Abstract
OBJECTIVE:
This study compares the clinical, ultrasonography, radiography, and laboratory outcomes of painless and painful chronic synovitis in patients with established rheumatoid arthritis.
METHODS:
This cross-sectional study involved 60 patients with rheumatoid arthritis and synovitis in the metacarpophalangeal joints; 30 of the patients did not experience pain, and 30 had experienced pain for at least 6 months prior to the study. The radiocarpal, distal radioulnar, and metacarpophalangeal joints were evaluated using the ultrasound gray scale, power Doppler, and radiography. Past and present clinical and laboratory findings were also evaluated.
RESULTS:
There were no statistically significant differences between the groups for most of the outcomes. The group with pain scored worse on the disease activity indices (e.g., DAS 28 and SDAI), function questionnaires (HAQ and Cochin), and pinch strength test. A logistic regression analysis revealed that the use of an immunobiological agent was associated with a 3-fold greater chance of belonging to the group that experienced pain. The painless group had worse erosion scores in the second and fifth metacarpophalangeal with odd ratios (ORs) of 6.5 and 3.5, respectively. The painless group had more cartilage with grade 4 damage in the third metacarpophalangeal.
CONCLUSIONS:
The rheumatoid arthritis patients with both painless and painful synovitis exhibited similar disease histories and radiographic and ultrasound findings. However, the ultrasonography evaluation revealed worse scores in the second and fifth metacarpophalangeal of the synovitis patients who did not experience pain.
Rheumatoid Arthritis; Synovitis; Pain; Ultrasound; Radiographic
INTRODUCTION
The clinical presentation of rheumatoid arthritis (RA) varies, but most patients have
intermittent polyarthritis with swelling and tenderness to palpation (11. Grassi W, Angelis RD, Lamanna G, Cervini C. The clinical features of rheumatoid
arthritis. Eur J Radiol. 1998;27:S18-S24.). Some patients exhibit persistent chronic synovitis, which is marked by joint
swelling (22. Bugatti S, Manzo A, Caporati R, Montecucco C. Assessment of synovitis to predict
bone erosions in rheumatoid arthritis. Ther Adv Musculoskeletal Dis. 2012;4(4):235-44,
http://dx.doi.org/10.1177/1759720X12453092.
http://dx.doi.org/10.1177/1759720X124530...
) and may or may not be accompanied by pain. The
reason for the absence of pain despite the persistent joint swelling is unknown. Moreover, little is
known about the predictive factors of painless synovitis or its relationship to the past progression
of the disease, ultrasound inflammatory findings (e.g., power Doppler), or the degree of joint
damage (erosion).
Ultrasonography (US) allows the early detection of bone and cartilage damage and the evaluation
of synovitis (gray scale [GS-US] and power Doppler [PD-US]). US is more
sensitive than a clinical examination and simple radiography (X-ray) (33. Zordo T, Mlekusch SP, Feuchtner GM, Mur E, Schirmer M, Klauser AS. Value of
contrast-enhanced ultrasound in rheumatoid arthritis. Eur J Radiol.
2007;64(2):222-30.
4. Grassi W, Salaffi F, Filippucci E. Ultrasound in rheumatology. Best Pract Res
Clin Rheumatol. 2005;19(3):467-85, http://dx.doi.org/10.1016/j.berh.2005.01.002.
http://dx.doi.org/10.1016/j.berh.2005.01...
5. Naredo E, Bonilla G, Gamero F, Uson F, Carmona F, Laffon A. Assessment of
inflamatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with gray
scale e power Doppler ultrasonography. Ann Rheum Dis. 2005;64(3):375-81.
6. Cheung PP, Dougados M, Gossec L. Reliability of Ultrasonography to Detect
Synovitis in Rheumatoid Arthritis: A Systematic Literature Review of 35 Studies (1,415 Patients).
Arthritis Care Res (Hoboken). 2010;62(3):323-34,
http://dx.doi.org/10.1002/acr.20102.
http://dx.doi.org/10.1002/acr.20102...
7. Kortekaas MC, Kwok WY, Reijnierse M, Watt I, Huizinga TWJ, Kloppenburg M. Pain in
hand osteoarthritis is associated with inflammation: the value of ultrasound. Ann Rheum Dis
2010;69(7):1367-9.-88. Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, et al. Presence
of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic
drug-induced clinical remission - Evidence from an imaging study may explain structural progression.
Arthritis Rheum. 2006;54(12):3761-73, http://dx.doi.org/10.1002/art.22190.
http://dx.doi.org/10.1002/art.22190...
). PD-US enhances the specificity of US
(99. Wakefield RJ, Brown AK, O'Connor PJ, Emery P. Power-Doppler Sonography:
Improving Disease Activity Assessment in Inflammatory Musculoskeletal Disease. Arthritis Rheum.
2003;48(2):285-8, http://dx.doi.org/10.1002/art.10818.
http://dx.doi.org/10.1002/art.10818...
), assists in the diagnosis of active synovitis (1010. Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G. Clinical
and ultrasonographic remission determines different changes of relapse in early and long standing
rheumatoid arthritis. Ann Rheum Dis. 2011;70(1):172-15,
http://dx.doi.org/10.1136/ard.2010.129924.
http://dx.doi.org/10.1136/ard.2010.12992...
), and predicts joint damage (1111. Brown AK, Conaghan, Karim Z, Quinn MA, Ikeda K, Peterfy CG, et al. An
Explanation for the Apparent Dissociation Between Clinical Remission and Continued Structural
Deterioration in Rheumatoid Arthritis. Arthritis Rheum. 2008;58(10):2958-67,
http://dx.doi.org/10.1002/art.23945.
http://dx.doi.org/10.1002/art.23945...
).
No previous studies have addressed the importance of painless chronic synovitis in RA. Thus, the present study compared the clinical, US, radiographic, and laboratory outcomes of patients with established RA and chronic synovitis with or without pain.
PATIENTS AND METHODS
Study design
This cross-sectional study evaluated RA patients. The study was approved by the Human Research Ethics Committee of the Universidade Federal de São Paulo/Escola Paulista de Medicina (Brazil). All patients provided written informed consent.
The sample size of 30 individuals in each group was considered appropriate, and the PD-US was the primary study outcome. The study had a standard deviation (SD) of 0.4, a power of 90%, and a 5% significance level.
Patients
Adult patients who fulfilled the 1987 American College of Rheumatology criteria for RA (1212. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The
American Rheumatism Association 1987 revised criteria for the classification of rheumatoid
arthritis. Arthritis Rheum. 1988;31(3):315-24,
http://dx.doi.org/10.1002/art.1780310302.
http://dx.doi.org/10.1002/art.1780310302...
) were eligible for the study if they also met the following
criteria: joint swelling in at least 4 metacarpophalangeal (MCP) joints for at least 6 consecutive
months, female gender, and stable use of disease-modifying antirheumatic drugs (DMARDs) in the
previous 3 months. The visual analogue scale (VAS), which ranges from 0 to 10 cm, was used for the
pain criteria; the VAS score was at least 4 cm in the painful group and 0 in the painless group. The
following exclusion criteria were used: overlap syndromes, irreducible deformation and MCP surgery,
and comorbidities, such as uncontrolled hypothyroidism, uncontrolled fibromyalgia or diabetic
neuropathy.
Data collection
Sixty patients were selected from the rheumatology outpatient clinic of the Universidade Federal de São Paulo/Escola Paulista de Medicina (Brazil) between July 2011 and July 2012. The patients were recruited consecutively and assigned to the painful synovitis group or the painless synovitis group. The groups were age matched.
We collected the demographic data, life habits, and information about both the past and present progression of RA using a questionnaire.
Clinical examinations were performed by a rheumatologist who was “blinded” to each
patient's history and the results of the imaging exams. The evaluation included a patient and a
medical global assessment (on a 0-100 scale), grip strength using a Jamar®, and pinch strength
using a Preston Pinch Gauge®; the 28-joint Disease Activity Score (DAS 28) (1313. Prevoo MLL, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LBA, van
Riel PLC. Modified disease activity scores that include twenty-eight-joint counts - Development and
validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis
Rheum. 1995;30(1):44-48, http://dx.doi.org/10.1002/art.1780380107.
http://dx.doi.org/10.1002/art.1780380107...
), Clinical Disease Activity Index (CDAI) (1414. Aletaha D, Nell VPK, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute
phase reactants add little to composite disease activity indices for rheumatoid arthritis:
validation of a clinical activity score. Arthritis Res Ther. 2005;7(4):R796-R806,
http://dx.doi.org/10.1186/ar1740.
http://dx.doi.org/10.1186/ar1740...
), Simplified Disease Activity Index (SDAI) (1515. Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A
simplified disease activity index for rheumatoid arthritis for use in clinical practice.
Rheumatology (Oxford) 2003;42(2):244-57.), Stanford Health Assessment Questionnaire (HAQ) (1616. Ferraz MB, Liveira LM, Araujo PM, Atra E, Walter D. EPM-ROM Scale: na evaluative
instrument to be used in rheumatoid arthritis trials. Clin Exp Rheumatol.
1990;8(5):491-4.), and Cochin Hand Function Scale (CHFS) were also used (1717. Chiari A, Sardim CCS, Natour J. Translation, cultural adaptation and
reproducibility ot the Cochin Hand Functional Scale questionnaire for Brazil. Clinics.
2011;66(5):731-6, http://dx.doi.org/10.1590/S1807-59322011000500004.
http://dx.doi.org/10.1590/S1807-59322011...
).
The transverse US exam included the dorsal side of the radiocarpal (RC) and the palmar and dorsal sides of MCPs 1 to 5; the longitudinal US exam included the dorsal radioulnar (DRU), according to a quantitative synovitis measurement (in mm) in the largest synovial bursa and semiquantitative scores, as described above (Table 1).
Furthermore, a transverse evaluation of the cartilage of the dorsal side of MCPs 1 to 5 was performed with flexion of the fingers.
US was performed bilaterally on the hands and wrists by a “blinded” musculoskeletal
sonographer with 5 years of experience, using the ESAOTE MyLab 60 Xvision, with a multi-frequency
linear transducer (6-18 MHz). The sonographer followed the guidelines for musculoskeletal US
recommended by the European League Against Rheumatism (1818. Backhaus M, Burmester G-R, Gerber T, Grassi W, Machold KP, Swen WA, et al.
Guidelines for musculoskeletal ultrasound in Rheumatology. Ann Rheum Dis. 2001;60(7):641-9,
http://dx.doi.org/10.1136/ard.60.7.641.
http://dx.doi.org/10.1136/ard.60.7.641...
).
The US were measured based on the definitions published in the Outcome Measures in Rheumatology Clinical Trials (except cartilage) (1919. Wakefield RJ, Balint PV, Szkudlarek M, Filippucci E, Backhaus M, D'Agostino M, et al. Proceedings from the OMERACT Special Interest Group for Musculoskeletal Ultrasound including definitions for ultrasonographic pathology. J Rheumatol. 2005;32(12):2485-7.).
Semiquantitative synovitis, bone erosion, and PD-US were each evaluated using a 4-grade scale ranging from 0 to 3. The scores were defined as follows.
Grades 0-1 for bone erosion and synovitis were considered normal (Score I), whereas grades 2-3
indicated pathological changes (Score II) (2020. Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Ostergaard M.
Interobserver agreement in ultrassonography of the finger and toe joint in rheumatoid arthritis.
Arhtitis Rheum. 2003;48(4):955-62, http://dx.doi.org/10.1002/art.10877.
http://dx.doi.org/10.1002/art.10877...
).
For the PD-US signal, grade 0 was considered to be normal (Score I), whereas grades 1-3 were
considered to be pathological (Score II) (2020. Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Ostergaard M.
Interobserver agreement in ultrassonography of the finger and toe joint in rheumatoid arthritis.
Arhtitis Rheum. 2003;48(4):955-62, http://dx.doi.org/10.1002/art.10877.
http://dx.doi.org/10.1002/art.10877...
,2121. Filipucci E, Farina A, Carotti M, Salaffi F, Grassi W. Grey scale and power
Doppler sonografic changes induces by intra-articular steroid injection treatment. Ann Rheum Dis.
2004;63(6):740-3, http://dx.doi.org/10.1136/ard.2003.007971.
http://dx.doi.org/10.1136/ard.2003.00797...
).
Joint cartilage was evaluated using a semi-quantitative 5-grade score with the aforementioned
categories (2222. Disler DG, Raymond E, May DA, Wayne JS, McCauley TR. Articular Cartilage
Defects: In Vitro Evaluation of Accuracy and Interobserver Reliability for Detection and Grading
with US. Radiology. 2000; 215(3):846-51,
http://dx.doi.org/10.1148/radiology.215.3.r00jn20846.
http://dx.doi.org/10.1148/radiology.215....
,2323. Filippucci E, da Luz KR, Di Geso L, Salaffi F, Tardella M, Carotti M, et al.
Interobserver reliability of ultrasonography in the assessment of cartilage damage in rheumatoid
arthritis. Ann Rheum Dis. 2010;69(10):1845-8,
http://dx.doi.org/10.1136/ard.2009.125179.
http://dx.doi.org/10.1136/ard.2009.12517...
).
The inter-observer reliability for the US evaluation was determined based on the image evaluations recorded on 20% of the overall sample in the RC (a total of 52 joint recess). The evaluation was performed by a blinded rheumatologist trained in musculoskeletal US.
The radiological evaluation (plain X-ray of the hands and wrists) was performed by a single
experienced radiologist who was unaware of the clinical or US findings. The evaluation used the
modified method proposed by van der Heijde and collaborators (2424. van der Heijde DM. Plain x-rays in rheumatoid arthritis: overview of scoring
methods, their rehability and applicability. Baillieres Clin Rheumatol. 1996;10(3):435-53,
http://dx.doi.org/10.1016/S0950-3579(96)80043-4.
http://dx.doi.org/10.1016/S0950-3579(96)...
).
Statistical Analysis
The data were analyzed in SPSS v.17.0. We express the quantitative parameters as the mean, standard deviation, and range. Any value of p<0.05 was consider significant.
The data were compared using either the Student's t-test or the Mann-Whitney test.
The categorical variables were measured in percentages and were compared between the groups, using either the chi-squared or Fisher's exact tests. The correlations between variables were evaluated using either Pearson's or Spearman's correlation coefficients. Cohen's Kappa index and the intraclass correlation coefficient were used to evaluate the inter-observer reliability.
A subanalysis of the 2 groups was performed on the US findings for the joints that exhibited swelling in the clinical examination. Logistic regression analysis was applied to the semi-quantitative US variables to assess the ability of the variables to predict painful or painless synovitis and to identify the variables that were likely to be predictive of painless synovitis.
RESULTS
The sample consisted of 60 patients with established RA, for a total of 120 hands and wrists and 600 MCFs. The mean duration of the absence of joint pain in the painless group and the presence of joint pain in the painful group was, respectively, 30.3±32.6 months and 50.9±74.6 months (p = 0.740). There were no statistically significant differences between the groups for the majority of the demographic variables and laboratory findings or in the disease progression (Tables 2, 3).
Two patients in the painless group (7%) and 9 patients (30%) in the painful group were smokers (p = 0.042) (Table 2).
The medical diagnosis for RA took 13.2±23.6 months in the painless group and 21.2±26.1 months in the painful group (p = 0.028) (Table 3). The majority of patients were initially treated with monotherapy consisting of a DMARD associated with a corticosteroid. Furthermore, the majority of patients were primarily treated with a combination of DMARDs (Table 3).
There were statistically significant between-groups differences in the current DAS-28 measurement (using erytrocyte sedimentation rate-ESR) and for all variables influenced by the presence of joint pain, with higher scores in the painful group (p<0.05) (Tables 2 and 4). However, there was no statistically significant difference between the groups in the number of swollen joints.
Twenty-seven patients (90%) in the painless group and 13 (43%) patients in the painful group were classified as having mild dysfunction (HAQ scores 0 and 1, respectively) (2525. Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: Dimensions and Practical Applications. Health and Qual Life Outcomes. 2003:1-20.) (p = 0.001). There were statistically significant between-group differences for the CHFS, lateral pinch, and tripod pinch (p<0.001, p<0.001, and p = 0.039, respectively), with better scores in the painless group. The Jamar and pulp-to-pulp pinch scores were similar between the groups. There were no statistically significant between-group differences in the degree of joint deformities or in the number of prior surgeries (Table 3).
The most frequently used DMARDs in both groups at the time of the study were methotrexate and leflunomide. More than half of the painful group used corticosteroids but at a low mean dose of 5.0 mg±6.76 mg (Table 2). Eleven patients in the painful group and 5 patients in the painless group used immunobiological agents (p = 0.080).
In the univariate logistic regression analysis, only the variable “used an immunobiological agent after one year of the disease” was associated with painful synovitis; however, it was associated with a 3-fold increase in the odds of the patient belonging to the painful group (odds ratio [OR] = 3.0, 1.00-9.37, p = 0.049).
A total of 1.560 joint recesses were examined in the US evaluation. In the semi-quantitative analysis, there were no statistically significant between-group differences for the presence of synovitis (at least grade 2) or positive PD-US (Figure 1) in the majority of the joint recesses studied. Bone erosion (at least grade 2) was similar in the 2 groups, but the painless group had worse scores in some joints (Table 5). Statistically significant differences were found in the cartilage evaluation, with more scores of 4 in the third MCP in the painless group (p<0.004) and more scores of 2 in the second MCP (p<0.022) and 1 in the fourth MCP (p<0.004) in the painful group.
Dorsal longitudinal image of 2nd MCP; (A) Patient in group without pain with synovial hypertrophy and positive PD signal; (B) Patient in Painful group with synovial hypertrophy and positive PD signal; M = metacarpal; P = phalange.
Fifty-eight percent of the wrists in the painful group had pain on clinical examination, and 83% of the wrists in the painless group had no pain.
In the US subanalysis of the joints with swelling, there were no statistically significant between-group differences in the quantitative synovitis, the semi-quantitative synovitis, or the PD-US in the MCPs. The bone erosion scores were worse in the painless group for the palmar and lateral sides of the second MCP (p<0.022 and p<0.004, respectively). Regarding the joint cartilage, only the third MCP had more 0 scores in the painful group (p<0.030).
The univariate logistic regression revealed a greater likelihood of patients belonging to the painless group based on worse US scores for the following variables (Figure 2): the semiquantitative synovitis in the DRU, the PD-US in the RC, the erosion on the dorsal face of the 2nd MCP and the dorsal face of the 5th MCP, and the DRU (OR = 2.5, 1.09-5.64, p = 0.029; OR = 2.3, 1.07-5.16, p = 0.034; OR = 6.5, 1.76-23.77, p = 0.005; OR = 3.5, 1.06-11.57, p = 0.040; and OR = 5.7, 1.54-20.98, p = 0.009, respectively). The interobserver reliability was moderate to strong (Kappa = 0.435 to 1.00; p<0.018) for all US measures and strong for the PD-US (Kappa = 0.655 to 0.783, p = 0.001).
Probability of belonging to painless synovitis group with presence of Score II semi-quantitative synovial hypertrophy, PD and erosion in relation to Score 1 in joint recesses with statistically significant difference in the previous ultrasonographic evaluation and significant difference in regression analysis (p < 0.05); Statistical test: univariate logistic regression; OR = odds ratio; n = number.
No statistically significant differences were found in the radiographic evaluation, except for the proximal interphalangeal (PIP) joint, for which the painless group had a worse joint space reduction score (p = 0.018). The mean total Sharp score was 93.2±61.6 in the painless group and 65.4±40.6 in the painful group (p = 0.114).
DISCUSSION
Pain control is a priority in 90% of patients with RA. However, in a prospective study, Lee et
al. (2626. Lee YC, Cui J, Lu B, Frits ML, Iannaccone CK, Shadick NA, et al. Pain persist in
DAS28 rheumatoid arthritis remission but not in ACR/EULRA remission: a longitudinal observational
study. Arthritis Res Ther. 2011;13:R83, http://dx.doi.org/10.1186/ar3353.
http://dx.doi.org/10.1186/ar3353...
) demonstrated that the number of joints with swelling
at baseline was negatively associated with the presence of pain in a 1-year follow-up period. The
perception of pain is highly subjective and may be influenced by a number of issues, including
socio-cultural factors (2727. Couvoisier DS, Agoritsas T, Glauser J, Michaud K, Wolfe F, Cantoni E, et al.
Pain as an Important Predictor of Psychosocial Health in Patients with Rheumatoid Arthritis.
Arthritis Care Res (Hoboken). 2012;64(2):190-6,
http://dx.doi.org/10.1002/acr.20652.
http://dx.doi.org/10.1002/acr.20652...
28. Björk M, Trupin L, Thyberg I, Katz P, Yelin E. Differences in activity
limitation, pain intensity, and global health in patients with rheumatoid arthritis in Sweden and
the USA: a 5-year follow-up. Scand J Rheumatol. 2011;40(6):428-32.-2929. Ulus Y, Akyol Y, Tander B, et al. Sleep quality in fibromyalgia and rheumatoid
arthritis: associations with pain, fatigue, depression, and disease activity. Clin Exp Rheumatol.
2011;29(6 Suppl 69):S92-6.).
Few studies have assessed painless synovitis in RA. The absence of pain in patients with juvenile
idiopathic arthritis can delay the disease diagnosis, which could lead to greater joint damage and
disability (3030. Laaksonen LA, Laine V. A comparative study of joint pain in adult and juvenile
rheumatoid arthritis. Ann Rheum Dis. 1961;20:386-7,
http://dx.doi.org/10.1136/ard.20.4.386.
http://dx.doi.org/10.1136/ard.20.4.386...
,3131. Sherry DD, Bohnsack J, Salmonson K, Wallace CA, Mellins E. Painless juvenile
rheumatoid arthritis. J Pediatr. 1990;116(6):921-3,
http://dx.doi.org/10.1016/S0022-3476(05)80652-3.
http://dx.doi.org/10.1016/S0022-3476(05)...
).
The significance of painless synovitis for physicians and patients remains unknown.
In the present study, the majority of both the past and present variables were similar in the patients with and without pain. The time until the RA diagnosis was longer for patients in the painful group. Pain or the absence of pain may not be constant for each patient throughout the disease course. Smoking is an aggravating factor for RA (3232. Tehlirian CV, Bathon MJ. Rheumatoid Arthritis. Clinical and Laboratory Manifestations. In: Klippel JH, Stone JH, CroffordLJ, White PH, editors. Primer on the Rheumatic Diseases. 13th ed. Springer 2008;114-21.); this issue was also observed in this study through the association between smoking and painful synovitis.
The painful group had worse disease activity indices (DAS 28, SDAI, and CDAI), a greater number
of painful joints, and worse overall evaluations by both the physician and patient. However, the DAS
28 may not be a good measure of disease activity (3333. Felson D. Defining remission in rheumatoid arthritis. Ann Rheum Dis.
2012;71(Supp II):i86-i88, http://dx.doi.org/10.1136/annrheumdis-2011-200618.
http://dx.doi.org/10.1136/annrheumdis-20...
) because
joint pain is weighted twice as swelling in the DAS 28 score.
Felson et al. (3333. Felson D. Defining remission in rheumatoid arthritis. Ann Rheum Dis.
2012;71(Supp II):i86-i88, http://dx.doi.org/10.1136/annrheumdis-2011-200618.
http://dx.doi.org/10.1136/annrheumdis-20...
) have argued that joint swelling is the
true predictor of late radiographic progression in RA. In a prospective cohort study, Lukas et al.
(3434. Lukas C, van de Heijde D, Fatenajad S. Repair of erosions occurs almost
exclusively in damaged joints without swelling. Ann Rheum Dis. 2010;69(5):851-5,
http://dx.doi.org/10.1136/ard.2009.119156.
http://dx.doi.org/10.1136/ard.2009.11915...
) have found that joint swelling was the greatest
predictor of “repair” in radiographic erosion. Studying early arthritis, Filler et al.
(3535. Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P, et al.
Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very
early synovitis. Ann Rheum Dis. 2011; 70(3):500-7,
http://dx.doi.org/10.1136/ard.2010.131573.
http://dx.doi.org/10.1136/ard.2010.13157...
) have also found that the progression of RA was more
closely associated with the swollen joint count than with the tenderness joint count (3535. Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P, et al.
Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very
early synovitis. Ann Rheum Dis. 2011; 70(3):500-7,
http://dx.doi.org/10.1136/ard.2010.131573.
http://dx.doi.org/10.1136/ard.2010.13157...
).
Recently, Dougados et al. (3636. Dougados M, DEvauchelle-Pensec V, Ferlet JF, Jousse-Joulin S, D'Agostino
MA, Backhaus M, et al. The ability of synovitis to predict structural damage in rheumatoid
arthritis: a comparative study between clinical examination and ultrasound. Ann Rheum Dis.
2013;72(5):665-71, http://dx.doi.org/10.1136/annrheumdis-2012-201469.
http://dx.doi.org/10.1136/annrheumdis-20...
) have emphasized the
importance of persistent synovitis (both clinical and US examination) for predicting subsequent
structural deterioration in RA patients. In his study, the level of clinical disease activity was
defined by the number of swollen joints. Furthermore, the patients who had synovitis at baseline had
more structural progression (OR = 2.01, 1.36-2.98, p<0.001) in a
2-year follow-up period (3636. Dougados M, DEvauchelle-Pensec V, Ferlet JF, Jousse-Joulin S, D'Agostino
MA, Backhaus M, et al. The ability of synovitis to predict structural damage in rheumatoid
arthritis: a comparative study between clinical examination and ultrasound. Ann Rheum Dis.
2013;72(5):665-71, http://dx.doi.org/10.1136/annrheumdis-2012-201469.
http://dx.doi.org/10.1136/annrheumdis-20...
).
In this study, worse functional and dynamometric scores were found in the painful group. It is unsurprising that individuals with painful joints at the time of evaluation had worse functional scores than those without joint pain (3737. Figueiredo IM, Sampaio RF, Mancini MC, Silva FCM, Souza MAP. Teste de força de preensão utilizando o dinamômetro Jamar. Acta Fisiatr. 2007;14(2):104-10.). Nonetheless, no statistically significant between-group differences were found with respect to the grip strength or the pulp to pulp pinch strength.
Subclinical synovitis may be present in RA remission (88. Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, et al. Presence
of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic
drug-induced clinical remission - Evidence from an imaging study may explain structural progression.
Arthritis Rheum. 2006;54(12):3761-73, http://dx.doi.org/10.1002/art.22190.
http://dx.doi.org/10.1002/art.22190...
).
Furthermore, there is evidence indicating the progression of joint damage in RA patients during
clinical remission (1111. Brown AK, Conaghan, Karim Z, Quinn MA, Ikeda K, Peterfy CG, et al. An
Explanation for the Apparent Dissociation Between Clinical Remission and Continued Structural
Deterioration in Rheumatoid Arthritis. Arthritis Rheum. 2008;58(10):2958-67,
http://dx.doi.org/10.1002/art.23945.
http://dx.doi.org/10.1002/art.23945...
,1010. Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G. Clinical
and ultrasonographic remission determines different changes of relapse in early and long standing
rheumatoid arthritis. Ann Rheum Dis. 2011;70(1):172-15,
http://dx.doi.org/10.1136/ard.2010.129924.
http://dx.doi.org/10.1136/ard.2010.12992...
), which may be related to residual joint swelling (22. Bugatti S, Manzo A, Caporati R, Montecucco C. Assessment of synovitis to predict
bone erosions in rheumatoid arthritis. Ther Adv Musculoskeletal Dis. 2012;4(4):235-44,
http://dx.doi.org/10.1177/1759720X12453092.
http://dx.doi.org/10.1177/1759720X124530...
). The consideration of persistent joint swelling in RA patients, even in the absence of
pain, as in the present study, aligns with the hypothesis that residual swelling causes erosion and
is contrary to the notion of “cold,” “fibrous,” and innocuous
synovitis.
US has been proven effective at detecting subclinical synovitis (3838. Saleem B, Brown A, Keen H, Nizam S, Freeston J, Karim Z, et al. Disease
remission state in patients treated with the Combination of tumor necrosis factor blockade and
Methotrexate or with disease-modifying antirheumatic drugs. A clinical and imaging comparative
study. Arthritis Rheum. 2009;60(7):1915-22, http://dx.doi.org/10.1002/art.24596.
http://dx.doi.org/10.1002/art.24596...
,88. Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, et al. Presence
of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic
drug-induced clinical remission - Evidence from an imaging study may explain structural progression.
Arthritis Rheum. 2006;54(12):3761-73, http://dx.doi.org/10.1002/art.22190.
http://dx.doi.org/10.1002/art.22190...
,55. Naredo E, Bonilla G, Gamero F, Uson F, Carmona F, Laffon A. Assessment of
inflamatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with gray
scale e power Doppler ultrasonography. Ann Rheum Dis. 2005;64(3):375-81.), and
PD-US is an important tool for detecting active synovitis (1010. Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G. Clinical
and ultrasonographic remission determines different changes of relapse in early and long standing
rheumatoid arthritis. Ann Rheum Dis. 2011;70(1):172-15,
http://dx.doi.org/10.1136/ard.2010.129924.
http://dx.doi.org/10.1136/ard.2010.12992...
,3939. Naredo E, Valor L, De la Torre I, Martínez-Barrio J, Hinojosa M, Aramburu
F, et al. Ultrasound joint inflammation in rheumatoid arthritis in clinical remission: How many and
which joints should be assessed? Arthritis Care Res (Hoboken). 2013;65(4):512-7,
http://dx.doi.org/10.1002/acr.21869.
http://dx.doi.org/10.1002/acr.21869...
). In this study, no differences were found
between the painful and painless groups for the majority of US variables in the MCPs and wrists. The
detection of the PD-US signal is a predictor of disease evolution in RA (3535. Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P, et al.
Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very
early synovitis. Ann Rheum Dis. 2011; 70(3):500-7,
http://dx.doi.org/10.1136/ard.2010.131573.
http://dx.doi.org/10.1136/ard.2010.13157...
) and also of the progression of joint damage (1111. Brown AK, Conaghan, Karim Z, Quinn MA, Ikeda K, Peterfy CG, et al. An
Explanation for the Apparent Dissociation Between Clinical Remission and Continued Structural
Deterioration in Rheumatoid Arthritis. Arthritis Rheum. 2008;58(10):2958-67,
http://dx.doi.org/10.1002/art.23945.
http://dx.doi.org/10.1002/art.23945...
) and the reactivation of the disease (4040. Foltz V, Gandjbakhch F, Etchepare F, Carole Rosenberg, et al. Power Doppler
Ultrasound, but Not Low-Field Magnetic Resonance Imaging, Predicts Relapse and Radiographic Disease
Progression in Rheumatoid Arthritis Patients With Low Levels of Disease Activity. Arthritis Rheum.
2012;64(1):67-76, http://dx.doi.org/10.1002/art.33312.
http://dx.doi.org/10.1002/art.33312...
). In this
sample, PD-US was detected in 21% of the joint recesses analyzed, with no significant between-group
differences for the majority of joint recesses. This result suggests that there is no association
between active synovitis and the presence of joint pain. US also allows for earlier detection of
erosion than plain x-rays. In this respect, US is comparable to magnetic resonance imaging (4141. Szkudlarek M, Court-Payen M, Strandberg C, Klarlung M, Klausen T, Ostergaard M.
Power Doppler Ultrasonography for Assessment of Synovitis in the Metacarpophalangeal Joints of
Patients With Rheumatoid Arthritis. A Comparison With Dynamic Magnetic Resonance Imaging.
Arthritis Rheum. 2001;44(9):2018-23.
42. Grassi W and Filippucci E. Ultrasonography and the rheumatologist. Curr Opin
Rheumatol. 2007;19(1):55-60, http://dx.doi.org/10.1097/BOR.0b013e3280119648.
http://dx.doi.org/10.1097/BOR.0b013e3280...
-4343. Wakefield RJ, Gibbon WW, Conaghan PG, O'Connor P, McGonagle D, Pease C,
et al. The value of sonography in the detection of bone Erosions in patients with rheumatoid
arthritis. A Comparison with Conventional Radiography. Arthritis Rheum. 2000;43(12):2762-70,
http://dx.doi.org/10.1002/1529-0131(200012)43:12<2762::AID-ANR16>3.0.CO;2-#.
http://dx.doi.org/10.1002/1529-0131(2000...
). In the US analysis
of erosion, 5 joint recesses were statistically different between groups, with worse scores in the
painless group. For the joint cartilage, poorer scores were found more frequently in the painless
group, although the between-group difference did not achieve statistical significance.
The similarities between the painful and painless groups in the quantitative analysis of synovial hypertrophy, semi-quantitative analysis of GS-US variables, PD-US, and bone erosion may mean that painless synovitis can still result in joint damage and disability. Moreover, painless synovitis may make the patient and physician more passive in optimizing treatment. This hypothesis is in agreement with the findings that, after the first year of the disease, the painful group were more likely to use immunobiological agents (p = 0.045), and patients with worse US scores in some joint recesses were more likely to be in the painless group.
The radiographic analysis demonstrated that major previous structural damage was similar in both groups, except for IFP scores, which were worse in the painless group. This evidence further indicates that the continual presence of synovitis, instead of joint pain, is an important factor influencing structural damage in RA because both groups had a similar history of radiographic progression. These findings also aligned with the present analysis regarding the identification of joint deformities; there were no statistically significant differences between groups. However, a controlled prospective study with US and radiographic evaluations is needed to compare the evolution of structural joint damage in this sample of patients.
One of the limitations of this study is that was impossible to recruit patients in the painless group who had a complete absence of pain in all joints. The difficulty in obtaining individuals with a constant pain status (presence or absence) throughout the progression of RA constitutes another study limitation. This study is the first to compare patients with RA and painless synovitis with those patients with painful synovitis using clinical, ultrasonographic and radiographic variables. The majority of the findings suggest that patients with painless synovitis exhibit a similar profile to those patients with painful synovitis with respect to the presence of active synovitis and past joint damage.
Special thanks to the Fundação de Amparo à Pesquisa do Estado de São Paulo for financial support (FAPESP - 2012/04867-6) and to all volunteers from the UNIFESP community and Hospital do Servidor Público Estadual (IAMSPE).
REFERENCES
-
1Grassi W, Angelis RD, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27:S18-S24.
-
2Bugatti S, Manzo A, Caporati R, Montecucco C. Assessment of synovitis to predict bone erosions in rheumatoid arthritis. Ther Adv Musculoskeletal Dis. 2012;4(4):235-44, http://dx.doi.org/10.1177/1759720X12453092.
» http://dx.doi.org/10.1177/1759720X12453092 -
3Zordo T, Mlekusch SP, Feuchtner GM, Mur E, Schirmer M, Klauser AS. Value of contrast-enhanced ultrasound in rheumatoid arthritis. Eur J Radiol. 2007;64(2):222-30.
-
4Grassi W, Salaffi F, Filippucci E. Ultrasound in rheumatology. Best Pract Res Clin Rheumatol. 2005;19(3):467-85, http://dx.doi.org/10.1016/j.berh.2005.01.002.
» http://dx.doi.org/10.1016/j.berh.2005.01.002 -
5Naredo E, Bonilla G, Gamero F, Uson F, Carmona F, Laffon A. Assessment of inflamatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with gray scale e power Doppler ultrasonography. Ann Rheum Dis. 2005;64(3):375-81.
-
6Cheung PP, Dougados M, Gossec L. Reliability of Ultrasonography to Detect Synovitis in Rheumatoid Arthritis: A Systematic Literature Review of 35 Studies (1,415 Patients). Arthritis Care Res (Hoboken). 2010;62(3):323-34, http://dx.doi.org/10.1002/acr.20102.
» http://dx.doi.org/10.1002/acr.20102 -
7Kortekaas MC, Kwok WY, Reijnierse M, Watt I, Huizinga TWJ, Kloppenburg M. Pain in hand osteoarthritis is associated with inflammation: the value of ultrasound. Ann Rheum Dis 2010;69(7):1367-9.
-
8Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission - Evidence from an imaging study may explain structural progression. Arthritis Rheum. 2006;54(12):3761-73, http://dx.doi.org/10.1002/art.22190.
» http://dx.doi.org/10.1002/art.22190 -
9Wakefield RJ, Brown AK, O'Connor PJ, Emery P. Power-Doppler Sonography: Improving Disease Activity Assessment in Inflammatory Musculoskeletal Disease. Arthritis Rheum. 2003;48(2):285-8, http://dx.doi.org/10.1002/art.10818.
» http://dx.doi.org/10.1002/art.10818 -
10Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G. Clinical and ultrasonographic remission determines different changes of relapse in early and long standing rheumatoid arthritis. Ann Rheum Dis. 2011;70(1):172-15, http://dx.doi.org/10.1136/ard.2010.129924.
» http://dx.doi.org/10.1136/ard.2010.129924 -
11Brown AK, Conaghan, Karim Z, Quinn MA, Ikeda K, Peterfy CG, et al. An Explanation for the Apparent Dissociation Between Clinical Remission and Continued Structural Deterioration in Rheumatoid Arthritis. Arthritis Rheum. 2008;58(10):2958-67, http://dx.doi.org/10.1002/art.23945.
» http://dx.doi.org/10.1002/art.23945 -
12Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315-24, http://dx.doi.org/10.1002/art.1780310302.
» http://dx.doi.org/10.1002/art.1780310302 -
13Prevoo MLL, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LBA, van Riel PLC. Modified disease activity scores that include twenty-eight-joint counts - Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;30(1):44-48, http://dx.doi.org/10.1002/art.1780380107.
» http://dx.doi.org/10.1002/art.1780380107 -
14Aletaha D, Nell VPK, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther. 2005;7(4):R796-R806, http://dx.doi.org/10.1186/ar1740.
» http://dx.doi.org/10.1186/ar1740 -
15Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003;42(2):244-57.
-
16Ferraz MB, Liveira LM, Araujo PM, Atra E, Walter D. EPM-ROM Scale: na evaluative instrument to be used in rheumatoid arthritis trials. Clin Exp Rheumatol. 1990;8(5):491-4.
-
17Chiari A, Sardim CCS, Natour J. Translation, cultural adaptation and reproducibility ot the Cochin Hand Functional Scale questionnaire for Brazil. Clinics. 2011;66(5):731-6, http://dx.doi.org/10.1590/S1807-59322011000500004.
» http://dx.doi.org/10.1590/S1807-59322011000500004 -
18Backhaus M, Burmester G-R, Gerber T, Grassi W, Machold KP, Swen WA, et al. Guidelines for musculoskeletal ultrasound in Rheumatology. Ann Rheum Dis. 2001;60(7):641-9, http://dx.doi.org/10.1136/ard.60.7.641.
» http://dx.doi.org/10.1136/ard.60.7.641 -
19Wakefield RJ, Balint PV, Szkudlarek M, Filippucci E, Backhaus M, D'Agostino M, et al. Proceedings from the OMERACT Special Interest Group for Musculoskeletal Ultrasound including definitions for ultrasonographic pathology. J Rheumatol. 2005;32(12):2485-7.
-
20Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Ostergaard M. Interobserver agreement in ultrassonography of the finger and toe joint in rheumatoid arthritis. Arhtitis Rheum. 2003;48(4):955-62, http://dx.doi.org/10.1002/art.10877.
» http://dx.doi.org/10.1002/art.10877 -
21Filipucci E, Farina A, Carotti M, Salaffi F, Grassi W. Grey scale and power Doppler sonografic changes induces by intra-articular steroid injection treatment. Ann Rheum Dis. 2004;63(6):740-3, http://dx.doi.org/10.1136/ard.2003.007971.
» http://dx.doi.org/10.1136/ard.2003.007971 -
22Disler DG, Raymond E, May DA, Wayne JS, McCauley TR. Articular Cartilage Defects: In Vitro Evaluation of Accuracy and Interobserver Reliability for Detection and Grading with US. Radiology. 2000; 215(3):846-51, http://dx.doi.org/10.1148/radiology.215.3.r00jn20846.
» http://dx.doi.org/10.1148/radiology.215.3.r00jn20846 -
23Filippucci E, da Luz KR, Di Geso L, Salaffi F, Tardella M, Carotti M, et al. Interobserver reliability of ultrasonography in the assessment of cartilage damage in rheumatoid arthritis. Ann Rheum Dis. 2010;69(10):1845-8, http://dx.doi.org/10.1136/ard.2009.125179.
» http://dx.doi.org/10.1136/ard.2009.125179 -
24van der Heijde DM. Plain x-rays in rheumatoid arthritis: overview of scoring methods, their rehability and applicability. Baillieres Clin Rheumatol. 1996;10(3):435-53, http://dx.doi.org/10.1016/S0950-3579(96)80043-4.
» http://dx.doi.org/10.1016/S0950-3579(96)80043-4 -
25Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: Dimensions and Practical Applications. Health and Qual Life Outcomes. 2003:1-20.
-
26Lee YC, Cui J, Lu B, Frits ML, Iannaccone CK, Shadick NA, et al. Pain persist in DAS28 rheumatoid arthritis remission but not in ACR/EULRA remission: a longitudinal observational study. Arthritis Res Ther. 2011;13:R83, http://dx.doi.org/10.1186/ar3353.
» http://dx.doi.org/10.1186/ar3353 -
27Couvoisier DS, Agoritsas T, Glauser J, Michaud K, Wolfe F, Cantoni E, et al. Pain as an Important Predictor of Psychosocial Health in Patients with Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2012;64(2):190-6, http://dx.doi.org/10.1002/acr.20652.
» http://dx.doi.org/10.1002/acr.20652 -
28Björk M, Trupin L, Thyberg I, Katz P, Yelin E. Differences in activity limitation, pain intensity, and global health in patients with rheumatoid arthritis in Sweden and the USA: a 5-year follow-up. Scand J Rheumatol. 2011;40(6):428-32.
-
29Ulus Y, Akyol Y, Tander B, et al. Sleep quality in fibromyalgia and rheumatoid arthritis: associations with pain, fatigue, depression, and disease activity. Clin Exp Rheumatol. 2011;29(6 Suppl 69):S92-6.
-
30Laaksonen LA, Laine V. A comparative study of joint pain in adult and juvenile rheumatoid arthritis. Ann Rheum Dis. 1961;20:386-7, http://dx.doi.org/10.1136/ard.20.4.386.
» http://dx.doi.org/10.1136/ard.20.4.386 -
31Sherry DD, Bohnsack J, Salmonson K, Wallace CA, Mellins E. Painless juvenile rheumatoid arthritis. J Pediatr. 1990;116(6):921-3, http://dx.doi.org/10.1016/S0022-3476(05)80652-3.
» http://dx.doi.org/10.1016/S0022-3476(05)80652-3 -
32Tehlirian CV, Bathon MJ. Rheumatoid Arthritis. Clinical and Laboratory Manifestations. In: Klippel JH, Stone JH, CroffordLJ, White PH, editors. Primer on the Rheumatic Diseases. 13th ed. Springer 2008;114-21.
-
33Felson D. Defining remission in rheumatoid arthritis. Ann Rheum Dis. 2012;71(Supp II):i86-i88, http://dx.doi.org/10.1136/annrheumdis-2011-200618.
» http://dx.doi.org/10.1136/annrheumdis-2011-200618 -
34Lukas C, van de Heijde D, Fatenajad S. Repair of erosions occurs almost exclusively in damaged joints without swelling. Ann Rheum Dis. 2010;69(5):851-5, http://dx.doi.org/10.1136/ard.2009.119156.
» http://dx.doi.org/10.1136/ard.2009.119156 -
35Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P, et al. Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very early synovitis. Ann Rheum Dis. 2011; 70(3):500-7, http://dx.doi.org/10.1136/ard.2010.131573.
» http://dx.doi.org/10.1136/ard.2010.131573 -
36Dougados M, DEvauchelle-Pensec V, Ferlet JF, Jousse-Joulin S, D'Agostino MA, Backhaus M, et al. The ability of synovitis to predict structural damage in rheumatoid arthritis: a comparative study between clinical examination and ultrasound. Ann Rheum Dis. 2013;72(5):665-71, http://dx.doi.org/10.1136/annrheumdis-2012-201469.
» http://dx.doi.org/10.1136/annrheumdis-2012-201469 -
37Figueiredo IM, Sampaio RF, Mancini MC, Silva FCM, Souza MAP. Teste de força de preensão utilizando o dinamômetro Jamar. Acta Fisiatr. 2007;14(2):104-10.
-
38Saleem B, Brown A, Keen H, Nizam S, Freeston J, Karim Z, et al. Disease remission state in patients treated with the Combination of tumor necrosis factor blockade and Methotrexate or with disease-modifying antirheumatic drugs. A clinical and imaging comparative study. Arthritis Rheum. 2009;60(7):1915-22, http://dx.doi.org/10.1002/art.24596.
» http://dx.doi.org/10.1002/art.24596 -
39Naredo E, Valor L, De la Torre I, Martínez-Barrio J, Hinojosa M, Aramburu F, et al. Ultrasound joint inflammation in rheumatoid arthritis in clinical remission: How many and which joints should be assessed? Arthritis Care Res (Hoboken). 2013;65(4):512-7, http://dx.doi.org/10.1002/acr.21869.
» http://dx.doi.org/10.1002/acr.21869 -
40Foltz V, Gandjbakhch F, Etchepare F, Carole Rosenberg, et al. Power Doppler Ultrasound, but Not Low-Field Magnetic Resonance Imaging, Predicts Relapse and Radiographic Disease Progression in Rheumatoid Arthritis Patients With Low Levels of Disease Activity. Arthritis Rheum. 2012;64(1):67-76, http://dx.doi.org/10.1002/art.33312.
» http://dx.doi.org/10.1002/art.33312 -
41Szkudlarek M, Court-Payen M, Strandberg C, Klarlung M, Klausen T, Ostergaard M. Power Doppler Ultrasonography for Assessment of Synovitis in the Metacarpophalangeal Joints of Patients With Rheumatoid Arthritis. A Comparison With Dynamic Magnetic Resonance Imaging. Arthritis Rheum. 2001;44(9):2018-23.
-
42Grassi W and Filippucci E. Ultrasonography and the rheumatologist. Curr Opin Rheumatol. 2007;19(1):55-60, http://dx.doi.org/10.1097/BOR.0b013e3280119648.
» http://dx.doi.org/10.1097/BOR.0b013e3280119648 -
43Wakefield RJ, Gibbon WW, Conaghan PG, O'Connor P, McGonagle D, Pease C, et al. The value of sonography in the detection of bone Erosions in patients with rheumatoid arthritis. A Comparison with Conventional Radiography. Arthritis Rheum. 2000;43(12):2762-70, http://dx.doi.org/10.1002/1529-0131(200012)43:12<2762::AID-ANR16>3.0.CO;2-#.
» http://dx.doi.org/10.1002/1529-0131(200012)43:12<2762::AID-ANR16>3.0.CO;2-#
-
No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Feb 2014
History
-
Received
27 May 2013 -
Reviewed
24 June 2013 -
Accepted
23 July 2013