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Measuring function in rheumatoid arthritisIdentifying reversible and irreversible components.

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ARTHRITIS & RHEUMATISM
Vol. 54, No. 9, September 2006, pp 2784–2792
DOI 10.1002/art.22052
© 2006, American College of Rheumatology
Measuring Function in Rheumatoid Arthritis
Identifying Reversible and Irreversible Components
Daniel Aletaha,1 Josef Smolen,2 and Michael M. Ward3
(2–<5 years) to 0.38 (5–<10 years) to 0.55 (>10 years)
(P < 0.001). The reversibility of HAQ scores decreased
with the duration of RA (median 100%, 83.3%, 81.9%,
and 66.7%, respectively; P < 0.001). Findings were
similar in patients subgrouped by quartile of radiographic scores.
Conclusion. Differences in the sources of functional limitations should be considered in the interpretation of functional measures, and in their use for
prediction and in cost analyses.
Objective. Measurement of physical function at
one point in time cannot distinguish impairment caused
by the active disease process from chronic irreversible
impairment. We aimed to dissect these two components
of functional limitation in rheumatoid arthritis (RA) by
using the disability index of the Health Assessment
Questionnaire (HAQ) as the measure of function.
Methods. We performed a secondary analysis of
data from 6 contemporary clinical trials of RA (2,763
patients). Patients in whom remission was achieved in
the trials, based on a simplified disease activity index,
were identified. In an individual patient, HAQ scores at
trial entry represented both reversible and irreversible
impairments, while HAQ scores at the time of RA
remission represented the mostly irreversible component, and the difference between these corresponded to
the component related to disease activity. We tested the
concept that the HAQ has a reversible and an irreversible component by associating the HAQ score during
remission with 2 measures associated with the degree of
accrued damage: duration of RA and radiographic
severity.
Results. Among patients in whom clinical remission was achieved (n ⴝ 295), average HAQ scores
despite clinical remission increased progressively with
the duration of RA, from 0.19 (<2 years of RA) to 0.36
Many chronic diseases cause impairment of normal function, overall or in an individual organ. Restoring
normal functioning is a major therapeutic aim. However,
measures of function only describe the state of the organ
or the individual at the time of assessment and give no
indication of the cause or duration of the dysfunction.
Functional limitations may be due to acute reversible
problems or chronic irreversible factors. Single measurements of function do not permit isolation of the reversible component from the irreversible component; these
can only be identified by examining changes in measures
of function over time or in response to treatment.
This concept is commonly appreciated in clinical
medicine with respect to measures of organ function.
For example, a single elevated measurement of serum
creatinine concentration does not allow one to know if
renal dysfunction is temporary and completely reversible, if it is reflective of chronic renal damage that is
irreversible, or some combination of the two. Only
observations of the response to treatment and time can
distinguish these possibilities. Similar concepts likely
apply to the measurement of health status: functional
limitations may be due to acute reversible problems or
chronic irreversible ones. In contrast to organ function,
physical functioning is usually not interpreted in the
context of reversibility and irreversibility. When used to
assess treatment responses, the irreversible component
Supported in part by the Intramural Research Program of the
National Institute of Arthritis and Musculoskeletal and Skin Diseases,
NIH, and the Austrian Science Fund (FWF).
1
Daniel Aletaha, MD, MHS: National Institute of Arthritis
and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland,
and Medical University of Vienna, Vienna, Austria; 2Josef Smolen,
MD: Medical University of Vienna, and Hietzing Hospital, Vienna,
Austria; 3Michael M. Ward, MD, MPH: National Institute of Arthritis
and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
Address correspondence and reprint requests to Daniel Aletaha, MD, Department of Rheumatology, Internal Medicine III,
Medical University of Vienna, Waehringer Guertel 18-20, A-1090
Vienna, Austria. E-mail: daniel.aletaha@meduniwien.ac.at.
Submitted for publication January 19, 2006; accepted in
revised form May 24, 2006.
2784
MEASURES OF FUNCTIONING IN RA
of functional impairment decreases overall responsiveness of functional measures; when used to predict longterm consequences, the reversible component introduces measurement error. In this study, we attempted to
provide evidence of this concept of duality in functional
measures by estimating the reversible and irreversible
components of limitations in physical functioning in
rheumatoid arthritis (RA) (1–4).
In RA, reversible components of functional impairment comprise joint pain and swelling due to inflammation, or associated symptoms such as depression.
Potentially irreversible components may include joint
destruction, deformity, or muscle weakness, or may be
related to comorbid conditions. One advantage in RA is
that the active disease process can be readily characterized by joint counts, measurement of acute-phase reactants, and other measures, and that the disease-related
damage can be related to the duration of RA, since it
increases consistently over time (5), or assessed by joint
radiography (4,6,7).
We performed an analysis of individual patient
data from several large RA clinical trials. Patients had to
have active RA as a requirement for trial entry. Therefore, their functional limitation at entry was influenced
by acute reversible inflammation, as well as any irreversible processes, such as joint damage, that might have
been present. Among these patients, we examined the
subset of individuals in whom clinical remission was
achieved during the trials. In this subset, any change in
functional limitations could be attributed to reversible
RA activity or its correlates, such as depression. Any
residual functional limitations could be regarded as
irreversible, reflecting RA-related damage or other irreversible components, such as comorbidities. To support
the concept of an irreversible Health Assessment Questionnaire (HAQ) component that is associated with
RA-related damage, we compared functional limitations
that remained despite clinical remission and the reversibility of functional limitations among subgroups of
patients with different degrees of underlying damage, as
represented by the duration of RA or by the severity of
abnormalities seen on joint radiographs.
PATIENTS AND METHODS
Data sources. We contacted sponsors of recent clinical
trials in RA and asked for their permission to obtain patientlevel data for our study. We obtained and pooled individual
patient data from 6 trials: the Anti–Tumor Necrosis Factor
Trial in Rheumatoid Arthritis With Concomitant Therapy
(ATTRACT) (8) of infliximab and methotrexate (MTX) ver-
2785
sus placebo and MTX in patients with inadequate prior
response to MTX; the Active-Controlled Study of Patients
Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial (9) of infliximab plus MTX
versus MTX alone in MTX-naive patients with early RA of ⱕ3
years; the Anti–Tumor Necrosis Factor Research Study Program of the Monoclonal Antibody Adalimumab (D2E7) in
Rheumatoid Arthritis (ARMADA) (10) and the DE019 (11)
trials in patients with active RA despite prior MTX therapy,
who received additional adalimumab versus placebo; and the
European leflunomide trials, which compared leflunomide
with sulfasalazine and with placebo in patients with early and
established RA (12,13), or which compared leflunomide with
MTX in patients with RA of ⱕ10 years’ duration (14). We
were provided with data on an 80% random sample of subjects
from these trials. All patients had active RA at enrollment in
these studies, with requirements for ⬎6–10 swollen joints and
⬎6–12 tender joints (using a 68-joint count), or ⱖ6 swollen
and ⱖ6 tender joints (using a 28-joint count in the leflunomide
trials). With the exception of the ASPIRE trial, elevations in
acute-phase reactants were also required (C-reactive protein
[CRP] level ⱖ2.0 mg/dl and/or erythrocyte sedimentation rate
[ESR] ⱖ28 mm/hour). Data on scored radiographs were
available for all trials except the ARMADA trial.
Study variables. The disability index of the HAQ (15)
was used as the measure of functional limitations in each trial.
It includes 20 questions organized into 8 categories (dressing,
rising, eating, walking, hygiene, reach, grip, and errands or
chores). Each question was scored using a 4-level difficulty
scale ranging from 0 to 3, with 0 ⫽ no difficulty, 1 ⫽ some
difficulty, 2 ⫽ much difficulty, and 3 ⫽ unable to do. The HAQ
score is the mean of the highest score in each of the 8
categories, with a possible range of 0–3.
The duration of RA and radiographic severity were
used as 2 separate independent variables to measure chronicity
and damage. Duration of RA is useful for this purpose because
damage increases over time in patients with RA (4,5,16–18).
For analysis, we divided the patients into clinically meaningful
subgroups by RA duration: ⬍2 years, 2–⬍5 years, 5–⬍10 years,
and ⱖ10 years. Radiographic scores measure the extent and
severity of bone erosions and joint space narrowing in the
hands and feet, and are a direct measure of joint damage.
Radiographs had been graded using the original Sharp score
(19) (DE019 trial and leflunomide trials) or its modification by
van der Heijde et al (20) (ASPIRE and ATTRACT trials).
These scores generally produce very similar results, but can be
different in patients with extensive damage of joints in the feet.
To diminish these differences, we defined subgroups based on
quartiles of scores. Duration of RA and radiographic scores
were moderately highly correlated (r ⫽ 0.66, P ⬍ 0.001, by
Spearman’s rank correlation).
Definition of remission. We separated the reversible
RA activity–related component of the HAQ from the irreversible component by identifying patients in whom clinical remission was achieved during the trials (i.e., a state of absence of
RA activity). We defined remission as a state below a threshold value from a pooled index of RA activity, the simplified
disease activity index (SDAI) (21). The SDAI combines several measures of RA activity by calculating a linear sum of
tender and swollen joint counts (0–28 scale), patient and
evaluator global assessments of disease activity (each 0–10 cm
2786
ALETAHA ET AL
Table 1. Characteristics at baseline of RA patients in whom remission was achieved during the trials*
Patients grouped by duration of RA
(years) (n ⫽ 295)
No. of patients
Female, %
Age, mean ⫾ SD years
Race, %
Caucasian
African American
Other
Rheumatoid factor, % positive
Duration of RA, mean ⫾ SD years
Disease activity
Mean ⫾ SD swollen joint
count, 0–28 scale
Mean ⫾ SD tender joint count,
0–28 scale
Mean ⫾ SD CRP level, mg/dl
Mean ⫾ SD patient-reported
pain, 10-cm VAS
Mean ⫾ SD patient global
assessment, 10-cm VAS
Mean ⫾ SD evaluator global
assessment, 10-cm VAS
Mean ⫾ SD SDAI
HAQ, 0–3 scale
Patients grouped by radiographic scores
(quartiles) (n ⫽ 270)
All patients
⬍2
2–⬍5
5–⬍10
ⱖ10
P†
⬍2.5
2.6–8.9
9.5–22.0
⬎22.9
P†
295
62.7
51.0 ⫾ 12.8
180
59.4
49.8
44
59.1
51.7
37
70.3
52.0
34
76.5
54.8
NA
0.19
0.18
69
62.3
44.9
66
59.1
51.9
68
63.2
52.8
67
68.7
54.4
NA
0.72
⬍0.01
90.2
3.7
6.1
72.7
4.1 ⫾ 7.1
91.1
2.8
6.1
70.5
0.7
86.4
9.1
4.5
79.1
3.0
91.9
2.7
5.4
62.9
7.2
88.2
2.9
8.8
84.9
20.5
0.58
89.4
1.5
9.1
74.2
2.2
91.2
5.9
2.9
61.2
2.9
91.0
3.0
6.0
89.6
8.5
0.65
0.14
NA
89.9
2.9
7.3
67.7
0.9
⬍0.01
NA
9.5 ⫾ 4.8
8.7
10.1
10.8
11.1
0.01
9.2
9.7
8.9
10.7
0.12
12.0 ⫾ 6.0
11.9
12.2
12.6
11.4
0.85
12.4
12.3
11.5
12.5
0.79
2.6 ⫾ 2.9
4.68 ⫾ 2.91
3.0
5.01
1.7
3.67
2.0
4.01
1.8
4.95
0.01
0.02
2.9
4.73
2.5
4.74
2.6
5.15
2.3
4.53
0.62
0.66
5.36 ⫾ 2.52
5.55
5.03
5.29
4.83
0.36
5.44
5.41
5.47
4.95
0.60
6.01 ⫾ 1.85
6.20
5.49
5.49
6.22
0.04
5.99
6.04
6.10
5.99
0.99
35 ⫾ 11.8
1.29 ⫾ 0.62
35.9
1.31
35.2
1.22
36.3
1.27
36.0
1.28
0.98
0.88
36.4
1.26
36.2
1.31
34.4
1.34
36.7
1.20
0.70
0.57
* Remission was defined as a simplified disease activity index (SDAI) of ⱕ3.3 for the swollen joint count, the tender joint count, C-reactive protein
(CRP) level, patient global assessment, and evaluator global assessment (see Patients and Methods for details). RA ⫽ rheumatoid arthritis; NA ⫽
not applicable; VAS ⫽ visual analog scale; HAQ ⫽ disability index of the Health Assessment Questionnaire.
† By analysis of variance for continuous variables, and chi-square test for categorical variables.
on visual analog scales), and CRP level (in mg/dl). For
remission, the sum of these measures had to be ⱕ3.3, based on
the results of a recent investigation (22). The majority of
patients with results below this cutoff point do not show
progressive radiographic damage over time (22). Also, this
definition of remission is very stringent, allowing less residual
disease activity in the various component measures of RA
activity than definitions based on other pooled indices (23). In
a sensitivity analysis, we varied the cutoff point for remission to
values of 3.0 and 3.6 to assess the effects of residual RA activity
on our results.
We also derived a qualitatively different definition of
remission. First, we developed criteria for each individual RA
activity measure and required that several of them be met
simultaneously. We derived these criteria from the data from a
large survey (22,24), one part of which had been used to
develop the criteria for the composite index described above
(22). The survey included 35 rheumatologists who were asked
to rate the RA activity of 32 patient profiles. The data in each
patient profile comprised swollen and tender joint counts,
ESR, CRP level, patient-reported pain, as well as patient and
evaluator global assessments of disease activity. The rheumatologists rated each profile as remission, low, moderate, or
high disease activity (22,24).
In a first step, we used classification trees to identify
the measures that were most useful to discriminate patients
with remission from those with more active RA, using the
survey responses as a reference standard (AnswerTree soft-
ware, version 3.1; SPSS, Chicago, IL). Four measures were
identified in this analysis (swollen joint count, tender joint
count, CRP level, and evaluator global assessment of disease
activity). We then tested cutoff points for these measures in all
possible combinations (n ⫽ 256): swollen joint count 0, 1, 2,
and 3; tender joint count 0, 1, 2, and 3; CRP level 0.8, 1.3, 1.8,
and 2.3 mg/dl; and evaluator global assessment of disease
activity 10, 15, 20, and 25 mm. The level of detection of CRP
was 0.8 mg/dl in all trials; therefore, this cutoff point was used
as the most stringent CRP criterion. We identified all sets of
criteria for which both the sensitivity and the specificity were
ⱖ0.80, and from these sets, selected the set with the highest
specificity for use. This set had a specificity of 0.86 and a
sensitivity of 0.80 and was composed of swollen joint count ⱕ1,
tender joint count ⱕ3, CRP level ⱕ0.8 mg/dl, and evaluator
global assessment of disease activity ⱕ15 mm.
Statistical analysis. We identified patients in whom
clinical remission was achieved at the 3-month, 6-month,
9-month, or 12-month followup visit in the trials. Each patient’s first visit with remission was used for analysis. The HAQ
scores at this visit were considered to reflect the irreversible
component of functional limitations, which remained after
effective treatment that had resulted in complete or nearcomplete resolution of active RA. We termed this quantity the
“residual HAQ score,” and tested to determine whether it
increased with duration of RA or quartile of radiographic
damage scores, using one-way analysis of variance (ANOVA).
We also tested differences in measures of RA activity across
MEASURES OF FUNCTIONING IN RA
these subgroups at baseline and at the time of remission as
potential confounders, and adjusted the association between
residual HAQ scores and duration of RA using these variables
as covariates in linear regression models. Dividing the residual
HAQ score by the maximum possible HAQ score of 3 provided
the fraction of HAQ irreversibility in these patient subgroups.
We then calculated changes in HAQ scores from trial
entry to time of remission among those in whom clinical
remission was achieved. For each patient, we calculated the
reversibility of HAQ scores as (change in HAQ/baseline
HAQ) multiplied by 100%. Since baseline HAQ scores of 0
cannot improve, we excluded these patients (n ⫽ 5) from this
analysis. To determine whether reversibility was associated
with the degree of expected chronic damage, we compared the
proportion of reversibility among the subgroups by duration of
RA and radiographic scores, using the Kruskal-Wallis nonparametric test.
Analyses were first performed using the subset of
patients in whom SDAI remission was achieved (including the
use of different cutoff points in the sensitivity analysis), and
then were repeated using the subset of patients in whom
remission was achieved based on the individual RA activity
measures criterion (qualitative sensitivity analysis). Analyses
were performed using SAS software, version 9.0 (SAS Institute, Cary, NC). P values less than 0.05 were considered
significant.
RESULTS
Patients. Of the 2,763 patients, 295 (10.7%) met
the remission criterion based on the pooled index during
the first year of the trial, 39.0% of whom were identified
at the 3-month visit, 26.8% at the 6-month visit, and
34.2% at the 9-month visit. No additional patients were
first identified with remission at the 12-month visit.
Table 1 shows the characteristics of these patients at trial
entry.
Patients in different subgroups of RA duration
were similar in many baseline characteristics (Table 1),
but patients with a longer disease duration tended to be
older (P ⫽ 0.18) and had more swollen joints (P ⫽ 0.01).
For several other activity markers, at least 1 subgroup
was significantly different from the others. In contrast to
findings at baseline, CRP scores and pain scores at the
time of remission were significantly higher in patients
with more longstanding RA (P ⫽ 0.024 and P ⫽ 0.004,
respectively, by ANOVA).
Associations with the duration of RA. Figure 1A
shows the mean residual HAQ scores at the time of
clinical remission. The residual HAQ was lowest in
patients with an RA duration of ⬍2 years, while it was
consistently higher in patients with more established RA
(2–⬍10 years), and highest in those with late RA (ⱖ10
years) (P ⬍ 0.001 by ANOVA testing for a linear trend
component). This indicates that the HAQ had an irre-
2787
Figure 1. Analysis of Health Assessment Questionnaire (HAQ)
scores by duration of rheumatoid arthritis (RA). A, Residual scores on
the disability index of the HAQ at the time of remission in patients
(n ⫽ 295) grouped by duration of RA. Residual HAQ scores increased
significantly across subgroups (P ⬍ 0.001 by analysis of variance testing
for a linear trend component). Use of residual HAQ scores allows for
estimation of the maximum hypothetical reversibility by relating their
values to the total HAQ scale of 3, e.g., a residual score of 0.5
represents one-sixth of the total scale and, conversely, the hypothetically reversible component can be estimated as five-sixths of the scale.
B, Reversibility of HAQ scores. Reversibility is calculated as the
relative improvement in baseline HAQ scores at the time of remission
(n ⫽ 290). Data are shown as box plots. Boxes span the interquartile
range. Lines inside the boxes represent the median. Whiskers indicate
observations that are 1.5 interquartile ranges beyond the lower quartile. Circles indicate outliers. Reversibility of HAQ scores decreased
significantly across the 4 subgroups by duration of RA (P ⬍ 0.001 by
Kruskal-Wallis nonparametric test).
versible component in these patients, which progressively increased with the chronicity of RA.
We adjusted these associations for age and for
the clinical measures that were found to be different
among the 4 subgroups at baseline and at the time of
remission (Table 2). The results of these adjusted models were very similar to the unadjusted results, indicating
that differences in covariates among the various subgroups had no important impact on the comparison of
HAQ scores among subgroups.
Reversibility of the HAQ was assessed as the
difference in scores from baseline to the time of clinical
remission (Figure 1B). Although patient subgroups had
similar average HAQ scores at baseline (Table 1), the
reversibility varied with the duration of RA. HAQ scores
were 100% reversible in the majority of patients with
early RA (duration ⬍2 years), while the median reversibility was ⬃80% in established RA (2–⬍5 years and
5–⬍10 years), and ⬃67% in late RA (P ⬍ 0.001 by
Kruskal-Wallis nonparametric test), although there was
2788
ALETAHA ET AL
Table 2. Mean (95% confidence interval) residual scores on the disability index of the Health
Assessment Questionnaire across subgroups, by unadjusted and adjusted generalized linear models
Subgroup by
RA duration
⬍2 years (n ⫽ 180)
2–⬍5 years (n ⫽ 44)
5–⬍10 years (n ⫽ 37)
ⱖ10 years (n ⫽ 34)
P across subgroups
Unadjusted
analysis
Analysis adjusted for
differences at
baseline*
Analysis adjusted for
differences at the
time of remission†
0.19 (0.13–0.25)
0.36 (0.24–0.48)
0.38 (0.24–0.51)
0.55 (0.41–0.68)
⬍0.001
0.18 (0.12–0.24)
0.36 (0.24–0.49)
0.41 (0.27–0.54)
0.54 (0.40–0.68)
⬍0.001
0.21 (0.15–0.27)
0.36 (0.24–0.48)
0.35 (0.22–0.48)
0.50 (0.36–0.63)
0.001
* Age and variables that were different at baseline were adjusted for by setting their levels to the cohort
means in each subgroup of rheumatoid arthritis (RA) duration (i.e., age 51.0 years, baseline swollen joint
count 9.5, baseline C-reactive protein [CRP] level 2.6 mg/dl, baseline pain score 4.68 cm, and baseline
evaluator global assessment 6.01 cm) (see Table 1).
† Age and variables that were different at the time of remission were adjusted for by setting their values
to the cohort means in each subgroup of RA duration (age 51.0 years, CRP level at time of remission 0.8
mg/dl, and pain score at time of remission 0.53 cm).
considerable variation among patients within each disease duration subgroup (Figure 1B). The proportion of
patients who achieved a HAQ score of 0 decreased from
56.3% to 17.6% across subgroups (P ⬍ 0.001 by chisquare test). These results indicate that, among patients
with the same degree of functional limitation at baseline,
the reversible component of functional limitation may
be very different, and decreases with the chronicity of
RA.
Associations with radiographic damage. Radiographic data were available on 270 patients who met the
SDAI criterion for remission (Table 1). Residual HAQ
scores increased across subgroups of patients with increasing radiographic damage scores (P ⫽ 0.002 by
ANOVA testing for linear trend) (Figure 2A). Adjustment for differences in RA activity at baseline and at the
time of remission did not alter the results of this analysis
(data not shown).
Reversibility of HAQ scores also decreased
across quartiles of radiographic scores (P ⫽ 0.002 by
Kruskal-Wallis nonparametric test) (Figure 2B). Reversibility of functional limitation was more common among
patients in the lowest quartile of radiographic scores
than in patients in all other quartiles. These findings
parallel those found for associations with the duration of
RA.
Sensitivity analysis. Results of the analysis of
subgroups by RA duration did not change when we used
a more stringent criterion (SDAI ⱕ3.0) or a less stringent criterion (SDAI ⱕ3.6) for remission.
Table 3 shows the results of the sensitivity analysis that used a definition of remission constructed from
a combined set of cutoff points for individual RA activity
measures. The subset of patients identified by this
criterion was larger than in the analysis using the SDAI
criterion for remission, and included patients with more
RA activity among those with remission. Therefore,
residual HAQ scores were higher and the degree of
HAQ reversibility was smaller in patients in whom
Figure 2. Analysis of Health Assessment Questionnaire (HAQ)
scores by radiographic scores. A, Residual scores on the disability
index of the HAQ at the time of remission in patients (n ⫽ 270)
grouped by quartile of radiographic scores. Residual HAQ scores
increased significantly across subgroups (P ⫽ 0.002 by analysis of
variance testing for a linear trend component). Use of residual HAQ
scores also allowed for estimation of the maximum reversible HAQ
component (see legend to Figure 1). B, Reversibility of HAQ scores.
Reversibility is calculated as the relative improvement in baseline
HAQ scores at the time of remission (n ⫽ 265). Data are shown as box
plots. Boxes span the interquartile range. Lines inside the boxes
represent the median. Whiskers indicate observations that are 1.5
interquartile ranges beyond the lower quartile. Circles indicate outliers. Reversibility of HAQ scores decreased significantly across the 4
subgroups by quartile of radiographic scores (P ⫽ 0.002 by KruskalWallis nonparametric test).
MEASURES OF FUNCTIONING IN RA
Table 3.
2789
Analysis using remission definition based on individual RA activity measures*
Subgroups by duration of RA
All subgroups
⬍2 years
2–⬍5 years
5–⬍10 years
ⱖ10 years
Significance (P) across groups‡
Subgroups by radiographic score
All subgroups
1st quartile (⬍2.5)
2nd quartile (2.6–8.9)
3rd quartile (9.5–22.0)
4th quartile (⬎22.9)
Significance (P) across groups‡
Residual HAQ score,
mean ⫾ SEM (n)
% reversibility, median
(interquartile range)
(n)†
0.44 ⫾ 0.03 (410)
0.36 ⫾ 0.03 (247)
0.44 ⫾ 0.06 (64)
0.51 ⫾ 0.09 (43)
0.73 ⫾ 0.09 (56)
⬍0.001 (F ⫽ 19.1)
80.0 (50.0–100) (405)
85.7 (58.8–100) (243)
72.7 (47.8–100) (63)
66.7 (43.7–100) (43)
50.0 (29.7–89.7) (56)
⬍0.001 (␹2 ⫽ 22.8)
0.43 ⫾ 0.03 (384)
0.29 ⫾ 0.05 (95)
0.34 ⫾ 0.04 (98)
0.42 ⫾ 0.05 (95)
0.66 ⫾ 0.06 (96)
⬍0.001 (F ⫽ 26.5)
80.0 (50.0–100) (379)
94.7 (69.1–100) (93)
85.7 (60.0–100) (96)
75.8 (49.2–100) (94)
60.2 (32.0–92.7) (96)
⬍0.001 (␹2 ⫽ 27.8)
* Swollen joint count ⱕ1, tender joint count ⱕ3, C-reactive protein level ⱕ0.8 mg/dl, and evaluator global
assessment of disease activity ⱕ15 mm.
† All patients with baseline scores of 0 on the disability index of the Health Assessment Questionnaire
(HAQ) were excluded from this analysis due to the lack of ability to show improvement (n ⫽ 5 in both
analyses).
‡ By analysis of variance (testing for a linear trend component) for residual HAQ scores, and
Kruskal-Wallis nonparametric test for reversibility.
remission was achieved by this criterion. However, using
this criterion did not change the strength of association
between residual HAQ score or the proportion of
reversibility and either RA duration or radiographic
score (Table 3).
DISCUSSION
In this study, we showed that physical function in
RA, as measured by the HAQ, is composed of reversible
and irreversible components. At any one time, HAQ
scores reflect both functional limitations due to current
RA activity and functional limitations due to processes
that do not respond to aggressive treatment with antirheumatic drugs. These processes could include irreversible joint damage or musculoskeletal consequences of
RA, or limitations due to coexisting conditions. Single
measurements reflect a combination of functional limitations from these 2 sources.
Although this duality has been recognized previously, these components have not been directly demonstrated (1,2,4,7,25,26). Many longitudinal studies have
indicated that both RA activity and damage influence
HAQ scores during the course of the disease (4,7,25). In
these studies, the correlation of radiographic changes
with HAQ scores increases over time (6), while RA
activity is the most significant determinant of HAQ
scores at all times (4,7). These studies predicted total
HAQ scores, and did not separately quantify these
components of the HAQ. Here, we were able to isolate
the RA activity–related component and the irreversible
component of functional limitations by devising a strategy to identify patients whose disease changed from
active to being in remission in a short period of time.
This allowed us to emphasize the ultimately quantitative
nature of this duality and to demonstrate that the
reversible component, at least in this patient sample, is
far larger than would have been expected. Using data
from clinical trials provided standardized accurate measurements of RA activity, and pooling data from several
large trials of highly efficacious medications allowed us
to identify sufficient numbers of patients who achieved
the relatively rare event of clinical remission for our
analysis. Examining patients with remission, still a rare
event in the context of current treatments, enabled us to
demonstrate the dual nature of the HAQ, regardless of
how remission was achieved (i.e., regardless of the
treatment regimen used).
RA served as a useful model to test the hypothesis that both functional states and functional response
are dependent on the amount of accrued damage. In
contrast to other chronic diseases, such as glomerulonephritis, heart failure, and multiple sclerosis, disease
activity (or, more generally, the readily reversible disease component) is easily definable in RA, and there-
2790
fore its absence can be defined. Damage caused by RA
can also be readily estimated. Radiographic scores serve
as simple and direct measures of joint damage, while
duration of RA is a surrogate measure that captures
structural changes (joint deformities, muscle weakness,
debility) that may increase over time (6,18).
The strengths of the study include the use of a
large sample from well-designed clinical trials, consistency of results obtained using 2 different measures of
chronic damage, and sensitivity analyses demonstrating
that the findings are robust with different remission
cutoff points, but also with a set of qualitatively different
criteria for remission. One limitation of this study was
the identification of remission at different time points
after enrollment in the trials, which was done for reasons
of sample size. However, different rates of change in the
HAQ among patients would not be expected to influence the results, but the different time points of remission could potentially decrease reversibility of HAQ
scores, because the underlying damage component increased from baseline until the time of the remission
visit. Also, although our definition of remission was
stringent, it might not represent the complete absence of
RA activity in all patients. Therefore, our analysis
estimated the upper limit of the latent trait “irreversible
disability.”
Varying amounts of residual disease activity add
measurement error in our analysis, but there is no
reason to believe that the degree of error would vary
among the subgroups of RA duration or radiographic
score. We examined only 1 measure of functional limitation (HAQ), but would expect similar findings with
other measures of functional limitation. Using radiographic data from different trials introduces systematic
error due to different readers and scoring methods. We
used quartiles of radiographic scores to diminish the
potential influence of these effects. Although neither
radiography nor RA duration is a gold standard for
irreversibility, associations with the latent damage trait
would be expected for both measures, therefore allowing
for a test of our hypothesis.
While the design of this study ensured that the
reversible component of the functional limitation was
related to RA activity, the irreversible functional limitations may include limitations due to comorbidities as
well as consequences of joint damage from RA. In our
analyses, we assumed that comorbidities were similar
across subgroups, for several reasons: first, comorbidity
is largely age related, and ages were similar across
subgroups of duration and radiographic score; second,
findings were similar in analyses that adjusted for age;
ALETAHA ET AL
and third, patients had been enrolled in clinical trials
that excluded patients with major comorbid conditions.
It is important not to generalize the proportion of
reversibility of the HAQ reported here to other settings,
or to consider these proportions as typical of the findings
expected in populations of patients with RA. These
proportions were based on findings in patients with
active RA enrolled in clinical trials, and will be different
in patients who attend a general clinic or are enrolled in
a community-based survey, because they depend in part
on the degree of RA activity. Also, even the subgroup of
patients with RA of the longest duration might be
considered to have early disease, and the irreversible
part of the HAQ might be higher in patients with more
longstanding RA. Nevertheless, the importance of our
findings relates to the associations of function and
functional response with damage, which are likely to be
similar in all RA populations.
Our results have several implications. First, the
dual nature of measures of functional limitations complicates attempts to identify risk factors. Risk factors for
functional limitations associated with RA activity are
likely to be different from risk factors for functional
limitations associated with irreversible damage. Risk
factors may be overlooked, or their associations inaccurately specified, if heterogeneous groups of patients are
examined. Our findings suggest that risk factor analyses
should be stratified to separate, as best as possible, those
with functional limitations due to chronic damage from
those with functional limitations due to active disease.
Similar problems may complicate the prediction of
future outcomes, such as work loss or mortality, using
the HAQ.
Second, our findings suggest that claims of improvement of disability based on improvements in functional measures in short-term clinical trials should not be
interpreted to indicate alteration of functional limitations due to joint damage or the potential for progression of joint damage over time. The improvements
demonstrated in trials rest on the functional consequences of active symptoms and synovitis, which are
distinct from functional consequences related to chronic
damage. Regulatory claims for improvement in disability in RA recognize this distinction by requiring trials of
at least 2 years (27). However, even these claims will be
confounded by RA activity–related improvements if the
change in functional limitation from trial entry is taken
as the supporting evidence, rather than maintenance of
low levels of functional limitations.
Third, differing sources of functional limitations
may confound comparisons of treatment responses
MEASURES OF FUNCTIONING IN RA
across studies. Studies with a large proportion of patients who have reversible functional limitations due to
active RA will have greater treatment responses than
studies with a large proportion of patients whose functional limitations are irreversible, even though both
cohorts may have similar mean HAQ scores at baseline.
Different degrees of chronic damage will have, a priori,
limited the potential reversibility of functional impairment in some patients.
Fourth, methodologic studies of measures of
functional impairment need to take into account the
consequences of floor effects. Our results indicate that
the “floor” of a measure will differ depending on the
degree of irreversible damage present. These differences
will affect estimates of the measure’s sensitivity to
change, and other metrics based on change, such as the
minimal clinically important difference (MCID). Our
findings indicate that there is not likely to be a single
estimate of sensitivity to change or MCID for measures
of function, but that these estimates will vary depending
on the degree of irreversible limitation present in the
groups that are tested. This likely reduces our ability to
discriminate treatment effects in patients with longstanding RA. Generally, the floor effect related to the
irreversible functional limitations may also explain why
the HAQ is among the measures that are least sensitive
to change in many clinical trials in RA (10,28,29).
Further research on the responsiveness of functional
measures in different subgroups of patients will be of
interest to support these conclusions.
In addition, cost-effectiveness analyses that use
changes in functional limitations based on short-term
clinical trials as estimates of effect, and that project
these estimates to model future long-term disability
outcomes, may be confounded by these different components of functional disability (30–33). Changes in
functional limitations observed in short-term clinical
trials likely do not directly translate into similar changes
in long-term disability. Therefore, modeling of longterm cost-effectiveness should ideally be based on the
component of disability that is irreversible.
Taken together, our findings suggest that the
interpretation of functional scores, and not only in RA,
should be viewed more adaptively, with the specific
purpose of measurement in mind. Is the purpose to
measure the total functional limitation at a specific point
in time, which reflects the impact of the current and past
disease process (i.e., reversible and irreversible components)? Or is the purpose to measure the activity-related
component of functional limitation, which is the target
of most therapeutic interventions and can be expected to
2791
be fully reversible with effective treatment? Or is the
purpose to measure the damage-related component,
which reflects cumulative long-term consequences of
disease, irrespective of the current state of activity? In
treatment decision-making, expectations of changes in
functioning should take into account the degree of
irreversible limitations present, to prevent overestimation or underestimation of the patient’s prognosis and
potential for response to therapy. Therefore, recognition
of a “damage-related” HAQ can be helpful to assess the
risk of future disability and, at the same time, can be
informative regarding strategies to improve current disability.
We have presented a method to distinguish the
contribution of reversible and irreversible components
to one particular functional measure in a particular
disease. Other functional measures, self-reported or not,
are likely affected by similar issues. Even more important, our findings likely apply to functional measures in
any chronic disease. Health status measures of functioning share with measures of organ function, such as serum
creatinine concentration, forced expiratory volume, or
cardiac ejection fraction, the problem that these are
measures of overall functioning, that abnormalities in
functioning have different causes, and that only time and
effective treatment can distinguish acute reversible dysfunction from chronic irreversible dysfunction.
ACKNOWLEDGMENTS
We thank the rheumatologists who participated in the
survey, Dr. Peter Lipsky for his help, and Abbott, Centocor,
and Sanofi Aventis for kindly providing data from their trials.
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