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Evidence for a different anatomic basis for joint disease localization in polymyalgia rheumatica in comparison with rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 56, No. 10, October 2007, pp 3496–3501
DOI 10.1002/art.22942
© 2007, American College of Rheumatology
Evidence for a Different Anatomic Basis for Joint Disease
Localization in Polymyalgia Rheumatica in Comparison With
Rheumatoid Arthritis
Helena Marzo-Ortega,1 Laura A. Rhodes,2 Ai Lyn Tan,1 Steven F. Tanner,2
Philip G. Conaghan,2 Elizabeth M. A. Hensor,1 Philip O’Connor,3 Aleksandra Radjenovic,2
Colin T. Pease,2 Paul Emery,2 and Dennis McGonagle4
sular Gd-DTPA enhancement was assessed in both
conditions using semiquantitative scoring.
Results. No significant differences were seen in
the volume of synovitis (P ⴝ 0.294), degree of flexor
tenosynovitis (P ⴝ 0.532), periarticular erosions (P ⴝ
0.579), or degree of bone edema (P ⴝ 0.143) between RA
and PMR joints. However, despite comparable degrees
of synovitis, the proportion of MCP joints showing
extracapsular enhancement was higher in the PMR
group (100%) than in the RA group (50%) (P ⴝ 0.030).
One PMR patient, but none of the RA patients, had
bone edema at the capsular insertion.
Conclusion. Despite degrees of synovitis and tenosynovitis comparable with those in RA, PMR-related
hand disease is associated with prominent extracapsular changes, suggesting that inflammation in these
tissues is more prominent than joint synovitis, which is
common in both conditions. This suggests that the
anatomic basis for joint disease localization differs
between RA and PMR.
Objective. The anatomic basis for joint disease
localization in polymyalgia rheumatica (PMR) is poorly
understood. This study used contrast-enhanced and fat
suppression magnetic resonance imaging (MRI) to evaluate the relationship between synovial and extracapsular inflammation in PMR and early rheumatoid arthritis (RA).
Methods. Ten patients with new-onset PMR and
10 patients with early RA underwent dynamic contrastenhanced MRI and conventional MRI of affected metacarpophalangeal (MCP) joints. Synovitis and tenosynovitis were calculated based on the number of enhancing
voxels, initial rate of enhancement, and maximal enhancement of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). Periarticular bone erosion and
bone edema were scored according to the OMERACT
(Outcome Measures in Rheumatology Clinical Trials)
scoring system in both groups. The degree of extracapSupported by the Medical Research Council, UK, and the
Arthritis Research Campaign, UK. Dr. Emery is an Arthritis Research
Council Professor in Rheumatology.
1
Helena Marzo-Ortega, MRCP, Ai Lyn Tan, MD, MRCP,
Elizabeth M. A. Hensor, BSc, PhD: University of Leeds, and Chapel
Allerton Hospital, Leeds, UK; 2Laura A. Rhodes, PhD, Steven F.
Tanner, PhD, Philip G. Conaghan, FRACP, PhD, Aleksandra Radjenovic, PhD, Colin T. Pease, MD, FRCP, Paul Emery, MA, MD,
FRCP: University of Leeds, Leeds, UK; 3Philip O’Connor, FRCR:
Chapel Allerton Hospital, Leeds, UK; 4Dennis McGonagle, FRCPI,
PhD: University of Leeds, Leeds, UK, and Calderdale Royal Hospital,
Halifax, UK.
Dr. McGonagle has received consulting fees, speaking fees,
and/or honoraria (less than $10,000 each) from Pfizer, Abbott, Roche,
and LEO Pharma.
Address correspondence and reprint requests to Dennis
McGonagle, FRCPI, PhD, Professor of Investigative Rheumatology,
Academic Unit of Musculoskeletal Disease, University of Leeds,
Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK.
E-mail: d.g.mcgonagle@leeds.ac.uk.
Submitted for publication January 3, 2007; accepted in revised form June 29, 2007.
Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis characterized by prominent synovial
joint inflammation with progressive joint destruction.
Polymyalgia rheumatica (PMR) is also characterized by
synovial joint involvement, but compared with RA it is
associated with prominent muscle stiffness, absence of
joint destruction, and a good prognosis (1). The use of
magnetic resonance imaging (MRI) in RA has confirmed the primacy of synovitis and the relationship
between synovitis and erosions (2,3). In PMR, however,
MRI has not led to a consensus regarding an anatomic
basis for its rheumatic manifestations, with some studies
suggesting that PMR-associated joint disease represents
a synovial-based disease that can be distinguished from
3496
ANATOMIC BASIS FOR JOINT DISEASE LOCALIZATION IN PMR AND RA
RA on the basis of either shoulder joint bursitis (4) or
hand tenosynovitis (5). Using fat-suppressed MRI techniques to look at shoulder and hand involvement in
PMR, we have previously noted that edema in the
extracapsular tissues was more common in PMR than in
RA (6). One possible explanation for such differences
might be a relatively abrupt-onset synovitis in PMR with
nonspecific extension of the inflammatory processes into
the adjacent soft tissues; alternatively, the primary site of
inflammation in PMR might be capsular based (6).
Contrast agent gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) in dynamic contrastenhanced MRI (DCE-MRI) allows not only the estimation of the volume of synovitis, but also the degree and
kinetics of enhancement (7–9), including the initial rate
of enhancement (IRE) and maximal enhancement
(ME), both of which reflect synovial tissue vascularity
and permeability. In addition, using contrast enhancement with fat suppression allows an assessment of
extracapsular tissue edema, which may reflect an inflammatory process at that site. This study investigated the
relationship between synovial and extracapsular inflammation in hand disease–related PMR and early RA.
PATIENTS AND METHODS
Twenty patients were recruited from the early arthritis
clinic. The study had approval from the local ethics committee,
and all patients provided their informed consent. Ten consecutive patients fulfilling the 1987 revised criteria for RA of the
American College of Rheumatology (formerly, the American
Rheumatism Association) (10) (5 men and 5 women, mean age
55 years [range 28–72 years]) with clinical metacarpophalangeal (MCP) joint synovitis and 10 patients diagnosed as having
PMR (5 men and 5 women, mean age 74 years [range 68–83
years]) fulfilling the criteria described by Bird et al (11) with
recent onset of MCP joint swelling were eligible for study
entry. The mean duration of symptoms was 4.9 months for the
RA patients (range 2–11 months) and 10 weeks for the PMR
patients (range 3–24 weeks). All of the RA patients but none
of the PMR patients were seropositive for rheumatoid factor.
One of the PMR patients had received oral corticosteroids but
remained symptomatic, whereas all RA patients were treatment naive. Both groups had polyarticular joint disease (mean
swollen joint count 13 in the RA group and 7.4 in the PMR
group). Only 2 of the PMR patients had pitting edema in the
dorsum of the hand. The mean C-reactive protein level was 56
mg/liter (range 8–134) in the RA group and 46 mg/liter (range
⬍5–115) in the PMR group. Exclusion criteria included any
contraindication to undergoing MRI. The small joints of the
hands were used rather than the shoulder, since the imaging
resolution obtained in the hand is comparatively greater, and
confounding factors such as degenerative supraspinatus tendinitis, which is very common in the shoulder, were avoided.
3497
MRI. MRI of the clinically most swollen hand was
performed using a Philips 1.5T Gyroscan ACS-NT wholebody scanner (Philips Medical Systems, Best, The Netherlands). Patients were placed in the prone position with the
arm extended above the head, and a circular surface coil was
placed on the dorsum of the hand over the second-throughfifth MCP joints. A total of 80 joints were studied (40 in
each group). The sequences performed were as follows:
T1-weighted spin-echo on coronal and axial planes; axial
DCE-MRI and T1 spectral presaturation with inversion
recovery (SPIR) fat-suppressed pulse sequences post–GdDTPA administration in the coronal and axial planes. All
scoring was performed in a randomized manner with scorers
blinded to the clinical information.
Imaging processing of synovitis and tenosynovitis. For
the quantitative assessment of synovitis and tenosynovitis,
DCE-MRI data were analyzed using commercial software
(Analyze; Mayo Clinic, Rochester, MN) and software developed in house (7,8) to calculate values of IRE and ME on a
pixel-by-pixel basis as well as the number of enhancing voxels
(estimation of synovial volume) (Figure 1), as previously
described in detail (7). An assessor experienced in automated
MRI scoring (LAR) carried out the data analysis. The intrarater reliability of this system was as follows: intraclass
correlation coefficient (ICC) 0.994 (95% confidence interval
[95% CI] 0.992–0.996) for the IRE calculation and ICC 0.994
(95% CI 0.992–0.996) for the ME calculation.
Bone changes. Bone erosions and bone edema were
identified according to the recommendations of the OMERACT (Outcome Measures in Rheumatology Clinical Trials)
group (12). Images were scored by 1 experienced reader
(PGC) using the semiquantitative methods described in the
validated OMERACT RA-MRI scoring system (12). In addition, the location of bone edema with regard to the joint
margin or at the capsule insertion was documented as previously reported (13). The intraobserver reliabilities for the
presence or absence of bone erosions (94.30%, ␬ ⫽ 0.87) and
bone edema (97.60%, ␬ ⫽ 0.60) were completely concordant.
For the semiquantitative analysis, the ICCs were 0.98 and 0.65
for erosions and edema, respectively (14).
Pattern of extracapsular enhancement. Extracapsular
soft tissue edema and enhancement were scored in a blinded
manner on T1 SPIR post–Gd-DTPA coronal sequences by 1
experienced observer (DM) and defined as “synovial” where
maximum in the joint cavity and tendon sheaths or as “extracapsular” where changes were apparent outside the synovial
cavity adjacent to the joint capsule, as previously described
(14). First, each MCP joint was scored as being predominantly
synovial or extracapsular based on the presence of extrasynovial Gd-DTPA enhancement. Then, a global score was assigned to each patient on the basis of the overall enhancement
(i.e., the overall pattern of all 4 joints). The intrareader
reliabilities for synovial and extracapsular enhancement were
␬ ⫽ 0.847 and ␬ ⫽ 0.828, respectively.
Statistical analysis. Mixed between-within subjects
analysis of variance (ANOVA) was performed to test for
differences between the DCE-MRI parameters in both groups.
Nonparametric tests were used when appropriate. All statistical analyses were carried out using SPSS 12.0 (SPSS, Chicago,
IL).
3498
MARZO-ORTEGA ET AL
Figure 1. Image representing 1 of 6 axial slices from a dynamic contrast-enhanced magnetic
resonance imaging data set acquired in the right hand of a patient with rheumatoid arthritis, with
superimposed color data showing values of maximal enhancement (ME) across the synovial space
following gadolinium diethylenetriaminepentaacetic acid enhancement. The yellow pixels represent high ME values, while the red pixels represent lower values. The edge of synovitis was defined
manually around the metacarpophalangeal (MCP) head in the case of joint synovitis and around
the flexor tendons in the cases of tenosynovitis (arrows). There is synovitis around all MCP joints,
although this is more marked on the second and third joints. There is also inflammation around
tendons 2 and 3 (white numbers), as represented by the surrounding yellow coloration. The blue
numbers represent the 8 segments that were divided automatically by the software within the joint
synovitis.
RESULTS
After a mean followup of 6 years, 7 patients in the
PMR group had clinical remission of their disease, were
not receiving treatment, and were discharged from our
service. Three PMR patients have died (2 of cerebrovascular disease and 1 of bronchial carcinoma), whereas all
patients in the RA group have persistent disease requiring ongoing treatment.
Synovitis and tenosynovitis. There was no significant difference in the total volume of MCP synovitis
between the PMR and the RA groups (mean ⫾ SEM
voxel count 28,593 ⫾ 3,411 and 24,351 ⫾ 1,940, respectively; t ⫽ 1.08, P ⫽ 0.294) (mean ⫾ SEM IRE [arbitrary
units] 850 ⫾ 136 and 754 ⫾ 100, respectively; t ⫽ 0.57,
P ⫽ 0.576) (mean ⫾ SEM ME [arbitrary units] 58,508 ⫾
8,059 and 49,953 ⫾ 4,940, respectively; t ⫽ 0.91, P ⫽
0.377), although the absolute numbers of voxels were
higher in the PMR group. The same pattern was observed in the tendon analysis, with no significant differences for the degree of flexor tenosynovitis between
both groups (mean voxel count t ⫽ 0.64, P ⫽ 0.532;
mean IRE t ⫽ 0.68, P ⫽ 0.505; mean ME t ⫽ 0.89, P ⫽
0.383).
Periarticular bone erosion and bone edema.
MRI-determined bone erosions were seen in 80% of the
RA patients (n ⫽ 8 patients, 28 erosions) and 80% of the
PMR patients (n ⫽ 8 patients, 20 erosions). There was
no significant difference in the number of erosions
between the groups (total number of erosions per patient [z ⫽ ⫺0.692, P ⫽ 0.529 by Mann-Whitney U test]),
although a trend toward more erosions in the RA group
was observed. Likewise, the size of the erosions was
comparable between the groups (total erosion score [z ⫽
⫺0.577, P ⫽ 0.579 by Mann-Whitney U test]).
Bone edema was seen in 60% of the RA patients
(n ⫽ 6 patients, 20 regions of bone edema) and 20% of
the PMR patients (n ⫽ 2 patients, 7 regions of bone
edema) (continuity-corrected ␹2 ⫽ 1.88, P ⫽ 0.171). The
degree of bone edema was comparable between the
groups (z ⫽ ⫺1.67, P ⫽ 0.143 by Mann-Whitney U test).
With regard to location, bone edema was seen at the
periarticular margin in all of the RA patients. However,
bone edema related to the distal capsule insertion was
seen in 1 of the PMR patients but in none of the RA
patients (Figure 2E).
Pattern of extracapsular soft tissue enhancement. The overall pattern of enhancement was extracapsular in 80% of the PMR patients (n ⫽ 8) but in only
20% of the RA patients (n ⫽ 2) (continuity-corrected
␹2 ⫽ 5.00, P ⫽ 0.025). For the total joint score, the
pattern was extracapsular in 31 of 40 PMR joints and in
10 of 40 RA joints (continuity-corrected ␹2 ⫽ 20.01, P ⬍
0.0001). At the individual MCP joint level, betweensubjects two-way ANOVA indicated that although there
was no significant difference in voxel count between the
groups, joints with extracapsular enhancement had sig-
ANATOMIC BASIS FOR JOINT DISEASE LOCALIZATION IN PMR AND RA
3499
Figure 2. A–C, T1-weighted post–gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) sequences of the
metacarpophalangeal (MCP) joints of 3 of the study patients with rheumatoid arthritis (RA). A, High signal within
the second, third, and fourth MCP joints, corresponding to synovitis. Also shown is extracapsular enhancement on
the radial aspect of the second MCP joint (asterisk). B and C, High signal within the joint cavity representative of
synovitis (arrows). Arrowhead in C indicates a periarticular erosion. D–F, T1-weighted post–Gd-DTPA sequences
showing the MCP joints of 3 patients with polymyalgia rheumatica (PMR). D, Soft tissue enhancement seen at
extrasynovial sites (asterisks). E, Capsular lesion on the radial aspect of the proximal phalanx of the third MCP joint.
The lesion is located away from the joint margin at the site of the capsule insertion (arrow), something not noted
in the RA cohort. Arrowhead indicates extrasynovial enhancement typically seen in PMR joints. Asterisks indicate
extrasynovial soft tissue enhancement. F, Periarticular erosion in the radial aspect of the second MCP joint at the
same location as seen in RA (arrow). There is, however, prominent extracapsular Gd-DTPA enhancement typical
of PMR (asterisks).
nificantly higher voxel counts than those without extracapsular enhancement (P ⬍ 0.0001) in both groups.
However, for matched degrees of synovitis, the proportion of MCP joints showing extracapsular enhancement
was higher in the PMR group (100%) than in the RA
group (50%) (continuity-corrected ␹2 ⫽ 4.701, P ⫽
0.030) (Figure 3).
Only 2 of the PMR patients had clinical evidence
3500
MARZO-ORTEGA ET AL
Figure 3. Proportion of MCP joints that exhibited extracapsular
enhancement, according to the amount of synovitis present, measured
by voxel count (arbitrary units). See Figure 2 for definitions.
of pitting edema. These patients had an extracapsular
pattern of joint enhancement on MRI, but so did the
majority of patients without pitting edema.
DISCUSSION
The purpose of this study was to investigate
whether PMR-associated hand disease differed from
RA with respect to synovial compartment inflammation
or extracapsular inflammation. Despite nonsignificant
differences in the degree of synovitis in both conditions,
we noted that there was a much greater degree of
Gd-DTPA enhancement in the extracapsular tissues in
the PMR patients. Our findings are concordant with
those of some studies (6), but not with those of others
(4,5). We believe that these apparent contradictions can
be explained in part by the MRI sequences used, the
resolution of the imaging, and the criteria for patient
selection. The majority of the studies claiming that PMR
was primarily bursal- and tenosynovial-based were performed using non–fat-suppressed MRI techniques, making it difficult to evaluate extracapsular changes. The
second issue was that previous studies showing extracapsular edema were unable to quantify the degree of
synovitis, so the relationship between intra- and extracapsular disease could not be accurately assessed (6).
Furthermore, it is difficult to compare RA and PMR,
since the latter may have an abrupt onset with severe
disease. Therefore, it was possible that the extracapsular
changes reflected merely nonspecific extension of the
inflammatory process (13).
We addressed these issues by using fat suppression and DCE-MRI in early PMR and in a cohort of
patients with severe RA-related MCP disease. A greater
but nonsignificant magnitude of synovitis was noted in
the present study in the PMR group. In addition, the
pattern of enhancement of extracapsular edema was
very diffuse and was evident in tissue well away from
inflamed synovium. As previously reported, bone edema
adjacent to the joint capsule was also noted, which
supports the idea of capsular-based inflammation in
early PMR (13); however, our samples are small, and
larger numbers would need investigating to understand
the real meaning of these findings.
RA usually has an insidious onset compared with
PMR, which often has an abrupt onset; hence, more
synovitis and tenosynovitis may be expected in PMR at
clinical presentation. In this study we chose RA patients
with comparable degrees of clinically evident swelling in
their MCP joints so that a fair MRI comparison could be
made between diseases. We were also interested in
determining whether extracapsular enhancement correlated with the presence of pitting edema typical of hand
involvement in PMR. However, this pattern was also
seen in the majority of the remaining PMR patients
without pitting edema. Since extracapsular enhancement
is also seen in shoulder disease in PMR (6), we postulate
that these changes outside the joint may be contributing
to the severe joint stiffness seen in this condition.
A surprising finding was that MRI-determined
erosion and bone edema were equally common in both
groups, and indeed it has been recognized that PMR
may on occasion exhibit radiographically detectable
erosion (15). This likely reflects the fact that irrespective
of the trigger, synovitis will lead to the same pattern of
MRI-determined erosion and edema. The exquisite sensitivity of PMR to steroids is likely to lead to complete
suppression of the inflammatory process and may prevent the progression of MRI lesions to radiographically
evident disease. However, in RA, erosion formation is
more likely to occur, since disease tends to become
chronic and is harder to suppress (3). Long-term followup of our patients showed that all the RA patients
continue to have persistent disease necessitating diseasemodifying therapy, but the entire PMR cohort has had
complete remission of their disease with steroids alone.
In conclusion, our results provide evidence that
hand joint disease in early PMR shows amounts of
synovitis, tenosynovitis, and MRI-determined bone
damage comparable with those in early RA, while
ANATOMIC BASIS FOR JOINT DISEASE LOCALIZATION IN PMR AND RA
extracapsular inflammation is more common in PMR.
Further imaging and histopathologic studies are needed
to elucidate the meaning of these findings and to
determine whether they represent an event independent
of synovitis.
5.
6.
ACKNOWLEDGMENTS
We thank Sister Claire Brown for help with study
coordination, and we also thank the staff at the MRI Unit at
the Leeds General Infirmary.
7.
8.
AUTHOR CONTRIBUTIONS
Dr. McGonagle had full access to all of the data in the study
and takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Study design. Marzo-Ortega, Tan, Conaghan, Pease, McGonagle.
Acquisition of data. Marzo-Ortega, Rhodes, O’Connor, Radjenovic,
Pease, McGonagle.
Analysis and interpretation of data. Marzo-Ortega, Rhodes, Tan,
Tanner, Conaghan, Hensor, O’Connor, Radjenovic, Emery,
McGonagle.
Manuscript preparation. Marzo-Ortega, Tan, Conaghan, O’Connor,
Radjenovic, Pease, Emery, McGonagle.
Statistical analysis. Hensor.
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