Rheumatol Int (2012) 32:2569–2571
DOI 10.1007/s00296-011-2058-9
SHORT COMMUNICATION
Proposing a method of regional assessment and a novel outcome
measure in rheumatoid arthritis
Susumu Nishiyama • Tetsushi Aita • Yasuhiko Yoshinaga
Hiroki Kishimoto • Michio Toda • Yoshiki Yoshihara •
Shinya Miyoshi • Akira Manki • Shoji Miyawaki
•
Received: 14 March 2011 / Accepted: 10 July 2011 / Published online: 26 July 2011
Ó Springer-Verlag 2011
Abstract We proposed a method of regional assessment
in patients with rheumatoid arthritis. The utility of this
method was demonstrated by assessing drug efficacy in
patients who received infliximab (n = 31) or tocilizumab
(n = 6). Joints were divided into four regions: upper/large,
upper/small, lower/large, and lower/small. The total joint
index was calculated as follows: the sum of tender and
swollen joint counts divided by the number of evaluable
joints in each region. At the baseline, the total joint index
of the upper/small region was the lowest and that of the
lower/large region was the highest compared with other
regions. The change in the total joint index from the
baseline to the 30-week point (D) did not differ among the
four regions. There were significant close relations of D
between the upper/small and the upper/large region and
between the lower/small and the lower/large region. This
method allows us to focus on a specific region and to
compare and contrast among them.
Keywords Biologic agents Outcomes research
Rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) affects synovial joints. Small
peripheral joints are typical sites of involvement, whereas
larger joints such as shoulders and knees are also involved.
From the viewpoint of function, joints of the upper limb
S. Nishiyama (&) T. Aita Y. Yoshinaga H. Kishimoto
M. Toda Y. Yoshihara S. Miyoshi A. Manki S. Miyawaki
Rheumatic Disease Center, Kurashiki Medical Center,
Kurashiki, Japan
e-mail: susumu.nisiyama@ryumachi-jp.com
cooperate when carrying or throwing things and the lower
limbs work to support the torso. The impact against an
articular surface may differ between small and large joints,
as well as between upper and lower limbs.
It is not clear that antirheumatic drugs have an equal
effect on every joint. For this reason, we propose a method
of regional assessment that allows us to evaluate drug
efficacy on a specific region.
Methods
Patients with RA who visited our hospital from November
2003 to September 2009 were retrospectively reviewed.
We selected 37 patients who received infliximab (n = 31)
or tocilizumab (n = 6) for more than 30 weeks. Their
average (SD) age and RA duration was 55.6 (10.5) years
old and 10.6 (8.1) years, respectively. They had an
average of 12 tender joints and 8 swollen joints at the
initiation of biologic agents. DAS28-CRP3 was calculated
as previously described [1], and the average (SD) of
DAS28 at the baseline and at the 30-week point after the
initiation of biologics was 4.48 (1.14) and 2.84 (1.05),
respectively.
Joints were divided into four regions: upper/large
(shoulder, sternoclavicular, elbow, and wrist joints), upper/
small (proximal interphalangeal and metacarpophalangeal
joints), lower/large (hip, knee, ankle, and tarsometatarsal
joints) and lower/small (metatarsophalangeal joints).
The tender (swollen) joint index was calculated as follows: tender (swollen) joint counts divided by the number
of evaluable joints in a region of interest. The total joint
index is the sum of tender and swollen joint indices. Hip
joints were excluded from the lower/large region when
assessing swollen joints.
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The Mann–Whitney rank-sum test was used to compare
the two different groups, and the Student–Newman–Keuls
test was used for multiple-comparison procedures.
Table 3 Correlation coefficient of DBaseline,
Upper/large
Upper/small
0.64**
Upper/large
Lower/small
Lower/large
0.13
0.22
0.12
0.12
0.13
0.42**
0.07
Lower/large
We compared joint indices between upper- and lower-limb
joints and between small and large joints at the baseline
(Table 1). Tender and total joint indices of lower limbs
were significantly higher than those of upper limbs,
whereas the swollen joint index did not differ significantly
between the two. Significantly, high swollen and total joint
indices were found in large joints compared to small ones,
though the tender joint index did not differ among them.
Table 2 indicates the change in the total joint index from
the baseline to the 30-week point. At the baseline, the total
joint index of the upper/small region was the lowest and
that of the lower/large region was the highest compared
with other regions. At the 30-week point after the initiation
of biologics, the total joint index of each region differed
significantly (P \ 0.01) except for comparisons between
the upper/large and the lower/large region and between the
upper/small and the lower/small region. The change in the
total joint index from the baseline to the 30-week point did
not differ significantly among the four regions (Table 2).
Table 3 shows the correlation coefficient of change in
the total joint index and DAS28. There were significant
close relations of Dbaseline,30-week between the upper/small
DAS28
0.17
Lower/small
Results
30-week
0.08
** P \ 0.01
and the upper/large region (r = 0.64, P \ 0.01) and
between the lower/small and the lower/large region
(r = 0.42, P \ 0.01).
Discussion
We proposed a method of regional assessment in patients
with RA. We divided joints into four regions to test whether or not biologic agents have the same effect on every
region.
First, we compared joint indices between upper- and
lower-limb joints. As shown in Table 1, tender joints
localized in lower limbs rather than upper limbs. From the
viewpoint of function, lower limbs work to support the
torso. Thus, the impact against the articular surface of the
lower-limb joints must be stronger than that of the upperlimb joints, which may result in the higher tender joint
index in lower limbs compared with upper limbs.
Table 1 Comparison of joint indices at baseline between upper- and lower-limb joints and between small and large joints
Joint index
Upper limb versus lower limb
Small versus large
Tender
0.14 (0.05, 0.34) versus 0.28 (0.11, 0.58)*
0.20 (0.03, 0.35) versus 0.31 (0.13, 0.38)
Swollen
0.14 (0.36, 0.29) versus 0.13 (0.06, 0.31)
0.10 (0.00, 0.23) versus 0.21 (0.14, 0.43)**
Total
0.32 (0.09, 0.57) versus 0.51 (0.18, 0.76)*
0.33 (0.13, 0.60) versus 0.53 (0.33, 0.78)*
Data are shown as median (25th, 75th percentiles)
* P \ 0.05, ** P \ 0.01
Table 2 Change in total joint index from baseline to 30-week point
Baselinea
30 weekb
Dbaseline,30-week
Upper/small
0.25 (0.00, 0.53)
0.00 (0.00, 0.10)
-0.15 (-0.35, 0.00)
Upper/large
0.50 (0.25, 0.75)
0.25 (0.00, 0.31)
-0.38 (-0.50, 0.00)
Lower/small
0.50 (0.00, 0.95)
0.00 (0.00, 0.15)
-0.30 (-0.85, 0.00)
Lower/large
0.58 (0.31, 0.92)
0.17 (0.00, 0.29)
-0.46 (-0.67, -0.19)
Data are shown as median (25th, 75th percentiles)
a
Total joint index of lower/large region was significantly higher than that of upper/large and lower/small region (P \ 0.05) and that of upper/
small region (P \ 0.01). Total joint index of upper/small region was the lowest compared with any other region (P \ 0.01)
b
Total joint indices differed significantly (P \ 0.01) except for comparisons between upper/large and lower/large region and between upper/
small and lower/small region
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Next, we compared small joints with large ones. Large
joints had a higher swollen joint index than small ones at
the baseline (Table 1). RA affects synovial joints, where
cytokines play a pivotal role in inflammation and the
immune response [2, 3]. As large joints have a wider
articular surface than small joints, large inflamed joints
have massive inflamed synovial cells. Inflammatory cytokines are abundantly expressed in the inflamed RA synovium [3, 4], and large joints probably have higher levels of
cytokines than small joints. This may be the reason why
large joints had a higher swollen joint index compared with
small joints.
As expected from the previous findings, the upper/small
region had the lowest total joint index and the lower/large
region possessed the highest one at the baseline (Table 2).
After treatment with biologic agents, the large joints had a
higher joint index than the small ones, whereas the difference between the upper and lower limbs decreased
(Table 2). We next examined Dbaseline,30-week to test whether the drug effect was equal in every region. We found
that D did not differ significantly among the different
regions (Table 2). Research over the last two decades has
highlighted the important role of cytokines, such as tumor
necrosis factor alpha (TNFa) and interleukins (IL) 6 in the
pathogenesis of RA—these are potential therapeutic targets
[5]. Infliximab and tocilizumab block TNFa and IL-6,
respectively, and they likely have an antiinflammatory
effect on every joint equally and may be less influenced by
function or joint size.
The correlation coefficients of D indicate that the
response to biologic agents in the upper limbs was independent of that in the lower limbs (Table 3). The joints of
the upper limbs have mutually functional relations, as do
those of the lower limbs. For example, the joints of the
upper limbs cooperate when carrying or throwing things,
and damage of a single joint could impair total function.
Although other joints of the upper limbs compensate for
impaired function, these joints may also be damaged
eventually. The same holds in the lower limbs. Therefore,
there was a significant relation of D between the upper/
small and the upper/large region as well as between the
lower/small and the lower/large region.
The method of regional assessment has several advantages. This study demonstrated that the application of
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regional assessment enabled a specific region to be focused
on. Additionally, if the joint index is multiplied by 28 as a
substitute for the original 28 joint counts [6], DAS28 can
be calculated for a specific region. Although it is time
consuming to count the number of tender and swollen
joints in each region, a computer can reduce this burden.
In this study, we tested the method of regional assessment on a small number (n = 37) of patients. The patients
were not randomized and their medical charts were
reviewed retrospectively. Therefore, the obtained data
regarding the effect of biologics need to be confirmed by a
randomized study. However, we emphasize that this
method has the potential to indicate which region is the
major player in systemic arthritis.
As the joint index is the sum of tender and swollen joint
counts divided by evaluable joint counts, it is a composite
measure for RA. This index increases as arthritis worsens
and it is thought to be a proper measure for evaluating
arthritis. Another advantage is that it can be calculated on
all but unevaluable joints, such as artificial joints.
In summary, we proposed a method of regional assessment and a new outcome measure in RA. We tested this
method in patients with RA treated with biologic agents
and found that it was useful in the evaluation of arthritis.
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