Clinical Outcome Measures in Pediatric Rheumatic Diseases

American College of Rheumatology Pediatric Response Criteria

Until the mid-1990s, the assessment of clinical response in juvenile idiopathic arthritis (JIA) clinical trials was not standardized. A fundamental advance in the evaluation of therapeutic effectiveness was provided by the development of the core set of outcome measures and definition of improvement in JIA, which were published in 1997. The core set includes the following six variables: (1) physician global assessment of overall disease activity; (2) parent/patient global assessment of overall well-being; (3) physical functional ability, measured with an instrument validated in the pediatric population; (4) count of joints with active arthritis; (5) count of joints with restricted motion; and (6) an acute-phase reactant. According to the definition of improvement, patients are classified as responders in a clinical trial if they demonstrate an improvement of at least 30% from baseline in at least three of any six core set variables, with no more than one of the remaining variables worsening by more than 30%. Soon after their publication, these criteria became the gold standard for the assessment of response to therapy in JIA. They were then adopted by the American College of Rheumatology (ACR) and are currently known as the ACR Pediatric 30. The ACR Pediatric 30 criteria are accepted by both the U.S. Food and Drug Administration and the European Medicines Agency for all phase III trials in JIA seeking drug registration.

Owing to the remarkable therapeutic progresses that took place after the year 2000, particularly the shift toward early aggressive interventions and the introduction of the biological disease-modifying antirheumatic drugs (DMARDs), a 30% improvement in outcome variables was no longer considered sufficient to establish the effectiveness of a therapeutic intervention. Indeed, in most clinical trials performed in the 2000s, patients were also evaluated for more stringent levels of improvement, that is, using the ACR Pediatric 50, 70, 90, and 100 response criteria (at least 50%, 70%, 90%, or 100% improvement, respectively, in at least 3 of any 6 JIA core set variables, with no more than one of the remaining variables worsening >30%). Recently, the ACR Pediatric 30 was adapted for use in clinical trials in systemic JIA, by adding, in addition to the six core set variables, the demonstration of the absence of spiking fever (≥38°C) during the week preceding the evaluation. ^,

Outcome Measures in Rheumatology (OMERACT) JIA Core Domain Set

A limitation of the JIA core set is the lack of input from patients or caregivers in its development. A working group was recently created within the Outcome Measures in Rheumatology (OMERACT), an independent initiative of international health professionals interested in outcome measures in rheumatology, to update the core set by obtaining stakeholder input from patients with JIA, caregivers, health care providers, and researchers. According to OMERACT methodology, domains are structured as a three-layered “onion”: (1) the inner layer is a core set of domains mandatory for all clinical trials and observational studies, (2) the middle layer is important domains with optional inclusion, and (3) the outer layer is domains for research purposes. Candidate domains were identified through literature review, qualitative surveys, and online discussion among JIA patients and parents. A Delphi process was conducted with parents, patients, health care providers, researchers, and regulators to define the domain list and prioritize candidate domains. After presentation of the results, OMERACT workshop participants voted, and domains achieving consensus of more than 70% were selected ( Fig. 7.1 ).

Criteria for Clinically Inactive JIA

Recent advances in the management of JIA have increased the possibility of achieving complete disease quiescence or, at least, minimal levels of disease activity, and have consequently moved the therapeutic aim toward the achievement of an inactive disease status. A reliable documentation of these therapeutic goals has created the need for criteria that describe precisely the clinical states of remission or near-remission. In 2003 preliminary criteria for inactive disease and clinical remission on and off medication for select categories of JIA were developed through an international collaborative effort. Recently, these criteria have been revised by incorporating a more accurate definition of uveitis activity and of abnormal erythrocyte sedimentation rate and by adding the duration of morning stiffness of less than or equal to 15 minutes as an indicator of inactive disease.

Criteria for Low (or Minimal) Disease Activity

Although the complete abrogation of any sign or symptom of active disease is the ideal objective of any therapeutic intervention in JIA, this goal may be difficult to achieve in some patients with polyarticular or systemic JIA, particularly those with severe or long-standing disease. This issue has led to the definition of a state of low (or minimal) disease activity. This state is differentiated from clinical remission by the existence of residual signs and symptoms. However, it is assumed that physical function and quality of life would not be substantially worse than in clinical remission and that progression of structural damage, while possibly not halted, would be minimal.

Juvenile Arthritis Disease Activity Score (JADAS)

An alternative, pragmatic approach to the measurement of the level of disease activity in JIA is based on the so-called composite disease activity scores. These tools are created by pooling individual measures of disease activity into composite scores and are aimed to quantify the absolute level of disease activity by providing one summary number on a continuous scale. They are intended to create better consistency in disease activity evaluation across physicians and to allow patients to better understand the meaning of disease activity by providing a single number. The composite disease activity score currently used in JIA was developed in 2009 and was named Juvenile Arthritis Disease Activity Score (JADAS) .

This instrument includes the following four measures: (1) the physician’s global assessment of disease activity, measured on a 10-cm visual analog scale (VAS), where 0 = no activity and 10 = maximum activity; (2) parent/patient global assessment of well-being, measured on a 10-cm VAS where 0 = very well and 10 = very poor; (3) count of joints with active disease, assessed in 71 (JADAS71), 27 (JADAS27), or 10 (JADAS10) joints; (4) erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), both normalized to a 0 to 10 scale. The JADAS is calculated as the simple arithmetic sum of the scores of its four components, which yields a global score of 0 to 40, 0 to 57, and 0 to 101 for the JADAS10, JADAS27, and JADAS71, respectively.

Because inflammatory markers are not always obtained or available at a visit, a three-variable version of the JADAS that does not include the acute-phase reactant, termed the clinical JADAS (cJADAS) has been proposed. This version correlates well with the original JADAS and with the other JIA activity parameters. The cJADAS may increase the feasibility of the JADAS for use in daily practice and would not hinder the potential to make immediate therapeutic decisions based on the JADAS.

Definition of Disease Activity States Based on the JADAS

The cutoff values in the JADAS that correspond to the states of inactive disease and low (or minimal), moderate, and high disease activity, as well as to the disease state deemed acceptable by the parent or the child, have been developed for the original JADAS ^, and for the cJADAS10. The cutoffs were developed separately for the oligoarticular and polyarticular JIA phenotypes ( Table 7.1 ). In validation analyses, the cutoffs proved to have good construct and discriminant validity and ability to predict disease outcome. ^{, ,}

The establishment of criteria for identifying high and low levels of JIA activity is fundamental for interpreting the JADAS scores. Furthermore, it provides simple and intuitive reference values that can be used to monitor the course of the disease in an individual patient or to compare disease status across individual patients or patient groups. Categorization is also helpful to support decisions about entry into clinical trials, as well as requirements for changes in therapies and to define therapeutic goals. Therefore JADAS and its cutoffs constitute an easy and flexible method to guide therapeutic interventions aimed at pursuing tight disease control.

The criteria used for the definition of clinical inactive disease and low (or minimal) disease activity in JIA are presented in Table 7.2 .

Systemic JADAS

The JADAS, cJADAS, and respective cutoffs were validated only in children with oligoarthritis and polyarthritis. A recent multinational collaborative study has led to the development of a new version of the JADAS specific to systemic JIA, named systemic JADAS (sJADAS). This tool is composed of the four items that are part of the original JADAS, plus a fifth item, the Systemic Manifestation Score, aimed to quantify the burden of systemic symptoms on a 0 to 10 scale ( Table 7.3 ).

Juvenile Arthritis Damage Index

Morbidity in JIA patients has been traditionally evaluated in terms of functional disability or by assessing structural joint damage through radiographs. However, these tools may not capture several forms of damage that children with JIA may develop over time, such as micrognathia, height retardation, localized growth disturbances, pubertal delay, or visceral organ failure. The Juvenile Arthritis Damage Index (JADI) was devised to enable a thorough detection of articular and extraarticular damage in children with JIA and is completed by the physician using information obtained by physical examination and a review of the patient’s clinical history. It is aimed to capture damage, defined as persistent changes in anatomy, physiology, pathology, or function, which may be the consequence of previous active disease, side effects of therapy, or comorbid conditions, that is not due to currently active arthritis and is present for at least 6 months. Damage is often irreversible and cumulative and, thus, damage scores are frequently expected to increase or remain stable over time. However, because some forms of damage may improve or even resolve in growing children, scores may decrease in some cases. The index is composed of two parts, one devoted to the assessment of articular damage (JADI-A) and one devoted to the assessment of extraarticular damage (JADI-E). In the JADI-A, 36 joints or joint groups are evaluated for the presence of damage. The damage observed in each joint is scored on a 2-point scale (0 = no damage; 1 = partial damage; 2 = severe damage, ankylosis, or prosthesis). The maximum total score is 72. The JADI-E includes 13 items in 5 organs/systems: ocular, musculoskeletal non-articular, cutaneous, endocrine, and secondary amiloidosis. Each item is scored as either 0 or 1 according to whether damage is absent or present, respectively. Due to the relevant impact of ocular damage on the child’s health, a score of 2 is given for each eye when the patient has had ocular surgery and a score of 3 when the patient has developed legal blindness. The maximum total score is 17.

Juvenile Spondyloarthritis Disease Activity Index

In 2014, Weiss et al. developed and validated the Juvenile Spondyloarthritis Disease Activity index (JSpADA), a composite disease activity index for children and adolescents with juvenile spondyloarthropathy ( Table 7.4 ). The index development was based on a modified Delphi consensus survey among a group of 106 international experts, who were asked to evaluate and rank a series of clinical and laboratory features as well as parent/patient-reported and physician-centered outcome measures. Items with a minimum 80% consensus among raters were retained in the score. The following items were finally selected: arthritis, enthesitis, patient pain rating, acute-phase reactants, morning stiffness, clinical sacroiliitis, uveitis, and back mobility. The final version of the JSpADA consists of eight items, each of which is given the same importance (value=1). The range of possible score is 0 to 8, with higher scores indicating greater disease activity.

British Isles Lupus Assessment Group

This instrument enables an accurate assessment of disease activity in individual organs/systems and the detection of new activity or flare in one or more systems, specifying also in which system(s) the flare up occurs. Furthermore, it helps determine when a change in therapy is needed. There are two versions of the British Isles Lupus Assessment Group (BILAG): the original BILAG and the BILAG 2004. ^, An advantage of the 2004 version is that its numerical scoring system may overcome the inability to give an overall score in the original BILAG. All studies performed in pediatric systemic lupus erythematosus (SLE) have used the original version of the index. The excellent responsiveness to change seen in pediatric studies using this tool supports its use as a response measure in clinical trials in children and adolescents with lupus, particularly when the efficacy of a medication on single-organ involvement (e.g., nephritis, skin disease) is under scrutiny.

Systemic Lupus Erythematosus Disease Activity Index

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is a 24-item score that is considered the preferable lupus activity tool for use in routine clinical setting because it is concise and easy to complete. There are three versions of the SLEDAI: the original SLEDAI, the SLEDAI-2K, and the MEX-SLEDAI. In the original version, the items rash, alopecia, mucous membrane lesions, and proteinuria are scored only if they represent their first occurrence or a recurrence (or a recent increase for proteinuria), whereas in the SLEDAI-2K version these items are simply scored when present. This change in the 2K version was made to reflect ongoing disease activity in the affected organ systems. The MEX-SLEDAI has the advantage of avoiding the cost of immunological laboratory tests because it does not include anti–double-stranded DNA antibodies and complement levels.

Systemic Lupus International Collaborating Clinics/ACR Damage Index

The Systemic Lupus International Collaborating Clinics/ACR (SLICC/ACR) Damage Index (SDI) ^, provides a detailed and comprehensive assessment of the cumulative organ/system damage occurring in patients with SLE. Damage is defined as any nonreversible change not related to active inflammation occurring since onset of SLE, ascertained by clinical assessment and present for at least 6 months. Damage may be a result of the disease itself, its treatment, or comorbid conditions. Although the SLICC/ACR SDI was found to be a valid and reliable instrument in the assessment of patients with juvenile-onset SLE, it has been argued that it does not cover all forms of damage that are seen in children or adolescents with SLE, especially growth failure and delayed puberty. Furthermore, it covers only irreversible damage and, therefore, does not take into account that children have the ability to recover and regenerate to a greater degree than do adults. Based on the analysis of all forms of damage in a multinational sample of 1015 patients with pediatric SLE and considering the distinctive aspects of SLE in children and adolescents, a pediatric version of the SLICC/ACR SDI was proposed ( Table 7.5 ). The Ped-SDI includes all 12 organ systems/domains included in the original SDI, with the addition of two items devoted to the assessment of growth failure and pubertal delay. The possibility that some forms of damage are potentially reversible in children is also incorporated.

The Pediatric Rheumatology International Trials Organization Preliminary Core Set of Outcome Variables and Definition of Improvement in Juvenile SLE

Through a combination of data collection and consensus procedures, the Pediatric Rheumatology International Trials Organization (PRINTO) network developed a disease activity core set for juvenile SLE, which included the following variables: (1) the physician global assessment of disease activity, (2) the European Consensus Lupus Activity Measurement (ECLAM), (3) 24-hour proteinuria, (4) the parent global assessment of patient overall well-being, and (5) a health-related quality of life assessment. The second step of the process led to a definition of improvement for use in therapeutic trials, which states that a patient can be considered as a responder at the end of a trial if he or she exhibits at least 50% improvement from baseline in any two of the five core set measures, with no more than one of the remaining worsening by more than 30%.