It Is Worth Including Assessment of Disease Activity State in Juvenile Arthritis Clinical Trials

Authors


Until the mid-1990s, the assessment of clinical response in juvenile idiopathic arthritis (JIA) clinical trials was not standardized. Pediatric rheumatologists used multiple outcome measures, and the criteria adopted to assess the effects of antirheumatic drugs were often different. In addition, the amount of change that denoted clinically important improvement or worsening was not established. This lack of standardization hindered the efficiency of trials and made it impossible to compare different therapies using meta-analysis procedures.

The American College of Rheumatology (ACR) pediatric response criteria

The evaluation and comparison of treatment response became much easier with the development of the core set of outcome measures and definition of improvement in JIA, which were published in 1997 ([1]). The core set includes the following 6 variables: 1) physician global assessment of overall disease activity, 2) parent/patient global assessment of overall well being, 3) physical functional ability, 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 3 of any 6 core set variables, with no more than 1 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 ACR and are currently known as the ACR Pediatric 30. The ACR Pediatric 30 criteria are accepted by both the US Food and Drug Administration and the European Medicines Agency for all phase III trials in JIA seeking drug registration ([2]).

At the time when the ACR Pediatric 30 criteria were developed, the most effective antirheumatic medication for the treatment of JIA was low-dose methotrexate ([3]). With the shift toward the use of higher doses of methotrexate ([4]) and, later on, the introduction of biologic agents, 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 1 of the remaining variables worsening >30%) ([5-11]) (Table 1). Recently, the ACR Pediatric 30 was adapted for use in clinical trials in systemic JIA, by adding, besides the 6 core set variables, the demonstration of the absence of spiking fever (≤38°C) during the week preceding the evaluation ([10, 11]).

Table 1. Outcome end points included in registrative clinical trials in JIA*
Authors (reference)MedicationACR Pedi 30ACR Pedi 50ACR Pedi 70ACR Pedi 90ACR Pedi 100Inactive disease
  1. JIA = juvenile idiopathic arthritis; ACR Pedi 30 = American College of Rheumatology Pediatric 30 response criteria.
Lovell et al ([5])Etanercept+++
Ruperto et al ([6])Infliximab+++
Lovell et al ([7])Adalimumab++++
Ruperto et al ([8])Abatacept+++++
Yokota et al ([9])Tocilizumab+++
De Benedetti et al ([10])Tocilizumab+++++
Ruperto et al ([11])Canakinumab+++++

Percentage change versus disease activity state

The ACR Pediatric response criteria emphasize a change in disease state and are, therefore, a tool for assessment of clinically relevant improvement in disease activity. As such, they are well suited for use in studies that evaluate the efficacy of a new therapy in comparison to another therapy or a placebo. However, the nature of their calculation does not enable the measurement of patients' actual disease activity at the beginning or end of a clinical trial or the comparison of one patient's absolute response with that of another patient. Furthermore, they do not allow discernment of whether one group of patients has more active disease than another group. Thus, the evaluation of the sole percentage improvement in a clinical trial may lead to missing some important information about the effectiveness of the medications under scrutiny.

Another problem with assessment of percentage change is that the documentation of a statistically significant difference between active versus placebo treatment may not necessary reflect the achievement of an optimal disease status for an individual patient. It has been argued that the status of many patients at the conclusion of a clinical trial, in which the therapeutic response has been evaluated in terms of percentage change, may reflect significant residual disease activity ([12]). To give an example, let's assume a hypothetical patient who has 50 active joints at the beginning of a trial. In the case of improvement of 30% in the active joint count, the patient would have 35 active joints at the end of the trial. In case of an improvement of 50% or 70%, the number of active joints would be 25 or 15, respectively. Even with a 90% improvement, the patient would still have 5 active joints. If these joints were 1 hip, 1 knee, 1 ankle, 1 elbow, and 1 wrist, the patient's status would be hardly classifiable as “optimal.” These issues have led to arguments that achieving (and maintaining) a “satisfactory” state of disease activity in a clinical trial is probably more important, particularly in the long term, than the simple percentage improvement from a high level of disease activity ([13]).

Notably, the 2008 ACR/European League Against Rheumatism (EULAR) guidelines for the reporting of clinical trial outcomes in rheumatoid arthritis (RA) recommended that both response and disease state be reported in all interventional trials ([14]).

Toward a goal-directed treatment

The recent advances in the management of JIA have increased considerably the potential to achieve disease remission or, at least, minimal levels of disease activity, and have consequently moved the therapeutic aims increasingly toward the attainment of an inactive disease status ([15-18]). Complete disease quiescence is regarded as the ideal therapeutic target because its achievement helps prevent further joint damage and disability and may enhance physical function and quality of life ([19]).

Studies in adults with RA have shown that patient outcomes are improved if low levels of disease activity are aimed for by frequent adjustments of therapy according to quantitative indices ([20-22]). These observations have led to suggest that the strategy of tight control, aiming for remission, is more important than the medication ([23]). The recent EULAR recommendations for the management of RA have set remission as the primary treatment goal in everyday clinical practice ([24]), and have been strengthened by the treat-to-target approach ([25]). Nowadays, it is widely agreed that disease remission should be an overriding goal in the management of all children with JIA ([26-28]). However, the concept of targeted therapy has not yet been routinely implemented in pediatric rheumatology settings.

Remission as end point in JIA clinical trials

Until recently, reports concerning achieving disease remission with present treatment of JIA were scarce. Clinical remission has never been included as a primary end point in randomized controlled trials of traditional disease-modifying antirheumatic drugs. Recently, the preliminary definition of inactive disease in JIA ([15, 29]) has been used as a primary outcome measure in a randomized, double-blind, placebo-controlled trial of 2 aggressive treatment strategies in children with early JIA ([30]). Of the registrative trials of biologic medications in JIA published so far, only 3 have assessed, among secondary end points, the attainment of inactive disease ([8, 10, 11]) (Table 1).

Measures of disease activity state in JIA

In the past decade, there has been a great deal of effort to develop and validate measures of disease activity state in JIA. The first of such measures was the preliminary criteria for inactive disease and clinical remission for JIA, which were created in the early 2000s through an international collaborative effort ([15]). Based on these criteria, a patient is classified as having inactive disease at a specific point in time when he or she has no joints with active disease, no systemic manifestations attributable to JIA, no active uveitis, normal values of acute-phase reactants, and a physician global assessment of disease activity indicating no disease activity. When the criteria for inactive disease are met for a minimum of 6 consecutive months while the patient is receiving antirheumatic medications, the patient is classified as being in the state of clinical remission with medication. When the criteria for inactive disease are met for a minimum of 12 consecutive months after the patient has discontinued all antirheumatic medications, the patient is classified as being in the state of clinical remission without medication. Recently, the criteria have been refined by providing a specific definition for uveitis and abnormal erythrocyte sedimentation rate (ESR) and by adding the duration of morning stiffness of ≤15 minutes ([29]).

The definition of inactive disease requires the total absence of signs and symptoms of disease activity and is, therefore, very strict. However, achievement of true inactive disease either in routine practice or in clinical trials remains problematic in many patients, particularly those with polyarticular or systemic JIA. Some recent therapeutic studies have modified the inactive disease criteria to set the minimum score of the physician global rating at 1 ([10]) or even 2 ([8]), which is indirect evidence that the original definition is infrequently met in the short timeframe of a clinical trial. It has been proposed that a more attainable goal could be to induce and maintain at least a state of minimal disease activity, which is an intermediate state between high disease activity and remission, though very close to remission ([31]). This state is deemed to be a useful target of treatment by both the physician and the patient, given current treatment possibilities and limitations ([32]). The state of minimal disease activity in JIA has been defined as the presence of a physician's global disease activity rating of ≤3.4, a parent's global well-being rating of ≤2.5, and a swollen joint count of ≤1 in polyarthritis, and as the presence of a physician's global disease activity assessment of ≤2.5 and a swollen joint count of 0 in oligoarthritis ([31]). However, although a minimal disease activity state might be a suitable outcome measure for an efficacy trial, the achievement and maintenance of true inactive disease should be the ultimate goal for every child with JIA. Importantly, because magnetic resonance imaging and ultrasound data reveal that there can be subclinical disease in many patients in clinical remission ([33]), to classify a patient in the state of inactive disease the physician global rating must be zero.

A further approach to the measurement of disease activity is based on composite disease activity scores. These tools are aimed to quantify the absolute level of disease activity by providing one summary number on a continuous scale. Recently, the first composite disease activity score for JIA, named Juvenile Arthritis Disease Activity Score (JADAS), has been devised ([34]). The JADAS includes the following 4 variables: 1) physician global assessment of overall disease activity, measured on a 0–10-cm visual analog scale (VAS); 2) parent global assessment of overall well-being, measured on a 0–10-cm VAS; 3) count of joints with active arthritis, assessed in 71 (JADAS71), 27 (JADAS27), or 10 (JADAS10) joints; and 4) 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. A JADAS version including the C-reactive protein level instead of the ESR was found to perform similarly to the original format ([35]). The cutoff values of the JADAS that corresponded with inactive disease and minimal disease activity reflected the physician, parent, or child subjective rating of remission, or the parent or child satisfaction with the outcome of the illness were recently established ([36]). These cutoff values represent both qualified targets for clinical trials and a useful guide to pursuing tight disease control in routine care.

In summary, the ACR Pediatric 30 remains the preferred primary outcome measure for registrative trials in JIA, as it is best suited for sample size calculations and for the statistical comparison of the efficacy of an experimental agent versus that of an active comparator or a placebo ([37]). Because pediatric rheumatologists are no longer satisfied with merely assessing a 30% improvement, secondary outcomes should always include more stringent levels of response, such as the ACR Pediatric 50 or 70. However, considering that current clinical practice not only mandates higher levels of response, but also good overall disease control ([18, 28]), it would be desirable that future clinical trials incorporate, among secondary end points, the evaluation of disease activity state (e.g., the assessment of inactive disease and minimal disease activity, and JADAS cutoff values). Because the limited duration of most clinical trials may make it difficult to achieve such demanding levels of disease control in sizeable proportions of patients, reporting figures about these outcomes would be most important for long-term extension analyses. This information would help practitioners gain a more thorough knowledge of the effectiveness of the medication under study and may increase the relevance of trial results for day-to-day clinical practice.

AUTHOR CONTRIBUTIONS

Both authors were involved in drafting the article or revising it critically for important intellectual content, and both authors approved the final version to be published.

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