed to expand its applications (Table 1). The aim of the present review is to describe the main characteristics of the instrument and to provide an overview of its developmental process.

Table 1.

Composition and theoretical range of the different versions of the Juvenile Arthritis Disease Activity Score (JADAS)

	JADAS10	JADAS27	JADAS71	cJADAS10	sJADAS10	Par/PatJADAS
Physician global assessment	VAS or NRS (0–10)	VAS or NRS (0–10)	VAS or NRS (0–10)	VAS or NRS (0–10)	VAS or NRS (0–10)	-
Parent/Child global assessment£	VAS or NRS (0–10)	VAS or NRS (0–10)	VAS or NRS (0–10)	VAS or NRS (0–10)	VAS or NRS (0–10)	NRS (0–10)
Active joint count	Simple count$ (0–10)	Select count& (0–27)	Simple count (0–71)	Simple count$ (0–10)	Simple count$ (0–10)	Select count§ (0–10)
Acute phase reactant	ESR/CRP normalized# (0–10)	ESR/CRP normalized# (0–10)	ESR/CRP normalized# (0–10)	-	ESR/CRP normalized# (0–10)	-
mSMS	-	-	-	-	0–10^	-
Parent/Child assessment of pain	-	-	-	-	-	NRS (0–10)
Morning stiffness duration°	-	-	-	-	-	0–10
Score range	0–40	0–57	0-101	0–30	0–50	0–40

VAS, visual analog scale; NRS, numeric rating scale; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; mSMS, modified systemic manifestation score

^$The active joint count is cut to a maximum of 10. ^&The active joint count is assessed on 27 selected joints, as reported by Bazso A et al. J Rheumatol 2009;36:183 − 90. ^§See text for explanation. ^{^}See Table 2. ^#The ESR is normalized according to the following formula: (ESR, mm/hour – 20)/10. ESR values < 20 mm/hour are converted to 0 and ESR values > 120 m/hour are converted to 120. CRP is normalized according to the following formula: (CRP, mg/l − 10)/10. CRP values < 10 mg/l are converted to 0 and CRP values > 110 mg/l are converted to 110. °Score range from 0 (absent) to 10 (≥ 2 h)

Development and validation of the JADAS

In designing the JADAS, we started from the variables included in the core set [7], recognizing their role as key outcome endpoints for all categories of JIA. However, we reasoned that two of the six variables, namely physical function and the count of joints with restricted motion, cannot be regarded as sufficiently “pure” indicators of disease activity, as they are heavily influenced by the presence of damage, either functional or structural [17]. Another reason for not retaining functional status assessment was its relatively poor sensitivity to change [18–21]. Although the PaGA could also reflect functional impairment [17], it was decided to include this parameter to incorporate parents’ perception of disease activity. The PhGA was deemed essential owing to its strong capacity to detect change in disease activity over time [18–20]. Additional measures were considered. Pain rating was excluded because it is largely integrated in the PaGA. Swollen and tender joint counts were omitted due to their high correlation with active joint count [17, 22, 23]. Although health-related quality of life (HRQOL) is influenced by the disease process, it is affected by many factors unrelated to disease activity.

The final version of JADAS that came out from the developmental process included the following four variables: (1) PhGA, assessed on a 0–10 cm horizontal visual analog scale (VAS) or a 21-point 0 to 10 numerical rating scale (where 0 = no disease activity and 10 = maximum disease activity); (2) PaGA, assessed on a 0–10 cm horizontal VAS or a 21-point 0 to 10 numerical rating scale (where 0 = best and 10 = worst); (3) count of joints with active arthritis, assessed in 71 (JADAS71), 27 (JADAS27), or 10 (JADAS10) joints; and (4) erythrocyte sedimentation rate (ESR), normalized to a 0–10 scale. The JADAS is calculated as the arithmetic sum of the scores of its 4 components, which yields a global score of 0–101, 0–57, and 0–40 for JADAS71, JADAS27, and JADAS10, respectively [11]. A JADAS version including the C-reactive protein level, normalized on a 0–10 scale, instead of the ESR was found to perform equally as the original format [24]. Thus, the two acute-phase reactants can be used interchangeably.

Validation of the JADAS was conducted on four multinational datasets, which included > 4,500 patients with JIA. The tool was found to be feasible and to possess both face and content validity; furthermore, it exhibited good construct validity, discriminant validity, and responsiveness to clinically important change [11].

Clinical JADAS

In parallel with the use of the JADAS, it became clear that its applicability in routine care could be facilitated by a reduced version that lacks the acute-phase reactant. Inflammation biomarkers are often not requested or unavailable at the time of the visit, especially in patients who are not taking drug therapied and, thus, do not necessitate laboratory monitoring, or in children with persistent oligoarthritis, which is the less severe disease subset. The absence of these results during clinical evaluation would make it impossible to make therapeutic decisions based on the JADAS and, therefore, would preclude the benefit of treatment intensification. McErlane and co-workers reported that a 3-variable version of the JADAS that misses the acute-phase reactant correlated closely with the original tool [25]. To maintain consistency in nomenclature, we proposed to call this reduced version “clinical JADAS” (cJADAS) [26]. The application of the cJADAS at the time of the visit allows instantaneous assessment of disease activity through the sole information that is obtained from physical examination and parent or patient report. Immediate treatment decisions based on the score will, then, be possible.

Systemic JADAS

Although the JADAS was initially utilized in studies of systemic JIA (sJIA) [27], the concern was raised that it was validated only in children with oligoarthritis and polyarthritis, including sJIA without extraarticular features, but not in children with sJIA and active systemic manifestations [28]. Because systemic symptoms, especially fever, may affect markedly child’s well-being and play a prominent role in driving therapeutic decisions, it was argued that any instrument used to assess the level of disease activity in sJIA must incorporate their assessment [29]. However, until recently there was no established tool that enabled their specific measurement.

To fill this gap, we decided to devise a new version of the JADAS purposely devoted to the assessment of disease activity in children with sJIA. This tool, named systemic JADAS (sJADAS), was constructed by adding to the four components of the original instrument a fifth item aimed at measuring the burden of extraarticular manifestations. After the analysis of the published indices aimed to quantify systemic symptoms in sJIA [30–32], the Systemic Manifestation Score (SMS) [33] was selected, which was slightly modified to make up the modified SMS (mSMS) [34]. The mSMS includes the following seven clinical and/or laboratory features: (i) fever; (ii) rash; (iii) generalized lymphadenopathy; (iv) hepatomegaly and/or splenomegaly; (v) serositis; (vi) anemia (hemoglobin < 9 g/dl); (vii) platelet count > 600 10⁹/l or ferritin > 500ng/ml. The score of each mSMS component is shown in Table 2. Fever was assigned a greater weight owing to its major impact on a child’s well-being and importance in orienting treatment choices. The total mSMS ranges from 0 to 10, where 0 = absence of systemic manifestations and 10 = maximum activity of systemic manifestations. The addition of the mSMS leads to obtain a score of 0–67, 0–111 and 0–50, for the sJADAS27, sJADAS71 and sJADAS10, respectively.

Table 2.

Modified Systemic Manifestation Score (mSMS)

Clinical or laboratory features	Points
Fever£  37.5–38 °C  >38–39 °C  >39–40 °C  >40 °C	1 2 3 4
Evanescent erythematous rash	1
Generalized lymphadenopathy (enlargement of > 3 lymphnode stations)	1
Hepatomegaly and/or splenomegaly	1
Serositis (pleuritis, pericarditis or peritonitis)	1
Anemia (hemoglobin < g/dl)	1
Platelet count > 600 × 109/l or ferritin > 500 ng/ml	1
Maximum score	10

^£Fever is defined as the maximum temperature in the past 24 h. In the assessment of fever, the possible pharmacologic suppression of temperature by paracetamol, NSAIDs or glucocorticoids should be taken into account

Adapted from Saccomanno B et al. J Rheumatol 2019;46:416–21

The sJADAS was validated on a multinational inception cohort, comprising a total of 163 patients enrolled by pediatric rheumatologists practicing in 10 countries. In validation analyses, the tool was found to be feasible and easily applicable in routine clinical practice, and to possess good metrologic properties [34].

JADAS cutoffs for disease activity states

To facilitate interpretation of scores on the JADAS, criteria (i.e., cutoff values) are needed for identifying different states of JIA activity. These criteria may provide simple and intuitive reference values that can be used to monitor the disease course over time in an individual patient or to compare disease status across individual patients or patient groups. Furthermore, they may support decisions about enrollment into clinical trials as well as requirements for changes in therapies and for defining therapeutic goals in the context of the treat-to-target (T2T) strategy [35].

The cutoff values of the JADAS that distinguish the states of inactive disease, minimal (or low), moderate and high disease activity or reflect the physician, parent, or child subjective rating of remission, or the parent or child satisfaction with the outcome of the illness were established for the JADAS, the cJADAS, and the sJADAS [36–40]. Depending on the analysis, formal definitions [36, 37], therapeutic decisions made by the caring physician [38], or subjective perception by international pediatric rheumatologists [39, 40] were used as external reference for defining the various disease activity states. In validation analyses, all cutoffs exhibited good metrologic properties and proved able to predict disease outcome. If applied regularly in daily practice, the cutoffs may allow tighter therapeutic control of disease, support the optimization of treatment on an individual patient basis, and help prevent the development of disease damage and physical disability.

The cutoffs of different versions of the JADAS that define the various disease activity states in JIA are presented in Table 3.

Table 3.

Disease activity states based on JADAS cutoffs

Disease activity state	2012–2014 cutoffs£			2021 cutoffs$
	JADAS10	cJADAS10		JADAS10	cJADAS10		sJADAS10&
Oligoarthritis
Inactive disease	≤ 1	≤ 1		≤ 1.4	≤ 1.1		-
Minimal disease activity	1.1– 2	1.1– 1.5		1.5– 4	1.2– 4		-
Moderate disease activity	2.1– 4.2	1.51– 4		4.1– 13	4.1– 12		-
High disease activity	> 4.2	> 4		> 13	> 12		-
Polyarthritis
Inactive disease	≤ 1	≤ 1		≤ 2.7	≤ 2.5		-
Minimal disease activity	1.1– 3.8	1.1– 2.5		2.8– 6	2.6– 5		-
Moderate disease activity	3.9– 10.5	2.51– 8.5		6.1– 17	5.1– 16		-
High disease activity	10.5	> 8.5		> 17	> 16		-
Systemic arthritis
Inactive disease	-	-		-	-		≤ 2.9
Minimal disease activity	-	-		-	-		> 2.9–10
Moderate disease activity	-	-		-	-		> 10-20.6
High disease activity	-	-		-	-		> 20.6

^£From Consolaro A et al. Arthritis Rheumatol 2012;64:2366–74, Ann Rheum Dis 2014;73:1380– 3 and Arthritis Care Res 2014;66:1703– 9. ^$From Trincianti C et al. Arthritis Rheumatol 2021;73:1966-75. ^&From Rosina S et al. Arthritis Rheumatol 2024;76:1446-54

Parent/patient JADAS

The importance of incorporating parent- and child-reported outcome measures (PROMs) in pediatric rheumatology care has long been recognized, as these assessments provide valuable information on parent and child perceptions of the state and course of the disease and the effectiveness of treatment [41–50]. An emerging area of PROMs application is represented by remote patient monitoring, a form of telemedicine that is concerned with the collection and transmission of health data from a patient to their health care team by means of digital health technologies, such as mobile apps, telephone-based interactive voice response systems, media, websites, and others [51, 52]. Remote patient monitoring permits more frequent evaluation and communication compared with the traditional model of care and provides greater opportunities for the patient and family to share information with their health care providers. This methodology may help to optimize disease control and may contribute to the success of patient care and to reduce the pressure on healthcare systems. To qualify for use in this area of medical care, PROMs should prove reliable and demonstrate a close correlation with physician-derived scores and other disease outcomes.

Taking advantage of the recent update of the core domain set of outcome variables for JIA clinical trials, accomplished by the Outcome Measure in Rheumatology (OMERACT) JIA Core Set Working Group [7, 53, 54], we created a composite disease activity score entirely based on PROMs. This tool was modelled on the JADAS, and its parent and patient versions were called parJADAS and patJADAS, respectively [55]. The candidate domains were selected among those included in the OMERACT JIA core set [53, 54], considering only those that could be assessed by parents or patients and reflected disease activity. After testing the performance of all proposed variables with a thorough series of statistical analyses, the following four PROMs were retained in the final version of the score: (1) parent/patient assessment of overall disease activity, assessed on a 21-point 0 to 10 numerical rating scale (where 0 = no disease activity and 10 = maximum disease activity); (2) parent/patient assessment of pain, assessed on a 21-point 0 to 10 numerical rating scale (where 0 = no pain and 10 = maximum pain); (3) parent/patient assessment of the activity of joint disease, measured by asking the parent or the patient to report the presence of pain or swelling in the following joints/joint groups: cervical spine, lumbo-sacral spine, shoulders, elbows, wrists, finger joints, hips, knees, ankles and small foot joints. Each affected joint/joint group is counted as 1, but the active joint count is cut to a maximum of 10 joints; (4) morning stiffness duration, scored on a 10-point scale from 0 (absent) to 10 (≥ 2 h). As for the JADAS, the parJADAS and patJADAS are computed as the simple arithmetic sum of the scores of their four components. The total score ranges from 0 to 40 for both tools. An important difference with the JADAS, where the parent/patient global assessment is focused on the state of wellbeing, in the parJADAS and patJADAS parents and patients are asked to refer specifically this evaluation to the actual level of disease activity. To facilitate this judgement, a brief explanation of the concept of disease activity is provided.

Validation procedures were conducted on two large data sets, including > 8500 patients enrolled in 49 countries in all continents. In validation analyses, both parJADAS and patJADAS demonstrated good construct validity, satisfactory internal consistency and structure, strong discriminative validity, and fair responsiveness to clinically important change over time. Furthermore, they proved able to predict relevant disease outcomes and to potentially serve as surrogate for physicians’ evaluations [55]. The demonstration of these key measurement properties indicates that the two tools are valid for the assessment of the level of disease activity in JIA.

Conclusions and future directions

The introduction of the JADAS has provided pediatric rheumatologists with a simple and powerful tool that enables the measurement of the level of disease activity in children with JIA in a standardized and reliable manner. Validation analyses have shown that the JADAS is a valid instrument and is, therefore, suited for use in standard clinical care, observational studies, and clinical trials.

Over the years, the JADAS has gained increasing popularity within the international pediatric rheumatology community. Among the different versions, the one that includes the 10-joint reduced count (i.e. JADAS10) is preferred by most investigators because it is simpler and equally effective as the other versions. The 10-joint count requires the assessment of all active joints, but the count is cut to a maximum of 10.

By enhancing the accuracy of quantitative clinical assessments, the JADAS allows careful documentation of advances in therapeutic effectiveness and may contribute to the implementation of precision medicine and personalization of treatment. The tool also offers a well-established reference measure against which to confirm the role of proposed biomarkers and imaging modalities in estimating the level of disease activity [56, 57].

Application of the JADAS in each patient at every visit may assist the treating physician in making immediate therapeutic decisions based on the current score and on its comparison with scores obtained at previous visits. Because the JADAS offers a simple and intuitive appraisal of the level of disease activity in individual patients, it serves well for the application of a T2T strategy aimed to achieve and maintain tight disease control, with treatment escalation if a target JADAS is not reached [35]. Recently, the JADAS has been validated for use in adults with JIA [58], thereby opening the way for its use in the transition process.

Despite the important objectives achieved thus far, several open issues with the use of the JADAS remain. Although the validity of all versions has been scrutinized in multinational patient samples, additional studies involving parents and patients of different ethnicity and cultural environments are needed to define optimal JADAS criteria for disease activity states that could be uniformly applied in JIA patient populations seen worldwide. Furthermore, future analyses should address the impact in JADAS scoring of the variable perception of disease activity across physicians practicing in different regions or with diverse expertise and treatment availability. The capacity of the JADAS cutoffs to predict key disease outcomes, such as continued activity, cumulative damage, or functional disability, or the occurrence of major complications of sJIA, such as macrophage activation syndrome or inflammatory lung disease, is still uncertain. Although samples used in validation analyses have comprised children with all phenotypes of JIA, the results might not be extrapolated to the categories of enthesitis-related arthritis or psoriatic arthritis, which are characterized by peculiar extraarticular features that are not assessed specifically by the JADAS. Finally, the performance of the JADAS and its cutoffs as endpoints should be examined in the context of randomized clinical trials.

Author contributions

A.R. and A.C. wrote the manuscript text, R.N. and S.M.O. collected the relevant data from the literature discussed in the review, M.B. prepared the reference list, and S.R. prepared the tables. All authors reviewed and approved the manuscript.

Funding

No funding was available for the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors provide their consent for publication of the manuscript.

Competing interests

A.C. in an Editorial Board Member of Pediatric Rheumatology; A.R. is Guest Editor of the Topical Collection on Clinimetrics in Pediatric Rheumatology and Editor-in-Chief of Pediatric Rheumatology. None of the other authors declare competing interests.