Stability of the patient acceptable symptomatic state over time in outcome criteria in ankylosing spondylitis
The Patient Acceptable Symptomatic State (PASS) is the highest level of symptoms beyond which patients consider themselves well. It provides clinically meaningful information to interpret results from scales or questionnaires. Our goal was to determine the PASS in main outcome criteria when assessing patients with ankylosing spondylitis (AS) and to evaluate whether the PASS is stable over time.
We used data from a randomized controlled trial of 330 patients with AS. The PASS was estimated at weeks 2, 6, and 12 for the following patient-reported outcomes: global pain (measured on a visual analog scale [VAS]), nocturnal pain (VAS), patient's global assessment of disease activity (VAS), disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), and functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]). We used an anchoring method based on patients answering yes or no to, “Is your current condition satisfactory, when you take your general functioning and your current pain into consideration?” The PASS was defined as the 75th percentile of the score for patients who considered their state satisfactory. All patients were considered together in the analysis.
The values (95% confidence interval) of PASS were 33.5 (29.2–38.6) for pain, 28.0 (23.1–34.1) for night pain, 35.7 (31.3–41.1) for patient's global disease assessment, 31.4 (26.9–37.0) for BASFI, and 34.5 (30.9–38.9) for BASDAI. The PASS estimates were stable over time for all criteria during followup.
This study provides cutoff values for the PASS for the main outcome measures in AS and shows that PASS values are stable over time.
With a goal of standardization, the Assessment in Ankylosing Spondylitis (ASAS) Working Group has established a core set of domains that are important in assessing disease activity in persons with ankylosing spondylitis (AS) (1). The clinical domains are function, pain, spinal mobility, patient global assessment, stiffness, peripheral joints, entheses, and fatigue. This international working group has also selected specific assessment instruments (pain or patient's global assessment as measured on a visual analog scale [VAS] or the Bath Ankylosing Spondylitis Functional Index [BASFI] ), according to their relevance and feasibility, to assess each domain (3). Combined indices, such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (4) and the Bath Ankylosing Spondylitis Patient Global Score (BAS-G) (5), are also widely used in clinical trials aimed at assessing the efficacy of treatments in persons with AS.
The BASDAI, BAS-G, and BASFI are indices that are essentially based on patient-reported outcomes, reflecting the lack of objective symptoms for evaluating disease activity and patient disability. These indices are expressed as scores ranging from 0 to 100 that allow the level of symptoms in all domains addressed by the index (e.g., fatigue, spinal pain, joint pain/swelling, areas of localized tenderness, and morning stiffness for the BASDAI index) to be expressed in a single value. The clinical meaning of the results of trials involving such criteria, expressed as continuous variables, is difficult to address. Translating these continuous criteria (e.g., BASDAI score) to more clinically meaningful information such as therapeutic success (yes/no) would be helpful in better understanding the results of trials. The cutoff used for the dichotomization must be clinically relevant.
Based on the patient's perspective, the Patient Acceptable Symptomatic State (PASS) has recently been described for use in hip and knee osteoarthritis (6). The PASS is defined as the highest level of symptoms beyond which patients consider themselves well. The PASS addresses the concepts of low disease activity, partial remission in symptoms, and well-being (feeling good). Moreover, at the end of the trial, each patient is classified as either having therapeutic success or not based on whether or not the patient achieved the PASS (whether or not the level of symptoms is below the PASS cutoff). The results of the trial can be expressed as the proportion of therapeutic success (i.e., the proportion of patients in an acceptable symptomatic state at the end of the trial). The purpose of the present study was to determine the PASS in the main outcome criteria used to assess patients with AS and to evaluate whether the PASS is stable over time.
PATIENTS AND METHODS
Role of the study sponsor.
This study was performed within the context of a Norwegian double-blind, randomized, controlled clinical trial with Pfizer as the sponsoring company. The data for the current analyses were retrieved from a database that was established by Pfizer, Norway, and were analyzed before the randomization code was opened. The sponsor of the study was not involved in any part of the analyses and publication of the manuscript.
We used data from a multicenter, randomized, controlled trial designed to assess the symptomatic effects of 2 doses of celecoxib versus diclofenac in patients with AS. The study had a flare design and a 12-week treatment phase. In the present study, all patients were considered together in the analysis (whatever the treatment received).
This study involved 330 outpatients in Norway who had a clinical diagnosis of AS according to the modified New York criteria (7), with axial involvement (inflammatory back pain, buttock pain). To be included in the study, patients had to be 18–75 years of age and had to have received daily treatment with a nonsteroidal antiinflammatory drug (NSAID) during the previous 30 days. At the end of the washout period, patients with pain intensity ≥40 mm on a VAS that was at least 30% greater than that recorded at the screening visit were eligible to be randomized.
As previously described (6), we used an anchoring method based on patients' satisfaction with their current state to determine the PASS. The external anchor was patients' answer (yes or no) to the question, “Is your current condition satisfactory, when you take your general functioning and your current pain into consideration?” The PASS was estimated at each of the 3 followup visits (after 2, 6, and 12 weeks of treatment) for the following patient-reported outcomes: global pain intensity as measured on a 0–100-mm VAS, nocturnal pain as measured on a VAS, global assessment of disease activity as measured on a VAS, disease activity as measured on the BASDAI (high scores indicate high disease activity), and functional impairment as measured on the BASFI (high scores indicate high degree of functional impairment). All scores were normalized to 0–100 scores.
At each visit, the PASS was defined as the 75th percentile of the score for patients who considered their state to be satisfactory (6) (i.e., this level of symptoms [the PASS] or a lower level was achieved by 75% of patients with a satisfactory state). Logistic regression was used to model the observations and compute the 95% confidence intervals. Statistical analysis was performed with SAS, release 9.1 (SAS Institute, Cary, NC) and S-Plus 6.2 (Insightful, Seattle, WA).
The protocol was approved by the ethics committee. The trial was performed in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and applicable regulatory requirements. All patients gave written informed consent.
Among the 330 randomized patients, 304 (92.1%), 272 (82.4%), and 317 (96.1%) completed the followup visits after 2, 6, and 12 weeks of treatment, respectively. At the final visit (week 12), 161 (52%) patients considered their state to be satisfactory. Baseline characteristics of the patients are shown in Table 1.
Table 1. Baseline characteristics of patients with AS included in the analysis*
|Male sex, no. (%)||240 (72.7)|
|Age, years||43.8 ± 10.3|
|Global pain (0–100-mm VAS)||65.5 ± 15.5|
|Nocturnal pain (0–100-mm VAS)||60.4 ± 23.2|
|Patient's global assessment of disease activity (0–100-mm VAS)||65.3 ± 19.8|
|BASDAI (0–100)||55.7 ± 19.7|
|BASFI (0–100)||47.2 ± 21.3|
The PASS estimates for the 5 outcome criteria and their 95% confidence intervals are listed in Table 2. For instance, patients with AS considered their state to be satisfactory if their global pain score was <33.5 mm on the 0–100-mm VAS. At week 12, the estimates of PASS were 33.5 mm for global pain, 28.0 mm for nocturnal pain, 35.7 mm for global disease assessment, 34.5 for the BASDAI, and 31.4 for the BASFI. The PASS estimates were similar over time (i.e., at the 3 followup visits) for all criteria.
Table 2. Patient Acceptable Symptom State (PASS) estimates over time (by treatment duration) for clinical domains of ankylosing spondylitis*
|Global pain||33.2 (29.7–37.5)||33.1 (28.6–38.7)||33.5 (29.2–38.6)|
|Nocturnal pain||25.9 (22.2–30.6)||27.2 (21.8–34.4)||28.0 (23.1–34.1)|
|Patient's global assessment of disease activity||35.2 (32.2–40.4)||33.7 (29.2–39.5)||35.7 (31.3–41.1)|
|BASDAI||35.8 (33.1–39.0)||35.5 (32.2–39.6)||34.5 (30.9–38.9)|
|BASFI||32.3 (29.8–35.3)||29.4 (26.6–32.8)||31.4 (26.9–37.0)|
This prospective study is the first to determine the PASS for the main outcome criteria in a clinical trial of AS. Addressing the individual level by describing the proportion of patients achieving the PASS provides additional meaningful information from clinical trials and longitudinal observation studies. This approach will aid in the interpretation of results, add useful information for daily practice (8), and provide information that is complementary to the conventional presentation of results on a group level (mean changes in scores). The ASAS20, ASAS40, and BASDAI50 criteria also address the individual level in terms of improvement (9–11). The PASS addresses the concept of well-being, which is complementary and has been shown to be very important to patients (12).
The PASS estimates in this study were very similar (ranging from 27 to 35 on a 0–100-point scale) whatever the outcome criterion. Furthermore, for non–disease-specific outcome criteria such as global pain or patient global assessment, the PASS estimates were similar for AS and hip or knee osteoarthritis (6), which reinforces the relevance of the PASS estimates in AS and the robustness of this concept.
Using an anchoring method based on the patient's perspective is particularly relevant in symptomatic disease in which only the patient can perceive the symptom and thus assess the criterion. The PASS is a state satisfactory to patients, a state in which the patients would accept staying for quite a long time. It is a state that is acceptable but not necessarily good. However, the time component is key to define a state in which patients would accept staying. This should be more clearly addressed in the external anchor in future studies.
In this prospective study, we demonstrated that PASS values are remarkably stable over time, at least in a 10-week period. This is a major finding that allows for promoting the use of PASS in reporting the results of trials (proportion of patients in a satisfactory state) and in daily practice (to monitor a treatment or as a key point in goal-directed therapy: intensifying the treatment until the patient achieves the PASS). Furthermore, an important aspect of any desirable state is the time spent in that state (13). The stability of the PASS estimates over time is therefore a key finding that supports the use of the PASS to describe the number of patients achieving and maintaining such a state for a specified period. However, this consistency over time of the PASS estimates must be validated in studies with a longer followup period.
The PASS characterizes a state of partial remission and well-being (13, 14) and can undoubtedly be considered a treatment target in the patient's perspective. In this study and in the hip or knee osteoarthritis study (6), PASS estimates were determined in patients receiving NSAID therapy. However, it is not known whether patients consider a state to be satisfactory independent of the treatment they receive (i.e., whether the PASS values are related to the patients' expectations of the treatment). One may hypothesize, for instance, that patients expect stronger effects from tumor necrosis factor α (TNFα) antagonists than from NSAID therapy and therefore would consider a lower level of symptoms to be satisfactory with TNFα antagonist therapy. This point should be investigated in a future study.
In conclusion, this study, dealing with a concept of emerging use (the PASS), provides preliminary information facilitating the presentation and interpretation of results obtained in clinical trials of patients with AS. We demonstrated that PASS values are very consistent over a 10-week period in patients with AS. These values must be confirmed in further studies involving different treatments, clinical environments, and languages, and the PASS values need to be endorsed by international scientific societies.